Introduction

Modern immunosuppression has increased life expectancy among pediatric solid organ transplant recipients (SOTRs), increasing the burden of post-transplantation comorbidities including malignancies [1, 2]. As long-term cardiovascular outcomes improve, it is estimated that malignancy will become the leading cause of death post-transplantation [1, 3]. Pediatric SOTRs are a particularly susceptible group, with significantly higher cancer incidence and mortality than age-matched non-transplant populations [4,5,6,7,8]. This may relate to immune system immaturity at the time of immunosuppression initiation, naivety to oncogenic viruses (e.g., Epstein-Barr virus (EBV) and human papillomavirus (HPV)), local immune reaction to allograft tissue, and multiple transplants resulting in higher cumulative immunosuppression exposure over their lifespan [7]. Higher risks of cancer-related mortality among immunocompromised SOTRs may also reflect more aggressive cancer proliferation, coupled with less aggressive treatment due to concerns over side effects and patient comorbidities, including harm to the allograft [9, 10].

Post-transplantation malignancies can be classified by histological features (Table 1). Although significant variation exists between study populations, post-transplantation lymphoproliferative disorders (PTLDs) and non-melanoma skin cancer (NMSC) are consistently the most common cancer types among pediatric SOTRs [4, 5, 7, 8]. However, pediatric SOTRs are also at significantly higher risk of solid cancers, which often manifest late after transplant, in early adulthood [4]. The majority of post-transplant malignancies are de novo and occur outside the transplanted organ. Cancers can also be recurrent in children with pre-existing cancers, donor-transmitted (present in allograft at time of transplant) or donor-derived (arising in allograft after transplant).

Table 1 Classification of malignancies following transplantation
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Epidemiology

Multiple large population-based studies in adult SOTRs have demonstrated high cumulative incidence and standardized risk estimates for various cancer types (particularly infection-associated cancers) [11, 12]. Up to 30% of adult SOTRs develop cancer within 20 years post-transplantation, with a 2–4-fold greater overall cancer risk than the general population [1, 11,12,13]. In children, the cumulative incidence of cancer increases from 7%, by 10 years, to 13–15% by 20 years and 26–41% by 30 years post-transplantation (Fig. 1) [6,7,8, 14, 15]. The incidence of specific cancers varies significantly among pediatric studies (Fig. 2), due to differences in patient characteristics, transplanted organ, geographical exposures (e.g., ultraviolent (UV) radiation), and cancer screening practices. Overall, the long-term risk of cancer among pediatric SOTRs is 12–33 times greater than the general population (Table 2) [4, 5, 7, 8].

Fig. 1
figure 1

Incidence curves for (a) all cancer diagnoses; (b) all-cause mortality among pediatric transplant recipients and the age-matched general population. Reproduced with permission from Kitchlu et al. Elevated Risk of Cancer After Solid Organ Transplant in Childhood, Transplantation 103:588-596. https://doi.org/10.1097/TP.0000000000002378

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Fig. 2
figure 2

Cumulative cancer incidence among pediatric solid organ transplant recipients, by cancer type. Cumulative incidence for each cancer type varies based on study population, definitions, follow- up duration, and geographical location (e.g., UV exposure and NMSC risk). Cumulative incidence data extracted from multiple publications [2, 4,5,6,7,8, 14, 15]

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Table 2 Cancer risk among pediatric solid organ transplant recipients vs. age-matched general population (as standardized incidence or incidence rate ratios)
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PTLDs are significantly more common among pediatric SOTRs than adults, representing more than 50% of all cancers in this population [16, 17]. PTLDs are significantly more common among intestinal (~ 20%), lung, and cardiac recipients (~ 10%) vs. kidney (2–3%), which may reflect a higher degree of immunosuppression and more allograft lymphatic tissue [4, 18]. Skin cancers are the second most common, representing 20–26% of malignancies in pediatric SOTRs [16, 17]. Skin cancers are more common in kidney transplant recipients (41%) [17]. The risk of NMSC in pediatric SOTRs is significantly greater than that of the general population [5, 8], with a cumulative incidence of 20% by 25 years post-transplantation [6]. In the general population, basal cell carcinoma (BCC) is significantly more common than squamous cell carcinoma (SCC). Although SOTRs are at increased risk of both cancers, the risk of SCC is disproportionately increased, which is associated with HPV infection [8]. The risk of melanoma is also increased 2–5 times greater among pediatric SOTRs [4,5,6]. Although less common, pediatric SOTRs are at higher risk of multiple solid cancers, compared with an age-matched general population (Table 2). Solid cancers typically occur later after transplantation than PTLD [6, 15, 17]. Pediatric kidney transplant recipients with stage 5 chronic kidney disease are at particularly increased risk of renal cell carcinoma (RCC), as seen in dialysis populations [11, 12]. These cancers likely develop due to malignant transformation of acquired kidney cysts [19, 20].

