BACKGROUND:

The effects of pediatric solid organ transplantation on cancer risk may differ from those observed in adult recipients. We described cancers in pediatric recipients and compared incidence to the general population.

METHODS:

The US transplant registry was linked to 16 cancer registries to identify cancer diagnoses among recipients <18 years old at transplant. Standardized incidence ratios (SIRs) were estimated by dividing observed cancer counts among recipients by expected counts based on the general population rates. Cox regression was used to estimate the associations between recipient characteristics and non-Hodgkin’s lymphoma (NHL) risk.

RESULTS:

Among 17 958 pediatric recipients, 392 cancers were diagnosed, of which 279 (71%) were NHL. Compared with the general population, incidence was significantly increased for NHL (SIR = 212, 95% confidence interval [CI] = 188–238), Hodgkin’s lymphoma (SIR = 19, 95% CI = 13–26), leukemia (SIR = 4, 95% CI = 2–7), myeloma (SIR = 229, 95% CI = 47–671), and cancers of the liver, soft tissue, ovary, vulva, testis, bladder, kidney, and thyroid. NHL risk was highest during the first year after transplantation among recipients <5 years old at transplant (SIR = 313), among recipients seronegative for Epstein-Barr virus (EBV) at transplant (SIR = 446), and among intestine transplant recipients (SIR = 1280). In multivariable analyses, seronegative EBV status, the first year after transplantation, intestine transplantation, and induction immunosuppression were independently associated with higher NHL incidence.

CONCLUSIONS:

Pediatric recipients have a markedly increased risk for many cancers. NHL constitutes the majority of diagnosed cancers, with the highest risk occurring in the first year after transplantation. NHL risk was high in recipients susceptible to primary EBV infection after transplant and in intestine transplant recipients, perhaps due to EBV transmission in the donor organ.

What’s Known on This Subject:

Solid organ transplant recipients have a higher risk of cancer than the general population, attributable to use of immunosuppressant medications. Pediatric transplant recipients have a particularly elevated risk of non-Hodgkin’s lymphoma.

What This Study Adds:

This study of pediatric solid organ transplant recipients identifies an elevated risk of numerous cancer types in addition to non-Hodgkin’s lymphoma and provides evidence for a key role of Epstein-Barr virus in the etiology of most cancers in this population.

Currently in the United States, >1700 children and adolescents receive solid organ transplants per year.1 Because pediatric transplant recipients have the potential for longer life expectancies after transplantation than their adult counterparts, it is of particular importance to understand the long-term consequences of transplantation in this group.2 Transplant recipients have an elevated risk for many cancer types, in large part due to the requirement for chronic immunosuppressive therapy after transplantation.3 The effects of transplantation and immunosuppression may be different in pediatric recipients, especially the young, because they do not have fully developed immune systems before transplantation2 and because the typical distribution of cancers differs in pediatric and adult populations.4,5 

In the US general population, the malignancies most frequently diagnosed in children include leukemia, non-Hodgkin’s lymphoma (NHL), and brain tumors.4,6 Because transplantation strongly increases NHL risk, lymphomas make up more than half of cancers in pediatric transplant recipients.7,9 In transplant recipients, NHL comprises part of a spectrum of related malignant and nonmalignant conditions termed posttransplant lymphoproliferative disorder (PTLD).10 PTLD risk is highest in the first year posttransplant and is associated with younger age and acquisition of Epstein-Barr virus (EBV) infection after transplantation.10,14 

Because only a small number of pediatric transplants are performed annually at any single transplant center, it is difficult to comprehensively assess cancer risk in this group. The largest previous study, conducted among pediatric transplant recipients in Sweden, found that the risks of NHL, kidney cancer, multiple myeloma, and cancer of the vulva/vagina were >100 times higher than in the general pediatric population.7 However, this study included <600 recipients, and the expected number of cases for most types of cancers was <0.1. In the current study, we evaluated cancer risk and potential risk factors for cancer among pediatric recipients in the US Transplant Cancer Match (TCM) Study, which includes a pediatric population >20 times larger than the Swedish study.

The TCM Study links the Scientific Registry of Transplant Recipients (SRTR) to 16 US state or regional central cancer registries (http://transplantmatch.cancer.gov/).3 The SRTR captures all solid organ transplant recipients in the United States and collects information on recipient demographic characteristics, as well as relevant clinical characteristics, such as the indication for transplant, transplanted organ, and recipient EBV serostatus before transplant. Central cancer registries reliably ascertain all cancer diagnoses (other than basal cell and squamous cell carcinomas of the skin) within their geographic areas, including information on cancer site and histology. The TCM Study was approved by human subjects research review committees or exempted from human subjects research approval at the National Cancer Institute, the Health Resources and Services Administration, and each participating cancer registry.

