Pediatric Kidney Transplantation: Cancer and Cancer Risk

Summary

Children with end-stage kidney disease (ESKD) face a lifetime of complex medical care, alternating between maintenance chronic dialysis and kidney transplantation. Kidney transplantation has emerged as the optimal treatment of ESKD for children and provides important quality of life and survival advantages. Although transplantation is the preferred therapy, lifetime exposure to immunosuppression among children with ESKD is associated with increased morbidity, including an increased risk of cancer. Following pediatric kidney transplantation, cancer events occurring during childhood or young adulthood can be divided into two broad categories: post-transplant lymphoproliferative disorders and non-lymphoproliferative solid tumors. This review provides an overview of cancer incidence, types, outcomes, and preventive strategies in this population.

INTRODUCTION

When caring for children with end-stage kidney disease (ESKD), it is well established that optimal clinical outcomes strongly favor kidney transplantation over chronic dialysis. Kidney transplantation extends important advantages to children with respect to growth,¹ neurodevelopment,² and quality of life.³ As for adults, kidney transplantation offers clear survival benefits,^4-6 though racial disparities persist.⁷ Despite the survival advantage afforded by transplantation, mortality rates in children with kidney failure are significantly higher compared with the general population. A large cohort study reported mortality rates and quantified years of life lost among children who initiated renal replacement therapy at age 18 years or younger in Australia and New Zealand.⁸ This study modeled patients over their lifetime, including periods of dialysis, transplantation, and retransplantation. Results highlighted improvement in survival over time, though mortality rates remained alarming. Compared with the general population, excess deaths declined from 41 to 17 times expected from 1980 to 2017. The expected number of life-years lost ranged from 16 to 32 years, with the greatest loss among those who were younger at the time of kidney failure and among female patients.

Studies investigating the cause of death after kidney transplant during childhood or adolescence identify the most common causes to be cardiovascular, infection, and cancer. Analysis of the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) found that 24% of 1,810 children and young adults transplanted between 1970 and 2015 and followed for a median of 13.4 years had died.⁹ Of these, 40% died of cardiovascular causes, 17% of infection, and 12% of cancer. Survival improved considerably over time. Compared with patients transplanted from 1970 to 1985, mortality risk was 72% lower for those transplanted in 2005-2015. Notably, the decreased mortality in the more recent era was directly related to marked reductions in cardiovascular- and infection-related deaths; cancer death rates did not change and occurred just as often during transplant function or dialysis (two deaths per 1,000 patient-years).

A dreaded complication after pediatric kidney transplantation, cancer warrants a high index of suspicion informed by the individual’s risks. There are a variety of risk factors known to contribute to the development of cancer, including exposure to oncologic viruses and the intensity and cumulative burden of immunosuppression. In addition to immunosuppression exposure while the kidney transplant functions, many children are continued on immunosuppression, often at reduced intensity, after transplant failure to prevent sensitization and facilitate retransplantation.¹⁰ This review reports the epidemiology, treatment, and outcomes of cancer in children and young adults after kidney transplantation and discusses other topics related to cancer risks.

EPIDEMIOLOGY OF CANCER AFTER PEDIATRIC KIDNEY TRANSPLANTATION

Much of what has been learned regarding the epidemiology of cancer following pediatric kidney transplantation includes outcomes reported well into adulthood. Furthermore, the reported frequencies of specific cancers among pediatric kidney transplant recipients relate to the duration of follow-up after transplant. Post-transplant lymphoproliferative disorder (PTLD) is more commonly reported in studies with shorter-term follow-up, and skin cancer is more prevalent with longer-term follow-up. A single-center experience following 219 pediatric kidney transplant recipients for up to 20 years (median, 10.4 years) found that 16 patients (7.3%) developed malignancy, with a cumulative incidence of cancer of 10.2% at 15 years post-transplant.¹¹ PTLD accounted for 10 cases, and the 10-year incidence of PTLD was 4.5%. Other cancers included renal papillary carcinoma, thyroid papillary carcinoma, recurrent ovarian seminoma, and skin cancer. Analysis of ANZDATA found that 289 of 1,734 pediatric kidney transplant recipients (16.7%) developed at least one cancer over a median follow-up of 13.4 years.¹² The cumulative risk 25 years after the first transplant was 27% for all cancers, 20% for nonmelanoma skin cancer (NMSC), and 14% for non-skin cancer, a grouping that included melanoma (Fig. 1). The most common incident skin cancer was squamous cell carcinoma (SCC) (n = 129) followed by basal cell carcinoma (BCC) (n = 67). The most common non-skin cancer was PTLD (n = 40) followed by cervical cancer (n = 18). The Late Effects of Renal Insufficiency Study reported long-term outcomes of all Dutch children transplanted during the period 1972-1992 and followed up to 38 years (median, 25.3 years).¹³ Of 249 patients, 54 (21.7%) developed primary malignancies, and NMSC was the most frequent, accounting for 78% of all de novo tumors. Patients aged 25-30 years developed 16.5 times as many tumors and 991 times as many SCCs as their counterparts in the general population. Of note, an adherence study found adult kidney transplant recipients who were the most adherent to their immunosuppression regimen experienced higher cancer rates, and those cancers appeared earlier.¹⁴

Figure 1.