For PTLD, the median time to diagnosis is 2–5 years post-transplant [7, 17]. Incidence peaks within the first 3 years (typically EBV-positive PTLD) and then increases again years later (more EBV-negative PTLD) [21]. Skin and solid cancers generally present late post-transplant: 17–26 years (skin cancers) [5, 6, 8, 22] and 5–28 years (solid cancers) [6,7,8, 17]. Pediatric SOTRs frequently present with these cancers as young adults (25–40 years) and are therefore at risk of developing cancer earlier than population-based screening programs would detect. Pediatric SOTRs can have more biologically aggressive cancers, which are more frequently invasive at diagnosis [17]. This contributes to high cancer mortality (20–60%) among pediatric SOTRs [2, 7, 8, 15]. A considerable amount of this mortality (~ 70%) is attributable to PTLD [7].

Pathophysiology and risk factors

General risk factors for malignancy

Unique risk factors exist for PTLD, and skin and solid cancers post-transplantation, underpinned by impaired immunological surveillance for malignant cells and suppressed anti-viral function [1, 11]. Higher cumulative immunosuppression is a consistent risk factor for all cancer types [17, 23]. Immunosuppressive agents can have direct carcinogenic effects or potentiate other carcinogens (e.g., photosensitivity and UV radiation). A number of induction agents, including monoclonal anti-CD3 antibody (OKT3), anti-lymphocyte globulin (ALG), and anti-thymocyte globulin (ATG), have been shown to increase PTLD risk [1, 24,25,26]. Alemtuzumab has also been associated with an increased risk of PTLD, as well as colorectal and thyroid cancers [27]. Other anti-IL-2R induction agents (e.g., basiliximab and daclizumab) have not been associated with increased PTLD or solid cancer risks [26,27,28]. Polyclonal induction has been associated with an increased melanoma risk [27]. Following induction, the literature regarding cancer risks associated with specific immunosuppressive agents is conflicting. By 3 years post-transplant, no immunosuppressive regimen has been shown to have a lower risk of non-skin cancers [29]. It is highly likely that the overall degree of immunosuppression is more important that the carcinogenic properties of individual agents [21, 30], which are extensively reviewed elsewhere [1, 17, 31]. However, mycophenolate mofetil (MMF) may have some anti-proliferative activity and does not appear to increase PTLD or solid cancer risks [1, 32]. Azathioprine and cyclosporine have both been associated with increased risks of skin cancer, due to potentiation of UV radiation–related carcinogenesis [33, 34]. A dose-dependent relationship has been observed between calcineurin inhibitors (tacrolimus and cyclosporine) and the risks of PTLD and solid cancers post-transplantation [31, 35, 36]. In animal studies, calcineurin inhibitors have pro-angiogenic effects and increase the production of transforming growth factor (TGF)-beta 1, which may promote tumor growth and invasive behavior [31, 37, 38]. Sirolimus, an mTOR inhibitor developed initially as a cancer therapy, was shown in a 2014 systematic review to reduce skin cancer risk among SOTRs (adjusted HR 0.44, 95% CI 0.30–0.63) [39]. However, the widespread use of sirolimus is limited by its increased risks of acute rejection/graft loss, sepsis, and death in multiple studies [29, 39].