For the current study, we included all recipients in the TCM Study who received solid organ transplants during 1987 to 2011 (calendar years covered by the cancer registries) when they were <18 years of age. Race/ethnicity was classified as white, African American, Hispanic, Asian, and other/unknown. Recipients of other/unknown race were excluded because this category was too heterogeneous to compare with general population cancer incidence rates. The unit of analysis was the transplant, and when recipients had multiple organ transplants before the age of 18, each transplant was included as an independent observation. At-risk time for cancer started at the later of: transplant date or start of cancer registry coverage. At-risk time ended at the first of: death, graft failure, retransplantation, loss-to-follow-up by SRTR, or end of cancer registry coverage. Follow-up for cancer risk extended beyond 18 years of age, because a transplant during childhood/adolescence could influence cancer risk into adulthood. For the evaluation of liver cancer, the first 6 months after liver transplantation were excluded to omit cancers that may have been the indication for transplant.

Cancers in transplant recipients were identified by using the linked cancer registry data and classified using International Classification of Diseases for Oncology, Third Edition topography and morphology codes as described previously.3,13 For individuals with multiple cancers of different types, each cancer type was included. Because our study assessed the risk of malignant cancer, 2 diagnoses of lymphoproliferative disease (morphology code of 9970) were excluded. The observed cancer counts were divided by the expected counts based on general population rates within strata of sex, 2-year age groups, race/ethnicity, and calendar year periods (1989–1993, 1994–1998, 1999–2003, 2004–2008, and 2009–2011), yielding standardized incidence ratios (SIRs). We calculated an overall SIR for total cancer, SIRs for specific cancer types with at least 2 observed cancer cases, and a combined SIR for cancer types with <2 observed cancer cases. We also calculated SIRs for common NHL subtypes, and within diffuse large B-cell lymphoma (DLBCL; the most common NHL subtype), we evaluated tumors with immunoblastic (morphology code 9684) and nonimmunoblastic morphology.

Because NHL made up the majority of observed cases, we assessed the risk factors for NHL and combined non-NHL cancers. We calculated incidence and SIRs according to age at transplantation, organ type, and time since transplantation. For NHL, we additionally calculated incidence and SIRs by EBV serostatus before transplantation, considering that seronegative status indicates a risk of developing primary EBV infection after transplantation. We additionally examined associations with potential risk factors by using multivariable Cox regression with calendar time as the time scale.

During 1987 to 2011, there were 40 570 solid organ transplants performed in recipients <18 years of age in the United States. Of these, 18 150 (45%) were in geographic regions covered by linked cancer registries in the TCM Study. One hundred ninety-two transplants (1%) were excluded because the recipients did not belong to 1 of the 4 main race/ethnicity groups. For our final study population, we evaluated 17 958 transplants performed in 16 732 individuals.

Among the included pediatric recipients, 54% were males, 54% were white, 24% were Hispanic, 18% were African American, and 5% were Asian/Pacific Islander (Table 1). Most transplants were for recipients <10 years of age at the time of transplantation, with 39% in recipients <5 years of age. The median year of transplantation was 2001 (interquartile range [IQR]: 1995–2005). With regard to the transplanted organ, 44% were kidney, 32% were liver, 21% were heart and/or lung, and 1% were intestine transplants. Ninety percent of transplants were first transplants. EBV serostatus before transplant was known for 8601 transplants (48% of included transplants), 46% of whom were EBV seronegative (N = 3984). The median length of follow-up was 4 years (IQR: 1–7 years), with a maximum follow-up of 22 years. A quarter of recipients were 18 years of age or older by the end of follow-up, with the oldest age of a recipient during follow-up being 38 years.

TABLE 1

Characteristics of Pediatric Transplant Recipients in the US TCM Study

CharacteristicN (%)
Total 17 958a 
Age at transplant, y  
 0–4 6935 (38.6) 
 5–9 2853 (15.9) 
 10–14 4149 (23.1) 
 15–17 4021 (22.4) 
Sex  
 Male 9748 (54.3) 
 Female 8210 (45.7) 
Race/ethnicity  
 White, Non-Hispanic 9656 (53.8) 
 African American, Non-Hispanic 3227 (18.0) 
 Hispanic 4258 (23.7) 
 Asian/Pacific Islander 817 (4.6) 
Transplanted organ  
 Kidney 7822 (43.6) 
 Kidney/pancreas or pancreas 9 (0.1) 
 Liver 5713 (31.8) 
 Heart and/or lung 3735 (20.8) 
 Intestine 162 (0.9) 
 Other or multiple 517 (2.9) 
Transplant number  
 First 16 120 (89.8) 
 Second 16 06 (8.9) 
 Third or higher 232 (1.3) 
Calendar year of transplant  
 1987–1994 3763 (21.0) 
 1995–1999 4280 (23.8) 
 2000–2004 4755 (26.5) 
 2005–2009 4697 (26.2) 
 2010–2011 463 (2.6) 
EBV serostatus at transplant  
 Positive 4617 (25.7) 
 Negative 3984 (22.2) 
 Unknown 9357 (52.1) 
CharacteristicN (%)
Total 17 958a 
Age at transplant, y  
 0–4 6935 (38.6) 
 5–9 2853 (15.9) 
 10–14 4149 (23.1) 
 15–17 4021 (22.4) 
Sex  
 Male 9748 (54.3) 
 Female 8210 (45.7) 
Race/ethnicity  
 White, Non-Hispanic 9656 (53.8) 
 African American, Non-Hispanic 3227 (18.0) 
 Hispanic 4258 (23.7) 
 Asian/Pacific Islander 817 (4.6) 
Transplanted organ  
 Kidney 7822 (43.6) 
 Kidney/pancreas or pancreas 9 (0.1) 
 Liver 5713 (31.8) 
 Heart and/or lung 3735 (20.8) 
 Intestine 162 (0.9) 
 Other or multiple 517 (2.9) 
Transplant number  
 First 16 120 (89.8) 
 Second 16 06 (8.9) 
 Third or higher 232 (1.3) 
Calendar year of transplant  
 1987–1994 3763 (21.0) 
 1995–1999 4280 (23.8) 
 2000–2004 4755 (26.5) 
 2005–2009 4697 (26.2) 
 2010–2011 463 (2.6) 
EBV serostatus at transplant  
 Positive 4617 (25.7) 
 Negative 3984 (22.2) 
 Unknown 9357 (52.1) 
a

