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Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®)

  • Last Modified: 06/27/2014

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Table of Contents

General Information About Childhood Kidney Tumors

Wilms Tumor
Incidence
Syndromes and Other Conditions Associated With Wilms Tumor
        Syndromic causes of Wilms tumor
        Nonsyndromic causes of Wilms tumor
Genes Associated With Wilms Tumor
        Wilms tumor 1 gene (WT1)
        Wilms tumor 2 locus (WT2)
        Wilms tumor gene on the X chromosome (WTX)
        Other genes and chromosomal alterations
Bilateral Wilms Tumor
Screening Children Predisposed to Wilms Tumor
        Genetic counseling
Clinical Features
Diagnostic and Staging Evaluation
Prognosis and Prognostic Factors
        Adolescents and young adults with Wilms tumor
Histologic Findings in Wilms Tumor
        Favorable histology (FH)
        Anaplastic histology
        Nephrogenic rests
Stage Information for Wilms Tumor
        Stage I
        Stage II
        Stage III
        Stage IV
        Stage V
Treatment for Wilms Tumor
        Treatment overview
        Standard treatment options for stage I Wilms tumor
        Standard treatment options for stage II Wilms tumor
        Standard treatment options for stage III Wilms tumor
        Standard treatment options for stage IV Wilms tumor
        Treatment options for stage V and those predisposed to developing bilateral Wilms tumor
        Treatment options under clinical evaluation
        Follow-up after treatment
        Late effects following Wilms tumor therapy

Renal Cell Carcinoma (RCC)

Rhabdoid Tumors of the Kidney

Clear Cell Sarcoma of the Kidney

Congenital Mesoblastic Nephroma

Ewing Sarcoma (Neuroepithelial Tumor) of the Kidney

Desmoplastic Small Round Cell Tumor of the Kidney

Cystic Partially Differentiated Nephroblastoma

Multilocular Cystic Nephroma

Primary Renal Synovial Sarcoma

Anaplastic Sarcoma of the Kidney

Nephroblastomatosis

Treatment of Recurrent Childhood Kidney Tumors

Changes to This Summary (06/27/2014)

About This PDQ Summary

Get More Information From NCI

General Information About Childhood Kidney Tumors

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer need to be referred to medical centers that have multidisciplinary teams of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for more information.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials under the auspices of cooperative groups such as the Children's Oncology Group (COG), the Children's Cancer and Leukaemia Group (CCLG), and the Société Internationale d’Oncologie Pédiatrique (SIOP). Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2006, childhood cancer mortality decreased by more than 50%.[1] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood kidney cancers account for about 7% of all childhood cancers. Most childhood kidney cancers are Wilms tumor, but in the 15- to 19-year age group, most tumors are renal cell carcinoma. Wilms tumor can affect one kidney (unilateral) or both kidneys (bilateral). Other types of childhood kidney tumors include rhabdoid tumors, clear cell sarcoma, congenital mesoblastic nephroma, neuroepithelial tumors, desmoplastic small round cell tumor, cystic partially differentiated nephroblastoma, multilocular cystic nephroma, primary renal synovial sarcoma, and anaplastic sarcoma. Nephroblastomatosis of the kidney is a type of nonmalignant neoplasia.[3,4]

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.  [PUBMED Abstract]

  2. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.  [PUBMED Abstract]

  3. 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 Abstract]

  4. 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 Abstract]

Wilms Tumor



Incidence

The incidence of Wilms tumor is 7.1 cases per 1 million children younger than 15 years. Approximately 500 cases of Wilms tumor are diagnosed in the United States each year. The incidence is substantially lower in Asians. The male to female ratio in unilateral cases of Wilms tumor is 0.92:1.00, but in bilateral cases it is 0.60:1.00. The mean age at diagnosis is 44 months in unilateral cases of Wilms tumor and 31 months in bilateral cases.[1,2] About 10% of children with Wilms tumor have an associated congenital malformation syndrome.[3]

Syndromes and Other Conditions Associated With Wilms Tumor

Wilms tumor typically develops in otherwise healthy children; however, approximately 10% of children with Wilms tumor have been reported to have a congenital anomaly.[3,4] Of 295 consecutive patients with Wilms tumors seen at the Institute 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.[5] Children with Wilms tumors may have associated hemihypertrophy and urinary tract anomalies, including cryptorchidism and hypospadias. Children may have a recognizable phenotypic syndrome (including 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 nonovergrowth categories. Overgrowth syndromes and conditions are the result of excessive prenatal and postnatal somatic growth.[6,7]

Table 1. Syndromes and Conditions Associated With Wilms Tumor
Syndrome/Condition  Gene Overgrowth Phenotype  Nonovergrowth Phenotype 
WAGR = Wilms tumor, aniridia, genitourinary anomaly, and mental retardation.
9q22.3 microdeletion syndrome9q22.3X
Beckwith-Wiedemann syndromeWT2 X
Isolated hemihypertrophyX
Perlman syndromeDIS3L2 X
Simpson-Golabi-Behemel syndromeGPC3 X
Sotos syndromeNSD1 X
Bloom syndromeBLM X
Denys-Drash syndromeWT1 X
Familial Wilms tumorFWT1 X
FWT2
Frasier syndromeWT1 X
Genitourinary anomaliesWT1 X
Fanconi anemia with biallelic mutations in BRCA2 (FANCD1) or PALB2 (FANCN)BRCA2 X
PALB2
Li-Fraumeni syndromeTP53 X
CHEK2
Sporadic aniridiaWT1 X
Trisomy 18X
WAGR syndromeWT1 X

For information about the genes associated with Wilms tumor, including Wilms tumor 1 (WT1) and Wilms tumor 2 (WT2), refer to the Genes Associated With Wilms Tumor section of this summary.

Syndromic causes of Wilms tumor
  • WT1-related syndromes include the following:
    • WAGR syndrome. WAGR syndrome is characterized by Wilms tumor, aniridia, genitourinary anomaly, and mental retardation. The constellation of WAGR syndrome occurs in association with an interstitial deletion on chromosome 11 (del(11p13)) (prevalence is about 0.4% of children with Wilms tumors).[8,9] The incidence of bilateral Wilms tumor in children with WAGR syndrome is about 15%.[10] (Refer to the WT1 deletion and WAGR syndrome section of this summary for more information.)

    • Denys-Drash syndrome and Frasier syndrome. Genitourinary anomalies including hypospadias, undescended testis, and others are associated with WT1 deletions (prevalence is about 8%–10% of children with Wilms tumor). Children with pseudo-hermaphroditism and/or renal disease (glomerulonephritis or nephrotic syndrome) who develop Wilms tumor may have Denys-Drash or Frasier syndrome (characterized by male hermaphroditism, primary amenorrhea, chronic renal failure, and other abnormalities),[11] both of which are associated with mutations in the WT1 gene.[12] Specifically, germline missense mutations in the WT1 gene are responsible for most Wilms tumors that occur as part of Denys-Drash syndrome.[13,14] The risk of Wilms tumor is about 90% for children with Denys-Drash syndrome.[14]

  • WT2-related syndromes include the following:
    • Beckwith-Wiedemann syndrome. Beckwith-Wiedemann syndrome is an overgrowth syndrome characterized by asymmetric growth of one or more parts of the body, large tongue, omphalocele or umbilical hernia at birth, creases or pits in the skin near the ears, hypoglycemia (in infants), and kidney abnormalities. It is also characterized by the development of Wilms tumor, rhabdomyosarcoma, and hepatoblastoma. It is caused by either altered methylation at the imprinted 11p15 region or mutation in that region. The prevalence is about 1% of children with Wilms tumor.[15-18] Between 20% and 30% of Beckwith-Wiedemann syndrome patients will develop Wilms tumor.[17] (Refer to the WT2 and Beckwith-Wiedemann syndrome section of this summary for more information.)

  • Other syndromes include the following:
    • Perlman syndrome. Perlman syndrome is characterized by fetal gigantism, renal dysplasia, Wilms tumor, islet cell hypertrophy, multiple congenital anomalies, and mental retardation.[19,20] Germline inactivating mutations in DIS3L2 on chromosome 2q37 are associated with Perlman syndrome.[21]

    • Simpson-Golabi-Behemel syndrome. Simpson-Golabi-Behemel syndrome is characterized by macroglossia, macrosomia, renal and skeletal abnormalities, and increased risk of embryonal cancers. It is caused by mutations in GPC3 and is believed to enhance the risk of Wilms tumor.[22]

    • Sotos syndrome. Sotos syndrome is characterized by cerebral gigantism and learning disability, ranging from mild to severe. Sotos syndrome is associated with behavioral problems, congenital cardiac anomalies, neonatal jaundice, and renal anomalies such as Wilms tumor, scoliosis, and seizures. NSD1 is the only gene in which mutations are known to cause Sotos syndrome.[23]

    • 9q22.3 microdeletion syndrome. 9q22.3 microdeletion syndrome is characterized by craniofacial abnormalities, metopic craniosynostosis, hydrocephalus, macrosomia, and learning disabilities. Three patients presented with Wilms tumor in addition to a constitutional 9q22.3 microdeletion and dysmorphic/overgrowth syndrome. Although the size of the deletions was variable, all encompassed the PTCH1 gene.[24]

    • Bloom syndrome. Bloom syndrome is characterized by short stature and being thinner than other family members, sun-sensitive skin changes, and an increased risk of Wilms tumor. BLM is the only gene in which mutations are known to cause Bloom syndrome.[25]

    • Li-Fraumeni syndrome. Li-Fraumeni syndrome is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults. The cancers most often associated with Li-Fraumeni syndrome include breast cancer, osteosarcoma, soft tissue sarcoma, brain tumor, leukemia, adrenocortical carcinoma, and Wilms tumor. The TP53 gene mutation is present in most families with Li-Fraumeni syndrome. The CHEK2 gene mutation is also known to cause Li-Fraumeni syndrome.[26]

    • Alagille syndrome.[27]

Nonsyndromic causes of Wilms tumor

Nonsyndromic causes of Wilms tumor include the following:

  • Familial Wilms tumor. Despite the number of genes that appear to be involved in the development of Wilms tumor, familial Wilms tumor is uncommon, with approximately 2% of patients having a positive family history for Wilms tumor. Siblings of children with Wilms tumor have a less than 1% chance of developing Wilms tumor.[28-30] The risk of Wilms tumor among offspring of persons who have had unilateral (sporadic) tumors is less than 2%.[31]

    Two familial Wilms tumor genes have been localized to FWT1 (17q12-q21) and FWT2 (19q13.4).[32-34] There are occasional Wilms tumor families with a germline mutation in WT1. In these families, most, but not all, family members have genitourinary tract malformations.[35,36]

  • WT1-related.
    • Sporadic aniridia. Sporadic aniridia may result from small germline deletions of one copy of the PAX6 gene that includes part or all of the adjacent WT1 gene but does not result in genitourinary abnormalities or retardation (i.e., not obviously WAGR syndrome). Therefore, many patients with sporadic aniridia develop Wilms tumors and are candidates for screening. The relative risk of Wilms tumor in sporadic aniridia is 67-fold.[37] About half of individuals with sporadic aniridia and PAX6 and WT1 deletions develop Wilms tumor.[38]

  • Isolated hemihypertrophy. Hemihypertrophy is an asymmetric overgrowth of one or more body parts and is associated with Wilms tumor. It can also be associated with other predisposition syndromes such as Beckwith-Wiedemann syndrome. Clinical signs may not be very evident, and hemihypertrophy may be noted after tumor diagnosis. The overall Wilms tumor incidence was 5.9% in a study of 168 patients with isolated hemihypertrophy.[39] The prevalence is about 2.5% of children with Wilms tumor.[15,39]

  • Trisomy 18.[40]

  • Fanconi anemia with biallelic mutations in BRCA2 (FANCD1) or PALB2 (FANCN). BRCA2 and PALB2 play central roles in homologous recombination DNA repair. Biallelic mutations in either BRCA2 or PALB2 lead to Fanconi anemia and to increased risks of selected childhood cancers, including Wilms tumor.[41-43]

Genes Associated With Wilms Tumor

Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of at least ten genes. The changes may be somatic or germline. Several genes, but not all, will be discussed here.

Aberrations in germline or clonal WT1, WT2, and Wnt activation, when combined with stage of development of the nephron, characterize different subsets of Wilms tumor that can be differentiated by using gene expression profiling. This genetic/ontogenic categorization describes some of the heterogeneity among Wilms tumors.[44]

Wilms tumor 1 gene (WT1)

The WT1 gene is located on the short arm of chromosome 11 (11p13). The normal function of WT1 is required for normal genitourinary development and is important for differentiation of the renal blastema.

When modern molecular genetic techniques are used in testing, the incidence of germline WT1 mutations is about 11%. Most of these mutations may be diagnosed, or at least highly suspected, on the basis of clinical syndromic findings at or before diagnosis of Wilms tumor. In a United Kingdom Children's Cancer Study Group study of patients entered in clinical trials, about 2% of Wilms tumor patients had germline mutations in WT1 but no genitourinary abnormalities, as detected by WT1 heteroduplex DNA screen followed by sequencing.[36] These were mostly de novo mutations in children presenting before age 2 years, and the tumors were mostly unilateral with stromal histology. The relatively low number of reports of parent and child pairs with Wilms tumors and WT1 mutations may be the result of decreased fertility. However, the offspring of a child who has a parent with Wilms tumor and WT1 mutation will be at risk for developing Wilms tumor.

Germline WT1 mutations in children with Wilms tumors do not confer poor prognoses per se.

Because deletion of WT1 was the first mutation found to be associated with Wilms tumor, WT1 was assumed to be a conventional tumor suppressor gene. However, non-inactivating mutations can result in altered WT1 protein function that also results in Wilms tumor, such as in Denys-Drash syndrome.

WT1 mutations are more common in children with Wilms tumor and one of the following:

  • WAGR syndrome, Denys-Drash syndrome,[14] or Frasier syndrome.[11]
  • Genitourinary anomalies, including hypospadias and cryptorchidism.
  • Bilateral Wilms tumor.
  • Unilateral Wilms tumor with nephrogenic rests in the contralateral kidney.
  • Stromal and rhabdomyomatous differentiation.
WT1 deletion and WAGR syndrome

The observation that led to the discovery of WT1 was that children with WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) were at high risk (>30%) for developing Wilms tumor. Germline mutations were then identified at chromosome 11p13 in children with WAGR syndrome. Deletions involved a set of contiguous genes that included WT1 and the PAX6 gene.

