References

1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PMC free article: PMC4136455] [PubMed: 24853691]
2. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed August 23, 2024.
3. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed September 5, 2024.
4. Ahmed HU, Arya M, Levitt G, et al.: Part I: Primary malignant non-Wilms' renal tumours in children. Lancet Oncol 8 (8): 730-7, 2007. [PubMed: 17679083]
5. Ahmed HU, Arya M, Levitt G, et al.: Part II: Treatment of primary malignant non-Wilms' renal tumours in children. Lancet Oncol 8 (9): 842-8, 2007. [PubMed: 17765193]

Incidence of Wilms Tumor

Wilms tumor is the most frequent tumor of the kidney in infants and children. The incidence of Wilms tumor is 10.4 cases for every 1 million children younger than 15 years, and 0.2 cases per 10,000 infants.[1,2] Approximately 650 cases of Wilms tumor are diagnosed in the United States each year. The incidence is substantially lower in Asian people.[1,3]

The male to female ratio in unilateral cases of Wilms tumor is 0.92 to 1.00, but in bilateral cases, there is a female excess (0.60). The mean age at diagnosis is 44 months in unilateral cases and 31 months in bilateral cases of Wilms tumor.[4,5] About 10% of children with Wilms tumor have an associated congenital malformation syndrome.[6]

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.[6,7] In patients with congenital anomalies and Wilms tumor, nephrogenic rests have been reported in 60% of cases.[8] 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.[9]

Children with Wilms tumor may have associated hemihypertrophy 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 (see Table 1). Overgrowth syndromes and conditions are the result of excessive prenatal and postnatal somatic growth.[10,11]

It is important to recognize that the absolute risk of developing Wilms tumor varies with the underlying condition or anomaly. For example, most patients with hemihypertrophy will not develop Wilms tumor.

For information about the genes associated with Wilms tumor, including WT1 and WT2, see the Genomics of Wilms Tumor section.

Genomics of Wilms Tumor

Molecular Features of Wilms Tumor

A Wilms tumor may arise during embryogenesis on the background of an otherwise genomically normal kidney, or it may arise from nongermline somatic genetic precursor lesions residing in histologically and functionally normal kidney tissue. Hypermethylation of H19, a known component of a subset of Wilms tumors, is a very common genetic abnormality found in these normal-appearing areas of precursor lesions.[69]

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.[70] The tumors were selected for either favorable histology (FH) Wilms that had relapsed or those with diffuse anaplasia. The study showed the following:[70]

• Wilms tumors commonly arise through more than one genetic event.
• Wilms tumors show differences in gene expression and methylation patterns with different genetic aberrations.
• Wilms tumors have a large number of candidate driver genes, most of which are altered in less than 5% of Wilms tumors.
• Wilms tumors have recurrent variants in genes with common functions, with most involved in either early renal development or epigenetic regulation (e.g., chromatin modifications, transcription elongation, and miRNA).

Approximately one-third of Wilms tumor cases involve variants in WT1, CTNNB1, or AMER1 (WTX).[71,72] Another subset of Wilms tumor cases results from variants in miRNA processing genes (miRNAPG), including DROSHA, DGCR8, DICER1, and XPO5.[73-76] Other genes critical for early renal development that are recurrently altered in Wilms tumor include SIX1 and SIX2 (transcription factors that play key roles in early renal development),[73,74] EP300, CREBBP, and MYCN.[70] Of the variants 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.[70] Anaplastic Wilms tumor is characterized by the presence of TP53 variants.

Elevated rates of Wilms tumor are observed in patients with a number of genetic disorders, including WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and range of developmental delays) syndrome (WAGR spectrum), Beckwith-Wiedemann syndrome, hemihypertrophy, Denys-Drash syndrome, and Perlman syndrome.[77] Other genetic causes that have been observed in familial Wilms tumor cases include germline variants in REST and CTR9.[58,78]

The genomic and genetic characteristics of Wilms tumor are summarized below.

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:

• 1q. Gain of chromosome 1q is associated with an inferior outcome and is the single most powerful predictor of outcome.[107,108] Gain of chromosome 1q is one of the most common cytogenetic abnormalities in Wilms tumor and is observed in approximately 30% of tumors.
  In an analysis of FH Wilms tumor from 1,114 patients from NWTS-5 (COG-Q9401/NCT00002611), 28% of the tumors displayed 1q gain.[107]

  • The 8-year event-free survival (EFS) rate was 77% for patients with 1q gain and 90% for those lacking 1q gain (P < .001). Within each disease stage, 1q gain was associated with inferior EFS.
  • The 8-year overall survival (OS) rate was 88% for those with 1q gain and 96% for those lacking 1q gain (P < .001). OS was significantly inferior in cases with stage I disease (P < .0015) and stage IV disease (P = .011).
  • Similar results were reported in the International Society of Paediatric Oncology (SIOP) WT 2001 study of 586 children with Wilms tumor.[108]
  One study included a cohort of FH Wilms tumor that was enriched for patients who relapsed. The study found that the prevalence of 1q gain was higher in the relapsed Wilms tumor specimens (75%) than in the matched primary samples (47%).[109] The increased prevalence of 1q gain at relapse supports its association with poor prognosis and disease progression.
• 16q and 1p. Additional tumor-suppressor or tumor-progression genes may lie on chromosomes 16q and 1p, as evidenced by LOH for these regions in 17% and 11% of Wilms tumor cases, respectively.[110]

  -

  In large NWTS studies, patients with tumor-specific loss of these loci had significantly worse relapse-free survival and OS rates. Combined loss of 1p and 16q are criteria used to select FH Wilms tumor patients for more aggressive therapy in the current Children's Oncology Group (COG) study. However, a U.K. study of more than 400 patients found no significant association between 1p deletion and poor prognosis, but a poor prognosis was associated with 16q LOH.[111]

  -

  An Italian study of 125 patients, using treatment quite similar to that in the COG study, found significantly worse prognosis in those with 1p deletions but not 16q deletions.[112]

  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.[107] 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.[113]
• miRNAPG. Variants in selected miRNAPG are observed in approximately 20% of Wilms tumor cases and appear to perpetuate the progenitor state.[70,73-76] The products of these genes direct the maturation of miRNAs from the initial pre-miRNA transcripts to functional cytoplasmic miRNAs (see Figure 1).[114] The most commonly altered miRNAPG is DROSHA, with a recurrent variant (E1147K) affecting a metal-binding residue of the RNase IIIb domain, representing about 80% of DROSHA-altered tumors. Other miRNAPG that are altered in Wilms tumor include DGCR8, DICER1, TARBP2, DIS3L2, and XPO5. These variants are generally mutually exclusive, and they appear to be deleterious and result in impaired expression of tumor-suppressing miRNAs. A striking sex bias was noted for patients with variants in DGCR8 (located on chromosome 22q11), with 38 of 43 cases (88%) arising in girls.[73,74]
  Germline variants in miRNAPG are observed for DICER1 and DIS3L2, with variants in the former causing DICER1 syndrome and variants in the latter causing Perlman syndrome.

  • DICER1 syndrome is typically caused by inherited truncating variants in DICER1, with tumor formation following acquisition of a missense variant in a domain of the remaining allele of DICER1 (the RNase IIIb domain) responsible for processing miRNAs derived from the 5p arms of pre-miRNAs.[115] Tumors associated with DICER1 syndrome include pleuropulmonary blastoma, cystic nephroma, ovarian sex cord–stromal tumors, multinodular goiter, and embryonal rhabdomyosarcoma.[115] Wilms tumor is an uncommon presentation of the DICER1 syndrome. In one study, three families with DICER1 syndrome included children with Wilms tumor, with two of the Wilms tumor cases showing the typical second DICER1 variant in the RNase IIIb domain.[116] Another study identified DICER1 variants in 2 of 48 familial Wilms tumor families.[117] Large sequencing studies of Wilms tumor cohorts have also observed occasional cases with DICER1 variants.[74,75]
  • Perlman syndrome is a rare autosomal recessive overgrowth disorder caused by variants in DIS3L2, which encodes a ribonuclease that is responsible for degrading pre-let-7 miRNA.[39,118] Heterozygous DIS3L2 germline inactivations are also associated with Wilms tumor development.[36] Patients with Perlman syndrome have a poor prognosis, with a high neonatal mortality rate. In a survey of published cases of Perlman syndrome (N = 28), in infants who survived beyond the neonatal period, approximately two-thirds developed Wilms tumor, and all patients showed developmental delay. Fetal macrosomia, ascites, and polyhydramnios are frequent manifestations.[119]
    

    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/.

• SIX1 and SIX2. SIX1 and SIX2 are highly homologous transcription factors that play key roles in early renal development and are expressed in the metanephric mesenchyme, where they maintain the mesenchymal progenitor population. In patients with Wilms tumors, the frequency of SIX1 variants is 3% to 4%, and the frequency of SIX2 variants is 1% to 3%.[73,74]

  • Virtually all SIX1 and SIX2 variants are in exon 1 and result in a glutamine-to-arginine variant at position 177 (Q177R).
  • Variants in WT1, AMER1, and CTNNB1 are infrequent in cases with SIX1, SIX2, or miRNAPG variants. Conversely, SIX1 or SIX2 variants and miRNAPG variants tend to occur together.
  • In Wilms tumor, SIX1 and SIX2 variants are associated with the high-risk blastemal subtype and the presence of undifferentiated blastema in chemotherapy-naïve samples.
  • In a study of 82 cases of FH Wilms tumor, SIX1 Q177R hotspot variants were identified at a higher rate in tumor specimens at relapse (11 cases; 13.4%) than in those at diagnosis (4%). For 45 cases that had both diagnostic and relapse specimens, there were 6 cases with SIX1 Q177R at relapse, 3 of which did not have SIX1 Q177R at diagnosis. This finding suggests that this variant is not required for tumor development in some individuals with Wilms tumor.[109]

  MLLT1. Approximately 4% of Wilms tumor cases have variants in the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation by RNA polymerase II during early development.[86] The altered MLLT1 protein shows altered binding to acetylated histone tails. Patients with MLLT1-altered tumors present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests, supporting a model whereby activating MLLT1 variants early in renal development result in the development of Wilms tumor.
• TP53 (tumor suppressor gene). Most anaplastic Wilms tumor cases show variants in the TP53 tumor suppressor gene.[120-122] TP53 may be useful as an unfavorable prognostic marker.[120,121]
  In a study of 118 prospectively identified patients with diffuse anaplastic Wilms tumor registered on the NWTS-5 trial, 57 patients (48%) demonstrated TP53 variants, 13 patients (11%) demonstrated TP53 segmental copy number loss without variants, and 48 patients (41%) lacked both (wild-type TP53 [wtTP53]). All TP53 variants 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). The TP53 status had no effect on patients with stage I or stage II tumors.[123]

  • 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.[123]
• FBXW7. FBXW7, a ubiquitin ligase component, is an established tumor suppressor gene that has been identified as recurrently altered at low rates in Wilms tumor and other malignancies. Variants of this gene have been associated with epithelial-type tumor histology.[124]; [125][Level of evidence C1]
• TRIM28. TRIM28 encodes a multidomain protein involved in the regulation of many cellular processes and is an autosomal dominant Wilms tumor predisposition gene. TRIM28 accounts for about 8% of familial Wilms tumor and 2% of unselected Wilms tumor.[55,126-128]; [125][Level of evidence C1]

  • A strong association between TRIM28 variants and epithelial Wilms tumor has been observed, and most individuals with a TRIM28 variant have a Wilms tumor of predominantly epithelial histology.[55,126,127]; [125][Level of evidence C1]
  • In a cohort of 91 affected individuals from 49 families with Wilms tumor pedigrees, 33 individuals were identified as having constitutional cancer-predisposing variants, 21 of whom had a variant in TRIM28. There was a strong parent-of-origin effect, with all ten evaluable cases having inherited variants that were maternally transmitted.[125][Level of evidence C1]
  • Most TRIM28-altered cases have either frameshift, nonsense, or splice-site variants in one allele combined with LOH in the second allele, leading to loss of TRIM28 protein expression in the tumor. Immunohistochemistry staining for loss of TRIM28 protein expression can be used to identify most patients whose tumors have TRIM28 variants.[128]
• 9q22.3 microdeletion syndrome. Patients with 9q22.3 microdeletion syndrome have an increased risk of Wilms tumor.[43] The chromosomal region with germline deletion includes PTCH1, the gene that is altered in Gorlin syndrome (nevoid basal cell carcinoma syndrome associated with osteosarcoma). 9q22.3 microdeletion syndrome is characterized by the clinical findings of Gorlin syndrome, as well as developmental delay and/or intellectual disability, metopic craniosynostosis, obstructive hydrocephalus, prenatal and postnatal macrosomia, and seizures. Five patients who presented with Wilms tumor in the context of a constitutional 9q22.3 microdeletion have been reported.[43,129,130]
• MYCN. Genomic alterations involving the MYCN network (e.g., MYCN, MAX, MGA, NONO) have been reported to occur in 25% to 30% of Wilms tumor cases.[109] Specific genomic alterations associated with the MYCN network include the following:

  • MYCN copy number gain was observed in approximately 13% of Wilms tumor cases. MYCN gain was more common in anaplastic cases (7 of 23 cases, 30%) than in nonanaplastic cases (11.2%), and it was associated with poorer relapse-free survival (RFS) and overall survival, independent of histology.[131] MYCN tandem duplication was reported in 11 of 82 (13%) FH Wilms tumor specimens from relapse.[109]
  • Germline copy number gain at MYCN has been reported in a bilateral Wilms tumor case,[131] and germline MYCN duplication was also reported for a child with prenatal bilateral nephroblastomatosis and a family history of nephroblastoma.[132]
  • Variants at codon 44 (p.P44L) of MYCN are observed in approximately 3% to 4% of Wilms tumor cases at diagnosis [131,133] and in 8.5% of cases at relapse.[109] In a study of 810 Wilms tumor cases, 24 (3%) had MYCN P44L hotspot variants. RFS was significantly lower (68.6%) in patients with P44L variants than in patients with wild-type MYCN status (87.1%).[133]
  • The MYCN interacting protein MAX was altered at codon 60 (R60Q) in 7 of 782 Wilms tumor cases (0.9%).[133] RFS was significantly lower in patients with the MAX R60Q hotspot variant than in patients with wild-type MAX status.
• CTR9. Inactivating CTR9 germline variants were identified in 4 of 36 familial Wilms tumor pedigrees.[58,134] CTR9, which is located at chromosome 11p15.3, is a key component of the polymerase-associated factor 1 complex (PAF1c), which has multiple roles in RNA polymerase II regulation and is implicated in embryonic organogenesis and maintenance of embryonic stem cell pluripotency.
• REST. Inactivating germline variants in REST (encoding RE1-silencing transcription factor) were identified in four familial Wilms tumor pedigrees.[78] REST is a transcriptional repressor that functions in cellular differentiation and embryonic development. Most REST variants clustered within the portion of REST encoding the DNA-binding domain, and functional analyses showed that these variants compromise REST transcriptional repression. When screened for REST variants, 9 of 519 individuals with Wilms tumor who had no history of relatives with the disease tested positive for the variant; some had parents who also tested positive.[78] These observations indicate that REST is a Wilms tumor predisposition gene associated with approximately 2% of Wilms tumor.

Figure 2 summarizes the genomic landscape of a selected cohort of Wilms tumor patients selected because they experienced relapse despite showing FH.[86] The 75 FH Wilms tumor cases were clustered by unsupervised analysis of gene expression data, resulting in six clusters. Five of six MLLT1-altered tumors with available gene expression data were in cluster 3, and two were accompanied by CTNNB1 variants. This cluster also contained four tumors with a variant or small segment deletion of WT1, all of which also had either a variant of CTNNB1 or small segment deletion or variant of AMER1. It also contained a substantial number of tumors with retention of imprinting of 11p15 (including all MLLT1-altered tumors). The miRNAPG-altered cases clustered together and were mutually exclusive with both MLLT1 and with WT1-, AMER1-, or CTNNB1-altered 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.[139] The most common predisposition variants are variants of WT1 and 11p15 loss of imprinting.[26,79]

Bilateral disease can be synchronous (both kidneys affected at the same time) or metachronous (one affected after the other) and occurs in 6.3% and 0.85% of patients with Wilms tumor, respectively.[4] In general, perilobar nephrogenic rests are associated with synchronous bilateral Wilms tumor, whereas intralobar nephrogenic rests are more strongly associated with metachronous Wilms tumors.[140]

Bilateral Wilms tumors with WT1 variants are associated with early presentation in pediatric patients (age 10 months vs. age 39 months for those without a variant) and a high frequency of WT1 nonsense variant in exon 8. Three percent of patients with bilateral Wilms tumor have affected family members.[141]

Genomic analysis of kidney tissue in bilateral Wilms tumor indicates that a clonal expansion early in the nephrogenesis of normal-appearing but genetically aberrant precursor lesions occurred before the divergence of left and right kidney primordia.[69]

Screening Children Predisposed to Wilms Tumor

The primary purpose of screening is to enable earlier detection of a small and localized tumor (stage I or II), improve prognosis, and use less intensive treatment (such as to facilitate nephron-sparing surgery).[142] 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 hemihypertrophy) are usually screened with ultrasonography every 3 months until they reach at least age 8 years.[92,142]

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.[143]

On the basis of a literature search of patients with Beckwith-Wiedemann spectrum and Wilms tumor where the age at diagnosis was compared against data collected through the Surveillance, Epidemiology, and End Results (SEER) Program, screening patients with Beckwith-Wiedemann spectrum seems to significantly decrease the age and stage at the time of diagnosis in this population. Screening until age 7 years is effective in detecting close to 95% of all Wilms tumors in Beckwith-Wiedemann spectrum. Screening until age 30 months may also prove useful for patients with ICR2-LoM, consistent with the recommendations for hepatoblastoma screening in this population.[144]

• Beckwith-Wiedemann syndrome. Approximately 8% of patients with Beckwith-Wiedemann syndrome will develop a malignancy, with the most common being either Wilms tumor or hepatoblastoma, although adrenal tumors can also occur.[103]
  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.[145]
  Screening for Wilms tumor usually continues until age 8 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.[143]
  Proposed screening guidelines for Wilms tumor are available for patients with Beckwith-Wiedemann syndrome who have undergone molecular subtyping.[103] The four main molecular subtypes of Beckwith-Wiedemann syndrome (ICR1-GoM, ICR2-LoM, UPD, and CDKN1C variant) are characterized by specific genotype-phenotype correlations, including tumor risk. For more information about the molecular subtypes, see the Genomics of Wilms Tumor section.
  Proposed screening for specific molecular subtypes of Beckwith-Wiedemann syndrome is as follows:

  -

  Patients with a defect of the ICR1 region (ICR1-GoM) and UPD should undergo abdominal ultrasonography every 3 months until age 8 to 10 years. A clinical examination of the abdomen and muscle mass occurs monthly for the first year and then at 3-month intervals, between ultrasonography scans, until age 6 years.

  -

  For patients with loss of imprinting at ICR2 (ICR2-LoM), an abdominal ultrasonography is performed at the time of clinical or molecular diagnosis. Only patients with organomegaly or severe hemihypertrophy require surveillance by ultrasonography scans. Monthly clinical examinations are performed for the first 2 years, followed by clinical examinations every 3 to 6 months until age 6 years.

  -

  Patients with a CDKN1C variant are not at high risk of developing Wilms tumor. There are no data to support routine screening.

• WAGR Syndrome (or WAGR Spectrum). Patients with WAGR spectrum tend to experience an earlier age of initial Wilms tumor development compared with patients with nonsyndromic Wilms tumor. Using data from the WAGR Syndrome Patient Registry (n = 91), the reported median age at initial development of Wilms tumor or isolated nephrogenic rests was 19 months (range, 11–28 months). All patients with reported Wilms tumor developed their initial Wilms tumor by age 8 years, and 95% of patients developed their tumor by age 5 years.[13] Other investigators have reported that approximately 20% of patients developed their Wilms tumor after age 4 years.[15,16]
  Multiple patients have been diagnosed with the development of Wilms tumor past the age of 7 to 8 years and/or relapse occurring years after initial diagnosis. Some cases labeled as relapses have been de novo disease in the contralateral kidney.[16] In the WAGR Syndrome Patient Registry, late presentation of relapse occurred in one participant at age 19 years, 7 months, which was more than 17 years from their first Wilms tumor diagnosis and represented the third occurrence.[13]
  Investigators from SIOP have reported about the benefit of surveillance in a cohort of 43 patients with WAGR Syndrome and Wilms tumor/nephroblastomatosis enrolled in SIOP treatment studies. Of 39 patients, 27 (69%) were asymptomatic and the tumors were detected by surveillance, whereas 12 patients (31%) presented with a palpable/visible abdominal mass and/or other symptoms. Of these 12 patients, 2 had not been diagnosed with WAGR syndrome. Tumors detected by surveillance had a significantly decreased volume compared with tumors that were symptomatic (18 mL vs. 375 mL; P = .001), which enabled a high rate of nephron-sparing surgery (85%).[146] The authors recommend the use of preoperative chemotherapy as treatment for patients with WAGR syndrome in order to facilitate nephron-sparing surgery. This surgery can improve outcomes for patients with chronic kidney disease associated with WAGR syndrome.[147] Preoperative chemotherapy has been reported to decrease tumor size in 50% of WAGR patients.[146]
  Surveillance options for the WAGR population at age 8 years and older should be discussed with the patient’s family and multidisciplinary health care team to determine the appropriate follow-up schedule for Wilms tumor monitoring. Factors such as the patient's previous medical history and presence of nephrogenic rests and nephroblastomatosis should be considered.[13]
• Hemihypertrophy (also known as lateralized overgrowth or hemihyperplasia). Children with isolated hemihypertrophy are also at risk of developing liver tumors, adrenal tumors, and Wilms tumor (risk, 3%–4%). Screening with abdominal ultrasonography and serum AFP is suggested 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.[143]
  Hemihypertrophy can occur as part of a syndrome (most commonly Beckwith-Wiedemann syndrome) or an isolated phenomenon. The Beckwith-Wiedemann Syndrome International Consensus Group suggested that individuals with florid Beckwith-Wiedemann syndrome phenotype and those with isolated hemihypertrophy who have similar molecular findings as those with Beckwith-Wiedemann syndrome should be considered part of the Beckwith-Wiedemann Syndrome spectrum and managed according to the subtype of Beckwith-Wiedemann syndrome. Molecular testing may be considered for patients with isolated hemihypertrophy based on the clinical scoring system proposed by the Beckwith-Wiedemann Syndrome International Consensus Group.[148]
  Children with isolated hemihypertrophy and negative molecular tests may not need surveillance because the risk may be very low. However, more studies of large cohorts of molecularly tested children with isolated hemihypertrophy are needed to determine the risk.[92,148]
• Sporadic aniridia. Newborns born with sporadic aniridia should undergo molecular testing for deletion analysis of PAX6 and WT1, which are consistent with WAGR syndrome. Approximately 30% of patients with sporadic aniridia have WAGR.[149] If a deletion of WT1 is observed, the child should be screened with ultrasonography every 3 months until age 8 years, and the parents should be educated about the need for early identification and treatment of Wilms tumor.[92,150,151]
• Children of survivors of bilateral Wilms tumor. Although the risk of Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown and likely varies with the gene in which the variant occurred, some experts recommend screening such children with serial ultrasonography examinations every 3 months until age 8 years.[77]
• Bohring-Opitz syndrome. Bohring-Opitz syndrome is a rare genetic condition associated with ASXL1 variants. Overall, about 7% of individuals with Bohring-Opitz syndrome develop Wilms tumors.[152] Screening with abdominal ultrasonography every 3 to 4 months in the first 8 years of life has been suggested.[48]
• Simpson-Golabi-Behmel syndrome. Affected males with Simpson-Golabi-Behmel syndrome with GPC3 variants or deletions have an approximate 10% risk of Wilms tumor. Regular age-dependent screening for tumors, including abdominal ultrasonography, urinalysis, and biochemical markers, has been recommended for males with Simpson-Golabi-Behmel syndrome, although the true benefit has not been determined. It was previously thought that carrier females were not at increased risk of Wilms tumor and did not require surveillance. However, there are reports of rare cases where Simpson-Golabi-Behmel syndrome may have a significant clinical expression in females and Wilms tumors have occurred.[92] In clearly affected females, screening should be considered for embryonic tumors, including Wilms tumors.[153]
• Klippel-Trénaunay syndrome. The risk of Wilms tumor in children with Klippel-Trénaunay syndrome (a unilateral limb overgrowth syndrome) was no different than the risk in the general population when assessed using the National Wilms Tumor Study (NWTS) database. Routine ultrasonography surveillance is not recommended.[154]
• Perlman syndrome. Perlman syndrome is a rare congenital overgrowth syndrome that has an autosomal recessive inheritance pattern. A molecular diagnosis can be made by the presence of inactivating variants in DIS3L2 on chromosome 2q37.1. Fifty-three percent of children will die in the neonatal period. The kidneys show nephroblastomatosis in about 75% of cases. The incidence of Wilms tumor is 64% in infants who survive beyond the neonatal period.[39] It is recommended that these patients be offered regular surveillance similar to that offered to patients with Beckwith-Wiedemann syndrome.[143]
• DICER1 syndrome. Cystic nephroma is seen in 10% of families presenting with pleuropulmonary blastoma, typically occurring before age 4 years. Rare progression to anaplastic sarcoma of the kidney may occur. DICER1 syndrome includes an elevated risk of Wilms tumor, which is not a consequence of a prior cystic nephroma. Surveillance consists of abdominal ultrasonography, which starts with the first chest computed tomography (CT) screening for pleuropulmonary blastoma, and it is done every 6 to 12 months to age 8 years. Surveillance may be continued annually until age 12 years, depending on the individual patient.[155] Thirteen years is the oldest reported age of a Wilms tumor diagnosis in a DICER1 variant carrier.[117,156] Surveillance aims to identify cystic nephromas when they are small and nephron-sparing surgery is still possible, since tumors that progress to anaplastic sarcoma of the kidney have higher morbidity rates. Because anaplastic sarcoma of the kidney can be diagnosed at wider age ranges than cystic nephroma, extending abdominal ultrasonography screening to age 12 years should be considered. This time frame is the highest risk period for anaplastic sarcoma of the kidney (90% of germline cases presumably detected).[157]
• Germline pathogenic or likely pathogenic variant in Wilms tumor predisposition genes (CTR9, REST, TP53, TRIM28) in the absence of syndrome features or a family history suggestive of any specific cancer predisposition syndrome. Surveillance should be considered throughout the period of increased Wilms tumor risk (typically up to age 8 years), but may vary depending on the condition.[158]

