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Posttransplantation Lymphoproliferative Disorder After Original article JeongKorean HJ, J Pediatr et al. • 2017;60(3):86-93 Posttransplantation lymphoproliferative disorder after pediatric solid organ transplantation https://doi.org/10.3345/kjp.2017.60.3.86 pISSN 1738-1061•eISSN 2092-7258 Korean J Pediatr Posttransplantation lymphoproliferative disorder after pediatric solid organ transplantation: experiences of 20 years in a single center Hyung Joo Jeong, MD1, Yo Han Ahn, MD2, Eujin Park, MD1, Youngrok Choi, MD3, Nam-Joon Yi, MD, PhD3, Jae Sung Ko, MD, PhD1, Sang Il Min, MD, PhD3, Jong Won Ha, MD, PhD3, Il-Soo Ha, MD, PhD1, Hae Il Cheong, MD, PhD1, Hee Gyung Kang, MD, PhD1 1Department of Pediatrics, Seoul National University College of Medicine, Seoul, 2Department of Pediatrics, Hallym University Kangnam Sacred Heart Hospital, Seoul, 3Department of Surgery, Seoul National University College of Medicine, Seoul, Korea Purpose: To evaluate the clinical spectrum of posttransplantation lymphoproliferative disorder (PTLD) Corresponding author: Hee Gyung Kang, MD, PhD after solid organ transplantation (SOT) in children. Department of Pediatrics, Seoul National University Children’s Hospital, 101 Deahangno, Jongno-gu, Methods: We retrospectively reviewed the medical records of 18 patients with PTLD who underwent Seoul 03080, Korea liver (LT) or kidney transplantation (KT) between January 1995 and December 2014 in Seoul National Tel: +82-2-2072-0658 University Children’s Hospital. Fax: +82-2-2072-0274 Results: Eighteen patients (3.9% of pediatric SOTs; LT:KT, 11:7; male to female, 9:9) were diagnosed as E-mail: [email protected] having PTLD over the last 2 decades (4.8% for LT and 2.9% for KT). PTLD usually presented with fever or Received: 29 August, 2016 gastrointestinal symptoms in a median period of 7 months after SOT. Eight cases had malignant lesions, Revised: 21 October, 2016 and all the patients except one had evidence of Epstein-Barr virus (EBV) involvement, assessed by using Accepted: 25 October, 2016 in situ hybridization of tumor tissue or EBV viral load quantitation of blood. Remission was achieved in all patients with reduction of immunosuppression and/or rituximab therapy or chemotherapy, although 1 patient had allograft kidney loss and another died from complications of chemotherapy. The first case of PTLD was encountered after the introduction of tacrolimus for pediatric SOT in 2003. The recent increase in PTLD incidence in KT coincided with modification of clinical practice since 2012 to increase the tacrolimus trough level. Conclusion: While the outcome was favorable in that all patients achieved complete remission, some patients still had allograft loss or mortality. To prevent PTLD and improve its outcome, monitoring for EBV infection is essential, which would lead to appropriate modification of immunosuppression and enhanced surveillance for PTLD. Key words: Posttransplantation lymphoproliferative disorder, Solid organ transplantation, Pediatric recipient, EBV viral load monitoring, Tacrolimus Introduction Posttransplant lymphoproliferative disorder (PTLD) is a well-known, potentially fatal complication of solid organ transplantation (SOT) with high mortality (30%–60%)1). The incidence of PTLD in SOT recipients varies from 1% to 13% depending on the type of Copyright © 2017 by The Korean Pediatric Society allograft, ages of recipients and the length of follow-up2,3). The majority of PTLD cases are associated with Epstein-Barr virus (EBV) infection, either primary infection or reactivation This is an open-access article distributed under the 4) terms of the Creative Commons Attribution Non- due to immunosuppression . Risk factors of PTLD include EBV-naïve recipients with EBV- Commercial License (http://creativecommons.org/ positive donors, younger age at SOT, more aggressive immunosuppression, and within the licenses/by-nc/4.0/) which permits unrestricted non- 5) commercial use, distribution, and reproduction in any first year of SOT . medium, provided the original work is properly cited. 86 https://doi.org/10.3345/kjp.2017.60.3.86 Korean J Pediatr 2017;60(3):86-93 In pediatric allograft transplantation, PTLD is relatively common Results because the recipients are often EBV seronegative at the time of transplantation5). As Korean experience, Heo et al.6) had reported 5 1. Characteristics of PTLD patients (Table 1) cases of PTLD among 41 pediatric liver allograft recipients (12.2%) Over the last 2 decades (January 1995 to December 2014), 18 in 2004. Another study of 43 Korean PTLD cases reported 12 pedi- patients (LT:KT, 11:7) were diagnosed with PTLD, rendering the atric cases, but the incidence among pediatric SOT recipients was incidence of PTLD 4.8% for pediatric LT (of total 230 recipients) not described7). Recently, our center has experienced several con- and 2.9% for pediatric KT (of 234 cases). For these PTLD cases, secutive cases of pediatric PTLD, which lead us to review the median age at transplantation was 11 months (range, 3 months to clinical