Inactivating mutations or deletions in the PAX6 gene lead to aniridia, while deletion of WT1 confers the increased risk of Wilms tumor. Some of the sporadic cases of aniridia are caused by large chromosomal deletions that also include WT1. This results in a 67-fold increased relative risk (95% confidence interval [CI], 8.1–241) of developing Wilms tumor in children with sporadic aniridia.[37] The incidence of Wilms tumor in children with sporadic aniridia is estimated to be about 5%.[10] Seventy-seven percent of aniridia patients with submicroscopic WT1 deletions detectable by high-resolution fluorescence in situ hybridization (FISH) analysis presented with Wilms tumor compared with 42.5% of aniridia patients with visible deletions detected by microscopy.[45] Patients with sporadic aniridia and a normal WT1 gene, however, are not at increased risk of developing Wilms tumor. Children with familial aniridia, generally occurring for many generations, and without renal abnormalities, have a normal WT1 gene and are not at an increased risk of Wilms tumor.[15,46]

Children with WAGR syndrome or other germline WT1 mutations are at increased risk of developing hypertension, nephropathy, and renal failure and are monitored throughout their lives.[47] Patients with Wilms tumor and aniridia without genitourinary abnormalities are at less risk but are monitored for nephropathy or renal failure.[48] Children with Wilms tumor and any genitourinary anomalies are also at increased risk for late renal failure and are monitored. Features associated with germline WT1 mutations that increase the risk of developing renal failure include the following:[47]

  • Stromal predominant histology.
  • Bilateral disease.
  • Intralobar nephrogenic rests.
  • Wilms tumor diagnosed before age 2 years.

Age at tumor diagnosis, frequency of bilaterality, and risk of late-onset renal compromise may vary with the type of mutation.[13]

The mental retardation in WAGR syndrome may be secondary to deletion of other genes, including SLC1A2 or BDNF (brain-derived neurotrophic factor).[49]

WT1 mutations and 11p15 loss of heterozygosity were associated with relapse in patients with very low-risk Wilms tumor in one study of 56 patients who did not receive chemotherapy.[50] These findings await validation but may provide biomarkers by which to stratify patients in the future.

WT1 interaction with beta-catenin

Activating mutations of the beta-catenin gene (CTNNB1) have been reported to occur in 15% of Wilms tumor patients. In one study, all but one tumor with a beta-catenin mutation had a WT1 mutation, and at least 50% of the tumors with WT1 mutations had a beta-catenin mutation.[51,52] Activation of beta-catenin in the presence of intact WT1 protein appears to be inadequate to promote tumor development because CTNNB1 mutations are rarely found in the absence of a WT1 or WTX mutation.[53,54] About one-third of Wilms tumors have a somatic mutation in WT1, WTX, and/or CTNNB1.[53]

Wilms tumor 2 locus (WT2)

When modern molecular genetic techniques are used in testing, the incidence of germline WT2 aberrations is about 8%. Most of these aberrations may be diagnosed, or at least highly suspected, on the basis of clinical syndromic findings at or before diagnosis of Wilms tumor.[55] However, when 437 children with nonsyndromic Wilms tumor were screened for germline mutations in the WT2 locus, 13 mutations (3% of patients) were found. None of these children had signs of Beckwith-Wiedemann syndrome, although they did have a higher frequency of bilateral tumors and perilobar nephrogenic rests. All were de novo abnormalities, except one novel microdeletion in one child, and their mother was not affected. A similar mutation at the WT2 locus was found in 1 of 22 familial Wilms tumor families tested.[49]

WT2 and Beckwith-Wiedemann syndrome

A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5, which, when it is a germline mutation, causes the Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumors have germline epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. Like children with Beckwith-Wiedemann syndrome, these children have an increased incidence of bilateral Wilms tumor or familial Wilms tumor.[49]

Several candidate genes at the WT2 locus comprise the two independent imprinted domains IGF2/H19 and KIP2/LIT1.[56] Loss of heterozygosity, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations. A study of 35 sporadic primary Wilms tumors suggests that more than 80% have somatic loss of heterozygosity or loss of imprinting at 11p15.5.[57] The mechanism resulting in loss of imprinting can be either genetic mutation or epigenetic change of methylation.[49,56] Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5.[58] Interestingly, Wilms tumors in Asian children are not associated with either nephrogenic rests or IGF2 loss of imprinting.[59]

Beckwith-Wiedemann syndrome results from loss of imprinting or heterozygosity of WT2 germline mutations. Observations suggest genetic heterogeneity in the etiology of Beckwith-Wiedemann syndrome, with differing levels of association with risk of tumor formation.[60] Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[15-17] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the National Wilms Tumor Study (NWTS).[1,17]

A relationship between epigenotype and phenotype has been shown in Beckwith-Wiedemann syndrome, with a different rate of cancer in Beckwith-Wiedemann syndrome according to the type of alteration of the 11p15 region.[61] The overall tumor risk in Beckwith-Wiedemann syndrome was estimated between 5% and 10%, with a risk between 1% (loss of imprinting at IC2) and 30% (gain of methylation at IC1 and paternal 11p15 isodisomy). Patients with IC1 gain of methylation only developed Wilms tumor, whereas other tumors such as neuroblastoma or hepatoblastoma could occur in patients with paternal 11p15 isodisomy.[62]

Wilms tumor gene on the X chromosome (WTX)

A third gene, WTX, has been identified on the X chromosome and plays a role in normal kidney development. This gene is inactivated in approximately one-third of Wilms tumors, but germline mutations have not been observed in patients with Wilms tumor.[63] WTX mutations are equally distributed between males and females. WTX inactivation is a frequent, but late, event in tumorigenesis and has no apparent effect on clinical presentation or prognosis.[64]

Other genes and chromosomal alterations

Additional genes have been implicated in the pathogenesis and biology of Wilms tumor, including the following:

  • 1q: Gain of 1q or overexpression of genes from 1q has been associated with an adverse outcome.

    In an analysis of 212 patients from NWTS-4 and the Pediatric Oncology Group Wilms Biology study, 27% of patients displayed 1q gain. A strong relationship between 1q gain and 1p/16q loss was observed. The 8-year event-free survival (EFS) rate was 76% (95% CI, 63%–85%) for patients with 1q gain and 93% (95% CI, 87%–96%) for those lacking 1q gain (P = .0024). The 8-year overall survival (OS) rate was 89% (95% CI, 78%–94%) for those with 1q gain and 98% (95% CI, 94–99%) for those lacking 1q gain (P = .0075). Gain of 1q was not found to correlate with disease stage. After stratification for stage of disease, 1q gain was associated with a significantly increased risk of disease recurrence (risk ratio estimate, 2.72; P = .0089).[65]

    Similar results have been reported by European investigators.[66]

  • 16q and 1p: Additional tumor-suppressor or tumor-progressive genes may lie on chromosomes 16q and 1p as evidenced by loss of heterozygosity for these regions in 17% and 11% of Wilms tumors, respectively.[67]
    • In large NWTS studies, patients with tumor-specific loss of these loci had significantly worse relapse-free survival (RFS) and OS rates. Combined loss of 1p and 16q are used to select favorable-histology (FH) Wilms tumor patients for more aggressive therapy in the current 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 loss of heterozygosity.[68]

    • 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.[69]

    These conflicting results may arise from the greater prognostic significance of 1q gain described above. The loss of heterozygosity of 16q and 1p appear to arise from complex chromosomal events that result in 1q loss of heterozygosity or 1q gain. The change in 1q appears to be the critical tumorigenic genetic event.[65]

  • CACNA1E: Overexpression and amplification of the gene CACNA1E located at 1q25.3, which encodes the ion-conducting alpha-1 subunit of R-type voltage-dependent calcium channels, may be associated with relapse in FH Wilms tumor.[70]

  • 7p21: A consensus region of loss of heterozygosity has been identified in 7p21 containing ten known genes, including two candidate tumor suppressor genes (Mesenchyme homeobox 2 [MEOX2] and Sclerostin domain containing 1 [SOSTDC1]).[71]

  • SKCG-1: Somatic loss of a growth regulatory gene, SKCG-1, located at 11q23.2, was found in 38% of examined sporadic Wilms tumors, particularly the highly proliferative Wilms tumors. Additional studies of siRNA silencing of the SKCG-1 gene in human embryonic kidney epithelial cells resulted in a 40% increase in cell growth, suggesting that this gene may be involved in loss of growth regulation and Wilms tumorigenesis.[72]

  • TP53 (tumor suppressor gene): Most anaplastic Wilms tumors show mutations in the p53 tumor suppressor gene. It may be useful as an unfavorable prognostic marker.[73,74] Microdissection of focally anaplastic Wilms tumors demonstrated TP53 mutation in anaplastic but not nonanaplastic areas of the tumor, suggesting that acquisition of TP53 mutation may be inherent in the process of becoming anaplastic.[75]

  • FBXW7: FBXW7, a ubiquitin ligase component, has been identified as a novel Wilms tumor gene. Mutations of this gene have been associated with epithelial-type tumor histology.[76]

  • PTCH1: Patients with germline 9q22.3 microdeletion syndrome have an increased risk of Wilms tumor. PTCH1 has a role in the pathogenesis of nephroblastoma. This is supported by the germline deletion of one copy of the PTCH1 gene in all described patients, as well as the presence of a nonsense mutation in the remaining allele in a Wilms tumor of one of the patients.[24]

  • DICER1: Germline mutations in DICER1 have been associated with a pleiotropic tumor predisposition syndrome, and Wilms tumor is a rare manifestation of this syndrome. A subset of Wilms tumors have been reported to exhibit two “hits” in DICER1, suggesting that these mutations could be key events in the pathogenesis of these tumors.

    The pathology of WT1-associated and DICER1-associated Wilms tumors appears to differ. WT1-associated Wilms tumors are often stromal rich, with rhabdomyomatous differentiation and intralobar nephrogenic rests that are thought to occur early in renal development, while DICER1-associated Wilms tumors are triphasic with abundant blastema and are not associated with nephrogenic rests.[77]

  • MYCN: Genomic gain or amplification of MYCN is relatively common in Wilms tumors and associated with diffuse anaplastic histology.[76]

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; however, 85% of individuals with WAGR or Beckwith-Wiedemann syndrome have unilateral tumors.[18,78]

Only 16% of persons with bilateral Wilms tumor have a WT1 germline mutation, and only 3% of persons with bilateral Wilms tumors have affected family members. Bilateral Wilms tumor with WT1 mutations are associated with early presentation in pediatric patients (age 10 months vs. age 39 months for those without a mutation) and a high frequency of WT1 nonsense mutations in exon 8.[79] The presence of bilateral or multifocal disease implies that a patient has a genetic predisposition for Wilms tumor.

Screening Children Predisposed to Wilms Tumor

Children with a significantly 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 ultrasound every 3 months at least until they reach age 8 years.[6,7,15,46] Early-stage, asymptomatic, small Wilms tumors may be discovered and potentially removed with renal-sparing surgery.[46]

Tumor screening programs for each overgrowth syndrome have been suggested, based on published age and incidence of tumor type.[7] Approximately 10% 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.[80] Children with hemihypertrophy are also at risk for developing liver and adrenal tumors. Screening with abdominal ultrasound and serum alpha-fetoprotein is suggested until age 4 years. After age 4 years, most hepatoblastomas will have occurred, and imaging may be limited to renal ultrasound, which is quicker and does not require fasting before the exam.[81]

Newborns with sporadic aniridia are usually screened with ultrasound every 3 months until they reach age 8 years, unless genetic testing confirms that they are negative for WT1 deletion.[46,82]

Although the risk for Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown and likely varies with the gene in which the mutation occurred, some experts recommend screening such children with serial ultrasound examinations every 3 months until age 8 years.[83]

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 NWTS database. Routine ultrasound surveillance is not recommended.[84]

Genetic counseling

The frequency of malformations observed in patients with Wilms tumor underlines the need for genetic counseling, molecular and genetic explorations, and follow-up.

A French study [5] concluded that patients need to be referred for genetic counseling if they have one of the following:

  • One major abnormality such as:
    • Beckwith-Wiedemann symptoms (macroglossia, neonatal or postnatal macrosomia, abdominal wall defects, or visceromegaly); or
  • One condition such as:
    • Hemihypertrophy.
    • Overgrowth syndrome or mental retardation.
    • Aniridia.
    • Diffuse mesangial sclerosis.
  • Two or more minor malformations such as:
    • Inguinal or umbilical hernia.
    • Hypospadias.
    • Renal abnormalities.
    • Ectopic testis.

Simple oncological follow-up is indicated when there is no malformation or when there is only one minor malformation.[5]

After genetic counseling takes place, a search for WT1 mutations should be considered for patients who have the following:

  • Bilateral Wilms tumor.
  • Familial Wilms tumor.
  • Wilms tumor and age younger than 6 months.
  • Genitourinary abnormality.
  • Mental retardation association.

A search for an 11p15 abnormality should be considered for patients exhibiting any symptoms of Beckwith-Wiedemann syndrome, hemihypertrophy, or bilateral or familial Wilms tumor.

Clinical Features

The following symptoms may be caused by Wilms or other childhood kidney tumors:

  • A lump, swelling, or pain in the abdomen. Most children present with an asymptomatic mass that is noted when they are bathed or dressed. Abdominal pain is present in 40% of children.

  • Fever. Fever is occasionally noted.

  • Blood in the urine. Although gross hematuria occurs in about 25% of children with Wilms tumor, most children with gross hematuria do not have Wilms tumor.[85]

  • Hypertension. About 25% of children have hypertension at presentation, which is caused by excessive renin excretion and responds to angiotensin-converting enzyme (ACE) inhibitors or surgical removal of the tumor.[86]

  • Hypercalcemia. Symptomatic hypercalcemia can sometimes be seen at presentation of rhabdoid tumors.

Children with Wilms tumors or other renal malignancies may also come to medical attention as a result of the following:

  • Vascular obstruction or metastasis, including pulmonary symptoms due to lung metastasis.
  • Abdominal pain due to liver metastasis, prominent abdominal wall vessels, or varicocele due to inferior vena cava obstruction.
  • Pulmonary embolus (rare).
Diagnostic and Staging Evaluation

About 5% of renal masses thought to be Wilms tumor on the basis of clinical and radiological findings are diagnosed as another condition.[87,88] The German Pediatric Oncology study group entered 188 patients on the SIOP-9 trial from 1988 to 1991. However, only 136 patients received preoperative chemotherapy because imaging was regarded as atypical on central review. Nine of the 188 patients (5%) had other diagnoses, including benign tumors and renal cell carcinoma.[88]

Tests and procedures used to evaluate and stage Wilms tumor and other childhood kidney tumors include the following:

  1. Physical exam and history.
  2. Complete blood count (CBC).
  3. Liver function test.
  4. Renal function test.
  5. Urinalysis.
  6. Abdominal imaging.
    • Abdominal X-ray.
    • Computed tomography (CT) scan with contrast or magnetic resonance imaging (MRI) of abdomen.
    • Ultrasound exam of the abdomen. Ultrasound exam of the abdomen is often performed before a more definitive CT scan with contrast or MRI with contrast of the abdomen is done. This procedure is unnecessary after the definitive diagnostic study has been performed.
  7. CT scan of chest.
  8. X-ray of the chest and bones.
  9. Bone scan.
  10. Cystoscopy.
  11. 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT. Wilms tumor is 18F-FDG avid, and 18F-FDG-PET-CT imaging adds clinically applicable information to conventional imaging, which 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.[89]
  12. von Willebrand disease work-up. About 1% to 8% of patients presenting with Wilms tumor have acquired von Willebrand disease, although many are asymptomatic. von Willebrand multimers bind to Wilms tumor, reducing the plasma concentration to low levels.[90] Some clinicians recommend evaluation for von Willebrand disease before surgery.
  13. Biopsy or resection. In children with a renal mass that clinically appears to be stage I or stage II Wilms tumor, biopsy is not performed so that tumor cells are not spread during the biopsy. 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 for Wilms tumor. Biopsy tissue from inoperable Wilms tumor obtained before chemotherapy may be used for histologic review and initial treatment decisions. The use of biopsy to determine histology in an inoperable tumor remains controversial because biopsy may cause local tumor spread.[91] It is important to recognize that data from NWTS-4 and NWTS-5 have shown conclusively that, because of histologic heterogeneity of Wilms tumor, a significant number of patients have unfavorable histology that is missed during an upfront biopsy but revealed at the time of definitive surgery following chemotherapy.

