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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2013  |  Volume : 24  |  Issue : 1  |  Page : 1-7
Post-transplantation lymphoproliferative disorders in renal vs. simultaneous renal-pancreas allograft recipients: A survey and analysis of data from the literature


1 Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
2 Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences; Dr. Taheri Medical Research Group, Tehran, Iran

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Date of Web Publication22-Jan-2013
 

   Abstract 

The epidemiology and other aspects of post-transplantation lymphoproliferative disorders (PTLD) are different in different transplant populations. In this study, we sought to determine the clinical, histopathological and various other features of PTLD in recipients of pancreas-renal allografts and to compare their data with renal-only transplant patients, based on the current available literature. We conducted a comprehensive search for the available data using the Pubmed and Google scholar search engines for reports of lymphoproliferative disorders after renal and simultaneous pancreas-renal (SPR) transplantations. A total of 229 recipients of renal and pancreas-renal allografts were included in the analysis. Localizations for SPR recipients were significantly higher than renal recipients in the pancreas (P <0.0001), skin (P = 0.035), liver (P = 0.043) and bone marrow (P = 0.022). Involvement of lymph nodes was more prevalent in renal recipients (P = 0.046). The occurrence of metastasis was more common among SPR recipients (P = 0.005). Hodgkin's and Hodgkin's-like PTLD were also more prevalent among SPR transplant patients (P <0.0001). Time to development of PTLD was significantly shorter among recipients of SPR (P <0.0001). In this study of international data, we found that PTLD in SPR transplant recipients have various characteristics in their site of involvement, disease presentation time and histopathological features. However, no difference in outcome was detected in these groups of PTLD patients. Future studies with larger study populations are needed for confirming and extending our study results.

How to cite this article:
Khedmat H, Taheri S. Post-transplantation lymphoproliferative disorders in renal vs. simultaneous renal-pancreas allograft recipients: A survey and analysis of data from the literature. Saudi J Kidney Dis Transpl 2013;24:1-7

How to cite this URL:
Khedmat H, Taheri S. Post-transplantation lymphoproliferative disorders in renal vs. simultaneous renal-pancreas allograft recipients: A survey and analysis of data from the literature. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2014 Oct 24];24:1-7. Available from: http://www.sjkdt.org/text.asp?2013/24/1/1/106230

   Introduction Top


Post-transplant lymphoproliferative disorders (PTLD) are one of the most common malignnancies complicating solid-organ recipients, including simultaneous renal and pancreas (SPR) transplant (Tx) recipients. [1],[2],[3],[4],[5],[6] PTLD represent a spectrum of heterogeneous pathologic lymphoid proliferations developing due to an abnormal response by the lymphoid system to Epstein-Barr virus (EBV) infection in hematological cells, chronic immunological response to the allograft antigens and pharmacologic immunosuppression after organ transplantation. [7],[8] PTLD are generally considered to be more prevalent and extremely more aggressive diseases compared with malignant lymphomas in the general population. [8],[9],[10],[11],[12],[13] The epidemiology and other aspects of PTLD are different in different transplant populations. [14],[15] Recipients of some allograft types are at higher risk of developing PTLD, and the features of PTLD are quite different between them. Previous reports on PTLD occurring in SPR Tx recipients are on limited patient population without comparing the results with other Tx populations. Thus, we do not have a reliable view on the characteristics of PTLD occurring after SPR Tx. In this study, we sought to determine the clinical, histopathological and various other features of PTLD in recipients of SPR allografts and to compare their data with renal-only transplant recipients.


   Materials and Methods Top


Approach to the study

We conducted a comprehensive search for the available data using the Pubmed and Google scholar search engines for reports of lymphoproliferative disorders after renal and SPR Tx. Keywords used for this purpose were "lymphoproliferative disorders + renal transplantation," "lymphoproliferative disorders + pancreas + renal transplantation," "PTLD + renal transplantation," "PTLD + pancreas + renal transplantation" and "PTLD + simultaneous pancreas + renal transplantation." In cases where we were not able to access the full text of the articles, an email was sent to the correspondent authors requesting for the article. We only included studies in which data of each patient was presented separately, and excluded the others. To minimize selection bias, we only included studies reporting their series of patients from single or multicenter populations; studies with any specific selection criterion were excluded from the analysis; SPR allograft recipients were considered as the case group and renal transplant patients were used as controls. A standard questionnaire was developed to collect data from different published studies. Finally, data from 23 previously published studies from various countries [4],[7],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34] were included in the analysis. The time between transplantation and onset of PTLD was defined as the period between the date of transplantation and the first signs of PTLD or diagnosis, depending on the studies.

