Warning: fopen(/home/virtual/pediatrics/journal/upload/ip_log/ip_log_2024-12.txt) [function.fopen]: failed to open stream: Permission denied in /home/virtual/pediatrics/journal/ip_info/view_data.php on line 93

Warning: fwrite(): supplied argument is not a valid stream resource in /home/virtual/pediatrics/journal/ip_info/view_data.php on line 94
Posttransplantation lymphoproliferative disorder after pediatric solid organ transplantation: experiences of 20 years in a single center

Volume 60(3); March

< Previous     Next >

Article Contents

Clin Exp Pediatr > Volume 60(3); 2017
Jeong, Ahn, Park, Choi, Yi, Ko, Min, Ha, Ha, Cheong, and Kang: Posttransplantation lymphoproliferative disorder after pediatric solid organ transplantation: experiences of 20 years in a single center

Abstract

Purpose

To evaluate the clinical spectrum of posttransplantation lymphoproliferative disorder (PTLD) after solid organ transplantation (SOT) in children.

Methods

We retrospectively reviewed the medical records of 18 patients with PTLD who underwent liver (LT) or kidney transplantation (KT) between January 1995 and December 2014 in Seoul National University Children's Hospital.

Results

Eighteen patients (3.9% of pediatric SOTs; LT:KT, 11:7; male to female, 9:9) were diagnosed as having PTLD over the last 2 decades (4.8% for LT and 2.9% for KT). PTLD usually presented with fever or gastrointestinal symptoms in a median period of 7 months after SOT. Eight cases had malignant lesions, and all the patients except one had evidence of Epstein-Barr virus (EBV) involvement, assessed by using 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.

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 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 due to immunosuppression4). Risk factors of PTLD include EBV-naïve recipients with EBV-positive donors, younger age at SOT, more aggressive immunosuppression, and within the first year of SOT5).
In pediatric allograft transplantation, PTLD is relatively common because the recipients are often EBV seronegative at the time of transplantation5). As Korean experience, Heo et al.6) had reported 5 cases of PTLD among 41 pediatric liver allograft recipients (12.2%) in 2004. Another study of 43 Korean PTLD cases reported 12 pediatric cases, but the incidence among pediatric SOT recipients was not described7). Recently, our center has experienced several consecutive cases of pediatric PTLD, which lead us to review the clinical spectrum of PTLD in pediatric SOT recipients. In this study, we present our experience of pediatric PTLD of 20 years.

Materials and methods

We retrospectively reviewed the medical records of PTLD cases among pediatric SOT recipients of liver (LT) or kidney transplantation (KT) that had been performed from January 1995 to December 2014 at Seoul National University Children's Hospital. The study was approved by the Institutional Review Boards of our center (IRB#H-1312-068-541). PTLD was clinically suspected when SOT recipients presented persistent lymphadenopathy or tumorous lesions, which were confirmed pathologically and classiied following the classification of the World Health Organization system8). We categorized the patients into the malignant group and the benign group according to the pathology. Early PTLD was defined as PTLD occurring within the first year of SOT5). EBV association was assessed in tissue specimens by in situ hybridization of Epstein-Barr virus encoded RNA. EBV viral loads in the patients were measured by real-time polymerase chain reaction of EBV DNA in the peripheral blood of the patients.
Characteristics of the patients were reviewed as follows: clinical features at the time of transplantation (underlying disease, transplanted organ, age at transplantation, EBV serologic status of the donor and the recipient at transplantation, Human Leukocyte Antigen [HLA] typing); posttransplantation history (rejection episode, immunosuppressive treatment, cytomegalovirus [CMV] reactivation status); and characteristics of PTLD (clinical presentation, histopathologic diagnosis, expression of CD20 on tumor cells, detection of EBV in tumor cells, stage, treatment, outcome, graft survival, overall survival [OS]). OS is defined as the duration from diagnosis of PTLD to the last follow-up or death. Clinical staging was performed retrospectively according to the Ann Arbor staging system for lymphoma9).
Differences between PTLD patient subsets were assessed by chi-square test for categorized variables and Welch-Aspin test for continuous variables. A P value of less than 0.05 was considered statistically significant. The statistical analysis was performed using IBM SPSS Statistics ver. 23.0 (IBM Co., Armonk, NY, USA).