    If the initial imaging studies suggested a possible lesion on the contralateral kidney, the contralateral kidney is formally explored to rule out bilateral involvement. This is done before nephrectomy to exclude bilateral Wilms tumor.

    Biopsy is also controversial in patients with bilateral tumors because biopsy rarely detects anaplasia in bilateral Wilms tumor,[92] and the incidence of bilateral tumors being other than Wilms is very low. The current COG study of bilateral Wilms tumor and of patients with unilateral Wilms tumor predisposed to developing bilateral tumors tries to avoid initial biopsy and mandates biopsy after 6 weeks of three-drug chemotherapy.

Children with a renal mass are carefully assessed for signs of associated syndromes such as aniridia, developmental delay, hypospadias, cryptorchidism, pseudohermaphrodism, overgrowth, and hemihypertrophy.

For patients with suspected Wilms tumor, preoperative staging studies include a CT or MRI scan of the abdomen/pelvis and chest to assess intravascular extension or rupture of Wilms tumor.[93]

  • 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 after CT has been performed but is not necessarily required.[94] Large tumor thrombi need to be controlled before surgical approach to the renal mass.

  • Wilms tumor rupture. CT has moderate specificity but relatively low sensitivity in the detection of preoperative Wilms tumor rupture. Ascites beyond the cul-de-sac is most predictive of preoperative Wilms tumor rupture, irrespective of attenuation. In the presence of ascites, fat stranding around the tumor and the presence of retroperitoneal fluid are highly predictive of rupture.[95]

Prognosis and Prognostic Factors

Wilms tumor is a curable disease in most affected children. Since the 1980s, the 5-year survival rate for Wilms tumor with FH has been consistently above 90%.[96] This favorable outcome occurred despite reductions in the length of therapy, dose of radiation, extent of fields irradiated, and the percentage of patients receiving radiation therapy.[97]

The prognosis for patients with Wilms tumor depends on the following:[98-101]

  • Stage of disease at diagnosis.
  • Tumor size.
  • Histopathologic features of the tumor (FH vs. anaplastic histology). (Refer to the Histologic Findings in Wilms Tumor section of this summary for more information.)
  • Molecular features of the tumor. B7-H1, an immune costimulatory molecule, has been found to be associated with an increased risk of tumor recurrence in favorable histology Wilms tumor.[102]
  • Patient age (adolescents and young adults).
Adolescents and young adults with Wilms tumor

In an analysis of Wilms tumor patients in the Surveillance, Epidemiology, and End Results (SEER) database, adults (n = 152) had a statistically worse OS (69% vs. 88%, P < .001) than did pediatric patients (n = 2,190),[103] despite previous studies showing comparable outcome with treatment on protocol.[104,105] The inferior outcome of the adult patients on this study may be the result of differences in tumor biology between children and adults, incorrect diagnosis, inadequate staging (e.g., more likely to be staged as localized disease or to not receive lymph node sampling), or undertreatment (e.g., not receiving radiation therapy). Additional factors in this SEER report that may have contributed to a worse OS in adult patients include the size of the study and lack of central review of pathology.[103] Adolescent and young adult patients up to age 30 years are now eligible for treatment on the COG Wilms tumor protocols.

The inferior outcome of older patients is not explained entirely by inadequate treatment or not being treated according to the pediatric Wilms tumor protocol. In a U.K. study looking at the outcome of patients aged 10 to 16 years (N = 50) registered on the U.K. Wilms Tumor 3 and SIOP 2001 Wilms tumor trials, patients in this age group had a higher percentage of diffuse anaplastic tumors. The overall 5-year survival was 63% for patients aged 10 to 16 years (43% for anaplastic tumors), which is significantly lower than the outcome for younger patients with Wilms tumor.[106] However, SEER 5-year relative survival of nephroblastoma between 2003 and 2009 did not show differences among age groups from younger than 1 year to age 10 to 14 years.[107]

Histologic Findings in Wilms Tumor

Although most patients with a histologic diagnosis of Wilms tumor do well with current treatment, approximately 10% of patients have histopathologic features that are associated with a worse prognosis, and in some types, with a high incidence of relapse and death. Wilms tumor can be separated into the following two prognostic groups on the basis of tumor and kidney histopathology:

Favorable histology (FH)

Histologically, Wilms tumor mimics the triphasic development of a normal kidney consisting of blastemal, epithelial (tubules), and stromal cell types. Not all tumors are triphasic, and monophasic patterns may present diagnostic difficulties.

While associations between histologic features and prognosis or responsiveness to therapy have been suggested, with the exception of anaplasia, none of these features have reached statistical significance in North American treatment algorithms, and therefore, do not direct the initial therapy.[108]

Anaplastic histology

Anaplastic histology accounts for about 10% of Wilms tumors. Anaplastic histology is the single most important histologic predictor of response and survival in patients with Wilms tumor. Tumors occurring in older patients (aged 10–16 years) have a higher incidence of anaplastic histology.[106] In bilateral tumors, 12% to 14% have been reported to have anaplastic histology in one kidney.[109,110]

The following two histologic criteria must be present for the diagnosis of anaplasia:

  • Presence of multipolar polyploid mitotic figures with marked nuclear enlargement.
  • Hyperchromasia.

Changes on 17p consistent with mutations in the p53 gene have been associated with foci of anaplastic histology.[73] Focal anaplasia is defined as the presence of one or more sharply localized regions of anaplasia in a primary tumor. All of these factors lend support to the hypothesis that anaplasia evolves as a late event from a subpopulation of Wilms tumor cells that have acquired additional genomic lesions.[111] Focal anaplasia does not confer as poor a prognosis as does diffuse anaplasia.[100,112,113]

Anaplasia correlates best with responsiveness to therapy rather than to tumor aggressiveness. It is most consistently associated with poor prognosis when it is diffusely distributed and when identified at advanced stages. These tumors are more resistant to the chemotherapy traditionally used in children with FH Wilms tumor.[100]

Nephrogenic rests

Nephrogenic rests are abnormally retained embryonic kidney precursor cells arranged in clusters. Nephrogenic rests are found in about 1% of unselected pediatric autopsies, 35% of kidneys with unilateral Wilms tumors, and nearly 100% of kidneys with bilateral Wilms tumors.[114,115]

The term nephroblastomatosis is defined as the presence of diffuse or multifocal nephrogenic rests. There are two types: intralobar nephrogenic rests and perilobar nephrogenic rests. Diffuse hyperplastic perilobar nephroblastomatosis is defined as nephroblastomatosis forming a thick rind around one or both kidneys and is considered a preneoplastic condition.[108]

The type and percentage of nephrogenic rests vary in patients with unilateral or bilateral disease. Patients with bilateral Wilms tumor have a higher proportion of perilobar rests (52%) than of intralobar or combined rests (32%) and higher relative proportions of rests, compared with patients with unilateral tumors (18% perilobar and 20% intralobar or both).[47]

Patients with any type of nephrogenic rest in a kidney removed for nephroblastoma are considered at increased risk for tumor formation in the remaining kidney. This risk decreases with patient age.[34]

Extrarenal nephrogenic rests are rare and may develop into extrarenal Wilms tumor.[116]

Stage Information for Wilms Tumor

Both the results of the imaging studies and the surgical and pathologic findings at nephrectomy are used to determine the stage of disease. The stage is the same for tumors with FH or anaplastic histology. Thus, the stage information is characterized by a statement of both criteria (for example, stage II, FH or stage II, anaplastic histology).[108,117]

The staging system was originally developed by the NWTS Group and is still used by the COG. The staging system and incidence by stage are outlined below.[108]

Stage I

In stage I Wilms tumor (43% of patients), all of the following criteria must be met:

  • Tumor is limited to the kidney and is completely resected.

  • The renal capsule is intact.

  • The tumor is not ruptured or biopsied before being removed.

  • No involvement of renal sinus vessels.

  • No evidence of the tumor at or beyond the margins of resection.

 [Note: For a tumor to qualify for certain therapeutic protocols such as very low-risk stage I, regional lymph nodes must be examined microscopically. Lymph node sampling is recommended for all patients.]

Stage II

In stage II Wilms tumor (20% of patients), the tumor is completely resected, and there is no evidence of tumor at or beyond the margins of resection. The tumor extends beyond the kidney as evidenced by any one of the following criteria:

  • There is regional extension of the tumor (i.e., penetration of the renal sinus capsule, or extensive invasion of the soft tissue of the renal sinus, as discussed below).

  • Blood vessels in the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor cells.

  • Vascular extension of tumor is considered stage II only if it is completely removed en bloc in the nephrectomy specimen.

 [Note: Rupture or spillage confined to the flank, including biopsy of the tumor, is now included in stage III by the COG Renal Tumor Committee; however, data to support this approach are controversial.[118]]

Stage III

In stage III Wilms tumor (21% of patients), there is postsurgical residual nonhematogenous tumor that is confined to the abdomen. Any one of the following may occur:

  • Lymph nodes in the abdomen or pelvis are involved by tumor. (Lymph node involvement in the thorax or other extra-abdominal sites is a criterion for stage IV.)

  • The tumor has penetrated through the peritoneal surface.

  • Tumor implants are found on the peritoneal surface.

  • Gross or microscopic tumor remains postoperatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination).

  • The tumor is not completely resectable because of local infiltration into vital structures.

  • Tumor spillage occurs either before or during surgery.

  • Any biopsy is performed, regardless of type—Tru-cut biopsy, open biopsy, or fine-needle aspiration—before the tumor is removed.

  • The tumor is removed in more than one piece (e.g., tumor cells are found in a separately excised adrenal gland; a tumor thrombus in the renal vein is removed separately from the nephrectomy specimen). Extension of the primary tumor in the vena cava into the thoracic vena cava and heart is considered stage III, rather than stage IV, even though outside the abdomen—and it can even be stage II if completely resected en bloc with the nephrectomy specimen.

Lymph node involvement and microscopic residual disease are highly predictive of outcome in patients with stage III FH Wilms tumor.[119]

Stage IV

In stage IV Wilms tumor (11% of patients), hematogenous metastases (lung, liver, bone, brain) or lymph node metastases outside the abdominopelvic region are present. The presence of tumor within the adrenal gland is not interpreted as metastasis and staging depends on all other staging parameters present. According to the criteria described above, the primary tumor is assigned a local stage, which determines local therapy. For example, a patient may have stage IV, local stage III disease.

Stage V

In stage V Wilms tumor (5% of patients), bilateral involvement by tumor is present at diagnosis. A previous attempt was made to stage each side according to the above criteria on the basis of the extent of disease. The ongoing COG-AREN0534 protocol is testing the approach of preoperative chemotherapy without local biopsy in hopes of reducing tumor size to allow renal-sparing surgical procedures. In these patients, renal failure rates approach 15% at 15 years posttreatment, making renal-sparing treatment important.[120]

Treatment for Wilms Tumor

Treatment overview

Because of the relative rarity of Wilms tumor, all patients with this tumor should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon and/or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) who have experience treating Wilms tumor is necessary to determine and implement optimal treatment.

Most randomized clinical studies for treatment of children with Wilms tumor have been conducted by two large clinical groups. There are differences between the two groups that affect staging and classification.

  • The COG (includes the previous NWTS Group): The NWTS Group established standard treatment for Wilms tumor in North America, consisting of initial nephrectomy followed by chemotherapy and, in some patients, radiation therapy.[121-123]

  • Société Internationale d’Oncologie Pédiatrique (SIOP): The SIOP is a European consortium, and their trials provide preoperative chemotherapy before definitive resection for patients with renal tumors.

This summary focuses on the NWTS (now COG Renal Tumor Committee) results and studies.

The major treatment and study conclusions of NWTS-1 through NWTS-5 are as follows:

  1. Routine, postoperative radiation therapy of the flank is not necessary for children with stage I tumors or stage II tumors with favorable histology (FH) when postnephrectomy combination chemotherapy consisting of vincristine and dactinomycin is administered.[123]

  2. The prognosis for patients with stage III FH is best when treatment includes either (a) dactinomycin, vincristine, doxorubicin, and 10.8 Gy of radiation therapy to the flank; or (b) dactinomycin, vincristine, and 20 Gy of radiation therapy to the flank. Whole abdominal radiation is indicated for extensive intraperitoneal disease or widespread intraperitoneal tumor spill.[123]

  3. The addition of cyclophosphamide at the protocol dose (10 mg/kg/d for 3 days every 6 weeks) to the combination of vincristine, dactinomycin, and doxorubicin does not improve prognosis for patients with stage IV FH tumors.[123]

  4. A single dose of dactinomycin per course (stages I–II FH, stage I anaplastic, stage III FH, stages III–IV, or stages I–IV clear cell sarcoma of the kidney) is equivalent to the divided-dose courses, results in the same EFS, achieves greater dose intensity, and is associated with less toxicity and expense.[124]

  5. Eighteen weeks of therapy is adequate for patients with stage I and II FH, whereas other patients can be treated with 6 months of therapy instead of 15 months.[97,121,124-126]

  6. Tumor-specific loss of heterozygosity for combined 1p and 16q predicts recurrence of FH Wilms tumor.[67]

Surgery

The following operative principles have also evolved from NWTS trials:

  1. The most important role for the surgeon is to ensure complete tumor removal without rupture and assess the extent of disease. Radical nephrectomy and lymph node sampling via a transabdominal or thoracoabdominal incision is the procedure of choice.[127] A flank incision is not performed because it provides limited exposure to the kidney. For patients with resectable tumors, preoperative or intraoperative biopsy is not performed because it potentially upstages the tumor.[127]

  2. Routine exploration of the contralateral kidney is not necessary if technically adequate imaging studies do not suggest a bilateral process. If the initial imaging studies are suggestive of bilateral kidney involvement, treatment approaches should facilitate renal-sparing surgery.