Study population

Overall, 229 recipients of SPR allografts were included in the analysis. Twenty (9%) patients the study population were recipients of SPR allografts and the remaining 209 (91%) patients were recipients of renal transplants. Because data used for this study were from different studies, and they had no unique approaches, we were not able to get all the data needed from all the included patients. Thus, data for sites of malignancy were available for 189 patients (82%) only. Renal allograft localization was seen in 47 patients (25%), thyroid in three (2%), bone (including vertebrae) in seven (4%), heart in three (2%), pancreas in six (3%), retroperitoneal tumor in nine (5%), adrenal gland in two (1%), skin in eight (4%), spleen in six (3%), lymph nodes in 71 (38%), central nervous system in 22 (12%), pharynx in 11 (6%), liver in 21 (11%), gastrointestinal tract (including stomach and small and large intestines) in 70 (37%), stomach in 10 (5%), genitalia in four (2%), bone marrow in 12 (6%) and lung in 18 (9%). Disseminated lymphoma was reported in six patients (3%). Multi-organ involvement was noted in 75 patients (40%), while 114 (57%) were reported to have only one PTLD localization site. [Table 1] shows the localization of malignancy according to the allograft types. At diagnosis of lymphoma, all patients were receiving immunosuppressive regimens including varying combinations of azathioprine, prednisone, cyclosporine, mycophenolate mofetil, antithymocyte/ lymphocyte globulin (ATG/ALG) and OKT3. More or less, a rather uniform approach was used to manage all PTLD patients in the included reports. On diagnosis of PTLD, the first step in almost all reports was to decrease or discontinue immunosuppressive therapy; different regimens of chemotherapy, with or without surgical interventions, were used for some of the patients.
Table 1: Characteristics of the study population regarding their allograft type.

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Laboratorial findings and disease progression

The EBV serologic status was documented in 132 patients (58%), of whom 96 (73%) were seropositive. For categorizing a parameter for defining "metastasis," we considered all subjects with more than one PTLD localizations as having metastatic disease; patients with over one PTLD localization that were defined as having non-metastatic disease by the authors were considered non-metastatic. With this definition criteria, in addition to patients in whom metastasis was definitely documented by the authors (31 patients), 82 patients (36%) presented with metastatic disease while 18 patients (8%) were documented as having no metastases by the authors.

Response to treatment

Response to treatment was defined as any favorable change in the cancer measures as well as patients' clinical condition; data of PTLD response to treatment was reported for 119 patients (52%), of whom 75 patients (68%; 65 patients completely remitted) responded to anti-malignancy treatment while 12 (of the 45 reported cases; 27%) experienced episodes of relapse. Overall, 116 patients (51%) died; death due to PTLD was defined when (a) if authors stated it or (b) when patient died within six months post-diagnosis and (c) when patients died due to complications related to PTLD treatment. Overall, 71 patients (63%) died of the disease based on the above-mentioned criteria.


   Statistical Analysis Top


The software used for data analyses was SPSS v.13.0. Statistical differences between patients' sub-groups were performed using χ2 and Fisher's exact tests for proportions and the Student's t test for continuous data. Survival analysis was performed with life tables and Kaplan-Meier methods and log-rank test. All statistical tests were performed at the 0.05 significance level.