Results

1. Characteristics of PTLD patients (Table 1)

Over the last 2 decades (January 1995 to December 2014), 18 patients (LT:KT, 11:7) were diagnosed with PTLD, rendering the incidence of PTLD 4.8% for pediatric LT (of total 230 recipients) and 2.9% for pediatric KT (of 234 cases). For these PTLD cases, median age at transplantation was 11 months (range, 3 months to 18 years) and PTLD was diagnosed at median 7 months (range, 2 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 months; range 44 months to 13 years) than LT recipients (median age, 7 months; range, 3 to 18 months) on their diagnosis of PTLD.
All patients with PTLD were taking tacrolimus targeting trough levels of 10–15 mg/mL in immediate postoperation periods, then 6–8 mg/mL (before 2012) or 8–10 mg/mL (since 2012) for KT and 5–8 ng/mL for LT. Basiliximab was administered in eight patients as induction immunosuppression, and 6 of LT patients with PTLD were treated for acute rejection before diagnosis of PTLD. EBV serology of the recipients at the time of SOT was antibody negative in 7, positive in 5, and unknown in 6. HLA types of the patients were predominantly HLA-A2, A33, B44, B58, DR13, and DR15. None of the patients had malignancy before SOT.
Since we recently experienced several consecutive cases of PTLD we compared recent cases with those before 2012 (Table 2). While KT cases were more common after 2012 along with different age at SOT and PTLD (Fig. 1A), there were no statistically significant differences in time interval between SOT to PTLD, immunosuppression, EBV viral load, or pathologic malignancy (Fig. 1B).

2. Presentation of PTLD (Table 3)

Initial symptoms of PTLD were mostly fever (n=10, 55.6%) or gastrointestinal problems, such as abdominal pain, vomiting, diarrhea, and blood tinged stool (n=11, 61.1%). Fifteen patients had lymph node enlargement (83.3%) and 3 patients had mass or nodular lesions (16.7%), mostly in the intraperitoneal cavity. The majority of the patients had gastrointestinal organ involvement, including small bowel (n=9, 50%) and intraperitoneal lymph nodes (n=8, 44.4%).
Pathologic diagnosis of PTLD revealed 5 cases of early lesion (27.8%), 4 cases of polymorphic type (22.2%), 1 case of monomorphic type (5.6%), 4 cases of diffuse large B-cell lymphoma (22.2%), 3 cases of Burkitt lymphoma (16.7%), and 1 case of malignant lymphoblastic lymphoma (5.6%). CD20 expression of tumor was positive in all patients tested (n=17), suggesting B-cell proliferation. Seventeen patients showed EBV positive-tumors (94.4%). At the time of PTLD diagnosis, EBV viral loads were 555–3,506,000 copies/mL whole blood (median, 166,571 copies/mL) when measured (n=15). Four patients showed evidence of CMV coinfection by CMV IgM seroprevalence, CMV antigenemia or CMV viral load, reactivation in two and de novo infection in others.
When compared to benign PTLD patients (median, 6.5 months after SOT), those with malignant PTLD seemed to be diagnosed with PTLD later (median, 9 months after SOT), although there was no statistically significant difference (Table 4), and female patients seemed to be common in the malignant group (P=0.058). There was no statistically significant difference in B symptoms, involved organs, or EBV titers at diagnosis of PTLD.

3. Treatment and outcome

Upon recognition of PTLD, maintenance immunosuppression was reduced in all patients, similar to what was reported in the literature10,11), and additional treatments were applied as appropriate (Table 3, Fig. 2). Surgery was considered as the primary treatment for localized lesion and primary tumors were removed by surgery in one third of the patients (n=6, 33.3%). Rituximab (RTX) was administered in every case since 2013 and one malignant case in 2006 (72.2%). Before RTX was established as the first line treatment for PTLD, ganciclovir (GCV) had been tried as an initial treatment of PTLD (n=6). GCV was also used along with RTX when there was CMV coinfection (patient numbers 7 and 16). Chemotherapy was administered for malignant PTLD (n=8). The first line chemotherapy in our institute was CCG 106B protocol12) (prednisolone, vincristine, daunomycin, cyclophosphamide, and intrathecal chemotherapy of cytarabine, hydrocortisone, and methotrexate) along with RTX.
All patients achieved complete remission of PTLD (Fig. 2). Four patients achieved remission with GCV monotherapy, and 2 patients (patient numbers 12 and 18) achieved remission with RTX monotherapy. Median OS was 35 months (range, 3 months to 12 years). However, patient number 11 lost her allograft kidney during chemotherapy, and patient number 6 expired from complication of chemotherapy (sepsis) with functioning graft after achieving remission of malignant lymphoma. At last follow-up, all the surviving patients showed no evidence of PTLD, and their EBV titers were median 3,145 copies/mL (range, 0–43,101 copies/mL).

