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Home > Health Library > Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For children younger than 15 years with Wilms tumor, the 5-year survival rate has increased over the same time from 74% to 88%. Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Childhood kidney cancers account for about 7% of all childhood cancers. Most childhood kidney cancers are Wilms tumor, but in the 15- to 19-year age group, most tumors are renal cell carcinoma. Wilms tumor can affect one kidney (unilateral) or both kidneys (bilateral). Less common types of childhood kidney tumors include rhabdoid tumors, clear cell sarcoma, congenital mesoblastic nephroma, Ewing sarcoma of the kidney, primary renal myoepithelial carcinoma, cystic partially differentiated nephroblastoma, multilocular cystic nephroma, primary renal synovial sarcoma, and anaplastic sarcoma. Nephroblastomatosis of the kidney is a type of nonmalignant neoplasia.[2,3]
Incidence of Wilms Tumor
Wilms tumor is the most frequent tumor of the kidney in infants and children. The incidence of Wilms tumor is 8.2 cases for every 1 million children younger than 15 years, or one case per 10,000 infants. Approximately 650 cases of Wilms tumor are diagnosed in the United States each year. The incidence is substantially lower in Asians.
The male to female ratio in unilateral cases of Wilms tumor is 0.92 to 1.00, but in bilateral cases, it is 0.60 to 1.00. The mean age at diagnosis is 44 months in unilateral cases and 31 months in bilateral cases of Wilms tumor.[2,3] About 10% of children with Wilms tumor have an associated congenital malformation syndrome.
Syndromes and Other Conditions Associated With Wilms Tumor
Wilms tumor typically develops in otherwise healthy children without any predisposition to developing cancer; however, approximately 10% of children with Wilms tumor have been reported to have a congenital anomaly.[4,5] In patients with congenital anomalies and Wilms tumor, nephrogenic rests have been reported in 60% of cases. Of 295 consecutive patients with Wilms tumor seen at the Institut Curie in Paris, 52 (17.6%) had anomalies or syndromes, 43 of which were considered major, and 14 of which were genetically proven tumor predisposition syndromes.
Children with Wilms tumor may have associated hemihyperplasia and urinary tract anomalies, including cryptorchidism and hypospadias. Children may have recognizable phenotypic syndromes such as overgrowth, aniridia, genetic malformations, and others. These syndromes have provided clues to the genetic basis of the disease. The phenotypic syndromes and other conditions have been grouped into overgrowth and non-overgrowth categories (refer to Table 1). Overgrowth syndromes and conditions are the result of excessive prenatal and postnatal somatic growth.[8,9]
It is important to recognize that the absolute risk of Wilms tumor varies with the underlying condition or anomaly. For example, most patients with hemihyperplasia will not develop Wilms tumor.
For information about the genes associated with Wilms tumor, including WT1 and WT2, refer to the Genomics of Wilms Tumor section of this summary.
Syndromic causes of Wilms tumor
WT1-related syndromes include the following:
The constellation of WAGR syndrome occurs in association with an interstitial deletion on chromosome 11 (del(11p13)) (prevalence is about 0.4% of children with Wilms tumor).[11,12] The risk of Wilms tumor development in children with WAGR syndrome is approximately 50%; these children will present earlier and have a higher incidence of bilateral Wilms tumors (15%) than will children with nonsyndromic Wilms tumors. (Refer to the Genomics of Wilms Tumor section of this summary for more information.)
WT2-related syndromes include the following:
Beckwith-Wiedemann syndrome is caused by altered expression of two gene clusters involved in growth control and cell-cycle progression regulated by two independent imprinting control regions (ICR1 [termed telomeric ICR] and ICR2 [termed centromeric ICR]) at chromosome 11p15.5. The two ICRs are characterized by differential methylation of maternal and paternal alleles. A variety of molecular mechanisms are implicated in Beckwith-Wiedemann syndrome pathogenesis, leading to unbalanced expression of imprinted genes within these two domains. Tumor predisposition results primarily from dysregulation at the telomeric domain of 11p15 (ICR1 gain of methylation [ICR1-GoM] and paternal uniparental disomy [UPD]) rather than at the centromeric domain of 11p15 (ICR2 loss of methylation [ICR2-LoM] and CDKN1C mutation). Approximately 15% of cases with clear-cut phenotypes have no molecular defects established so far.[22,23]
The molecular subtypes of the syndrome predispose patients to the development of different tumor histotypes.[24,25,26]
The prevalence of Beckwith-Wiedemann syndrome is about 1% of children with Wilms tumor.[20,27,28,29] Approximately 10% of Beckwith-Wiedemann syndrome patients will develop Wilms tumor. Beckwith-Wiedemann syndrome patients with hemihyperplasia have a fourfold increased tumor risk over that of Beckwith-Wiedemann syndrome patients without hemihyperplasia. (Refer to the Genomics of Wilms Tumor section of this summary for more information.)
Other syndromic causes of Wilms tumor include the following:
Germline inactivating mutations in DIS3L2 on chromosome 2q37 are associated with Perlman syndrome. Preliminary data suggest that DIS3L2 plays a role in normal kidney development and in a subset of sporadic Wilms tumor cases.
The syndrome is caused by mutations or deletions in glypican genes GPC3 and GPC4, and these genetic aberrations are believed to enhance the risk of Wilms tumor (8%).
This syndrome results from postzygotic, somatic mutations in PIK3CA, which may involve large or small regions of the child.
NSD1 is the only gene in which mutations are known to cause Sotos syndrome.
Three patients presented with Wilms tumor in addition to a constitutional 9q22.3 microdeletion and dysmorphic/overgrowth syndrome. Although the size of the deletions was variable, all encompassed the PTCH1 gene.
BLM is the only gene in which mutations are known to cause Bloom syndrome.
The TP53 gene mutation is present in most families with Li-Fraumeni syndrome. The CHEK2 gene mutation is also known to cause Li-Fraumeni syndrome.
The syndrome is associated with ASXL1 mutations and an estimated 7% incidence of Wilms tumor.
Nonsyndromic causes of Wilms tumor
Nonsyndromic causes of Wilms tumor include the following:
Two familial Wilms tumor genes have been localized to FWT1 (17q12-q21) and FWT2 (19q13.4).[45,46,47] Occasional Wilms tumor families have a germline mutation in WT1. In these families, most, but not all, family members have genitourinary tract malformations.[48,49]
Inactivating mutations in CTR9 have been identified in 3 of 35 Wilms tumor families. CTR9 is located at 11p15.3 and is a key component of the polymerase-associated factor 1 (PAF1) complex, which has multiple roles in RNA polymerase II regulation and transcriptional elongation and is implicated in embryonic organogenesis.
A few families with familial Wilms tumor have germline microdeletion or microinsertion mutations in the H19 region of 11p15.3 that result in hypermethylation of the site.
The overall Wilms tumor incidence was 5.9% in a study of 168 patients with isolated hemihyperplasia, although this result may have been affected by ascertainment bias. The prevalence is about 2.5% of children with Wilms tumor.[27,54]
Genomics of Wilms Tumor
Wilms tumors, similar to other pediatric embryonal neoplasms, typically arise after a limited number of genetic aberrations. One study performed genome-wide sequencing, mRNA and miRNA expression, DNA copy number, and methylation analysis on 117 Wilms tumors followed by targeted sequencing of 651 Wilms tumors. The tumors were selected for either favorable histology (FH) Wilms that had relapsed or those with diffuse anaplasia. The study showed the following:
Approximately one-third of Wilms tumor cases involve mutations in WT1, CTNNB1, or WTX.[60,61] Another subset of Wilms tumor cases results from mutations in miRNA processing genes (miRNAPG), including DROSHA, DGCR8, DICER1, and XPO5.[62,63,64,65] Other genes critical for early renal development that are recurrently mutated in Wilms tumor include SIX1 and SIX2 (transcription factors that play key roles in early renal development),[62,63]EP300, CREBBP, and MYCN. Of the mutations in Wilms tumors, 30% to 50% appear to converge on the process of transcriptional elongation in renal development and include the genes MLLT1, BCOR, MAP3K4, BRD7, and HDAC4. Anaplastic Wilms tumor is characterized by the presence of TP53 mutations.
Elevated rates of Wilms tumor are observed in patients with a number of genetic disorders, including WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, Beckwith-Wiedemann syndrome, hemihypertrophy, Denys-Drash syndrome, and Perlman syndrome. Other genetic causes that have been observed in familial Wilms tumor cases include germline mutations in REST and CTR9.[50,67]
The genomic and genetic characteristics of Wilms tumor are summarized below.
The WT1 gene is located on the short arm of chromosome 11 (11p13). WT1 is a transcription factor that is required for normal genitourinary development and is important for differentiation of the renal blastema.WT1 mutations are observed in 10% to 20% of cases of sporadic Wilms tumor.[60,68,69]
Wilms tumor with a WT1 mutation is characterized by the following:
Germline WT1 mutations are more common in children with Wilms tumor and one of the following:
Syndromic conditions with germline WT1 mutations include WAGR syndrome, Denys-Drash syndrome, and Frasier syndrome.
Inactivating mutations or deletions in the PAX6 gene lead to aniridia, while deletion of WT1 confers the increased risk of Wilms tumor. Sporadic aniridia in which WT1 is not deleted is not associated with increased risk of Wilms tumor. Accordingly, children with familial aniridia, generally occurring for many generations, and without renal abnormalities, have a normal WT1 gene and are not at an increased risk of Wilms tumor.[27,78]
Wilms tumor in children with WAGR syndrome is characterized by an excess of bilateral disease, intralobar nephrogenic rests, early age at diagnosis, and stromal-predominant histology in FH tumors. The mental retardation in WAGR syndrome may be secondary to deletion of other genes, including SLC1A2 or BDNF.
Germline WT1 point mutations produce genetic syndromes that are characterized by nephropathy, 46XY disorder of sex development, and varying risks of Wilms tumor.[79,80]
WT1 mutations in Denys-Drash syndrome are most often missense mutations in exons 8 and 9, which code for the DNA binding region of WT1. By contrast, WT1 mutations in Frasier syndrome typically occur in intron 9 at the KTS site, and create an alternative splicing variant, thereby preventing production of the usually more abundant WT1 +KTS isoform.
Studies evaluating genotype/phenotype correlations of WT1 mutations have shown that the risk of Wilms tumor is highest for truncating mutations (14 of 17 cases, 82%) and lower for missense mutations (27 of 67 cases, 42%). The risk is lowest for KTS splice site mutations (1 of 27 cases, 4%).[79,80] Bilateral Wilms tumor was more common in cases with WT1-truncating mutations (9 of 14 cases) than in cases with WT1 missense mutations (3 of 27 cases).[79,80] These genomic studies confirm previous estimates of elevated risk of Wilms tumor for children with Denys-Drash syndrome and low risk of Wilms tumor for children with Frasier syndrome.
Late effects associated with WAGR syndrome and Wilms tumor include the following:
(Refer to the Late effects after Wilms tumor therapy section of the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for more information about the late effects associated with Wilms tumor.)