   Results Top


Overall, 229 patients with lymphoproliferative disorders after renal transplantation were enrolled in the analysis. There were 126 male (65%) and 66 female (34%) patients (37 missing data). Mean age at diagnosis of PTLD was 41 ± 15 years. The mean interval between transplantation and the diagnosis of PTLD was 61 ± 67 months, while the follow-up duration after diagnosis of PTLD was 26 ± 62 months. The characteristics of the patients regarding their allograft types are summarized in [Table 1]. Chi square test showed that PTLD localizations for SPR recipients were significantly higher than in renal recipients as follows: (a) pancreas [five (26%) vs. one (1%), respectively; P <0.0001]; (b) skin [three (16%) vs. five (3%), respectively; P = 0.035]; (c) liver [five (26%) vs. 16 (9%), respectively; P = 0.043]; and (d) bone marrow [four (21%) vs. eight (5%), respectively; P = 0.022]; while renal recipients were significantly more likely to develop PTLD within lymph nodes [68 (40%) vs. three (16%), respectively; P = 0.046]. Multi-organ involvement was more likely to occur in SPR recipients [13 (68%) vs. 62 (36%), respectively; P = 0.012]. The occurrence of metastasis was also significantly more prevalent among SPR recipients compared with renal transplant recipients [14 (74%) vs. 68 (40%), respectively; P = 0.005]. SPR recipients were more likely to develop PTLD of T-cell type than renal recipients [five (26%) vs. two (3%), respectively; P = 0.005]. Hodgkin's and Hodgkin's-like PTLD were also more prevalent among SPR Tx patients compared with renal recipients [13 (87%) vs. 29 (36%), respectively; P <0.0001; 133 missing data]. Because of the lack of data for histological patterns, including clonality and morphology for SPR PTLD patients, we were not able to compare these parameters between the two groups. Time to PTLD development was significantly shorter among recipients of SPR (26 ± 35 vs. 64 ± 69 months, respectively; P <0.0001); EBV sero-positivity was equal between the two transplant groups [85 (73%) for renal recipients vs. 11 (73%) for SPR transplant patients; P = 1.0]. At last follow-up, 94 patients (45%) were alive (19 missing data). One-year survival rates for renal transplant and SPR recipients with PTLD were 45% and 29%, respectively (P = 0.7). Bivariate analysis did not show any difference in patient survival between renal transplant patients and SPR recipients (P = 0.2), although after the first six months post-diagnosis, the survival curve dropped for SPR recipients [Figure 1]. Similar results were found when death due to PTLD (excluding other reasons) was used as the end point (P = 0.2).
Figure 1: Survival curves for renal transplant patients and simultaneous pancreas-renal recipients after PTLD diagnosis

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   Discussion Top


PTLD is an important complication in allograft recipients who are treated with immunosuppression that mainly targets the T-cell response; [35],[36],[37] this disorder is also one of the interfering factors that restricts the long-term outcome of transplantation. Until now, several studies have been published on PTLD occurring in organ transplant recipients. Renal transplant patients are the most commonly investigated transplant population on the epidemiology, features and prognosis of PTLD. However, there is shortage of data on PTLD occurring after SPR Tx and its potential differences with PTLD in renal-only transplant recipients. Because most studies in the existing literature deal with a limited number of PTLD patients, analyses may not properly demonstrate specific features of the disease in different populations. In this study, we attempted summation of data from different studies to have a larger population in which analyses may represent a more accurate result. Our analyses on the pooled data from 23 international studies have demonstrated several new pieces of information on PTLD occurring after SPR transplantation. We found that SPR recipients have comparable patient survival to recipients of kidney-only allografts despite their diverse characteristics, including occurrence of metastasis and multi-organ involvement. SPR recipients had a significantly shorter time to PTLD development. This finding is in contrast to a previous report in which no difference was seen between different allograft recipients. [15] Histopathological features were also significantly different between the two transplant groups, with SPR transplant recipients significantly more likely to develop PTLD of T-cell type and Hodgkin's disease. Paraskevas et al [15] also reported that T-cell PTLD was more prevalent in their series of pancreas transplant patients; however, to our knowledge, our study is the first reporting a higher incidence of Hodgkin's and Hodgkin's-like diseases among SPR recipients. Localization of PTLD was also significantly different between SPR recipients and renal transplant patients. We found that PTLD was more likely to involve the pancreas, skin, liver and bone marrow in SPR recipients, while lymph nodes were the predominant involvement site in renal allograft recipients. Gastrointestinal tract localization was also more prevalent among SPR recipients, although it did not reach a significance level (P = 0.07). Additionally, the initial response to treatment was relatively lower among SPR recipients (P = 0.09). Moreover, occurrence of metastasis was more prevalent among SPR recipients than in renal transplant patients. We are aware of the limitations of our study protocol. First, our study population was gathered from different reports with inconsistent approaches. Also, another major limitation of this study is the substantial missing data for some of study variables thus decreasing the power of some of our analyses. This limitation was most prominent for special data that are not typically included in all reports on PTLD patients. On the other hand, we studied different series of patients from 23 studies in this analysis. Some studies were simple series reported from individual centers while others focused on graft involvement or other specific criteria. Thus, we were not able to globalize our observation on the incidence or frequencies in our study population. Another limitation was that results of different studies were not presented in the same way. For example, report of response to treatment was presented in different ways in different studies. In one study, "partial and complete remission" was used to describe the response to treatment, while in some other studies, "response to treatment" was used and in yet other studies, no specific terminology was employed. Hence, we ought to invent new methods to cumulate the existing data for analysis.

