SEARCH

SEARCH BY CITATION

Solid-organ transplant recipients have an elevated risk for some malignancies because of the requirement for immunosuppression [1]. In particular, non-Hodgkin's lymphoma (NHL) is common and comprises one end of a spectrum of post-transplant lymphoproliferative disorder (PTLD) ranging from benign hyperplasia to lymphoid malignancy [2]. PTLD risk is influenced by the type of organ transplanted, the age and Epstein-Barr virus (EBV) serostatus of the transplant recipient, and the intensity of immunosuppression [3–9]. PTLD incidence is high immediately after transplantation, decreases subsequently, and then rises again 4–5 years from transplantation [10, 11]. This incidence pattern suggests the presence of separate early-onset and late-onset PTLD subtypes. Early-onset PTLDs tend to be EBV-positive and, when extranodal, are more likely than late-onset PTLDs to be localized to the transplanted organ [12, 13]. Late-onset PTLD is less likely to be associated with EBV and, overall, is more likely than early-onset PTLD to be extranodal [13, 14]. The Scientific Registry of Transplant Recipients (SRTR) includes data on a large number of solid-organ transplant recipients in the United States and information on malignancies diagnosed post-transplantation. We used these data to conduct a retrospective cohort study among kidney transplant recipients to examine differences in risk factors between early-onset PTLD and late-onset PTLD.

The study included 156,740 kidney transplant recipients (Table I). During follow-up, 762 cases of PTLD were diagnosed. Cumulative incidence of PTLD at 5 and 10 years after transplantation was 0.7% and 1.4%, respectively. As shown in Fig. 1, a “U-shaped” pattern of incidence with time since transplantation was observed, with high PTLD incidence shortly after transplantation, decreasing until 2–4 years from transplantation, and rising thereafter. Early-onset PTLD (i.e., within the first 2 years after transplantation, n = 361) was more likely to be monomorphic than polymorphic (48.2% vs. 41.6%, with 10.2% of unknown pathology), and late-onset PTLD (more than 2 years after transplantation, n = 401) was even more likely to be of monomorphic pathology (55.9% vs. 31.4%, 12.7% unknown). Early-onset PTLD was predominantly of B-cell origin (72.3% B-cell vs. 4.2% T-cell, 23.6% unknown). Late-onset PTLD showed a slightly higher proportion of T-cell PTLD (64.3% B-cell vs. 9.7% T-cell, 25.9% unknown).

thumbnail image

Figure 1. Incidence of post-transplant lymphoproliferative disorder (PTLD) among kidney recipients during 1999–2007. Incidence and 95% confidence intervals are shown as a function of time since transplantation. PTLD incidence is displayed as PTLD events per 100,000 person-years. Follow-up for all recipients began 30 days (0.083 years) after transplantation.

Download figure to PowerPoint

Table I. Demographic and Transplant Characteristics of Kidney Recipients Followed During 1999–2007 in the United States (N = 156,740)
CharacteristicRecipients, n (%)
  • Recipients accrued a total of 532,342 person-years of follow-up (mean, 3.4 years per recipient).

  • a

    Medication information was missing for 1,909 kidney recipients.

  • b

    T-cell-directed therapies included thymoglobulin, antithymocyte globulin (ATG), Campath, OKT3, OKT4, NRATG, and antilymphocyte globulin (ALG).

  • c

    HLA mismatch information was missing for 1,333 kidney recipients.

  • Abbreviations: EBV, Epstein-Barr virus; CMV, cytomegalovirus; HLA, human leukocyte antigen.

Gender
 Male93,830 (59.9)
 Female62,910 (40.1)
Age at transplantation, years
 0–1910,711 (6.8)
 20–5082,186 (52.4)
 >5063,843 (40.7)
 Median age47.0
Race/ethnicity
 Non-Hispanic white91,867 (58.6)
 Other64,873 (41.4)
Calendar year of transplantation
 1987–199529,081 (18.6)
 1996–199825,902 (16.5)
 1999–2007101,757 (64.9)
EBV serostatus
 Positive49,790 (31.8)
 Negative9,666 (6.2)
 Missing/not done97,284 (62.1)
CMV serostatus
 Positive56,877 (36.3)
 Negative34,250 (21.8)
 Missing/not done65,613 (41.9)
Antibody inductiona
 Yes84,458 (54.5)
 No70,373 (45.5)
T-cell antibody inductiona
 Yes45,984 (29.7)
 No108,847 (70.3)
Steroid maintenancea
 Yes135,635 (87.6)
 No19,196 (12.4)
Antirejection therapya
 Yes12,780 (8.3)
 No142,051 (91.7)
T-cell antirejection therapyb
 Yes5,729 (3.7)
 No149,102 (96.3)
HLA mismatch, number of allelesc
 0–246,838 (30.1)
 3–466,269 (42.6)
 5–642,300 (27.2)