  3. About 2% of Wilms tumors have ureteral involvement. The presence of gross hematuria, nonfunctioning kidney, or hydronephrosis suggests the tumor may extend into the ureter, and cystoscopy is recommended. En bloc resection to avoid tumor spill is recommended.[128]

Renal-sparing surgery remains controversial and is not recommended, except for children with the following:[129]; [130][Level of evidence: 3iiB]

  • Predisposition to bilateral tumors. Some children who are predisposed to bilateral tumors and who have very small tumors detected by ultrasound screening may be considered for renal-sparing surgery to preserve renal tissue.[129]

  • A solitary kidney.

  • Horseshoe kidney. Wilms tumor arising in a horseshoe kidney is rare, and accurate preoperative diagnosis is important for planning the operative approach. Primary resection is possible in most cases. Inoperable cases can usually be resected after chemotherapy.[131]

  • Wilms tumor in infants with Denys-Drash or Frasier syndrome (to delay the need for dialysis).

The use of renal-sparing surgery for bilateral tumors is under investigation.

In North America, renal-sparing surgery (partial nephrectomy) of unilateral Wilms tumor following administration of chemotherapy to shrink the tumor mass is considered investigational.[132,133]

Hilar and periaortic lymph node sampling is appropriate even if the nodes appear normal.[127,134] Furthermore, any suspicious node basin is sampled. Margins of resection, residual tumor, and any suspicious node basins are marked with titanium clips.

Wilms tumor rarely invades adjacent organs; therefore, resection of contiguous organs is rarely indicated. There is an increased incidence of complications occurring in more extensive resections that involve removal of additional organs beyond the diaphragm and adrenal gland. This has led to the recommendation in current COG protocols that these patients should be considered for initial biopsy, neoadjuvant chemotherapy, and then secondary resection.[135] Primary resection of liver metastasis is not recommended.[136]

Chemotherapy

Preoperative chemotherapy before nephrectomy is indicated in the following situations:[127,135,137-140]

  • Synchronous bilateral Wilms tumor.
  • Wilms tumor in a solitary kidney.
  • Extension of tumor thrombus in the inferior vena cava above the level of the hepatic veins.
  • Tumor involves contiguous structures whereby the only means of removing the kidney tumor requires removal of the other structures (e.g., spleen, pancreas, or colon but excluding the adrenal gland).
  • Inoperable Wilms tumor.
  • Pulmonary compromise due to extensive pulmonary metastases.

Preoperative chemotherapy follows a biopsy unless the patient is being treated on COG-AREN0534. The biopsy may be performed through a flank approach.[141-146] Preoperative chemotherapy includes doxorubicin in addition to vincristine and dactinomycin unless anaplastic histology is present; in such cases, then chemotherapy includes treatment with regimen I (refer to Table 2 below). The chemotherapy generally makes tumor removal easier by decreasing the size and vascular supply of the tumor; it may also reduce the frequency of surgical complications.[91,135,137,146,147]

Newborns and all infants younger than 12 months who will be treated with chemotherapy require a 50% reduction in chemotherapy dose compared with the dose given to older children.[148] This reduction diminishes the toxic effects reported in children in this age group enrolled in NWTS studies while maintaining an excellent overall outcome.[149]

Liver function tests in children with Wilms tumor are monitored closely during the early course of therapy because hepatic toxic effects (sinusoidal obstructive syndrome, previously called veno-occlusive disease) have been reported in these patients.[150,151] Dactinomycin or doxorubicin should not be administered during radiation therapy. Patients who develop renal failure while undergoing therapy can continue receiving chemotherapy with vincristine, dactinomycin, and doxorubicin. Vincristine and doxorubicin can be given at full doses; however, dactinomycin is associated with severe neutropenia. Reductions in dosing these agents may not be necessary, but accurate pharmacologic and pharmacokinetic studies are needed while the patient is receiving therapy.[152,153]

Postoperative radiation therapy to the tumor bed is required when a biopsy is performed or in the setting of local tumor stage III.

Table 2 describes the standard chemotherapy regimens used to treat Wilms tumor.

Table 2. Standard Chemotherapy Regimens for Wilms Tumor
Regimen Name Regimen Description 
Regimen EE-4A [67]Vincristine, dactinomycin × 18 weeks postnephrectomy
Regimen DD-4A [67]Vincristine, dactinomycin, doxorubicin × 24 weeks; baseline nephrectomy or biopsy with subsequent nephrectomy
Regimen I [100]Vincristine, doxorubicin, cyclophosphamide, etoposide × 24 weeks postnephrectomy

Standard treatment options for stage I Wilms tumor

Table 3 provides an overview of the standard treatment and survival data for stage I Wilms tumor, based on published results.

Table 3. Overview of Standard Treatment for Stage I Wilms Tumor
Stage Histology 4-Year RFS or EFS 4-Year OS Treatment (refer to Table 2 for chemotherapy regimen descriptions) 
Stage I [67,100,101]FH <24 mo/tumor weight <550g85%98%Surgery only (not standard treatment; should be done only in the context of a clinical trial)
FH >24 mo/tumor weight >550g94% RFS98%Nephrectomy + lymph node sampling followed by regimen EE-4A
FA68%a89%Nephrectomy + lymph node sampling followed by regimen EE-4A and XRT
DA68% EFS79% (n = 10)Nephrectomy + lymph node sampling followed by regimen EE-4A and XRT

DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
aFewer than five patients have survived 4 years; therefore, results should be interpreted with caution.

The COG addressed the question of whether a subset of stage I Wilms tumor patients could be treated with surgery alone. The NWTS-5 (COG-Q9401) trial investigated this approach for children younger than 2 years at diagnosis with stage I FH Wilms tumors that weigh less than 550 g.

Evidence (surgery only for children younger than 24 months at diagnosis with stage I FH tumor that weighed <550 g):

  1. In the NWTS-5 study, the omission of adjuvant chemotherapy was tested for children younger than 2 years at diagnosis with stage I FH Wilms tumors that weighed less than 550 g.[101] Stringent stopping rules were designed to ensure closure of the study if the 2-year RFS rate was 90% or lower. The expectation was that approximately 50% of the surgery-only children would be salvaged after recurrence, thus attaining the 95% predicted survival of children with very low-risk Wilms tumor treated with standard chemotherapy according to regimen EE-4A.
    • The study was discontinued in 1998 when the predicted 2-year EFS fell below 90%.[154]

    • Long-term follow-up of this study's surgery-only cohort and the EE-4A group with a median follow-up of 8.2 years reported the estimated 5-year EFS for surgery-only patients was 84% (95% CI, 73%–91%); for the EE-4A patients, it was 97% (95% CI, 92%–99%, P = .002). One death was observed in each treatment group. The estimated 5-year OS was 98% (95% CI, 87%–99%) for surgery only and 99% (95% CI, 94%–99%) for EE-4A (P = .70).[101]

    • Investigators observed that the children who relapsed were more successfully retreated than prior stage I/FH children, probably because they were naive to both radiation therapy and chemotherapy.[101]

Standard treatment options for stage II Wilms tumor

Table 4 provides an overview of the standard treatment and survival data for stage II Wilms tumor, based on published results.

Table 4. Overview of Standard Treatment for Stage II Wilms Tumor
Stage Histology 4-Year RFS or EFS 4-Year OS Treatment (refer to Table 2 for chemotherapy regimen descriptions) 
DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
Stage II [67,100]FH86% RFS98%Nephrectomy + lymph node sampling followed by regimen EE-4A
FA80% EFS80% (n = 5)Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
DA83% EFS82%Nephrectomy + lymph node sampling followed by abdominal XRT and regimen I

On NWTS-3 through NWTS-5, patients with intraoperative spill were divided into two groups: (1) those with diffuse spillage involving the whole abdominal cavity; and (2) those with local spillage confined to the flank. Patients with diffuse spillage were treated with radiation therapy to the entire abdomen and three-drug chemotherapy (vincristine, dactinomycin, and doxorubicin), whereas patients with local spillage were treated with vincristine and dactinomycin only. On the basis of an analysis of patients treated on NWTS-3 and NWTS-4 indicating that patients with stage II disease and local spillage had inferior OS compared with patients with stage II disease without local spillage, ongoing COG studies treat patients with local spillage with doxorubicin and flank radiation.[155] This approach is controversial and has not been tested; therefore, it should not be considered standard.

In a review of 499 patients from NWTS-4 with stage II, FH Wilms tumor, 95 of the patients experienced tumor spill. The 8-year RFS and OS for patients who experienced tumor spill and were treated with vincristine and dactinomycin without flank radiation therapy was lower, at 75.7% and 90.3%, than the 85% and 95.6% rates for those who did not experience tumor spill. None of these differences achieved statistical significance.[118]

Standard treatment options for stage III Wilms tumor

Table 5 provides an overview of the standard treatment and survival data for stage III Wilms tumor, based on published results.

Table 5. Overview of Standard Treatment for Stage III Wilms Tumor
Stage Histology 4-Year RFS or EFS 4-Year OS Treatment (refer to Table 2 for chemotherapy regimen descriptions) 
DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
Stage III [67,100]FH87% RFS94%Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
FA88% RFS100% (n = 8)Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
FA (preoperative treatment)71% RFS71% (n = 7)Preoperative treatment with regimen DD-4A followed by nephrectomy + lymph node sampling and abdominal XRT
DA46% EFS53% (n = 16)Preoperative treatment with regimen I followed by nephrectomy + lymph node sampling and abdominal XRT
DA65% EFS67%Immediate nephrectomy + lymph node sampling followed by abdominal XRT and regimen I

The outcome of patients with peritoneal implants treated with gross resection, three-drug chemotherapy, and total-abdominal radiation (10.5 Gy) is similar to that of other stage III patients.[156][Level of evidence: 2A]

For patients classified as stage III purely on the basis of local spill, refer to the Standard treatment options for stage II Wilms tumor section of this summary.

Standard treatment options for stage IV Wilms tumor

Table 6 provides an overview of the standard treatment and survival data for stage IV Wilms tumor, based on published results.

Table 6. Overview of Standard Treatment for Stage IV Wilms Tumor
Stage Histology 4-Year RFS or EFS 4-Year OS Treatment (refer to Table 2 for chemotherapy regimen descriptions) 
Stage IV [67,100]FH76% RFS86%Nephrectomy + lymph node sampling, followed by abdominal XRT,a radiation to sites of metastases, bilateral pulmonary XRT,b and regimen DD-4A
FA61% EFS72% (n = 11)Nephrectomy + lymph node sampling, followed by abdominal XRT,a radiation to sites of metastases, bilateral pulmonary XRT,b and regimen DD-4A
DA33% EFS33% (n = 15)Immediate nephrectomy + lymph node sampling followed by abdominal XRT,a radiation to sites of metastases, whole-lung XRT,b and regimen I
DA (preoperative treatment)31% EFS44% (n = 13)Preoperative treatment with regimen I followed by nephrectomy + lymph node sampling, followed by abdominal XRT,a radiation to sites of metastases, and whole-lung XRTb

DA = diffuse anaplasia; EFS = event-free survival; FA = focal anaplasia; FH = favorable histology; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
aAbdominal XRT is planned according to local stage of renal tumor.
bPulmonary XRT is reserved for patients with chest X-ray/chest CT evidence of pulmonary metastases.

Stage IV disease is defined by the presence of hematogenous metastases to the lung, liver, bone, brain, or other sites, with the lung being the most common site. Historically, chest X-rays were used to detect pulmonary metastases. The introduction of CT created controversy because many patients had lung nodules detected by chest CT scans that were not seen on chest X-rays. Management of newly diagnosed patients with FH Wilms tumor who have lung nodules detected only by CT scans (with negative chest X-ray) has elicited controversy as to whether they need to be treated with additional intensive treatment that is accompanied by acute and late toxicities.

Evidence (treatment of pulmonary nodules detected by chest CT scan only):

  1. A retrospective review of 186 patients from NWTS-4 and NWTS-5 (COG-Q9401) with CT-only–detected lung nodules reported on the use of doxorubicin, vincristine, and dactinomycin with or without lung radiation versus the use of two drugs.[157]
    • Patients who received doxorubicin, vincristine, and dactinomycin with or without lung radiation had a 5-year EFS of 80% versus an EFS of 56% for patients receiving only two drugs (P = .004).

    • There was no difference in the 5-year OS (87% vs. 86%).

The issue of whether radiation can be omitted in patients with FH Wilms tumor and pulmonary metastases (identified by chest CT scans) has been studied prospectively in North America in the COG-AREN0533 trial. COG-AREN0533 patients underwent 6 weeks of chemotherapy consisting of vincristine, dactinomycin, and doxorubicin and were reevaluated to assess the response of their pulmonary metastases. Patients whose pulmonary metastases had completely resolved were spared pulmonary irradiation and continued with the same chemotherapy. If the pulmonary metastases were still present at that time, patients were treated with chemotherapy in which cyclophosphamide and etoposide were added, and they also underwent pulmonary irradiation. The trial is closed, and results are pending.

Retrospective studies from Europe have examined the impact of omitting pulmonary radiation in patients with pulmonary metastases diagnosed by chest X-ray. European investigators omitted radiation from the treatment of most patients with Wilms tumor and pulmonary metastases as identified on chest X-ray who were treated on the SIOP-93-01 trial. The European approach to renal tumors differs from the approach used in North America. All patients who were shown to have a renal tumor by imaging underwent 9 weeks of prenephrectomy chemotherapy consisting of vincristine, dactinomycin, and doxorubicin.

Evidence (treatment of pulmonary nodules detected by chest X-ray):

  1. In a retrospective study, 234 newly diagnosed patients with Wilms tumor presenting with pulmonary metastases were treated according to the response of the pulmonary metastases to the prenephrectomy chemotherapy.[158]
    1. Patients who were in complete remission after 9 weeks of therapy continued with the same chemotherapy and did not require radiation to their lungs.
      • The 5-year EFS was 77%, and the OS was 88%.

    2. Patients who had residual pulmonary metastases were evaluated for metastasectomy; 37 patients obtained complete remission with surgery, and their outcome was similar to that of the group of patients who were treated with chemotherapy. Tumor viability in the resected pulmonary metastases was not a factor for omitting radiation therapy.
      • The 5-year EFS was 84%, and the OS was 92%.

    3. Patients with residual pulmonary metastases that were incompletely resected or inoperable received more aggressive chemotherapy consisting of ifosfamide/anthracycline alternating with carboplatin/etoposide for 9 weeks.
      • Patients showing a complete remission at that time were spared pulmonary radiation and continued with chemotherapy, whereas patients with residual pulmonary metastases continued with additional chemotherapy (to complete 34 weeks) and pulmonary irradiation. The 5-year OS was 48%, compared with the OS for patients who responded to chemotherapy alone (88%) and those who underwent metastasectomy (92%) (P < .001).

