General Information

The National Cancer Institute (NCI) provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Fortunately, 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 should be referred to medical centers that have a multidisciplinary team 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 in order 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 specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[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. 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.[1] Between 1975 and 2006, childhood cancer mortality has decreased by more than 50%. Childhood and adolescent cancer survivors require close follow-up since 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.)

Prognosis

Wilms tumor is a curable disease in the majority of affected children. Approximately 500 cases are diagnosed in the United States each year. Since the 1980s, the 5-year survival rate for Wilms tumor has been consistently above 90%.[1] 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.[3] The prognosis for patients with Wilms tumor is related not only to the stage of disease at diagnosis, the histopathologic features of the tumor, patient age, and tumor size, but also to the team approach provided to each patient by the pediatric surgeon, radiation oncologist, and pediatric oncologist (COG-AREN9404).[4,5,6,7] Patients who develop Wilms tumor in their second decade of life have a poorer survival (5-year survival, 63%) than younger patients with Wilms tumor.[8]

Congenital Anomalies and Syndromes Predisposing to Wilms Tumor

Wilms tumor typically develops in otherwise healthy children; however, approximately 10% of children with Wilms tumor have a congenital anomaly.[9] Children with Wilms tumor may have associated urinary tract anomalies, including hemihypertrophy, cryptorchidism, and hypospadias. Children may have a recognizable phenotypic syndrome (including overgrowth disease, aniridia, genetic malformations, and others). These syndromes have provided clues to the genetic basis of the disease. The phenotypic syndromes have been divided into overgrowth and nonovergrowth categories.

• Overgrowth syndromes. Overgrowth syndromes are the result of excessive prenatal and postnatal somatic growth.[10,11]Examples of overgrowth syndromes include the following:
  • Beckwith-Wiedemann syndrome (prevalence is about 1% of children with Wilms tumor).[12,13,14,15]
  • Isolated hemihypertrophy (prevalence is about 2.5% of children with Wilms tumor).[12,16]
  • Perlman syndrome (characterized by fetal gigantism, renal dysplasia, Wilms tumor, islet cell hypertrophy, multiple congenital anomalies, and mental retardation).[17]Germline inactivating mutations inDIS3L2on chromosome 2q37 are associated with Perlman syndrome.[18]
  • Sotos syndrome (characterized by cerebral gigantism).
  • Simpson-Golabi-Behemel syndrome (characterized by macroglossia, macrosomia, renal and skeletal abnormalities, and increased risk of embryonal cancers).
• Nonovergrowth syndromes. Examples of nonovergrowth syndromes associated with Wilms tumor include the following:
  • WAGR syndrome (aniridia, genitourinary anomaly, and mental retardation). The constellation of WAGR syndrome occurs in association with an interstitial deletion on chromosome 11 (del[11p13]).[19,20](prevalence is about 0.4% of children with Wilms tumor). The incidence of bilateral Wilms tumor in children with WAGR syndrome is about 15%.[21]
  • Isolated aniridia.
  • Genitourinary anomalies including hypospadias, undescended testis, and others are associated withWilms tumor 1 (WT1)mutations (prevalence is over 6% of children with Wilms tumor). Children with pseudo-hermaphroditism and/or renal disease (glomerulonephritis or nephrotic syndrome) who develop Wilms tumor may have the Denys-Drash or Frasier syndrome (characterized by male hermaphroditism, primary amenorrhea, chronic renal failure, and other abnormalities),[22]both of which are associated with mutations in the WT1gene.[23]Specifically, germline missense mutations in theWT1gene are responsible for most Wilms tumors that occur as part of the Denys-Drash syndrome.[24,25]
  • Bloom syndrome.
  • Alagille syndrome.[26]
  • Trisomy 18.
  • Li-Fraumeni syndrome (familial cancer syndrome).

Screening Children Predisposed to Wilms Tumor

Children with a significantly increased predisposition to develop Wilms tumor (e.g., most children with Beckwith-Wiedemann syndrome, WAGR syndrome, Denys-Drash syndrome, idiopathic hemihypertrophy, or sporadic aniridia) should be screened with ultrasound every 3 months at least until they reach age 8 years.[10,11,12,27]

Approximately 10% of patients with Beckwith-Wiedemann syndrome will develop a malignancy, with either Wilms tumor or hepatoblastoma being the most common, although adrenal tumors can also occur.[28] 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, most hepatoblastomas will have occurred, and imaging may be limited to renal ultrasound, which is quicker and does not require the child to fast for the exam.[29]

Children with Klippel-Trénaunay syndrome, a unilateral limb overgrowth syndrome, had been considered to be at increased risk for developing Wilms tumor. The risk of Wilms tumor in children with Klippel-Trénaunay syndrome, when assessed using the National Wilms Tumor Study (NWTS) database, was no different than in the general population and routine ultrasound surveillance is not recommended.[30]

Genetics of Wilms Tumor

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

Wilms tumor 1gene (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. Germline mutations in WT1 have been found in about 2% of phenotypically normal children with Wilms tumor.[31] Germline WT1 mutations in children with Wilms tumor does not confer a poor prognosis per se. The offspring of those with germline mutation in WT1 may also be at increased risk of developing Wilms tumor. 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 the Denys-Drash syndrome.

WT1 mutation is more common in those children with Wilms tumor and one of the following:

• WAGR syndrome, Denys-Drash syndrome, or sporadic aniridia.
• Genitourinary anomalies, including hypospadias and cryptorchidism.
• Bilateral Wilms tumor.
• Unilateral Wilms tumor with nephrogenic rests in the contralateral kidney.
• Stromal and rhabdomyomatous differentiation.[22]

WT1mutation, aniridia, and genitourinary malformation

The observation that lead to the discovery of WT1 was that children with WAGR syndrome (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 (responsible for aniridia). Aniridia is characterized by hypoplasia of the iris and it occurs in sporadic or familial cases and has an autosomal dominant inheritance. Mutations in the PAX6 gene lead to aniridia. The PAX6 gene is located on chromosome 13 closely associated with the WT1 gene, deletion of which confers the increased risk of Wilms tumor. Some of the sporadic cases of aniridia are caused by large chromosomal deletions that also include the Wilms tumor gene – WT1. This results in an increased relative risk of 67-fold (95% confidence interval [CI], 8.1–241) of developing Wilms tumor in children with sporadic aniridia.[32] Patients with sporadic aniridia and a normal WT1 gene, however, are not at increased risk for developing Wilms tumor. Children with familial aniridia generally have a normal WT1 gene and are not at an increased risk of Wilms tumor. The mental retardation in WAGR syndrome may be secondary to deletion of other genes including SLC1A2 or BDNF (brain-derived neurotrophic factor).[33]

The incidence of Wilms tumor in children with sporadic aniridia is estimated to be about 5%.[21] Patients with sporadic aniridia should be screened with ultrasound every 3 months until they reach age 8 years, unless genetic testing confirms that they are negative for WT1.[12,27]

Monitoring for late renal failure

Children with WAGR syndrome or other germline WT1 mutations are at increased risk of eventually developing hypertension, nephropathy, and renal failure and should be monitored throughout their lives.[34] Patients with Wilms tumor and aniridia without genitourinary abnormalities are at lesser risk but should be monitored for nephropathy or renal failure.[35] Children with Wilms tumor and any genitourinary anomalies are also at increased risk for late renal failure and should be monitored. Features associated with germline WT1 mutations that increase the risk for developing renal failure are stromal predominant histology, bilaterality, intralobular nephrogenic rests, and Wilms tumor diagnosed before age 2 years.[34]

WT1interactions

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.[36,37] That CTNNB1 mutations are rarely found in the absence of a WT1 or WTX mutation suggests that activation of beta-catenin in the presence of intact WT1 protein must be inadequate to promote tumor development.[38,39]

WT1 mutations and 11p15 loss of heterozygosity are associated with relapse in patients with very low-risk Wilms tumor who do not receive chemotherapy.[40] These may provide biomarkers to stratify patients in the future.

Wilms tumor 2gene (WT2)

A second Wilms tumor locus, WT2 gene, maps to an imprinted region of chromosome 11p15.5, which, when constitutional, causes the Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumors have constitutional epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. These children may be more likely to have bilateral Wilms tumor or familial Wilms tumor.[33] There are several candidate genes at the WT2 locus, comprising the two independent imprinted domains IGF2/H19 and KIP2/LIT1.[41] Loss of heterozygosity (LOH), which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally inactive 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 LOH or loss of imprinting at 11p15.5.[42] The mechanism resulting in loss of imprinting can be either genetic mutation or epigenetic change of methylation.[33,41] Loss of imprinting or gene methylation are rarely found at other loci, supporting the specificity of loss of imprinting at IGF2.[43] Interestingly, Wilms tumors in Asian children are not associated with either nephrogenic rests or IGF2 loss of imprinting.[44]

Beckwith-Wiedemann syndrome results from constitutional loss of imprinting or heterozygosity of WT2. Observations suggest genetic heterogeneity in the etiology of Beckwith-Wiedemann syndrome with differing levels of association with risk of tumor formation.[45] Molecularly defined subsets of Beckwith-Wiedemann patients may not require ultrasound screening for malignancies. Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, though metachronous bilateral disease is also observed.[12,13,14] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the NWTS.[14,46,47]

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. WTX mutations were identified in 17% of Wilms tumors, equally distributed between males and females.[48] This gene is inactivated in approximately one-third of Wilms tumors but germline mutations have not been observed in patients with Wilms tumor.[49]