CTNNB1 is the most commonly mutated gene in Wilms tumor, reported to occur in 15% of patients with Wilms tumor.[59,61,69,71,83] These CTNNB1 mutations result in activation of the WNT pathway, which plays a prominent role in the developing kidney.CTNNB1 mutations commonly occur with WT1 mutations, and most cases of Wilms tumor with WT1 mutations have a concurrent CTNNB1 mutation.[69,71,83] Activation of beta-catenin in the presence of intact WT1 protein appears to be inadequate to promote tumor development because CTNNB1 mutations are rarely found in the absence of a WT1 or WTX mutation, except when associated with a MLLT1 mutation.[61,85]CTNNB1 mutations appear to be late events in Wilms tumor development because they are found in tumors but not in nephrogenic rests.
WTXgene on the X chromosome
WTX, which is also called AMER1, is located on the X chromosome at Xq11.1. It is altered in 15% to 20% of Wilms tumor cases.[60,61,69,86,87] Germline mutations in WTX cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (MIM300373). Despite having germline WTX mutations, individuals with osteopathia striata congenita are not predisposed to tumor development. The WTX protein appears to be involved in both the degradation of beta-catenin and in the intracellular distribution of APC protein.[85,89]WTX is most commonly altered by deletions involving part or all of the WTX gene, with deleterious point mutations occurring less commonly.[60,69,86] Most Wilms tumor cases with WTX alterations have epigenetic 11p15 abnormalities.
WTX alterations are equally distributed between males and females, and WTX inactivation has no apparent effect on clinical presentation or prognosis.
Imprinting cluster regions (ICRs) on chromosome 11p15 (WT2) and Beckwith-Wiedemann syndrome
A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5; when it is a germline mutation, it causes Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumor have germline epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. Like children with Beckwith-Wiedemann syndrome, these children have an increased incidence of bilateral Wilms tumor or familial Wilms tumor.
Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[27,28,29] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the National Wilms Tumor Study (NWTS).[2,29]
Approximately 80% of patients with Beckwith-Wiedemann syndrome have a molecular defect of the 11p15 domain. Various molecular mechanisms underlying Beckwith-Wiedemann syndrome have been identified. Some of these abnormalities are genetic (germline mutations of the maternal allele of CDKN1C, paternal uniparental isodisomy of 11p15, or duplication of part of the 11p15 domain) but are more frequently epigenetic (loss of methylation of the maternal ICR2/KvDMR1 or gain of methylation of the maternal ICR1).[51,91]
Several candidate genes at the WT2 locus comprise the two independent imprinted domains IGF2/H19 and KIP2/LIT1. LOH, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations.[51,90,91]
A relationship between epigenotype and phenotype has been shown in Beckwith-Wiedemann syndrome, with a different rate of cancer in Beckwith-Wiedemann syndrome according to the type of alteration of the 11p15 region.
The following four main molecular subtypes of Beckwith-Wiedemann syndrome are characterized by specific genotype-phenotype correlations:
Other tumors such as neuroblastoma or hepatoblastoma were reported in patients with paternal 11p15 isodisomy.[21,25,94] For patients with Beckwith-Wiedemann syndrome, the relative risk of developing hepatoblastoma is 2,280 times that of the general population.
Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5. Interestingly, Wilms tumor in Asian children, which occur at a lower incidence than in European children, is not associated with either nephrogenic rests or IGF2 loss of imprinting.
Other genes and chromosomal alterations
Additional genes and chromosomal alterations that have been implicated in the pathogenesis and biology of Wilms tumor include the following:
In an analysis of FH Wilms tumor from 1,114 patients from NWTS-5 (COG-Q9401/NCT00002611), 28% of the tumors displayed 1q gain.
These conflicting results may arise from the greater prognostic significance of 1q gain described above. LOH of 16q and 1p loses significance as independent prognostic markers in the presence of 1q gain. However, in the absence of 1q gain, LOH of 16q and 1p retains their adverse prognostic impact. The LOH of 16q and 1p appears to arise from complex chromosomal events that result in 1q LOH or 1q gain. The change in 1q appears to be the critical tumorigenic genetic event.
Germline mutations in miRNAPG are observed for DICER1 and DIS3L2, with mutations in the former causing DICER1 syndrome and mutations in the latter causing Perlman syndrome.
Figure 1. The miRNA processing pathway is commonly mutated in Wilms tumor. Expression of mature miRNA is initiated by RNA polymerase–mediated transcription of DNA-encoded sequences into pri-miRNA, which form a long double-stranded hairpin. This structure is then cleaved by a complex of Drosha and DGCR8 into a smaller pre-miRNA hairpin, which is exported from the nucleus and then cleaved by Dicer (an RNase) and TRBP (with specificity for dsRNA) to remove the hairpin loop and leave two single-stranded miRNAs. The functional strand binds to Argonaute (Ago2) proteins into the RNA-induced silencing complex (RISC), where it guides the complex to its target mRNA, while the nonfunctional strand is degraded. Targeting of mRNAs by this method results in mRNA silencing by mRNA cleavage, translational repression, or deadenylation. Let-7 miRNAs are a family of miRNAs highly expressed in ESCs with tumor suppressor properties. In cases in which LIN28 is overexpressed, LIN28 binds to pre-Let-7 miRNA, preventing DICER from binding and resulting in LIN28-activated polyuridylation by TUT4 or TUT7, causing reciprocal DIS3L2-mediated degradation of Let-7 pre-miRNAs. Genes involved in miRNA processing that have been associated with Wilms tumor are highlighted in blue (inactivating) and green (activating) and include DROSHA, DGCR8, XPO5 (encoding exportin-5), DICER1, TARBP2, DIS3L2, and LIN28. Copyright © 2015 Hohenstein et al.; Published by Cold Spring Harbor Laboratory Press. Genes Dev. 2015 Mar 1; 29(5): 467–482. doi: 10.1101/gad.256396.114. This article is distributed exclusively by Cold Spring Harbor Laboratory Press under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
In a study of 118 prospectively identified patients with diffuse anaplastic Wilms tumor registered on the NWTS-5 trial, 57 patients (48%) demonstrated TP53 mutations, 13 patients (11%) demonstrated TP53 segmental copy number loss without mutation, and 48 patients (41%) lacked both (wild-type TP53 [wtTP53]). All TP53 mutations were detected by sequencing alone. Patients with stage III or stage IV disease with wtTP53 had a significantly lower relapse rate and mortality rate than did patients with TP53 abnormalities (P = .00006 and P = .00007, respectively). There was no effect of TP53 status on patients with stage I or stage II tumors. In-depth analysis of a subset of 39 patients with diffuse anaplastic Wilms tumor showed that 7 patients (18%) were wtTP53. These wtTP53 tumors demonstrated gene expression evidence of p53 pathway activation. Retrospective pathology review of wtTP53 tumors revealed no or very low volume of anaplasia in six of seven tumors. These data support the key role of TP53 loss in the development of anaplasia in Wilms tumor and support its significant clinical influence in patients who have residual anaplastic disease after surgery.
Figure 2 summarizes the genomic landscape of a selected cohort of Wilms tumor patients selected because they experienced relapse despite showing FH. The 75 FH Wilms tumor cases were clustered by unsupervised analysis of gene expression data, resulting in six clusters. Five of six MLLT1-mutant tumors with available gene expression data were in cluster 3, and two were accompanied by CTNNB1 mutations. This cluster also contained four tumors with a mutation or small segment deletion of WT1, all of which also had either a mutation of CTNNB1 or small segment deletion or mutation of WTX. It also contained a substantial number of tumors with retention of imprinting of 11p15 (including all MLLT1-mutant tumors). The miRNAPG-mutated cases clustered together and were mutually exclusive with both MLLT1 and with WT1/WTX/CTNNB1-mutated cases.
Figure 2. Unsupervised analysis of gene expression data. Non-negative Matrix Factorization (NMF) analysis of 75 FH Wilms tumor resulted in six clusters. Five of six MLLT1 mutant tumors with available gene expression data occurred in NMF cluster 3, and two were accompanied by CTNNB1 mutations. This cluster also contained a substantial number of tumors with retention of imprinting of 11p15 (including all MLLT1-mutant tumors), in contrast to other clusters, where most cases showed 11p15 loss of heterozygosity or retention of imprinting. Almost all miRNAPG-mutated cases were in NMF cluster 2, and most WT1, WTX, and CTNNB1 mutations were in NMF clusters 3 and 4. Copyright © 2015 Perlman, E. J. et al. MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology wilms tumours. Nat. Commun. 6:10013 doi: 10.1038/ncomms10013 (2015). This article is distributed by Nature Publishing Group, a division of Macmillan Publishers Limited under a Creative Commons Attribution 4.0 International License, as described at http://creativecommons.org/licenses/by/4.0/.
Bilateral Wilms Tumor
Approximately 5% to 10% of individuals with Wilms tumor have bilateral or multicentric tumors. The prevalence of bilateral involvement is higher in individuals with genetic predisposition syndromes than in those without predisposition syndromes. For example, in 545 cases of bilateral Wilms tumors, bona fide pathogenic germline variants were found in 22% of patients. The most common predisposition variants are mutations of WT1 and 11p15 loss of imprinting.[20,68]
Bilateral Wilms tumor with WT1 mutations are associated with early presentation in pediatric patients (age 10 months vs. age 39 months for those without a mutation) and a high frequency of WT1 nonsense mutations in exon 8. Three percent of patients with bilateral Wilms tumor have affected family members.
Screening Children Predisposed to Wilms Tumor
Children with a significant increased predisposition to develop Wilms tumor (e.g., most children with Beckwith-Wiedemann syndrome or other overgrowth syndromes, WAGR syndrome, Denys-Drash syndrome, sporadic aniridia, or isolated hemihyperplasia) are usually screened with ultrasonography every 3 months until they reach at least age 8 years.[78,122] Early-stage, asymptomatic, small Wilms tumors may be discovered and potentially removed with renal-sparing surgery.
Tumor screening programs for each overgrowth syndrome have been suggested. These programs were based on published age, incidence of tumor type, and recommendations from the 2016 American Association for Cancer Research (AACR) Childhood Cancer Predisposition Workshop. Although data about different cancer risks based on genetic or epigenetic subgroups for certain syndromes are emerging, and subgroup-specific recommendations have been developed in Europe, these practices have not been adopted in the United States. The AACR workshop committee proposed a uniform screening approach for all syndromes associated with a greater-than-1% risk of Wilms tumor. Additional screening for hepatoblastoma by serum alpha-fetoprotein (AFP) measurement and ultrasonography is also recommended for patients with Beckwith-Wiedemann syndrome, trisomy 18, and Simpson-Golabi-Behmel syndrome.
The AACR workshop committee has published screening guidelines that include Beckwith-Wiedemann syndrome. Screening for hepatoblastoma or adrenal tumors with abdominal ultrasonography and serum AFP usually begins at birth or when the syndrome is diagnosed and continues until age 4 years. After age 4 years, most hepatoblastomas will have occurred, and imaging may be limited to renal ultrasonography, which is quicker and does not require fasting before the exam. Screening for Wilms tumor usually continues until age 7 years. Physical examination by a specialist (geneticist or pediatric oncologist) is recommended twice per year, and ongoing education regarding tumor manifestations, reinforcing the rationale for screening and compliance with the screening regimen, is discussed.
Proposed screening guidelines for Wilms tumor are available for patients with Beckwith-Wiedemann syndrome who have undergone molecular subtyping  (refer to the Genomics of Wilms Tumor section of this summary for more information about the molecular subtypes). The four main molecular subtypes of Beckwith-Wiedemann syndrome (ICR1-GoM, ICR2-LoM, UPD, and CDKN1C mutation) are characterized by specific genotype-phenotype correlations, including tumor risk.
