Renal solid tumors account for ~5% of all childhood tumors with 8.3–15.1 cases per one million person-years worldwide (1–3). Over 90% of these renal malignancies are Wilms tumors (WT; syn. nephroblastoma) presenting at a peak incidence of 2–3 years of age (4). The majority of cases are sporadic, whereas 10–15% present in relation to genetic malformation syndromes predisposing to tumor development such as Beckwith-Wiedemann, Denys-Drash or WAGR (i.e., WT, aniridia, genitourinary anomalies and range of intellectual disabilities) (5).

The first successful nephrectomy for a WT in a 2-year-old boy by Thomas Richard Jessop in 1877 (Leeds, England), the first histopathological description of WTs by “Max” Wilms in 1899 (Leipzig, Germany) as well as the introduction of radiation therapy and cytotoxic chemotherapy in the 1950s and 1960s are the foremost origins of what has led to today's treatment standards for WT patients (6–8). Collaborative studies by the National Wilms Tumor Study Group (NWTS)/Renal Tumor Committee of the Children's Oncology Group (COG) in North America and by the International Society of Pediatric Oncology (SIOP) in Europe laid the groundwork for protocol-driven treatment plans. Today, a combination therapy of surgical resection, adjuvant and/or neoadjuvant chemotherapy and in some cases irradiation achieves an overall survival (OS) exceeding 90% for localized WT, 75% for metastasized WT and 50% in the case of WT recurrence (9).

Despite the good outcome for the majority of patients with WT, some remain at risk for poor survival or have a treatment related long-term risk of side effects (10). Risk factors for reduced event-free survival (EFS) and OS are: more than two-third blastemal cells within the tumor after induction chemotherapy (SIOP protocol, 8–9% of patients), anaplastic histology (5–10% of patients), loss of heterozygosity (LOH) at chromosomes 1p/16q (12 and 17% of patients, respectively), (non-resolving) metastasis (12–17% of patients), bilateral WT (5–8% of patients) and recurrent WT (20% of patients) (11–19). These patients need intensive chemotherapy and radiation therapy, thus putting them at risk for treatment related side effects. Overall, 25% of WT patients suffer from subsequent side effects such as renal failure, cardiac toxicity, pulmonary restrictive disease, infertility and secondary malignancies (20, 21).

Recent and ongoing clinical trials drive treatment strategies toward a more and more risk-based and individualized therapy approach. The identification of personal risk factors will eventually confine intensive therapy to smaller subgroups of patients, thus reducing chemotherapy-related and radiation-related side effects for others without reducing survival.

This article provides a comprehensive overview of current multidisciplinary treatment strategies for WT, whilst also addressing recent technical innovations including nephron-sparing surgery (NSS) and minimally invasive approaches. In addition, surgical concepts for the treatment of metastatic disease, advances in tumor imaging technology and potentially prognostic biomarkers will be discussed.

The incidental palpation of an asymptomatic abdominal mass is the most common presentation of a child with WT. In only 20% of cases, the presentation consists of malaise, pain, fever, gross hematuria or renal hypertension (22, 23). Rarely, an acute abdomen due to tumor rupture is the first presentation of a WT. In other cases, WT is diagnosed by routine ultrasonography in patients with conditions predisposing for WT such as Beckwith-Wiedemann syndrome or in patients in whom metachronous metastasis is suspected.

Abdominal ultrasonography is the first diagnostic choice to confirm a renal mass. To differentiate a WT from other renal masses (e.g., kidney malformations) or masses in close proximity to the kidney (e.g., neuroblastoma), abdominal MRI- and CT-scans are the current standards of imaging. Urine analysis for catecholamines and metaiodobenzylguanidine scintigraphy can also help to discriminate neuroblastoma from WT. Further work-up includes laboratory tests screening for tumor-associated anemia and thrombocytopenia, kidney malfunction, altered liver enzymes in case of liver metastasis and disrupted coagulation such as WT-acquired von Willebrand disease.

In the NWTS-4, patients with a diagnostic biopsy had a higher risk for local recurrence leading to an upgrading of a stage I and II tumor to a stage III tumor in later protocols (24). An upstaging is not recommended in the SIOP protocol, as studies have not confirmed local recurrence (except in case of open tumor biopsy) (25). In general, biopsies should only be considered when a tumor different to WT is suspected. This is usually the case when renal tumors present at an age older than 6 years, the mass is completely extra renal or imaging shows distinct calcifications suggesting a histology other than WT (26).