Other genes

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

• 16q and 1p: Additional tumor-suppressor or tumor-progressive genes may lie on chromosomes 16q and 1p as evidenced by LOH for these regions in 17% and 11% of Wilms tumors, respectively. Patients classified by tumor-specific loss of these loci had significantly worse relapse-free and overall survival rates. Combined loss of 1p and 16q are used to select favorable-histology Wilms tumor patients for more aggressive therapy in the current Children's Oncology Group study.[50]
• CACNA1E: Overexpression and amplification of the geneCACNA1Elocated at 1q25.3, which encodes the ion-conducting alpha-1 subunit of R-type voltage-dependent calcium channels, may be associated with relapse in favorable-histology Wilms tumor.[51]
• 7p21: A consensus region of LOH has been identified within 7p21 containing ten known genes, including two candidate suppressor genes (Mesenchyme homeobox 2[MEOX2] andSclerostin domain containing 1[SOSTDC1]).[52]
• SKCG-1: Genomic loss of a growth regulatory gene,SKCG-1, located at 11q23.2, was found in 38% of examined sporadic Wilms tumors and particularly the highly proliferative Wilms tumors. Additional studies of si-RNA silencing of theSKCG-1gene in human embryonic kidney epithelial cells resulted in a 40% increase in cell growth, which suggests that this gene may be involved in loss of growth regulation and Wilms tumorigenesis.[53]
• p53 tumor suppressor gene: A small subset of anaplastic Wilms tumors show mutations in thep53tumor suppressor gene. Although it is unlikely that it plays a major role in Wilms tumorigenesis, it may be useful as an unfavorable prognostic marker.[54,55]
• 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.[56]
• MYCN: Genomic gain or amplification ofMYCNis relatively common in Wilms tumors and associated with diffuse anaplastic histology.[56]

Genetics of Familial Wilms Tumor

Despite the number of genes that appear to be involved in the development of Wilms tumor, hereditary 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 low likelihood of developing Wilms tumor.[57] The risk of Wilms tumor among offspring of persons who have had unilateral (sporadic) tumors is less than 2%.[58] Two familial Wilms tumor genes have been localized to FWT1 (17q12-q21) and FWT2 (19q13.4).[59,60,61]

Bilateral Wilms Tumor

About 4% to 5% of patients have bilateral Wilms tumors, but these are not usually hereditary.[62] Many bilateral tumors are present at the time Wilms tumor is first diagnosed (i.e., synchronous), but a second Wilms tumor may also develop later in the remaining kidney of 1% to 3% of children treated successfully for Wilms tumor. The incidence of such metachronous bilateral Wilms tumors is much higher in children whose original Wilms tumor was diagnosed before age 12 months and/or whose resected kidney contains nephrogenic rests. Periodic abdominal ultrasound is recommended for early detection of metachronous bilateral Wilms tumor as follows:[60,61]

• Children with nephrogenic rests in the resected kidney (if younger than 48 months at initial diagnosis)—every 3 months for 6 years.
• Children with nephrogenic rests in the resected kidney (if older than 48 months at initial diagnosis)—every 3 months for 4 years.
• Other patients—every 3 months for 2 years, then yearly for an additional 1 to 3 years.

Clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, neuroepithelial tumor of the kidney, and cystic partially-differentiated nephroblastoma are childhood renal tumors unrelated to Wilms tumor.[63,64] (Refer to the Cellular Classification section of this summary for more information.)

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Cellular Classification

Wilms Tumor

Although most patients with a histologic diagnosis of Wilms tumor fare well with current treatment, approximately 10% of patients have histopathologic features that are associated with a poorer prognosis, and in some types, with a high incidence of relapse and death. Wilms tumor can be separated into three prognostic groups on the basis of histopathology—favorable histology, anaplastic histology, and nephrogenic rests.

Favorable histology

Histologically, Wilms tumor mimics development of a normal kidney consisting of three cell types: blastemal, epithelial (tubules), and stromal. 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 and therefore do not direct the initial therapy.[1]

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.[2] There are two histologic criteria for anaplasia, both of which must be present for the diagnosis. They are the presence of multipolar polyploid mitotic figures with marked nuclear enlargement and hyperchromasia. Mutations in the p53 gene have been associated with anaplastic histology.[3] Anaplasia correlates best with responsiveness to therapy rather than to 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 favorable-histology Wilms tumor.[4] This is the reason why focal anaplasia and diffuse anaplasia are differentiated, both pathologically and therapeutically. Focal anaplasia is defined as the presence of one or a few sharply localized regions of anaplasia within a primary tumor. Focal anaplasia does not confer as poor a prognosis as does diffuse anaplasia.[4,5,6]

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 in nearly 100% of kidneys with bilateral Wilms tumors.[7,8] 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.[1] Patients with any type of nephrogenic rest in a kidney removed for nephroblastoma should be considered at increased risk for tumor formation in the remaining kidney. This risk decreases with patient age.[9] Extrarenal nephrogenic rests rarely occur, but may develop into extrarenal Wilms tumor.[10]

Clear Cell Sarcoma of the Kidney

Clear cell sarcoma of the kidney (CCSK) is not a Wilms tumor variant, but it is an important primary renal tumor associated with a significantly higher rate of relapse and death than favorable-histology Wilms tumor.[11] In addition to pulmonary metastases, clear cell sarcoma also spreads to bone, brain, and soft tissue. The classic pattern of CCSK is defined by nests or cords of cells separated by regularly spaced fibrovascular septa.[11] Previously, 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.[12] The brain is a frequent site of recurrent disease.[13,14]

Rhabdoid Tumors of the Kidney

Rhabdoid tumors (RTs) are extremely aggressive malignancies that generally occur in infants and young children. The most common locations are the kidney and central nervous system (CNS) (atypical teratoid/rhabdoid tumor [AT/RT]), although RTs can also arise in most soft tissue sites. Initially they were thought to be a rhabdomyosarcomatoid variant of Wilms tumor when they occurred in the kidney.

Histologically, the most distinctive features of rhabdoid tumors of the kidney (RTK) are rather large cells with large vesicular nuclei, a prominent single nucleolus, and in some cells, the presence of globular eosinophilic cytoplasmic inclusions. A distinct clinical presentation with fever, hematuria, young age (mean age 11 months), and high tumor stage at presentation suggests a diagnosis of RTK.[15] Approximately two-thirds of patients will present with advanced stage. Bilateral cases have been reported.[16] RTK tends to metastasize to the lungs and the brain. As many as 10% to 15% of patients with RTK also have CNS lesions.[17] Relapses occur early (median time from diagnosis is 8 months).[16,18]

RTs in all anatomical locations have a common genetic abnormality—the mutation and/or deletion of the SMARCB1 (also called hSNF5 or INI1) gene located at chromosome 22q11. This gene encodes a component of the SWI/SNF chromatin remodeling complex that has an important role in transcriptional regulation.[19,20] Based on gene expression analysis in rhabdoid tumors, it is hypothesized that rhabdoid tumors arise within 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.[21] 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.[22,23] Approximately 35% of patients with RTs have germline SMARCB1 alterations.[24] In most cases, the mutations are de novo, and not inherited from a parent. 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.[25]

Rhabdoid predisposition syndrome (RPS)

Early-onset, multifocal disease and familial cases strongly support the possibility of an RPS. This has been confirmed by the presence of constitutional mutations of SMARCB1 in rare familial cases and in a subset of patients with apparently sporadic RTs. In a cohort of 74 RTs, 60% of the tumors occurring before age 6 months were linked to the presence of a germline mutation. However, in this same series, tumors that occurred after age 2 years were also found to be associated with germline mutations (7 of 35 cases). Germline analysis is suggested for all individuals with RTs, whatever their ages. Genetic counseling is recommended 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 is feasible and should be considered.[26]

Recommendations for surveillance in patients with germline SMARCB1 mutations have been developed based on the 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 screening patients with germline SMARCB1 mutations. The aggressive natural history of the disease, apparently high penetrance, and well-defined age of onset for CNS AT/RT suggest that screening could prove beneficial. Given the potential survival benefit of surgically resectable disease, it is postulated that early detection might improve overall survival.[27] From birth to age 1 year, it is suggested that patients have thorough physical and neurologic examinations, as well as head ultrasounds monthly 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. 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 6 months.[27]

Congenital Mesoblastic Nephroma

Mesoblastic nephroma (MN) comprises about 5% of childhood kidney tumors. It is the most common kidney tumor found in infants younger than 3 months. The median age of diagnosis is 1 to 2 months and more than 90% of cases appear within the first year of life. Twice as many males are diagnosed as females. The diagnosis should be questioned when applied to individuals older than 2 years.[28] When 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%.[29]

Grossly, MNs appear as solitary, unilateral masses indistinguishable from nephroblastoma. Microscopically, they consist of spindled mesenchymal cells. They can be divided into two major types: classic and cellular. Classic MN is often diagnosed by prenatal ultrasound or within 3 months after birth and closely resembles infantile fibromatosis.[30] Infantile fibrosarcoma and cellular MN contain the same t(12;15)(p13;q25) chromosomal translocation suggestive of a potential linkage.[31] The risk for recurrence within MN is closely associated with the presence of a cellular component and with stage.[30]

Renal Cell Carcinoma

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 CCSK or RTK. Renal cell carcinoma (RCC), the most common primary malignancy of the kidney in adults, occurs rarely 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.[32] The annual incidence rate is approximately 4 per 1 million children compared with an incidence of Wilms tumor of the kidney that is at least 29-fold higher. RCC in young patients has a different genetic and morphologic spectrum than that seen in older adults.[33,34,35,36]

RCC may be associated with other conditions, including the following:

• von Hippel-Lindau (VHL) disease: VHL disease is an autosomal dominant condition in which blood vessels within the retina and cerebellum grow excessively.[33]The gene for VHL disease is located on chromosome 3p25.3 and is a tumor-suppressor gene, which is either mutated or deleted in patients with the syndrome.