Proposed screening for specific molecular subtypes of Beckwith-Wiedemann syndrome is as follows:
The frequency of malformations observed in patients with Wilms tumor underlines the need for genetic counseling, molecular and genetic explorations, and follow-up.
A French study concluded that patients need to be referred for genetic counseling if they have one of the following:
Simple oncological follow-up is indicated when there is no malformation or when there is only one minor malformation.
After genetic counseling takes place, testing for WT1 mutations should be considered for patients who have the following:
Testing for an 11p15 abnormality should be considered for patients exhibiting any symptoms of Beckwith-Wiedemann syndrome, hemihyperplasia, or bilateral or familial Wilms tumor.
Clinical Features of Wilms Tumor
Most Wilms tumor patients present asymptomatically with an abdominal mass noticed by a parent or pediatrician on a well-child visit. In children with known predisposing clinical syndromes, renal tumors can be found during routine screening. Other findings include the following:
Children with Wilms tumor or other renal malignancies may also come to medical attention as a result of the following:
Diagnostic and Staging Evaluation for Wilms Tumor
Tests and procedures used to diagnose and stage Wilms tumor and other childhood kidney tumors include the following:
Biopsy tissue from inoperable Wilms tumor obtained before chemotherapy may be used for histologic review and initial treatment decisions. However, the use of biopsy to determine histology in an inoperable tumor remains controversial because biopsy may cause local tumor spread and the histologic classification of the Wilms tumor cannot be determined by biopsy.
If a child undergoes a biopsy as the first procedure, they are considered stage III because they have gross residual tumors.
In children with a renal mass that clinically appears to be stage I or stage II Wilms tumor, biopsy is not performed so that tumor cells are not spread during the biopsy. A biopsy would upstage such a patient to stage III. Nephrectomy (in North America) or chemotherapy (in Europe) is performed instead. Therefore, the diagnostic pathology is first seen when the nephrectomy specimen is examined.
Children who have bilateral Wilms tumor are often treated without a biopsy.
Biopsy of a renal mass may be indicated if the mass is atypical by radiographic appearance for Wilms tumor, and the patient is not going to undergo immediate nephrectomy. Biopsy tissue from inoperable Wilms tumor obtained before chemotherapy may be used for histologic review and initial treatment decisions.
Anaplastic histology can be difficult to detect in any biopsy sample because of tumor heterogeneity. It is important to recognize that data from NWTS-4 and NWTS-5 (COG-Q9401/NCT00002611) have shown that, because of the histologic heterogeneity of Wilms tumor, a significant number of patients have anaplastic histology that is missed during an upfront biopsy whether it be a core needle biopsy or an incisional biopsy  but revealed at the time of definitive surgery after chemotherapy.
Detection of a contralateral renal lesion in a child with Wilms tumor can change the stage and initial management of the patient, indicating a role for a renal-sparing approach without up-front surgery. The detection of contralateral renal lesions is important at baseline imaging because routine intraoperative exploration of the contralateral kidney is no longer recommended on the basis of the results of the NWTS-4 study.[133,136] If the initial imaging studies suggests a bilateral process, treatment as a bilateral Wilms tumor is recommended by the authors. If the origin of the other lesion is indeterminate, the authors recommend pathological assessment of that lesion before proceeding with a nephrectomy.[133,136]
In children with bilateral Wilms tumor, biopsy can be avoided if the child is of typical age and radiographic appearance. This was assessed on the COG AREN0534 (NCT00945009) study where 187 of 189 patients were treated initially without a biopsy. All had Wilms tumors. If after 6 weeks of therapy, response was less then 30% by RECIST1.1 criteria, bilateral biopsies were performed to assess for anaplasia, stromal differentiation, and rhabdomyomatous changes. If anaplasia was detected, the chemotherapy treatment was changed. If the other two were detected, further chemotherapy was unlikely to result in tumor shrinkage and definitive surgery was recommended by the authors.
About 5% of renal masses thought to be Wilms tumor on the basis of clinical and radiological findings are diagnosed as another condition.
For patients with suspected Wilms tumor, additional preoperative staging studies are performed to assess intravascular extension or rupture of Wilms tumor.
In North America, local staging of Wilms tumor is performed with CT or MRI of the abdomen and pelvis. Contrast-enhanced CT for Wilms tumor patients has high sensitivity and specificity for detection of cavoatrial tumor thrombus that may impact surgical approach. Routine Doppler evaluation after CT has been performed but is not necessarily required. If the tumor is at or above the hepatic veins, a biopsy with preoperative chemotherapy is suggested because of the lower rate of serious intraoperative complications. Before surgical approach to the renal mass is performed, large tumor thrombi need to be controlled, especially when they extend above the hepatic vein, to avoid embolization of the tumor. In some cases, cardiopulmonary bypass is required.
Prognosis and Prognostic Factors for Wilms Tumor
Wilms tumor is a curable disease in most affected children. Since the 1980s, the 5-year survival rate for Wilms tumor with favorable histology (FH) has been consistently above 90%. This favorable outcome occurred despite reductions in the length of therapy, dose of radiation, extent of fields irradiated, and the percentage of patients receiving radiation therapy.
The prognosis for patients with Wilms tumor depends on the following:[149,150,151,152]
Older adolescents and adults with Wilms tumor
Wilms tumor in patients older than 16 years is rare, with an incidence rate of less than 0.2 cases per 1 million per year. In Europe, the median age at diagnosis for adult patients with Wilms tumor (defined as age >15 years) is 34 years; however, patients older than 60 years have been reported. Three percent of Wilms tumors occur in adults. Wilms tumor represents less than 1% of all renal tumors in adults and may be an unexpected finding after nephrectomy for presumed renal cell carcinoma, which is the most common adult renal cancer.
The outcome for adolescent and young adult (AYA) patients (aged 15 to 39 years) is inferior to the outcome for children. In an analysis of patients with Wilms tumor in the Surveillance, Epidemiology, and End Results (SEER) database, AYA patients (n = 104) had a statistically worse 5-year OS (69% vs. 94%; P < .001) than did pediatric patients (n = 2,574).[Level of evidence: 3iA] Better results have been reported for adults when they are treated in pediatric trials. The National Wilms Tumor Study (NWTS) Group reported the outcomes for adult patients with Wilms tumor from the NWTS-1, -2, and -3 trials. The 3-year OS rate for adults on the NWTS-1 trial was 24% (compared with 74% in children) and improved to a 5-year OS rate of 82.6% on the NWTS-3 trial, although the number of adult patients treated on each trial was 31 or fewer.[156,157,158] These data suggest that many adults with Wilms tumor, if treated appropriately, can expect to be cured, especially if the tumor has not spread and/or is completely resected. The inferior outcome of the adult patients may be the result of differences in tumor biology between children and adults, incorrect diagnosis, inadequate staging (e.g., more likely to be staged as localized disease or to not receive lymph node sampling), undertreatment/poor compliance (e.g., not receiving radiation therapy), unfamiliarity of medical oncologists and pathologists with Wilms tumors in adults (possibly leading to diagnostic error and delay), delays in initiating the appropriate risk-adapted therapy, and lack of specific treatment protocols for adults. For adults with refractory or recurrent disease, screening for potential therapeutic targets in the tumor should be considered.
The following recommendations from the renal tumor committees of the International Society of Pediatric Oncology (SIOP) and COG encourage a uniform approach to improve outcome for adults with Wilms tumor.
Histologic Findings in Wilms Tumor
Although most patients with a histologic diagnosis of Wilms tumor do well with current treatment, approximately 10% of patients have histopathologic features that are associated with a worse prognosis, and in some types, with a high incidence of relapse and death. Wilms tumor can be separated into the following two prognostic groups on the basis of tumor and kidney histopathology:
Favorable histology (FH)
Histologically, Wilms tumor mimics the triphasic development of a normal kidney consisting of blastemal, epithelial (tubules), and stromal cell types. Not all tumors are triphasic, and monophasic patterns may present diagnostic difficulties.
While associations between histologic features and prognosis or responsiveness to therapy have been suggested, with the exception of anaplasia, none of these features have reached statistical significance in North American treatment algorithms, and therefore, do not direct the initial therapy.
Anaplastic histology accounts for about 10% of Wilms tumor cases. Anaplastic histology is the single most important histologic predictor of response and survival in patients with Wilms tumor. Tumors occurring in older patients (aged 10–16 years) have a higher incidence of anaplastic histology. In bilateral tumors, 12% to 14% have been reported to have anaplastic histology in one kidney.[163,164]
The following two histologic criteria must be present to confirm the diagnosis of anaplasia:
Changes on 17p consistent with mutations in the TP53 gene have been associated with foci of anaplastic histology. Focal anaplasia is defined as the presence of one or more sharply localized regions of anaplasia in a primary tumor. All of these factors lend support to the hypothesis that anaplasia evolves as a late event from a subpopulation of Wilms tumor cells that have acquired additional genomic lesions. Focal anaplasia does not confer as poor a prognosis as does diffuse anaplasia.[151,166,167]
Anaplasia correlates best with responsiveness to therapy rather than to tumor aggressiveness. It is most consistently associated with poor prognosis when it is diffusely distributed and when identified at advanced stages. These tumors are more resistant to the chemotherapy traditionally used in children with FH Wilms tumor.
Nephrogenic rests are abnormally retained embryonic kidney precursor cells arranged in clusters. Nephrogenic rests are found in about 1% of unselected pediatric autopsies, 35% of kidneys with unilateral Wilms tumor, and nearly 100% of kidneys with bilateral Wilms tumor.[168,169] Preoperative chemotherapy does not appear to affect the overall prevalence of nephrogenic rests. Congenital anomalies have been reported in 12% of patients with nephrogenic rests, including in 9% of patients with unilateral Wilms tumor and in 33% of patients with bilateral disease.
The term nephroblastomatosis is defined as the presence of diffuse or multifocal nephrogenic rests. Nephrogenic rests can be subclassified according to the category of rest (intralobar or perilobar nephrogenic rests) and their growth phase (incipient or dormant nephrogenic rests, hyperplastic nephrogenic rests, and regressing or sclerosing nephrogenic rests). Diffuse hyperplastic perilobar nephroblastomatosis represents one unique category of nephroblastomatosis that forms a thick rind around one or both kidneys and is considered a preneoplastic condition. Distinguishing between Wilms tumor and diffuse hyperplastic perilobar nephrogenic rests may be a challenge, and it is critical to examine the juncture between the lesion and the surrounding renal parenchyma. Incisional biopsies are of no diagnostic value unless they include the margin between the lesion and the normal renal parenchyma.
The type and percentage of nephrogenic rests vary in patients with unilateral or bilateral disease. Patients with bilateral Wilms tumor have a higher proportion of perilobar rests (52%) than of intralobar or combined rests (32%) and higher relative proportions of rests, compared with patients with unilateral tumors (18% perilobar and 20% intralobar or both). Intralobar nephrogenic rests have been associated with stromal-type Wilms tumor and younger age at diagnosis.
Patients with any type of nephrogenic rest in a kidney removed for nephroblastoma are considered at increased risk for tumor formation in the remaining kidney. This risk decreases with patient age.