In conclusion, in this study of international data, we found that PTLD arising in SPR Tx recipients have various characteristics in their involvement site, disease presentation time and histopathological features. However, no outcome difference was detected in these groups of PTLD patients. Future studies with larger study populations are needed for confirming and extending our study results.

 
   References Top

1.Khedmat H, Taheri S. Early onset post transplantation lymphoproliferative disorders: Analysis of international data from 5 studies. Ann Transplant 2009;14:74-7.  Back to cited text no. 1
[PUBMED]    
2.Khedmat H, Taheri S. Late onset post transplantation lymphoproliferative disorders: Analysis of international data from 5 studies. Ann Transplant 2009;14:80-5.  Back to cited text no. 2
[PUBMED]    
3.Khedmat H, Alavian SM, Taheri S. Significance of Epstein - Barr virus infection on the outcome of renal transplant patients with lymphoproliferative disorders. Ann Transplant 2010;15:40-4.  Back to cited text no. 3
    
4.Pourfarziani V, Taheri S, Lessan-Pezeshki M, et al Lymphoma after living donor kidney transplantation: An Iranian multicenter experience. Int Urol Nephrol 2008;40:1089-94.   Back to cited text no. 4
    
5.Khedmat H, Taheri S. Characteristics and prognosis of post transplantation lymphoproliferative disorders within renal allograft: report from PTLD. Int. survey. Ann Transplant 2010;15:80-6.  Back to cited text no. 5
    
6.Mihalov ML, Gattuso P, Abraham K, Holmes EW, Reddy V. Incidence of post-transplant malignancy among 674 solid-organ-transplant recipients at a single center. Clin Transplant 1996;10:248-55.  Back to cited text no. 6
[PUBMED]    
7.Hanto DW, Frizzera G, Gajl Peczalska J, et al. The Epstein-Barr virus (EBV) in the pathogenesis of posttransplant lymphoma. Transplant Proc 1981;13:756-60.   Back to cited text no. 7
    
8.Morrison VA, Dunn DL, Manivel JC, Gajl Peczalska KJ, Peterson BA. Clinical characteristics of post-transplant lymphoproliferative disorders. Am J Med 1994;97:14-24.  Back to cited text no. 8
    
9.Leblond V, Sutton L, Dorent R, et al. Lymphoproliferative disorders after organ transplantation: A report of 24 cases observed in a single center. J Clin Oncol 1995;13:961-8.   Back to cited text no. 9
[PUBMED]    
10.Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet 1993;342:1514-6.   Back to cited text no. 10
[PUBMED]    
11.Penn I. Tumors of the immunocompromised patient. Annu Rev Med 1988;39:63-73.   Back to cited text no. 11
[PUBMED]    
12.Penn I. Cancers complicating organ. N Engl J Med 1990;323:1767-9.   Back to cited text no. 12
[PUBMED]    
13.Penn I, Brunson ME. Cancers after cyclosporine therapy. Transplant Proc 1988;20:885-92.  Back to cited text no. 13
[PUBMED]    
14.Jain M, Badwal S, Pandey R, Srivastava A, Sharma RK, Gupta RK. Post-transplant lymphoproliferative disorders after live donor renal transplantation. Clin Transplant 2005;19: 668-73.  Back to cited text no. 14
[PUBMED]    
15.Paraskevas S, Coad JE, Gruessner A, et al. Posttransplant lymphoproliferative disorder in pancreas transplantation: A single-center experience. Transplantation 2005;80:613-22.  Back to cited text no. 15
[PUBMED]    
16.Muti G, Cantoni S, Oreste P, et al. Post-transplant lympoproliferative disorders: improved outcome after clinico-pathologically tailored treatment. Haematologica 2002;87:67-77.  Back to cited text no. 16
[PUBMED]    
17.Mamzer-Bruneel MF, Lomé C, Morelon E, et al. Durable remission after aggressive chemotherapy for very late post-kidney transplant lymphoproliferation: A report of 16 cases observed in a single center. J Clin Oncol 2000;18:3622-32.  Back to cited text no. 17
    
18.Vakiani E, Basso K, Klein U, et al. Genetic and phenotypic analysis of B-cell posttransplant lymphoproliferative disorders provides insights into disease biology. Hematol Oncol 2008;26: 199-211.  Back to cited text no. 18
[PUBMED]    
19.Koike J, Yamaguchi Y, Hoshikawa M, et al. Post-transplant lymphoproliferative disorders in kidney transplantation: histological and molecular genetic assessment. Clin Transplant 2002;16 (Suppl. 8):12-7.  Back to cited text no. 19
    