Time to first cancer following kidney transplantation in childhood stratified by type and adjusted for competing risk of death. Reprinted with permission.¹²

When assessing the types of cancer that occur during childhood or young adulthood after kidney transplantation, PTLD is the predominant malignancy. Since 1987, the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry has collected clinical information on children and young adults (<21 years of age) undergoing renal transplantation. A comprehensive analysis of nearly 12,000 pediatric recipients over a 30-year period in NAPRTCS identified 316 malignancy events, and of these, 85% were PTLD.¹⁵ Further analysis of the NAPTRCS registry with respect to the development of non-PTLD cancers found young kidney transplant recipients to be at 6.7 times increased risk compared with the general population.¹⁶ Non-PTLD malignancy developed in 35 participants, and the most common types of malignancies were renal cell carcinoma (RCC) and thyroid carcinoma and melanoma. A single-center cohort study in Japan found that pediatric kidney transplant recipients were 9.9 times more likely to develop cancer during their lifetime than the general population.¹⁷ Of the 13 cancers identified, five were PTLD, which occurred at a median age of 11.5 years (interquartile range, 6.2-22.2). Other cancer types occurring during childhood or young adulthood included one case each of RCC, brain tumor, and Wilms tumor.

POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER

PTLD is the most common malignancy related to chronic immunosuppression among pediatric kidney transplant recipients and is often driven by the oncogenic Epstein-Barr virus (EBV). This malignancy arises from impaired tumor surveillance, resulting in abnormal proliferation of lymphoid immune cells.^18,19 Based on 2021 registry data from the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients (OPTN/SRTR), the incidence of PTLD in pediatric kidney transplant recipients is approximately 2% at 5 years.²⁰ In comparison with age-matched peers, pediatric kidney transplant recipients in ANZDATA were found to have a 30-fold increased risk of lymphoma, and this was in contrast to the approximately 8-fold increase experienced by adult recipients.²¹ Of note, among pediatric solid organ transplant (SOT) recipients, kidney transplant recipients have the lowest incidence of PTLD, with recent OPTN/SRTR data reporting a 5-year incidence of 3.7% in liver, 4.7% in heart, and 5% in lung transplant recipients.^22-24

With respect to risk factors for PTLD in children, the effect of primary infection with oncogenic EBV is of great importance. Although more than 90% of adults have been infected and carry latent EBV, children are much less likely to have been exposed.²⁵ Thus, seronegative pediatric patients are expected to develop primary infection after transplantation by either transmission of latent virus from the donor organ or environmental exposure. Children who are EBV seronegative at the time of transplantation and receive a kidney from an EBV seropositive donor (D+/R−) are at highest risk.^21,26-28 In the United States, the 5-year incidence of PTLD in EBV seronegative and seropositive pediatric kidney transplant recipients is 3.5% and 0.9%, respectively (Fig. 2).²⁰

Figure 2.

Incidence of PTLD among pediatric kidney transplant recipients by recipient EBV status at transplant, 2010-2016. Abbreviations: EBV, Epstein-Barr virus; PTLD, post-transplant lymphoproliferative disorder. Reprinted with permission.²⁰

OPTN/SRTR 2021 Annual Data Report

As the development of PTLD is unique to the effects of transplant immunosuppression and impaired immune surveillance, various studies have examined the effects of type and burden of immunosuppression on development of PTLD. Pediatric-centered studies evaluating the association of PTLD with the use of induction agents have not been conclusive. Although the choice of lymphodepleting versus nondepleting agents may be guided by specific patient characteristics, such as high immunologic risk, for many recipients this choice rests on center practice.²⁹ Upon review of SRTR data from 2000 to 2018, it was found that antithymocyte globulin induction was associated with significantly higher rates of PTLD (2.2%) compared with alemtuzumab (0.8%) and interleukin 2 receptor blockade (1%) among living donor pediatric kidney transplants.³⁰ However, this association was not detected among deceased donor recipients.³¹ Furthermore, a retrospective analysis of 830 pediatric living and deceased donor recipients from 2010 to 2019 in the NAPRTCS transplant registry who received antithymocyte globulin, alemtuzumab, or interleukin 2 receptor blockade found that choice of induction agent was not associated with an increased risk of PTLD.³² It is generally accepted that the overall intensity of immunosuppression confers an increased risk of PTLD.³³ A pediatric study aiming to determine the safety of steroid withdrawal using basiliximab, calcineurin inhibitor, sirolimus, and steroids was terminated given a high rate of PTLD.²⁶ In this early study of steroid withdrawal, calcineurin inhibitor and sirolimus troughs were higher than currently targeted in combination therapy, underscoring the importance of avoiding excessive maintenance immunosuppression.