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. Clinical findings may include the following:

• A lump, swelling, or pain in the abdomen. Most children present with a nontender, large flank mass that is noted when they are bathed or dressed. If noted on physical examination, the mass does not move with respiration in contrast to splenomegaly. Abdominal pain is present in 40% of children.
• Blood in the urine. Gross hematuria occurs in about 18% of children with Wilms tumor at presentation, and microscopic hematuria is seen in 24% of patients.[160]
• Hypertension. About 25% of children have hypertension at presentation, which is attributed to activation of the renin-angiotensin system.
• Hypercalcemia. Symptomatic hypercalcemia can sometimes be seen at presentation of rhabdoid tumors.
• Constitutional symptoms such as fever, anorexia, and weight loss occur in 10% of cases.

Children with Wilms tumor or other renal malignancies may also seek medical attention as a result of the following:

• Vascular obstruction or metastasis, including pulmonary symptoms such as dyspnea caused by lung metastasis.
• Abdominal pain caused by liver metastasis, prominent abdominal wall vessels, or varicocele due to inferior vena cava obstruction.
• Pulmonary embolus (rare).
• Rapid abdominal enlargement, anemia, and severe pain may be seen in the few children who develop subcapsular hemorrhage.

Diagnostic and Staging Evaluation for Wilms Tumor

The Children's Oncology Group Diagnostic Imaging Committee and the Society for Pediatric Radiology Oncology Committee have published a white paper with recommendations for the imaging of pediatric renal tumors.[161] Tests and procedures used to diagnose and stage Wilms tumor and other childhood kidney tumors include the following:

1. Physical examination and history. Children with a renal mass are carefully assessed for signs of associated syndromes such as aniridia, developmental delay, hypospadias, cryptorchidism, pseudohermaphrodism, overgrowth, and hemihypertrophy.
2. Complete blood count.
3. Liver function test.
4. Renal function test.
5. Urinalysis.
6. Abdominal imaging.

   • Abdominal x-ray.
   • Ultrasonography exam of the abdomen. Ultrasonography exam of the abdomen is often performed before a more definitive CT scan with contrast or magnetic resonance imaging (MRI) with contrast of the abdomen. This procedure is unnecessary after the definitive diagnostic study has been performed.[161]
   • CT scan with contrast (oral contrast is not necessary) or MRI of abdomen and pelvis (with and without intravenous contrast).[161]

     -

     CT scan of the abdomen will confirm the renal origin of the mass and determine whether there are bilateral tumors.[162] About 5% of renal masses thought to be Wilms tumor on the basis of clinical and radiological findings are diagnosed as another condition.[163]

     -

     A review of children with bilateral Wilms tumor demonstrated that only 0.25% of bilateral tumors were missed with modern helical CT scans, all of which were small tumors.[164]

     -

     Preoperative assessment by imaging of intravascular extension of Wilms tumor is essential to guide management. Four percent of Wilms tumor patients present with inferior vena cava or atrial involvement and 11% with renal vein involvement, which may lead to differences in management. Embolization of a caval thrombus to the pulmonary artery is rare but can be lethal, and the presence of a thrombus must be identified preoperatively to prevent this occurrence and guide treatment. A report from the COG shows that CT can accurately identify cavoatrial thrombus, obviating the need for ultrasonography if CT has already been performed.[165]

     -

     Ascites beyond the cul-de-sac is most predictive of preoperative Wilms tumor rupture, regardless of attenuation. In the presence of ascites, fat stranding around the tumor and the presence of retroperitoneal fluid are highly predictive of rupture.[162]

     -

     The concern about CT is radiation exposure, but the procedure is quick, allows continuous imaging of the chest and abdomen, has moderate specificity for detection of preoperative spill, may help distinguish nephrogenic rests from Wilms tumor, and provides excellent pulmonary detail.[162,166]

     -

     The main drawback with abdominal MRI is that moderate to deep sedation is often required in young children. However, it provides excellent organ detail in patients with bilateral involvement or liver metastases. Abdominal MRI is preferred for better assessment of potential nephrogenic rests and their distinction from true Wilms tumor.[167] If the decision is to perform an abdominal MRI, then a CT scan of the lungs should be done first to avoid obscuration of the lung bases by atelectasis.[168] MRI is the preferred imaging modality in children with known bilateral Wilms tumors or known bilateral tumor predisposition.[168]

7. CT scan of chest. Approximately 15% to 20% of patients will present with metastases. The common sites of metastases for Wilms tumor are the lungs (85%), liver (10%), and bone and spine (rarely). CT scanning provides the most sensitive method of detecting metastatic lung nodules. The use of iodinated intravenous contrast is preferred for baseline chest CTs because it allows simultaneous evaluation of the lung parenchyma, regional vasculature, and other mediastinal structures.[161] Approximately 7.5% of patients may present with a pleural effusion.[169][Level of evidence C1]
8. Chest x-ray is unnecessary if chest CT is performed initially.
9. Fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography (PET)-CT. PET scanning is not routinely used in Wilms tumor, although Wilms tumor is 18F-FDG avid. 18F-FDG PET-CT imaging adds clinically applicable information to conventional CT scan imaging. PET-CT may be particularly helpful in patients with bilateral disease or those receiving preoperative chemotherapy. 18F-FDG PET-CT highlights FDG-avid areas in the tumor and metastases, which corresponds to histologically confirmed active disease.[170]
10. Bone scan or cross-sectional imaging of other sites is reserved for patients with signs or symptoms of distant extrapulmonary metastases.
11. von Willebrand disease work-up. About 4% of patients presenting with Wilms tumor have an acquired form of von Willebrand disease, although many are asymptomatic. von Willebrand multimers bind to Wilms tumor, reducing the plasma concentration to low levels.[171] Some clinicians recommend evaluation for von Willebrand disease before surgery, because, although uncommon, it may be associated with substantial bleeding risks and can be managed preemptively. Acquired von Willebrand disease in the context of Wilms tumor will usually resolve once chemotherapy is started or the tumor is resected.[172]
12. Biopsy or resection. In children with a renal mass that clinically appears to be resectable or stage I or stage II Wilms tumor, a 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.
    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. If a primary nephrectomy cannot be performed, a biopsy, either open or with multiple cores, is required. The contraindications to primary nephrectomy are the following:

    • Extension of tumor thrombus to the level of the hepatic veins. These patients should be considered for tumor resection after neoadjuvant chemotherapy when there is evidence of regression of the vena caval thrombus regardless of the degree of response of the primary tumor.
    • The tumor involves contiguous structures whereby the only means of removing the kidney tumor requires removal of the other structure (e.g., spleen, pancreas, colon but excluding the adrenal gland and diaphragm). While Wilms tumors are frequently adherent to adjacent organs, in most cases, there is not frank invasion by the tumor and it can be dissected freely from the organs. Radical en bloc resection (e.g., partial hepatectomy) is not generally warranted. If removal of a small section of diaphragm, psoas muscle, or tip of the pancreas allows the tumor to be removed intact, this is considered safe and appropriate.
    • The surgeon's judgment that nephrectomy would result in significant or unnecessary morbidity/mortality, significant tumor spill, or residual tumor.[173]
    • If there is pulmonary compromise because of extensive pulmonary metastases or, in rare cases, hepatic disease.
    If a child undergoes a biopsy as the first procedure, they are considered stage III because they have gross residual tumors.
    Biopsy tissue from inoperable Wilms tumor obtained before chemotherapy may be used for histological 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 histological classification of the Wilms tumor cannot be determined by biopsy.[173]
    Anaplastic histology can be difficult to detect in any biopsy sample because of tumor heterogeneity. Data from NWTS-4 and NWTS-5 (COG-Q9401/NCT00002611) demonstrated that, because of the histological heterogeneity of Wilms tumor, a significant number of patients have anaplastic histology that is missed during an up-front biopsy whether it be a core needle biopsy or an incisional biopsy [174] 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.[164,175] Treatment as a bilateral Wilms tumor should be considered if the initial imaging studies suggests a bilateral process. If the origin of the other lesion is indeterminate, a pathological assessment of that lesion should be considered before proceeding with a nephrectomy.[164,175]
    Children who have bilateral Wilms tumor are often treated without a biopsy.[176] Biopsy can be avoided if the child is of typical age and the tumor has the usual radiographic appearance. This was assessed on the COG AREN0534 (NCT00945009) study where 187 of 189 patients with Wilms tumor were treated initially without a biopsy. If after 6 weeks of therapy, response was less than 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 stromal differentiation or rhabdomyomatous changes were detected, further chemotherapy was unlikely to result in tumor shrinkage and definitive surgery was the suggested approach.[176]

For patients with suspected Wilms tumor, additional preoperative staging studies are performed to assess lymph node status, intravascular extension, and rupture of Wilms tumor.[163]

• Lymph node sampling is required to locally stage all Wilms tumor patients. Lymph nodes have been shown to be of major prognostic value for both short-term and long-term survival. Gross inspection is notoriously inaccurate, with a false-negative rate of 31.3% and a false-positive rate of 18.1%.[177]
• Intravascular extension of the Wilms tumor. Preoperative assessment of intravascular extension of Wilms tumor is essential to guide management. The presence of intravenous tumor thrombus in the lumen of the renal vein, inferior vena cava, and right atrium has been reported in up to 11.3% of Wilms tumor patients and may lead to differences in management.
  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 may be done after CT has been performed but is not necessarily required.[165] 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.[178]
• Wilms tumors can rupture before surgery. The term rupture is used to imply a break in the tumor capsule before surgery, whereas the term spill refers to a break in the tumor during surgery. Based on their similar diagnostic performances, either CT or MRI can be used to detect rupture. Although imaging findings of rupture have high specificity (88%), the diagnosis of rupture has to be confirmed at surgery. Imaging alone cannot be used for initial staging because of the low sensitivity and specificity for preoperative rupture and lymph node status.[168]

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 greater than 90%.[179] This favorable outcome occurred with changes in therapy that included reductions in the length of therapy, dose of radiation, extent of fields irradiated, and the percentage of patients receiving radiation therapy.[180]

The prognosis for patients with Wilms tumor depends on the following:[181-184]

• Histopathological features of the tumor (FH vs. anaplastic histology). For more information, see the Histological Findings in Wilms Tumor section.
• Stage of disease at diagnosis.
• Molecular features of the tumor such as 1q gain and loss of heterozygosity of 1p and 16q. 1q gain, affecting 28% of Wilms tumors, is the most powerful predictor of outcome and is associated with an adverse outcome.[107,108,110] Loss of heterozygosity of 11p15 and loss of imprinting of 11p15 is associated with relapse in very low-risk patients who do not receive chemotherapy.[110,185] For more information, see the Genomics of Wilms Tumor section.
• Age. Age at presentation is commonly between 2 and 5 years, and the incidence of Wilms tumor in children older than age 10 years is rare. Older age is associated with an adverse prognosis.[186,187]

Older Adolescents and Adults With Wilms Tumor

Wilms tumor in patients older than 16 years is rare, with an incidence rate of around 0.2 cases per 1 million per year in patients aged 15 to 39 years.[2] The 5-year relative survival rate is 75% for this group of patients.[2,188] 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.[189] 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.

Wilms tumor occurring in adults differs from that occurring in children in several ways. Adults rarely present with bilateral disease (<1%). More adult patients had additional primary malignancies (both before and after the diagnosis of Wilms tumor) compared with their pediatric counterparts.[190] Wilms tumors occurring in adults have not been shown to develop in association with nephrogenic rests or be associated with developmental conditions such as WAGR, Denys-Drash, or Beckwith-Wiedemann syndromes.[136] For information about the molecular features of Wilms tumor in adults, see the Genomics of Wilms Tumor section.