      • Patients with high-risk histologies, such as anaplastic Wilms tumor, were treated with more aggressive chemotherapy but had a poorer outcome, compared with that of patients with nonanaplastic histologies (5-year OS, 87% vs. 33%; P < .001).

    It is important to note that patients in Europe receive higher cumulative doses of dactinomycin and doxorubicin before their pulmonary metastases are reevaluated than do patients in North America. The European experience cannot be directly applied to North America, although it suggests that for patients with nonanaplastic histology who are in a complete remission with chemotherapy, radiation may be omitted without impacting outcome.

The presence of liver metastases at diagnosis is not an independent adverse prognostic factor in patients with stage IV Wilms tumor.[136]

Treatment options for stage V and those predisposed to developing bilateral Wilms tumor

Currently, there is not a standard approach for the treatment of stage V Wilms tumor (bilateral Wilms tumor at diagnosis) and those predisposed to developing Wilms tumor.

Management of a child with bilateral Wilms tumor is very challenging. The goals of therapy are to eradicate all tumor and to preserve as much normal renal tissue as possible, with the hope of decreasing the risk of chronic renal failure among these children.[120]

In the NWTS-4 trial, bilateral Wilms tumor patients had a lower EFS and OS than did patients with localized Wilms tumor (including anaplastic histology), except for stage IV disease, in which OS was higher for patients with bilateral Wilms. The NWTS-4 study reported that the 8-year EFS for patients with bilateral FH Wilms tumor was 74% and the OS was 89%; for patients with anaplastic histology, the EFS was 40% and the OS was 45%.[110] The NWTS-5 (COG-Q9401) study reported the 4-year EFS for bilateral Wilms tumor patients was 61% and the OS was 81%; for patients with anaplastic histology, the EFS was 44% and the OS was 55%.[100,159] Similar outcomes for patients with bilateral Wilms tumor have been reported in Europe.[109,109,160] In a single-institution experience in the Netherlands (N = 41), there was significant morbidity in terms of renal failure (32%) and secondary tumors (20%).[160] The incidence of end-stage renal failure in the Dutch study may be a reflection of a longer follow-up period.

Therapy for stage V Wilms tumor is being studied by the COG. Traditionally, patients have undergone bilateral renal biopsies, with staging of each kidney followed by preoperative chemotherapy. Currently on COG trials, pretreatment biopsies are not required if results of imaging tests are consistent with Wilms tumor. In the past the surgical approach varied according to the size of the tumor, with small tumors being resected and larger tumors being biopsied followed by prenephrectomy chemotherapy. The COG-AREN0534 trial is expected to provide data on whether using vincristine, dactinomycin, and doxorubicin initially is appropriate; in previous studies, approximately 40% of stage V patients did not require anthracyclines.[110]

Preoperative chemotherapy and resection

In the first COG trial to formally study bilateral Wilms tumors (COG-AREN0534), the treatment approach consists of preoperative chemotherapy with vincristine, dactinomycin, and doxorubicin to attempt to shrink the tumor and spare renal parenchyma. As part of this trial, an initial biopsy, laparotomy, or primary tumor excision is not recommended.

Evidence (preoperative chemotherapy):

  1. In a series of 49 patients with Wilms tumor who received preoperative therapy according to the SIOP-93-01 guidelines, the timing of surgery was determined when there was no longer imaging evidence of tumor regression. The mean treatment duration was 80 days before renal-sparing surgery.[161]
    • The 5-year EFS rate was 83.4% and the OS rate was 89.5%.

    • All but one of the patients had renal-sparing surgery in at least one kidney.

    • Despite the good survival, 14% of the patients developed end-stage renal disease.

  2. In a retrospective review from St. Jude Children's Research Hospital, investigators described their experience with preoperative chemotherapy followed by renal-sparing procedures in children with bilateral FH Wilms tumor.[162]
    • In a series, nine out of ten patients with bilateral FH Wilms tumors underwent successful bilateral renal-sparing procedures after receiving preoperative chemotherapy.

    • One patient in the series developed renal failure after bilateral renal-sparing surgery. Two patients with anaplastic histology died, although one patient died from complications of treatment rather than tumor. The OS for this group of patients was 83%.

    • The authors concluded that bilateral renal-sparing surgery should be considered for all patients who have bilateral Wilms tumor, even if preoperative imaging studies suggest that the lesions are unresectable.[162]

For patients who are treated with preoperative chemotherapy, the tumor pathology needs to be evaluated after 4 to 8 weeks. For patients not treated on a clinical trial, the ideal time to perform a biopsy or resection is unknown because minimal shrinkage may reflect chemotherapy-induced differentiation or anaplastic histology. A planned attempt at resection or biopsy of apparently unresectable tumor is undertaken no later than 12 weeks from diagnosis. Continuing therapy without evaluating tumor pathology in a patient with bilateral Wilms tumor may miss anaplastic histology or chemotherapy-induced differentiation (including rhabdomyomatous differentiation) and thus increase toxicity for the patient without providing additional benefit for tumor control. Anaplastic histology occurs in 10% of patients with bilateral Wilms tumor, and these tumors respond poorly to chemotherapy.[110]

Once the diagnosis is confirmed, a complete resection is performed. Histologic confirmation of the diagnosis is not straightforward. In a series of 27 patients from NWTS-4, discordant pathology was seen in 20 cases, which highlights the need to obtain tissue from both kidneys. Seven children who were later diagnosed with diffuse anaplastic tumors had core biopsies performed to establish the diagnosis; however, anaplasia was not found. Anaplasia was identified in only three of the nine patients when an open-wedge biopsy was performed and in seven of nine patients who had a partial or complete nephrectomy.[110]

The decision to administer chemotherapy and/or radiation therapy following biopsy or second-look operation is dependent on the tumor's response to initial therapy. More aggressive therapy is required for patients with inadequate response to initial therapy observed at the second procedure or in the setting of anaplasia.[117,159,163-167]

Renal transplantation

Renal transplantation for children with stage V Wilms tumor is usually delayed until 1 to 2 years have passed without evidence of malignancy.[168] Similarly, renal transplantation for children with Denys-Drash syndrome and Wilms tumor, all of whom require bilateral nephrectomy, is generally delayed 1 to 2 years after completion of initial treatment.[168]

Treatment options under clinical evaluation

Stage V and those predisposed to developing bilateral Wilms tumor

The following treatment option is currently under investigation in COG clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Patients with multicentric tumors, patients with high-risk bilateral tumors, and patients with diffuse hyperplastic nephrogenic rests are being treated on the following protocol:

  1. COG-AREN0534 (Combination Chemotherapy and Surgery in Treating Young Patients With Wilms Tumor): Children with bilateral tumors are eligible for COG-AREN0534, which is the first protocol to prospectively study bilateral tumors. The goals of therapy are to eradicate all tumor and to preserve as much normal renal tissue as possible, with the hope of decreasing the risk of chronic renal failure among these children.[48,169] When children are identified with bilateral tumors by CT or MRI, central radiologic review will be performed to exclude tumor extension, invasion, rupture, metastases, or thrombus. Central review will also assess characteristics of nephrogenic rests versus tumor and differentiate active from sclerotic rests or tumors. Biopsy will not be mandated.

    Upfront intensification with three drugs (vincristine, doxorubicin, and dactinomycin) will be used in large part to move patients to definitive surgery earlier. Repeat imaging will be mandated at 6 weeks. On the basis of patient response to treatment, surgery, definitive surgery, biopsy, or continued chemotherapy will be performed. If biopsy or surgery is performed, chemotherapy or radiation therapy will be given on the basis of histology. Patients undergoing biopsy or continued chemotherapy will have repeat imaging performed at 12 weeks, with definitive surgery performed if results of imaging studies are at all positive.

    This approach will identify patients with anaplasia, rhabdomyomatous differentiation, complete necrosis, or stromal differentiation; select them for early surgery; and define the intensity of chemotherapy to be administered.[162,164,170] The decision to administer chemotherapy and/or radiation therapy following the second-look operation is dependent on the response to initial therapy, with more aggressive therapy required for patients with inadequate response to initial therapy observed at the second procedure.[117,163-167]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I Wilms tumor, stage II Wilms tumor, stage III Wilms tumor, stage IV Wilms tumor and stage V Wilms tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Follow-up after treatment

For patients who have completed therapy for Wilms tumor and exhibit features consistent with genetic predisposition, such as bilateral Wilms tumor, screening involves renal ultrasound examination every 3 months for metachronous tumors during the risk period for that particular syndrome (5 years for WT1-related syndromes; 8 years for Beckwith-Wiedemann syndrome).

Late effects following Wilms tumor therapy

Children treated for Wilms tumor are at increased risk of developing the following:

  • Second malignant neoplasms.[171,172]
  • Congestive heart failure (influenced by dose of doxorubicin received, radiation to the heart, and female gender).[172,173]
  • Complications of pregnancy.[174]

The cumulative incidence of end-stage renal disease due to chronic renal failure at 20 years from diagnosis of Wilms tumor is low at 3.1% for patients with bilateral Wilms tumor and less than 1% for those with unilateral Wilms tumor.[47] Efforts, therefore, have been aimed toward reducing the intensity of therapy when possible.

(Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)

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Renal Cell Carcinoma (RCC)



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. 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.[1] 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.

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.[2] The gene for VHL disease is located on chromosome 3p26 and is a tumor-suppressor gene, which is either mutated or deleted in patients with the syndrome.

    Screening for the VHL gene is available.[3] To detect clear cell renal carcinoma in these individuals when the lesions are smaller than 3 cm and renal-sparing surgery can be performed, annual screening with abdominal ultrasound or magnetic resonance imaging (MRI) is recommended, beginning at age 8 to 11 years.[4]

    (Refer to the Von Hippel-Lindau Syndrome section of the PDQ summary on Genetics of Kidney Cancer (Renal Cell Cancer) for more information.)

  • 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.[5,6]

  • Familial RCC: Familial RCC has been associated with an inherited chromosome translocation involving chromosome 3.[7] A high incidence of chromosome 3 abnormalities has also been demonstrated in nonfamilial renal tumors.

    Succinate dehydrogenase (SDHB, SDHC, and SDHD) is a Krebs cycle enzyme gene that has been associated with the development of familial RCC occurring with pheochromocytoma/paraganglioma. Germline mutations in a subunit of the gene have been reported in individuals with renal cancer and no history of pheochromocytoma.[8,9]

  • Renal medullary carcinoma: A rare subtype of RCC, renal medullary carcinoma may be associated with sickle cell hemoglobinopathy.[10] Renal medullary carcinomas are highly aggressive malignancies characterized clinically by a high stage at the time of detection, with widespread metastases and lack of response to chemotherapy and radiation therapy.[11][ Level of evidence: 3iiA] Survival is poor and ranges from 2 weeks to 15 months, with a mean survival of 4 months.[10-13]

  • Hereditary leiomyomatosis: Hereditary leiomyomatosis (of skin and uterus) and RCC is a distinct phenotype caused by dominant inheritance of a mutation in the fumarate hydratase gene. Screening for RCC starting as early as age 5 years has been recommended.[14,15]

  • Second malignant neoplasm: RCCs have been described in patients several years after diagnosis and therapy for pediatric malignancies such as neuroblastoma, rhabdomyosarcoma, nephroblastoma, and leiomyosarcoma.[16-21] Early detection and resection may improve survival in these patients.[22]

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 7.

Table 7. Indications for Germline Genetic Analysis (Screening) of Children and Adolescents with Renal Cell Carcinoma (RCC)a
Indication for Testing Tumor Histology Gene Test Related Syndrome 
Multifocal RCC or VHL lesionsClear cellVHL genevon Hippel-Lindau syndrome
Family history of clear cell RCC or multifocal RCC with absent VHL mutationClear cellChromosome 3 gene translocationsHereditary non-VHL clear cell RCC syndrome
Multifocal papillary RCC or family history of papillary RCCPapillaryMET geneHereditary papillary RCC syndrome
Multifocal RCC or cutaneous fibrofolliculoma or pulmonary cysts or spontaneous pneumothoraxChromophobe or oncocytic or clear cellGermline sequence BHD geneBirt-Hogg-Dubé syndrome
Personal or family history of early-onset uterine leiomyomata or cutaneous leiomyomataType 2 papillary or collecting duct carcinomaFH geneHereditary leiomyomata/RCC syndrome
Multifocal RCC or early-onset RCC or presence of paraganglioma/pheochromocytoma or family history of paraganglioma/pheochromocytomaClear cell or chromophobeSDHB gene, SDHC gene, SDHD geneHereditary paraganglioma/pheochromocytoma syndrome

VHL = von Hippel-Lindau.
aAdapted from Linehan et al.[23]

Xp11 Translocations Associated With RCC

Translocation-positive carcinomas of the kidney are recognized as a distinct form of RCC and may be the most common form of RCC in children. They are characterized by translocations involving the transcription factor E3 gene (TFE3) located on Xp11.2. The TFE3 gene may partner with one of the following genes:

  • ASPSCR in t(X;17)(p11.2;q25).
  • PRCC in t(X;1)(p11.2;q21).
  • SFPQ in t(X;1)(p11.2;p34).
  • NONO in inv(X;p11.2;q12).
  • Clathrin heavy chain (CLTC) in t(X;17)(p11;q23).

Another less-common translocation subtype, t(6;11)(p21;q12), involving a fusion Alpha/TFEB, induces overexpression of transcription factor EB (TFEB). The translocations involving TFE3 and TFEB induce overexpression of these proteins, which can be identified by immunohistochemistry.[24]

Previous exposure to chemotherapy is the only known risk factor for the development of Xp11 translocation RCCs. The postchemotherapy interval ranged from 4 to 13 years. All reported patients received either a DNA topoisomerase II inhibitor and/or an alkylating agent.[25,26]

Controversy exists as to the biological behavior of the translocation RCC in children and young adults. Whereas some series have suggested a good prognosis when RCC is treated with surgery alone despite presenting at a higher stage (III/IV) than TFE-RCC, a meta-analysis reported that these patients have poorer outcomes.[27-29] The outcomes for these patients are being studied in the ongoing COG-AREN03B2 (NCT00898365) Biology and Classification Study. VEGFR-targeted therapies and mTOR inhibitors seem to be active in Xp11 translocation metastatic RCC.[30] Recurrences have been reported 20 to 30 years after the initial resection of the translocation-associated RCC.[19]

Histology of RCC

Pediatric RCC differs histologically from the adult counterparts. Although the two main morphological subgroups of papillary and clear cell can be identified, about 25% of RCCs show heterogeneous features that do not fit into either of these categories. Childhood RCCs are more frequently of the papillary subtype (20%–50% of pediatric RCCs) and can sometimes occur in the setting of Wilms tumor, metanephric adenoma, and metanephric adenofibroma.