  Screening for the VHL gene is available.[37] To detect clear cell renal carcinoma in these individuals when the lesions are less than 3 cm and nephron-sparing surgery can be performed, annual screening with abdominal ultrasound or MRI is recommended beginning at age 8 to 11 years.[27]

• 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.[38,39]
• Familial RCC: Familial RCC has been associated with an inherited chromosome translocation involving chromosome 3.[40]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 renal cell carcinoma occurring with pheochromocytoma/paraganglioma. Germline mutations in a subunit of the gene have been reported in individuals with renal cancer with no history of pheochromocytoma.[41,42]

• Renal medullary carcinoma: A rare subtype of RCC, renal medullary carcinoma, may be associated with sickle cell hemoglobinopathy.[43]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.[44][ Level of evidence: 3iiA] Survival is poor and ranges from 2 weeks to 15 months, with a mean survival of 4 months.[43,44,45,46]
• Hereditary leiomyomatosis: Hereditary leiomyomatosis (of skin and uterus) and RCC is a distinct phenotype caused by dominant inheritance of a mutation in thefumarate hydratasegene. Screening for RCC starting as early as age 5 years has been recommended.[47,48]
• Second malignant neoplasm: RCCs have been described in patients several years after diagnosis and therapy for pediatric malignancies such as neuroblastoma, rhabdomyosarcoma, and leiomyosarcoma.[49,50,51,52,53]

Indications for germline genetic testing of children and adolescents with RCC to screen for a related syndrome are described in Table 1.

Table 1. 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
VHL = von Hippel-Lindau.
a Adapted from Linehan et al.[54]
Multifocal RCC or VHL lesions	Clear cell	VHLgene	von Hippel-Lindau syndrome
Family history of clear cell RCC or multifocal RCC with absent VHL mutation	Clear cell	Chromosome 3 gene translocations	Hereditary non-VHL clear cell RCC syndrome
Multifocal papillary RCC or family history of papillary RCC	Papillary	METgene	Hereditary papillary RCC syndrome
Multifocal RCC or cutaneous fibrofolliculoma or pulmonary cysts or spontaneous pneumothorax	Chromophobe or oncocytic or clear cell	Germline sequenceBHDgene	Birt-Hogg-Dubé syndrome
Personal or family history of early-onset uterine leiomyomata or cutaneous leiomyomata	Type 2 papillary orcollecting duct carcinoma	FHgene	Hereditary leiomyomata/RCC syndrome
Multifocal RCC or early-onset RCC or presence of paraganglioma/pheochromocytoma or family history of paraganglioma/pheochromocytoma	Clear cell or chromophobe	SDHBgene,SDHCgene,SDHDgene	Hereditary paraganglioma/pheochromocytoma syndrome

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 one 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.

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 (TFE3) located on Xp11.2. The TFE3 gene may partner with one of the following genes:

• ASPSCRin t(X;17)(p11.2;q25).
• PRCCin t(X;1)(p11.2;q21).
• SFPQin t(X;1)(p11.2;p34).
• NONOin 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.[55] Prior 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.[36,56] 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 reports that these patients have poorer outcomes.[57,58,59] Recurrences have been reported 20 to 30 years after the initial resection of the translocation-associated RCC.[52] VEGFR-targeted therapies and mTOR inhibitors seem to be active in Xp11 translocation metastatic RCC.[60]

RCC may present with an abdominal mass, abdominal pain, or hematuria. In a series of 41 children with RCC, the median age was 124 months with 46% presenting with localized stage I and stage II disease, 29% with stage III disease, and 22% with stage IV disease using the Robson classification system. The sites of metastases were the lungs, liver, and lymph nodes. EFS and 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.[61] 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.[62] In another series of 49 patients from a population-based cancer registry, the findings were essentially confirmed. 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.[63]

Nephroblastomatosis

Some nephrogenic rests may become hyperplastic which may produce a thick rind of blastemal or tubular cells that enlarge the kidney. The diagnosis may be made radiographically, most readily 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 following the administration of chemotherapy. Current recommendations are for treatment with vincristine and dactinomycin until nearly complete resolution as determined by imaging. Even with treatment (vincristine and dactinomycin), about half of children diagnosed with nephroblastomatosis will develop Wilms tumor within 36 months. In a series of 52 patients, three patients died of recurrent Wilms tumor.[64] 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 followed 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.[64] These patients will be eligible for treatment on the COG-AREN0534 trial with vincristine and dactinomycin.

Neuroepithelial Tumors of the Kidney

Neuroepithelial tumors of the kidney (NETK) are extremely rare and demonstrate a unique proclivity for young adults. It is a highly aggressive neoplasm, more often presenting with penetration of the renal capsule, extension into the renal vein, and metastases.[65,66] Primary NETK consist of primitive neuroectodermal tumors characterized by CD99 (MIC-2) positivity and the detection of EWS/FLI-1 fusion transcripts. Within NETK, focal, atypical histologic features have been seen including clear cell sarcoma, RT, malignant peripheral nerve sheath tumors, and paraganglioma.[65,67] (Refer to the PDQ summary on Ewing Sarcoma Family of Tumors for more information about neuroepithelial tumors.)

Desmoplastic Small Round Cell Tumor of the Kidney

Desmoplastic small round cell tumor of the kidney (DSRCT) is a rare, small, round blue tumor of the kidney. It is diagnosed by its characteristic EWS-WT1 translocation.[68] (Refer to the PDQ summary on Childhood Soft Tissue Sarcoma Treatment for more information about DSRCT.)

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. Patients with stage I disease have a 100% survival rate with surgery alone. Patients with stage II disease have an excellent outcome with tumor resection followed by postoperative vincristine and dactinomycin.[9]

Multilocular Cystic Nephroma

Multilocular cystic nephromas (MCNs) are benign lesions consisting of cysts lined by renal epithelium. These lesions can occur bilaterally and a familial pattern has been reported. MCN has been associated with pleuropulmonary blastomas, so radiographic imaging studies of the chest should be followed in patients with MCN.[69] Recurrence has been reported following tumor spillage at surgery.[70][Level of evidence: 3iiiA]

Primary Renal Synovial Sarcoma

Primary renal synovial sarcoma (PRSS) 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. PRSS contains cystic structures derived from dilated, trapped renal tubules. PRSS occurs more often in young adults and this type of renal tumor should be treated with different chemotherapy regimens than traditional Wilms tumor.[71]

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. These tumors show pathologic features similar to pleuropulmonary blastoma of childhood (see the PDQ summary on Unusual Cancers of Childhood for more information) and undifferentiated embryonal sarcoma of the liver (see the PDQ summary on Childhood Liver Cancer for more information). Optimal therapy for this diagnosis is not clear. In the past, these tumors have been identified as anaplastic Wilms tumor and treated accordingly.[72]

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58.	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.
59.	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.
60.	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.
61.	Indolfi P, Terenziani M, Casale F, et al.: Renal cell carcinoma in children: a clinicopathologic study. J Clin Oncol 21 (3): 530-5, 2003.
62.	Geller JI, Dome JS: Local lymph node involvement does not predict poor outcome in pediatric renal cell carcinoma. Cancer 101 (7): 1575-83, 2004.
63.	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.
64.	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.
65.	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.
66.	Jimenez RE, Folpe AL, Lapham RL, et al.: Primary Ewing's sarcoma/primitive neuroectodermal tumor of the kidney: a clinicopathologic and immunohistochemical analysis of 11 cases. Am J Surg Pathol 26 (3): 320-7, 2002.
67.	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.
68.	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.
69.	Ashley RA, Reinberg YE: Familial multilocular cystic nephroma: a variant of a unique renal neoplasm. Urology 70 (1): 179.e9-10, 2007.
70.	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.
71.	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.
72.	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.

Stage Information

Wilms Tumor

The stage is determined by the results of the imaging studies and both the surgical and pathologic findings at nephrectomy and is the same for tumors with favorable or anaplastic histology. Thus, patients should be characterized by a statement of both criteria (for example, stage II, favorable histology or stage II, anaplastic histology).[1,2]

The staging system was originally developed by the National Wilms Tumor Study Group and still used by the Children's Oncology group. The staging system and incidence by stage are outlined below.[2]

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 prior to removal.
• No involvement of renal sinus vessels.
• No evidence of the tumor at or beyond the margins of resection.

For a tumor to qualify for certain therapeutic protocols as stage I, regional lymph nodes must be examined microscopically.

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 within the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor.

Rupture or spillage confined to the flank, including biopsy of the tumor, is no longer included in stage II and is now included in stage III.

Stage III

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

• Lymph nodes within 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.
• The tumor is treated with preoperative chemotherapy and was biopsied (using Tru-cut biopsy, open biopsy, or fine-needle aspiration) before removal.
• The tumor is removed in more than one piece (e.g., tumor cells are found in a separately excised adrenal gland; a tumor thrombus within the renal vein is removed separately from the nephrectomy specimen). Extension of the primary tumor within vena cava into thoracic vena cava and heart is considered stage III, rather than stage IV, even though outside the abdomen.

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. The primary tumor should be assigned a local stage following the above criteria which determines local therapy. For example, a patient may have stage IV, local stage III disease.

Stage V and those predisposed to developing Wilms tumor

In stage V Wilms tumor (5% of patients), bilateral involvement by tumor is present at diagnosis. Previously an attempt was made to stage each side according to the above criteria on the basis of the extent of disease. The current COG-AREN0534 protocol recommends preoperative chemotherapy 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.[3]

References:

1.	Wilms' tumor: status report, 1990. By the National Wilms' Tumor Study Committee. J Clin Oncol 9 (5): 877-87, 1991.
2.	Perlman EJ: Pediatric renal tumors: practical updates for the pathologist. Pediatr Dev Pathol 8 (3): 320-38, 2005 May-Jun.
3.	Breslow NE, Collins AJ, Ritchey ML, et al.: End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol 174 (5): 1972-5, 2005.

Treatment Option Overview

Wilms Tumor

Because of the relative rarity of this tumor, all patients with Wilms tumor 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 Wilms tumor is required to determine and implement optimum treatment.