Bilateral diffuse hyperplastic perilobar nephroblastomatosis is generally treated with chemotherapy to reduce the risk of developing Wilms tumor; however, the risk of developing Wilms tumor remains high, 55% in one series. Patients who have been treated with chemotherapy for a prolonged period of time remain at high risk of developing Wilms tumor. If these patients develop Wilms tumor, they have a poorer prognosis than do other bilateral Wilms tumor patients, presumably because of the increased incidence of anaplasia in these cases (more than one-third of cases), and perhaps as a result of the development and selection of anaplasia in the surviving abnormal kidney cells.[170,171]
Extrarenal nephrogenic rests are rare and may develop into extrarenal Wilms tumor.
Stage Information for Wilms Tumor
Both the results of the imaging studies and the surgical and pathologic findings at nephrectomy are used to determine the stage of disease. The stage is the same for tumors with FH or anaplastic histology. Thus, the stage information is characterized by a statement of both criteria (for example, stage II, FH or stage II, anaplastic histology).[161,173]
The staging system was originally developed by the NWTS Group and is still used by the COG. The staging system used in North America and incidence by stage are outlined below.
In stage I Wilms tumor (43% of patients), all of the following criteria must be met:
For a tumor to qualify for certain therapeutic protocols such as very low-risk stage I, regional lymph nodes must be examined microscopically. Lymph node sampling is strongly recommended for all patients, even in the absence of clinical abnormal nodes, to achieve the most accurate stage.
In stage II Wilms tumor (20% of patients), the tumor is completely resected, and there is no evidence of tumor at or beyond the margins of resection. The tumor extends beyond the kidney as evidenced by any one of the following criteria:
All lymph nodes sampled are negative.
Rupture or spillage confined to the flank, including biopsy of the tumor, is now included in stage III by the COG Renal Tumor Committee (COG RTC); however, data to support this approach are controversial.[140,174]
In stage III Wilms tumor (21% of patients), there is postsurgical residual nonhematogenous tumor that is confined to the abdomen. Any one of the following may occur:
Lymph node involvement and microscopic residual disease are reported as highly predictive of outcome in patients with stage III FH Wilms tumor.
In stage IV Wilms tumor (11% of patients), one of the following is present:
The presence of tumor within the adrenal gland is not interpreted as metastasis and staging depends on all other staging parameters present. According to the criteria described above, the primary tumor is assigned a local stage, which determines local therapy. For example, a patient may have stage IV, local stage III disease.
In stage V Wilms tumor (5% of patients), bilateral involvement by tumor is present at diagnosis. The current paradigm treats all patients with bilateral Wilms tumor the same for the first 6 or 12 weeks. After definitive surgery, the treatment is based on the highest stage of the remaining kidneys and the posttreatment pathology.
Treatment of Wilms Tumor
Treatment option overview for Wilms tumor
Because of the relative rarity of Wilms tumor, all patients with this tumor should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon and/or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) who have experience treating children with Wilms tumor is necessary to determine and implement optimal treatment.
Most randomized clinical studies for treatment of children with Wilms tumor have been conducted by two large clinical groups (COG RTC and SIOP). Differences between the two groups affect staging and classification. There are two standard approaches to Wilms tumor treatment: the COG RTC uses immediate surgery for all unilateral tumors and the SIOP uses preoperative chemotherapy as the first step in treatment. Both groups use postoperative chemotherapy, except for selected cases who do not receive chemotherapy, and in advanced stages, radiation therapy is used in a risk-adapted approach.
This summary focuses on the NWTS (now COG RTC) results and studies.
The major treatment and study conclusions of NWTS-1, NWTS-2, NWTS-3, NWTS-4, and NWTS-5 are as follows:
The following operative principles have also evolved from NWTS trials:
For patients with resectable tumors, preoperative biopsy or intraoperative biopsy is not performed because either would upstage the tumor in the current COG staging system.
Renal-sparing surgery remains controversial and is not recommended, except for children with the following:[188,189]; [Level of evidence: 3iiB]
Renal-sparing surgery does not appear to be feasible for most patients at the time of diagnosis because of the location of the tumor within the kidney, even in patients with very low-risk tumors. In North America, renal-sparing surgery (partial nephrectomy) of unilateral Wilms tumor after administration of chemotherapy to shrink the tumor mass is considered investigational.[193,194]
Hilar and periaortic lymph node sampling is appropriate even if the nodes appear normal.[185,195] Furthermore, any suspicious node basin is sampled. Margins of resection, residual tumor, and any suspicious node basins are marked with titanium clips.
Wilms tumor rarely invades adjacent organs; therefore, resection of contiguous organs is seldom indicated. There is an increased incidence of complications occurring in more extensive resections that involve removal of additional organs beyond the diaphragm and adrenal gland. This finding has led to the recommendation in current COG protocols that patients in whom nephrectomy will require removal of additional organs should be considered for initial biopsy, neoadjuvant chemotherapy, and then secondary resection. Primary resection of liver metastasis is not recommended.
Preoperative chemotherapy before nephrectomy is indicated in the following situations, which have been listed previously under situations requiring a biopsy (refer to the Diagnostic and Staging Evaluation for Wilms Tumor section of this summary for more information):[185,196,198,199,200,201]
Preoperative chemotherapy follows a biopsy. The biopsy may be performed through a flank approach.[145,202,203,204,205,206] Adequate tissue is essential for accurate histological assessment and molecular studies. Preoperative chemotherapy includes doxorubicin in addition to vincristine and dactinomycin unless anaplastic histology is present; in such cases, chemotherapy then includes treatment with regimen I (refer to Table 2). The chemotherapy generally makes tumor removal easier by decreasing the size and vascular supply of the tumor; it may also reduce the frequency of surgical complications.[140,145,196,198,207,208]
In North America, the use of preoperative chemotherapy in patients with evidence of a contained preoperative rupture has been suggested to avoid intraoperative spill, but this is controversial.[209,210] The preoperative diagnosis of a contained retroperitoneal rupture on CT is difficult, even for experienced pediatric radiologists.
Newborns and all infants younger than 12 months who will be treated with chemotherapy require a 50% reduction in chemotherapy dose compared with the dose given to older children. Dosing for infants (younger than 12 months) will be calculated per kilogram of weight, not body surface area. This reduction diminishes the toxic effects reported in children in this age group enrolled in NWTS studies while maintaining an excellent overall outcome.
Liver function tests in children with Wilms tumor are monitored closely during the early course of therapy because hepatic toxic effects (sinusoidal obstructive syndrome, previously called veno-occlusive disease) have been reported in these patients.[213,214] Dactinomycin or doxorubicin should not be administered during radiation therapy. Patients who develop renal failure while undergoing therapy can continue receiving chemotherapy with vincristine, dactinomycin, and doxorubicin. Vincristine and doxorubicin can be given at full doses; however, dactinomycin is associated with severe neutropenia. Reductions in dosing these agents may not be necessary, but accurate pharmacologic and pharmacokinetic studies are needed while the patient is receiving therapy.[215,216]
Augmentation of therapy improves EFS for patients with FH Wilms tumor and loss of heterozygosity of 1p/16q. In the AREN0532 (NCT00352534) and AREN0533 (NCT00379340) trials, patients with stage I and stage II FH Wilms tumor who were treated with the DD-4A regimen (dactinomycin, vincristine, and doxorubicin) demonstrated a 4-year EFS rate of 87.3%, compared with the 4-year EFS rate of 68.8% (P = .042) for stage I and stage II patients treated on the NWTS-5 trial. Patients with stage III and stage IV disease had a 4-year EFS rate of 90.2% when treated with regimen M, compared with a 61.3% 4-year EFS rate (P = .001) for stage III and stage IV patients treated on the NWTS-5 trial. Trends toward improved 4-year survival rates were seen in stage I and II patients and in stage III and IV patients.[Level of evidence: 3iiiDi]
Postoperative radiation therapy to the tumor bed is required when a biopsy is performed or in the setting of local tumor stage III. In a study of 1,488 patients with Wilms tumors who underwent surgery and radiation therapy, delay in starting radiation therapy after surgery of greater than 14 days was associated with an increased risk of mortality for patients with nonmetastatic Wilms tumor.[Level of evidence: 3iiiA]
Table 2 describes the accepted chemotherapy regimens used to treat Wilms tumor.
Radiation therapy is used to improve local control and treat sites of metastatic disease. Radiation therapy has historically been dependent on stage and histology, but more recently is also guided by the tumor molecular signature.
Upfront surgery provides histologic confirmation and tumor extent, providing the rationale for adjuvant therapy, including radiation therapy. Besides histology, postoperative risk factors for worse local control include: (1) incomplete resection, (2) positive margins, and (3) nodal involvement. Radiation therapy is not used in patients with stage I or stage II FH Wilms tumor. For patients with FH Wilms tumor, flank or abdominal radiation therapy is used for treatment in stage III tumors. In cases of unfavorable histology (focal or diffuse anaplasia), flank or abdominal radiation therapy is indicated for all patients. (Refer to Table 3 for more information.)
Children who need radiation therapy undergo postoperative treatment to the flank and/or metastatic sites on the basis of the experience of previous SIOP trials. The SIOP 1 to 9 trials demonstrated that preoperative radiation therapy or preoperative chemotherapy decreased the proportion of patients who developed tumor spillage, from more than 20% to 5%. The noninferiority of preoperative chemotherapy to preoperative radiation therapy in the SIOP 5 trial, and the concern over secondary malignancies with preoperative radiation therapy, led SIOP to recommend preoperative chemotherapy as the standard initial treatment. Over time, the percentage of children who were treated with postoperative radiation therapy decreased, from more than 90% to 15% and 25% in SIOP trials 6 to 9, SIOP 93-01, and SIOP-2001, respectively.
Treatment of stage I Wilms tumor
Table 4 provides an overview of the standard treatment options and survival data for patients with stage I Wilms tumor, based on published results.
The COG validated the hypothesis that nephrectomy only is appropriate therapy for patients younger than 2 years at diagnosis with stage I FH Wilms tumor that weighed less than 550 g in the AREN0532 (NCT00352534) trial. The NWTS-5 trial investigated this approach for children younger than 2 years at diagnosis with stage I FH Wilms tumor that weighed less than 550 g.
Evidence (surgery only for children younger than 2 years at diagnosis with stage I FH tumor that weighed <550 g):
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Treatment of stage II Wilms tumor
Table 5 provides an overview of the standard treatment options and survival data for patients with stage II Wilms tumor, based on published results.
On NWTS-3, NWTS-4, and NWTS-5, patients with intraoperative spill were divided into two groups: (1) those with diffuse spillage involving the whole abdominal cavity; and (2) those with local spillage confined to the flank. Patients with diffuse spillage were treated with radiation therapy to the entire abdomen and three-drug chemotherapy (vincristine, dactinomycin, and doxorubicin), whereas patients with local spillage were treated with vincristine and dactinomycin only. On the basis of an analysis of patients treated on NWTS-3 and NWTS-4 indicating that patients with stage II disease and local spillage had inferior OS compared with patients with stage II disease without local spillage, COG studies treat patients with local spillage with doxorubicin and flank radiation. This approach is controversial and has not been tested; therefore, it should not be considered standard.