We examined PTLD risk factors stratified by onset time (Table II). Gender was not associated with early-onset PTLD risk, but males had significantly higher late-onset PTLD risk than females (hazard ratio [HR], 1.23). Young age was more strongly associated with risk of early-onset PTLD than late-onset PTLD (HRs 6.59 and 2.98, respectively, for age 0–19 years compared to age 20–50 years at transplantation; P < 0.0001 for difference in HRs), whereas older age (>50 years) was significantly associated only with late-onset PTLD risk (HR, 1.29). Non-Hispanic whites were at significantly higher risk of early-onset and late-onset PTLD than other racial or ethnic groups (HRs 2.09 and 1.76, respectively). EBV seronegativity was associated with significantly increased risk of both early-onset and late-onset PTLD, although the association was much stronger for early-onset PTLD (HRs 4.76 vs. 1.52, P < 0.0001). Cytomegalovirus (CMV) seronegativity was also associated with increased early-onset PTLD risk more strongly than late-onset PTLD risk (HRs 2.44 vs. 1.25, P = 0.0001).

Table II. PTLD Risk Factors Among Kidney Transplant Recipients in the United States During 1999–2007
CharacteristicEarly-onset PTLD, HR (95% CI)aLate-onset PTLD, HR (95% CI)aP-valueb
  • a

    Early-onset PTLD is defined as that occurring less than 2 years after transplantation; late-onset PTLD is defined as that occurring 2 or more years after transplantation. Hazard ratio is based on a univariate proportional hazards regression model.

  • b

    P-value compares hazard ratios for early-onset and late-onset PTLDs and is based on the significance of an interaction term between the variable of interest and an indicator variable that distinguished early and late follow-up periods.

  • c

    T-cell-directed therapies included thymoglobulin, anti-thymocyte globulin (ATG), Campath, OKT3, OKT4, NRATG, and anti-lymphocyte globulin (ALG).

  • PTLD, post-transplant lymphoproliferative disorder; HR, hazard ratio; CI, confidence interval; EBV, Epstein-Barr virus; CMV, cytomegalovirus; HLA, human leukocyte antigen.

Gender
 Male1.00 (0.81–1.24)1.23 (1.01–1.51)0.16
 Female1.0 (ref)1.0 (ref) 
Age at transplantation, years
 0–196.59 (5.12–8.48)2.98 (2.26–3.92)<0.0001
 20–501.0 (ref)1.0 (ref) 
 >501.04 (0.81–1.33)1.29 (1.04–1.61)0.19
Race/ethnicity
 Non-Hispanic white2.09 (1.66–2.64)1.76 (1.41–2.21)0.30
 Other1.0 (ref)1.0 (ref) 
EBV serostatus
 Positive1.0 (ref)1.0 (ref) 
 Negative4.76 (3.70–5.88)1.52 (1.12–2.08)<0.0001
CMV serostatus
 Positive1.0 (ref)1.0 (ref) 
 Negative2.44 (1.89–3.13)1.25 (0.97–1.61)0.0001
Antibody induction
 Yes1.08 (0.87–1.34)1.23 (1.00–1.50)0.39
 No1.0 (ref)1.0 (ref) 
T-cell antibody induction
 Yes1.19 (0.95–1.49)1.22 (0.99–1.51)0.86
 No1.0 (ref)1.0 (ref) 
Steroid maintenance
 Yes1.33 (0.96–1.84)0.64 (0.44–0.95)0.005
 No1.0 (ref)1.0 (ref) 
Antirejection therapy
 Yes0.68 (0.40–1.14)1.15 (0.84–1.57)0.09
 No1.0 (ref)1.0 (ref) 
T-cell antirejection therapyc
 Yes0.62 (0.26–1.51)1.08 (0.67–1.74)0.29
 No1.0 (ref)1.0 (ref) 
HLA mismatch, number of alleles
 0–21.0 (ref)1.0 (ref) 
 3–41.12 (0.88–1.44)1.02 (0.82–1.28)0.56
 5–60.85 (0.64–1.13)1.02 (0.78–1.34)0.36

Steroid maintenance therapy did not impact early-onset PTLD risk, but significantly decreased the risk of late-onset PTLD (HR 0.64). Use of antibody induction or antirejection therapies was not associated with PTLD risk, even when restricted to T-cell-based therapies (Table II). The degree of human leukocyte antigen (HLA) mismatch was also not associated with PTLD risk, regardless of the timing of PTLD onset.