This is the total number of transplants among 16 372 unique pediatric recipients.

After transplantation, 392 cancers were diagnosed. Overall, the median age at cancer diagnosis was 12 years. The age at diagnosis ranged from <1 year to 35 years, with 18% of cancers occurring at ≥18 years of age (N = 72). The median time since transplantation at diagnosis was 2.5 years (IQR = 0.6–6.2 years). Of the cancers, 71% were NHL (N = 279), with a median age at diagnosis of 11 years (IQR = 5–17), and occurred a median of 1.6 years posttransplant (IQR = 0.6–5.5 years). Among NHL diagnoses, the most common subtype was DLBCL (N = 178; Supplemental Table 4), including 18 immunoblastic DLBCLs and 160 nonimmunoblastic DLBCLs. Thirty-nine percent of DLBCLs were extranodal tumors (N = 69), and among these, 16 occurred at sites corresponding to the transplanted organ. Of 5 extranodal DLBCLs identified in the kidney, 4 occurred in kidney recipients; of 9 identified in the liver, 7 occurred in liver recipients; and of 4 identified in the lung, 2 occurred in lung recipients. The second most frequently diagnosed NHL subtype was Burkitt lymphoma (N = 25).

Other common cancer diagnoses in pediatric transplant recipients were Hodgkin’s lymphoma (N = 30) and leukemia (N = 16), making up 8% and 4% of all cancers, respectively. For Hodgkin’s lymphoma, the median age at diagnosis was 12 years (IQR = 8–17 years), and mixed cellularity Hodgkin’s lymphoma was the most common subtype (N = 7; Supplemental Table 4). For leukemia, the median age at diagnosis was 14 years (IQR = 7–16 years), and the most common subtype was acute lymphocytic leukemia (N = 9). Among the less common cancers, we observed a number of subtypes that are typically disproportionately observed in children or adolescents, including 3 nephroblastomas, 2 hepatoblastomas, 2 Ewing sarcomas, and 2 dysgerminomas of the ovary (Supplemental Table 4).

Overall, cancer incidence among pediatric transplant recipients was >19 times higher than in the general population (SIR = 19.1, 95% confidence interval [CI] = 17.3–21.1) (Fig 1, Supplemental Table 5). NHL incidence was 212 times higher (SIR = 212, 95% CI = 188–238), Hodgkin’s lymphoma incidence was 19 times higher (SIR = 18.5, 95% CI = 12.5–26.4), and leukemia incidence was 4 times higher (SIR = 4.31, 95% CI = 2.46–6.99) in pediatric transplant recipients (Fig 1, Supplemental Table 4). Across all cancer types, the largest elevation in incidence was for myeloma (SIR = 229, 95% CI = 47.4–671), based on 3 observed cases (2 plasmacytomas and 1 multiple myeloma). Pediatric recipients also had elevated incidence of cancers of the kidney (SIR = 15.5), thyroid (SIR = 6.00), liver (SIR = 30.8), testis (SIR = 3.98), soft tissue (SIR = 4.45), ovary (SIR = 7.40), bladder (SIR = 28.1), and vulva (SIR = 17.4), again based on small numbers of cases (Fig 1, Supplemental Table 5).

FIGURE 1

SIRs for cancer among US pediatric transplant recipients. Diamonds represent the point estimates for each SIR. Vertical error bars represent the 95% CIs for each SIR.

FIGURE 1

SIRs for cancer among US pediatric transplant recipients. Diamonds represent the point estimates for each SIR. Vertical error bars represent the 95% CIs for each SIR.

Among NHLs, DLBCL incidence was 451 times higher than in the general population (SIR = 451, 95% CI = 397–511). For immunoblastic DLBCL specifically, incidence was 1027 times higher than in the general population (SIR = 1027, 95% CI = 609–1623), whereas nonimmunoblastic DLBCL incidence was 424 times higher (SIR = 424, 95% CI = 361–495). There was also elevated Burkitt lymphoma risk (SIR = 99, 95% CI = 64–146).