In a review of 499 patients from NWTS-4 with stage II FH Wilms tumor, 95 of the patients experienced tumor spill. The 8-year RFS and OS rates for patients who experienced intraoperative tumor spill and were treated with vincristine and dactinomycin without flank radiation therapy were lower, at 75.7% and 90.3%, than the 85% and 95.6% rates for those who did not experience tumor spill. None of these differences achieved statistical significance.
Treatment of stage III Wilms tumor
Table 6 provides an overview of the standard treatment options and survival data for patients with stage III Wilms tumor, based on published results.
Loss of heterozygosity of 1p or 16q was shown to influence EFS but not OS in 588 patients with stage III FH Wilms tumor treated on the COG AREN0532 protocol. When combined, lymph node status and loss of heterozygosity status provided a strong predictor of excellent EFS and OS when both were absent, with a 4-year EFS rate of 97%, and an OS rate of 99%.[Level of evidence: 2Di] The outcome was poorer for patients having both positive lymph nodes and loss of heterozygosity of 1p or 16q, with a 4-year EFS rate of 74%. However, the 4-year OS rate was not influenced, at 92%. On the basis of these results, therapy was augmented for patients with loss of heterozygosity of 1p/16q for patients enrolled on the AREN0533 trial. Patients with stage III and stage IV Wilms tumor with loss of heterozygosity were treated with regimen M. The 4-year EFS rate was 90.2%, and the OS rate was 96.1%, compared with a 4-year EFS rate of 61.3% (P = .001) and a 4-year OS rate of 86.0% (P = .087) for patients in the NWTS-5 trial. There was a suggestion of improvement in survival; however, the study was not powered to detect differences in survival.[Level of evidence: 3iiiDi]
Early initiation of radiation therapy is a critical component of multimodal therapy for patients with nonmetastatic Wilms tumor. In a review of 1,488 patients with Wilms tumor who underwent surgery and radiation therapy, a surgery-to-radiation therapy interval of greater than 14 days was associated with an increased risk of mortality (hazard ratio, 2.13; P = .013). This underscores the importance of initiating radiation therapy within 14 days of surgery, which is specified in Wilms tumor treatment protocols.[Level of evidence: 3iiiA]
For patients classified as stage III purely on the basis of local spill, refer to the Treatment of stage II Wilms tumor section of this summary.
Treatment of stage IV Wilms tumor
Table 7 provides an overview of the standard treatment options and survival data for patients with stage IV Wilms tumor, based on published results.
Stage IV disease is defined by the presence of hematogenous metastases to the lung, liver, bone, brain, or other sites, with the lung being the most common site. Historically, chest x-rays were used to detect pulmonary metastases. The introduction of CT created controversy because many patients had lung nodules detected by chest CT scans that were not seen on chest x-rays. Management of newly diagnosed patients with FH Wilms tumor who have lung nodules detected only by CT scans (with negative chest x-ray) has elicited controversy as to whether they need to be treated with additional intensive treatment that is accompanied by acute and late toxicities.
Evidence (treatment of pulmonary nodules detected by chest CT scan only):
Retrospective studies from Europe have examined the impact of omitting pulmonary radiation in patients with pulmonary metastases diagnosed by chest x-ray. European investigators omitted radiation from the treatment of most patients with Wilms tumor and pulmonary metastases as identified on chest x-ray who were treated on the SIOP-93-01 (NCT00003804) trial. The European approach to renal tumors differs from the approach used in North America. All patients who were shown to have a renal tumor by imaging underwent 9 weeks of prenephrectomy chemotherapy consisting of vincristine, dactinomycin, and doxorubicin.
Evidence (omission of pulmonary irradiation):
Although fewer patients were spared pulmonary radiation when treated in the COG trial than in the European trials, it is important to note several differences between the studies and why the studies cannot be directly compared.[219,232] Patients in Europe receive a more dose-dense regimen of dactinomycin and doxorubicin before their pulmonary metastases are reevaluated than do patients in North America (135 ug/kg dactinomycin and 100 mg/m2 doxorubicin in Europe, compared with 45 ug/kg dactinomycin and 45 mg/m2 of doxorubicin in North America). European studies allow lung radiation therapy to be omitted for patients with a complete remission achieved by chemotherapy or pulmonary metastasectomy, whereas radiation therapy was only omitted in the United States for patients with a complete remission with chemotherapy alone. Imaging studies were not centrally reviewed in the European studies, whereas they were in the United States, and the definition of complete remission may have been more stringent in the AREN0533 (NCT00379340) trial.
The presence of liver metastases at diagnosis is not an independent adverse prognostic factor in patients with stage IV Wilms tumor.
In the AREN0321 (NCT00335556) study, the combination of vincristine and irinotecan (VI) was tested in an upfront window for patients with diffuse anaplastic Wilms tumor and measurable disease. Fourteen patients with stage IV diffuse anaplastic Wilms tumor with measurable disease received the window therapy; one patient achieved a complete response (CR), ten patients achieved partial responses (PRs), and no patients had stable disease. This resulted in a CR and PR rate of 79%. Patients who responded to VI in the window therapy had VI incorporated into their regimen (UH2). Because of the observed cardiac/pulmonary toxicities encountered in this trial, the study was interrupted and amended with reduced doses of doxorubicin, cyclophosphamide, and etoposide (when combined with carboplatin). Further study of the modified regimen is planned in patients with newly diagnosed diffuse anaplastic Wilms tumor.[Level of evidence: 3iiiDii]
Treatment of stage V Wilms tumor and those predisposed to developing bilateral Wilms tumor
Currently, there is not a standard approach for the treatment of stage V Wilms tumor (bilateral Wilms tumor at diagnosis) and those predisposed to developing Wilms tumor; however, for the first time, a prospective study of the treatment of patients with bilateral Wilms tumor has been completed and provides guidance for the approach.
Management of a child with bilateral Wilms tumor is very challenging. The goals of therapy are to eradicate all tumor and to preserve as much normal renal tissue as possible, with the hope of decreasing the risk of chronic renal failure among these children.
Historically, based on the NWTS-4 and NWTS-5 trials and trials performed in Europe, patients with bilateral Wilms tumor have had a lower EFS and OS than have patients with localized Wilms tumor. The NWTS-4 study reported that the 8-year EFS rate for patients with bilateral FH Wilms tumor was 74%, and the OS rate was 89%; for patients with anaplastic histology, the EFS rate was 40%, and the OS rate was 45%. The NWTS-5 study reported that the 4-year EFS rate for all bilateral Wilms tumor patients was 56%, and the OS rate was 81%; the 4-year EFS rates for patients with FH (65%), focal anaplastic histology (76%), and diffuse anaplastic histology (25%) were also reported.[99,151] Similar outcomes for patients with bilateral Wilms tumor have been reported in Europe.[163,234] In a single-institution experience in the Netherlands (N = 41), there was significant morbidity in terms of renal failure (32%) and secondary tumors (20%). The incidence of end-stage renal failure in the Dutch study may be a reflection of a longer follow-up period.
Treatment options for stage V Wilms tumor include the following:
Preoperative chemotherapy and resection for bilateral Wilms tumor
For patients with bilateral Wilms tumor, the goal of therapy is to preserve as much renal tissue as possible without compromising overall outcome. This approach is used to avoid the late effect of end-stage renal disease, which can be caused by underlying germline genetic aberrations and treatment-related loss of functional renal tissue. End-stage renal disease occurs more frequently in patients with bilateral Wilms tumor (12% nonsyndromic) than in patients with unilateral Wilms tumor (<1%). Functional renal outcome is considerably better after bilateral nephron-sparing surgery than after other types of surgery.
Traditionally, patients have undergone bilateral renal biopsies, with staging of each kidney followed by preoperative chemotherapy. In the first prospective multi-institutional treatment trial (COG AREN0534 [NCT00945009]), pretreatment biopsies were not required if results of imaging tests were consistent with Wilms tumor. This approach was taken because the bilateral occurrence of non-Wilms renal tumors is very low. Also, core-needle and wedge biopsies are not highly successful in identifying anaplasia in Wilms tumor. In the setting of an unusual clinical situation, such as age older than 10 years or atypical imaging features, when a diagnosis other than Wilms should be considered, a tissue diagnosis is obtained.
For patients who are treated with preoperative chemotherapy, the tumor pathology needs to be evaluated after 4 to 8 weeks. For patients not treated in a clinical trial, the ideal time to perform a biopsy or resection is unknown because minimal shrinkage may reflect chemotherapy-induced differentiation or anaplastic histology. A planned attempt at resection or biopsy of apparently unresectable tumor is undertaken no later than 12 weeks from diagnosis. Continuing therapy without evaluating tumor pathology in a patient with bilateral Wilms tumor may miss anaplastic histology or chemotherapy-induced differentiation (including rhabdomyomatous differentiation) and thus increase toxicity for the patient without providing additional benefit for tumor control. Anaplastic histology occurs in 10% of patients with bilateral Wilms tumor, and these tumors respond poorly to chemotherapy.
Once the diagnosis is confirmed, a complete resection is performed. Histologic confirmation of the diagnosis is not straightforward. In a series of 27 patients from NWTS-4, discordant pathology (unilateral anaplastic tumor) was seen in 20 cases (74%), which highlights the need to obtain tissue from both kidneys. Seven children who were later diagnosed with diffuse anaplastic tumors had core biopsies performed to establish the diagnosis; however, anaplasia was not found. Anaplasia was identified in only three of the nine patients when an open-wedge biopsy was performed and in seven of nine patients who had a partial or complete nephrectomy.
The decision to administer chemotherapy and/or radiation therapy after biopsy or a second-look operation is dependent on the tumor's response to initial therapy. More aggressive therapy is required for patients with inadequate response to initial therapy observed at the second procedure or in the setting of anaplasia.[173,235,236]
End-stage renal disease is the most clinically significant morbidity in patients with bilateral Wilms tumor and can be caused by underlying germline genetic aberrations, as well as treatment-related loss of functional renal tissue. Long-term monitoring of renal function is required after treatment for bilateral disease.
Evidence (preoperative chemotherapy and resection for bilateral Wilms tumor):
Renal transplant for children with stage V Wilms tumor is usually delayed until 1 to 2 years have passed without evidence of malignancy because most relapses occur within 2 years of diagnosis. Similarly, renal transplant for children with Denys-Drash syndrome and Wilms tumor, all of whom require bilateral nephrectomy, is generally delayed 1 to 2 years after completion of initial treatment.
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
(Refer to the Treatment of Recurrent Childhood Kidney Tumors section of this summary for information about recurrent disease.)
Follow-up after treatment
For patients who have completed therapy for Wilms tumor and exhibit features consistent with genetic predisposition, such as bilateral Wilms tumor, screening involves renal ultrasonography examination every 3 months for metachronous tumors during the risk period for that particular syndrome (5 years for WT1-related syndromes; 8 years for Beckwith-Wiedemann syndrome).
Late effects after Wilms tumor therapy
Children treated for Wilms tumor are at increased risk of developing the following:
(Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)
Incidence of RCC
Malignant epithelial tumors arising in the kidneys of children account for more than 5% of new pediatric renal tumors; therefore, they are more common than clear cell sarcoma of the kidney or rhabdoid tumors of the kidney. The annual incidence rate is approximately 4 cases per 1 million children, compared with an incidence of Wilms tumor of the kidney that is at least 29-fold higher.