Results of separate multivariate models for early-onset and late-onset PTLD are shown in Table III. When EBV and CMV serostatus were not included (Model 1), young age was significantly associated with both early-onset and late-onset PTLD risk (HRs 6.47 and 2.92, respectively, compared with age 20–50 years), and non-Hispanic whites were at significantly increased risk of both early-onset PTLD and late-onset PTLD, compared with other racial or ethnic groups (HRs 2.11 and 1.73, respectively). The association with young age was stronger for early-onset than for late-onset PTLD (P < 0.0001).

Table III. Multivariate Analysis of Risk Factors for PTLD Among Kidney Transplant Recipients in the United States During 1999–2007
CharacteristicModel 1Model 2
Early-onset PTLD, HR (95% CI)aLate-onset PTLD, HR (95% CI)aP-valuebEarly-onset PTLD, HR (95% CI)aLate-onset PTLD, HR (95% CI)aP-valueb
  • a

    Early-onset PTLD is defined as that occurring less than 2 years after transplantation; late-onset PTLD is defined as that occurring 2 or more years after transplantation. Hazard ratios are based on a multivariate proportional hazards regression model with the indicated variables.

  • b

    P-value compares hazard ratios for early-onset and late-onset PTLDs and is based on the significance of an interaction term between the variable of interest and an indicator variable that distinguished early and late follow-up periods.

  • PTLD, post-transplant lymphoproliferative disorder; HR, hazard ratio; CI, confidence interval; EBV, Epstein-Barr virus; CMV, cytomegalovirus.

Gender
 Male1.00 (0.81–1.23)1.20 (0.98–1.47)0.210.93 (0.75–1.15)1.19 (0.97–1.47)0.10
 Female1.0 (ref)1.0 (ref) 1.0 (ref)1.0 (ref) 
Age at transplantation, years
 <0–196.47 (5.02–8.33)2.92 (2.21–3.84)<0.00013.97 (3.02–5.22)2.68 (1.97–3.64)0.06
 20–501.0 (ref)1.0 (ref) 1.0 (ref)1.0 (ref) 
 >500.98 (0.77–1.26)1.26 (1.02–1.57)0.141.09 (0.85–1.41)1.28 (1.02–1.60)0.37
Race/ethnicity
 Non-Hispanic white2.11 (1.68–2.67)1.73 (1.38–2.16)0.221.82 (1.43–2.32)1.77 (1.39–2.25)0.87
 Other1.0 (ref)1.0 (ref) 1.0 (ref)1.0 (ref) 
EBV serostatus
 Positive 1.0 (ref)1.0 (ref) 
 Negative   3.13 (2.44–4.17)1.26 (0.91–1.79)<0.0001
CMV serostatus
 Positive 1.0 (ref)1.0 (ref) 
 Negative   1.49 (1.15–1.96)0.99 (0.75–1.30)0.02

With addition of information for EBV and CMV serostatus (Model 2), young age remained significantly associated with both early-onset and late-onset PTLD risk (HRs 3.97 and 2.68, respectively, compared with age 20–50 years), although the association was attenuated for early-onset PTLD compared with the results of Model 1. Non-Hispanic whites continued to be at significantly increased risk of both early-onset PTLD and late-onset PTLD compared with other racial or ethnic groups (HRs 1.82 and 1.77, respectively). EBV and CMV seronegativity were significantly associated with increased risk of early-onset PTLD only (HRs 3.13 and 1.49, respectively). In both multivariate models, gender was no longer associated with risk of either early-onset or late-onset PTLD. When added to Model 2, steroid maintenance therapy remained a significant predictor of decreased late-onset PTLD risk (HR 0.66).

This large retrospective cohort study of kidney transplant recipients showed a clear bimodal pattern in onset for PTLD, and there were distinct differences in pathology and risk factors between early-onset PTLD and late-onset PTLD. Independent risk factors for early-onset PTLD included young age at transplantation, and EBV and CMV seronegativity. By comparison, independent risk factors for late-onset PTLD included older age at transplantation, and non-Hispanic white race or ethnicity. Although the differences in risk factors were not large, the results suggest that early-onset and late-onset PTLD comprise different entities with somewhat different etiologies.