NHL incidence in pediatric transplant recipients was higher than in the general population regardless of age, organ type, time since transplantation, or EBV serostatus (Table 2). However, the magnitude of the elevation differed by subgroup. Specifically, elevations in NHL incidence were highest among recipients <5 years of age at transplantation (SIR = 313, 95% CI = 258–376) and decreased with older age (P value for heterogeneity <.001). Among the different organ types, the largest elevation was observed in intestine recipients (SIR = 1280, 95% CI = 516–2640) followed by heart/lung recipients (SIR = 318, 95% CI = 254–393), liver recipients (SIR = 197, 95% CI = 155–247), and kidney recipients (SIR = 159, 95% CI = 130–193; P value for heterogeneity <.001). The elevation in NHL incidence was highest in the first year after transplantation, whereas a smaller elevation in incidence was observed consistently across time thereafter (P value for heterogeneity <.001; Table 2). The elevation was also greater among EBV-seronegative recipients than EBV-seropositive recipients (P value for heterogeneity <.001).

TABLE 2

SIRs for Subgroups of US Pediatric Transplant Recipients

SubgroupObserved CountSIR (95% CI)P for Heterogeneity
NHL
Total 279 212 (188–238)  
Age at transplant, y   <.001 
 <5 115 313 (258–376)  
 5–9 44 214 (155–287)  
 10–14 58 161 (122–208)  
 15–17 62 161 (124–207)  
Transplanted organ   <.001 
 Kidney 102 159 (130–193)  
 Liver 76 197 (155–247)  
 Heart/lung 85 318 (254–393)  
 Intestine 1280 (516–2640)  
 Other or multiple organ 458 (209–869)  
Years since transplantation   <.001 
 0–0.4 58 783 (594–1010)  
 0.5–0.9 63 837 (643–1070)  
 1–1.9 25 174 (112–256)  
 2–3.9 41 154 (111–210)  
 4+ 92 121 (97.7–149)  
EBV serostatus before transplant   <.001 
 Positive 36 154 (108–214)  
 Negative 81 446 (354–555)  
 Missing 162 179 (153–209)  
 Other Cancers Excluding NHL 
Total 113 5.89 (4.86–7.08)  
Age at transplant, y   .570 
 <10 54 6.24 (4.68–8.14)  
 10–17 59 5.61 (4.27–7.23)  
Transplanted organ type   .319 
 Kidney 56 6.50 (4.91–8.44)  
 Nonkidney or multiple organ 57 5.39 (4.09–6.99)  
Years since transplantation   .487 
 0–0.9 17 6.82 (3.97–10.9)  
 1–3.9 30 4.96 (3.35–7.08)  
 4+ 66 6.20 (4.80–7.89)  
SubgroupObserved CountSIR (95% CI)P for Heterogeneity
NHL
Total 279 212 (188–238)  
Age at transplant, y   <.001 
 <5 115 313 (258–376)  
 5–9 44 214 (155–287)  
 10–14 58 161 (122–208)  
 15–17 62 161 (124–207)  
Transplanted organ   <.001 
 Kidney 102 159 (130–193)  
 Liver 76 197 (155–247)  
 Heart/lung 85 318 (254–393)  
 Intestine 1280 (516–2640)  
 Other or multiple organ 458 (209–869)  
Years since transplantation   <.001 
 0–0.4 58 783 (594–1010)  
 0.5–0.9 63 837 (643–1070)  
 1–1.9 25 174 (112–256)  
 2–3.9 41 154 (111–210)  
 4+ 92 121 (97.7–149)  
EBV serostatus before transplant   <.001 
 Positive 36 154 (108–214)  
 Negative 81 446 (354–555)  
 Missing 162 179 (153–209)  
 Other Cancers Excluding NHL 
Total 113 5.89 (4.86–7.08)  
Age at transplant, y   .570 
 <10 54 6.24 (4.68–8.14)  
 10–17 59 5.61 (4.27–7.23)  
Transplanted organ type   .319 
 Kidney 56 6.50 (4.91–8.44)  
 Nonkidney or multiple organ 57 5.39 (4.09–6.99)  
Years since transplantation   .487 
 0–0.9 17 6.82 (3.97–10.9)  
 1–3.9 30 4.96 (3.35–7.08)  
 4+ 66 6.20 (4.80–7.89)  

In a multivariable regression model (Table 3), NHL incidence was higher in recipients of heart, lung, or intestine transplants compared with kidney recipients, with the highest incidence among intestine recipients. NHL incidence was substantially higher during the first year after transplant compared with later years (hazard ratio [HR] = 4.04, 95% CI = 3.12–5.23), in EBV seronegative recipients (HR = 2.71, 95% CI = 1.82–4.05), and in recipients who received induction immunosuppression (HR = 1.31, 95% CI = 1.01–1.72). Age at transplant, sex, and race were not associated with NHL incidence after accounting for other recipient characteristics (Table 3). The type of maintenance immunosuppressant regimen also was not associated with NHL incidence (data not shown).