RCC, the most common primary malignancy of the kidney in adults, is rare in children younger than 15 years. In the older age group of adolescents (aged 15–19 years), approximately two-thirds of renal malignancies are RCC. Children and adolescents with RCC (n = 515) present with more advanced disease than do those aged 21 to 30 years.
Conditions Associated With RCC
Conditions associated with RCC include the following:
Screening for the VHL gene is available. To detect clear cell renal carcinoma in these individuals when the lesions are smaller than 3 cm and renal-sparing surgery can be performed, annual screening with abdominal ultrasonography or magnetic resonance imaging (MRI) is recommended, beginning at age 8 to 11 years.
(Refer to the Von Hippel-Lindau Disease section in the PDQ summary on Genetics of Kidney Cancer [Renal Cell Cancer] for more information.)
Succinate dehydrogenase (SDHB, SDHC, and SDHD) is a Krebs cycle enzyme gene that has been associated with the development of familial RCC occurring with pheochromocytoma/paraganglioma. Germline mutations in a subunit of the gene have been reported in individuals with renal cancer and no history of pheochromocytoma.[9,10]
Genetic Testing for Children and Adolescents With RCC
Indications for germline genetic testing of children and adolescents with RCC to check for a related syndrome are described in Table 8.
Genomics of RCC
Translocation-positive carcinomas of the kidney are recognized as a distinct form of renal cell carcinoma (RCC) and may be the most common form of RCC in children, accounting for 40% to 50% of pediatric RCC. In a Children's Oncology Group (COG) prospective clinical trial of 120 childhood and adolescent patients with RCC, nearly one-half of patients had translocation-positive RCC.[28,29] These carcinomas are characterized by translocations involving the TFE3 gene located on Xp11.2. The TFE3 gene may partner with one of the following genes:
Another less-common translocation subtype, t(6;11)(p21;q12), involving a TFEB gene fusion, induces overexpression of TFEB. The translocations involving TFE3 and TFEB induce overexpression of these proteins, which can be identified by immunohistochemistry.
Previous exposure to chemotherapy is the only known risk factor for the development of Xp11 translocation RCCs. In one study, the postchemotherapy interval ranged from 4 to 13 years. All reported patients received either a DNA topoisomerase II inhibitor and/or an alkylating agent.[31,32]
Controversy exists as to the biological behavior of translocation RCC in children and young adults. Whereas some series have suggested a good prognosis when RCC is treated with surgery alone despite presenting at a more advanced stage (III/IV) than translocation-associated RCC, a meta-analysis reported that these patients have poorer outcomes.[33,34,35] The outcomes for these patients are being studied in the ongoing COG AREN03B2 (NCT00898365) biology and classification study. Vascular endothelial growth factor receptor–targeted therapies and mammalian target of rapamycin (mTOR) inhibitors seem to be active in Xp11 translocation metastatic RCC. Recurrences have been reported 20 to 30 years after initial resection of the translocation-associated RCC.
Diagnosis of Xp11 translocation RCC needs to be confirmed by a molecular genetic approach, rather than using TFE3 immunohistochemistry alone, because reported cases have lacked the translocation. There is a rare subset of RCC cases that is positive for TFE3 and lack a TFE3 translocation, showing an ALK translocation instead. This subset of cases represents a newly recognized subgroup within RCC that is estimated to involve 15% to 20% of unclassified pediatric RCC. In the eight reported cases in children aged 6 to 16 years, the following was observed:[37,38,39,40]
Histology of RCC
Pediatric RCC differs histologically from the adult counterparts. Although the two main morphological subgroups of papillary and clear cell can be identified, about 25% of RCCs show heterogeneous features that do not fit into either of these categories. Childhood RCCs are more frequently of the papillary subtype (20%–50% of pediatric RCCs) and can sometimes occur in the setting of Wilms tumor, metanephric adenoma, and metanephric adenofibroma.
RCC in children and young adults has a different genetic and morphologic spectrum than that seen in older adults.[3,32,41,42]
Prognosis and Prognostic Factors for RCC
Prognostic factors for RCC include the following:
The primary prognostic factor for RCC is stage of disease. In 304 children and adolescents with RCC identified in the National Cancer Data Base, the median age was 13 years; 39% of patients presented with localized stage I disease, 16% with stage II disease, 33% with stage III disease, and 12% with stage IV disease. The 5-year overall survival (OS) rates were 100% for patients with stage I and stage II disease, 71% for stage III disease, and 8% for stage IV disease. Age and sex had no significant impact on survival. Survival was negatively impacted by increasing tumor size (P < .001), positive nodal status (P = .001), and higher pathologic stage (P < .001). The data attained in this article from the National Cancer Data Base are limited, as some patient details are not available and follow up is incomplete. Tumor size of 4 cm or smaller may or may not impact survival and local lymph node involvement may not be as significant in children.
An important difference between the outcomes in children and adults with RCC is the prognostic significance of local lymph node involvement. Adults presenting with RCC and involved lymph nodes have a 5-year OS rate of approximately 20%, but the literature suggests that 72% of children with RCC and local lymph node involvement at diagnosis (without distant metastases) survive their disease. In another series of 49 patients from a population-based cancer registry, the findings were similar. In this series, 33% of the patients had papillary subtype, 22% had translocation type, 6% had clear-cell subtype, and 16% were unclassified. The survival rates at 5 years were 96% for patients with localized disease, 75% for patients with positive regional lymph nodes, and 33% for patients with distant metastatic RCC.
Clinical Features and Diagnostic Evaluation of RCC
RCC may present with the following:
Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors. In a COG prospective clinical trial of 40 patients with small (7 cm) primary tumors whose lymph nodes were adequately sampled, 19 had positive nodes. Outcome results of this trial are pending. (Refer to the Stage Information for Renal Cell Cancer section in the PDQ summary on adult Renal Cell Cancer Treatment summary for more information about the staging evaluation.)
Treatment of RCC
Survival of patients with RCC is affected by stage of disease at presentation and the completeness of resection at radical nephrectomy. OS rates for all patients with RCC range from 64% to 87%. The 5-year survival rates for pediatric RCC are 90% or higher for stage I, higher than 80% for stage II, 70% for stage III, and lower than 15% for stage IV. Retrospective analyses and the small number of patients involved place limitations on the level of evidence in the area of treatment.
Standard treatment options for RCC include the following:
Radical nephrectomy with lymph node dissection
The primary treatment for RCC includes total surgical removal of the kidney and associated lymph nodes.
Renal-sparing surgery with lymph node dissection
Renal-sparing surgery may be considered for carefully selected patients with low-volume localized disease. In two small series, patients who had partial nephrectomies seemed to have outcomes equivalent to those who had radical nephrectomies.[32,45]
As with adult RCC, there is no standard treatment for unresectable metastatic disease in children. The response to radiation is poor, and chemotherapy is not effective. Immunotherapy with such agents as interferon-alpha and interleukin-2 may have some effect on cancer control.[46,47] Spontaneous regression of pulmonary metastasis rarely occurs with resection of the primary tumor.
Several targeted therapies (e.g., sorafenib, sunitinib, bevacizumab, temsirolimus, pazopanib, axitinib, and everolimus) have been approved for use in adults with RCC; however, these agents have not been tested in pediatric patients with RCC. Case reports of pediatric and adolescent patients with TFE3 translocation–positive RCC suggest responsiveness to multiple tyrosine kinase inhibitors.[29,48,49] Disease regression and improvement in symptoms have been reported with the use of cabozantinib in pediatric patients with translocation-positive RCC expressing MET. Any RCC that is positive for TFE3 and lacks a translocation should be tested for ALK expression and translocation. Recognition of this subtype may lead to consideration of ALK inhibitor therapy.
(Refer to the PDQ summary on adult Renal Cell Cancer Treatment for more information about the use of targeted therapies.)
Treatment Options Under Clinical Evaluation for RCC
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
General Information About Rhabdoid Tumors of the Kidney
Rhabdoid tumors are extremely aggressive malignancies that generally occur in infants and young children. The most common locations are the kidney (termed malignant rhabdoid tumors) and the central nervous system (CNS) (atypical teratoid/rhabdoid tumor), although rhabdoid tumors can also arise in most soft tissue sites. (Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for information about the treatment of CNS disease.) Relapses occur early (median time from diagnosis, 8 months).[1,2]
A distinct clinical presentation that suggests a diagnosis of rhabdoid tumor of the kidney includes the following:
(Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)
Approximately two-thirds of patients will present with advanced-stage disease. Bilateral cases have been reported. Rhabdoid tumors of the kidney tend to metastasize to the lungs and the brain. As many as 10% to 15% of patients with rhabdoid tumors of the kidney also have CNS lesions. The staging system used for rhabdoid tumor of the kidney is the same system used for Wilms tumor. (Refer to the Stage Information for Wilms Tumor section of this summary for more information.)
Histologically, the most distinctive features of rhabdoid tumors of the kidney are rather large cells with large vesicular nuclei, a prominent single nucleolus, and in some cells, the presence of globular eosinophilic cytoplasmic inclusions.
Genomics of Rhabdoid Tumors of the Kidney
Rhabdoid tumors in all anatomical locations have a common genetic abnormality—loss of function of the SMARCB1 (INI1/SNF5/BAF47) gene located at chromosome 22q11.2. The following text refers to rhabdoid tumors without regard to their primary site. SMARCB1 encodes a component of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex that has an important role in controlling gene transcription.[5,6] Loss of function occurs by deletions that lead to loss of part or all of the SMARCB1 gene and by mutations that are commonly frameshift or nonsense mutations that lead to premature truncation of the SMARCB1 protein.[6,7] A small percentage of rhabdoid tumors are caused by alterations in SMARCA4, which is the primary ATPase in the SWI/SNF complex.[8,9] Exome sequencing of 35 cases of rhabdoid tumor identified a very low mutation rate, with no genes having recurring mutations other than SMARCB1, which appeared to contribute to tumorigenesis.
Germline mutations of SMARCB1 have been documented in patients with one or more primary tumors of the brain and/or kidney, consistent with a genetic predisposition to the development of rhabdoid tumors.[11,12] Approximately one-third of patients with rhabdoid tumors have germline SMARCB1 alterations.[6,13] In most cases, the mutations are de novo and not inherited. The median age at diagnosis of children with rhabdoid tumors and a germline mutation or deletion is younger (6 months) than that of children with apparently sporadic disease (18 months). Germline mosaicism has been suggested for several families with multiple affected siblings. It appears that patients with germline mutations may have the worst prognosis.[15,16] Germline mutations in SMARCA4 have also been reported in patients with rhabdoid tumors.[8,17]
Rhabdoid Tumor Predisposition Syndrome
Early-onset, multifocal disease and familial cases strongly support the possibility of a rhabdoid tumor predisposition syndrome. This has been confirmed by the presence of germline mutations of SMARCB1 in rare familial cases and in a subset of patients with apparently sporadic rhabdoid tumors. These cases have been labeled as rhabdoid tumor predisposition syndrome, type 1. Thirty-five patients (N = 100) with rhabdoid tumors of the brain, kidney, or soft tissues were found to have a germline SMARCB1 abnormality. These abnormalities included point and frameshift mutations, intragenic deletions and duplications, and larger deletions. Nine cases demonstrated parent-to-child transmission of a mutated copy of SMARCB1. In eight of the nine cases, one or more family members were also diagnosed with rhabdoid tumor or schwannoma; two of the eight families presented with multiple affected children, consistent with gonadal mosaicism.