The cumulative incidence of PTLD in our study was similar to that reported previously [9, 10, 15, 16]. As in prior studies [10, 11], we also observed a U-shaped pattern of PTLD incidence with time since transplantation. This pattern identifies early-onset PTLD, occurring in the 1–2-year period immediately after transplantation, and late-onset PTLD, occurring some years later. In our study, a greater proportion of late-onset PTLDs than early-onset PTLDs were of monomorphic pathology and of T-cell origin. Other studies have found similar biological differences between early-onset PTLD and late-onset PTLD [13, 17]. Although early-onset PTLD is more likely than late-onset PTLD to be localized in the transplanted organ [12, 13], we were unable to examine this pattern in our study because of insufficient data on tumor location.

The increased risk of PTLD seen in young recipients [9, 18] is likely due to the high percentage who are EBV naive at transplantation, leaving them susceptible to primary infection immediately after transplantation. Supporting this interpretation, we found that the association of young age at transplantation with early-onset PTLD became weaker when we included EBV serostatus in a multivariate model (Model 2 vs. Model 1, Table III). Primary infection during the period of intense immunosuppression immediately after transplantation allows for uncontrolled EBV-driven lymphoproliferation [4, 7, 19]. The vast majority of early-onset PTLDs express EBV proteins [13]. The role of CMV infection is less well understood. An earlier study pointed to a possible synergistic role of CMV disease with primary EBV infection in causing PTLD [20]. Nonetheless, the association that we observed between CMV serostatus and risk of early-onset PTLD could be the result of uncontrolled confounding because CMV serostatus is related to age, EBV serostatus, and perhaps other unmeasured factors. In our study, EBV seronegativity was not an independent risk factor for late-onset PTLD, although this has been suggested in other work [21].

We did not find an association between antibody induction therapy and early-onset PTLD risk, in contrast to earlier reports [9, 19, 22, 23]. The discrepancy could relate to calendar period differences, because we focused on a later calendar period (1999–2007), well after widespread introduction of antibody induction therapy during the mid to late 1990s [24]. When new therapies are introduced, the rate of PTLD has been observed to increase while transplant centers work to establish the appropriate dosing regimen to ensure a balance of efficacy and safety (“learning-curve” effect) [1]. We hypothesize that transplant centers had had sufficient time by 1999 to gain experience with antibody-based induction therapies, leading to an attenuation of associated PTLD risk.

In terms of pathology and clinical features, compared with early-onset PTLDs, late-onset PTLDs more closely resemble lymphomas seen in the general population [8]. In the general population, NHL incidence is higher among non-Hispanic whites than other races or ethnicities and increases monotonically with age [25, 26], which may explain the observed associations of these two factors with late-onset PTLD. Although the association with increasing age has been described previously [9, 27], the protective effect of steroid-based maintenance therapy on late-onset PTLD risk is a new finding. Of interest, research on NHLs in the general population has yielded inconsistent results on the possible effect of steroid-based medications, with some studies showing that they increase NHL risk and other studies showing no relationship [28].

Our study had several important strengths, including its large size and inclusion of both malignant and nonmalignant PTLDs. Limitations to our study also need to be considered. We likely did not have complete ascertainment of PTLD, especially for diagnoses that occurred late after transplantation. Transplant centers are typically able to follow a very high percentage of recipients in the first 1–2 years after transplantation, but this percentage decreases with time, and by 5 years after transplantation, up to 25% of kidney transplant recipients may be lost to follow-up [29]. Losses to follow-up would have led to underestimation of PTLD incidence but should not have differed across the risk factors we examined. Missing data on EBV and CMV serology for a large percentage of transplant recipients required that we impute the data using demographic and other characteristics; thus, these findings need to be interpreted with some caution. In addition, our data on immunosuppressive medications were limited to baseline and did not include specific dosing information. Thus, we could not assess the effect of immunosuppressive intensity or changes in the immunosuppressive regimen on PTLD risk.