TABLE 3

Risk Factors for NHL Among US Pediatric Transplant Recipients

CharacteristicHR (95% CI)
Age at transplant, y 1.01 (0.99–1.03) 
Sex  
 Male Ref 
 Female 1.08 (0.85–1.37) 
Race  
 White, non-Hispanic Ref 
 African American, non-Hispanic 0.77 (0.54–1.09) 
 Hispanic 0.91 (0.67–1.23) 
 Asian/Pacific Islander 0.41 (0.17–1.00) 
Transplanted organ  
 Kidney Ref 
 Liver 1.11 (0.79–1.56) 
 Heart and/or lung 1.97 (1.45–2.67) 
 Intestine 4.55 (2.08–9.95) 
 Other or multiple 1.68 (0.84–3.35) 
Years since transplantation  
 0–0.9 4.04 (3.12–5.23) 
 1+ Ref 
EBV serostatus before transplant  
 Positive Ref 
 Negative 2.71 (1.82–4.05) 
 Missing 1.74 (1.15–2.62) 
Induction immunosuppression  
 No Ref 
 Yes 1.31 (1.01–1.72) 
CharacteristicHR (95% CI)
Age at transplant, y 1.01 (0.99–1.03) 
Sex  
 Male Ref 
 Female 1.08 (0.85–1.37) 
Race  
 White, non-Hispanic Ref 
 African American, non-Hispanic 0.77 (0.54–1.09) 
 Hispanic 0.91 (0.67–1.23) 
 Asian/Pacific Islander 0.41 (0.17–1.00) 
Transplanted organ  
 Kidney Ref 
 Liver 1.11 (0.79–1.56) 
 Heart and/or lung 1.97 (1.45–2.67) 
 Intestine 4.55 (2.08–9.95) 
 Other or multiple 1.68 (0.84–3.35) 
Years since transplantation  
 0–0.9 4.04 (3.12–5.23) 
 1+ Ref 
EBV serostatus before transplant  
 Positive Ref 
 Negative 2.71 (1.82–4.05) 
 Missing 1.74 (1.15–2.62) 
Induction immunosuppression  
 No Ref 
 Yes 1.31 (1.01–1.72) 

Ref, reference.

For all non-NHL cancers combined, incidence was elevated compared with the general population (SIR = 5.89, 95% CI = 4.86–7.08), but elevations did not differ by age, transplanted organ, or time since transplantation (Table 2).

Overall, we found substantially elevated cancer risk among US pediatric transplant recipients. There was a particularly high elevation for NHL, which made up the majority of all cancer cases. For NHL, cancer risk differed across subgroups of recipients, with distinctly high elevations in intestine recipients and EBV-seronegative recipients. There were also significant elevations for non-NHL cancer overall and a number of specific cancer types.

Our finding that the majority of the cancer burden was attributable to NHL corresponds with results of previous studies in pediatric transplant populations.7,15 The predominance of NHL is due to the high frequency of NHL in the general pediatric population relative to other cancer types and the particularly strong elevation of NHL risk in pediatric transplant recipients. For transplant recipients overall, NHL risk is ∼8 times higher than in the general population,3 but this elevation is greatly magnified among pediatric recipients, with NHL risk >200 times higher than in the general population, as seen in our study. A similar pattern has been observed in children with AIDS, among whom NHL is the most frequently diagnosed cancer and elevations in risk are higher than those observed for NHL in adults with AIDS.16 NHL risk was particularly high within the first year after transplant, resembling the pattern seen for PTLD. This finding likely reflects primary EBV infection17 and early intensive immunosuppression, because use of induction immunosuppressant medications was also associated with NHL risk.

Within the pediatric transplant population, the elevation in NHL risk was especially increased for the youngest recipients, which is likely due to a number of factors. In the general population, NHL risk is typically lowest in the youngest age groups, but we did not observe this pattern in our pediatric transplant population. EBV seronegativity before transplantation was associated with a higher risk of NHL in our study, consistent with associations seen in adult transplant populations.18 However, most adults are already infected with EBV at the time of transplantation,18 whereas previous infection is much less common among children. In the setting of transplantation, EBV-seronegative recipients can experience a primary EBV infection after transplantation, when they are immunosuppressed and thus poorly able to control the infection, which puts them at increased risk for NHL.17,19 In our study, we saw high elevations in risk for 2 EBV-associated NHL subtypes, Burkitt lymphoma and DLBCL, with especially high elevations for immunoblastic DLBCL, which is more tightly linked to EBV than other DLBCL variants.20 

The increase in NHL risk differed by type of organ transplanted, with an especially high risk for intestine recipients. Intestine transplantation may confer high risk because of the large amount of lymphatic tissue that accompanies the intestine graft,21 which could carry EBV. The relatively high frequency of EBV seronegative status and intestine transplants among children contributes to the particularly high elevations in NHL risk. Consistent with transmission of EBV through the transplanted organ, or perhaps due to chronic immune stimulation by the allograft, we found that the site of extranodal NHL strongly correlated with the transplanted organ.

Of importance, there were also significant elevations in the risk for Hodgkin’s lymphoma and myeloma, which along with NHL are considered part of PTLD. In our study, Hodgkin’s lymphoma was the second most frequent cancer diagnosis. EBV can be detected in tumor cells for the majority of Hodgkin’s lymphoma tumors arising in transplant recipients.22 Consistent with this, mixed cellularity Hodgkin’s lymphoma, which is closely tied to EBV infection,23 was the most common subtype in our population. There were only 3 cases of myeloma, but this cancer is extremely rare in children, so these cases translated to a substantial elevation in risk. Myeloma is less clearly linked to EBV infection among immunocompetent adults, but in transplant populations, a considerable fraction of tumors is EBV positive.24,28 EBV seronegative status at transplantation is associated with risk of both cancers,22,26 indicating an etiologic role of primary EBV infection during immunosuppression similar to that of NHL.