A situation that is specific to adults is the diagnosis of Wilms tumor in pregnant women. This diagnosis is made incidentally during the ultrasonography monitoring of the pregnancy or because of clinical symptoms such as abdominal pain and fever.[191,192]

The outcomes for adolescent and young adult (AYA) patients (aged 15 to 39 years) and adult patients are inferior to the outcomes 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 rate (69% vs. 94%; P < .001) than did pediatric patients (n = 2,574).[193][Level of evidence C1]

The inferior outcome of the adult patients may be multifactorial, including 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.[194][Level of evidence C1]

Histological Findings in Wilms Tumor

Although most patients with a histological diagnosis of Wilms tumor do well with current treatment, approximately 10% of patients have histopathological 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).
• Anaplastic histology.

Stage Information for Wilms Tumor

Both the results of the imaging studies and the surgical and pathological 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).[200,216]

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.[200] Lymph node sampling is strongly recommended for all patients, even in the absence of clinically abnormal nodes, to achieve the most accurate stage.

Treatment of Wilms Tumor

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282. Szavay P, Luithle T, Graf N, et al.: Primary hepatic metastases in nephroblastoma--a report of the SIOP/GPOH Study. J Pediatr Surg 41 (1): 168-72; discussion 168-72, 2006. [PubMed: 16410128]
283. Fuchs J, Szavay P, Luithle T, et al.: Surgical implications for liver metastases in nephroblastoma--data from the SIOP/GPOH study. Surg Oncol 17 (1): 33-40, 2008. [PubMed: 17935976]
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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.[1]

Renal cell carcinoma (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.[2] In one study, children and adolescents with RCC (n = 515) presented with more advanced disease than those aged 21 to 30 years.[1]

Conditions Associated With RCC

Conditions associated with RCC include the following:

• von Hippel-Lindau (VHL) disease. VHL disease is an autosomal dominant condition in which blood vessels in the retina and cerebellum grow excessively.[3] The gene for VHL disease is located on chromosome 3p26 and is a tumor-suppressor gene, which is either altered or deleted in patients with the syndrome.
  Testing for the VHL gene is available.[4] Annual screening with abdominal ultrasonography or magnetic resonance imaging (MRI) is recommended, beginning at age 8 to 11 years. Annual screening is used to detect clear cell renal carcinoma in these individuals when the lesions are smaller than 3 cm, and thus, renal-sparing surgery can be performed.[5]
  For more information, see Von Hippel-Lindau Disease.
• Tuberous sclerosis. In tuberous sclerosis, the renal lesions may actually be epithelioid angiomyolipoma (also called perivascular epithelioid cell tumor or PEComa), which is associated with aggressive or malignant behavior and expresses melanocyte and smooth muscle markers.[6,7]
• Familial RCC. Familial RCC has been associated with an inherited chromosome translocation involving chromosome 3.[8] A high incidence of chromosome 3 abnormalities has also been demonstrated in nonfamilial renal tumors.
  SDHB, SDHC, and SDHD are Krebs cycle enzyme genes that have been associated with the development of familial RCC occurring with pheochromocytoma and paraganglioma. Germline variants in a subunit of the gene have been reported in individuals with renal cancer and no history of pheochromocytoma.[9,10]
• Renal medullary carcinoma. A rare subtype of RCC, renal medullary carcinoma may be associated with sickle cell hemoglobinopathy.[11] Renal medullary carcinomas are highly aggressive malignancies characterized clinically by an advanced stage at the time of detection, with widespread metastases and lack of response to chemotherapy and radiation therapy.[12,13][Level of evidence C1] Survival is poor and ranges from 2 weeks to 15 months, with a mean survival of 4 months.[11,13-16]
• Hereditary leiomyomatosis and renal cell cancer (HLRCC). This is an autosomal dominant syndrome caused by heterozygous pathogenic germline variants in the FH gene (located on chromosome region 1q42.1).[17,18] It is characterized by cutaneous and uterine leiomyomas and an increased risk of developing RCC, which is usually an adult-onset disease (median age of onset, 40–41 years). Twelve RCCs have been reported in FH variant carriers younger than 20 years.[19][Level of evidence C1] The absolute risk of developing an RCC is estimated to be 10% to 15%.[20,21] HLRCC-related RCC tends to be aggressive and can metastasize even when the primary tumor is small.[17,22,23] Histologically, papillary type 2 RCC or a complex tumor architecture with multiple histological patterns are suggestive of HLRCC.[19][Level of evidence C1] Genetic testing for FH variants and renal MRI surveillance, from the age of 8 to 10 years and onwards, is advised for family members of individuals with HLRCC. If renal cysts are detected, closer monitoring may be indicated.[20]; [19][Level of evidence C1]
• Previous treatment for childhood cancer. Survivors of childhood cancer who were treated with radiation and/or chemotherapy are at a higher risk of developing renal cancers than are the general population. Highest risk has been observed among neuroblastoma survivors who received renal-directed radiation therapy of 5 Gy or more or platinum-based chemotherapy.[24] Renal cancers have also been reported after treatment for rhabdomyosarcoma, leiomyosarcoma, acute lymphoblastic leukemia, primitive neuroectodermal tumors (PNET), and Wilms tumor.[25-30] For more information, see the Subsequent Neoplasms section in Late Effects of Treatment for Childhood Cancer.

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 9. For more information, see Genetics of Renal Cell Carcinoma.

Genomics of RCC

Histology of RCC

Pediatric RCC differs histologically from the adult counterpart. 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.[3] 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.[49]

RCC in children and young adults has a different genetic and morphological spectrum than that seen in older adults.[3,40,49,50]

Prognosis and Prognostic Factors for RCC

Prognostic factors for RCC include the following:

• Stage of disease.
• Lymph node involvement.

The primary prognostic factor for RCC is stage of disease. In 304 children and adolescents with RCC identified in the National Cancer Database, 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.[51] 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 pathological stage (P < .001).[51] The data attained in this article from the National Cancer Database 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.[32]

• 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 subtype, 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.[52]
• A series from the International Society of Paediatric Oncology (SIOP) included 111 pediatric patients with RCC registered in the SIOP and UK-IMPORT databases. In the 65 patients that could be tested for transcription factor E3 and/or EB, translocation-positive RCC was the most frequent subtype (56%), followed by the papillary subtype (30%), and the clear-cell subtype (6%). In the remaining 57 patients that could not undergo translocation testing, the most common histologies were papillary (45%) and clear cell (23%). The estimated 5-year OS rates were 96.8% for patients with localized disease, 92.3% for patients with regionally advanced disease, and 45.6% for patients with metastatic disease.[33][Level of evidence C1]

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.[34] Outcome results of this trial are pending.

Clinical Features and Diagnostic Evaluation of RCC

RCC may present with the following:

• Abdominal mass.
• Abdominal pain.
• Hematuria.

For more information about the clinical features and diagnostic evaluation of childhood kidney tumors, see the sections on Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor. For more information about the staging evaluation, see the Stage Information for Renal Cell Cancer section in Renal Cell Cancer Treatment.

Treatment of RCC

Survival of patients with RCC is affected by stage of disease at presentation and the completeness of resection at radical nephrectomy. In a COG prospective clinical trial of patients with newly diagnosed RCC, 68 patients (aged <30 years) were enrolled over a 6-year period. Complete surgical resection was attempted in all patients, regardless of the stage of their disease. Eight patients who had an incomplete surgical resection received chemotherapy. The 4-year event-free survival (EFS) rate was 80.2%, and the 4-year OS rate was 84.8%. For the 16 patients with N1M0 disease who underwent complete resection and no adjuvant therapy, the 4-year EFS and OS rates were 87.5% and 87.1%, respectively.[53][Level of evidence C1]

Standard treatment options for RCC include the following:

1. Radical nephrectomy with lymph node sampling.
2. Renal-sparing surgery with lymph node sampling.

Treatment Options Under Clinical Evaluation for RCC

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, see the ClinicalTrials.gov website.

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.

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41. Geller JI, Argani P, Adeniran A, et al.: Translocation renal cell carcinoma: lack of negative impact due to lymph node spread. Cancer 112 (7): 1607-16, 2008. [PubMed: 18278810]
42. Camparo P, Vasiliu V, Molinie V, et al.: Renal translocation carcinomas: clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature. Am J Surg Pathol 32 (5): 656-70, 2008. [PubMed: 18344867]
43. Qiu Rao, Bing Guan, Zhou XJ: Xp11.2 Translocation renal cell carcinomas have a poorer prognosis than non-Xp11.2 translocation carcinomas in children and young adults: a meta-analysis. Int J Surg Pathol 18 (6): 458-64, 2010. [PubMed: 20643670]
44. Malouf GG, Camparo P, Oudard S, et al.: Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma (RCC): a report from the Juvenile RCC Network. Ann Oncol 21 (9): 1834-8, 2010. [PubMed: 20154303]
45. Thorner PS, Shago M, Marrano P, et al.: TFE3-positive renal cell carcinomas are not always Xp11 translocation carcinomas: Report of a case with a TPM3-ALK translocation. Pathol Res Pract 212 (10): 937-942, 2016. [PubMed: 27450657]
46. Cajaiba MM, Jennings LJ, Rohan SM, et al.: ALK-rearranged renal cell carcinomas in children. Genes Chromosomes Cancer 55 (5): 442-51, 2016. [PubMed: 26773439]
47. Smith NE, Deyrup AT, Mariño-Enriquez A, et al.: VCL-ALK renal cell carcinoma in children with sickle-cell trait: the eighth sickle-cell nephropathy? Am J Surg Pathol 38 (6): 858-63, 2014. [PMC free article: PMC4352307] [PubMed: 24698962]
48. Cajaiba MM, Jennings LJ, George D, et al.: Expanding the spectrum of ALK-rearranged renal cell carcinomas in children: Identification of a novel HOOK1-ALK fusion transcript. Genes Chromosomes Cancer 55 (10): 814-7, 2016. [PMC free article: PMC4980203] [PubMed: 27225638]
49. Estrada CR, Suthar AM, Eaton SH, et al.: Renal cell carcinoma: Children's Hospital Boston experience. Urology 66 (6): 1296-300, 2005. [PubMed: 16360460]
50. Carcao MD, Taylor GP, Greenberg ML, et al.: Renal-cell carcinoma in children: a different disorder from its adult counterpart? Med Pediatr Oncol 31 (3): 153-8, 1998. [PubMed: 9722897]
51. Rialon KL, Gulack BC, Englum BR, et al.: Factors impacting survival in children with renal cell carcinoma. J Pediatr Surg 50 (6): 1014-8, 2015. [PMC free article: PMC4439356] [PubMed: 25805005]
52. Selle B, Furtwängler R, Graf N, et al.: Population-based study of renal cell carcinoma in children in Germany, 1980-2005: more frequently localized tumors and underlying disorders compared with adult counterparts. Cancer 107 (12): 2906-14, 2006. [PubMed: 17109448]
53. Geller JI, Cost NG, Chi YY, et al.: A prospective study of pediatric and adolescent renal cell carcinoma: A report from the Children's Oncology Group AREN0321 study. Cancer 126 (23): 5156-5164, 2020. [PMC free article: PMC7717658] [PubMed: 32926409]
54. Fyfe G, Fisher RI, Rosenberg SA, et al.: Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13 (3): 688-96, 1995. [PubMed: 7884429]
55. Coppin C, Porzsolt F, Awa A, et al.: Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev (1): CD001425, 2005. [PubMed: 15674877]
56. De Pasquale MD, Pessolano R, Boldrini R, et al.: Continuing response to subsequent treatment lines with tyrosine kinase inhibitors in an adolescent with metastatic renal cell carcinoma. J Pediatr Hematol Oncol 33 (5): e176-9, 2011. [PubMed: 21552143]
57. Chowdhury T, Prichard-Jones K, Sebire NJ, et al.: Persistent complete response after single-agent sunitinib treatment in a case of TFE translocation positive relapsed metastatic pediatric renal cell carcinoma. J Pediatr Hematol Oncol 35 (1): e1-3, 2013. [PubMed: 22995920]
58. Ray S, Jones R, Pritchard-Jones K, et al.: Pediatric and young adult renal cell carcinoma. Pediatr Blood Cancer 67 (11): e28675, 2020. [PubMed: 32869954]
59. Wedekind MF, Ranalli M, Shah N: Clinical efficacy of cabozantinib in two pediatric patients with recurrent renal cell carcinoma. Pediatr Blood Cancer 64 (11): , 2017. [PubMed: 28417541]

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. Relapses occur early (median time from diagnosis, 8 months).[1,2] For information about the treatment of CNS disease, see Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment.

A distinct clinical presentation that suggests a diagnosis of rhabdoid tumor of the kidney includes the following:[3]

• Fever.
• Hematuria.
• Young age (mean age, 11 months).
• Advanced tumor stage at presentation.