With respect to other potential risk factors, human leukocyte antigen (HLA) mismatching has been associated with increased risk of PTLD. The international Collaborative Transplant Study in Europe studied 9,209 pediatric renal transplant patients from 1988 to 2007.³⁴ Recipients with two mismatches at the HLA-DR locus had an incidence of non-Hodgkin lymphoma that was twice as high as those with zero to one mismatches. Pediatric data are otherwise limited in this area, although similar results were found in adult kidney transplant recipients with respect to higher degrees of HLA mismatch.³⁵ It is postulated that the HLA-DR mismatch increases immune reactivity, requiring intensified immunosuppression, but that there may also be increased tumorigenic effects from the antigen stimulus itself.³⁶

Recipient race, age, and donor source have also been studied with respect to risk of PTLD. White recipient race and deceased donor source were associated with an increased risk of PTLD within the NAPRTCS kidney transplant registry,³⁷ whereas male sex and young age were associated with higher PTLD rates among pediatric SOT recipients.^37,38 Specifically, age less than 18 years was associated with 2.8 times the risk of developing PTLD compared with age 18 years or older. As EBV seronegative status at time of transplant is strongly correlated with PTLD, one would expect the youngest children to have the greatest risk. When these data were analyzed based on age groups, patients aged 0-5 years demonstrated a 3.27% incidence compared with 2.18% in patients aged 6-17 years. This significant difference was primarily driven by patients with heart transplant, however, and was not found among pediatric kidney transplant recipients.³⁸ In fact, a few single-center studies suggest that adolescents may be at higher risk compared with younger children, which may reflect greater risk of rejection and thus more intense immunosuppression.³⁹

When PTLD develops, the timing of presentation can be categorized as early (within a year post-transplant) or late onset. PTLD often demonstrates a bimodal pattern, with early disease within the first 2 years and a later spike occurring 5-15 years after transplant.⁴⁰ Analysis of the ANZDATA transplant registry found that children were more likely to present within the first year after transplant compared with adults.²¹ A German study of pediatric SOT recipients found the median time of diagnosis of PTLD to be 3 years after transplant.⁴¹ Two high-risk periods were identified in this study, one within the first year of transplant (33% of patients) and the other at 3 years post-transplant (17% of patients); the early PTLD presentation was associated with younger age.

PTLD is a heterogeneous disorder with variable organ involvement and thus can present clinically in a variety of ways.^21,41-44 Clinical features can be nonspecific, such as fever and weight loss, or reflect localization of the mass. Lymph node involvement is common, especially in the lymph nodes of the tonsils, head, and neck. The gastrointestinal tract is one of the more common extranodal sites reported because of the high amount of lymphoid tissue. This can present as obstruction or intussusception. Central nervous system involvement should be considered with any acute neurologic changes.

If PTLD is suspected, tissue diagnosis is strongly preferred, and the World Health Organization classification of PTLD is widely used (Table 1).⁴⁵ Early lesions, termed “nondestructive PTLD,” generally preserve the architecture of the lymph node and are typically polymorphic and EBV-positive. The destructive forms of PTLD destroy the architecture of the lymph nodes and are further classified as polymorphic, monomorphic, and classical Hodgkin lymphoma. Classical Hodgkin lymphoma PTLD is uncommon in childhood.⁴² Although the vast majority of early and nondestructive forms are EBV-positive, late-onset PTLD with more aggressive pathology has a higher incidence of being EBV-negative; one study reported approximately 17% of late PTLD to be EBV-negative.⁴¹ After pathologic diagnosis is confirmed, staging with cross-sectional imaging is performed, often with positron emission tomography/computed tomography scan. Depending on pathology, bone marrow biopsy and lumbar puncture are often obtained.⁴⁴

Table 1.