There is currently no approved EBV vaccine, and there are no established strategies for preventing EBV-related lymphomas in transplant recipients. Some transplant centers monitor high-risk recipients for circulating EBV DNA during the first posttransplant year and, for those individuals with persistently detectable EBV, subsequently reduce the intensity of immunosuppression or administer preemptive treatment of PTLD.29 One observational study found that transplant recipients who received pooled immunoglobulin as prophylaxis for cytomegalovirus disease had a lower incidence of lymphoma,30 consistent with some activity in neutralizing EBV.

We also observed elevated risks for a number of solid cancers and leukemia. Kidney, thyroid, and bladder cancer risks are elevated in people with end-stage renal disease, and in transplant populations, the risk is particularly high in kidney recipients,3,31,32 suggesting that kidney dysfunction is an important risk factor. Risks for liver cancer, soft tissue cancer, vulvar cancer, and leukemia are heightened in transplant recipients as well as people with AIDS, suggesting a relationship with immunosuppression3,33,35; liver cancer is often caused by hepatitis C or B viruses and vulvar cancer by human papillomavirus. Although our results for pediatric transplant recipients appear to mirror those seen in the adult transplant population, cancer subtypes that are rarely seen in adults contributed to some of these elevated risks. For instance, the most frequent subtype of liver cancer was hepatoblastoma, which is not caused by hepatitis, and nephroblastoma (Wilms tumor) contributed to the kidney cancer cases. Also, elevations in ovarian and testicular cancer risk have not been found in previous studies of transplant recipients. Thus, unique mechanisms may underlie some of these associations in the pediatric population. Notably, there was not a significant elevation in incidence for brain or bone cancer, 2 common cancer types in pediatric populations. No factors were clearly predictive of the magnitude of elevation in non-NHL cancer risk overall, which was perhaps foreseeable, because this group includes diverse cancer types.

Our study has several strengths. Our study is the largest study of cancer incidence in pediatric recipients conducted to date, and cancer diagnoses were based on complete, standardized information available from population-based cancer registries. The larger sample size allowed us to document risk for a wider variety of cancer types than previous studies. However, because cancer is rare among children and young adults, the expected counts for many cancers were <1 (Supplemental Table 4), and we only had statistical power to detect large SIRs. Although we followed pediatric transplant recipients into adulthood, the oldest recipients were only in their thirties by the end of follow-up. As a result, we cannot make inferences about the effects of pediatric transplantation on cancer risk in later life, a time during which most cancers develop in the general population. As this population ages, additional studies with longer follow-up will be useful to expand on our current findings.

When compared with the general population, we observed higher cancer risk in pediatric transplant recipients for several cancer types. The majority of cancer diagnoses were NHL. Risk for NHL (and likely Hodgkin’s lymphoma and myeloma) is strongly related to the combination of immunosuppression and EBV infection, which in some instances might be directly transmitted from the transplanted organ. The epidemiologic evidence from this study underscores potential cancer prevention opportunities if EBV infection can be effectively prevented or controlled in pediatric transplant recipients.

     
  • CI

    confidence interval

  •  
  • DLBCL

    diffuse large B-cell lymphoma

  •  
  • EBV

    Epstein-Barr virus

  •  
  • HR

    hazard ratio

  •  
  • IQR

    interquartile range

  •  
  • NHL

    non-Hodgkin’s lymphoma

  •  
  • PTLD

    posttransplant lymphoproliferative disorder

  •  
  • SIR

    standardized incidence ratio

  •  
  • SRTR

    Scientific Registry of Transplant Recipients

  •  
  • TCM

    Transplant Cancer Match

Dr Yanik conceptualized and designed the study, carried out the initial analyses, and drafted the initial manuscript; Drs Smith and Shiels contributed to the study design and interpretation of results, and reviewed and revised the manuscript; Drs Clarke, Lynch, Kahn, Koch, and Pawlish contributed cancer registry data to the initial study, helped with the interpretation of results, and reviewed and revised the manuscript; Dr Engels conceptualized and designed the study and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.

The views expressed in this paper are those of the authors and should not be interpreted to reflect the views or policies of the National Cancer Institute, Health Resources and Services Administration, SRTR, cancer registries, or their contractors.

FUNDING: Supported by the Intramural Research Program of the National Cancer Institute. Funded by the National Institutes of Health (NIH).

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2017-0542.

We thank individuals at the Health Resources and Services Administration (Monica Lin), the SRTR (Ajay Israni, Bertram Kasiske, Paul Newkirk, Jon Snyder), and the following cancer registries for their support and assistance: the states of California, Colorado (Jack Finch), Connecticut (Lou Gonsalves), Georgia (Rana Bayakly), Hawaii (Brenda Hernandez), Iowa, Illinois, Kentucky (Jaclyn Nee), Michigan (Glenn Copeland), New Jersey (Xiaoling Niu), New York, North Carolina (Chandrika Rao), Texas (Leticia Nogueria), Utah (Janna Harrell), and the Seattle-Puget Sound area of Washington (Margaret Madeleine). We also thank analysts at Information Management Services for programming support (David Castenson, Matthew Chaloux, Michael Curry, and Ruth Parsons).