In conclusion, the bimodal timing of PTLD after transplantation and the observed differences in pathology and risk factors provide evidence that early-onset PTLD and late-onset PTLD are either distinct disease entities or, perhaps more likely, are composed of a variable mixture of subtypes with different etiologies. PTLD remains an important source of morbidity associated with solid-organ transplantation, and additional research on the risk factors and clinical features of PTLD, particularly late-onset PTLD, is required to better understand the role of prolonged immunosuppression and immune dysfunction in lymphomagenesis.

Methods

We conducted a retrospective cohort study of kidney transplant recipients in the United States using SRTR data. Data on all kidney transplants in the United States since 1986 are provided by transplantation centers and organ procurement organizations that together comprise the Organ Procurement and Transplantation Network (OPTN). Baseline data are collected at the time of registration and at transplantation, and follow-up data are collected 6 and 12 months after transplantation and annually thereafter. Recipients of first kidney transplants conducted between October 1, 1987, and August 31, 2007, were eligible for this study. Included recipients had no evidence of human immunodeficiency virus infection and had at least 30 days of follow-up after transplantation.

For each transplant recipient, SRTR data included demographic characteristics, HLA mismatches with the donor at the A, B, and DR loci, and serology results for EBV (EBV IgG) and CMV (CMV IgG). Information on the initial immunosuppressive regimen prescribed before hospital discharge was obtained.

Transplant centers reported on the occurrence of PTLD during follow-up, which was categorized according to pathology (polymorphic including hyperplasia, monomorphic, or unknown) and cell type (B-cell, T-cell, or unknown). Cases of multiple myeloma and Hodgkin's lymphoma were excluded. Reporting of PTLD to the SRTR changed over time. OPTN did not routinely collect PTLD data on kidney transplant recipients until March 1, 1997. In 1999, the SRTR transitioned from a paper-based to a web-based system for filing follow-up reports.

Statistical analysis

Recipients were followed up from 30 days after transplantation until the earliest of PTLD diagnosis, graft failure, retransplantation, death, loss to follow-up, or 10 years post-transplantation. To ensure uniform reporting of PTLD, we included only follow-up time and PTLD events from January 1, 1999, onward.

Based on the pattern of PTLD risk in relation to time since transplantation, we divided cases into early-onset PTLD (within 2 years of transplantation) and late-onset PTLD (2 or more years from transplantation). Risk factors for these two periods were evaluated using separate proportional hazards regression models. In these analyses, recipients contributed to each model during their person-time within the window of interest. To determine whether the strength of association differed for each risk factor between early-onset and late-onset PTLD, we tested the significance of an interaction term between the variable of interest and a time-dependent indicator variable that distinguished early and late follow-up periods. In multivariate models, we included variables that were significant in univariate models or seemed relevant based on earlier work.

Baseline EBV and CMV data were missing for 62.1% and 41.9% of recipients, respectively. We, therefore, used a multiple imputation approach to assign EBV and CMV baseline serostatus based on demographic and transplant characteristics for recipients initially missing this information. This full data set including the imputed values was used to estimate HRs associated with EBV and CMV serostatus. The imputation and estimation were repeated 10 times, and the results were combined using the Rubin method in the MIANALYZE procedure (SAS, Version 9.1; SAS Institute, Cary, NC) [30].