DISCUSSION

In the early 2000s, our center experienced its first PTLD cases. Similar to the observations of others5) this coincided with the introduction of tacrolimus, which replaced cyclosporine as the main immunosuppressant at our institute in June 2001. After starting regular monitoring of EBV viral load in 2007 and adjusting immunosuppressant accordingly, PTLD cases at our center decreased. However in 2013, recent consecutive cases of PTLD emerged once again. The majority of recent cases were KT recipients and the rate of malignant lymphoma seemed high, while statistically not significant. Changes in the clinical practice for KT recipients before the recent emergence of PTLD patients were not evident, except that the target trough level of tacrolimus was increased from 6–8 to 8–10 ng/mL since 2012. Otherwise characteristics of PTLD patients were similar between those before 2012 and after 2012, except their age at SOT; Generally LT patients are younger than KT patients at SOT, since their common cause of organ failure is biliary atresia in Korea13), and PTLD incidence is higher in LT patients along the line that younger age at SOT is a known risk factor of PTLD. While our number of patients was too small to do statistically appropriate analysis, it seems that with higher target trough level of tacrolimus, the main immunosuppressive agent for SOT, rendered KT patients after 2012 prone to PTLD, as much as younger age of recipient does.
Nevertheless, the clinical spectrum of our cases of PTLD were similar to what is known; the median age at the time of PTLD (4 years) and interval between PTLD diagnosis and transplantation (7 months) of our pediatric PTLD cohort are similar to those reported by Opelz and Döhler5). We achieved complete remission in every case with a low rate of graft loss (5.6%), which is much higher than reported in the early 2000's14,15) but similar to those of a recent report16). In order to assess risk factors of PTLD among pediatric SOT recipients, comparison between patients with PTLD and without PTLD should be done, which is beyond the scope of this report and it is the limitation of this report; Among the known risk factors14), frequency of CMV infection in our cases was 22%, not different from known frequency of CMV in pediatric SOT recipients of one forth17). HLA types of recipients A2, A11, A26, B5, B8, B18, B21, B38 and B40 had been reported to be of risk of PTLD18,19,20,21), and in our cases HLA-A2 was common; however in Korean population HLA A2 is common15), therefore significance thereof is yet elusive.
What called our attention during our review of pediatric PTLD cases again was that patients who were diagnosed at their early disease status suffered much less than those who found to have PTLD at later stage. While all the patients achieved remission eventually, those malignant cases had to experience long periods of chemotherapy and concomitant complications, including neutropenic fever, graft loss, and death due to sepsis. On the other hand, RTX with reduction of immunosuppression was enough to induce complete remission if the lesion was localized and benign, as experienced by patient numbers 12 and 18. These 2 patients were under surveillance because there was a sudden increase of EBV viral load, therefore more careful physical examination could detect well-defined benign lesion rather early, and they achieved remission without any severe complication. Therefore, we emphasize that early diagnosis and early intervention with appropriate management is necessary for good outcome of PTLD as reported in many studies16,22,23).
For early detection and furthermore prevention of PTLD, monitoring EBV viral load is considered as one of the crucial factors, even though the specificity and positive predictive value of EBV titer in predicting PTLD are still controversial24,25,26,27). As an example, right after that regular EBV viral load monitoring was adopted as standard clinical practice, our center encountered only one case of pediatric PTLD during 2008–2012; Upon recognition of high titer of EBV of >10,000 copies/mL immunosuppression was reduced when possible, and active surveillance of PTLD was adopted. While active monitoring of EBV viral load might not enough to overcome the hazardous effect of more aggressive immunosuppression as suspected as predisposing factor for our recent PTLD cases, we need to monitor EBV infection meticulously, since this is the only tool available to prevent PTLD.
In conclusion, during 20 years of SOT, our center experienced 18 cases of pediatric PTLD (3.9% of pediatric SOT). Most of the patients presented with abdominal symptom, and 44% were malignant. Higher incidence of PTLD coincided with the introduction of Tac and probably also with a higher target trough level of Tac. The outcomes of our PTLD patients were favorable with remission achievement in all patients and a low rate of graft loss and mortality. While previously considered as a fatal complication of SOT, the outcome of PTLD has much improved these days, and active monitoring of EBV infection might reduce this complication of pediatric SOT even further.