The Scientific Registry of Transplant Recipients (SRTR) is currently operated under contract HHSH250201500009C (Health Resources and Services Administration) by the Minneapolis Medical Research Foundation, Minneapolis, MN. Previously the SRTR was managed under contracts HHSH250201000018C and HHSH234200537009C. The following cancer registries were supported by the SEER Program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261201000035C, and HHSN261201000034C), Connecticut (HHSN261201000024C), Hawaii (HHSN261201000037C, N01-PC-35137, and N01-PC-35139), Iowa (HSN261201000032C and N01-PC-35143), New Jersey (HHSN261201300021I, N01-PC-2013-00021), Seattle-Puget Sound (N01-PC-35142), and Utah (HHSN2612013000171). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP003875-01), Illinois (5U58DP003883-03), Maryland (U58DP12-1205 3919-03), Michigan (5U58DP003921-03), New Jersey (5U58/DP003931-02), New York (U58DP003879), North Carolina (U58DP000832) and Texas (5U58DP000824-04). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, Massachusetts (Massachusetts Cancer Prevention and Control Cooperative Agreement 5458DP003920), New Jersey, New York (including the Cancer Surveillance Improvement Initiative), Texas, Utah, and Washington, as well as the University of Utah and Fred Hutchinson Cancer Research Center in Seattle, WA.