RCC in children and young adults has a different genetic and morphologic spectrum than that seen in older adults.[2,26,31,32]

Prognosis and Prognostic Factors for RCC

The primary prognostic factor for RCC is stage of disease. In a series of 41 children with RCC, the median age was 10 years, with 46% presenting with localized stage I and stage II disease, 29% with stage III disease, and 22% with stage IV disease, according to the Robson classification system. The sites of metastases were the lungs, liver, and lymph nodes. Event-free survival (EFS) and overall survival (OS) were each about 55% at 20 years posttreatment. Patients with stage I and stage II disease had an 89% OS rate, while those with stage III and stage IV disease had a 23% OS rate at 20 years posttreatment.[33]

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 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.[34] In another series of 49 patients from a population-based cancer registry, the findings were similar. In this series, 33% of the patients had papillary subtype, 22% had translocation type, 16% were unclassified, and 6% had clear-cell subtype. Survival at 5 years was 96% for patients with localized disease, 75% for patients with positive regional lymph nodes, and 33% for patients with distant metastatic RCC.[35]

Clinical Features and Diagnostic Evaluation

RCC may present with the following:

  • Abdominal mass.
  • Abdominal pain.
  • Hematuria.

Refer to the Wilms tumor Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors. (Refer to the Stage Information for Renal Cell Cancer section of the Renal Cell Cancer Treatment summary for more information about the staging evaluation.)

Standard Treatment Options for RCC

Survival of patients with RCC is affected by stage of disease at presentation and the completeness of resection at radical nephrectomy. OS rates for all patients with RCC range from 64% to 87%. The 5-year survival rates for pediatric RCC is 90% or higher for stage I, higher than 80% for stage II, 70% for stage III, and lower than 15% for stage IV.[34] Retrospective analyses and the small number of patients involved place limitations on the level of evidence in the area of treatment.

Standard treatment options for RCC include the following:

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

The primary treatment for RCC includes total surgical removal of the kidney and associated lymph nodes.[34]

Renal-sparing surgery with lymph node dissection

Renal-sparing surgery may be considered for carefully selected patients with low-volume localized disease. In two small series, patients who had partial nephrectomies seemed to have outcomes equivalent to those who had radical nephrectomies.[26,36]

Other approaches

As with adult RCC, there is no standard treatment for unresectable metastatic disease in children. The response to radiation is poor, and chemotherapy is not effective. Immunotherapy with such agents as interferon-alpha and interleukin-2 may have some effect on cancer control.[37] Rare spontaneous regression of pulmonary metastasis may occur with resection of the primary tumor.

Several targeted therapies (e.g., sorafenib, sunitinib, bevacizumab, temsirolimus, pazopanib, and everolimus) have been approved for use in adults with RCC; however, these agents have not been tested in pediatric patients with RCC. Case reports of pediatric and adolescent patients with a TFE3 RCC suggest responsiveness to multiple tyrosine kinase inhibitors.[38,39] (Refer to the PDQ summary on adult Renal Cell Cancer Treatment for more information on the use of targeted therapies.)

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood renal cell carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. Bernstein L, Linet M, Smith MA, et al.: Renal Tumors. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 79-90. Also available online. Last accessed May 29, 2014. 

  2. Bruder E, Passera O, Harms D, et al.: Morphologic and molecular characterization of renal cell carcinoma in children and young adults. Am J Surg Pathol 28 (9): 1117-32, 2004.  [PUBMED Abstract]

  3. Schimke RN, Collins DL, Stolle CA: Von Hippel-Lindau Syndrome. In: Pagon RA, Adam MP, Bird TD, et al., eds.: GeneReviews. Seattle, WA: University of Washington, 2013, pp. Available online. Last accessed May 29, 2014. 

  4. 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.  [PUBMED Abstract]

  5. Park HK, Zhang S, Wong MK, et al.: Clinical presentation of epithelioid angiomyolipoma. Int J Urol 14 (1): 21-5, 2007.  [PUBMED Abstract]

  6. Pea M, Bonetti F, Martignoni G, et al.: Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma. Am J Surg Pathol 22 (2): 180-7, 1998.  [PUBMED Abstract]

  7. Wang N, Perkins KL: Involvement of band 3p14 in t(3;8) hereditary renal carcinoma. Cancer Genet Cytogenet 11 (4): 479-81, 1984.  [PUBMED Abstract]

  8. Ricketts C, Woodward ER, Killick P, et al.: Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst 100 (17): 1260-2, 2008.  [PUBMED Abstract]

  9. Linehan WM, Bratslavsky G, Pinto PA, et al.: Molecular diagnosis and therapy of kidney cancer. Annu Rev Med 61: 329-43, 2010.  [PUBMED Abstract]

  10. Swartz MA, Karth J, Schneider DT, et al.: Renal medullary carcinoma: clinical, pathologic, immunohistochemical, and genetic analysis with pathogenetic implications. Urology 60 (6): 1083-9, 2002.  [PUBMED Abstract]

  11. Hakimi AA, Koi PT, Milhoua PM, et al.: Renal medullary carcinoma: the Bronx experience. Urology 70 (5): 878-82, 2007.  [PUBMED Abstract]

  12. Strouse JJ, Spevak M, Mack AK, et al.: Significant responses to platinum-based chemotherapy in renal medullary carcinoma. Pediatr Blood Cancer 44 (4): 407-11, 2005.  [PUBMED Abstract]

  13. Rathmell WK, Monk JP: High-dose-intensity MVAC for Advanced Renal Medullary Carcinoma: Report of Three Cases and Literature Review. Urology 72 (3): 659-63, 2008.  [PUBMED Abstract]

  14. Alrashdi I, Levine S, Paterson J, et al.: Hereditary leiomyomatosis and renal cell carcinoma: very early diagnosis of renal cancer in a paediatric patient. Fam Cancer 9 (2): 239-43, 2010.  [PUBMED Abstract]

  15. Bayley JP, Launonen V, Tomlinson IP: The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. BMC Med Genet 9: 20, 2008.  [PUBMED Abstract]

  16. Medeiros LJ, Palmedo G, Krigman HR, et al.: Oncocytoid renal cell carcinoma after neuroblastoma: a report of four cases of a distinct clinicopathologic entity. Am J Surg Pathol 23 (7): 772-80, 1999.  [PUBMED Abstract]

  17. Dhall D, Al-Ahmadie HA, Dhall G, et al.: Pediatric renal cell carcinoma with oncocytoid features occurring in a child after chemotherapy for cardiac leiomyosarcoma. Urology 70 (1): 178.e13-5, 2007.  [PUBMED Abstract]

  18. Schafernak KT, Yang XJ, Hsueh W, et al.: Pediatric renal cell carcinoma as second malignancy: reports of two cases and a review of the literature. Can J Urol 14 (6): 3739-44, 2007.  [PUBMED Abstract]

  19. Rais-Bahrami S, Drabick JJ, De Marzo AM, et al.: Xp11 translocation renal cell carcinoma: delayed but massive and lethal metastases of a chemotherapy-associated secondary malignancy. Urology 70 (1): 178.e3-6, 2007.  [PUBMED Abstract]

  20. Brassesco MS, Valera ET, Bonilha TA, et al.: Secondary PSF/TFE3-associated renal cell carcinoma in a child treated for genitourinary rhabdomyosarcoma. Cancer Genet 204 (2): 108-10, 2011.  [PUBMED Abstract]

  21. Breslow NE, Lange JM, Friedman DL, et al.: Secondary malignant neoplasms after Wilms tumor: an international collaborative study. Int J Cancer 127 (3): 657-66, 2010.  [PUBMED Abstract]

  22. Wilson CL, Ness KK, Neglia JP, et al.: Renal carcinoma after childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 105 (7): 504-8, 2013.  [PUBMED Abstract]

  23. Linehan WM, Pinto PA, Bratslavsky G, et al.: Hereditary kidney cancer: unique opportunity for disease-based therapy. Cancer 115 (10 Suppl): 2252-61, 2009.  [PUBMED Abstract]

  24. Argani P, Hicks J, De Marzo AM, et al.: Xp11 translocation renal cell carcinoma (RCC): extended immunohistochemical profile emphasizing novel RCC markers. Am J Surg Pathol 34 (9): 1295-303, 2010.  [PUBMED Abstract]

  25. Argani P, Laé M, Ballard ET, et al.: Translocation carcinomas of the kidney after chemotherapy in childhood. J Clin Oncol 24 (10): 1529-34, 2006.  [PUBMED Abstract]

  26. Ramphal R, Pappo A, Zielenska M, et al.: Pediatric renal cell carcinoma: clinical, pathologic, and molecular abnormalities associated with the members of the mit transcription factor family. Am J Clin Pathol 126 (3): 349-64, 2006.  [PUBMED Abstract]

  27. 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 Abstract]

  28. 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 Abstract]

  29. 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 Abstract]

  30. 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 Abstract]

  31. Estrada CR, Suthar AM, Eaton SH, et al.: Renal cell carcinoma: Children's Hospital Boston experience. Urology 66 (6): 1296-300, 2005.  [PUBMED Abstract]

  32. 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 Abstract]

  33. Indolfi P, Terenziani M, Casale F, et al.: Renal cell carcinoma in children: a clinicopathologic study. J Clin Oncol 21 (3): 530-5, 2003.  [PUBMED Abstract]

  34. Geller JI, Dome JS: Local lymph node involvement does not predict poor outcome in pediatric renal cell carcinoma. Cancer 101 (7): 1575-83, 2004.  [PUBMED Abstract]

  35. 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 Abstract]

  36. Cook A, Lorenzo AJ, Salle JL, et al.: Pediatric renal cell carcinoma: single institution 25-year case series and initial experience with partial nephrectomy. J Urol 175 (4): 1456-60; discussion 1460, 2006.  [PUBMED Abstract]

  37. 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 Abstract]

  38. 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 Abstract]

  39. 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 Abstract]

Rhabdoid Tumors of the Kidney



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 or MRT) and central nervous system (CNS) (atypical teratoid/rhabdoid tumor), although rhabdoid tumors can also arise in most soft tissue sites. (Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for information on the treatment of central nervous system disease.) Relapses occur early (median time from diagnosis is 8 months).[1,2]

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).
  • High tumor stage at presentation.

(Refer to the Wilms tumor Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Approximately two-thirds of patients will present with advanced-stage disease. Bilateral cases have been reported.[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. (Refer to the Stage Information for Wilms Tumor section of this summary for more information.)

Histologically, the most distinctive features of rhabdoid tumors of the kidney are rather large cells with large vesicular nuclei, a prominent single nucleolus, and in some cells, the presence of globular eosinophilic cytoplasmic inclusions.

Genes Associated With Rhabdoid Tumors of the Kidney

Rhabdoid tumors in all anatomical locations have a common genetic abnormality—loss of function of the SMARCB1/INI1/SNF5/BAF47 gene located at chromosome 22q11.2. SMARCB1 encodes a component of the SWI/SNF (SWItch/Sucrose NonFermentable) chromatin remodeling complex that has an important role in controlling gene transcription.[5,6] Based on gene expression analysis in rhabdoid tumors, it is hypothesized that rhabdoid tumors arise in early progenitor cells during a critical developmental window in which loss of SMARCB1 directly results in repression of neural development, loss of cyclin-dependent kinase inhibition, and trithorax/polycomb dysregulation.[7] Identical mutations may give rise to a brain or kidney tumor.

Germline mutations of SMARCB1 have been documented for patients with one or more primary tumors of the brain and/or kidney, consistent with a genetic predisposition to the development of rhabdoid tumors.[8,9] Approximately 35% of patients with rhabdoid tumors have germline SMARCB1 alterations.[6] In most cases, the mutations are de novo and not inherited from a parent. The median age of children with rhabdoid tumors and a germline mutation or deletion is younger (5 months) than that of children with apparently sporadic disease (18 months). Germline mosaicism has been suggested for several families with multiple affected siblings. It appears that those patients with germline mutations may have the worst prognosis.[10]

Rhabdoid Predisposition Syndrome

Early-onset, multifocal disease and familial cases strongly support the possibility of a rhabdoid predisposition syndrome. This has been confirmed by the presence of germline mutations of SMARCB1 in rare familial cases and in a subset of patients with apparently sporadic rhabdoid tumors. These cases have been labeled as rhabdoid tumor predisposition syndrome, type 1. Thirty-five patients (N = 100) with rhabdoid tumors of the brain, kidney, or soft tissues were found to have a germline SMARCB1 abnormality. These abnormalities included point and frameshift mutations, intragenic deletions and duplications, and larger deletions. Nine cases demonstrated parent-to-child transmission of a mutated copy of SMARCB1. In eight of the nine cases, one or more family members were also diagnosed with rhabdoid tumor or schwannoma; and two of the eight families presented with multiple affected children, consistent with gonadal mosaicism.[6]

Two cases of inactivating mutations in the SMARCA4 gene have been found in three children from two unrelated families, establishing the phenotypically similar syndrome now known as rhabdoid tumor predisposition syndrome, type 2.[11,12] In these cases, SMARCA4 behaves as a classical tumor suppressor, with one deleterious mutation inherited in the germline and the other acquired in the tumor. Another report describes an autosomal dominant pattern of inheritance discovered through an exome sequencing project.[13]

Genetic Testing and Surveillance

Germline analysis is suggested for individuals of all ages with rhabdoid tumors. Genetic counseling is also part of the treatment plan, given the low-but-actual risk of familial recurrence. In cases of mutations, parental screening should be considered, although such screening carries a low probability of positivity. Prenatal diagnosis can be performed in situations where a specific SMARCB1 mutation or deletion has been documented in the family.[6]

Recommendations for surveillance in patients with germline SMARCB1 mutations have been developed on the basis of epidemiology and clinical course of rhabdoid tumors. These recommendations were developed by a group of pediatric cancer genetic experts (including oncologists, radiologists, and geneticists). They have not been formally studied to confirm the benefit of monitoring patients with germline SMARCB1 mutations. The aggressive natural history of the disease, apparently high penetrance, and well-defined age of onset for CNS atypical teratoid/rhabdoid tumor suggest that surveillance could prove beneficial. Given the potential survival benefit of surgically resectable disease, it is postulated that early detection might improve overall survival (OS).[14]

  • Children younger than 1 year: It is suggested that patients have thorough physical and neurologic examinations and monthly head ultrasounds to assess for the development of a CNS tumor. It is suggested that patients undergo abdominal ultrasounds with focus on the kidneys every 2 to 3 months to assess for renal lesions.[14]

  • Children aged 1 to 4 years: From age 1 year to approximately age 4 years, after which the risk of developing a new rhabdoid tumor rapidly declines, it is suggested that brain and spine magnetic resonance imaging (MRI) and abdominal ultrasound be performed every 3 months.[14]

Standard Treatment Options for Rhabdoid Tumor of the Kidney

Because of the relative rarity of this tumor, all patients with rhabdoid tumor of the kidney should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) with experience treating renal tumors is required to determine and implement optimum treatment.

