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NCI/PDQ^® Health professionals: Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®)

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National Cancer Institute
Last Modified: November 27, 2012

TABLE OF CONTENTS

• General Information
  • Prognosis
  • Congenital Anomalies and Syndromes Predisposing to Wilms Tumor
  • Screening Children Predisposed to Wilms Tumor
  • Genetics of Wilms Tumor
    • • Monitoring for late renal failure
    • Other genes
  • Genetics of Familial Wilms Tumor
  • Bilateral Wilms Tumor

• Cellular Classification
  • Wilms Tumor
    • Favorable histology
    • Anaplastic histology
    • Nephrogenic rests
  • Clear Cell Sarcoma of the Kidney
  • Rhabdoid Tumors of the Kidney
    • Rhabdoid predisposition syndrome
  • Congenital Mesoblastic Nephroma
  • Renal Cell Carcinoma
  • Nephroblastomatosis
  • Neuroepithelial Tumors of the Kidney
  • Desmoplastic Small Round Cell Tumor of the Kidney
  • Cystic Partially Differentiated Nephroblastoma
  • Multilocular Cystic Nephroma
  • Primary Renal Synovial Sarcoma
  • Anaplastic Sarcoma of the Kidney

• Stage Information
  • Wilms Tumor
    • Stage I
    • Stage II
    • Stage III
    • Stage IV
    • Stage V and those predisposed to developing Wilms tumor

• Treatment Option Overview
  • Wilms Tumor

• Treatment of Wilms Tumor
  • Standard Treatment Options
  • Additional Treatment Considerations
    • Stage I
    • Stage III
    • Stage IV
    • Stage V and those predisposed to developing bilateral Wilms tumor
    • Inoperable Wilms tumors
    • Adults with Wilms tumor
  • Treatment Options Under Clinical Evaluation
    • Stage I
    • Stage II
    • Stage III
    • Stage IV
    • Stage V and those predisposed to developing Wilms tumor
    • Current Clinical Trials

• Treatment of Clear Cell Sarcoma of the Kidney
  • Standard Treatment Options
  • Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

• Treatment of Rhabdoid Tumor of the Kidney
  • Standard Treatment Options
  • Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

• Treatment of Neuroepithelial Tumor of the Kidney
  • Current Clinical Trials

• Treatment of Congenital Mesoblastic Nephroma
  • Current Clinical Trials

• Treatment of Renal Cell Carcinoma
  • Standard Treatment Options
  • Current Clinical Trials

• Treatment of Recurrent Wilms Tumor and Other Childhood Kidney Tumors
  • Treatment of Standard-Risk Relapsed Wilms Tumor
  • Treatment of High-Risk Relapsed Wilms Tumor
  • Treatment of Recurrent Clear Cell Sarcoma of the Kidney
  • Treatment Options Under Clinical Evaluation
    • Current Clinical Trials

• Changes to This Summary (11/27/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information

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

In an analysis of Wilms tumor patients in the Surveillance, Epidemiology and End Results database, adults (n = 152) had a statistically worse overall survival (OS) (69% vs. 88%, P < .001) than pediatric patients (n = 2,190), despite previous studies showing comparable outcome when treated on protocol. 9 10 Adults with Wilms tumor were more likely than pediatric patients to be staged as having localized disease, to not receive any lymph node sampling, and to not receive any radiation treatment. The investigators recommended that all adult patients diagnosed with Wilms tumor should undergo lymph node sampling and that there should be close collaboration with pediatric surgeons and oncologists in treatment planning. The Children's Oncology Group has increased the enrollment age for their Wilms tumor trials to include patients up to age 30 years. 11