Acknowledgment

This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI12C0014).

Notes

Conflict of interest:
No potential conflict of interest relevant to this article was reported.

References

1. Mucha K, Foroncewicz B, Ziarkiewicz-Wróblewska B, Krawczyk M, Lerut J, Paczek L. Post-transplant lymphoproliferative disorder in view of the new WHO classification: a more rational approach to a protean disease? Nephrol Dial Transplant 2010;25:2089–2098.
crossref pmid pdf
2. Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet 1993;342:1514–1516.
crossref pmid
3. Caillard S, Lelong C, Pessione F, Moulin B. Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: report of 230 cases from the French Registry. Am J Transplant 2006;6:2735–2742.
crossref pmid
4. Smets F, Latinne D, Bazin H, Reding R, Otte JB, Buts JP, et al. Ratio between Epstein-Barr viral load and anti-Epstein-Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease. Transplantation 2002;73:1603–1610.
crossref pmid
5. Opelz G, Döhler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004;4:222–230.
crossref pmid
6. Heo JS, Park JW, Lee KW, Lee SK, Joh JW, Kim SJ, et al. Posttransplantation lymphoproliferative disorder in pediatric liver transplantation. Transplant Proc 2004;36:2307–2308.
crossref pmid
7. Yoon SO, Yu E, Cho YM, Suh C, Kim KM, Han DJ, et al. Post-transplant lymphoproliferative disorders: clinicopathological analysis of 43 cases in a single center, 1990-2009. Clin Transplant 2012;26:67–73.
crossref pmid
8. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon (FR): International Agency for Research on Cancer, 2008.

9. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 1993;329:987–994.
crossref pmid
10. Tsai DE, Hardy CL, Tomaszewski JE, Kotloff RM, Oltoff KM, Somer BG, et al. Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: analysis of prognostic variables and long-term follow-up of 42 adult patients. Transplantation 2001;71:1076–1088.
crossref pmid
11. Reshef R, Vardhanabhuti S, Luskin MR, Heitjan DF, Hadjiliadis D, Goral S, et al. Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder. Am J Transplant 2011;11:336–347.
crossref pmid pmc
12. Park ES, Kim H, Lee JW, Lim JY, Kang HJ, Park KD, et al. Treatment outcomes in children with Burkitt lymphoma and L3 acute lymphoblastic leukemia treated using the lymphoma malignancy B protocol at a single institution. Korean J Hematol 2011;46:96–102.
crossref pmid pmc
13. Kim JM, Kim KM, Yi NJ, Choe YH, Kim MS, Suh KS, et al. Pediatric liver transplantation outcomes in Korea. J Korean Med Sci 2013;28:42–47.
crossref pmid pmc
14. Zallio F, Primon V, Tamiazzo S, Pini M, Baraldi A, Corsetti MT, et al. Epstein-Barr virus reactivation in allogeneic stem cell transplantation is highly related to cytomegalovirus reactivation. Clin Transplant 2013;27:E491–E497.
crossref pmid
15. Park MH, Whang DH, Kang SJ, Han KS. HLA-A*02 allele frequencies and haplotypic associations in Koreans. Tissue Antigens 2000;55:250–256.
crossref pmid
16. Evens AM, David KA, Helenowski I, Nelson B, Kaufman D, Kircher SM, et al. Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J Clin Oncol 2010;28:1038–1046.
crossref pmid pmc
17. Suresh S, Lee BE, Robinson JL, Akinwumi MS, Preiksaitis JK. A risk-stratified approach to cytomegalovirus prevention in pediatric solid organ transplant recipients. Pediatr Transplant 2016;20:970–980.
crossref pmid
18. Reshef R, Luskin MR, Kamoun M, Vardhanabhuti S, Tomaszewski JE, Stadtmauer EA, et al. Association of HLA polymorphisms with post-transplant lymphoproliferative disorder in solid-organ transplant recipients. Am J Transplant 2011;11:817–825.
crossref pmid pmc
19. Subklewe M, Marquis R, Choquet S, Leblond V, Garnier JL, Hetzer R, et al. Association of human leukocyte antigen haplotypes with posttransplant lymphoproliferative disease after solid organ transplantation. Transplantation 2006;82:1093–1100.
crossref pmid
20. Pourfarziani V, Einollahi B, Taheri S, Nemati E, Nafar M, Kalantar E. Associations of Human Leukocyte Antigen (HLA) haplotypes with risk of developing lymphoproliferative disorders after renal transplantation. Ann Transplant 2007;12:16–22.
pmid
21. Lustberg ME, Pelletier RP, Porcu P, Martin SI, Quinion CD, Geyer SM, et al. Human leukocyte antigen type and posttransplant lymphoproliferative disorder. Transplantation 2015;99:1220–1225.
crossref pmid
22. Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, et al. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol 2012;13:196–206.
crossref pmid
23. Fernández MC, Bes D, De Dávila M, López S, Cambaceres C, Dip M, et al. Post-transplant lymphoproliferative disorder after pediatric liver transplantation: characteristics and outcome. Pediatr Transplant 2009;13:307–310.
crossref pmid
24. Soriano-López DP, Alcántar-Fierros JM, Hernández-Plata JA, González-Jorge AL, Velázquez-Ramos S, Flores-Hernández MA, et al. A scheduled program of molecular screening for epstein-barr virus decreases the incidence of post-transplantation lymphoproliferative disease in pediatric liver transplantation. Transplant Proc 2016;48:654–657.
crossref pmid
25. Jang JY, Kim KM, Lee YJ, Lee SG, Chi HS. Quantitative Epstein-Barr virus viral load monitoring in pediatric liver transplantation. Transplant Proc 2008;40:2546–2548.
crossref pmid
26. Narkewicz MR, Green M, Dunn S, Millis M, McDiarmid S, Mazariegos G, et al. Decreasing incidence of symptomatic Epstein-Barr virus disease and posttransplant lymphoproliferative disorder in pediatric liver transplant recipients: report of the studies of pediatric liver transplantation experience. Liver Transpl 2013;19:730–740.
crossref pmid pmc
27. Lee TC, Savoldo B, Rooney CM, Heslop HE, Gee AP, Caldwell Y, et al. Quantitative EBV viral loads and immunosuppression alterations can decrease PTLD incidence in pediatric liver transplant recipients. Am J Transplant 2005;5:2222–2228.
crossref pmid
Fig. 1

The annual occurrence of posttransplantation lymphoproliferative disorder in Seoul National University Children's Hospital presented according to transplanted organ (A) and pathologic malignancy (B). LT, liver transplantation; KT, kidney transplantation.

kjped-60-86-g001.jpg
Fig. 2

Treatment and response. RI, reduction of immunosuppression; Chemo, chemotherapy; RTX, rituximab; GCV, ganciclovir; NR, no response; CR, complete remission; R-ICE, rituximab, ifosfamide, carboplatin, etoposide. *CCG 106B protocol. (GCV) GCV was used for CMV coinfection. Expired from complication of chemotherapy (sepsis) after remission of posttransplantation lymphoproliferative disorder (PTLD). Graft loss during chemotherapy after remission of PTLD.

kjped-60-86-g002.jpg
Table 1

Characteristics of patients (n=18)

kjped-60-86-i001.jpg
Characteristic Value
Sex
 Male:female 9:9
Organ transplanted
 Liver:kidney 11:7
Age at transplantation 11 mo (3 mo–18 yr)
Donor type
 Deceased 3 (16.7)
 Living related 15 (83.3)
Prophylactic basiliximab* 8 (44.4)
Rejection history and treatment 6 (33.3)
 Steroid 3
 Increasing Immunosuppressant 2
 Re-TPL 1
Age at PTLD 4 yr (10 mo–18 yr)
Time since transplantation 7 mo (2 mo–98 mo)
 Early:late 14:4
EBV serologic status (recipient/donor)
 EBV VCA IgG(-/+) 3 (16.7)
 EBV VCA IgG(-/NA) 4 (22.2)
 EBV VCA IgG(+/+) 4 (22.2)
 EBV VCA IgG(+/NA) 1 (5.6)
 EBV VCA IgG(NA/+) 4 (22.2)
 EBV VCA IgG(NA/NA) 2 (11.1)

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.