Uncontrolled oncogenic infections play a fundamental role in the development of a number of post-transplantation malignancies [12]. EBV infections are strongly associated with PTLD, in addition to nasopharyngeal cancers. There is conflicting data on the association between cytomegalovirus (CMV) infections and post-transplant malignancies [36]. Some studies have suggested an elevated risk of cancers (particularly colorectal, lung, and skin cancers) [40, 41], whereas others have not observed this association [42, 43]. HPV is associated with squamous cell skin, anogenital, oropharyngeal, and laryngeal cancers. Helicobacter pylori, and hepatitis B and C are associated with gastric adenocarcinoma and hepatocellular carcinoma (HCC), respectively [11]. In the case of PTLD, local immune response to allograft lymphatic tissue may increase the risk of malignant transformation in the transplanted organ. This hypothesis is supported by higher rates of renal and cardiothoracic lymphomas in corresponding organ recipients [18, 44].

PTLD

The pathophysiology and risk factors for PTLD are extensively described elsewhere [21, 45, 46]. To summarize, PTLD is closely associated with EBV infection, which is found in up to 80% of cases [21]. Following primary EBV infection, the virus enters host B cells and becomes latent, escaping immune system detection. In immunocompromised hosts, EBV reactivation or primary infection leads to B cell transformation and uncontrolled proliferation [47]. The cause of EBV-negative, T cell, and NK-cell PTLDs is less clearly understood. There are a number of well-established PTLD risk factors. EBV seromismatch (D+/R−) can result in primary EBV infection at time of transplantation under maximal immunosuppression, which results in an 8–15 times increased risk of subsequent PTLD [21, 30]. Although PTLD risk may be reduced by matching EBV-seronegative recipients to donors (D−/R−), this may be impractical due to the prevalence of EBV-seropositivity among adult donors (> 90%) and high numbers of seronegative pediatric recipients [48, 49]. Other PTLD risk factors include younger age at transplant; males; Caucasian recipients; and intestinal, heart, and lung recipients [4, 21, 45].

Skin cancers

The most important environmental risk factor for skin cancers is UV radiation exposure. It is estimated that approximately 50% of our lifetime sun exposure occurs by age 20 and considerable geographic variation exists in the risk of excessive sun exposure [50]. Caucasian and fair-skinned SOTRs are at highest risk [5, 6, 34]. HPV infections (particularly epidermodysplasia verruciformis and beta-HPV) are strongly associated with SCC [51]. Beta-HPV infections are more common among SOTRs, but no vaccine currently exists for these HPV types [52, 53]. Other skin cancer risk factors include prolonged voriconazole exposure (due to phototoxicity), azathioprine use, older male recipients, and pre-transplant skin cancers [34, 54].

Solid cancers

The risk of RCC is highest among kidney transplant recipients, more commonly affects the native kidneys, and is associated with prolonged pre-transplant dialysis exposure [55]. The risk of RCC is also significantly higher among SOTRs than individuals with HIV/AIDS, indicating that RCC risk may be driven primarily by kidney failure–related factors, with immunosuppression contributing to a lesser degree [11]. Among adult SOTRs, the risk of lung cancer is higher in older males [12]. Lung cancers may be detected incidentally in the explanted lung or arise de novo in the native lung (following a single-lung transplant), particularly in individuals with a smoking history [56]. Liver cancer is significantly more common among liver transplant recipients, which may relate to HCC relapse or de novo HCC in the context of chronic viral hepatitis [12]. Gastric cancer is infrequent in Western countries but more common in areas of high H. pylori prevalence, such as Japan and Korea, where the risk among SOTRs is 31 times higher than the general population [57]. Among pediatric SOTRs, risk factors for skin and solid cancers include deceased donor allografts, Black or Hispanic recipients, OKT3 antibody induction, and tacrolimus use [2].

Clinical features and management

General approach to management

Post-transplantation malignancies may be detected incidentally during routine post-transplant imaging, during planned cancer screening or following clinical presentation with associated signs and symptoms. Clinical features vary widely between cancer types, locations, and staging, and SOTRs may not present with typical cancer features. Imaging studies play key roles in cancer screening (i.e., breast mammography, and kidney and liver ultrasound), diagnosis and staging, monitoring treatment response, and recurrence surveillance [58]. Computed tomographic (CT) imaging is preferred for diagnosis and staging of PTLD, NMSC, melanoma, and lung cancers [58]. Magnetic resonance imaging (MRI) is useful for anogenital, prostate, kidney, liver, and brain cancers. Positron emission tomography (PET) imaging may be used for staging and detection of distant metastases, including PTLD. Certain hematological malignancies (i.e., leukemias) may be detectable by complete blood count/differential and peripheral blood smear. Various tumor markers may be useful for screening or diagnosis of certain cancer types (e.g., prostate, colorectal, HCC). If PTLD or solid cancer is suspected based on clinical and/or imaging findings, confirmatory tissue biopsy should be performed. If the lesion is inaccessible, a presumptive diagnosis may be based on imaging and laboratory findings. For skin cancers, a biopsy procedure may also be therapeutic.