Classification of PTLD With EBV Status and Tumor Clonality

Histologic Classification	EBV Positivity	Clonality
Nondestructive PTLD Plasmacytic hyperplasia Infectious mononucleosis PTLD Florid follicular hyperplasia	Almost 100%	Polyclonal
Polymorphic PTLD	>90%	Variable
Monomorphic PTLD	Variable	Monoclonal
Classical Hodgkin lymphoma PTLD	>90%	Monoclonal

Abbreviations: EBV, Epstein-Barr virus; PTLD, post-transplant lymphoproliferative disorder. Adapted from Schober et al⁴¹ and Tsai et al.⁴⁶

Management of PTLD is dependent on a variety of factors, including histological classification and staging of the disease, and treatment decisions are often made using a multidisciplinary approach. Reduction of immunosuppression is a common initial practice to allow for partial reconstitution of immune surveillance. This can be effective as sole treatment of early nondestructive PTLD lesions,⁴⁶ although other treatment modalities are often required^47,48 EBV-negative and monomorphic PTLD has been found to be poorly responsive to immunosuppression reduction alone.⁴⁹ There are no available data to support specific strategies of immunosuppression reduction, and this intervention inherently carries the risk of rejection. One registry study reported a 20.7% rejection rate among 92 pediatric recipients receiving PTLD treatment.⁵⁰ Some reports describe planned transition from calcineurin inhibitor to mammalian target of rapamycin (mTOR) inhibitor therapy with overall favorable outcomes. In a small study of 12 pediatric renal transplant patients with PTLD, all of whom received immunosuppression reduction and 10 of whom transitioned from calcineurin inhibitor to mTOR inhibitor, there was no change in mean graft function at 3 years after PTLD treatment.⁵¹ One patient lost their allograft secondary to chronic antibody-mediated rejection 10 years after PTLD diagnosis, and three lost their grafts because of recurrent glomerular disease.

In conjunction with reduced immunosuppression, rituximab, a monoclonal antibody targeting the B-cell surface protein CD20, has been established as the standard treatment of patients with CD20-positive B-cell PTLD. A regimen of four weekly doses has been used,⁴³ though risk-adapted extended treatment providing four additional rituximab doses increased the complete response rate from 34% to 61% in adults with PTLD.⁵² A common strategy includes four weekly rituximab doses followed by four additional doses every 21 days with or without chemotherapy depending on the pattern of response.⁵³ In a study of 49 pediatric SOT recipients, of whom 18 were renal transplant recipients, 53% of patients responded to rituximab therapy and remained in continuous complete remission, thus sparing the need for chemotherapy. Rituximab alone was not sufficient in all patients with Burkitt pathology.⁵¹ Low-dose chemotherapy regimens that include cyclophosphamide and prednisolone in combination with rituximab have proven efficacious and safe in pediatric SOT patients,^54,55 though traditional chemotherapy may be required for cases of more aggressive or refractory disease.

Novel emerging therapies for refractory or relapsing cases of PTLD include adoptive cell therapies. EBV-specific T cells allow for temporary reconstitution of immunity without reduction of immunosuppression, and more recently, “third-party” HLA-matched EBV-specific T cells have been used to eliminate the long periods needed to prepare these cells.⁴² Both autologous EBV T cells and third-party EBV T cells demonstrate response in adult SOT;⁵⁶ however, pediatric data are limited. A small retrospective study reviewed 10 pediatric SOT patients who had received EBV-specific T-cell therapy, and eight achieved remission; only transient and mild adverse events were reported.⁵⁷ Other potential emerging therapies include chimeric antigen receptor T-cell therapy and immune checkpoint inhibitor therapy; reported pediatric experience is extremely limited,^58,59 and further studies in adults and children are needed. Immune checkpoint inhibitor therapy is associated with a high risk of rejection among adult SOT recipients (~40%),⁶⁰ though this risk may be acceptable in the context of refractory PTLD in a kidney transplant recipient if initiation of chronic dialysis is feasible.

With respect to outcomes, survival among pediatric kidney transplant recipients with PTLD is improving. A cross-sectional review of NAPRTCS data including 235 cases of PTLD from 1988 to 2010 demonstrated improved survival in patients from later eras (1997-2010) compared with earlier eras (1988-1996) (Fig. 3).⁵⁰ Furthermore, survey-based follow-up of 92 of the more recent cases in this cohort reported the 5-year patient and allograft survival to be 87.4% and 65%, respectively. Among the larger cohort of 235 cases, late PTLD and age over 13 years at diagnosis were associated with worse survival. In the survey group, EBV negativity, absence of CD20 positivity, central nervous system involvement, and monoclonal and monomorphic tumors were not associated with higher mortality. It should be noted that these results were based on voluntary center response, and only seven cases were reported to have CD20-negative PTLD. Among pediatric SOT recipients, CD20 expression has been associated with better outcomes, even independent of rituximab therapy.⁶¹ With respect to EBV-negative monomorphic PTLD, the 3-year overall survival was 80% among 36 pediatric SOT recipients, which included 17 kidney transplant recipients.⁶² The initial site of PTLD presentation has also been associated with outcomes in SOT recipients; disease presenting in the tonsils and adenoids had a significantly lower overall and PTLD-related mortality than disease presenting in other sites.⁶³

Figure 3.