Table 2

Characteritics of PTLD patients before and after 2012

kjped-60-86-i002.jpg
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 (%).

PTLD, posttransplantation lymphoproliferative disorder; GI, gastrointestinal; EBV, Epstein-Barr virus.

*P value by chi-square test. P value by Welch-Aspin test. B symptoms: night sweats, weight loss of >10% or fevers.

Table 3

Clinical features at the time of presentation of PTLD, 1st line treatment, and outcome

kjped-60-86-i003.jpg
Case No./sex/age/year of Dx. Underlying disease/type of SOT/time from SOT to PTLD Immunosuppression (mg/kg/day) Presentation Involved site Ann Arbor stage Histologic Dx. EBV viral load (copies/mL whole blood) Treatment other than immunesuppression reduction OS (mo)
1/F /1 yr /2003 Biliary atresia/LT/7 mo Tac (0.294) Abdominal mass, intussusception Small bowel, mesenteric LNs 2B Early lesion†,‡ NA Surgery, GCV 149
2/M/10 mo/2005 Biliary atresia//LT/3 mo Tac (0.889), Pd (0.666) Fever, diarrhea Paraaortic, aortocaval, mesenteric, inguinal LNs, small bowel 3B Early lesion†,‡ NA (+CMV) GCV 125
3/M /1 yr/2006 Biliary atresia/LT/3 mo Tac (0.316), Pd (0.316) Fever, blood tinged stool Large bowel, splenomegaly 2B Monomorphic type†,‡ 775,600 GCV 120
4/M/5 yr/2006 Biliary atresia/LT/60 mo Tac (0.087) Fever, melena, abdominal pain Small bowel 4B Burkitt lymphoma†,‡ 48,000 Surgery, GCV, Chemotherapy, RTX 117
5/M/2 yr/2006 Alagille syndrome/LT/6 mo Tac (0.05) Diarrhea, blood tinged stool Colon 2A Polymorphic type†,‡ 413,800 (+CMV) GCV 117
6/F/4 yr/2006 Biliary atresia/LT/42 mo Tac (0.034) Fever, abdominal pain, abdominal mass, eriorbital edema Paratracheal LNs, periorbital soft tissue, paranasal sinuses, pericardium, intraperitoneal mass, stomach, small bowel, peritoneum, omentum, mesentery, kidney nodules 4B Malignant lymphoma, lymphoblastic, B-lineage NA Surgery, GCV, Chemotherapy, RTX 3*
7/M/10 mo/2007 Byler disease/LT/10 mo Tac (0.222), Pd (0.555) Vomiting, blood tinged stool Submandibular, cervical, paraaortic, mesenteric LNs, small bowel, colon, splenomegaly 3A Early lesion†,‡ 3,506,000 (+CMV) RTX (GCV) 106
8/F/5 yr/2007 FSGS/KT/9 mo Tac (0.187), MMF (26.74), Pd (0.134) Fever, cough, cervical LNE Neck mass, jugular LNs, portocaval LN 3B Diffuse large B-cell lymphoma†,‡ 1,830 Chemotherapy, RTX 101
9/F/11 mo/2009 Biliary atresia/LT/4 mo Tac (0.4), Pd (0.2) Fever Mesenteric LNs 2B Early lesion (CD20 staining not done) 108,517 GCV 73
10/F/6 yr/2013 FSGS/KT/5 mo Tac (0.076), Pd (0.19), Sirolimus (0.075) Vomiting, abdominal pain Cervical, axillary, inguinal LNs, stomach, small bowel, umbilicus, vagina 4A Diffuse large B-cell lymphoma†,‡ 166,571 Surgery, Chemotherapy, RTX 34
11/F/13 yr/2013 FSGS/KT/4 mo Tac (0.154), MMF (9.23), Pd (0.064) Epigastric pain Cervical LNs, tonsil, diaphragmatic LNs, subpleural nodules, lung, stomach, duodenum, mesenteric nodules 4A Diffuse large B-cell lymphoma†,‡ 152,987 Chemotherapy, RTX 34§
12/M/1 yr/2013 Osteogenesis imperfecta/LT/9 mo Tac (0.236) Fever, rash Cervical, paratracheal, carinal, paraesophageal, mesenteric LNs 3B Polymorphic type†,‡ 2,583,544 RTX 33
13/F/1 yr/2013 Biliary atresia/LT/3 mo Tac (0.432), Pd (0.74) Fever Cervical, mediastinal, mesenteric, retroperitoneal, inguinal LNs, liver, spleen, scalp 4B Diffuse large B-cell lymphoma†,‡ 1,726,477 Chemotherapy, RTX 32
14/M/4 yr/2013 Biliary atresia/LT/43 mo Tac (0.037) Fever, abdominal pain Supraclavicular, paratracheal, hilar LNs, lung, liver, subhepatic mass, bowel, peritonium, spleen 4B Burkitt lymphoma†,‡ 184,217 Chemotherapy, RTX 27
15/F/15 yr/2013 Congenial renal hypoplasia/KT/98 mo Tac (0.069), AZT (0.69) Diarrhea, abdominal mass with tenderness Perigastric, mesenteric LNs, stomach, small bowel 4A Burkitt lymphoma†,‡ 27,161 Chemotherapy, RTX 26
16/M/18 yr/2014 FSGS/KT/2 mo Tac (0.526), MMF (12.63), Pd (0.088) Head and neck LNE Cervical LNs 1A Polymorphic type†,‡ 555 (+CMV) Surgery, RTX (GCV) 17
17/F/7 yr/2015 Congenital nephrotic syndrome/KT/8 mo Tac (0.25), Pd (0.125) Tonsilar hypertrophy Bilateral tonsils, cervical LNs 1A Early lesion†,‡ 32,286 Surgery, RTX 7
18/M/4 yr/2015 MCDK/KT/9 mo Tac (0.128), Pd (0.16) Fever, cervical LNE Cervical LNs 1B Polymorphic type†,‡ 637,031 RTX 4