Two cases of inactivating mutations in the SMARCA4 gene have been found in three children from two unrelated families, establishing the phenotypically similar syndrome now known as rhabdoid tumor predisposition syndrome, type 2.[8,9] In these cases, SMARCA4 behaves as a classical tumor suppressor, with one deleterious mutation inherited in the germline and the other acquired in the tumor. Another report describes an autosomal dominant pattern of inheritance discovered through an exome sequencing project.
Genetic Testing and Surveillance of Rhabdoid Tumors of the Kidney
Germline analysis is suggested for individuals of all ages with rhabdoid tumors. Genetic counseling is also part of the treatment plan, given the low-but-actual risk of familial recurrence. In cases of mutations, parental screening should be considered, although such screening carries a low probability of positivity. Prenatal diagnosis can be performed in situations in which a specific SMARCB1 mutation or deletion has been documented in the family.
To date, there is little evidence regarding the effectiveness of surveillance for patients with rhabdoid tumor predisposition syndrome, type 1 caused by loss-of-function germline SMARCB1 mutations. However, because of the aggressive nature of the tumors with significant lethality and young age of onset in SMARCB1 carriers with truncating mutations, consensus recommendations have been developed. These recommendations were developed by a group of pediatric cancer genetic experts (including oncologists, radiologists, and geneticists). They have not been formally studied to confirm the benefit of monitoring patients with germline SMARCB1 mutations. Given the potential survival benefit of surgically resectable disease, it is postulated that early detection might improve overall survival (OS).[19,20,21]
Surveillance for patients with germline SMARCB1 mutations includes the following:
Prognosis and Prognostic Factors for Rhabdoid Tumors of the Kidney
Patients with rhabdoid tumors of the kidney continue to have a poor prognosis. In a review of 142 patients from the National Wilms Tumor Studies (NWTS) (NWTS-1, NWTS-2, NWTS-3, NWTS-4, and NWTS-5 [COG-Q9401/NCT00002611]), age and stage were identified as important prognostic factors:
Treatment of Rhabdoid Tumor of the Kidney
Because of the relative rarity of this tumor, all patients with rhabdoid tumor of the kidney should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) with experience treating renal tumors is required to determine and implement optimal treatment.
There is no standard treatment option for rhabdoid tumor of the kidney.
The following results have been observed in studies of rhabdoid tumor of the kidney:
Treatment Options Under Clinical Evaluation for Rhabdoid Tumors of the Kidney
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
General Information About Clear Cell Sarcoma of the Kidney
Clear cell sarcoma of the kidney is not a Wilms tumor variant, but it is an important primary renal tumor associated with a higher rate of relapse and death than is favorable histology (FH) Wilms tumor. The classic pattern of clear cell sarcoma of the kidney is defined by nests or cords of cells separated by regularly spaced fibrovascular septa. In addition to pulmonary metastases, clear cell sarcoma also spreads to bone, brain, and soft tissue. (Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)
Younger age and stage IV disease have been identified as adverse prognostic factors for event-free survival (EFS).
Historically, relapses have occurred in long intervals after the completion of chemotherapy (up to 14 years); however, with current therapy, relapses after 3 years are uncommon. The brain is a frequent site of recurrent disease, suggesting that it is a sanctuary site for cells that are protected from the intensive chemotherapy that patients currently receive.[2,3,4,5] An awareness of the clinical signs of recurrent disease in the brain is important during regular follow-up. There are no standard recommendations for the frequency of brain imaging during follow-up.
Genomics of Clear Cell Sarcoma of the Kidney
Clear cell sarcoma of the kidney is an uncommon renal tumor that comprises approximately 5% of all primary renal malignancies in children, accounts for approximately 20 new cases per year in the United States, and is observed most often before age 3 years. The molecular background of clear cell sarcoma of the kidney is poorly understood because of its rarity and lack of experimental models.
Several biological features of clear cell sarcoma of the kidney have been described, including the following:
Treatment of Clear Cell Sarcoma of the Kidney
Because of the relative rarity of this tumor, all patients with clear cell sarcoma of the kidney should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) with experience treating renal tumors is required to determine and implement optimal treatment.
The approach for treating clear cell sarcoma of the kidney is different from the approach for treating Wilms tumor because the overall survival (OS) of children with clear cell sarcoma of the kidney remains lower than that for patients with FH Wilms tumor. All patients undergo postoperative radiation to the tumor bed and receive doxorubicin as part of their chemotherapy regimen.
The standard treatment option for clear cell sarcoma of the kidney is the following:
Surgery, chemotherapy, and radiation therapy
Evidence (surgery, chemotherapy, and radiation therapy):
(Refer to the Treatment of Recurrent Clear Cell Sarcoma of the Kidney section of this summary for information about recurrent disease.)
General Information About Congenital Mesoblastic Nephroma
Mesoblastic nephroma comprises about 5% of childhood kidney tumors, and more than 90% of cases appear within the first year of life. More than 15% of the cases are detected prenatally. It is the most common kidney tumor found in infants younger than 6 months. The median age of diagnosis is 1 to 2 months. Twice as many males as females are diagnosed. The diagnosis should be questioned when applied to individuals older than 2 years.
When patients are diagnosed in the first 7 months of life, the 5-year event-free survival rate is 94%, and the overall survival (OS) rate is 96%. In a report from the United Kingdom of 50 children with mesoblastic nephroma studied on clinical trials and 80 cases from the national registry in the same time period, there were no deaths. However, in a comprehensive review of the literature, 12 deaths were reported; of these 12 deaths, 7 were from surgical complications in infants.[Level of evidence: 3iiiDii]
Grossly, mesoblastic nephromas appear as solitary, unilateral masses indistinguishable from nephroblastoma. Microscopically, they consist of spindled mesenchymal cells. Mesoblastic nephroma can be divided into the following three histologic subtypes:
A frequent genetic alteration is the translocation t(12;15)(q13;q25), resulting in a fusion of the ETV6 and NTRK3 genes on 15p15 that occurs almost exclusively in the cellular type of mesoblastic nephroma. In a cohort of 79 mesoblastic nephromas analyzed for the translocation, all classical (n = 38) and mixed (n = 12) mesoblastic nephromas were translocation negative. The same translocation was initially described in infantile fibrosarcoma, and besides the similar morphologic appearance, cases of cellular mesoblastic nephroma and infantile fibrosarcoma share other genetic changes such as gains of chromosome 11.
The risk of recurrence for patients with mesoblastic nephroma is closely associated with the presence of a cellular subtype and with stage III disease. In an International Society of Pediatric Oncology (SIOP) series of 79 patients with congenital mesoblastic nephromas, patients within the cellular subgroup who had translocation-positive tumors had a significantly superior relapse-free survival (RFS) rate when compared with patients who did not have the gene fusion (100% vs. 73%, respectively).
(Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)
Treatment of Congenital Mesoblastic Nephroma
The OS of patients with congenital mesoblastic nephroma is excellent; however, reported causes of death in about one-half of the cases are treatment related, and most of these patients were very young (median age, <1 year). This underscores the special attention that infants with renal tumors require, with respect to timing and type of treatment and the importance of a dedicated expert pediatric oncology setting.
Standard treatment options for stages I and II (80% of patients) and stage III (classic and mixed subtypes) congenital mesoblastic nephroma include the following:
Treatment options for stage III (cellular subtype) congenital mesoblastic nephroma include the following:
Adjuvant chemotherapy has been recommended for patients with stage III cellular subtype mesoblastic nephromas who are aged 3 months or older at diagnosis. In a study of stage III cellular type congenital mesoblastic nephroma, 7 of 12 patients who were treated with surgery only suffered from a relapse, while 4 of 14 patients who were treated with adjuvant chemotherapy (primarily dactinomycin/vincristine and sometimes doxorubicin) developed a relapse.[1,5,10] Cyclophosphamide and ifosfamide have been combined with these agents and have shown activity.
Infants younger than 2 months with incompletely resected, stage III disease may not need chemotherapy.
(Refer to the Treatment of Recurrent Congenital Mesoblastic Nephroma section of this summary for information about recurrent disease.)
Treatment options under clinical evaluation for congenital mesoblastic nephroma
General Information About Ewing Sarcoma of the Kidney
Ewing sarcoma (previously known as neuroepithelial tumor) of the kidney is extremely rare and demonstrates a unique proclivity for young adults. It is a highly aggressive neoplasm, more often presenting with large tumors and penetration of the renal capsule, extension into the renal vein, and in 40% of cases, evidence of metastases.[1,2,3]
Ewing sarcoma of the kidney is characterized by CD99 (MIC-2) positivity and the detection of EWS/FLI-1 fusion transcripts. In Ewing sarcoma of the kidney, focal, atypical histologic features have been seen, including clear cell sarcoma, rhabdoid tumor, malignant peripheral nerve sheath tumors, and paraganglioma.[1,4] (Refer to the PDQ summary on Ewing Sarcoma Treatment for more information.)
Treatment of Ewing Sarcoma of the Kidney
There is no standard treatment option for Ewing sarcoma of the kidney. However, treatment with chemotherapy and radiation therapy and an aggressive surgical approach seem to be associated with a better outcome than previously reported. Consideration should also be given to substituting cyclophosphamide for ifosfamide in patients after they have undergone a nephrectomy. [2,3]
Treatment according to Ewing sarcoma protocols should be considered.
General Information About Primary Renal Myoepithelial Carcinoma
Myoepithelial carcinomas are aggressive malignancies primarily affecting soft tissues with occasional visceral origin. Approximately 20% of all reported cases have been described in children and are associated with a particularly unfavorable outcome, frequent development of metastases, and short overall survival.
Two cases of primary renal myoepithelial carcinoma have occurred in children, and both cases had a translocation involving EWSR1 and the novel fusion partner KLF15, a transcription factor uniquely functioning within the kidney. Helpful features to establish the diagnosis include coexpression of cytokeratins, S-100, and smooth muscle markers, and the documentation of EWSR1 rearrangements.
Treatment of Primary Renal Myoepithelial Carcinoma
Although no standard therapy has been established, surgical resection of the primary tumor and pulmonary nodules (if present) has been used in addition to chemotherapy and radiation therapy.
General Information About Cystic Partially Differentiated Nephroblastoma
Cystic partially differentiated nephroblastoma is a rare cystic variant of Wilms tumor (1%), with unique pathologic and clinical characteristics. It is composed entirely of cysts, and their thin septa are the only solid portion of the tumor. The septa contain blastemal cells in any amount with or without embryonal stromal or epithelial cell type. Several pathologic features distinguish this neoplasm from standard Wilms tumor. DICER1 mutations have not been reported in cystic partially differentiated nephroblastoma, which supports a distinction between multilocular cystic nephromas and cystic partially differentiated nephroblastoma.
Recurrence has been reported after tumor spillage during surgery.[Level of evidence: 3iiiA]
Treatment of Cystic Partially Differentiated Nephroblastoma
Standard treatment options for cystic partially differentiated nephroblastoma include the following:
General Information About Multilocular Cystic Nephroma
Multilocular cystic nephromas are uncommon benign lesions consisting of cysts lined by renal epithelium. They are characterized by a bimodal age distribution, affecting either infants/young children or adult females. These lesions can occur bilaterally, and a familial pattern has been reported.