Kaplan-Meier calculated patient survival following PTLD diagnosis stratified by era of PTLD diagnosis. Abbreviation: PTLD, post-transplant lymphoproliferative disorder. Reprinted with permission.⁵¹

Routine surveillance of EBV DNA in peripheral blood post-transplant remains an important strategy to guide intervention and reduce the risk of EBV-positive PTLD. The Kidney Disease: Improving Global Outcomes guidelines from 2009 recommend routine EBV monitoring of “high-risk” recipients (D+/R−) once in the first week after transplant, at least monthly in the first 3-6 months post-transplant, and then at least every 3 months until the end of the first post-transplant year.⁶⁴ More recently, the International Pediatric Transplant Association (IPTA) proposed an EBV monitoring algorithm for pediatric SOT based on EBV donor and recipient serostatus.⁶⁵ High-risk recipients (D+/R−) are recommended to have more frequent monitoring, with weekly monitoring in the first 3 months, biweekly monitoring in months 3-6, and then monthly monitoring or at follow-up to 12 months, with additional screening thereafter depending on the specifics of the case. If EBV polymerase chain reaction becomes positive, weekly EBV monitoring is recommended until the viral load has decreased from peak by at least 1 log₁₀. For recipients who are seropositive and on the deceased donor waitlist, the recommendation is to distinguish between recent and remote infection for risk stratification using results of anti-viral capsid antigen IgM and IgG, anti-EBV nuclear antigen IgG, and quantitative EBV polymerase chain reaction. In the proposed IPTA algorithm, recipients with remote EBV infection do not require routine surveillance.

A significant elevation or rise in EBV viral load, especially in seronegative patients, predicts an increased risk of PTLD development⁶⁶ and presents a crucial time for intervention. The IPTA guidelines suggest that a change in viral load exceeding 0.5 log₁₀ IU/mL is a clinically significant increase on which to intervene.⁶⁵ Importantly, however, not all patients with high viral load will develop PTLD, and patients with low viral load can develop PTLD.²⁸ With a significant rise in EBV viral load, immunosuppression reduction is recommended.⁶⁴ Evidence is lacking regarding the role for antiviral prophylaxis or preemptive treatment with antiviral therapy in cases of high EBV viral load.⁶⁷ Phase I and II trials have demonstrated immune response in early EBV vaccines, but no vaccine is yet available.⁶⁸

SKIN CANCER

Skin cancer is a major morbidity after organ transplantation. In addition to acquired reduced immune surveillance, there may be direct carcinogenic effects of immunosuppressive agents. Among adult SOT recipients, more than 50% of White and approximately 6% of non-White patients develop at least one cutaneous malignancy.^69,70 Among adult kidney transplant recipients, the incidences of SCC and BCC are up to 250 times and 10 times higher, respectively, than in the general population,⁷⁰ accounting for more than 90% of cases of skin cancer in this population.⁷¹

Given the duration of exposure to immunosuppression, the risk of skin cancer after pediatric transplantation is staggering. Among populations of pediatric kidney transplant recipients, the standardized risk of NMSC is up to 222 times higher compared with the general population.^72,73 In the ANZDATA transplant registry, 11.3% of pediatric kidney transplant recipients developed NMSC, with a median time to development of 17.2 years and a median age of 32 years.¹² Trends of skin cancer in pediatric SOT recipients have proven different than those in adult recipients. In both adult and pediatric groups, SCC is more common than BCC, though the ratio of SCC to BCC in pediatric recipients (2.8:1) is considerably higher than in adults (1.7:1), and pediatric recipients develop NMSC of the lip more frequently (23% versus 12%).⁷⁴

As the development of skin cancer in kidney transplant recipients is delayed, reports of skin cancer diagnosed during childhood are limited.^74,75 One study investigated differences in cancer outcomes among adult and pediatric SOT recipients and found skin cancer to be the second most common malignancy among pediatric recipients, though only 16 patients (16%) developed tumors during childhood.⁷⁴ Furthermore, six of these 16 patients developed malignant melanoma, and when compared with adult SOT recipients, the eventual development of malignant melanoma was more common in pediatric SOT recipients (12% versus 5% of skin cancers). Melanoma occurring during childhood was also reported in the NAPRTCS transplant registry.¹⁶ Four of 35 cases of solid tumors were reported to be melanoma, and no cases of SCC or BCC were described. Not all studies have noted skin cancer to be prevalent among pediatric kidney transplant recipients. A single-center study of 98 pediatric SOT recipients from the United Kingdom did not detect cancerous or precancerous skin lesions 5-27 years after transplant.^76,77 Furthermore, there was not an increase in atypical melanocytic nevi during long-term follow-up, though a significant increase in the development of benign nevi, particularly in sun-exposed skin, was noted.⁷⁷