The majority of the randomized clinical studies for treatment of children with Wilms tumor have been conducted by two large clinical groups. The National Wilms Tumor Study (NWTS) Group, which is now part of the Children's Oncology Group (COG), has established standard treatment for Wilms tumor in North America, which consists of initial surgery followed by chemotherapy and, in some patients, radiation therapy.[1,2,3] The Société Internationale d'Oncologie Pédiatrique (SIOP) is a European consortium. There are differences between the two groups that affect staging and classification. The SIOP trials provide preoperative chemotherapy before definitive resection. This statement will focus on the NWTS (now COG Renal Tumor Committee) results and studies. The major treatment conclusions of the National Wilms Tumor Studies (NWTS 1–5) 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.
2.	The prognosis for patients with stage III FH is best when treatment includes: (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.
3.	The addition of cyclophosphamide to the combination of vincristine, dactinomycin, and doxorubicin does not improve prognosis for patients with stage IV FH tumors.
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 event-free survival, achieves greater dose intensity, and is associated with less toxicity and expense.[4]
5.	Eighteen weeks of therapy is adequate for patients with stage I FH whereas other patients can be treated with 6 months of therapy instead of 15 months.[1,4,5,6,7]
6.	Tumor-specific loss of heterozygosity for combined 1p and 16q predicts recurrence of FH Wilms tumor.[8]
7.	About 2% of Wilms tumors have ureteral involvement. 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.[9]

Operative principles have evolved from NWTS trials. The most important role for the surgeon is to ensure complete tumor removal without rupture and perform an assessment of the extent of disease. Radical nephrectomy and lymph node sampling via a transabdominal or thoracoabdominal incision is the procedure of choice.[10] A flank incision should not be performed because of the limited exposure it provides. For patients with resectable tumors, preoperative or intraoperative biopsy should not be performed.[10] 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 and depending on the size of the tumor, biopsy or wedge resection may be performed. Alternatively, the contralateral kidney should be explored to rule out bilateral involvement. This should be done prior to nephrectomy since the diagnosis of bilateral disease would dramatically alter the approach.[11]

Partial nephrectomy remains controversial and is not recommended except for children with bilateral tumors, children with a solitary kidney, or rare cases of horseshoe kidney. However, partial nephrectomy has been suggested for Wilms tumor in infants with Denys-Drash or Frasier syndrome in order to delay the need for dialysis.[12]; [13][Level of evidence: 3iiB] Also, some children who are predisposed to bilateral tumors who have very small tumors detected by ultrasound screening may be considered for partial nephrectomy to preserve renal tissue.[12] In North America, renal-sparing partial nephrectomy of unilateral Wilms tumor following administration of chemotherapy to shrink the tumor mass is considered investigational.[14,15]

Hilar, periaortic, iliac, and celiac lymph node sampling is mandatory even if the nodes appear normal.[10,16] Furthermore, any suspicious node basin should be sampled. Margins of resection, residual tumor, and any suspicious node basins should be marked with titanium clips. Resection of contiguous organs is rarely indicated and there is an increased incidence of complications occurring in more extensive resections involving 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.[17] Pathologically, Wilms tumor rarely invades adjacent organs. Primary resection of liver metastasis is not recommended.[18] Wilms tumor arising in a horseshoe kidney is rare and accurate preoperative diagnosis is important in planning the operative approach. Primary resection is possible in most cases. Inoperable cases can usually be resected after chemotherapy.[19]

Preoperative chemotherapy prior to nephrectomy is indicated in the following situations:[10,17,17,20,21,22,23]

• Metachronous bilateral Wilms tumor.
• Wilms tumor in a solitary kidney.
• Extension of tumor thrombus 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, colon but excluding the adrenal gland).
• Pulmonary compromise due to extensive pulmonary metastases.
• Retroperitoneal rupture with free fluid contained by Gerota fascia.

Patients with massive, nonresectable unilateral tumors, bilateral tumors, or venacaval tumor thrombus extending above the hepatic veins are candidates for preoperative chemotherapy because of the risk of initial surgical resection.[10,17,20,21] Preoperative chemotherapy should follow a biopsy, except in the setting of bilateral disease (COG-AREN0534). The biopsy may be performed percutaneously through a flank approach.[24,25,26,27,28,29] Preoperative chemotherapy should include doxorubicin in addition to vincristine and dactinomycin unless there is anaplastic histology present, which then includes treatment with other agents. The chemotherapy generally makes tumor removal easier because of the decreased size and vascular supply of the tumor and may reduce the frequency of surgical complications.[17,20,29,30,31] Postoperative radiation therapy to the tumor bed is required when a biopsy is performed or in the setting of local tumor stage III.

Newborns and all infants younger than 12 months require a reduction in chemotherapy doses to 50% of those given to older children.[32] This reduction diminishes toxic effects reported in children in this age group enrolled in NWTS studies while maintaining an excellent overall outcome.[33] Liver function tests in children with Wilms tumor should be monitored closely during the early course of therapy based on hepatic toxic effects (sinusoidal obstructive syndrome, previously called veno-occlusive disease) reported in those patients.[34,35] Dactinomycin should not be administered during radiation therapy. Patients who develop renal failure while on 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 the therapy.[36,37]

Children treated for Wilms tumor are at increased risk for developing second malignant neoplasms.[38] Congestive heart failure has been shown to be a risk in children treated with doxorubicin with the degree of risk influenced by cumulative doxorubicin dose, radiation to the heart, and gender (females are at increased risk).[39] 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.)

As mentioned previously, clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, neuroepithelial tumor of the kidney, and cystic partially-differentiated nephroblastoma are childhood renal tumors unrelated to Wilms tumor. Because of their renal location, they have been treated on clinical trials developed by the NWTS Group. The approach to their treatment, however, is distinctive from that of Wilms tumor, and requires timely and accurate diagnosis by a pathologist and pediatric oncologist with experience with these types of renal tumors.[40]

References:

1.	D'Angio GJ, Breslow N, Beckwith JB, et al.: Treatment of Wilms' tumor. Results of the Third National Wilms' Tumor Study. Cancer 64 (2): 349-60, 1989.
2.	Jereb B, Burgers JM, Tournade MF, et al.: Radiotherapy in the SIOP (International Society of Pediatric Oncology) nephroblastoma studies: a review. Med Pediatr Oncol 22 (4): 221-7, 1994.
3.	Green DM: The treatment of stages I-IV favorable histology Wilms' tumor. J Clin Oncol 22 (8): 1366-72, 2004.
4.	Green DM, Breslow NE, Beckwith JB, et al.: Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms' tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 16 (1): 237-45, 1998.
5.	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.
6.	D'Angio GJ, Evans AE, Breslow N, et al.: The treatment of Wilms' tumor: Results of the national Wilms' tumor study. Cancer 38 (2): 633-46, 1976.
7.	D'Angio GJ, Evans A, Breslow N, et al.: The treatment of Wilms' tumor: results of the Second National Wilms' Tumor Study. Cancer 47 (9): 2302-11, 1981.
8.	Grundy PE, Breslow NE, Li S, et al.: Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 23 (29): 7312-21, 2005.
9.	Ritchey M, Daley S, Shamberger RC, et al.: Ureteral extension in Wilms' tumor: a report from the National Wilms' Tumor Study Group (NWTSG). J Pediatr Surg 43 (9): 1625-9, 2008.
10.	Ehrlich PF, Ritchey ML, Hamilton TE, et al.: Quality assessment for Wilms' tumor: a report from the National Wilms' Tumor Study-5. J Pediatr Surg 40 (1): 208-12; discussion 212-3, 2005.
11.	Ritchey ML, Shamberger RC, Hamilton T, et al.: Fate of bilateral renal lesions missed on preoperative imaging: a report from the National Wilms Tumor Study Group. J Urol 174 (4 Pt 2): 1519-21; discussion 1521, 2005.
12.	McNeil DE, Langer JC, Choyke P, et al.: Feasibility of partial nephrectomy for Wilms' tumor in children with Beckwith-Wiedemann syndrome who have been screened with abdominal ultrasonography. J Pediatr Surg 37 (1): 57-60, 2002.
13.	Auber F, Jeanpierre C, Denamur E, et al.: Management of Wilms tumors in Drash and Frasier syndromes. Pediatr Blood Cancer 52 (1): 55-9, 2009.
14.	Ritchey ML: Renal sparing surgery for Wilms tumor. J Urol 174 (4 Pt 1): 1172-3, 2005.
15.	Cozzi DA, Zani A: Nephron-sparing surgery in children with primary renal tumor: indications and results. Semin Pediatr Surg 15 (1): 3-9, 2006.
16.	Zhuge Y, Cheung MC, Yang R, et al.: Improved survival with lymph node sampling in Wilms tumor. J Surg Res 167 (2): e199-203, 2011.
17.	Ritchey ML, Kelalis PP, Breslow N, et al.: Surgical complications after nephrectomy for Wilms' tumor. Surg Gynecol Obstet 175 (6): 507-14, 1992.
18.	Ehrlich PF, Ferrer FA, Ritchey ML, et al.: Hepatic metastasis at diagnosis in patients with Wilms tumor is not an independent adverse prognostic factor for stage IV Wilms tumor: a report from the Children's Oncology Group/National Wilms Tumor Study Group. Ann Surg 250 (4): 642-8, 2009.
19.	Neville H, Ritchey ML, Shamberger RC, et al.: The occurrence of Wilms tumor in horseshoe kidneys: a report from the National Wilms Tumor Study Group (NWTSG). J Pediatr Surg 37 (8): 1134-7, 2002.
20.	Ritchey ML: Primary nephrectomy for Wilms' tumor: approach of the National Wilms' Tumor Study Group. Urology 47 (6): 787-91, 1996.
21.	Lall A, Pritchard-Jones K, Walker J, et al.: Wilms' tumor with intracaval thrombus in the UK Children's Cancer Study Group UKW3 trial. J Pediatr Surg 41 (2): 382-7, 2006.
22.	Ritchey ML, Pringle KC, Breslow NE, et al.: Management and outcome of inoperable Wilms tumor. A report of National Wilms Tumor Study-3. Ann Surg 220 (5): 683-90, 1994.
23.	Ritchey ML, Shamberger RC, Haase G, et al.: Surgical complications after primary nephrectomy for Wilms' tumor: report from the National Wilms' Tumor Study Group. J Am Coll Surg 192 (1): 63-8; quiz 146, 2001.
24.	Tournade MF, Com-Nougué C, Voûte PA, et al.: Results of the Sixth International Society of Pediatric Oncology Wilms' Tumor Trial and Study: a risk-adapted therapeutic approach in Wilms' tumor. J Clin Oncol 11 (6): 1014-23, 1993.
25.	Oberholzer HF, Falkson G, De Jager LC: Successful management of inferior vena cava and right atrial nephroblastoma tumor thrombus with preoperative chemotherapy. Med Pediatr Oncol 20 (1): 61-3, 1992.
26.	Saarinen UM, Wikström S, Koskimies O, et al.: Percutaneous needle biopsy preceding preoperative chemotherapy in the management of massive renal tumors in children. J Clin Oncol 9 (3): 406-15, 1991.
27.	Dykes EH, Marwaha RK, Dicks-Mireaux C, et al.: Risks and benefits of percutaneous biopsy and primary chemotherapy in advanced Wilms' tumour. J Pediatr Surg 26 (5): 610-2, 1991.
28.	Thompson WR, Newman K, Seibel N, et al.: A strategy for resection of Wilms' tumor with vena cava or atrial extension. J Pediatr Surg 27 (7): 912-5, 1992.
29.	Shamberger RC, Ritchey ML, Haase GM, et al.: Intravascular extension of Wilms tumor. Ann Surg 234 (1): 116-21, 2001.
30.	Shamberger RC, Guthrie KA, Ritchey ML, et al.: Surgery-related factors and local recurrence of Wilms tumor in National Wilms Tumor Study 4. Ann Surg 229 (2): 292-7, 1999.
31.	Szavay P, Luithle T, Semler O, et al.: Surgery of cavoatrial tumor thrombus in nephroblastoma: a report of the SIOP/GPOH study. Pediatr Blood Cancer 43 (1): 40-5, 2004.
32.	Corn BW, Goldwein JW, Evans I, et al.: Outcomes in low-risk babies treated with half-dose chemotherapy according to the Third National Wilms' Tumor Study. J Clin Oncol 10 (8): 1305-9, 1992.
33.	Morgan E, Baum E, Breslow N, et al.: Chemotherapy-related toxicity in infants treated according to the Second National Wilms' Tumor Study. J Clin Oncol 6 (1): 51-5, 1988.
34.	Green DM, Norkool P, Breslow NE, et al.: Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: a report from the National Wilms' Tumor Study. J Clin Oncol 8 (9): 1525-30, 1990.
35.	Raine J, Bowman A, Wallendszus K, et al.: Hepatopathy-thrombocytopenia syndrome--a complication of dactinomycin therapy for Wilms' tumor: a report from the United Kingdom Childrens Cancer Study Group. J Clin Oncol 9 (2): 268-73, 1991.
36.	Feusner JH, Ritchey ML, Norkool PA, et al.: Renal failure does not preclude cure in children receiving chemotherapy for Wilms tumor: a report from the National Wilms Tumor Study Group. Pediatr Blood Cancer 50 (2): 242-5, 2008.
37.	Veal GJ, English MW, Grundy RG, et al.: Pharmacokinetically guided dosing of carboplatin in paediatric cancer patients with bilateral nephrectomy. Cancer Chemother Pharmacol 54 (4): 295-300, 2004.
38.	Breslow NE, Takashima JR, Whitton JA, et al.: Second malignant neoplasms following treatment for Wilm's tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 13 (8): 1851-9, 1995.
39.	Green DM, Grigoriev YA, Nan B, et al.: Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study group. J Clin Oncol 19 (7): 1926-34, 2001.
40.	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.