PTLD

PTLDs are an uncommon but major complication following transplantation, defined by the World Health Organization as “lymphoid or plasmacytic proliferations that develop as a consequence of immunosuppression in a recipient of a solid organ or stem cell allograft” and classified as per Table 1 [59]. Some PTLDs are not conventionally neoplastic; they do not disrupt tissue architecture and regress with immunosuppression reduction [21]. The clinical presentation of PTLD varies by location and size. The most common findings are lymph node/tonsillar enlargement, abdominal masses, and constitutional symptoms [21, 25]. Imaging-proven lymphadenopathy and a high or increasing EBV viral load further supports the diagnosis. Definitive diagnosis is made by tissue histopathology of biopsy specimen, which should be further tested for EBV and CD20 status.

First-line management for the majority of PTLDs is immunosuppression reduction, which can induce remission in up to 50% of early cases [21]. The optimal strategy for immunosuppression reduction has not been established (Table 3), and these decisions must be balanced carefully against the risk of acute rejection and graft loss. Among pediatric kidney transplant recipients, 35% experience graft loss by 5 years post-PTLD diagnosis [65]. Second-line therapies include rituximab (for CD20-positive tumors) and/or chemotherapy, typically using the CHOP regimen (cyclophosphamide, vincristine, daunorubicin, and prednisone) [21]. Due to concerns regarding toxicity and treatment-related mortality with full-dose CHOP, reduced intensity CHOP has been successfully trialed in children, with 73% (no rituximab) and 83% (plus rituximab) 2-year survival rates [66, 67]. Complete remission following chemotherapy occurs in 60–70% of cases [17, 64]. Localized PTLD may be treated by surgical excision with or without radiotherapy. Central nervous system (CNS) disease carries a poor prognosis but may partially respond to external beam radiation [68]. The role of anti-viral agents in the management of EBV-associated PTLD remains unclear [21]. EBV-directed cytotoxic T lymphocytes are a potential future therapy, derived from either the affected patient or the population cell banks [69]. Survival rates among children with PTLD range from 73–87% (2–5 years) and have improved in recent eras [65,66,67]. Poor prognostic factors include CNS or multifocal disease, T cell lineage or CD20-negative tumors, late-onset PTLD, older age, and higher International Prognostic Index score (prognostic tool developed for non-Hodgkin lymphoma; higher scores indicate lower survival probability) [1, 24, 70].

Table 3 Immunosuppression reduction strategies in PTLD
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Skin cancers

NMSC typically develop on sun-exposed areas of the scalp, face, and hands. As for immunocompetent individuals, BCC can have variable appearances and are rarely metastatic. Management options include topical therapies, excision, or Mohs micrographic surgery, based upon tumor characteristics, location, and size. Pediatric SOTRs are also at risk of SCC at an early age, and these behave more aggressively, with lymphatic or distant spread in 10–15% of cases [1, 16]. Early diagnosis is therefore critical to prevent metastases and improve patient survival. These patients should be managed by a multidisciplinary cancer team, and the aim of treatment is surgical excision with appropriate margins, which may also require Mohs micrographic surgery. Up to 50% of patients with NMSC will have recurrence within 3.5 years [71]. Sirolimus has been shown to reduce the risk of recurrent SCC in patients with prior skin cancer [72, 73] and should therefore be considered for high-risk patients with pre-malignant lesions or a history of excessive sun exposure.

Melanoma typically present with features of the ABCDE criteria (Asymmetry, Border irregularity, Color variation, Diameter > 6 mm, and Evolution). However, in children, amelanotic lesions are more common [74]. Melanoma are highly aggressive cancers, with a 5-year survival < 5% in SOTRs [75]. Multidisciplinary management is therefore essential, and treatment options include surgical excision with wide margins, with or without sentinel node biopsies, adjuvant immunotherapy, and/or targeted therapies.

