Successful Treatment of Posttransplant Lymphoproliferative Disorder with Removal of Small Bowel Graft and Subsequent Second Bowel Transplant

INTRODUCTION Posttransplantation lymphoproliferative disorder (PTLD) is frequently associated with primary Epstein-Barr virus (EBV) infection in previously seronegative recipients of solid organ transplants. It occurs as a consequence of immune system suppression necessary to prevent graft rejection. Currently, there is no standardized treatment strategy. Reduction of immunosuppression in hopes of tumor regression is the mainstay of therapy with simultaneous antiviral therapy and selected chemotherapeutic agents. Outcomes with these strategies for PTLD after solid organ transplant are unsatisfactory with mortality as high as 50% to 80% in children (1). When PTLD occurs after transplant of an organ not directly life-supporting, we propose that prompt removal of the graft, discontinuation of immune-suppressive therapy, and retransplantation at a later date may be associated with lower mortality and lower risk of recurrent PTLD. CASE PRESENTATION A 2-year-old Hispanic male born with gastroschisis developed ultra-short bowel syndrome soon after birth. His course on intravenous nutrition (IVN) was complicated by recurrent line sepsis, progressive loss of central venous access, and cholestatic liver disease. The patient was listed for cadaver bowel transplantation at 10 months of age. However, no suitable donor was found in the ensuing 5 months. Because of worsening clinical condition and the recognized high mortality on the waiting list in transplant candidates less than 5 years of age (2), he was considered for live-donor bowel transplantation. The donor was the maternal grandmother, who was EBV and cytomegalovirus (CMV) positive, ABO compatible, but completely human leukocyte antigen mismatched. The transplant was performed at the age of 15 months according to established techniques (3). After initial induction therapy with four doses of Thymoglobulin (1.5 mg/kg), the patient was maintained on a combination of tacrolimus and prednisone. He was seronegative for EBV before transplant and received pretransplant and posttransplant gancyclovir as prophylaxis for EBV/CMV. The patient developed a moderate to severe acute cellular rejection of the graft 4 weeks posttransplant and was successfully treated with steroid boluses and five additional doses of Thymoglobulin. Thereafter, the patient did well until 4 months after transplant when he developed an entero-cutaneous fistula. At this time, the patient had a well-functioning graft and was receiving all calorie needs enterally. A bowel graft biopsy obtained at the time of fistula repair demonstrated multiple sheets of an Epstein-Barr early region-positive monoclonal line of transformed lymphoid cells, revealing an aggressive monomorphic PTLD lymphoma with necrosis. The biopsy was indistinguishable from Hodgkin lymphoma. On the basis of the reported high mortality of PTLD treated medically, we choose to resect the transplanted bowel graft and discontinue immunosuppressive therapy with the long-term plan of seeking a second bowel transplant. Pathologic examination of the resected graft confirmed the presence of PTLD confined within normal appearing bowel graft without evidence of rejection. No additional treatment for the PTLD was instituted, and the patient was restarted on IVN. Six months later, after documenting that the patient was completely free of PTLD, the option of retransplant was offered to the family. Unfortunately, the child's cholestatic liver disease by this time had progressed to advanced cirrhosis. Therefore, a bowel transplant and segmental liver transplant were performed electively at 2 years of age, using the patient's mother as donor. The immunosuppressive therapy used was similar to that used after the first transplant. At the time of retransplant, the patient was EBV positive and received long-term prophylaxis initially with intravenous gancyclovir and then with oral valgancyclovir. Serial biopsies since transplant have revealed satisfactory villous growth and no evidence of rejection. Sixteen months posttransplant, the patient is off IVN and has no evidence of rejection or PTLD. DISCUSSION First described in 1968 as “reticulum cell sarcomas,” (4) PTLD encompasses a wide spectrum of lymphoproliferative processes. PTLD results from over suppression of cytotoxic T cells, which play a crucial role in limiting viral infections through the eradication of infected cells (5). Chronic EBV infection of seronegative naïve B cells results in B-cell transformation and clonal or polyclonal expansion. Although PTLD can occur in previously seropositive patients, seronegativity