Treatment of Wilms Tumor

Standard Treatment Options

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[1]	Vincristine, dactinomycin x 18 weeks postnephrectomy
Regimen DD-4A[1]	Vincristine, dactinomycin, doxorubicin x 24 weeks postnephrectomy
Regimen I[2]	Vincristine, doxorubicin, cyclophosphamide, etoposide x 24 weeks

Table 3 provides an overview of the standard treatment based on published results for all stages of Wilms tumor and survival information.

Table 3. Overview of Wilms Tumor Standard Treatment by Stage

Stage	Histology	4 Year RFS or EFS	4 Year OS	Treatment (seeTable 2for chemotherapy regimen descriptions)
AH = anaplastic histology; DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy
a Abdominal XRT is planned according to local stage of renal tumor.
b Pulmonary XRT is reserved for patients with chest x-ray evidence of pulmonary metastases.
c 90% of the relapses occurred by 3.8 years from diagnosis and 90% of the deaths occurred within 5.7 years from diagnosis.[3]
d This approach is changing as noted on the AREN0534 study.
Stage I[1,2,4]	FH <24 mo/tumor weight <550g	85%	98%	Surgery only (should be done only within the context of a clinical trial)
	FH >24 mo/tumor weight >550g	94% RFS	98%	Nephrectomy + lymph node sampling followed by regimen EE-4A
	DA	68% EFS	79%; (n = 10)	Nephrectomy + lymph node sampling followed by regimen EE-4A and XRT
Stage II[1,2]	FH	86% RFS	98%	Nephrectomy + lymph node sampling followed by regimen EE-4A
	FA	80% EFS	80%; (n = 5)	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
	DA	83% EFS	82%	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen I
Stage III[1,2]	FH	87% RFS	94%	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
	FA	88% RFS	100%; (n = 8)	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
	FA (preoperative treatment)	71% RFS	71%; (n = 7)	Preoperative treatment with regimen DD-4A followed by nephrectomy + lymph node sampling and abdominal XRT
	DA	46% EFS	53%; (n = 16)	Preoperative treatment with regimen I followed by nephrectomy + lymph node sampling and abdominal XRT
	DA	65% EFS	67%	Immediate nephrectomy + lymph node sampling followed by abdominal XRT and regimen I
Stage IV[1,2]	FH	76% RFS	86%	Nephrectomy + lymph node sampling, followed by abdominal XRT,a bilateral pulmonary XRT,b and regimen DD-4A
	FA	61% EFS	72%; (n = 11)	Nephrectomy + lymph node sampling, followed by abdominal XRT,a bilateral pulmonary XRT,b and regimen DD-4A
	DA	33% EFS	33%; (n = 15)	Immediate nephrectomy + lymph node sampling followed by abdominal XRT,a whole-lung XRT,b and regimen I
	DA (preoperative treatment)	31% EFS	44%; (n = 13)	Preoperative treatment with regimen I followed by nephrectomy + lymph node sampling, followed by abdominal XRT,a and whole-lung XRTb
Stage V[1,2,3]	Overall	61% EFS	80%; (n = 158)
	FH	65%	87% (4-yr OS); 78% (10-yr OS)c	Bilateral renal biopsies and staging of each kidney followed by preoperative treatment with regimen EE-4A (if disease in both kidneys ≤ stage II) or regimen DD-4A (if disease in both kidneys > stage II), followed by second-look surgery and possibly more chemotherapy and/or XRTd
	FA	76%	88%; (n = 9)	Bilateral renal biopsies and staging of each kidney followed by preoperative treatment with regimen I, followed by second-look surgery and possibly more chemotherapy and/or XRTd
	DA	25%	42%; (n = 20)	Bilateral renal biopsies and staging of each kidney followed by preoperative treatment with regimen I, followed by second-look surgery and possibly more chemotherapy and/or XRTd

Additional Treatment Considerations

Stage I

It may be possible to treat a subset of stage I Wilms tumor patients with surgery alone without chemotherapy. The Children's Oncology Group (COG) addressed this question in the National Wilms Tumor Study-5 (NWTS-5 [COG-Q9401]) trial for children younger than 2 years at diagnosis with stage I favorable histology (FH) Wilms tumors that weigh less than 550 g. In the NWTS-5 study, the omission of adjuvant chemotherapy was tested for this group of patients.[4] Stringent stopping rules were designed to ensure closure of the study if the 2-year relapse-free survival 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. This study was discontinued in 1998 when the predicted 2-year EFS fell below 90%.[5] Long-term follow-up of this study of the 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 was 84% (95% confidence interval [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).[4] COG study COG-AREN0532 is assessing this cohort again and is evaluating biological markers for this very low-risk group.[4,6]

Stage III

The outcome of patients with peritoneal implants treated with gross resection, three-drug chemotherapy, and total abdominal radiation (10.5 Gy) is similar to other stage III patients.[7][Level of evidence: 2A]

Stage IV

For patients with stage IV FH Wilms tumor, the role of pulmonary irradiation has been examined retrospectively (based on chest x-ray results) and is being examined prospectively (based on computerized tomography scan results) to identify clinical and radiologic features in patients that suggest that radiation can be omitted in certain subsets. Investigators in the United Kingdom reviewed outcomes in children with stage IV Wilms tumor with pulmonary metastases at diagnosis and the factors that contributed to the decision to withhold pulmonary radiation. Patients who underwent pulmonary irradiation had a 9-year EFS of 79% versus 53% in patients who did not, although there was no difference in OS. Pulmonary radiation decreased the chance of lung relapse (8% vs 23%). No consistent features could be identified to aid in the selection of patients who could safely avoid pulmonary irradiation.[8] In a retrospective review of newly diagnosed patients with Wilms tumor and pulmonary metastases enrolled on the SIOP-93-01 and SIOP-WT-2001 studies, the 5-year OS was 83% and the 5-year EFS was 72% for all children (N = 207). Survival was poorer for high-risk primary tumor histology patients (5-year OS 44%, EFS 39%) than for low- and intermediate-risk patients (5-year OS 90%, EFS 77%). Complete response of patients with pulmonary metastases to 6 weeks of chemotherapy was associated with better outcome (5-year OS 91%, 5-year EFS 79%), compared with patients with stable or progressive disease (5-year OS and EFS 17%). The presence of viable tumor in the resected pulmonary metastases was associated with a poorer survival (5-year OS 55%, 5-year EFS 35%), compared with completely necrotic metastases (5-year OS 97%, 5-year EFS 85%). Of patients whose pulmonary lesions showed a complete remission to chemotherapy alone, approximately 20% relapsed.[9] The presence of liver metastases at diagnosis is not an independent adverse prognostic factor in patients with stage IV Wilms tumor.[10]