Data defining risks of skin cancer specific to pediatric kidney transplant recipients are lacking, particularly for lesions that develop during childhood. It is presumed the risks associated with adult skin cancer are applicable. Sun exposure and fair phenotypic features confer increased risk of NMSC in the general and transplant populations, though non-White organ recipients remain at significant risk of skin cancer. Among Black recipients, lesions are often in sun-protected sites and have been associated with human papillomavirus.⁷⁸ The intensity and duration of immunosuppression are widely accepted as primary drivers of increased risk, especially for NMSC. Some studies have linked an increased risk of skin cancer to azathioprine compared with mycophenolate mofetil,⁷⁹ with a potential mechanism of increased mutagenic effects when exposed to ultraviolet light.⁸⁰ mTOR inhibitors have been associated with a lower risk of skin malignancies,^81-83 though this has not been a consistent finding.⁸⁴ For children who develop skin cancer after transplantation, transition to an mTOR inhibitor-based regimen after consideration of allogeneic immunologic risks may be of benefit.⁸²

With respect to prevention, repeated education regarding the necessity of sun protection measures should begin prior to and maintained after transplantation, as clinician counsel has been associated with increased sunscreen use after SOT.⁸⁵ With respect to reduction of immunosuppression, proposed guidelines are available for adult populations who have developed skin cancer,⁸⁶ though there are no randomized trials evaluating the effect of reduction of immunosuppression to prevent skin cancer. Given the risk of rejection, hazards of adjusting the level of immunosuppression must be considered carefully. For pediatric kidney transplant recipients, vigilance in avoiding excessive immunosuppression should be maintained, with careful attention to ensure that trough levels of calcineurin or mTOR inhibitors are within the target range and weight-based dosing of antimetabolites is not excessive. There are no definitive guidelines for initial and subsequent skin cancer screening performed by a dermatologist for adult SOT, though recommendations are available based on individual risks.^87,88 At least annual examinations have been associated with a reduction in advanced NMSC.⁸⁹ Determination of appropriate skin cancer screening guidelines for child and adolescent recipients is needed, recognizing that early attention to this risk with formal evaluation and education would likely have a beneficial impact on long-term outcomes.

RENAL CELL CARCINOMA

RCC is an uncommon finding among pediatric kidney transplant recipients, but it is important to detect in a timely manner to permit early intervention. RCC is the most common renal tumor in adults but accounts for only 2-6% of renal cancers among children in the general population.^90,91 RCC is diagnosed more frequently in older children, representing approximately 50% of renal tumors by the age of 14 years.^91-93 In contrast to the typical male predominance in adult RCC, the male-to-female ratio is approximately 1:1 in children younger than 15 years old.⁹³ In a retrospective analysis of the German Childhood Cancer Registry identifying 49 cases of RCC (24 boys, 25 girls), nearly one-third of children were found to have an underlying condition or exposure associated with an increased risk of developing RCC, such as tuberous sclerosis or prior chemotherapy.⁹² In this report, RCC in children after kidney transplant was not specifically described.

Among adult kidney transplant recipients, RCC occurs five to 10 times more frequently than in the general population, though the absolute risk is low (<1% of adult kidney transplant recipients).⁹⁴ Among pediatric kidney transplant recipients, RCC is an uncommon malignancy, and the true incidence is unknown. Unlike adult kidney transplant recipients, in whom RCC arises predominantly in the native kidney (~90%),⁹⁴ most reported cases among pediatric recipients involve the allograft. A recent review of all reported cases of allograft RCC after pediatric kidney transplantation between 1993 and 2018 yielded 12 cases.⁹⁵ In this series, three cases were asymptomatic and detected by routine ultrasound, and in one case the RCC was detected after transplant nephrectomy performed for intractable rejection.¹¹ Presenting signs for those in whom RCC was recorded included hematuria, epigastric pain, and uncontrolled hypertension. All tumors were relatively small at initial detection, measuring 1.5-4 cm. One tumor was multifocal in the kidney transplant, one demonstrated intra-abdominal dissemination, and one presented with lung metastasis. Histopathology was available in eight cases and revealed three papillary, three clear cell, one chromophobe, and one anaplastic. In nine patients, DNA studies confirmed donor origin of the RCC.