spectrum of PTLD in pediatric SOT recipients. In this study, 18 years) and PTLD was diagnosed at median 7 months (range, 2 we present our experience of pediatric PTLD of 20 years. to 98 months) after SOT, mostly during the first year (n=14, 77.7%), at their median age of 51 months (range, 10 months to 18 years). KT patients with PTLD were older at SOT (median age, 76 Materials and methods months; range 44 months to 13 years) than LT recipients (median age, 7 months; range, 3 to 18 months) on their diagnosis of PTLD. We retrospectively reviewed the medical records of PTLD cases All patients with PTLD were taking tacrolimus targeting trough among pediatric SOT recipients of liver (LT) or kidney transplanta- levels of 10–15 mg/mL in immediate postoperation periods, then tion (KT) that had been performed from January 1995 to Decem- 6–8 mg/mL (before 2012) or 8–10 mg/mL (since 2012) for KT and ber 2014 at Seoul National University Children’s Hospital. The 5–8 ng/mL for LT. Basiliximab was administered in eight patients study was approved by the Institutional Review Boards of our as induction immunosuppression, and 6 of LT patients with PTLD center (IRB#H-1312-068-541). PTLD was clinically suspected were treated for acute rejection before diagnosis of PTLD. EBV when SOT recipients presented persistent lymphadenopathy or tumorous lesions, which were confirmed pathologically and classi- Table 1. Characteristics of patients (n=18) ied following the classification of the World Health Organi zation Characteristic Value 8) system . We categorized the patients into the malignant group and Sex the benign group according to the pathology. Early PTLD was Male:female 9:9 5) defined as PTLD occurring within the first year of SOT . EBV asso- Organ transplanted ciation was assessed in tissue specimens by in situ hybridization Liver:kidney 11:7 of Epstein-Barr virus encoded RNA. EBV viral loads in the patients Age at transplantation 11 mo (3 mo–18 yr) were measured by real-time polymerase chain reaction of EBV Donor type DNA in the peripheral blood of the patients. Deceased 3 (16.7) Characteristics of the patients were reviewed as follows: clinical Living related 15 (83.3) features at the time of transplantation (underlying disease, trans- Prophylactic basiliximab* 8 (44.4) planted organ, age at transplantation, EBV serologic status of the Rejection history and treatment 6 (33.3) donor and the recipient at transplantation, Human Leukocyte Steroid 3 Antigen [HLA] typing); posttrans plantation history (rejection Increasing Immunosuppressant 2 episode, immunosuppressive treat ment, cytomegalovirus [CMV] Re-TPL 1 reactivation status); and charac teristics of PTLD (clinical presenta- Age at PTLD 4 yr (10 mo–18 yr) tion, histopathologic diagnosis, expression of CD20 on tumor cells, Time since transplantation 7 mo (2 mo–98 mo) detection of EBV in tumor cells, stage, treatment, outcome, graft Early:late 14:4 survival, overall survival [OS]). OS is defined as the duration from EBV serologic status (recipient/donor) diagnosis of PTLD to the last follow-up or death. Clinical staging was performed retrospec tively according to the Ann Arbor staging EBV VCA IgG(-/+) 3 (16.7) system for lymphoma9). EBV VCA IgG(-/NA) 4 (22.2) Differences between PTLD patient subsets were assessed by chi- EBV VCA IgG(+/+) 4 (22.2) square test for categorized variables and Welch-Aspin test for EBV VCA IgG(+/NA) 1 (5.6) continuous variables. A P value of less than 0.05 was considered EBV VCA IgG(NA/+) 4 (22.2) statistically significant. The statistical analysis was performed EBV VCA IgG(NA/NA) 2 (11.1) using IBM SPSS Statistics ver. 23.0 (IBM Co., Armonk, NY, USA). Values are presented as number, median (range), or number (%). TPL, transplantation; PTLD, posttransplantation lymphoproliferative disorder; EBV, Epstein-Barr virus; VCA, viral capsid antigen; NA, not available. *All done for acute rejection prophylaxis right after transplantation. https://doi.org/10.3345/kjp.2017.60.3.86 87 Jeong HJ, et al. • Posttransplantation lymphoproliferative disorder after pediatric solid organ transplantation Table 2. Characteritics of PTLD patients before and after 2012 Variable Before 2012 (n=9) After 2012 (n=9) P value Sex Male:female 5:4 4:5 0.637* Transplanted organ Liver:kidney 8:1 3:6 0.016* Age at transplantation 7 mo (3 mo–53 mo) 71 mo (8 mo–18 yr) 0.032† Age of PTLD 1 yr (10 mo–5 yr) 6 yr (1 yr–18 yr) 0.027† Time since transplantation 7M (3 mo–5 yr) 8 mo (2 mo–8 yr) 0.724† Tacrolimus dosage (mg/kg/day) 0.154 (0.037–0.526) 0.222 (0.034–0.889) 0.552† Basiliximab prophylaxis 1 (11.1) 7 (77.8) 0.004* History of acute rejection 3 (33.3) 3 (33.3) 1.000* Ann Arbor stage ≥III 5 (55.6) 6 (66.7) 0.629* B symptoms‡ 4 (44.4) 6 (66.7) 0.343* GI involvement 7 (77.8) 4 (44.4) 0.147* Extranodal involvement 7 (77.8) 5 (55.6) 0.317* Early lesion:malignancy 4:3 (44.4:33.3) 1:5 (11.1:55.6) 0.114* : 0.343* EBV viral load (copies/mL) 261,159 (1,830–3,506,000) 166,571 (555–2,583,544) 0.763† Values are presented as number, median (range), or number (%).
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