For more information about the clinical features and diagnostic evaluation of childhood kidney tumors, see the sections on Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor.

Approximately two-thirds of patients will present with advanced-stage disease. Bilateral cases have been reported.[1] 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.[4] The staging system used for rhabdoid tumor of the kidney is the same system used for Wilms tumor. For more information, see the Stage Information for Wilms Tumor section.

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

Genetic Testing and Surveillance of Rhabdoid Tumors of the Kidney

Germline analysis should be considered 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 variants, 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 variant or deletion has been documented in the family.[7]

To date, there is little evidence regarding the effectiveness of surveillance for patients with rhabdoid tumor predisposition syndrome type 1 (RTPS1) caused by loss-of-function germline SMARCB1 variants. However, because of the aggressive nature of the tumors with significant lethality and young age of onset in SMARCB1 carriers with truncating variants, 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 variants. Given the potential survival benefit of surgically resectable disease, it is postulated that early detection might improve overall survival (OS).[20-22]

Surveillance for patients with germline SMARCB1 variants includes the following:

• Brain magnetic resonance imaging (MRI) every 3 months from birth (or diagnosis) until age 5 years.
• Abdominal ultrasonography with a focus on the kidneys every 3 months.

For more information about SMARCB1 and RTPS1, see Rhabdoid Tumor Predisposition Syndrome Type 1.

Prognosis and Prognostic Factors for Rhabdoid Tumors of the Kidney

Patients with rhabdoid tumors of the kidney 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:[4]

• Age at diagnosis. Infants younger than 6 months at diagnosis demonstrated a 4-year OS rate of 9%, whereas the OS rate in patients aged 2 years and older was 41% (highly significant).
• Stage of disease. Patients with stage I and stage II disease had an OS rate of 42%. Patients with a higher stage of disease had an OS rate of 16%.
• Presence of a CNS lesion. All but one patient with a CNS lesion (n = 32) died.

One study that used the National Cancer Database identified 202 patients (aged younger than 18 years) with non-CNS malignant rhabdoid tumors.[23][Level of evidence C1]

• The 1-year OS rate was 48.8%, and the 5-year OS rate was 35.9%.
• Multivariate analysis demonstrated that age younger than 1 year and presence of metastasis were negative prognostic indications (P = .058).
• In the cohort of surgical patients (n = 143), the presence of residual disease was associated with a clinically significant worse outcome (hazard ratio, 1.54; 95% confidence interval, 0.88–2.69; P = .13).

Treatment of Rhabdoid Tumor of the Kidney

Because of the relative rarity of this tumor, all patients with rhabdoid tumor of the kidney should consider entering 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 are no standard treatment options for rhabdoid tumor of the kidney.[24]

The following results have been observed in studies of rhabdoid tumor of the kidney:

1. On the basis of a retrospective comparison of tumor response to preoperative treatment with vincristine/dactinomycin versus vincristine/dactinomycin/doxorubicin, doxorubicin is considered an active drug in malignant rhabdoid tumor of the kidney.[25][Level of evidence C3]
2. The NWTS-5 trial closed the arm for patients with rhabdoid tumor who were treated with cyclophosphamide, etoposide, and carboplatin because poor outcomes were observed. Combinations of etoposide and cisplatin; etoposide and ifosfamide; and ifosfamide, carboplatin, and etoposide (ICE chemotherapy) have been used.[26,27]
3. Treatment with high-dose alkylator therapy followed by consolidation with high-dose chemotherapy and, in some cases, autologous hematopoietic stem cell transplant (HSCT) after achieving a radiographic remission has resulted in some long-term survival (5 of 13 patients). None of the patients with unresectable primary tumors survived in this small series (N = 21).[28]
4. A retrospective analysis of 58 patients with malignant rhabdoid tumor of the kidney from the International Society of Paediatric Oncology (SIOP), Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH), and European Rhabdoid Tumor Registry was performed.[29]

   • For the entire group, the 2-year event-free survival (EFS) rate was 37%, and the OS rate was 38%.
   • Patients with multifocal involvement (n = 12) had significantly inferior survival than did patients with pulmonary or mediastinal metastases or local disease.
   • Patients who underwent up-front chemotherapy had a lower, but not statistically significant, 2-year EFS rate than did patients who underwent immediate surgical resection.
   • Younger age (<12 months) and local stage III disease were associated with significantly inferior survival than were stage I and stage II disease.
   • No difference was seen in 2-year EFS rates for patients without progression within 90 days consolidated by high-dose HSCT (n = 10) compared with patients without consolidation by HSCT (n = 21).
   • In a separate analysis of the same patient population, investigators examined the role of radiation therapy for local control in patients with higher-stage disease. Twenty-one patients (stages II and III) received radiation therapy during first-line treatment, 18 of whom received radiation therapy to all involved sites. The local failure rate was 29% for patients with local stage II or stage III disease who received radiation therapy to all sites, compared with 68% for nonirradiated patients. The progression-free survival rate was 67% for patients with local stage II and stage III disease who were treated with radiation therapy during first-line treatment (adjusted for early relapse or treatment abandonment), compared with 15% for patients who did not receive radiation therapy (P < .0001).[30][Level of evidence C1]

Treatment Options Under Clinical Evaluation for Rhabdoid Tumors of the Kidney

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, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

• PEPN2121 (NCT05286801) (Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1- or SMARCA4-Deficient Tumors): This study is evaluating the combination of a PD-L1 targeting antibody (atezolizumab) with a TIGIT targeting antibody (tiragolumab) for patients with SMARCB1- or SMARCA4-deficient tumors.

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.

References

1. van den Heuvel-Eibrink MM, van Tinteren H, Rehorst H, et al.: Malignant rhabdoid tumours of the kidney (MRTKs), registered on recent SIOP protocols from 1993 to 2005: a report of the SIOP renal tumour study group. Pediatr Blood Cancer 56 (5): 733-7, 2011. [PubMed: 21370404]
2. Reinhard H, Reinert J, Beier R, et al.: Rhabdoid tumors in children: prognostic factors in 70 patients diagnosed in Germany. Oncol Rep 19 (3): 819-23, 2008. [PubMed: 18288421]
3. Amar AM, Tomlinson G, Green DM, et al.: Clinical presentation of rhabdoid tumors of the kidney. J Pediatr Hematol Oncol 23 (2): 105-8, 2001. [PubMed: 11216700]
4. Tomlinson GE, Breslow NE, Dome J, et al.: Rhabdoid tumor of the kidney in the National Wilms' Tumor Study: age at diagnosis as a prognostic factor. J Clin Oncol 23 (30): 7641-5, 2005. [PubMed: 16234525]
5. Versteege I, Sévenet N, Lange J, et al.: Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394 (6689): 203-6, 1998. [PubMed: 9671307]
6. Imbalzano AN, Jones SN: Snf5 tumor suppressor couples chromatin remodeling, checkpoint control, and chromosomal stability. Cancer Cell 7 (4): 294-5, 2005. [PubMed: 15837618]
7. Eaton KW, Tooke LS, Wainwright LM, et al.: Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer 56 (1): 7-15, 2011. [PMC free article: PMC3086793] [PubMed: 21108436]
8. Haruta M, Arai Y, Okita H, et al.: Frequent breakpoints of focal deletion and uniparental disomy in 22q11.1 or 11.2 segmental duplication region reveal distinct tumorigenesis in rhabdoid tumor of the kidney. Genes Chromosomes Cancer 60 (8): 546-558, 2021. [PubMed: 33896058]
9. Schneppenheim R, Frühwald MC, Gesk S, et al.: Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet 86 (2): 279-84, 2010. [PMC free article: PMC2820190] [PubMed: 20137775]
10. Hasselblatt M, Gesk S, Oyen F, et al.: Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression. Am J Surg Pathol 35 (6): 933-5, 2011. [PubMed: 21566516]
11. Lee RS, Stewart C, Carter SL, et al.: A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest 122 (8): 2983-8, 2012. [PMC free article: PMC3408754] [PubMed: 22797305]
12. Biegel JA, Zhou JY, Rorke LB, et al.: Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59 (1): 74-9, 1999. [PubMed: 9892189]
13. Biegel JA: Molecular genetics of atypical teratoid/rhabdoid tumor. Neurosurg Focus 20 (1): E11, 2006. [PubMed: 16459991]
14. Bourdeaut F, Lequin D, Brugières L, et al.: Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clin Cancer Res 17 (1): 31-8, 2011. [PubMed: 21208904]
15. Geller JI, Roth JJ, Biegel JA: Biology and Treatment of Rhabdoid Tumor. Crit Rev Oncog 20 (3-4): 199-216, 2015. [PMC free article: PMC6087667] [PubMed: 26349416]
16. Janson K, Nedzi LA, David O, et al.: Predisposition to atypical teratoid/rhabdoid tumor due to an inherited INI1 mutation. Pediatr Blood Cancer 47 (3): 279-84, 2006. [PubMed: 16261613]
17. Sévenet N, Sheridan E, Amram D, et al.: Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet 65 (5): 1342-8, 1999. [PMC free article: PMC1288286] [PubMed: 10521299]
18. Hasselblatt M, Nagel I, Oyen F, et al.: SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis. Acta Neuropathol 128 (3): 453-6, 2014. [PubMed: 25060813]
19. Andrianteranagna M, Cyrta J, Masliah-Planchon J, et al.: SMARCA4-deficient rhabdoid tumours show intermediate molecular features between SMARCB1-deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type. J Pathol 255 (1): 1-15, 2021. [PubMed: 33999421]
20. Teplick A, Kowalski M, Biegel JA, et al.: Educational paper: screening in cancer predisposition syndromes: guidelines for the general pediatrician. Eur J Pediatr 170 (3): 285-94, 2011. [PMC free article: PMC3086787] [PubMed: 21210147]
21. Mitchell SG, Pencheva B, Porter CC: Germline Genetics and Childhood Cancer: Emerging Cancer Predisposition Syndromes and Psychosocial Impacts. Curr Oncol Rep 21 (10): 85, 2019. [PubMed: 31414239]
22. Foulkes WD, Kamihara J, Evans DGR, et al.: Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome. Clin Cancer Res 23 (12): e62-e67, 2017. [PMC free article: PMC7309678] [PubMed: 28620006]
23. Morgan KM, Siow VS, Strotmeyer S, et al.: Characteristics and Outcomes in Pediatric Non-Central Nervous System Malignant Rhabdoid Tumors: A Report from the National Cancer Database. Ann Surg Oncol 29 (1): 671-678, 2022. [PubMed: 34251553]
24. Ahmed HU, Arya M, Levitt G, et al.: Part II: Treatment of primary malignant non-Wilms' renal tumours in children. Lancet Oncol 8 (9): 842-8, 2007. [PubMed: 17765193]
25. Furtwängler R, Nourkami-Tutdibi N, Leuschner I, et al.: Malignant rhabdoid tumor of the kidney: significantly improved response to pre-operative treatment intensified with doxorubicin. Cancer Genet 207 (9): 434-6, 2014. [PubMed: 25242089]
26. Waldron PE, Rodgers BM, Kelly MD, et al.: Successful treatment of a patient with stage IV rhabdoid tumor of the kidney: case report and review. J Pediatr Hematol Oncol 21 (1): 53-7, 1999 Jan-Feb. [PubMed: 10029814]
27. Wagner L, Hill DA, Fuller C, et al.: Treatment of metastatic rhabdoid tumor of the kidney. J Pediatr Hematol Oncol 24 (5): 385-8, 2002 Jun-Jul. [PubMed: 12142788]
28. Venkatramani R, Shoureshi P, Malvar J, et al.: High dose alkylator therapy for extracranial malignant rhabdoid tumors in children. Pediatr Blood Cancer 61 (8): 1357-61, 2014. [PubMed: 24789740]
29. Furtwängler R, Kager L, Melchior P, et al.: High-dose treatment for malignant rhabdoid tumor of the kidney: No evidence for improved survival-The Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) experience. Pediatr Blood Cancer 65 (1): , 2018. [PubMed: 28843054]
30. Melchior P, Dzierma Y, Rübe C, et al.: Local Stage Dependent Necessity of Radiation Therapy in Rhabdoid Tumors of the Kidney (RTK). Int J Radiat Oncol Biol Phys 108 (3): 667-675, 2020. [PubMed: 32407933]

General Information About 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.[1]

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.[1] 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.[1] For more information about the clinical features and diagnostic evaluation of childhood kidney tumors, see the sections on Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor.

Younger age and stage IV disease have been identified as adverse prognostic factors for event-free survival (EFS).[2]

Historically, relapses have occurred up to 14 years after the completion of chemotherapy. However, with current therapy, relapses after 3 years are uncommon.[3] 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 receive.[2-5] 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.