20.Hoshida Y, Li T, Dong Z, et al. Lymphoproliferative disorders in renal transplant patients in Japan. Int J Cancer 2001;91:869-75.  Back to cited text no. 20
[PUBMED]    
21.Cockfield SM, Preiksaitis JK, Jewell LD, Parfrey NA. Post-transplant lymphoproliferative disorders in renal allograft recipients. Transplantation 1993;56:88-96.  Back to cited text no. 21
[PUBMED]    
22.Schaar CG, van der Pijl JW, van Hoek B, et al. Successful outcome with a quintuple approach of posttransplant lymphoproliferative disorders. Transplantation 2001;71:47-52.  Back to cited text no. 22
[PUBMED]    
23.Poirel HA, Bernheim A, Schneider A. Characteristic pattern of chromosomal imbalances in posttransplantation lymphoproliferative disorders: Correlation with histopathological sub-categories and EBV status. Transplantation 2005;80:176-84.  Back to cited text no. 23
    
24.Jain A, Nalesnik M, Reyes J, et al. Post-transplant lymphoproliferative disorders in liver transplantation: A 20-year experience. Ann Surg 2002;236:429-36.  Back to cited text no. 24
[PUBMED]    
25.Ali MG, Coakley FV, Hricak H, Bretan PN. Complex post-transplantation abnormalities of renal allografts: Evaluation with MR Imaging. Radiology 1999;211:95-100.  Back to cited text no. 25
[PUBMED]    
26.Bakker NA, van Imhoff GW, Verschuuren EA, et al. Early onset post-transplant lymphoproliferative disease is associated with allograft localization. Clin Transplant 2005;19:327-34.   Back to cited text no. 26
[PUBMED]    
27.Randhawa PS, Magnone M, Jordan M, Shapiro R, Demetris AJ, Nalesnik M. Renal allograft involvement by EBV associated posttransplant lymphoproliferative disease. Am J Surg Pathol 1996;20:563-71.  Back to cited text no. 27
[PUBMED]    
28.Herzig KA, Juffs HG, Norris D, et al. A single-centre experience of post-renal transplant lymphoproliferative disorder. Transpl Int 2003; 167:529-36.  Back to cited text no. 28
    
29.Wasson S, Zafar MN, Best J, Reddy HK. Post-transplantation lymphoproliferative disorder in heart and kidney transplant patients: A single-center experience. J Cardiovasc Pharmacol Ther 2006;11:77-83.  Back to cited text no. 29
[PUBMED]    
30.Comoli P, Labirio M, Basso S, et al. Infusion of autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication. Blood 2002;99: 2592-8.  Back to cited text no. 30
[PUBMED]    
31.Wilde GE, Moore DJ, Bellah RD. Post-transplantation lymphoproliferative disorder in pediatric recipients of solid organ transplants: Timing and location of disease. AJR Am J Roentgenol 2005;185:1335-41.  Back to cited text no. 31
[PUBMED]    
32.Trappe R, Riess H, Babel N. Salvage Chemotherapy for Refractory and Relapsed Posttransplant Lymphoproliferative Disorders (PTLD) After Treatment With Single-Agent Rituximab. Transplantation 2007;83:912-8.  Back to cited text no. 32
    
33.Tsai DE, Hardy CL, Tomaszewski JE, 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.  Back to cited text no. 33
[PUBMED]    
34.Aigner F, Boeckle E, Albright J. Malignancies of the colorectum and anus in solid organ recipients. Transplant Int 2007;20:497-504.  Back to cited text no. 34
    
35.Carpentier L, Tapiero B, Alvarez F, Viau C, Alfieri C. Epstein-Barr virus (EBV) early-antigen serologic testing in conjunction with peripheral blood EBV DNA load as a marker for risk of posttransplantation lymphoproliferative disease. J Infect Dis 2003;188:1853-64.  Back to cited text no. 35
[PUBMED]    
36.Tanner JE, Alfieri C. Interactions involving cyclosporine A, interleukin-6, and Epstein-Barr virus lead to the promotion of B-cell lymphoproliferativedisease. Leuk Lymphoma 1996;21:379-90.  Back to cited text no. 36
[PUBMED]    
37.Walz G, Zanker B, Melton LB, Suthanthiran M, Strom TB. Possible association of the immunosuppressive and B cell lymphoma-promoting properties of cyclosporine. Transplantation 1990;49:191-4.  Back to cited text no. 37
[PUBMED]    

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Correspondence Address:
Hossein Khedmat
Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran
Iran
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DOI: 10.4103/1319-2442.106230

PMID: 23354184

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