Multilocular cystic nephroma has been associated with pleuropulmonary blastoma and the DICER1 mutation. Anaplastic sarcoma of the kidney has also been associated with the DICER1 mutation. This is in contrast to adult cystic nephromas, which lack DICER1 mutations, and supports the difference between adult and pediatric cases. Genetic counseling, DICER1 mutation testing, and screening for lung lesions of a solid or cystic nature should be considered.[2,3,4,5]
Treatment of Multilocular Cystic Nephroma
The standard treatment option for multilocular cystic nephroma is surgery.
General Information About Primary Renal Synovial Sarcoma
Primary renal synovial sarcoma is a subset of embryonal sarcoma of the kidney and is characterized by the t(x;18)(p11;q11) SS18-SSX translocation. It is similar in histology to the monophasic spindle cell synovial sarcoma and is considered an aggressive tumor with adverse patient outcomes in more than 50% of cases (n = 16). A second alternative gene fusion variant, SS18-NEDD4, has been identified in a primary renal synovial sarcoma. Primary renal synovial sarcoma contains cystic structures derived from dilated, trapped renal tubules. Primary renal synovial sarcoma occurs more often in young adults.
Treatment of Primary Renal Synovial Sarcoma
The standard treatment option for primary renal synovial sarcoma is chemotherapy. The chemotherapy regimens used for primary renal synovial sarcoma differ from those traditionally used for Wilms tumor.
General Information About Anaplastic Sarcoma of the Kidney
Anaplastic sarcoma of the kidney is a rare renal tumor that has been identified mainly in patients younger than 15 years.
Patients present with a renal mass, with the most common sites of metastases being the lungs, liver, and bones. (Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)
Cytogenetic abnormalities such as rearrangement between 10q21 and 18p11.2 have been reported. These tumors show pathologic features similar to those of pleuropulmonary blastoma of childhood (refer to the PDQ summary on Childhood Pleuropulmonary Blastoma Treatment for more information) and undifferentiated embryonal sarcoma of the liver (refer to the Treatment Options for Undifferentiated Embryonal Sarcoma of the Liver section in the PDQ summary on Childhood Liver Cancer Treatment for more information). Because of the relationship between pleuropulmonary blastoma and renal sarcomas, genetic counseling and testing for a germline DICER1 mutation should be considered. Screening for lung lesions of a solid or cystic nature should also be considered on the basis of age and DICER1 mutation testing.
Treatment of Anaplastic Sarcoma of the Kidney
There is no standard treatment option for anaplastic sarcoma of the kidney. In the past, these tumors have been identified as anaplastic Wilms tumor and treated accordingly.
General Information About Nephroblastomatosis (Diffuse Hyperplastic Perilobar Nephroblastomatosis)
Some multifocal nephrogenic rests may become hyperplastic, which may produce a thick rind of blastemal or tubular cells that enlarge the kidney. Radiological studies may be helpful in making the difficult distinction between diffuse hyperplastic perilobar nephroblastomatosis and Wilms tumor. On magnetic resonance imaging, nephrogenic rests appear homogeneous and hypointense with contrast, whereas Wilms tumor has mixed echogenicity and inhomogeneous appearance. Incisional biopsies are difficult to interpret, and it is essential that the biopsy includes the juncture between the lesion and surrounding renal parenchyma. Differentiation may occur after chemotherapy is administered.
Treatment of Nephroblastomatosis (Diffuse Hyperplastic Perilobar Nephroblastomatosis)
Treatment options for diffuse hyperplastic perilobar nephroblastomatosis include the following:
Evidence (preoperative chemotherapy and surgery):
On the basis of this report, it is recommended that patients with diffuse hyperplastic perilobar nephroblastomatosis are monitored by imaging at a maximum interval of 3 months, for a minimum of 7 years; complete resection of growing lesions should be strongly considered because of this high incidence of anaplasia after chemotherapy.
Patients with recurrent rhabdoid tumor of the kidney, clear cell sarcoma of the kidney, neuroepithelial tumor of the kidney, and renal cell carcinoma should be considered for treatment on available phase I and phase II clinical trials.
Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.
Table 9 describes the treatment options for recurrent childhood kidney tumors.
Prognosis, Prognostic Factors, and Risk Categories for Recurrent Wilms Tumor
Approximately 15% of patients with favorable histology (FH) Wilms tumor and 50% of patients with anaplastic histology Wilms tumor experience recurrence. The most common site of relapse is lung, followed by abdomen/flank and liver. Recurrence in the brain (0.5%) or bone is rare in children with Wilms tumor.[2,3] Historically, the salvage rate for patients with recurrent FH Wilms tumor was 25% to 40%. As a result of modern treatment combinations, the outcome after recurrence has improved up to 60%.[4,5]
A number of potential prognostic features influencing postrecurrence outcome have been analyzed, but it is difficult to determine whether these factors are independent of each other. Also, the following prognostic factors appear to be changing as therapy for primary and recurrent Wilms tumor evolves:
The National Wilms Tumor Study (NWTS)-5 trial (NWTS-5 [COG-Q9401/NCT00002611]) showed that time to recurrence and site of recurrence are no longer prognostically significant.[4,7] However, in an International Society of Pediatric Oncology (SIOP) study, patients who experienced a pulmonary relapse within 12 months of diagnosis had a poorer prognosis (5-year overall survival [OS] rate, 47%) than did patients who experienced a pulmonary relapse 12 months or more after diagnosis (5-year OS rate, 75%).
On the basis of these results, the following three risk categories have been identified:
Treatment of Standard-Risk Relapsed Wilms Tumor
In children who had small stage I Wilms tumor and were treated with surgery alone, the EFS rate was 84%. All but one child who relapsed was salvaged with treatment tailored to the site of recurrence.[7,10]
Successful retreatment can be accomplished for Wilms tumor patients whose initial therapy consisted of immediate nephrectomy followed by chemotherapy with vincristine and dactinomycin and who relapse.
Treatment options for standard-risk relapsed Wilms tumor include the following:
Surgery, radiation therapy, and chemotherapy
Evidence (surgery, radiation therapy, and chemotherapy):
Treatment of High-Risk and Very High-Risk Relapsed Wilms Tumor
Treatment options for high-risk and very high-risk relapsed Wilms tumor include the following:
Chemotherapy, surgery, and/or radiation therapy
Evidence (chemotherapy, surgery, and/or radiation therapy):
Patients with stage II, stage III, and stage IV anaplastic tumors at diagnosis have a very poor prognosis upon recurrence. The combination of ifosfamide, etoposide, and carboplatin demonstrated activity in this group of patients, but significant hematologic toxic effects have been observed.
High-dose chemotherapy followed by autologous HSCT has been utilized for recurrent high-risk patients.[12,13]; [Level of evidence: 3ii]
No randomized trials of chemotherapy versus transplant have been reported, and case series suffer from selection bias.
Patients in whom such salvage attempts fail should be offered treatment on available phase I or phase II studies.
Treatment Options Under Clinical Evaluation for Recurrent Wilms Tumor
Treatment of Recurrent Clear Cell Sarcoma of the Kidney
Clear cell sarcoma of the kidney has been characterized by late relapses. However, in trials after 1992, most relapses occurred within 3 years, and the most common sites of recurrence were the brain and the lungs.[16,17] In a series of 37 patients with clear cell sarcoma of the kidney who relapsed, the 5-year EFS rate after relapse was 18%, and the OS rate after relapse was 26%.
The optimal treatment of relapsed clear cell sarcoma of the kidney has not been established. Treatment of patients with recurrent clear cell sarcoma of the kidney depends on initial therapy and site of recurrence.
Treatment options for recurrent clear cell sarcoma of the kidney include the following:
Cyclophosphamide and carboplatin should be considered if not used initially. Patients with recurrent clear cell sarcoma of the kidney, in some cases involving the brain, have responded to treatment with ifosfamide, carboplatin, and etoposide (ICE) coupled with local control consisting of surgical resection, radiation therapy, or both.; [Level of evidence: 2A]
The use of high-dose chemotherapy followed by HSCT is undefined in patients with recurrent clear cell sarcoma of the kidney. A total of 24 patients with relapsed clear cell sarcoma of the kidney received high-dose chemotherapy followed by autologous HSCT. Of those patients, 12 (50%) were alive without disease after a median of 52 months. It should be noted that patients who had already achieved a second complete remission were more likely to receive high-dose chemotherapy.[13,17,18]
Treatment options under clinical evaluation for recurrent clear cell sarcoma of the kidney
Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
Treatment of Recurrent Congenital Mesoblastic Nephroma
Relapses were reported in 4% of patients with congenital mesoblastic nephroma, and all relapses occurred within 12 months after diagnosis. Most relapses occur locally, although metastatic relapses have been reported. About 70% of patients who relapsed survived with individualized treatment comprising combinations of surgery, chemotherapy, and radiation therapy.
Targeted therapy should be considered for patients with recurrent or refractory disease containing the ETV6-NTRK3 fusion. Larotrectinib and entrectinib are NTRK inhibitors that are approved for adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, who are either metastatic or when surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed after treatment.[20,21]
Treatment options under clinical evaluation for recurrent congenital mesoblastic nephroma
The cellular subtype of congenital mesoblastic nephroma, which commonly harbors the ETV6-NTRK3 fusion, is associated with relapsed disease. Patients should consider enrolling on this trial because one of the treatment arms (APEC1621A [NCT03213704]) uses larotrectinib, which inhibits NTRK fusions.
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer need to be referred to medical centers that have multidisciplinary teams of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials under the auspices of cooperative groups such as the Children's Oncology Group (COG) and the International Society of Pediatric Oncology (SIOP). Information about ongoing clinical trials is available from the NCI website.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Revised Table 2 to include the descriptions of regimen UH1 and regimen UH2 (cited Daw et al. as reference 220).
Revised text about the radiation doses used by the Children's Oncology Group (COG). Also added text to state that the radiation therapy regimen used in the COG AREN0321 trial remains the current standard of treatment.
Added text about the radiation therapy approach used by the International Society of Pediatric Oncology (SIOP).
Added text about the results of the COG study that reported the outcome for patients of all ages with stage I favorable-histology Wilms tumors showing epithelial-predominant histology (cited Parsons et al. as reference 228 and level of evidence 3iiiA).
Revised Table 5 to include the outcome results for patients with stage II diffuse anaplastic Wilms tumors in the COG AREN0321 study.
Revised Table 6 to include the outcome results for patients with stage III diffuse anaplastic Wilms tumors in the COG AREN0321 study.
Revised Table 7 to include the outcome results for patients with stage IV diffuse anaplastic Wilms tumors in the COG AREN0321 study.
Added text about the results of the AREN0321 study that tested the combination of vincristine and irinotecan in an upfront window for patients with diffuse anaplastic Wilms tumor and measurable disease (added level of evidence 3iiiDii).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of Wilms tumor and other childhood kidney tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Wilms Tumor and Other Childhood Kidney Tumors Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Wilms Tumor and Other Childhood Kidney Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/kidney/hp/wilms-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389282]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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Last Revised: 2020-06-08
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Raleigh, NC 27607
901 Ridgefield Drive
Raleigh, NC 27609
934 Vandora Springs Road
Garner, NC 27529
1505 SW Cary Parkway
Cary, NC 27511
501 Health Park Drive
Garner, NC 27529