LT, liver transplantation; KT, kidney transplantation; OS, overall survival; FSGS, focal segmental glomerulosclerosis; MCDK, multicystic dysplastic kidney; NA, not available; LN, lymph node; LNE, lymph node enlargement; Ag, CMV antigenemia; PCR, viral load polymerase chain reaction; Tac, tacrolimus; Pd, prednisolone; MMF, mycophenolate mofetil; AZT, azathioprine; RTX, rituximab; GCV, ganciclovir.

*Expired from complication of chemotherapy (sepsis) after remission of PTLD. CD20 positive. EBV In situ hybridization positive. (GCV) GCV was used for CMV coinfection. (+CMV) CMV infection at PTLD diagnosis. §Graft loss during chemotherapy after remission of PTLD. On maintenance chemotherapy on last follow-up.

Table 4

Comparison of malignancy group with benign group

kjped-60-86-i004.jpg
Variable Malignancy (n=8) Benign (n=10) P value
Sex
 Male:female 2:6 7:3 0.058*
Transplanted organ
 Liver:kidney 4:4 7:3 0.387*
Age at transplantation 53 mo (5 mo –13 yr) 10 mo (3 mo –18 yr) 0.724
Date of transplantation, year 2005 (2001–2013) 2008 (2003–2014) 0.588
Age of PTLD 5 yr (1 yr –15 yr) 1Y (10 mo –18 yr) 0.207
Date of PTLD 2013 (2006–2013) 2008 (2003–2015) 0.534
Time since transplantation 9 mo (3 mo –8 yr) 6.5 mo (2 mo –9 mo) 0.059
Tacrolimus dosage (mg/kg/day) 0.082 (0.037–0.432) 0.272 (0.050–0.889) 0.042
Basiliximab prophylaxis 4 (50) 4 (40) 0.671*
History of acute rejection 2 (25) 3 (30) 0.737*
B symptoms 5 (62.5) 5 (50) 0.596*
GI involvement 6 (75) 5 (50) 0.280*
Extranodal involvement 7 (87.5) 5 (50) 0.094*
EBV viral load (copies/mL) 100,494 (1,830–1,726,477) 70,402 (555–3,506,000) 0.221

Values are presented as number, median (range), or number (%).

PTLD, posttransplantation lymphoproliferative disorder; GI, gastrointestinal; EBV, Epstein-Barr virus.

*P value by chi-square test. P value by Welch-Aspin test. B symptoms: night sweats, weight loss of >10% or fevers.

METRICS Graph View
  • 13 Crossref
  • 14 Scopus
  • 9,882 View
  • 258 Download