Clear cell sarcoma of the kidney is rare in adults but has been reported. In a series of 17 patients, the median age was 25 years (range, 19–62 years). The ratio of male to female patients was 13:4. The pathological diagnosis can be achieved with microscopy and immunohistochemistry panels that include BCOR. The primary treatment for adult patients is nephrectomy and regional lymphadenectomy, although chemotherapy with or without radiation therapy may be helpful in preventing local recurrence and distant metastases.[6]; [7][Level of evidence C3]

Genomics of Clear Cell Sarcoma of the Kidney

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 consider entering 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, except those who have lymph nodes sampled and are stage I, undergo postoperative radiation therapy to the tumor bed and receive doxorubicin as part of their chemotherapy regimen.

The standard treatment option for stage I (must have lymph nodes sampled) clear cell sarcoma of the kidney is the following:

1. Surgery and chemotherapy.[16]

The standard treatment option for stages II through IV clear cell sarcoma of the kidney is the following:

1. Surgery, chemotherapy, and radiation therapy.[16]

Treatment of Recurrent Clear Cell Sarcoma of the Kidney

Patients with most forms of recurrent childhood cancer should consider enrolling in available phase I and phase II clinical trials. Other treatment options for clear cell sarcoma of the kidney are discussed below.

Palliative care remains a central focus of management regardless of whether disease-directed therapy is pursued at the time of progression. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.

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.[3,5,16] 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%.[5]

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:

1. Chemotherapy, complete surgical resection (if possible), and/or radiation therapy.

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.[5]; [4][Level of evidence B4]

The use of high-dose chemotherapy followed by hematopoietic stem cell transplant (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. Patients who had already achieved a second complete remission were more likely to receive high-dose chemotherapy.[4,5,19]

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.

References

1. Argani P, Perlman EJ, Breslow NE, et al.: Clear cell sarcoma of the kidney: a review of 351 cases from the National Wilms Tumor Study Group Pathology Center. Am J Surg Pathol 24 (1): 4-18, 2000. [PubMed: 10632483]
2. Furtwängler R, Gooskens SL, van Tinteren H, et al.: Clear cell sarcomas of the kidney registered on International Society of Pediatric Oncology (SIOP) 93-01 and SIOP 2001 protocols: a report of the SIOP Renal Tumour Study Group. Eur J Cancer 49 (16): 3497-506, 2013. [PubMed: 23880476]
3. Seibel NL, Chi YY, Perlman EJ, et al.: Impact of cyclophosphamide and etoposide on outcome of clear cell sarcoma of the kidney treated on the National Wilms Tumor Study-5 (NWTS-5). Pediatr Blood Cancer 66 (1): e27450, 2019. [PMC free article: PMC6249042] [PubMed: 30255545]
4. Radulescu VC, Gerrard M, Moertel C, et al.: Treatment of recurrent clear cell sarcoma of the kidney with brain metastasis. Pediatr Blood Cancer 50 (2): 246-9, 2008. [PubMed: 17226850]
5. Gooskens SL, Furtwängler R, Spreafico F, et al.: Treatment and outcome of patients with relapsed clear cell sarcoma of the kidney: a combined SIOP and AIEOP study. Br J Cancer 111 (2): 227-33, 2014. [PMC free article: PMC4102945] [PubMed: 24937667]
6. Cao M, Zhang J, Ma H, et al.: Clear cell sarcoma of the kidney in an adult: a case report and literature review. Transl Cancer Res 11 (1): 288-294, 2022. [PMC free article: PMC8841692] [PubMed: 35261904]
7. Tao J, Yang H, Hao Z, et al.: Positive response of a recurrent clear cell sarcoma to anlotinib combined with chemotherapy: A case report. Medicine (Baltimore) 101 (48): e32109, 2022. [PMC free article: PMC9726286] [PubMed: 36482604]
8. Ueno-Yokohata H, Okita H, Nakasato K, et al.: Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet 47 (8): 861-3, 2015. [PubMed: 26098867]
9. Argani P, Kao YC, Zhang L, et al.: Primary Renal Sarcomas With BCOR-CCNB3 Gene Fusion: A Report of 2 Cases Showing Histologic Overlap With Clear Cell Sarcoma of Kidney, Suggesting Further Link Between BCOR-related Sarcomas of the Kidney and Soft Tissues. Am J Surg Pathol 41 (12): 1702-1712, 2017. [PMC free article: PMC5680139] [PubMed: 28817404]
10. Karlsson J, Valind A, Gisselsson D: BCOR internal tandem duplication and YWHAE-NUTM2B/E fusion are mutually exclusive events in clear cell sarcoma of the kidney. Genes Chromosomes Cancer 55 (2): 120-3, 2016. [PubMed: 26493387]
11. Astolfi A, Melchionda F, Perotti D, et al.: Whole transcriptome sequencing identifies BCOR internal tandem duplication as a common feature of clear cell sarcoma of the kidney. Oncotarget 6 (38): 40934-9, 2015. [PMC free article: PMC4747379] [PubMed: 26516930]
12. Roy A, Kumar V, Zorman B, et al.: Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney. Nat Commun 6: 8891, 2015. [PMC free article: PMC4660214] [PubMed: 26573325]
13. Wong MK, Ng CCY, Kuick CH, et al.: Clear cell sarcomas of the kidney are characterised by BCOR gene abnormalities, including exon 15 internal tandem duplications and BCOR-CCNB3 gene fusion. Histopathology 72 (2): 320-329, 2018. [PubMed: 28833375]
14. Kao YC, Sung YS, Zhang L, et al.: Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy: Overlapping Genetic Features With Clear Cell Sarcoma of Kidney. Am J Surg Pathol 40 (8): 1009-20, 2016. [PMC free article: PMC4942366] [PubMed: 26945340]
15. Argani P, Pawel B, Szabo S, et al.: Diffuse Strong BCOR Immunoreactivity Is a Sensitive and Specific Marker for Clear Cell Sarcoma of the Kidney (CCSK) in Pediatric Renal Neoplasia. Am J Surg Pathol 42 (8): 1128-1131, 2018. [PMC free article: PMC6041176] [PubMed: 29851702]
16. Benedetti DJ, Renfro LA, Tfirn I, et al.: Treatment and outcomes of clear cell sarcoma of the kidney: A report from the Children's Oncology Group studies AREN0321 and AREN03B2. Cancer 130 (13): 2361-2371, 2024. [PMC free article: PMC11162327] [PubMed: 38396300]
17. Kalapurakal JA, Perlman EJ, Seibel NL, et al.: Outcomes of patients with revised stage I clear cell sarcoma of kidney treated in National Wilms Tumor Studies 1-5. Int J Radiat Oncol Biol Phys 85 (2): 428-31, 2013. [PubMed: 22658515]
18. Seibel NL, Li S, Breslow NE, et al.: Effect of duration of treatment on treatment outcome for patients with clear-cell sarcoma of the kidney: a report from the National Wilms' Tumor Study Group. J Clin Oncol 22 (3): 468-73, 2004. [PubMed: 14752069]
19. Pein F, Michon J, Valteau-Couanet D, et al.: High-dose melphalan, etoposide, and carboplatin followed by autologous stem-cell rescue in pediatric high-risk recurrent Wilms' tumor: a French Society of Pediatric Oncology study. J Clin Oncol 16 (10): 3295-301, 1998. [PubMed: 9779704]

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.[1] It is the most common kidney tumor found in infants younger than 6 months, with a median age at diagnosis of 1 to 2 months.[2] Twice as many males as females are diagnosed. The diagnosis should be questioned when applied to individuals older than 2 years.[1]

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%.[3] 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.[1] However, in a comprehensive review of the literature, 12 deaths were reported, 7 of which were the result of surgical complications in infants.[4][Level of evidence C2]

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 histological subtypes:

• Classic. [5]
• Cellular. The cellular subtype is identical to infantile fibrosarcoma.[6]
• Mixed. The mixed subtype (<10%) is a mixture of classic and cellular patterns.[7]

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.[8] Other rare variants in cellular congenital mesoblastic nephroma include EML4::NRTK3 and LMNA::NRTK1 fusions, BRAF internal duplications, RET fusions, and ALK fusions.[9,10] Classic congenital mesoblastic nephroma can also harbor EGFR internal tandem duplications.[11] Cellular congenital mesoblastic nephroma shares its genetic and morphological hallmarks with infantile fibrosarcoma because variants of NRTK3 and BRAF have been reported in both tumor types.[12]

The risk of recurrence for patients with mesoblastic nephroma is closely associated with the presence of a cellular subtype and with stage III disease.[5] In an International Society of Paediatric 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).[8]

For more information about the clinical features and diagnostic evaluation of childhood kidney tumors, see the sections on Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor.

Treatment of Congenital Mesoblastic Nephroma

The OS of patients with congenital mesoblastic nephroma is excellent. However, reported causes of death are treatment related in about one-half of the cases. Additionally, most of these patients were very young (median age, <1 year).[4] 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:

1. Nephrectomy only (stages I and II all subtypes and stage III classic and mixed subtypes).
2. Adjuvant chemotherapy (stage III cellular subtype).

Treatment Options Under Clinical Evaluation for Congenital Mesoblastic Nephroma

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, see the ClinicalTrials.gov website.

Treatment of Recurrent Congenital Mesoblastic Nephroma

Patients with most forms of recurrent childhood cancer should consider enrolling in available phase I and phase II clinical trials. Other treatment options for recurrent congenital mesoblastic nephroma are discussed below.

Palliative care remains a central focus of management regardless of whether disease-directed therapy is pursued at the time of progression. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.

Relapses were reported in 4% of patients with congenital mesoblastic nephroma, and all relapses occurred within 12 months after diagnosis. Most relapses occurred locally, although metastatic relapses have been reported.[4] About 70% of patients who relapsed survived with individualized treatment comprising combinations of surgery, chemotherapy, and radiation therapy.[4]

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 variant, 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.[15,16]

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.

References

1. England RJ, Haider N, Vujanic GM, et al.: Mesoblastic nephroma: a report of the United Kingdom Children's Cancer and Leukaemia Group (CCLG). Pediatr Blood Cancer 56 (5): 744-8, 2011. [PubMed: 21370406]
2. Jehangir S, Kurian JJ, Selvarajah D, et al.: Recurrent and metastatic congenital mesoblastic nephroma: where does the evidence stand? Pediatr Surg Int 33 (11): 1183-1188, 2017. [PubMed: 28856451]
3. van den Heuvel-Eibrink MM, Grundy P, Graf N, et al.: Characteristics and survival of 750 children diagnosed with a renal tumor in the first seven months of life: A collaborative study by the SIOP/GPOH/SFOP, NWTSG, and UKCCSG Wilms tumor study groups. Pediatr Blood Cancer 50 (6): 1130-4, 2008. [PubMed: 18095319]
4. Gooskens SL, Houwing ME, Vujanic GM, et al.: Congenital mesoblastic nephroma 50 years after its recognition: A narrative review. Pediatr Blood Cancer 64 (7): , 2017. [PubMed: 28124468]
5. Furtwaengler R, Reinhard H, Leuschner I, et al.: Mesoblastic nephroma--a report from the Gesellschaft fur Pädiatrische Onkologie und Hämatologie (GPOH). Cancer 106 (10): 2275-83, 2006. [PubMed: 16596620]
6. El Demellawy D, Cundiff CA, Nasr A, et al.: Congenital mesoblastic nephroma: a study of 19 cases using immunohistochemistry and ETV6-NTRK3 fusion gene rearrangement. Pathology 48 (1): 47-50, 2016. [PubMed: 27020209]
7. Argani P, Ladanyi M: Recent advances in pediatric renal neoplasia. Adv Anat Pathol 10 (5): 243-60, 2003. [PubMed: 12973047]
8. Vokuhl C, Nourkami-Tutdibi N, Furtwängler R, et al.: ETV6-NTRK3 in congenital mesoblastic nephroma: A report of the SIOP/GPOH nephroblastoma study. Pediatr Blood Cancer 65 (4): , 2018. [PubMed: 29286563]
9. Davis JL, Vargas SO, Rudzinski ER, et al.: Recurrent RET gene fusions in paediatric spindle mesenchymal neoplasms. Histopathology 76 (7): 1032-1041, 2020. [PubMed: 31994201]
10. Tan SY, Al-Ibraheemi A, Ahrens WA, et al.: ALK rearrangements in infantile fibrosarcoma-like spindle cell tumours of soft tissue and kidney. Histopathology 80 (4): 698-707, 2022. [PubMed: 34843129]
11. Wegert J, Vokuhl C, Collord G, et al.: Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants. Nat Commun 9 (1): 2378, 2018. [PMC free article: PMC6006309] [PubMed: 29915264]
12. Knezevich SR, Garnett MJ, Pysher TJ, et al.: ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res 58 (22): 5046-8, 1998. [PubMed: 9823307]
13. Bayindir P, Guillerman RP, Hicks MJ, et al.: Cellular mesoblastic nephroma (infantile renal fibrosarcoma): institutional review of the clinical, diagnostic imaging, and pathologic features of a distinctive neoplasm of infancy. Pediatr Radiol 39 (10): 1066-74, 2009. [PubMed: 19629465]
14. McCahon E, Sorensen PH, Davis JH, et al.: Non-resectable congenital tumors with the ETV6-NTRK3 gene fusion are highly responsive to chemotherapy. Med Pediatr Oncol 40 (5): 288-92, 2003. [PubMed: 12652616]
15. Drilon A, Laetsch TW, Kummar S, et al.: Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 378 (8): 731-739, 2018. [PMC free article: PMC5857389] [PubMed: 29466156]
16. Entrectinib Shows Pediatric Potential. Cancer Discov 9 (7): OF4, 2019. [PubMed: 31113803]