MRI, CT and ultrasound scans contribute to pretreatment staging. The contralateral kidney should be screened for synchronous bilateral disease. Aortocaval and hilar lymph nodes, lung and liver need to be screened for metastasis. CT scans (with or without contrast) have replaced plain X-ray images of the chest to detect lung metastasis (27–30). Contrast MRI (or CT) and ultrasound examinations will need to assess extension of the tumor into the renal vein and vena cava. Echocardiography is warranted to assess heart function and the venous extension of a tumor thrombus into the atrium (31–33).

Current staging systems of WT are based on imaging and surgical findings such as local tumor stage (e.g., complete vs. incomplete resection, perioperative tumor rupture or lymph node metastasis), bilateral disease and hematogenous metastasis to the lung and liver (rarely bone, brain or other sites) (Table 1). The histopathology of the resected tumor defines the prognostic risk group. The NWTS/COG classifies tumors in favorable and unfavorable, whereas SIOP differentiates low-, intermediate- and high-risk tumor histopathology according to the predominant cell components within the tumor (30, 34, 35) (Table 2).

In recent years, central review panels assist in staging, radiology interpretation, surgical decision-making and histology examinations of patients with WT [established by the NWTS/COG (i.e., AREN03B2 umbrella study) as well as by the SIOP-Renal Tumor Study Group (RTSG) (i.e., UMBRELLA SIOP-RTSG 2016; https://fnkc.ru/docs/SIOP-RTSG2016.pdf)] (30, 34, 36). It has been shown that the COG central review adjusted the initial risk stratification in ~20% of cases (23). Centralized review and assistance by WT study groups may eventually lead to more concise outcome data. To integrate and combine the complex sets of medical data, e-health tools have been developed such as “p-medicine” utilized by the UMBRELLA SIOP-RTSG protocol.

The two most commonly applied treatment regimens for WT derive from the NWTS/COG and SIOP. Current treatment protocols of both groups are based on the concept of risk-adapted therapy including surgery, chemotherapy and irradiation. Throughout the multiple WT studies, patients have been identified as requiring either intensified or reduced therapy according to their individual risk factors. The NWTS/COG-based protocols have followed the concept of upfront tumor resection to plan therapy according to biological information and local stage of the tumor. In contrast, the SIOP protocol includes upfront chemotherapy before surgical resection to shrink and downstage the tumor, thus increasing the chance for complete resection and minimizing the operative risk of a tumor rupture. However, in case of a kidney tumor in a child under 6 months of age, the SIOP protocol recommends upfront tumor resection, as most kidney tumors in this age group either need no further therapy (e.g., congenital mesoblastic nephroma) or need intensified chemotherapy at the outset (e.g., malignant rhabdoid tumors) (30). Local stage and tumor biology findings are used for a risk-modified treatment. Despite these strategic treatment differences between the NWTS/COG and SIOP approach, patient outcome is nearly identical.

Diffusion-weighted imaging (DWI) MRI technique has added a new quality to the available imaging modalities for WT. By defining the whole-tumor apparent diffusion coefficient, it provides information on the “cell density” of a tumor lesion, assisting the radiologist in defining necrotic from viable lesions after chemotherapy and small lesions in nephroblastomatosis (97–99). Imaging research studies aim at defining histological subtypes of WTs by DWI for radiologic assistance in risk stratification (100–102).

Detecting hiliar and retroperitoneal metastatic lymph node disease is critically important in WT (103, 104). Lymph node metastasis can be occult and may not necessarily be apparent by lymph node enlargement during the operation. To improve lymph node sampling in WT, first feasibility studies have been conducted to establish the concept of intraoperative sentinel lymph node detection. Two techniques have been described in the attempt to delineate the lymphatic drainage of the involved kidney: injection of a radioactive tracer (e.g., technetium-99 m phytate detected with an intraoperative gamma probe) or a fluorescence dye (e.g., indocyanine green visible under near-infra red laparoscopy) (103, 104). In this recently published study, including unilateral WTs with indication for tumor nephrectomy, sentinel lymph nodes were most frequently detected in the aorto-caval space after injection of a radioactive tracer into the normal kidney tissue adjacent to the WT (104). Further systematic studies will be needed to standardize and verify the advantages of this technique.