With respect to donor characteristics, the age of donors at transplant ranged from 15 to 47 years and RCC developed from 6 months to 11 years after transplant. The “age” of these kidneys at the time of detection of RCC was generally younger than the reported mean age of 53 years in adult kidney transplant recipients, 56 years among dialysis-dependent adults, and peak incidence of 60-70 years in the general population^94,96 and may reflect the effects of chronic immunosuppression. Although there were relatively few cases overall, 10 of the 12 donors were male, consistent with male predominance in the general adult population. Since this review, an additional case of papillary RCC in an adolescent detected by routine ultrasound 12 years after transplant has been described.⁹⁷ With regard to RCC detected in the native kidneys of pediatric kidney transplant recipients, two cases have been described, and in both reports there was bilateral involvement and no genetic predisposition identified.^98,99

With respect to interventions in the series of 12 cases of RCC in the renal allograft, all with available details reported transplant nephrectomy.⁹⁵ In two cases, nephrectomies were performed prior to the diagnosis of RCC (one for intractable acute rejection and one for severe chronic rejection and gross hematuria).^11,100 In the case associated with anaplastic histopathology the tumor was confirmed to be donor-derived and resolution of multiple pulmonary metastases occurred with transplant nephrectomy and withdrawal of immunosuppression.¹⁰¹ In the more recently reported case of allograft RCC, partial allograft nephrectomy was performed, with no evidence of recurrence of metastasis at 1 year.⁹⁷ With respect to outcomes of RCC in pediatric kidney transplant recipients, data are limited but appear overall favorable. Reported outcomes have generally been good, with no deaths reported, including the case with anaplastic pathology and lung metastases. Favorable outcomes may relate to the small size of tumors at detection, many of which were detected by routine surveillance ultrasound. Further study is needed, particularly as it pertains to nephron-sparing surgery to maintain allograft function in appropriately selected cases.^94,102 With regard to early detection and screening, there are no current guidelines for routine surveillance imaging after pediatric kidney transplant, though yearly renal ultrasound (native and allograft) is practiced at some pediatric transplant centers and would be expected to facilitate earlier detection.

KIDNEY TRANSPLANT FOR ESKD SECONDARY TO WILMS TUMOR

For the child who develops ESKD secondary to Wilms tumor and required treatments, planning for kidney transplantation requires careful consideration. Wilms tumor is the most common renal malignancy in infants and young children.⁹⁰ Although primarily sporadic, Wilms tumors can occur as part of recognizable malformation syndromes, 10% of which are associated with known genetic predisposition to Wilms tumors, including Denys-Drash syndrome; Frasier syndrome; Wilms tumor, aniridia, genitourinary anomalies, and a range of developmental delays (WAGR); and Beckwith-Wiedemann syndrome.¹⁰³ Implementation of international cooperative group trials has contributed greatly to improvements in the management of Wilms tumor, resulting in overall survival of greater than 90%. ESKD is rare following treatment for Wilms tumor and typically associated with bilateral disease. Approximately 5% of children present with bilateral involvement,¹⁰⁴ and the care of this group is particularly challenging, with the dual goals of adequately treating tumor burden and maintaining kidney function. In children with bilateral disease, the use of intensive preoperative chemotherapy for 6-12 weeks followed by a strategy of kidney-sparing resections has been associated with improved outcomes, including overall survival of nearly 95%, though outcomes among those with anaplastic disease are significantly worse.^105,106 Most receive unilateral total nephrectomy with contralateral partial nephrectomy or bilateral partial nephrectomy; bilateral total nephrectomies have been performed in less than 3% of patients. Recent reports describe unilateral or bilateral ex vivo tumor dissection followed by kidney autotransplantation in children with bilateral Wilms tumor as an option for nephron-sparing surgery.^107,108 During long-term follow-up of children with bilateral disease, ESKD occurs in approximately 4-20% overall, though rates are much higher in those with mutations of the WT1 gene.^109,110

For those who develop ESKD secondary to Wilms tumor, the associated morbidity and mortality are notable. A NAPRTCS registry study reporting the outcomes of children on dialysis secondary to bilateral Wilms tumor found that 10 of 37 children (27%) with bilateral Wilms tumor died on dialysis, and eight deaths were related to Wilms tumor.¹¹¹ This rate was much higher than the 8.8% of children who died on dialysis related to other causes of ESKD. Among the eight deaths related to Wilms tumor, five occurred within the first year of dialysis, one occurred in the second year of dialysis, and two occurred after more than 2 years of dialysis. Determining the optimal timing of kidney transplantation can be challenging, and available studies to support this decision are few and dated. Early reports of limited cases recommended waiting 1-2 years after treatment given the high rate of infection and recurrence or metastasis when performed within 1 year after treatment.¹¹² The prudence of deferring transplant up to 2 years after treatment has been questioned given advances in the care of children with kidney transplants.¹¹³ Timing of transplantation should be a shared decision with the family and multidisciplinary team and take into consideration the specifics of the case, including biology of the tumor and risks of prolonged dialysis. Well-designed studies are greatly needed to support these decisions.