General Information About Ewing Sarcoma of the Kidney

Ewing sarcoma (previously known as neuroepithelial tumor) of the kidney is extremely rare (<5% of renal tumors) and demonstrates a unique proclivity for young adults. It is a highly aggressive neoplasm, more often presenting with large tumors, penetration of the renal capsule, and extension into the renal vein.[1,2] In a literature review of 362 patients, the metastatic rate was 53.2%. Lymph node involvement was noted in 24% of the cases (13.9% in patients aged <18 years vs. 28.4% in adult patients; P = .07). All age groups showed a male predilection for nodal involvement, with significant sex differences seen in adolescent and young adult groups and adult groups (P = .007 and P = .002, respectively). The mortality rate was 21.5% at 1 year after diagnosis and 59.7% at 3 years after diagnosis.[3][Level of evidence C1]

Ewing sarcoma of the kidney is characterized by CD99 (MIC-2) positivity and the detection of EWS::FLI1 fusion transcripts. Focal, atypical histological features have been seen, including clear cell sarcoma, rhabdoid tumor, malignant peripheral nerve sheath tumors, and paraganglioma.[1,4]

Treatment of Ewing Sarcoma of the Kidney

There is no consensus for the optimal treatment of Ewing sarcoma of the kidney because data are lacking. The current treatment approach is extrapolated from the experience of treating Ewing sarcoma at other sites with multimodal therapy consisting of multiagent chemotherapy, surgery, and/or radiation therapy for local control. The MD Anderson Cancer Center reported their experience with 30 patients (median age, 30.5 years) with Ewing sarcoma of the kidney over a period of 23 years.[5]

• Twenty percent of the patients had tumors confined to the kidney, 23% had tumors extending locally beyond the kidney, and 57% had metastasis at diagnosis (lungs, liver, and bone). The 4-year EFS and OS rates were 54% and 85%, respectively, for patients without metastasis at diagnosis, compared with 35% and 47%, respectively, for patients with metastasis.
• Patients with tumors confined to the kidney and treated with nephrectomy and adjuvant chemotherapy have favorable outcomes compared with patients who did not complete adjuvant therapy. Twelve of 13 patients with nonmetastatic disease who underwent upfront nephrectomy had a favorable outcome when adjuvant chemotherapy was used.
• Presence of tumor thrombus in the renal vein and/or inferior vena cave was associated with worse EFS (P = .053).
• Unfavorable prognostic factors were local tumor extension beyond the kidney, tumor thrombus, and distant metastasis.
• The most commonly used chemotherapy was vincristine, cyclophosphamide, doxorubicin, ifosfamide, etoposide, cisplatin, irinotecan, and temozolomide. The most common initial chemotherapy used was vincristine, doxorubicin, and cyclophosphamide, either alone (23%) or in combination with ifosfamide and etoposide (23%). The second most common combination used was vincristine, doxorubicin, and ifosfamide.

Treatment according to Ewing sarcoma protocols should be considered.[1]

For more information, see Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment.

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.

References

1. Parham DM, Roloson GJ, Feely M, et al.: Primary malignant neuroepithelial tumors of the kidney: a clinicopathologic analysis of 146 adult and pediatric cases from the National Wilms' Tumor Study Group Pathology Center. Am J Surg Pathol 25 (2): 133-46, 2001. [PubMed: 11176062]
2. Tagarelli A, Spreafico F, Ferrari A, et al.: Primary renal soft tissue sarcoma in children. Urology 80 (3): 698-702, 2012. [PubMed: 22784490]
3. Bradford K, Nobori A, Johnson B, et al.: Primary Renal Ewing Sarcoma in Children and Young Adults. J Pediatr Hematol Oncol 42 (8): 474-481, 2020. [PMC free article: PMC7554078] [PubMed: 32282650]
4. Ellison DA, Parham DM, Bridge J, et al.: Immunohistochemistry of primary malignant neuroepithelial tumors of the kidney: a potential source of confusion? A study of 30 cases from the National Wilms Tumor Study Pathology Center. Hum Pathol 38 (2): 205-11, 2007. [PubMed: 17134738]
5. Tarek N, Said R, Andersen CR, et al.: Primary Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Kidney: The MD Anderson Cancer Center Experience. Cancers (Basel) 12 (10): , 2020. [PMC free article: PMC7599660] [PubMed: 33050651]

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.[1]

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, smooth muscle markers, and the documentation of EWSR1 rearrangements.[2]

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.[2]

References

1. Gleason BC, Fletcher CD: Myoepithelial carcinoma of soft tissue in children: an aggressive neoplasm analyzed in a series of 29 cases. Am J Surg Pathol 31 (12): 1813-24, 2007. [PubMed: 18043035]
2. Cajaiba MM, Jennings LJ, Rohan SM, et al.: Expanding the Spectrum of Renal Tumors in Children: Primary Renal Myoepithelial Carcinomas With a Novel EWSR1-KLF15 Fusion. Am J Surg Pathol 40 (3): 386-94, 2016. [PubMed: 26523541]

General Information About Cystic Partially Differentiated Nephroblastoma

Cystic partially differentiated nephroblastoma is a rare cystic variant of Wilms tumor (1%), with unique pathological and clinical characteristics. The median age at presentation is 12 months. No patients with metastatic disease have been reported. Bilateral disease has occurred (4.4%). It has also been reported to occur in combination with contralateral Wilms tumor. Two of 113 patients identified in the literature had previous, concomitant, or subsequent other tumors.[1] 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 pathological features distinguish this neoplasm from standard Wilms tumor. DICER1 variants have not been reported in cystic partially differentiated nephroblastoma, which supports a distinction between multilocular cystic nephromas and cystic partially differentiated nephroblastoma.[2] Somatic hyperdiploidy has been reported in nonsyndromic patients (7 of 8 karyotyped cases).[1]

Recurrence has been reported after tumor spillage during surgery.[3][Level of evidence C1]

For more information about the clinical features and diagnostic evaluation of childhood kidney tumors, see the sections on Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor.

Treatment of Cystic Partially Differentiated Nephroblastoma

Surgery is the main treatment. Preoperative chemotherapy administration was reported in 20 of 98 patients. None of the preoperatively treated patients showed response to chemotherapy on imaging or histological examination.[1]

Standard treatment options for cystic partially differentiated nephroblastoma include the following:

1. Surgery. Patients with stage I disease have a 100% survival rate with surgery alone.[4]
2. Surgery and adjuvant chemotherapy. Patients with stage II disease have an excellent outcome with tumor resection followed by postoperative vincristine and dactinomycin.[4]

References

1. van Peer SE, Pleijte CJH, de Krijger RR, et al.: Clinical and Molecular Characteristics and Outcome of Cystic Partially Differentiated Nephroblastoma and Cystic Nephroma: A Narrative Review of the Literature. Cancers (Basel) 13 (5): , 2021. [PMC free article: PMC7957568] [PubMed: 33673661]
2. Cajaiba MM, Khanna G, Smith EA, et al.: Pediatric cystic nephromas: distinctive features and frequent DICER1 mutations. Hum Pathol 48: 81-7, 2016. [PMC free article: PMC4979561] [PubMed: 26772403]
3. Baker JM, Viero S, Kim PC, et al.: Stage III cystic partially differentiated nephroblastoma recurring after nephrectomy and chemotherapy. Pediatr Blood Cancer 50 (1): 129-31, 2008. [PubMed: 16786584]
4. Blakely ML, Shamberger RC, Norkool P, et al.: Outcome of children with cystic partially differentiated nephroblastoma treated with or without chemotherapy. J Pediatr Surg 38 (6): 897-900, 2003. [PubMed: 12778388]

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. In the 167 cases reported in the literature, the median age at diagnosis was 16 months, with a range from prenatal diagnosis to age 16 years.[1] These lesions can occur bilaterally (5.3%), and a familial pattern has been reported. They have been reported to occur in combination with contralateral Wilms tumor.[1]

DICER1 variants (germline and/or somatic) were identified in 33 of 35 cases tested. In the series of 167 patients with cystic nephromas, 10 of the 12 patients with germline DICER1 variants had previously or subsequently developed other tumors in addition to the cystic nephroma.[1] Multilocular cystic nephroma has been associated with pleuropulmonary blastoma and the DICER1 variant. Anaplastic sarcoma of the kidney has also been associated with the DICER1 variant.[2] This is in contrast to adult cystic nephromas, which lack DICER1 variants, and supports the difference between adult and pediatric cases. Genetic counseling, DICER1 variant testing, and screening for lung lesions of a solid or cystic nature should be considered.[1,3-6]

For more information about the clinical features and diagnostic evaluation of childhood kidney tumors, see the sections on Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor.

Treatment of Multilocular Cystic Nephroma

The standard treatment option for multilocular cystic nephroma is surgery.

References

1. van Peer SE, Pleijte CJH, de Krijger RR, et al.: Clinical and Molecular Characteristics and Outcome of Cystic Partially Differentiated Nephroblastoma and Cystic Nephroma: A Narrative Review of the Literature. Cancers (Basel) 13 (5): , 2021. [PMC free article: PMC7957568] [PubMed: 33673661]
2. Wu MK, Goudie C, Druker H, et al.: Evolution of Renal Cysts to Anaplastic Sarcoma of Kidney in a Child With DICER1 Syndrome. Pediatr Blood Cancer 63 (7): 1272-5, 2016. [PubMed: 26928971]
3. Dehner LP, Messinger YH, Schultz KA, et al.: Pleuropulmonary Blastoma: Evolution of an Entity as an Entry into a Familial Tumor Predisposition Syndrome. Pediatr Dev Pathol 18 (6): 504-11, 2015 Nov-Dec. [PMC free article: PMC9743680] [PubMed: 26698637]
4. Doros LA, Rossi CT, Yang J, et al.: DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma. Mod Pathol 27 (9): 1267-80, 2014. [PMC free article: PMC4117822] [PubMed: 24481001]
5. Cajaiba MM, Khanna G, Smith EA, et al.: Pediatric cystic nephromas: distinctive features and frequent DICER1 mutations. Hum Pathol 48: 81-7, 2016. [PMC free article: PMC4979561] [PubMed: 26772403]
6. Li Y, Pawel BR, Hill DA, et al.: Pediatric Cystic Nephroma Is Morphologically, Immunohistochemically, and Genetically Distinct From Adult Cystic Nephroma. Am J Surg Pathol 41 (4): 472-481, 2017. [PMC free article: PMC5350016] [PubMed: 28177962]

General Information About Anaplastic Sarcoma of the Kidney

Anaplastic sarcoma of the kidney, a DICER1-related neoplasm, is a rare renal tumor that is distinct from Wilms tumor and resembles pleuropulmonary blastoma (PPB). There have been approximately 47 reported cases.[1] Anaplastic sarcoma of the kidney is predominantly diagnosed in females, with a higher proportion than that seen in patients with Wilms tumor and other renal tumors of childhood. The average presenting age is 11.6 years. The median age of presentation is 8.7 years. The youngest presenting age was 7 months, and the oldest reported age was 41 years.[1,2]

Patients with anaplastic sarcoma of the kidney present with a renal mass. The abdomen (liver and regional lymph nodes), lung, and bone are the most common sites of metastases. Unlike PPB, there have been no reported cases of anaplastic sarcoma of the kidney–related brain metastases. Bone metastases occurred in 5 of 47 patients. After initial staging, 8 of 47 patients developed pulmonary metastases, suggesting that ongoing monitoring for pulmonary metastatic disease should be considered.[1] For more information about the clinical features and diagnostic evaluation of childhood kidney tumors, see the sections on Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor.

The relationship between anaplastic sarcoma of the kidney and DICER1 was established in a study that showed cystic nephromas had DICER1 somatic variants. These variants are not present in cystic partially differentiated nephroblastoma and Wilms tumor.[3] Additional studies showed that, like PPB, anaplastic sarcoma of the kidney has the potential to progress from a cystic lesion (i.e., cystic nephroma) to a high-grade, multipatterned, primitive sarcoma similar to PPB.[2,4,5] Pathogenic variants in DICER1 have been identified in anaplastic sarcoma of the kidney.[6-8]

Anaplastic sarcomas of the kidney share oncogenetic events with other DICER1-associated neoplasms. For example, both can progress beyond cystic lesions. Anaplasia and TP53 missense variants are present in Type II and Type III PPB. Strong TP53 expression (detected by immunohistochemistry) was reported in most anaplastic sarcoma of the kidney cases in the International PPB/DICER1 Registry.[1,6] BRAF V600E variants and PDGFRA variants have been reported in patients with anaplastic sarcoma of the kidney.[9,10] For more information about PPB, see Childhood Pleuropulmonary Blastoma Treatment.