Patients with rhabdoid tumors of the kidney continue to have a poor prognosis. In a review of 142 patients from the National Wilms Tumor Studies (NWTS) NWTS-1 through NWTS-5, age and stage are important prognostic factors:[4]

  • Age at diagnosis. Infants younger than 6 months at diagnosis demonstrated a 4-year OS of 9%, whereas OS 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%; higher stage was associated with a 16% OS.
  • Presence of a CNS lesion. All but one patient with a CNS lesion (n = 32) died.

There is no standard treatment option for rhabdoid tumor of the kidney.[15] The Société Internationale d’Oncologie Pédiatrique (SIOP) renal tumor group has noted that preoperative chemotherapy does not seem to translate into improved survival. Delays in surgery lead to worse survival, compared with patients treated according to direct surgery strategies.[1]

The NWTS-5 (COG-Q9401) trial closed the arm for rhabdoid tumor treatment with cyclophosphamide, etoposide, and carboplatin because poor outcome was observed. Combinations of etoposide and cisplatin; etoposide and ifosfamide; and ifosfamide, carboplatin, and etoposide (ICE chemotherapy) have been used (COG-Q9401).[16,17]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with rhabdoid tumor of the kidney. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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 Abstract]

  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 Abstract]

  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 Abstract]

  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 Abstract]

  5. Imbalzano AN, Jones SN: Snf5 tumor suppressor couples chromatin remodeling, checkpoint control, and chromosomal stability. Cancer Cell 7 (4): 294-5, 2005.  [PUBMED Abstract]

  6. 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.  [PUBMED Abstract]

  7. Gadd S, Sredni ST, Huang CC, et al.: Rhabdoid tumor: gene expression clues to pathogenesis and potential therapeutic targets. Lab Invest 90 (5): 724-38, 2010.  [PUBMED Abstract]

  8. 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 Abstract]

  9. Biegel JA: Molecular genetics of atypical teratoid/rhabdoid tumor. Neurosurg Focus 20 (1): E11, 2006.  [PUBMED Abstract]

  10. 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 Abstract]

  11. 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.  [PUBMED Abstract]

  12. 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 Abstract]

  13. Witkowski L, Lalonde E, Zhang J, et al.: Familial rhabdoid tumour 'avant la lettre'--from pathology review to exome sequencing and back again. J Pathol 231 (1): 35-43, 2013.  [PUBMED Abstract]

  14. 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.  [PUBMED Abstract]

  15. 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 Abstract]

  16. 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 Abstract]

  17. 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 Abstract]

Clear Cell Sarcoma of the Kidney



General Information About Clear Cell Sarcoma of the Kidney

Clear cell sarcoma of the kidney is not a Wilms tumor variant, but it is an important primary renal tumor associated with a higher rate of relapse and death than 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] (Refer to the Wilms tumor Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

While little is known about the biology of clear cell sarcoma of the kidney, the t(10;17)(q22;p13) translocation has been reported. As a result of the translocation, the YWHAE-FAM22 fusion transcript is formed; this transcript was detected in 12% of cases of clear cell sarcoma of the kidney in one series. 17p13 is the site of the P53 gene; however, this gene does not show abnormal expression and most likely is not involved.[2] Gene expression studies revealed the upregulation of neural markers, with ensuing activation of the sonic hedgehog and Akt pathways.[3] When DNA methylation profiling was used, the epigenetic characteristics of clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, and Ewing sarcoma of the kidney, in comparison with those of the non-neoplastic kidney, exhibited distinct DNA methylation profiles in a tumor type–specific manner. The DNA methylation pattern of the THBS1 CpG site is sufficient for distinction of clear cell sarcoma of the kidney from other pediatric renal tumors.[4]

Younger age and stage IV disease have been identified as adverse prognostic factors for event-free survival (EFS).[5]

Historically, relapses have occurred in long intervals after the completion of chemotherapy (up to 10 years); however, with current therapy, relapses after 3 years are uncommon.[6] The brain is a frequent site of recurrent disease, suggesting that it is a sanctuary site for cells that are protected from the intensive chemotherapy that patients currently receive.[5,7,8] 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.

Standard Treatment Options for Clear Cell Sarcoma of the Kidney

Because of the relative rarity of this tumor, all patients with clear cell sarcoma of the kidney should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) with experience treating renal tumors is required to determine and implement optimum treatment.

The approach for treating clear cell sarcoma of the kidney is different from the approach for treating Wilms tumor because the overall survival (OS) of children with clear cell sarcoma of the kidney remains lower than that for patients with FH Wilms tumor. All patients undergo postoperative radiation to the tumor bed and receive doxorubicin as part of their chemotherapy regimen.

The standard treatment option for clear cell sarcoma of the kidney is the following:

  1. Surgery, chemotherapy, and radiation therapy.
Surgery, chemotherapy, and radiation therapy

Evidence (surgery, chemotherapy, and radiation therapy):

  1. In the NWTS-3 trial, the addition of doxorubicin to the combination of vincristine, dactinomycin, and radiation therapy resulted in an improvement in disease-free survival for patients with clear cell sarcoma of the kidney.[1]

  2. The NWTS-4 trial used regimen DD-4A, which consisted of vincristine, dactinomycin, and doxorubicin for 15 months and radiation therapy.[6]
    • NWTS-4 reported that patients who were treated with vincristine, doxorubicin, and dactinomycin for 15 months had an improved relapse-free survival compared with patients who were treated for 6 months (88% vs. 61% at 8 years).

  3. In the NWTS-5 (COG-Q9401) trial, children with stages I to IV clear cell sarcoma of the kidney were treated with a new chemotherapeutic regimen combining vincristine, doxorubicin, cyclophosphamide, and etoposide in an attempt to further improve the survival of these high-risk groups. All patients received radiation therapy to the tumor bed.[7]
    • With this treatment, the 5-year EFS was approximately 79%, and the OS was approximately 89%.

    • Stage I patients had 5-year EFS and OS rates of 100%.

    • Stage II patients had a 5-year EFS of approximately 87% and a 5-year OS of approximately 97%.

    • Stage III patients had a 5-year EFS of approximately 74% and a 5-year OS of approximately 87%.

    • Stage IV patients had a 5-year EFS of approximately 36% and a 5-year OS of 45%.

  4. A review of stage I clear cell sarcoma of the kidney treated on the NWTS-1 through NWTS-5 trials showed an excellent 100% OS with a wide variety of chemotherapy and radiation therapy regimens.[9]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with clear cell sarcoma of the kidney. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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 Abstract]

  2. O'Meara E, Stack D, Lee CH, et al.: Characterization of the chromosomal translocation t(10;17)(q22;p13) in clear cell sarcoma of kidney. J Pathol 227 (1): 72-80, 2012.  [PUBMED Abstract]

  3. Cutcliffe C, Kersey D, Huang CC, et al.: Clear cell sarcoma of the kidney: up-regulation of neural markers with activation of the sonic hedgehog and Akt pathways. Clin Cancer Res 11 (22): 7986-94, 2005.  [PUBMED Abstract]

  4. Ueno H, Okita H, Akimoto S, et al.: DNA methylation profile distinguishes clear cell sarcoma of the kidney from other pediatric renal tumors. PLoS One 8 (4): e62233, 2013.  [PUBMED Abstract]

  5. 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 Abstract]

  6. 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 Abstract]

  7. Seibel NL, Sun J, Anderson JR, et al.: Outcome of clear cell sarcoma of the kidney (CCSK) treated on the National Wilms Tumor Study-5 (NWTS). [Abstract] J Clin Oncol 24 (Suppl 18): A-9000, 502s, 2006. 

  8. 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 Abstract]

  9. 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 Abstract]

Congenital Mesoblastic Nephroma



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. It is the most common kidney tumor found in infants younger than 3 months. The median age of diagnosis is 1 to 2 months. Twice as many males as females are diagnosed. The diagnosis should be questioned when applied to individuals older than 2 years.[1]

When patients are diagnosed in the first 7 months of life, the 5-year event-free survival (EFS) rate is 94%, and the overall survival (OS) rate is 96%.[2] 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]

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 two major types:

  • Classic. Classic mesoblastic nephroma is often diagnosed by prenatal ultrasound or within 3 months after birth and closely resembles infantile fibromatosis.[3]

  • Cellular. A potential linkage between infantile fibrosarcoma and cellular mesoblastic nephroma is suggested because both contain the same t(12;15)(p13;q25) translocation, which results in the ETV6/NTRK3 fusion.[4]

The risk for recurrence in mesoblastic nephroma is closely associated with the presence of a cellular component and with stage.[3]

(Refer to the Wilms tumor Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Standard Treatment Options for Congenital Mesoblastic Nephroma

Standard treatment options for congenital mesoblastic nephroma include the following:

  1. Nephrectomy.
  2. Adjuvant chemotherapy.
Nephrectomy

Evidence (nephrectomy):

  1. A prospective clinical trial enrolled 50 patients with congenital mesoblastic nephroma.[3]
    • The results confirmed that complete surgical resection, which includes the entire capsule, is adequate therapy for most patients with mesoblastic nephroma.

    • Only 2 of 50 patients died.

    • Patients were at increased risk of local and eventually metastatic recurrence if there was stage III disease (incomplete resection and/or histologically positive resection margin), cellular subtype, and age 3 months or older at diagnosis. Because of the small numbers of patients and the overlapping incidence of these characteristics (5 of 50 patients), the significance of the individual characteristics could not be discerned.

Adjuvant chemotherapy

Adjuvant chemotherapy has been recommended for patients with stage III cellular subtype who are aged 3 months or older at diagnosis. However, the benefit of adjuvant therapy will remain unproven with such a low incidence of disease.[3] Infants younger than 2 months with incompletely resected, stage III disease may not need chemotherapy.[1]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with congenital mesoblastic nephroma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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 Abstract]

  2. 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 Abstract]

  3. 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 Abstract]

  4. Vujanić GM, Sandstedt B, Harms D, et al.: Revised International Society of Paediatric Oncology (SIOP) working classification of renal tumors of childhood. Med Pediatr Oncol 38 (2): 79-82, 2002.  [PUBMED Abstract]

Ewing Sarcoma (Neuroepithelial Tumor) of the Kidney



General Information About Ewing Sarcoma (Neuroepithelial Tumor) of the Kidney

Ewing sarcoma (neuroepithelial tumor) of the kidney is extremely rare and demonstrates a unique proclivity for young adults. It is a highly aggressive neoplasm, more often presenting with large tumors and penetration of the renal capsule, extension into the renal vein, and in 40% of cases, evidence of metastases.[1-3]

Primary Ewing sarcoma of the kidney consists of primitive neuroectodermal tumors characterized by CD99 (MIC-2) positivity and the detection of EWS/FLI-1 fusion transcripts. In Ewing sarcoma of the kidney, focal, atypical histologic features have been seen, including clear cell sarcoma, rhabdoid tumor, malignant peripheral nerve sheath tumors, and paraganglioma.[1,4] (Refer to the PDQ summary on Ewing Sarcoma Treatment for more information.)

Standard Treatment Options for Ewing Sarcoma of the Kidney

There is no standard treatment option for Ewing sarcoma of the kidney. However, multimodal treatment (chemotherapy and radiation therapy) and aggressive surgical approach seem to be associated with a better outcome than previously reported.[2] Consideration should also be given to substituting cyclophosphamide for ifosfamide in patients after they have undergone a nephrectomy. [2,3]

Treatment according to Ewing sarcoma/primitive neuroectodermal tumor protocols should be considered.[1]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with peripheral primitive neuroectodermal tumor of the kidney. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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 Abstract]

  2. Tagarelli A, Spreafico F, Ferrari A, et al.: Primary renal soft tissue sarcoma in children. Urology 80 (3): 698-702, 2012.  [PUBMED Abstract]

  3. Rowe RG, Thomas DG, Schuetze SM, et al.: Ewing sarcoma of the kidney: case series and literature review of an often overlooked entity in the diagnosis of primary renal tumors. Urology 81 (2): 347-53, 2013.  [PUBMED Abstract]

  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 Abstract]

Desmoplastic Small Round Cell Tumor of the Kidney

Desmoplastic small round cell tumor of the kidney is a rare, small, round blue tumor of the kidney. It is diagnosed by its characteristic EWS-WT1 translocation.[1] (Refer to the Desmoplastic small round cell tumor section in the PDQ summary on Childhood Soft Tissue Sarcoma Treatment for more information about desmoplastic small round cell tumor of the kidney.)

References
  1. Wang LL, Perlman EJ, Vujanic GM, et al.: Desmoplastic small round cell tumor of the kidney in childhood. Am J Surg Pathol 31 (4): 576-84, 2007.  [PUBMED Abstract]

Cystic Partially Differentiated Nephroblastoma



General Information About Cystic Partially Differentiated Nephroblastoma

Cystic partially differentiated nephroblastoma is a rare cystic variant of Wilms tumor (1%), with unique pathologic and clinical characteristics. It is composed entirely of cysts, and their thin septa are the only solid portion of the tumor. The septa contain blastemal cells in any amount with or without embryonal stromal or epithelial cell type. Several pathologic features distinguish this neoplasm from standard Wilms tumor.

Recurrence has been reported following tumor spillage at surgery.[1][Level of evidence: 3iiiA]

(Refer to the Wilms tumor Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Standard Treatment Options for Cystic Partially Differentiated Nephroblastoma

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.[2]

  2. Surgery and adjuvant chemotherapy. Patients with stage II disease have an excellent outcome with tumor resection followed by postoperative vincristine and dactinomycin.[2]

References
  1. 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 Abstract]

  2. 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 Abstract]

Multilocular Cystic Nephroma



General Information About Multilocular Cystic Nephroma

Multilocular cystic nephromas are benign lesions consisting of cysts lined by renal epithelium. These lesions can occur bilaterally, and a familial pattern has been reported.

Multilocular cystic nephroma has been associated with pleuropulmonary blastomas, so radiographic imaging studies of the chest are monitored in patients with multilocular cystic nephroma.[1] (Refer to the Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Standard Treatment Options for Multilocular Cystic Nephroma

The standard treatment for multilocular cystic nephroma is surgery.

References
  1. Ashley RA, Reinberg YE: Familial multilocular cystic nephroma: a variant of a unique renal neoplasm. Urology 70 (1): 179.e9-10, 2007.  [PUBMED Abstract]

Primary Renal Synovial Sarcoma



General Information About Primary Renal Synovial Sarcoma

Primary renal synovial sarcoma is a subset of embryonal sarcoma of the kidney and is characterized by the t(x;18)(p11;q11) SYT-SSX translocation. It is similar in histology to the monophasic spindle cell synovial sarcoma and is considered an aggressive tumor with adverse patient outcomes in more than 50% of cases (n = 16).[1] Primary renal synovial sarcoma contains cystic structures derived from dilated, trapped renal tubules. Primary renal synovial sarcoma occurs more often in young adults.