References

  1. Top of page
  2. Supporting Information
  • 1
    Penn I. Post-transplant malignancy: The role of immunosuppression. Drug Saf 2000; 23: 101113.
  • 2
    Harris NL,Swerdlow SH,Frizzera G,Knowles DM. Post-transplant lymphoproliferative disorders. In: JaffeES, HarrisNL, SteinH, VardimanJW, editors. Pathology and Genetics—Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001. pp 264269.
  • 3
    Epstein-Barr virus and lymphoproliferative disorders after transplantation. Am J Transplant 2004; 4( Suppl 10): 5965.
  • 4
    Andreone P,Gramenzi A,Lorenzini S, et al. Posttransplantation lymphoproliferative disorders. Arch Intern Med 2003; 163: 19972004.
  • 5
    Cockfield SM. Identifying the patient at risk for post-transplant lymphoproliferative disorder. Transpl Infect Dis 2001; 3: 7078.
  • 6
    LaCasce AS. Post-transplant lymphoproliferative disorders. Oncologist 2006; 11: 674680.
  • 7
    Opelz G,Daniel V,Naujokat C,Dohler B. Epidemiology of pretransplant EBV and CMV serostatus in relation to posttransplant non-Hodgkin lymphoma. Transplantation 2009; 88: 962967.
  • 8
    Taylor AL,Marcus R,Bradley JA. Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation. Crit Rev Oncol Hematol 2005; 56: 155167.
  • 9
    van Leeuwen MT,Grulich AE,Webster AC, et al. Immunosuppression and other risk factors for early and late non-Hodgkin lymphoma after kidney transplantation. Blood 2009; 114: 630637.
  • 10
    Faull RJ,Hollett P,McDonald SP. Lymphoproliferative disease after renal transplantation in Australia and New Zealand. Transplantation 2005; 80: 193197.
  • 11
    Morton LM,Landgren O,Chatterjee N, et al. Hepatitis C virus infection and risk of posttransplantation lymphoproliferative disorder among solid organ transplant recipients. Blood 2007; 110: 45994605.
  • 12
    Bakker NA,van Imhoff GW,Verschuuren EA, et al. Early onset post-transplant lymphoproliferative disease is associated with allograft localization. Clin Transplant 2005; 19: 327334.
  • 13
    Ghobrial IM,Habermann TM,Macon WR, et al. Differences between early and late posttransplant lymphoproliferative disorders in solid organ transplant patients: Are they two different diseases? Transplantation 2005; 79: 244247.
  • 14
    Leblond V,Davi F,Charlotte F, et al. Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: A distinct entity? J Clin Oncol 1998; 16: 20522059.
  • 15
    Caillard S,Lelong C,Pessione F,Moulin B. Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: Report of230 cases from the French Registry. Am J Transplant 2006; 6: 27352742.
  • 16
    Opelz G,Dohler B. Lymphomas after solid organ transplantation: A collaborative transplant study report. Am J Transplant 2004; 4: 222230.
  • 17
    Nelson BP,Nalesnik MA,Bahler DW, et al. Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: A distinct entity? Am J Surg Pathol 2000; 24: 375385.
  • 18
    Dharnidharka VR,Tejani AH,Ho PL,Harmon WE. Post-transplant lymphoproliferative disorder in the United States: Young Caucasian males are at highest risk. Am J Transplant 2002; 2: 993998.
  • 19
    Caillard S,Dharnidharka V,Agodoa L, et al. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation 2005; 80: 12331243.
  • 20
    Manez R,Breinig MC,Linden P, et al. Posttransplant lymphoproliferative disease in primary Epstein-Barr virus infection after liver transplantation: The role of cytomegalovirus disease. J Infect Dis 1997; 176: 14621467.
  • 21
    Shahinian VB,Muirhead N,Jevnikar AM, et al. Epstein-Barr virus seronegativity is a risk factor for late-onset posttransplant lymphoproliferative disorder in adult renal allograft recipients. Transplantation 2003; 75: 851856.
  • 22
    Bustami RT,Ojo AO,Wolfe RA, et al. Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant 2004; 4: 8793.
  • 23
    Swinnen LJ,Costanzo-Nordin MR,Fisher SG, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 1990; 323: 17231728.
  • 24
    Meier-Kriesche HU,Li S,Gruessner RW, et al. Immunosuppression: Evolution in practice and trends, 1994–2004. Am J Transplant 2006; 6(5 Pt 2): 11111131.
  • 25
    Alexander DD,Mink PJ,Adami HO, et al. The non-Hodgkin lymphomas: A review of the epidemiologic literature. Int J Cancer 2007; 120( Suppl 12): 139.
  • 26
    Grulich AE,Vajdic CM. The epidemiology of non-Hodgkin lymphoma. Pathology 2005; 37: 409419.
  • 27
    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: 27352742.
  • 28
    Ekstrom-Smedby K. Epidemiology and etiology of non-Hodgkin lymphoma—A review. Acta Oncol 2006; 45: 258271.
  • 29
    Levine GN,McCullough KP,Rodgers AM, et al. Analytical methods and database design: Implications for transplant researchers, 2005. Am J Transplant 2006; 6(5 Pt 2): 12281242.
  • 30
    Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons; 1986.

Scott C. Quinlan*, Ruth M. Pfeiffer*, Lindsay M. Morton*, Eric A. Engels*, * Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Supporting Information

  1. Top of page
  2. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
AJH_21911_sm_suppinfotables1-2.doc70KSupplemental Table 1 – PTLD risk factors among U.S. kidney transplant recipients during 1999–2007 Supplemental Table 2 – Multivariate analysis of risk factors for polymorphic PTLD and monomorphic PTLD among U.S. kidney transplant recipients during 1999–2007

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.