Solid cancers

Overall, there is a lack of evidence justifying immunosuppression reduction or withdrawal in the management of established solid cancers. Extrapolating data derived from studies evaluating de novo cancers is highly problematic. However, reducing immunosuppression or substituting sirolimus for other agents has theoretical potential to limit cancer progression or metastasis [23]. In very well HLA-matched transplant recipients, the risk of rejection is low and immunosuppression reduction may be safe. However, these potential benefits must be cautiously weighed against the risks of acute rejection and graft loss. Important considerations are the cancer stage and prognosis, the likelihood that immunosuppression is exacerbating that cancer (i.e., a high standardized incidence ratio), the therapeutic options available, and interactions with current immunosuppressants [23].

Cancer immunotherapies

The role of the immune system in cancer treatment has gained significant recent attention with the introduction of a number of cancer immunotherapies. Immune checkpoint inhibitors (CPI) were initially approved for the treatment of melanoma, but their use has rapidly expanded to advanced SCC, lung, urothelial, and other cancers [76, 77]. Several CPIs are approved by the FDA; e.g., modulating cytotoxic T lymphocyte–associated protein 4 (CTLA-4), programmed cell death 1 receptor (PD-1), or programmed cell death ligand-1 (PD-L1) [77]. They have gained attention due to the high tumor response rates in clinical trials, for advanced or aggressive cancers with few alternative treatment options. However, SOTRs have been systematically excluded from these trials due to concerns of allograft rejection. Pre-clinical research has implicated PD-1 and CTLA-4 pathways in allograft tolerance and raised concerns that disruption of these pathways may result in acute rejection [77, 78]. However, a number of small clinical series have evaluated CPI use among adult SOTRs (mostly kidney or liver transplant recipients and melanoma or HCC cancer type) [76,77,78]. Among SOTRs receiving CPIs, 35–67% demonstrate tumor response or stabilization, while 33–42% experience acute allograft rejection. Allograft loss occurs in more than 80% of rejections, and mortality following CPI use is 46%, largely driven by complications of allograft rejection. Only 21% of SOTRs have tumor response without allograft rejection. Immunosuppression reduction or modification may increase the efficacy of CPIs. However, there is currently insufficient data to determine optimal immunosuppression during CPI administration. In the case series reported, immunosuppressive strategies with the highest tumor response rates (i.e., low-dose prednisone or mTOR inhibitor monotherapy) also carry the highest risks of acute rejection [76]. Based on the evidence available, CPI administration may be considered for SOTRs with refractory cancers, following comprehensive discussion of the risks of acute rejection, allograft loss, and mortality with the patient/family. A combination immunosuppression strategy (e.g., prednisone and calcineurin inhibitor, with or without MMF, or an mTOR inhibitor) may reduce the risk of rejection while achieving reasonable tumor response rates.

Chimeric antigen receptor (CAR)-T cell therapy is a form of genetically engineered antigen-specific Treg cells. T cells are harvested from the patient by leukapheresis, combined with CAR ex vivo, and re-infused into the patient for the purpose of tumor cell identification and destruction [79]. Since 2017, these agents have been approved by the FDA for the treatment of acute lymphoblastic leukemia in children and advanced lymphoma in adults. To our knowledge, there are no reports of CAR-T therapy use in SOTRs. In hematopoietic stem cell transplant recipients, CAR-T therapy has been used to treat refractory B cell malignancies, with 8/20 (40%) achieving remission and 12 (60%) experiencing grades 3–4 toxicities [80]. However, CAR-T therapy has also been demonstrated to prevent allograft rejection in murine models without additional immunosuppression [81]. CAR-T therapy could therefore have a role in inducing transplant tolerance, which may reduce the need for other non-specific immunosuppressants and their associated cancer risk.

Cancer screening and prevention

There are a number of measures that can be taken to reduce the incidence and morbidity associated with malignancies post-transplantation. Enhanced pre-transplant cancer screening for donors and recipients can reduce the risk of early cancers. Adherence to specified wait times [61, 82] between completion of cancer treatment and transplantation may reduce the risk of cancer recurrence. Avoiding prolonged dialysis through pre-emptive or expedited transplantation may reduce the incidence of urothelial cancers. Immunosuppression minimization and diversification may reduce cumulative exposure and associated cancer risk.