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. 12 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. 13 14 Examples of overgrowth syndromes include the following:
  • Beckwith-Wiedemann syndrome (prevalence is about 1% of children with Wilms tumor). 15 16 17 18
  • Isolated hemihypertrophy (prevalence is about 2.5% of children with Wilms tumor). 15 19
  • Perlman syndrome (characterized by fetal gigantism, renal dysplasia, Wilms tumor, islet cell hypertrophy, multiple congenital anomalies, and mental retardation). 20 Germline inactivating mutations in DIS3L2 on chromosome 2q37 are associated with Perlman syndrome. 21
  • 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]). 22 23 (prevalence is about 0.4% of children with Wilms tumor). The incidence of bilateral Wilms tumor in children with WAGR syndrome is about 15%. 24
  • Isolated aniridia.
  • Genitourinary anomalies including hypospadias, undescended testis, and others are associated with Wilms 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), 25 both of which are associated with mutations in the WT1 gene. 26 Specifically, germline missense mutations in the WT1 gene are responsible for most Wilms tumors that occur as part of the Denys-Drash syndrome. 27 28
  • Bloom syndrome.
  • Alagille syndrome. 29
  • 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. 13 14 15 30

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. 31 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. 32

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. 33

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 1WT1

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. 34 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. 25

WT1

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], 8.1241) of developing Wilms tumor in children with sporadic aniridia. 35 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). 36

The incidence of Wilms tumor in children with sporadic aniridia is estimated to be about 5%. 24 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. 15 30

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. 37 Patients with Wilms tumor and aniridia without genitourinary abnormalities are at lesser risk but should be monitored for nephropathy or renal failure. 38 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. 37

WT1

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. 39 40 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. 41 42

WT1 mutations and 11p15 loss of heterozygosity are associated with relapse in patients with very low-risk Wilms tumor who do not receive chemotherapy. 43 These may provide biomarkers to stratify patients in the future.

Wilms tumor 2WT2

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. 36 There are several candidate genes at the WT2 locus, comprising the two independent imprinted domains IGF2/H19 and KIP2/LIT1. 44 Loss of heterozygosity, 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 loss of heterozygosity or loss of imprinting at 11p15.5. 45 The mechanism resulting in loss of imprinting can be either genetic mutation or epigenetic change of methylation. 36 44 Loss of imprinting or gene methylation are rarely found at other loci, supporting the specificity of loss of imprinting at IGF2. 46 Interestingly, Wilms tumors in Asian children are not associated with either nephrogenic rests or IGF2 loss of imprinting. 47

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. 48 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. 15 16 17 The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the NWTS. 17 49 50

Wilms tumor gene on the X chromosomeWTX)

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. 51 This gene is inactivated in approximately one-third of Wilms tumors but germline mutations have not been observed in patients with Wilms tumor. 52

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 loss of heterozygosity 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 OS 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. 53
• CACNA1E: Overexpression and amplification of the gene CACNA1E located at 1q25.3, which encodes the ion-conducting alpha-1 subunit of R-type voltage-dependent calcium channels, may be associated with relapse in favorable-histology Wilms tumor. 54
• 7p21: A consensus region of loss of heterozygosity has been identified within 7p21 containing ten known genes, including two candidate suppressor genes (Mesenchyme homeobox 2 [MEOX2] and Sclerostin domain containing 1 [SOSTDC1]). 55
• 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 the SKCG-1 gene 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. 56
• p53 tumor suppressor gene: A small subset of anaplastic Wilms tumors show mutations in the p53 tumor suppressor gene. Although it is unlikely that it plays a major role in Wilms tumorigenesis, it may be useful as an unfavorable prognostic marker. 57 58
• 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. 59
• MYCN: Genomic gain or amplification of MYCN is relatively common in Wilms tumors and associated with diffuse anaplastic histology. 59

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. 60 The risk of Wilms tumor among offspring of persons who have had unilateral (sporadic) tumors is less than 2%. 61 Two familial Wilms tumor genes have been localized to FWT1 (17q12-q21) and FWT2 (19q13.4). 62 63 64

Bilateral Wilms Tumor

About 4% to 5% of patients have bilateral Wilms tumors, but these are not usually hereditary. 65 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: 63 64

• 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 patientsevery 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. 66 67 (Refer to the Cellular Classification section of this summary for more information.)