remains the highest risk factor for this condition (6). The histology of PTLD ranges from mild benign B-cell hyperplasia associated with EBV to neoplastic transformation including polymorphic and monomorphic PTLD (7). Monomorphic PTLD is the highest grade and histologically is indistinguishable from Hodgkin lymphoma. PTLD was first reported to have a wide array of classification in 1981 by Frizzera et al. (8). In 1997, Harris et al. (9) developed a classification system that is used as a standard guide for treatment decisions. Transplant induced lymphoproliferative disorders are the most common tumors in children after organ transplantation, representing 52% of all posttransplant tumors (10). Variation in frequency from center to center may be explained by differences in definitions used by different institutions (7). The incidence of PTLD varies with the organ transplanted as well. In solid organ transplants, PTLD may occur in 14.6% (11). Incidence in renal transplant recipients is reported to be 1.95% (8) and in liver transplants 5% to 15% (12). The highest incidence of PTLD in solid organ transplants is reported in small bowel grafts (5), but reports from large pediatric transplant centers are not available. The reason for increased rates of PTLD in the small bowel transplant population has not been established but may be caused by the higher immune suppression needed to maintain the graft. Overall, because of the age specific risk factors involved, PTLD is more common in children than adults. Optimal management of PTLD is not established (7). Treatment choice depends mainly upon viral load and pathologic classification. The likelihood that polymorphic PTLD will progress to monomorphic PTLD is also not well established. In a study of 21 pediatric patients, 10 of whom had polymorphic PTLD, 7 progressed to monomorphic PTLD. In the six patients with atypical lymphoid hyperplasia, only one patient progressed to polymorphic PTLD and none to the monomorphic variety (5). Treatment options currently available include reduction of immune suppression, use of prednisone in conjunction with cyclophosphamide, antiviral therapy, monoclonal antibodies such as Rituximab, chemotherapy, and cytotoxic T-lymphocyte infusion (6,7,13-20). Despite the various therapeutic options, a PTLD may convey mortality rates up to 50% to 80% (15). In a multicenter report from Canada, 48.9% of patients with PTLD died within 2 years (11). Current survival rates after EBV-associated PTLD for children undergoing heart, lung, kidney, and intestinal transplantation have been reported as 69%, 70%, 100%, and 56%, respectively (7). Finn et al. (5) studied the pathology of 41 children who underwent small bowel transplant complicated by EBV. Three children developed monomorphic PTLD, and all three patients died within 7 to 22 months. Ten patients developed grade 3 or polymorphic PTLD, and only three were alive at 64 months follow-up. The reason for the high mortality in this population is unknown. Because the failure of vital transplanted organs such as heart and liver is uniformly fatal, organ resection and withdrawal of immunosuppression obviously can not be implemented. We are also not advocating resection of a well-functioning organ in a recipient with benign reactive hyperplasia or atypical lymphoid proliferation. However, organs such as the kidney or small bowel in which function can be temporarily replaced can be resected without significant acute risk to the patient. In these cases, when there is polymorphic or monomorphic PTLD involving the transplanted organ, we advocate organ resection and discontinuation of immunosuppressive therapy. This option should potentially be considered even for the management of PTLD limited to native tissue, especially when there is an aggressive monomorphic lymphoma. Maintaining the patient on parenteral nutrition or hemodialysis while seeking a second transplant is a viable option. In our patient with monomorphic PTLD, we felt the best chance for success in treating PTLD was immediate resection and withdrawal of immune suppression. CONCLUSION The risk of PTLD in pediatric transplant patients is high, and the treatment remains a challenge. When our patient developed PTLD, we found removal of the graft and discontinuation of immunosuppression to be effective. Sixteen months after a second transplant, our patient has a good functioning intestinal graft with no signs of rejection. On the basis of the high mortality rate of monomorphic PTLD with current nonsurgical treatment strategies, the immediate removal of the graft when possible and cessation of immunosuppression may be the best therapeutic option for these patients.

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