Stage V 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.[11] Traditionally, patients have undergone bilateral renal biopsies with staging of each kidney. In NWTS-4, bilateral Wilms tumor patients had a lower EFS and OS compared with patients with localized Wilms tumor (including anaplastic histology), except for stage IV patients, in which OS was higher for patients with bilateral Wilms. The NWTS-4 study reported that the 8-year EFS for patients with bilateral Wilms tumor with favorable histology was 74% and the OS was 89%; for anaplastic histology, the EFS was 40% and OS was 45%.[12] The NWTS-5 (COG-Q9401) study reported the 4-year EFS for bilateral Wilms tumor patients was 61% and the OS was 81%; with anaplastic histology, the EFS was 44% and the OS was 55%.[2,3] Similar outcomes for patients with bilateral Wilms tumor have been reported in a single-institution experience in the Netherlands, with a 10-year OS of 78% (N = 41). In this study, there was significant morbidity in terms of renal failure (32%) and secondary tumors (20%).[13] The incidence of end-stage renal failure in the Dutch study may be a reflection of a longer follow-up period.

Treatment has changed from an initial surgical approach to an attempt to shrink the tumor and spare renal parenchyma with preoperative chemotherapy. The first COG trial to formally study bilateral Wilms tumors (COG-AREN0534) reflects the present recommendation to not perform an initial biopsy or laparotomy. Primary tumor excision should not be attempted, but patients should be given preoperative chemotherapy consisting of vincristine, dactinomycin, and doxorubicin. The Société Internationale d'Oncologie Pédiatrique (SIOP) reported their experience with 28 patients with bilateral Wilms tumor who were all treated with preoperative chemotherapy. Survival was 85% and relapse-free survival was 81%.[14] Nine out of ten patients with bilateral favorable-histology Wilms tumors underwent successful bilateral nephron-sparing procedures after receiving preoperative chemotherapy as detailed in a retrospective review from St. Jude Children's Research Hospital. One patient in the series developed renal failure after bilateral nephron-sparing surgery. Two patients with anaplastic histology died, although one patient died from complications of treatment rather than tumor. The overall survival for this group of patients was 83%. The authors recommend that bilateral nephron-sparing surgery should be considered for all patients who have bilateral Wilms tumor with favorable histology, even if preoperative imaging studies suggest that the lesions are unresectable.[15] For patients who are treated with preoperative chemotherapy, it is essential to evaluate the tumor pathology after 4 to 8 weeks. The ideal time to do a biopsy or resection is not clear for patients who are not being treated on a protocol, since minimal shrinkage may reflect chemotherapy-induced differentiation or anaplastic histology. However, continuing therapy without evaluating tumor pathology in a patient with bilateral Wilms tumor may increase toxicity for the patient without providing additional benefit for tumor control. Anaplastic histology occurs in 10% of patients with bilateral Wilms tumor and responds poorly to chemotherapy. Once the diagnosis is made, a complete resection should be performed. Making the diagnosis is not straightforward, since 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 eventually found to have diffuse anaplastic tumors had core biopsies performed to establish the diagnosis but anaplasia was not found on the core biopsies. Anaplasia was identified in only three out of the nine patients when an open wedge biopsy was performed and in seven out of nine patients who had a partial or complete nephrectomy.[12]

Chemotherapy and/or radiation therapy following biopsy or 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 or in the setting of anaplasia.[3,16,17,18,19,20,21]

Renal transplantation for children with Wilms tumor is usually delayed until 1 to 2 years have passed without evidence of malignancy.[22] 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 treatment for the tumor.[22]

Inoperable Wilms tumors

In North America, standard therapy for Wilms tumor is primary nephrectomy and lymph node sampling followed by adjuvant chemotherapy. However, certain clinical presentations of Wilms tumor are referred to as inoperable Wilms tumor and include the following:

• Metachronous bilateral Wilms tumor.
• Wilms tumor in a solitary kidney.
• Extension of tumor thrombus 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, colon but excluding the adrenal gland).
• Pulmonary compromise due to extensive pulmonary metastases.
• Retroperitoneal rupture with free fluid contained by Gerota fascia.

Neoadjuvant chemotherapy consisting of vincristine, dactinomycin, and doxorubicin followed by resection and radiation therapy is the usual treatment for inoperable Wilms tumor. In the case of bilateral Wilms tumor or occurrence in a solitary kidney, the purpose of chemotherapy prior to surgery is to reduce the size of the tumor and allow preservation of maximal renal parenchyma at resection. In the case of extensive vena caval infiltration, initial chemotherapy also results in tumor shrinkage and minimizes the complications associated with subsequent resection and avoids the use of cardiopulmonary bypass.

Treatment Options Under Clinical Evaluation

Stage I

The following treatment options are currently under investigation in Children's Oncology Group (COG) clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Favorable Histology

• COG-AREN0532(Vincristine, Dactinomycin, and Doxorubicin With or Without Radiation Therapy or Observation Only in Treating Younger Patients Who Are Undergoing Surgery for Newly Diagnosed Stage I, Stage II, or Stage III Wilms Tumor): In this study, all tumors will be stratified based on central pathology review and molecular analysis (loss of heterozygosity [LOH] at chromosomes 1p and 16q). Patients with LOH at 1p and 16q will be upstaged to receive treatment with regimen DD-4A (dactinomycin, doxorubicin, and vincristine for 24 weeks). Patients who are younger than 2 years and have Wilms tumors that weigh less than 550 g and who have a negative microscopic evaluation of lymph nodes are eligible for observation only. Other stage I patients will be treated with the standard therapy regimen EE-4A (dactinomycin and vincristine for 18 weeks) postnephrectomy.

Anaplastic (Focal or Diffuse) Histology

• COG-AREN0321(Combination Chemotherapy, Radiation Therapy, and/or Surgery in Treating Patients With High-Risk Kidney Tumors): In this study, patients with stage I will be treated with standard regimen DD-4A and radiation therapy.

Stage II

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

Favorable Histology

• COG-AREN0532(Vincristine, Dactinomycin, and Doxorubicin With or Without Radiation Therapy or Observation Only in Treating Younger Patients Who Are Undergoing Surgery for Newly Diagnosed Stage I, Stage II, or Stage III Wilms Tumor): In this study, all tumors will be stratified based on central pathology review and molecular analysis (LOH at chromosomes 1p and 16q). Patients with LOH at 1p and 16q will be upstaged to receive treatment with regimen DD-4A. Stage II patients without LOH will be treated with standard therapy regimen EE-4A postnephrectomy.

Focal Anaplastic

• Patients with stage II will be treated with standard regimen DD-4A and radiation therapy.

Diffuse Anaplastic

• COG-AREN0321(Combination Chemotherapy, Radiation Therapy, and/or Surgery in Treating Patients With High-Risk Kidney Tumors): In this study, patients will be treated with the UH-1 regimen (cyclophosphamide, carboplatin, and etoposide alternating with vincristine, doxorubicin, and cyclophosphamide for 30 weeks) and radiation therapy.

Stage III

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

Favorable Histology

• COG-AREN0532(Vincristine, Dactinomycin, and Doxorubicin With or Without Radiation Therapy or Observation Only in Treating Younger Patients Who Are Undergoing Surgery for Newly Diagnosed Stage I, Stage II, or Stage III Wilms Tumor): In this study, patients will be treated with standard therapy regimen DD-4A and radiation therapy. Patients who have LOH at chromosomes 1p and 16q will be moved to clinical trialCOG-AREN0533(Combination Chemotherapy With or Without Radiation Therapy in Treating Young Patients With Newly Diagnosed Stage III or Stage IV Wilms Tumor) with regimen M (vincristine, dactinomycin, and doxorubicin alternating with cyclophosphamide and etoposide for a total of 24 weeks) and radiation therapy.

Focal Anaplastic

• COG-AREN0321(Combination Chemotherapy, Radiation Therapy, and/or Surgery in Treating Patients With High-Risk Kidney Tumors): In this trial, patients with stage III will be treated with standard regimen DD-4A and radiation therapy.

Diffuse Anaplastic

• COG-AREN0321(Combination Chemotherapy, Radiation Therapy, and/or Surgery in Treating Patients With High-Risk Kidney Tumors): In this trial, patients will be treated with the UH-1 regimen and radiation therapy.

Stage IV

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

Favorable Histology

• COG-AREN0533(Combination Chemotherapy With or Without Radiation Therapy in Treating Young Patients With Newly Diagnosed Stage III or Stage IV Wilms Tumor): In this trial, patients with pulmonary metastases only (detected by chest computerized tomography [CT] scans) will start treatment with standard chemotherapy regimen DD-4A and undergo abdominal irradiation if local stage III. Pulmonary metastases will be re-evaluated at 6 weeks with chest CT scan. Patients with complete resolution of pulmonary metastases will be considered rapid complete responders and will continue therapy with regimen DD-4A without any pulmonary radiation therapy. Patients who do not have a complete response (slow incomplete responders) will be switched to regimen M (for a total of 24 weeks) and undergo radiation therapy to their lungs. It is recommended that biopsies of residual pulmonary lesions be performed before radiation therapy is delivered.