Surgical research on fluorescence-guided kidney surgery has also evolved. Surgical procedures delineating perfusion of the kidney including separation of the upper and lower pole, visualizing renal masses (cysts) or mapping lymphatic drainage (e.g., in lymphatic sparing varicocelectomy) have been successfully executed (105, 106). These new surgical imaging techniques may eventually have the potential to transform the surgical approach in WT treatment.

The number of newly identified biomarkers in WT is growing constantly. To date, more than 30 (epi-)genetic and protein biomarkers have been suggested (107). Most of these biomarkers are closely linked to tumorigenesis and predisposition of WT. Some may eventually play a role in targeted therapy. One such candidate is an antagonist of the Wnt/beta-catenin pathway, tegavivint (BC2059), which is currently under investigation by the COG for its antitumor activity in recurrent and refractory pediatric solid tumors including WT. Currently, patients with WT-associated CTNNB1 oncogene mutations leading to Wnt/beta-catenin pathway activation can be included in this study (https://clinicaltrials.gov/ct2/show/NCT04851119) (108).

So far, only one genetic biomarker, i.e., LOH at chromosomes 1p/16q, has been integrated as a decision-making factor into the current COG treatment protocol. In the presence of LOH at chromosomes 1p/16q, patients with stage I and II favorable WT histology will be upstaged from low to standard risk receiving regimen DD-4A (i.e., vincristine, dactinomycin and doxorubicine for 24 weeks) instead of regimen EE-4A (i.e., vincristine and actinomycin D for 16 weeks) after nephrectomy. The previous NWTS-5 showed a significantly improved EFS and OS in patients with intensified therapy (27). Intensified chemotherapy is also given to patients with LOH at chromosomes 1p/16q and lung metastasis in the NWTS/COG protocol. Although it serves as a sensitive marker for risk stratification, LOH at chromosomes 1p/16q is only applicable in a small subset of patients and presently it does not offer possible treatment targets.

With 30% of favorable histology WT cases, one of the most prevalent outcome predictors is gain of function (GOF) at chromosome 1q. It is associated with significantly poorer EFS and OS, as reported by the NWTS/COG and SIOP study groups, and is currently under reinvestigation in the UMBRELLA SIOP-RTSG protocol for its prognostic value (30, 109, 110).

In general, WT is considered an embryonal tumor consisting of primordial renal cells disrupted to mature into differentiated kidney tissue. Variable proportions of blastemal (i.e., renal stem cells), epithelial and stromal cells have great influence on tumor behavior and outcome. During kidney development, organogenesis passes the stage of nephrogenic differentiation. This stage of development can persist as intra- or perilobar nephrogenic rests throughout the first few years of life and is a very likely origin for WT tumorigenesis. One important factor in driving embryonal renal differentiation is the transcription factor WT1 on chromosome 11p13. Its mutation is linked to the development of WT. WT1 mutations are reported in 10–20% of sporadic WT cases (111). Together with mutations in the CTNNB1 and AMER1 (WTX) tumor suppressor genes, it unfolds its tumorigenic role by upregulation of the Wnt/beta-catenin pathway (112). As germline alterations, WT1 mutations are common in syndromic predisposition syndromes (e.g., Denys-Drash syndrome and WAGR syndrome), bilateral WT and WT with synchronous nephrogenic rests (5, 113, 114). Another transcription factor that plays a role in bilateral as well as in predisposing syndromes is WT2 on chromosome 11p15. Mutations in this gene are much more abundant (i.e., 70% of cases) with 40% in sporadic cases and 30% in Beckwith-Wiedemann syndrome (115).

In recent research, mutations have been identified in microRNA (miRNA) processing genes in about 20% of patients with WT (116, 117). These alterations in miRNA processing are thought to conserve the embryonal stage of kidney development (116, 118). However, data concerning their influence of clinical behavior in WT have not yet been specifically reported.

When analyzing molecular markers in tumor tissues, it is important to consider that tumors consist of miscellaneous tissue parts containing different levels of marker expression. This has been shown for GOF at chromosome 1q, leaving a general uncertainty in biopsies (109, 119).

In the majority of cases, biomarkers identify WTs with treatment resistance and poor prognosis. Table 4 provides an overview of transcription factors, oncogenes and tumor suppressor genes directing at multiple different pathways potentially involved in tumorigenesis of WT.