1
US Department of Health and Human Services
. National Data. Transplants in the U.S. by recipient age. 2017. Available at: https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/#.
2
Bartosh
SM
,
Ryckman
FC
,
Shaddy
R
,
Michaels
MG
,
Platt
JL
,
Sweet
SC
.
A national conference to determine research priorities in pediatric solid organ transplantation.
Pediatr Transplant
.
2008
;
12
(
2
):
153
166
[PubMed]
3
Engels
EA
,
Pfeiffer
RM
,
Fraumeni
JF
 Jr
, et al
.
Spectrum of cancer risk among US solid organ transplant recipients.
JAMA
.
2011
;
306
(
17
):
1891
1901
[PubMed]
4
Ward
E
,
DeSantis
C
,
Robbins
A
,
Kohler
B
,
Jemal
A
.
Childhood and adolescent cancer statistics, 2014.
CA Cancer J Clin
.
2014
;
64
(
2
):
83
103
[PubMed]
5
American Cancer Society
.
Cancer Facts and Figures 2014
.
Atlanta, GA
:
American Cancer Society
;
2014
6
Kaatsch
P
.
Epidemiology of childhood cancer.
Cancer Treat Rev
.
2010
;
36
(
4
):
277
285
[PubMed]
7
Simard
JF
,
Baecklund
E
,
Kinch
A
, et al
.
Pediatric organ transplantation and risk of premalignant and malignant tumors in Sweden.
Am J Transplant
.
2011
;
11
(
1
):
146
151
[PubMed]
8
Debray
D
,
Baudouin
V
,
Lacaille
F
, et al;
Pediatric Transplantation Working Group of the French Speaking Society of Transplantation
.
De novo malignancy after solid organ transplantation in children.
Transplant Proc
.
2009
;
41
(
2
):
674
675
[PubMed]
9
Buell
JF
,
Gross
TG
,
Thomas
MJ
, et al
.
Malignancy in pediatric transplant recipients.
Semin Pediatr Surg
.
2006
;
15
(
3
):
179
187
[PubMed]
10
Caillard
S
,
Dharnidharka
V
,
Agodoa
L
,
Bohen
E
,
Abbott
K
.
Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression.
Transplantation
.
2005
;
80
(
9
):
1233
1243
[PubMed]
11
Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients
.
United States Organ Transplantation: OPTN & SRTR Annual Data Report 2011
.
Rockville, MD
:
US Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation
;
2012
12
Cleper
R
,
Ben Shalom
E
,
Landau
D
, et al
.
Post-transplantation lymphoproliferative disorder in pediatric kidney-transplant recipients - a national study.
Pediatr Transplant
.
2012
;
16
(
6
):
619
626
[PubMed]
13
Clarke
CA
,
Morton
LM
,
Lynch
C
, et al
.
Risk of lymphoma subtypes after solid organ transplantation in the United States.
Br J Cancer
.
2013
;
109
(
1
):
280
288
[PubMed]
14
Smith
JM
,
Rudser
K
,
Gillen
D
, et al
.
Risk of lymphoma after renal transplantation varies with time: an analysis of the United States Renal Data System.
Transplantation
.
2006
;
81
(
2
):
175
180
[PubMed]
15
Mynarek
M
,
Hussein
K
,
Kreipe
HH
,
Maecker-Kolhoff
B
.
Malignancies after pediatric kidney transplantation: more than PTLD?
Pediatr Nephrol
.
2014
;
29
(
9
):
1517
1528
[PubMed]
16
Simard
EP
,
Shiels
MS
,
Bhatia
K
,
Engels
EA
.
Long-term cancer risk among people diagnosed with AIDS during childhood.
Cancer Epidemiol Biomarkers Prev
.
2012
;
21
(
1
):
148
154
[PubMed]
17
Mynarek
M
,
Schober
T
,
Behrends
U
,
Maecker-Kolhoff
B
.
Posttransplant lymphoproliferative disease after pediatric solid organ transplantation.
Clini Dev Immunol
.
2013
;
2013
:
814973
18
Gibson
TM
,
Engels
EA
,
Clarke
CA
,
Lynch
CF
,
Weisenburger
DD
,
Morton
LM
.
Risk of diffuse large B-cell lymphoma after solid organ transplantation in the United States.
Am J Hematol
.
2014
;
89
(
7
):
714
720
[PubMed]
19
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
(
3
):
630
637
[PubMed]
20
Grogg
KL
,
Miller
RF
,
Dogan
A
.
HIV infection and lymphoma.
J Clin Pathol
.
2007
;
60
(
12
):
1365
1372
[PubMed]
21
Salminen
S
,
Bouley
C
,
Boutron-Ruault
M-C
, et al
.
Functional food science and gastrointestinal physiology and function.
Br J Nutr
.
1998
;
80
(
suppl
1
):
S147
S171
[PubMed]
22
Quinlan
SC
,
Landgren
O
,
Morton
LM
,
Engels
EA
.
Hodgkin lymphoma among US solid organ transplant recipients.
Transplantation
.
2010
;
90
(
9
):
1011
1015
[PubMed]
23
Pallesen
G
,
Hamilton-Dutoit
SJ
,
Rowe
M
,
Young
LS
.
Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin’s disease.
Lancet
.
1991
;
337
(
8737
):
320
322
[PubMed]
24
Trappe
R
,
Zimmermann
H
,
Fink
S
, et al
.
Plasmacytoma-like post-transplant lymphoproliferative disorder, a rare subtype of monomorphic B-cell post-transplant lymphoproliferation, is associated with a favorable outcome in localized as well as in advanced disease: a prospective analysis of 8 cases.
Haematologica
.
2011
;
96
(
7
):
1067
1071
[PubMed]
25
Sun
X
,
Peterson
LC
,
Gong
Y
,
Traynor
AE
,
Nelson
BP
.
Post-transplant plasma cell myeloma and polymorphic lymphoproliferative disorder with monoclonal serum protein occurring in solid organ transplant recipients.
Mod Pathol
.
2004
;
17
(
4
):
389
394
[PubMed]
26
Engels
EA
,
Clarke
CA
,
Pfeiffer
RM
, et al
.
Plasma cell neoplasms in US solid organ transplant recipients.
Am J Transplant
.
2013
;
13
(
6
):
1523
1532
[PubMed]
27
Lorsbach
RB
,
Hsi
ED
,
Dogan
A
,
Fend
F
.
Plasma cell myeloma and related neoplasms.
Am J Clin Pathol
.
2011
;
136
(
2
):
168
182
[PubMed]
28
Mameli
G
,
Fozza
C
,
Niegowska
M
, et al
.
Epstein-Barr virus infection is associated to patients with multiple myeloma and monoclonal gammopathy of undetermined significance.
Leuk Lymphoma
.
2017
;
58
(
2
):
466
469
[PubMed]
29
Allen
UD
,
Preiksaitis
JK
;
AST Infectious Diseases Community of Practice
.
Epstein-Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation.
Am J Transplant
.
2013
;
13
(
suppl
4
):
107
120
[PubMed]
30
Opelz
G
,
Daniel
V
,
Naujokat
C
,
Fickenscher
H
,
Döhler
B
.
Effect of cytomegalovirus prophylaxis with immunoglobulin or with antiviral drugs on post-transplant non-Hodgkin lymphoma: a multicentre retrospective analysis.
Lancet Oncol
.
2007
;
8
(
3
):
212
218
[PubMed]
31
Maisonneuve
P
,
Agodoa
L
,
Gellert
R
, et al
.
Cancer in patients on dialysis for end-stage renal disease: an international collaborative study.
Lancet
.
1999
;
354
(
9173
):
93
99
[PubMed]
32
Lee
KF
,
Tsai
YT
,
Lin
CY
, et al
.
Cancer incidence among heart, kidney, and liver transplant recipients in Taiwan.
PLoS One
.
2016
;
11
(
5
):
e0155602
[PubMed]
33
Morton
LM
,
Gibson
TM
,
Clarke
CA
, et al
.
Risk of myeloid neoplasms after solid organ transplantation.
Leukemia
.
2014
;
28
(
12
):
2317
2323
[PubMed]
34
Bhatia
K
,
Shiels
MS
,
Berg
A
,
Engels
EA
.
Sarcomas other than Kaposi sarcoma occurring in immunodeficiency: interpretations from a systematic literature review.
Curr Opin Oncol
.
2012
;
24
(
5
):
537
546
[PubMed]
35
Engels
EA
,
Pfeiffer
RM
,
Goedert
JJ
, et al;
HIV/AIDS Cancer Match Study
.
Trends in cancer risk among people with AIDS in the United States 1980-2002.
AIDS
.
2006
;
20
(
12
):
1645
1654
[PubMed]

Competing Interests

POTENTIAL CONFLICT OF INTEREST: Dr Clarke is employed by GRAIL, Inc and has received grant funding from Genentech; the other authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Dr Clarke is employed by GRAIL, Inc and has received grant funding from Genentech; the other authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data