  Patients with LOH at chromosomes 1p and 16q will be treated with regimen M with radiation therapy to all sites of disease. Patients with metastases outside or in addition to lung metastases will be treated with regimen M and radiation therapy.

Focal Anaplastic

• COG-AREN0321(Combination Chemotherapy, Radiation Therapy, and/or Surgery in Treating Patients With High-Risk Kidney Tumors): In this trial, patients will be treated with the UH-1 regimen and radiation therapy.

Diffuse Anaplastic (No Measurable Disease)

• COG-AREN0321(Combination Chemotherapy, Radiation Therapy, and/or Surgery in Treating Patients With High-Risk Kidney Tumors): In this trial, patients will be treated with the UH-1 regimen and radiation therapy.

Diffuse Anaplastic (Measurable Disease)

• COG-AREN0321(Combination Chemotherapy, Radiation Therapy, and/or Surgery in Treating Patients With High-Risk Kidney Tumors): In this trial, patients will be treated with window therapy consisting of vincristine and irinotecan for 12 weeks. If they respond to the window therapy, they will receive therapy consisting of UH-2 (cyclophosphamide, carboplatin, and etoposide; vincristine, doxorubicin, and cyclophosphamide; vincristine, irinotecan, and radiation therapy) for 30 weeks. Patients not responding to the window therapy would then be treated on UH-1 and radiation therapy.

Stage V and those predisposed to developing 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 treated on the following protocol:

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.[23,24] When children are identified with bilateral tumors by CT or magnetic resonance imaging, 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 earlier to definitive surgery. Repeat imaging will be mandated at 6 weeks. Based on response to treatment surgery, biopsy or continued chemotherapy will be performed. If biopsy or surgery is performed, chemotherapy or radiation therapy will be given based on histology. Repeat imaging will be performed at 12 weeks. If there is a complete response, definitive surgery or continued therapy will be performed. 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.[15,17,25] 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.[16,17,18,19,20,21]

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, stage V Wilms tumor and 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.	Grundy PE, Breslow NE, Li S, et al.: Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 23 (29): 7312-21, 2005.
2.	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.
3.	Ehrlich PF: Bilateral Wilms' tumor: the need to improve outcomes. Expert Rev Anticancer Ther 9 (7): 963-73, 2009.
4.	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.
5.	Green DM, Breslow NE, Beckwith JB, et al.: Treatment with nephrectomy only for small, stage I/favorable histology Wilms' tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 19 (17): 3719-24, 2001.
6.	Sredni ST, Gadd S, Huang CC, et al.: Subsets of very low risk Wilms tumor show distinctive gene expression, histologic, and clinical features. Clin Cancer Res 15 (22): 6800-9, 2009.
7.	Kalapurakal JA, Green DM, Haase G, et al.: Outcomes of children with favorable histology wilms tumor and peritoneal implants treated in National Wilms Tumor Studies-4 and -5. Int J Radiat Oncol Biol Phys 77 (2): 554-8, 2010.
8.	Nicolin G, Taylor R, Baughan C, et al.: Outcome after pulmonary radiotherapy in Wilms' tumor patients with pulmonary metastases at diagnosis: a UK Children's Cancer Study Group, Wilms' Tumour Working Group Study. Int J Radiat Oncol Biol Phys 70 (1): 175-80, 2008.
9.	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.
10.	Ehrlich PF, Ferrer FA, Ritchey ML, et al.: Hepatic metastasis at diagnosis in patients with Wilms tumor is not an independent adverse prognostic factor for stage IV Wilms tumor: a report from the Children's Oncology Group/National Wilms Tumor Study Group. Ann Surg 250 (4): 642-8, 2009.
11.	Breslow NE, Collins AJ, Ritchey ML, et al.: End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol 174 (5): 1972-5, 2005.
12.	Hamilton TE, Ritchey ML, Haase GM, et al.: The management of synchronous bilateral Wilms tumor: a report from the National Wilms Tumor Study Group. Ann Surg 253 (5): 1004-10, 2011.
13.	Aronson DC, Slaar A, Heinen RC, et al.: Long-term outcome of bilateral Wilms tumors (BWT). Pediatr Blood Cancer 56 (7): 1110-3, 2011.
14.	Weirich A, Ludwig R, Graf N, et al.: Survival in nephroblastoma treated according to the trial and study SIOP-9/GPOH with respect to relapse and morbidity. Ann Oncol 15 (5): 808-20, 2004.
15.	Davidoff AM, Giel DW, Jones DP, et al.: The feasibility and outcome of nephron-sparing surgery for children with bilateral Wilms tumor. The St Jude Children's Research Hospital experience: 1999-2006. Cancer 112 (9): 2060-70, 2008.
16.	Ritchey ML, Green DM, Thomas PR, et al.: Renal failure in Wilms' tumor patients: a report from the National Wilms' Tumor Study Group. Med Pediatr Oncol 26 (2): 75-80, 1996.
17.	Fuchs J, Wünsch L, Flemming P, et al.: Nephron-sparing surgery in synchronous bilateral Wilms' tumors. J Pediatr Surg 34 (10): 1505-9, 1999.
18.	Horwitz JR, Ritchey ML, Moksness J, et al.: Renal salvage procedures in patients with synchronous bilateral Wilms' tumors: a report from the National Wilms' Tumor Study Group. J Pediatr Surg 31 (8): 1020-5, 1996.
19.	Wilms' tumor: status report, 1990. By the National Wilms' Tumor Study Committee. J Clin Oncol 9 (5): 877-87, 1991.
20.	Ritchey ML: The role of preoperative chemotherapy for Wilms' tumor: the NWTSG perspective. National Wilms' Tumor Study Group. Semin Urol Oncol 17 (1): 21-7, 1999.
21.	Zuppan CW, Beckwith JB, Weeks DA, et al.: The effect of preoperative therapy on the histologic features of Wilms' tumor. An analysis of cases from the Third National Wilms' Tumor Study. Cancer 68 (2): 385-94, 1991.
22.	Kist-van Holthe JE, Ho PL, Stablein D, et al.: Outcome of renal transplantation for Wilms' tumor and Denys-Drash syndrome: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant 9 (3): 305-10, 2005.
23.	Montgomery BT, Kelalis PP, Blute ML, et al.: Extended followup of bilateral Wilms tumor: results of the National Wilms Tumor Study. J Urol 146 (2 ( Pt 2)): 514-8, 1991.
24.	Breslow NE, Takashima JR, Ritchey ML, et al.: Renal failure in the Denys-Drash and Wilms' tumor-aniridia syndromes. Cancer Res 60 (15): 4030-2, 2000.
25.	Shamberger RC, Haase GM, Argani P, et al.: Bilateral Wilms' tumors with progressive or nonresponsive disease. J Pediatr Surg 41 (4): 652-7; discussion 652-7, 2006.

Treatment of Clear Cell Sarcoma of the Kidney

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Because of the relative rarity of this tumor, all patients with clear cell sarcoma of the kidney (CCSK) 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.

Standard Treatment Options

The approach for treating CCSK is different from Wilms tumor since the OS of children with CCSK remains lower than for patients with favorable histology Wilms tumor. In the National Wilms Tumor Study-3 (NWTS-3), the addition of doxorubicin to the combination of vincristine, dactinomycin, and radiation therapy resulted in an improvement in disease-free survival for patients with CCSK.[1] The National Wilms Tumor Study-4 (NWTS-4) showed that patients treated with vincristine, doxorubicin, and dactinomycin for 15 months had an improved relapse-free survival compared with patients treated for 6 months (88% vs. 61% at 8 years).[2] In the National Wilms Tumor Study-5 (COG-Q9401) trial, children with stages I to IV CCSK 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. With this treatment, the 5-year EFS was approximately 79% and OS was approximately 89%. Stage I patients had 100% 5-year EFS and OS. Stage II patients had a 5-year EFS of approximately 87% and OS of approximately 97%. Stage III patients had an approximately 74% 5-year EFS and an approximately 87% 5-year OS. Stage IV patients had a 5-year EFS of approximately 36% and 5-year OS of 45%. CCSK has been characterized by late relapses; however, in NWTS-5, most relapses occurred within 3 years. In NWTS-5, the most common site of recurrence was the brain,[3] which has been successfully treated with combination chemotherapy, surgery, and radiation therapy.[4][Level of evidence: 2A]

• Regimen DD-4A(vincristine, dactinomycin, and doxorubicin) for 15 months and radiation therapy.[2]
• Regimen I(vincristine, doxorubicin, cyclophosphamide, and etoposide) and radiation therapy.[3]

Treatment Options Under Clinical Evaluation

The following treatment option is currently under investigation in a Children's Oncology Group (COG) clinical trial. Information about ongoing clinical trials is available from the NCI Web site.

• COG-AREN0321(Combination Chemotherapy, Radiation Therapy, and/or Surgery in Treating Patients With High-Risk Kidney Tumors): In this trial, the role of radiation therapy is being evaluated in stage I disease. Patients who have undergone lymph node sampling will be treated only with regimen I. Patients with stage II and III will be treated with regimen I and radiation therapy. Stage IV patients will be treated with the UH-1 regimen (cyclophosphamide, carboplatin, and etoposide alternating with vincristine, doxorubicin, and cyclophosphamide for 30 weeks) and radiation therapy.

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.
2.	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.
3.	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.
4.	Radulescu VC, Gerrard M, Moertel C, et al.: Treatment of recurrent clear cell sarcoma of the kidney with brain metastasis. Pediatr Blood Cancer 50 (2): 246-9, 2008.