WT1 MUATIONS: PREVENTIVE STRATEGIES TO REDUCE THE RISK OF CANCER

WT1, the Wilms tumor suppressor gene, encodes a regulatory transcription factor essential for renal and gonadal development, and mutations in this gene can induce tumors and disrupt development.¹¹⁴ WAGR syndrome develops in children with a constitutional chromosomal deletion of the Wilms tumor gene located at 11p13. The risk of Wilms tumor in WAGR syndrome approaches 60%, with a reported cumulative risk of renal insufficiency of up to 60%.¹¹⁵ Renal insufficiency has been attributed to primary glomerular pathology and nephron loss in those who have had nephrectomies. Two other disorders affecting renal development related to WT1 mutations are Denys-Drash syndrome and Frasier syndrome. In contrast to WAGR syndrome, in which renal function can be maintained or renal findings limited, Denys-Drash syndrome and Frasier syndromes are associated with childhood onset of steroid-resistant nephrotic syndrome (SRNS) with anticipated progression to ESKD. The renal and extrarenal phenotypes in WT1-associated SRNS demonstrate variable expressivity and underscore the importance of screening for WT1 mutations in children and adolescents with persistent proteinuria or SRNS.

Denys-Drash syndrome results from a germline mutation in the eighth or ninth exon of the WT1 gene and is characterized by early-onset SRNS, Wilms tumor, and, in some, intersex disorders with increased risk of gonadoblastoma. Diffuse mesangial sclerosis and focal segmental glomerulosclerosis are the common pathologic findings, and children typically progress to ESKD before age 2-3 years.^116,117 Given the extremely high risk of Wilms tumor, which presents at a median age of onset of 1.3-1.6 years,^118,119 screening ultrasounds every 3 months are recommended through the seventh birthday.¹²⁰ When children with Denys-Drash syndrome reach ESKD, prophylactic bilateral nephrectomies should be performed to prevent the subsequent development of Wilms tumor. Determining the optimal timing of bilateral nephrectomies in young infants with ESKD can be challenging given the additional risks of hypotension in anephric infants on chronic dialysis,¹²¹ and individual risk factors should be considered. Denys-Drash syndrome is also associated with an increased risk of gonadoblastoma, and these tumors are primarily related to gonadal dysgenesis rather than postnatal WT1 expression.¹¹⁹ For those with intersex disorders, such as male pseudohermaphroditism characterized by ambiguous genitalia or female phenotype with dysgenic testes or streak gonads and 46,XY karyotype, bilateral gonadectomy should be considered.

Frasier syndrome is a rare disorder resulting from mutations in the intron 9 splice donor site of the WT1 gene and is classically characterized by progressive glomerulopathy, complete male gonadal dysgenesis (46,XY karyotype with female external genitalia), and high risk of developing gonadoblastoma.¹²² Nephropathy presents in early childhood, with persistent proteinuria that evolves into SRNS followed by progression to renal failure in adolescence or early adulthood.¹¹⁹ The renal pathology is almost invariably focal segmental glomerulosclerosis. Most patients with Frasier syndrome have external female genitalia and are raised as girls. Historically, the disorder was most often suspected when children with SRNS were evaluated for delayed puberty or primary amenorrhea. Given the availability of genetic screening for persistent proteinuria or SRNS, this would predict earlier diagnosis in current practice. Considering the high risk of gonadal tumor in classical Frasier syndrome, elective bilateral gonadectomy is recommended. Of note, unusual cases of Frasier syndrome have been reported in which male pseudohermaphroditism was absent. A review of published cases analyzed the prevalence rates of gonadal tumors in cases of classical and unusual forms of Frasier syndrome.¹²² Cases were categorized into three groups: classical Frasier syndrome characterized by female external genitalia with 46,XY (type 1, 72 cases), male external genitalia with 46,XY (type 2, eight cases), and female external genitalia with 46,XX (type 3, eight cases). Gonadal tumors were reported in 67% of the classical cases, three of eight of the type 2 cases, and none of the type 3 cases. Of note, Frasier syndrome also predisposes individuals to Wilms tumor, though at much lower rates than Denys-Drash syndrome.^119,123 For patients with Frasier syndrome and ESKD, prophylactic nephrectomies could be considered, though guidelines with respect to this decision are lacking.

CONCLUSIONS

Kidney transplantation is the preferred therapy for children with ESKD, though immunosuppression reduces tumor surveillance and is associated with increased cancer risk. PTLD is the most common cancer occurring during childhood, and recipients who are EBV-naive at transplant are at greatest risk. In addition to the development of cancer during childhood, the risk of cancer development is markedly enhanced throughout adulthood. Although advances in overall care have been achieved, immunosuppressive regimens used in pediatric kidney transplantation have not evolved sufficiently. Future advances will hopefully result in transplant regimens that maintain allograft function while minimizing cancer risk. Our understanding of cancer incidence and risks is hampered by reporting and should be enhanced by advances in data capture.