PTLD

Vaccination against EBV has the potential to dramatically reduce PTLD incidence. However, previous attempts to create a vaccine have been unsuccessful [83]. Anti-viral prophylaxis has in vitro activity against EBV and may reduce the risk of primary infection [84]. However, such treatments are ineffective against latent virus [85] and have not been proven to reduce PTLD incidence [86]. Therefore, anti-viral prophylaxis for EBV is not routinely administered to pediatric SOTRs. However, many at-risk SOTRs (D+/R−) do receive anti-viral prophylaxis for CMV (valganciclovir or ganciclovir) for 3–12 months post-transplantation [87], which may provide additional protection against EBV [88, 89]. Many centers perform EB viremia surveillance for at-risk SOTRs (D+/R−), with reduction in immunosuppression or pre-emptive rituximab administration triggered by high or increasing viral loads, in an attempt to prevent PTLD development [21, 90]. However, there are a number of limitations that complicate this approach. EBV viral loads have low positive and negative predictive values, they do not help detect EBV-negative PTLDs, and there is a lack of standardization in both testing and reporting procedures, as well as applicable cutoff values [21]. A persistently increasing viral load trend may be more clinically relevant than an absolute value [91], but it is unknown whether immunosuppression reduction at this stage can prevent PTLD or improve disease outcomes [21]. If monitoring is performed, EBV viral loads are typically measured in the first week post-transplant, at least monthly for the first 3–6 months, and then every 3 months until the end of the first year. Many centers continue to monitor EBV viral loads every 3–6 months thereafter, although the optimal surveillance duration has not been established.

Skin cancers

Although formal screening guidelines do not exist for pediatric SOTRs, most adult guidelines recommend periodic self-examination and annual physician visits for total body skin examination [22, 23]. Adequate photoprotection is the most important method of skin cancer prevention. This includes the use of SPF 30 or higher sunscreen, protective clothing and hats, sunglasses, and avoidance of midday or prolonged sun exposure. Phototoxic medications (e.g., voriconazole, doxycycline, hydrochlorothiazide, naproxen) should also be avoided. Nine-valent HPV vaccination may help prevent associated SCC [92, 93], although these do not protect against beta-HPV types [52, 53].

Solid cancers

Pediatric SOTRs are at risk of developing solid cancers earlier than would be detectable by population screening. Despite this, no specific pediatric guidelines exist and there is substantial variation in adult cancer screening recommendations. Although cancer screening for SOTRs has the potential to improve outcomes through earlier cancer detection, these individuals may also be at higher risk of screening harm (e.g., unnecessary procedures) [23]. Most cancer screening recommendations are not validated in transplant populations. Therefore, significant knowledge gaps persist regarding life years gained and cost-effectiveness of cancer screening in SOTRs. Until evidence-based cancer screening guidelines become available, physicians should develop an individualized screening plan with patients. This should account for medical comorbidities, family history, smoking status, life expectancy, and screening test performance. This approach is supported by the KDIGO 2009 guidelines [23]. Adhering to population screening guidelines may be appropriate for most cancers. Consistency with non-transplant population screening guidelines is likely to improve screening uptake. Colorectal, cervical, breast, and prostate cancer screening guidelines for SOTRs are generally consistent with population screening recommendations. However, earlier screening for cervical and colorectal cancers may be warranted for high-risk pediatric SOTRs and should be considered on a case-by-case basis.

There are a number of special screening considerations among transplant recipients. Given the risk of RCC in the native kidneys of kidney transplant recipients, ultrasonography every 1–3 years has been proposed as a surveillance method and is recommended by European guidelines [61], although this strategy may not be cost-effective [94, 95]. Patients with acquired cystic kidney disease are at significantly elevated RCC risk and may require more frequent ultrasonography and/or CT imaging [95, 96]. RCC and urological malignancy surveillance should also include urinalysis at least every 6 months to monitor for hematuria. Urine cytology may be unreliable for non-functioning native kidneys. Children at high-risk for HCC (recurrent viral hepatitis and/or cirrhosis) should undergo alpha-fetoprotein (AFP) and abdominal ultrasonography at least annually [23]. Lung cancer screening by chest X-ray or low-dose CT may be effective for certain high-risk groups (e.g., heart and lung transplant patients ≥ 60 years) but is associated with frequent false positives and not cost-effective for general transplant patients [94, 97]. Regular lifestyle counseling for SOTRs should include avoidance of smoking and excess alcohol consumption. Regular counseling on safe sex should be provided to all adolescents to reduce the risk of sexually transmitted infections. Screening for specific sexually transmitted infections (i.e., HIV, hepatitis B and C, and herpes simplex virus) should be performed prior to transplantation [82]. HPV and hepatitis B vaccinations should be administered pre-transplantation to help prevent associated cancers.