(Refer to the Wilms tumor Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Standard Treatment Options for Primary Renal Synovial Sarcoma

The standard treatment for primary renal synovial sarcoma is chemotherapy. Chemotherapy regimens that are different from those traditionally used for Wilms tumor are used.[2]

References
  1. 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 Abstract]

  2. 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 Abstract]

Anaplastic Sarcoma of the Kidney



General Information About Anaplastic Sarcoma of the Kidney

Anaplastic sarcoma of the kidney is a rare renal tumor that has been identified mainly in patients younger than 15 years.

Patients present with a renal mass, with the most common sites of metastases being the lung, liver, and bones. (Refer to the Wilms tumor Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Cytogenetic abnormalities such as rearrangement between 10q21 and 18p11.2 have been reported.[1] These tumors show pathologic features similar to pleuropulmonary blastoma of childhood (refer to the Pleuropulmonary Blastoma section in the PDQ summary on Unusual Cancers of Childhood for more information) and undifferentiated embryonal sarcoma of the liver (refer to the Treatment of Undifferentiated Embryonal Sarcoma of the Liver section in the PDQ summary on Childhood Liver Cancer for more information).

Standard Treatment Options for Anaplastic Sarcoma of the Kidney

There is no standard treatment for anaplastic sarcoma of the kidney. In the past, these tumors have been identified as anaplastic Wilms tumor and treated accordingly.[2]

References
  1. Gomi K, Hamanoue S, Tanaka M, et al.: Anaplastic sarcoma of the kidney with chromosomal abnormality: first report on cytogenetic findings. Hum Pathol 41 (10): 1495-9, 2010.  [PUBMED Abstract]

  2. Vujanić GM, Kelsey A, Perlman EJ, et al.: Anaplastic sarcoma of the kidney: a clinicopathologic study of 20 cases of a new entity with polyphenotypic features. Am J Surg Pathol 31 (10): 1459-68, 2007.  [PUBMED Abstract]

Nephroblastomatosis



General Information About Nephroblastomatosis

Some multifocal nephrogenic rests may become hyperplastic, which may produce a thick rind of blastemal or tubular cells that enlarge the kidney. Nephroblastomatosis may be diagnosed radiographically by magnetic resonance imaging, in which the homogeneity of the hypointense rind-like lesion on contrast-enhanced imaging differentiates it from Wilms tumor. Biopsy often cannot discriminate Wilms tumor from these hyperplastic nephrogenic rests. Differentiation may occur after chemotherapy is administered.

Standard Treatment Options for Nephroblastomatosis

Standard treatment options for nephroblastomatosis include the following:

  1. Preoperative chemotherapy.
  2. Renal-sparing surgery.
Preoperative chemotherapy

Current treatment includes vincristine and dactinomycin until nearly complete resolution, as determined by imaging.

Renal-sparing surgery

Even with treatment (vincristine and dactinomycin), about one-half of children diagnosed with nephroblastomatosis will develop Wilms tumor within 36 months. In a series of 52 patients, 3 patients died of recurrent Wilms tumor.[1] In treated children, as many as one-third of Wilms tumors are anaplastic, probably as a result of selection of chemotherapy-resistant tumors, so early detection is critical. Patients are monitored by imaging at a maximum interval of 3 months, for a minimum of 7 years. Given the high incidence of bilaterality and the subsequent Wilms tumors, renal-sparing surgery is indicated.[1]

These patients are eligible for treatment on the COG-AREN0534 trial with vincristine and dactinomycin.

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 Abstract]

Treatment of Recurrent Childhood Kidney Tumors

Patients with recurrent rhabdoid tumor of the kidney, clear cell sarcoma of the kidney, neuroepithelial tumor of the kidney, and renal cell carcinoma should be considered for treatment on available phase I and phase II clinical trials.

Table 8. Treatment Options for Recurrent Childhood Kidney Tumors
Tumor Type Treatment Options 
Standard-risk relapsed Wilms tumorSurgery, radiation therapy, and chemotherapy
High-risk and very high-risk relapsed Wilms tumorChemotherapy, surgery, and/or radiation therapy
Hematopoietic stem cell transplantation
Recurrent clear cell sarcoma of the kidneyChemotherapy, surgery, and/or radiation therapy

Prognosis, Prognostic Factors, and Risk Categories for Recurrent Wilms Tumor

Approximately 15% of patients with favorable-histology (FH) Wilms tumor and 50% of patients with anaplastic Wilms tumor experience recurrence.[1] Historically, the salvage rate for patients with recurrent FH Wilms tumor was 25% to 40%. As a result of modern treatment combinations, the outcome after recurrence has improved up to 60%.[2,3]

A number of potential prognostic features influencing outcome postrecurrence have been analyzed, but it is difficult to separate whether these factors are independent of each other. Also, the following prognostic factors appear to be changing over time as therapy for primary and recurrent Wilms tumor evolves:

  • Anaplastic histology.[4]
  • Advanced tumor stage.[4]
  • Gender: Gender was predictive of outcome, with males faring worse than females.[2,5]

The National Wilms Tumor Study-5 (NWTS-5) showed that time to recurrence and site of recurrence are no longer prognostically significant.[2,5] However, in a Société Internationale d’Oncologie Pédiatrique (SIOP) study, patients who experienced a pulmonary relapse within 12 months of diagnosis had a poorer prognosis (5-year overall survival [OS], 47%) than did patients who experienced a pulmonary relapse 12 months or more after diagnosis (5-year OS, 75%).[6]

On the basis of these results, the following three risk categories have been identified:

  • Standard risk: Patients with FH Wilms tumor who relapse after therapy with only vincristine and/or dactinomycin. These patients are expected to have an event-free survival (EFS) of 70% to 80%.[3] Standard-risk patients experience approximately 30% of recurrences.

  • High risk: Patients with FH Wilms tumor who relapse after therapy with three or more agents. These patients account for 45% to 50% of children with Wilms tumor who relapse and have survival rates in the 40% to 50% range.[3]

  • Very high risk: Patients with recurrent anaplastic or blastemal-predominant Wilms tumor. These patients are expected to have survival rates in the 10% range, and they experience 10% to 15% of all Wilms tumor relapses.[3,7]

Treatment of Standard-Risk Relapsed Wilms Tumor

In children who had small stage I Wilms tumor and were treated with surgery alone, the EFS was 84%. All but one child who relapsed was salvaged with treatment tailored to the site of recurrence.[8,5]

Successful retreatment can be accomplished for Wilms tumor patients whose initial therapy consisted of immediate nephrectomy followed by chemotherapy with vincristine and dactinomycin and who relapse.

Treatment options for standard-risk relapsed Wilms tumor include the following:

  1. Surgery, radiation therapy, and chemotherapy.
Surgery, radiation therapy, and chemotherapy

Evidence (surgery, radiation therapy, and chemotherapy):

  1. Fifty-eight patients were treated on the NWTS-5 (COG-Q9402) relapse protocol, with surgical excision when feasible, radiation therapy, and alternating courses of vincristine, doxorubicin, and cyclophosphamide; and etoposide and cyclophosphamide.[5]
    • Four-year EFS after relapse was 71%, and OS was 82%.

    • For patients whose site of relapse was only the lungs, the 4-year EFS rate was 68% and the OS rate was 81%.

Treatment of High-Risk and Very High-Risk Relapsed Wilms Tumor

Treatment options for high-risk and very high-risk relapsed Wilms tumor include the following:

  1. Chemotherapy, surgery, and/or radiation therapy.
  2. Hematopoietic stem cell transplantation (HSCT).
Chemotherapy, surgery, and/or radiation therapy

Evidence (chemotherapy, surgery, and/or radiation therapy):

  1. Approximately 50% of unilateral Wilms tumor patients who relapse or progress after initial treatment with vincristine, dactinomycin, and doxorubicin and radiation therapy can be successfully retreated. Sixty patients with unilateral Wilms tumor were treated on the NWTS-5 relapse protocol with alternating courses of cyclophosphamide/etoposide and carboplatin/etoposide, surgery, and radiation therapy.[2][Level of evidence: 2A]
    • The 4-year EFS rate for patients with high-risk Wilms tumor was 42%, and the OS rate was 48%.

    • High-risk patients who relapsed in the lungs only had a 4-year EFS rate of 49% and an OS rate of 53%.

Patients with stage II, stage III, and stage IV anaplastic-histology tumors at diagnosis have a very poor prognosis upon recurrence.[7] The combination of ifosfamide, etoposide, and carboplatin has demonstrated activity in this group of patients, but significant hematologic toxic effects have been observed.[9]

HSCT

High-dose chemotherapy followed by autologous HSCT has been utilized for recurrent high-risk patients.[10-12]

Evidence (HSCT):

  1. An intergroup study of the former Pediatric Oncology Group and the former Children’s Cancer Group used a salvage induction regimen of cyclophosphamide and etoposide (CE) alternating with carboplatin and etoposide (PE) followed by delayed surgery. Disease-free patients with FH tumors were assigned to maintenance chemotherapy with five cycles of alternating CE and PE, and the rest of the patients were assigned to ablative therapy and autologous stem cell rescue. All patients received local radiation therapy.[13]
    • The 3-year survival was 52% for all eligible patients, while the 3-year survival was 64% for the chemotherapy consolidation subgroup and 42% for the autologous stem cell rescue subgroup.

The outcome of autologous stem cell rescue in selected patients is favorable; however, patients with gross residual disease going into transplant do not do as well.[10,12,14] No randomized trials of chemotherapy versus transplant have been reported, and case series suffer from selection bias.

Patients in whom such salvage attempts fail should be offered treatment on available phase I or phase II studies.

Treatment of Recurrent Clear Cell Sarcoma of the Kidney

Clear cell sarcoma of the kidney has been characterized by late relapses. However, in NWTS-5, most relapses occurred within 3 years, and the most common site of recurrence was the brain.[15]

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, surgery, and/or radiation therapy.

Cyclophosphamide and carboplatin should be considered if not used initially. Patients with recurrent clear cell sarcoma of the kidney involving the brain have responded to treatment with ifosfamide, carboplatin, and etoposide (ICE) coupled with local control consisting of either surgical resection and/or radiation.[16][Level of evidence: 2A]

The use of high-dose chemotherapy followed by stem cell transplant is undefined in patients with recurrent clear cell sarcoma of the kidney.[17]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent Wilms tumor and other childhood kidney tumors. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. Green DM, Breslow NE, Beckwith JB, et al.: Effect of duration of treatment on treatment outcome and cost of treatment for Wilms' tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 16 (12): 3744-51, 1998.  [PUBMED Abstract]

  2. Malogolowkin M, Cotton CA, Green DM, et al.: Treatment of Wilms tumor relapsing after initial treatment with vincristine, actinomycin D, and doxorubicin. A report from the National Wilms Tumor Study Group. Pediatr Blood Cancer 50 (2): 236-41, 2008.  [PUBMED Abstract]

  3. Reinhard H, Schmidt A, Furtwängler R, et al.: Outcome of relapses of nephroblastoma in patients registered in the SIOP/GPOH trials and studies. Oncol Rep 20 (2): 463-7, 2008.  [PUBMED Abstract]

  4. Grundy P, Breslow N, Green DM, et al.: Prognostic factors for children with recurrent Wilms' tumor: results from the Second and Third National Wilms' Tumor Study. J Clin Oncol 7 (5): 638-47, 1989.  [PUBMED Abstract]

  5. Green DM, Cotton CA, Malogolowkin M, et al.: Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D: a report from the National Wilms Tumor Study Group. Pediatr Blood Cancer 48 (5): 493-9, 2007.  [PUBMED Abstract]

  6. Warmann SW, Furtwängler R, Blumenstock G, et al.: Tumor biology influences the prognosis of nephroblastoma patients with primary pulmonary metastases: results from SIOP 93-01/GPOH and SIOP 2001/GPOH. Ann Surg 254 (1): 155-62, 2011.  [PUBMED Abstract]

  7. Dome JS, Cotton CA, Perlman EJ, et al.: Treatment of anaplastic histology Wilms' tumor: results from the fifth National Wilms' Tumor Study. J Clin Oncol 24 (15): 2352-8, 2006.  [PUBMED Abstract]

  8. Shamberger RC, Anderson JR, Breslow NE, et al.: Long-term outcomes for infants with very low risk Wilms tumor treated with surgery alone in National Wilms Tumor Study-5. Ann Surg 251 (3): 555-8, 2010.  [PUBMED Abstract]

  9. Abu-Ghosh AM, Krailo MD, Goldman SC, et al.: Ifosfamide, carboplatin and etoposide in children with poor-risk relapsed Wilms' tumor: a Children's Cancer Group report. Ann Oncol 13 (3): 460-9, 2002.  [PUBMED Abstract]

  10. Garaventa A, Hartmann O, Bernard JL, et al.: Autologous bone marrow transplantation for pediatric Wilms' tumor: the experience of the European Bone Marrow Transplantation Solid Tumor Registry. Med Pediatr Oncol 22 (1): 11-4, 1994.  [PUBMED Abstract]

  11. 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 Abstract]

  12. Campbell AD, Cohn SL, Reynolds M, et al.: Treatment of relapsed Wilms' tumor with high-dose therapy and autologous hematopoietic stem-cell rescue: the experience at Children's Memorial Hospital. J Clin Oncol 22 (14): 2885-90, 2004.  [PUBMED Abstract]

  13. Tannous R, Giller R, Holmes E, et al.: Intensive therapy for high risk (HR) relapsed Wilms' tumor (WT): a CCG-4921/POG-9445 study report. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A2315, 2000. 

  14. Spreafico F, Bisogno G, Collini P, et al.: Treatment of high-risk relapsed Wilms tumor with dose-intensive chemotherapy, marrow-ablative chemotherapy, and autologous hematopoietic stem cell support: experience by the Italian Association of Pediatric Hematology and Oncology. Pediatr Blood Cancer 51 (1): 23-8, 2008.  [PUBMED Abstract]

  15. Seibel NL, Sun J, Anderson JR, et al.: Outcome of clear cell sarcoma of the kidney (CCSK) treated on the National Wilms Tumor Study-5 (NWTS). [Abstract] J Clin Oncol 24 (Suppl 18): A-9000, 502s, 2006. 

  16. 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 Abstract]

  17. Gooskens SL, Furtwängler R, Vujanic GM, et al.: Clear cell sarcoma of the kidney: a review. Eur J Cancer 48 (14): 2219-26, 2012.  [PUBMED Abstract]

Changes to This Summary (06/27/2014)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was reformatted.

This summary was comprehensively reviewed and extensively revised.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary



Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of Wilms tumor and other childhood kidney tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • 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)
  • Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)
  • Nita Louise Seibel, MD (National Cancer Institute)
  • Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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National Cancer Institute: PDQ® Wilms Tumor and Other Childhood Kidney Tumors Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/wilms/HealthProfessional. Accessed <MM/DD/YYYY>.

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