The concept of “personalized medicine” has already improved the treatment of children with WT. The future trend will increasingly be driven by two principles: (1) de-escalation of therapy with the aim to define the appropriate level of treatment to achieve the best outcome while minimizing secondary side effects, and (2) identifying tumor-related and personal risk factors justifying escalation of therapy. To address these principles, the two large WT consortia of the COG and SIOP have designed new prospective studies (i.e., AREN03B2 umbrella study within the COG registry “Project: Every Child” and UMBRELLA SIOP-RTSG protocol, respectively) to collect and overlay clinical and biological data on a profound scale. Within these registries, both groups have established systematic biospecimen banks with tumor and blood samples available for prospective and retrospective analysis. Due to the fact that many prognostic (bio-)markers, such as blastemal histology or LOH at chromosomes 1p/16q, are only identified in a small subset of patients, treatment centers worldwide are encouraged to enroll patients (30).

Molecular research has identified a multitude of genetic and protein biomarkers for WT that may eventually assign patients into more specific risk groups. Among the most prevalent and promising prognostic markers for adverse outcome is GOF at chromosome 1q, which is currently under investigation as part of the UMBRELLA SIOP-RTSG protocol. Other markers may potentially serve as therapeutic targets. Patients with recurrent or refractory WT and alteration of the Wnt/beta-catenin pathway can be included in a therapeutic phase I/II application study of tegavivint (BC2059). The study is open for a number of different pediatric solid tumors with refractory treatment response and mutational activation of the Wnt/beta-catenin pathway.

Genomic sequencing programs such as TARGET (Therapeutically Applicable Research to Generate Effective Treatments) in the United States and FACT (Factors Associated with Childhood Tumors) in the United Kingdom have accelerated the discovery of inherited and acquired factors possibly responsible for the development of WT (128–130). The growing knowledge on tumor biology and genetics will increasingly influence the decision-making process, and contribute to the general understanding of tumorigenesis of WT.

Another important field of research with respect to WT biomarkers is the identification of tumor DNA in blood or urine samples. In patients enrolled in SIOP and UKCCSG/CCLG (United Kingdom Children's Cancer Study Group/Children's Cancer and Leukemia Group), a 5–12% rate of misdiagnosis has been reported in patients without biopsy or primary surgery (131). In the near future, so-called “liquid biopsies” may aid in establishing WT diagnosis and screening patients in follow-up programs for recurrent WT (131–133).

Recent studies have focused on the global epidemiology of WT, offering a broad picture of who is at risk for the development of WT not only by world region, ethnic background, gender and age, but also by socioeconomic status and health care accessibility (1, 3, 134). The highest WT incidence rates have been reported in North America in children of African-American descent, whereas the lowest was seen in children in East Asia (2). Differences in genetics have also been reported by ethnicity and world region. For instance, the genetic alteration of the IGF-2 gene locus playing the driving role in overgrowth syndromes and WT was less frequently seen in children with WT from Japan in comparison to Caucasian children (2, 135, 136). Future research will need to overlay epidemiology with genetic data in larger patient cohorts to identify populations at risk for WT development, treatment resistance or worse outcome.

Centralized review of WT imaging and pathology as well as treatment guidance has more and more been integrated in current treatment protocols. In previous studies, discrepancies in institutional and central histopathology interpretation have been reported in 20–50% of cases (9, 35). Ultimately, centralized data review may lead to more coherent data sets.

Despite significant progress in molecular biology, research defining biomarkers and identification of new treatment targets for WT, technical advances in imaging, surgery and radiation therapy will evenly be important. In the future, artificial intelligence algorithms of tumor imaging and 3-D reconstructions of WT may assist the surgeon in defining surgical resection lines, thus improving surgical outcome particularly in cases of NSS (106, 137). In addition, advances in the application of radiotherapy such as intensity-modulated radiation therapy sparing non-tumorous tissue and limiting radiation-associated toxicity will be beneficial for the WT patients (138, 139).

T-MT, YB, KB, UR, HF, and FF performed the literature search for the work. T-MT and YB outlined and wrote the initial manuscript draft. KB, UR, HF, and FF critically revised the initial manuscript draft for important intellectual content. All authors approved the final version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

This work was supported by the German Research Foundation and the Institutional Open Access Fund of the Goethe University Frankfurt within the program of Open Access Publishing.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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