Treatment of Rhabdoid Tumor of the Kidney

Because of the relative rarity of this tumor, all patients with rhabdoid tumor of the kidney (RTK) 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 RTK continue to have a poor prognosis with 4-year overall survival (OS) rates of 42% for stages I and II (n = 40) and 16% for stages III, IV, and V (n = 102).[1]

Standard Treatment Options

• No satisfactory treatment has been developed for these children.[2]The National Wilms Tumor Study (NWTS)-5 (COG-Q9401) closed the treatment arm for rhabdoid tumor 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).[3,4]In a review of 142 patients from NWTS-1 through NWTS-5, stage and age are significant prognostic factors. Patients with stage I and stage II disease had an OS rate of 42%; higher stage was associated with a 16% OS. 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%. All except one patient with a central nervous system lesion died.[1]
• 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.[5]

Treatment Options Under Clinical Evaluation

The following treatment option is currently under investigation in a Children's Oncology Group (COG) clinical trial. Information about ongoing clinical trials is available from the NCI Web site.

• COG-AREN0321(Combination Chemotherapy, Radiation Therapy, and/or Surgery in Treating Patients With High-Risk Kidney Tumors): In this trial, patients with stages I, II, III, and IV (without measurable disease) will be treated with UH-1 (which consists of cyclophosphamide, carboplatin, and etoposide alternating with vincristine, doxorubicin, and cyclophosphamide for 30 weeks) and radiation therapy.

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.	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.
2.	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.
3.	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.
4.	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.
5.	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.

Treatment of Neuroepithelial Tumor of the Kidney

Optimal treatment has not been established for these tumors. Treatment according to Ewings/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.

Treatment of Congenital Mesoblastic Nephroma

When diagnosed in the first 7 months of life, the 5-year event-free survival rate is 94% and the overall survival rate is 96%.[1] 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.[2]

A prospective clinical trial that enrolled 50 patients confirmed that complete surgical resection, which includes the entire capsule, is adequate therapy for most patients with mesoblastic nephroma.[3] In this study, only 2 of 50 patients died. Patients were at increased risk for local and eventually metastatic recurrence if there was stage III (incomplete resection and/or histologically positive resection margin), cellular subtype, and aged 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 discriminated. Adjuvant chemotherapy has been recommended for patients who share these three characteristics, though the benefit of adjuvant therapy will remain unproven with such a low incidence of disease.[3] Although incompletely resected, stage III infants younger than 2 months may not need chemotherapy.[2]

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.	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.
2.	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.
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.

Treatment of Renal Cell Carcinoma

Standard Treatment Options

Survival of patients with renal cell carcinoma (RCC) is affected by stage of disease at presentation and the completeness of resection at radical nephrectomy. Overall survival rates range from 64% to 87%. The 5-year survival for stage I is 90% or higher, for stages II and III it is 50% to 80%, and for stage IV it is 9%, which is similar to the stage-for-stage survival in RCC in adults. Retrospective analyses and the small number of patients involved place limitations on the level of evidence in the area of treatment. The primary treatment for RCC includes total surgical removal of the kidney and associated lymph nodes.[1] In two small series, patients who had partial nephrectomies seemed to have outcomes equivalent to those who had radical nephrectomies. Partial nephrectomy may be considered in carefully selected patients with low-volume localized disease.[2,3] There is some suggestion that regional lymph node involvement does not portend the same poor prognosis as adult renal cell carcinoma.[1] However, this is controversial as the finding are based on only 13 patients. Treatment of unresectable metastatic disease is presently unsatisfactory, similar to adult RCC; it is poorly responsive to radiation and there is no effective chemotherapy regimen. Immunotherapy, such as interferon-alpha and interleukin-2, may have some effect on cancer control.[4] Rare spontaneous regression of pulmonary metastasis may occur with resection of the primary tumor. Several targeted agents (for example, 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. However, a case report of an adolescent with a TFE-3 RCC suggests responsiveness to multiple tyrosine kinase inhibitors.[5] (Refer to the PDQ summary on adult Renal Cell Cancer Treatment for more information.)

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.	Geller JI, Dome JS: Local lymph node involvement does not predict poor outcome in pediatric renal cell carcinoma. Cancer 101 (7): 1575-83, 2004.
2.	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.
3.	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.
4.	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.
5.	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.

Treatment of Recurrent Wilms Tumor and Other Childhood Kidney Tumors

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Approximately 15% of patients with favorable histology Wilms tumor and 50% of patients with anaplastic Wilms tumor experience recurrence.[1] Historically, the salvage rate for patients with recurrent favorable histology Wilms tumor was 25% to 40%. As a result of modern treatment combinations, the outcome after recurrence has increased up to 60%.[2,3] A number of potential prognostic features influencing outcome post-recurrence have been analyzed, but it is difficult to separate whether these factors are independent of each other. In addition, 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]

NWTS-5 showed that time to recurrence and site of recurrence were no longer prognostically significant.[2,5] However, patients who experienced a pulmonary relapse within 12 months of diagnosis had a poorer prognosis (5-year OS, 47%) than did patients who experienced a pulmonary relapse 12 months or more after diagnosis (5-year OS, 75%).[6]

Based on the above, the following three risk categories have been identified:

• Standard risk: Patients with favorable histology Wilms tumor with 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]These patients make up approximately 30% of recurrences.
• High risk: Patients with favorable histology Wilms tumor with 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 make up 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] Wilms tumor patients whose initial therapy consisted of immediate nephrectomy followed by chemotherapy with vincristine and dactinomycin who relapse can be successfully retreated. Fifty-eight patients were treated on the National Wilms Tumor Study-5 (COG-Q9401) relapse protocol with surgical excision when feasible, radiation therapy, and alternating courses of vincristine, doxorubicin and cyclophosphamide, and etoposide and cyclophosphamide. Four-year EFS after relapse was 71% and overall survival (OS) was 82%. For patients whose site of relapse was only the lungs, the 4-year EFS rate was 68% and OS rate was 81%.[5]

Treatment of High-Risk Relapsed Wilms Tumor

Approximately 50% of unilateral Wilms tumor patients who relapse or progress after initial treatment with vincristine, dactinomycin, and doxorubicin and radiation can be successfully retreated. Sixty patients were treated on the NWTS-5 relapse protocol with alternating courses of cyclophosphamide/etoposide and carboplatin/etoposide, surgery, and radiation therapy. The 4-year EFS rate with high-risk Wilms tumor was 42% and OS rate was 48%. For high-risk patients who relapsed in the lungs only the 4-year EFS rate was 49% and OS rate was 53%.[2]

Patients with stages II, III, and 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] While high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation has been utilized for recurrent high-risk favorable-histology patients,[10,11,12] 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 were assigned to maintenance chemotherapy with five cycles of alternating CE and PE, and the remainder of patients to ablative therapy and autologous marrow transplant. All patients received local radiation therapy. 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 marrow transplant subgroup.[13]; [2][Level of evidence: 2A] The outcome of hematopoietic stem cell rescue in selected patients may be superior;[12,14] however, patients with gross residual disease going into transplant do not do as well.[10] 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

Treatment of patients with recurrent clear cell sarcoma of the kidney (CCSK) depends on initial therapy. Cyclophosphamide and carboplatin should be considered if not used initially. Patients with recurrent CCSK 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.[15][Level of evidence: 2A] In NWTS-5, patients with CCSK and brain metastases have been successfully treated with combination chemotherapy, surgery, and radiation therapy.[16]

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

Treatment Options Under Clinical Evaluation

The following treatment option is currently under investigation in a Children's Oncology Group (COG) clinical trial. Information about ongoing clinical trials is available from the NCI Web site.

• COG-ADVL1121(Sorafenib Tosylate in Treating Younger Patients With Relapsed or Refractory Rhabdomyosarcoma, Wilms Tumor, Liver Cancer, or Thyroid Cancer): A phase II study of sorafenib, a Raf kinase and receptor tyrosine kinase inhibitor, in children and young adults with relapsed/refractory rhabdomyosarcoma, Wilms tumor, hepatocellular carcinoma, and papillary thyroid carcinoma. The goal of this study is to determine the objective response rate of sorafenib in children with refractory or relapsed rhabdomyosarcoma. Patients must be aged 2 to 30 years.

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
15.	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.
16.	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.

Changes to This Summary (03 / 29 / 2012)

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.

General Information

Added text to state that patients who develop Wilms tumor in their second decade of life have a poorer survival than younger patients with Wilms tumor (cited Popov et al. as reference 8).

Added text to state that germline inactivating mutations in DIS3L2 on chromosome 2q37 are associated with Perlman syndrome (cited Astuti et al. as reference 18).

Added text to state that approximately 10% of patients with Beckwith-Wiedemann syndrome will develop a malignancy, with either Wilms tumor or hepatoblastoma being the most common, although adrenal tumors can also occur (cited Tan et al. as reference 28).

Added text to state that features associated with germline WT1 mutations that increase the risk for developing renal failure are stromal predominant histology, bilaterality, intralobular nephrogenic rests, and Wilms tumor diagnosed before age 2 years (cited Lange et al. as reference 34).

Cellular Classification

Added text to state that tumors occurring in older patients have a higher incidence of anaplastic histology (cited Popov et al. as reference 2).

Added text to state that recommendations for surveillance in patients with germline SMARCB1 mutations have been developed based on the epidemiology and clinical course of rhabdoid tumors. From birth to age 1 year, it is suggested that patients have thorough physical and neurologic examinations, as well as head ultrasounds monthly. It is suggested that patients undergo abdominal ultrasounds with focus on the kidneys every 2 to 3 months. From age 1 year to approximately age 4 years, it is suggested that brain and spine magnetic resonance imaging and abdominal ultrasound be performed every 6 months.

Treatment of Renal Cell Carcinoma

Added text to state that a case report of an adolescent with a TFE-3 renal cell carcinoma suggests responsiveness to multiple tyrosine kinase inhibitors (cited De Pasquale et al. as reference 5).

Treatment of Recurrent Wilms Tumor and Other Childhood Kidney Tumors

Added text about the COG-ADVL1121 clinical trial as a treatment option under clinical evaluation.

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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Last Revised: 2012-03-29