Future directions

As allograft and patient survival among pediatric SOTRs continues to improve, malignancies are likely to become a leading cause of morbidity and mortality post-transplantation. Enhanced counseling around cancer prevention strategies may become a fundamental component of the pre-transplant workup. Cancer screening recommendations should be validated among pediatric SOTRs, with the aim to develop specific pediatric guidelines (including starting age and frequency). Increased utilization of induction agents that are not associated with increased PTLD risk may help reduce the burden of early-onset disease. Standardization of EBV viral load monitoring, laboratory techniques, and protocols for EB viremia management could reduce PTLD incidence and improve survival. The development of an EBV vaccine and novel anti-EBV therapeutics may also dramatically change the landscape of PTLD management.

Future research should evaluate the long-term safety and efficacy of various immunosuppression minimization strategies, coupled with accessible pharmacokinetic monitoring protocols. Continued advances in the field of transplant immunology, improved allograft matching, and novel agents (e.g., CAR-T therapy) may facilitate additional immunosuppression minimization. The efficacy and safety of various cancer immunotherapies (e.g., immune checkpoint inhibitors) has yet to be established among SOTRs. Strategies for modifying immunosuppression to facilitate immunotherapy are also poorly understood. However, the advanced stage and immunological basis of many post-transplantation malignancies suggests that immunotherapy may play an important role in future cancer treatment for SOTRs. For stage 5 chronic kidney disease patients, there have been a number of recent advances in wearable dialysis devices, artificial kidney technology, and stem cell therapies. These have the potential to reduce or eliminate the need for immunosuppressive medications in the future, dramatically lowering cancer risks.

Key summary points

  • Pediatric SOTRs are at high risk for PTLD, and skin and multiple solid cancer types: one in three children will develop cancer within 30 years post-transplantation.

  • The strongest cancer risk factors among pediatric SOTRs are cumulative immunosuppression exposure and oncogenic infections (e.g., EBV, HPV).

  • Regular carcinogen avoidance counseling and improved cancer screening uptake among SOTRs may reduce cancer-related morbidity and mortality.

  • Immunosuppression reduction or modification may be beneficial for certain cancers, but must be balanced against the risk of rejection and allograft loss.

  • Future therapeutic and technological developments may facilitate immunosuppression minimization strategies, reducing the incidence of post-transplantation malignancies.

Multiple-choice questions

(answers are provided following the reference list)

  1. 1.

    Which is the most common overall cancer type among pediatric SOTRs?

    1. a)

      Non-melanoma skin cancer

    2. b)

      PTLD

    3. c)

      Renal cell carcinoma

    4. d)

      Melanoma

    5. e)

      Leukemia

  1. 2.

    Which induction agent has not been demonstrated to increase the risk of PTLD?

    1. a)

      Basiliximab

    2. b)

      Anti-lymphocyte globulin (ALG)

    3. c)

      Monoclonal anti-CD3 antibody (OKT3)

    4. d)

      Anti-thymocyte globulin (ATG)

  1. 3.

    Which immunosuppressive agent has been shown to decrease the risk of skin cancers?

    1. a)

      Prednisone

    2. b)

      Tacrolimus

    3. c)

      Sirolimus

    4. d)

      Mycophenolate mofetil (MMF)

    5. e)

      Azathioprine

  2. 4.

    Which of the following features would be a poor prognostic factor for PTLD?

    1. a)

      T cell lineage

    2. b)

      Early-onset PTLD

    3. c)

      Lower International Prognostic Index score

    4. d)

      CD20-positive status

  3. 5.

    Which cancer type has the highest standardized incidence ratio among pediatric SOTRs, compared with age-matched general populations?

    1. a)

      Leukemia

    2. b)

      Brain

    3. c)

      Melanoma

    4. d)

      Breast

    5. e)

      Renal