Patients diagnosed with anaplastic sarcoma of the kidney should consider genetic counseling and DICER1 testing (both somatic tumor testing and germline genetic testing).[1] Screening for lung lesions of a solid or cystic nature should also be considered based on age and DICER1 variant testing.[3]

Treatment of Anaplastic Sarcoma of the Kidney

There is no standard treatment option for anaplastic sarcoma of the kidney.

In a series of 40 patients with anaplastic sarcoma of the kidney who had staging data available, 13 had stage I disease, 12 had stage II disease, 10 had stage III disease, and 5 had stage IV disease.[1]

• Most patients (38 of 46) received up-front chemotherapy, and 14 patients received up-front radiation therapy. The 2-year event-free survival (EFS) rate was 81.8% for patients with stage I and stage II disease, compared with 46.6% for patients with stage III and stage IV disease (P = .07). The 2-year overall survival (OS) rate was 88.9% for patients with stage I and stage II disease, compared with 70.0% for patients with stage III and stage IV disease (P = .20).
• Chemotherapy was associated with improved EFS and OS (hazard ratios [HRs], 0.09 and 0.08, respectively).
• Patients (including those with stage I and stage II disease) treated with chemotherapy and surgery had lower risks of recurrence than those who had surgery alone.
• The most common treatment protocols are based on Ewing sarcoma– and anaplastic Wilms tumor–directed therapies. These protocols use combinations of vincristine, doxorubicin, cyclophosphamide, and etoposide with or without ifosfamide, dactinomycin, and carboplatin.
• Up-front radiation therapy was used in 14 patients. Only two recurrences were reported.
• Older age at diagnosis was associated with worse outcomes (EFS HR, 1.08; OS HR, 1.07). Age groups of 0 to 3 years and 4 to 9 years had similar 2-year EFS rates (80% and 84.6%, respectively) and OS rates (100% and 92.3%, respectively). Patients older than 9 years had lower 2-year EFS rates (54.2%) and OS rates (68.4%) (EFS, P < .01; OS, P = .07).

In the posttherapy setting, surveillance for PPB, thyroid tumors, and/or ovarian tumors should be considered. Surveillance strategies will depend on which germline DICER1 variant is detected and whether mosaicism is present.[1,11]

References

1. Schoettler PJ, Smith CC, Nishitani M, et al.: Anaplastic sarcoma of the kidney (DICER1-sarcoma of the kidney): A report from the International Pleuropulmonary Blastoma/DICER1 Registry. Pediatr Blood Cancer 71 (8): e31090, 2024. [PubMed: 38807260]
2. Wu MK, Cotter MB, Pears J, et al.: Tumor progression in DICER1-mutated cystic nephroma-witnessing the genesis of anaplastic sarcoma of the kidney. Hum Pathol 53: 114-20, 2016. [PubMed: 27036314]
3. Doros LA, Rossi CT, Yang J, et al.: DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma. Mod Pathol 27 (9): 1267-80, 2014. [PMC free article: PMC4117822] [PubMed: 24481001]
4. Wu MK, Goudie C, Druker H, et al.: Evolution of Renal Cysts to Anaplastic Sarcoma of Kidney in a Child With DICER1 Syndrome. Pediatr Blood Cancer 63 (7): 1272-5, 2016. [PubMed: 26928971]
5. González IA, Stewart DR, Schultz KAP, et al.: DICER1 tumor predisposition syndrome: an evolving story initiated with the pleuropulmonary blastoma. Mod Pathol 35 (1): 4-22, 2022. [PMC free article: PMC8695383] [PubMed: 34599283]
6. Wu MK, Vujanic GM, Fahiminiya S, et al.: Anaplastic sarcomas of the kidney are characterized by DICER1 mutations. Mod Pathol 31 (1): 169-178, 2018. [PubMed: 28862265]
7. Yoshida M, Hamanoue S, Seki M, et al.: Metachronous anaplastic sarcoma of the kidney and thyroid follicular carcinoma as manifestations of DICER1 abnormalities. Hum Pathol 61: 205-209, 2017. [PubMed: 27697588]
8. Apellaniz-Ruiz M, Colón-González G, Perlman EJ, et al.: A child with neuroblastoma and metachronous anaplastic sarcoma of the kidney: Underlying DICER1 syndrome? Pediatr Blood Cancer 67 (12): e28488, 2020. [PubMed: 32568472]
9. Kroll-Wheeler L, Heider A: Anaplastic Sarcoma of the Kidney With Heterologous Ganglioneuroblastic Differentiation: Another DICER1-Associated Tumor. Pediatr Dev Pathol 25 (2): 186-191, 2022 Mar-Apr. [PubMed: 34515577]
10. Antonescu CR, Reuter VE, Keohan ML, et al.: DICER1-Associated Anaplastic Sarcoma of the Kidney With Coexisting Activating PDGFRA D842V Mutations and Response to Targeted Kinase Inhibitors in One Patient. JCO Precis Oncol 6: e2100554, 2022. [PMC free article: PMC9489182] [PubMed: 35797510]
11. Fraire CR, Mallinger PR, Hatton JN, et al.: Intronic Germline DICER1 Variants in Patients With Sertoli-Leydig Cell Tumor. JCO Precis Oncol 7: e2300189, 2023. [PMC free article: PMC10860953] [PubMed: 37883719]

General Information About Primary Renal Synovial Sarcoma

Primary renal synovial sarcoma is a subset of embryonal sarcoma of the kidney that occurs more often on the right side in young adults (median age, 36.2 years).[1] It is similar in histology to the monophasic spindle cell synovial sarcoma and contains cystic structures derived from dilated, trapped renal tubules. It is considered an aggressive tumor, with adverse patient outcomes in more than 50% of cases (n = 16).[2] Primary renal synovial sarcoma is characterized by the t(x;18)(p11;q11) SS18::SSX translocation. A second alternative gene fusion variant, SS18::NEDD4, has also been identified.

For more information about the clinical features and diagnostic evaluation of childhood kidney tumors, see the sections on Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor.

Treatment of Primary Renal Synovial Sarcoma

Although no standard treatment guidelines exist, surgery is considered the treatment of choice. Chemotherapy (ifosfamide with doxorubicin or epirubicin) has been used in about 31% of cases in the adjuvant setting.[1] The chemotherapy regimens used differ from those traditionally used for Wilms tumor.[3]

References

1. Blas L, Roberti J: Primary Renal Synovial Sarcoma and Clinical and Pathological Findings: a Systematic Review. Curr Urol Rep 22 (4): 25, 2021. [PubMed: 33704587]
2. Schoolmeester JK, Cheville JC, Folpe AL: Synovial sarcoma of the kidney: a clinicopathologic, immunohistochemical, and molecular genetic study of 16 cases. Am J Surg Pathol 38 (1): 60-5, 2014. [PubMed: 24061517]
3. Argani P, Faria PA, Epstein JI, et al.: Primary renal synovial sarcoma: molecular and morphologic delineation of an entity previously included among embryonal sarcomas of the kidney. Am J Surg Pathol 24 (8): 1087-96, 2000. [PubMed: 10935649]

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.[1] Differentiation may occur after chemotherapy is administered.

Treatment of Nephroblastomatosis (Diffuse Hyperplastic Perilobar Nephroblastomatosis)

Left untreated, all patients with diffuse hyperplastic perilobar nephroblastomatosis have been reported to develop Wilms tumors.[1,2] Although most cases of diffuse hyperplastic perilobar nephroblastomatosis are bilateral, a few cases have been reported with unilateral occurrence.[1] Until recently, diffuse hyperplastic perilobar nephroblastomatosis had not been prospectively studied by any of the pediatric oncology groups. As a result, patients have been treated in a variety of ways (observation, multiple chemotherapeutic agents in a nonstandard manner, or flank radiation therapy).[2] Additionally, a consistent definition of diffuse hyperplastic perilobar nephroblastomatosis has not been uniformly applied to all cases.

Treatment options for diffuse hyperplastic perilobar nephroblastomatosis include the following:

1. Preoperative chemotherapy.[3]
2. Renal-sparing surgery. Given the high incidence of bilaterality and subsequent Wilms tumors, renal-sparing surgery may be indicated.[1]

Evidence (preoperative chemotherapy and surgery):

1. The Children’s Oncology Group AREN0534 (NCT00945009) study was the first clinical trial to prospectively enroll and uniformly treat patients with diffuse hyperplastic perilobar nephroblastomatosis. Patients were enrolled after having central radiological review. Diffuse hyperplastic perilobar nephroblastomatosis was defined as the cortical surface of the kidney being composed of hyperplastic rests, with the entire nephrogenic zone involved, and with a thick rind capping all of one or both kidneys. Patients were treated with induction chemotherapy consisting of vincristine and dactinomycin (regimen EE-4A) and had cross-sectional imaging at weeks 6 and 12. Therapy could be continued if the patient's disease was stable or decreasing. Maximum treatment duration was 19 weeks.[3][Level of evidence: C1]

   • Nine patients were enrolled, and the median age was 10 months. One patient was not evaluable based on radiological criteria for diffuse hyperplastic perilobar nephroblastomatosis. Eight patients had confirmed bilateral diffuse hyperplastic perilobar nephroblastomatosis and started chemotherapy without tissue diagnosis. One patient had an upfront partial nephrectomy that was found to have diffuse hyperplastic perilobar nephroblastomatosis in the specimen and was subsequently treated with EE-4A. All patients were alive at a median follow-up of 6.6 years (range, 4.5–9.1 years).
   • No patients were anephric. Fourteen of the 16 kidneys were functioning (87.5%).
   • Three of eight patients did not develop Wilms tumor. One of these patients had a complete radiographic response, one had a few sclerotic lesions at the end of therapy, and one had significant response but still had radiographic abnormalities.
   • Five of eight patients had Wilms tumor at some point in their disease: one at diagnosis, one during therapy, and three after therapy (at 2 months and again at 4 months, 6 months, and 8 months). Only one of the patients developed a Wilms tumor with anaplastic histology.
   • A 19-week course of EE-4A prevents some patients from developing Wilms tumor (three of eight), but it is not fully effective. The ideal duration of therapy remains unknown.
2. In a retrospective series of 52 patients with diffuse hyperplastic perilobar nephroblastomatosis (46 with confirmed diffuse hyperplastic perilobar nephroblastomatosis), 33 patients were treated with chemotherapy and/or radiation therapy initially, 16 patients underwent unilateral nephrectomy followed by adjuvant therapy, and 3 patients were observed only.[1]

   • A total of 24 patients developed Wilms tumor (including the 3 patients who were observed only), at a median of 30 months.
   • Eighteen of the 33 patients who received chemotherapy alone developed a Wilms tumor.
   • Of 16 patients who underwent a nephrectomy and adjuvant therapy, 3 developed Wilms tumor, despite the fact that 14 of 16 patients had bilateral disease.
   • Thirty-three percent of the patients who developed Wilms tumor had anaplastic Wilms tumor at some time during their course, probably as a result of selection of chemotherapy-resistant tumors; thus, early detection is critical.

References

1. Perlman EJ, Faria P, Soares A, et al.: Hyperplastic perilobar nephroblastomatosis: long-term survival of 52 patients. Pediatr Blood Cancer 46 (2): 203-21, 2006. [PubMed: 15816029]
2. Furtwängler R, Schmolze M, Gräber S, et al.: Pretreatment for bilateral nephroblastomatosis is an independent risk factor for progressive disease in patients with stage V nephroblastoma. Klin Padiatr 226 (3): 175-81, 2014. [PubMed: 24819388]
3. Ehrlich PF, Tornwall B, Chintagumpala MM, et al.: Kidney Preservation and Wilms Tumor Development in Children with Diffuse Hyperplastic Perilobar Nephroblastomatosis: A Report from the Children's Oncology Group Study AREN0534. Ann Surg Oncol 29 (5): 3252-3261, 2022. [PMC free article: PMC9254258] [PubMed: 35072864]

References

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PMC free article: PMC2881732] [PubMed: 20404250]
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed August 23, 2024.

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 in the care of their 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:

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• be cited with text, or
• replace or update an existing article that is already cited.

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:

• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Andrea A. Hayes-Dixon, MD, FACS, FAAP (Howard University)
• Michael V. Ortiz, MD (Memorial Sloan Kettering Cancer Center)
• Nita Louise Seibel, MD (National Cancer Institute)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)
• Malcolm A. Smith, MD, PhD (National Cancer Institute)

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Levels of Evidence

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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]

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