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51. Wegert J, Wittmann S, Leuschner I, et al.: WTX inactivation is a frequent, but late event in Wilms tumors without apparent clinical impact. Genes Chromosomes Cancer 48 (12): 1102-11, 2009. [PUBMED Abstract]
52. Rivera MN, Kim WJ, Wells J, et al.: An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science 315 (5812): 642-5, 2007. [PUBMED Abstract]
53. 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. [PUBMED Abstract]
54. Natrajan R, Little SE, Reis-Filho JS, et al.: Amplification and overexpression of CACNA1E correlates with relapse in favorable histology Wilms' tumors. Clin Cancer Res 12 (24): 7284-93, 2006. [PUBMED Abstract]
55. Blish KR, Clausen KA, Hawkins GA, et al.: Loss of heterozygosity and SOSTDC1 in adult and pediatric renal tumors. J Exp Clin Cancer Res 29: 147, 2010. [PUBMED Abstract]
56. Singh KP, Roy D: SKCG-1: a new candidate growth regulatory gene at chromosome 11q23.2 in human sporadic Wilms tumours. Br J Cancer 94 (10): 1524-32, 2006. [PUBMED Abstract]
57. Bardeesy N, Falkoff D, Petruzzi MJ, et al.: Anaplastic Wilms' tumour, a subtype displaying poor prognosis, harbours p53 gene mutations. Nat Genet 7 (1): 91-7, 1994. [PUBMED Abstract]
58. el Bahtimi R, Hazen-Martin DJ, Re GG, et al.: Immunophenotype, mRNA expression, and gene structure of p53 in Wilms' tumors. Mod Pathol 9 (3): 238-44, 1996. [PUBMED Abstract]
59. Williams RD, Al-Saadi R, Chagtai T, et al.: Subtype-specific FBXW7 mutation and MYCN copy number gain in Wilms' tumor. Clin Cancer Res 16 (7): 2036-45, 2010. [PUBMED Abstract]
60. Bonaíti-Pellié C, Chompret A, Tournade MF, et al.: Genetics and epidemiology of Wilms' tumor: the French Wilms' tumor study. Med Pediatr Oncol 20 (4): 284-91, 1992. [PUBMED Abstract]
61. Li FP, Williams WR, Gimbrere K, et al.: Heritable fraction of unilateral Wilms tumor. Pediatrics 81 (1): 147-9, 1988. [PUBMED Abstract]
62. Ruteshouser EC, Huff V: Familial Wilms tumor. Am J Med Genet C Semin Med Genet 129 (1): 29-34, 2004. [PUBMED Abstract]
63. Paulino AC, Thakkar B, Henderson WG: Metachronous bilateral Wilms' tumor: the importance of time interval to the development of a second tumor. Cancer 82 (2): 415-20, 1998. [PUBMED Abstract]
64. Coppes MJ, Arnold M, Beckwith JB, et al.: Factors affecting the risk of contralateral Wilms tumor development: a report from the National Wilms Tumor Study Group. Cancer 85 (7): 1616-25, 1999. [PUBMED Abstract]
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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 histopathologyfavorable 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 1016 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. Changes on 17p consistent with mutations in the p53 gene have been associated with foci of anaplastic histology. 3 All of these characteristics lend support to the hypothesis that anaplasia evolves as a late event from a subpopulation of Wilms tumor cells that have acquired additional genetic lesions. 4 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. 5 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. 5 6 7

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. 8 9 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. 10 Extrarenal nephrogenic rests rarely occur, but may develop into extrarenal Wilms tumor. 11

Clear Cell Sarcoma of the Kidney

Clear cell sarcoma of the kidney is not a Wilms tumor variant, but it is an important primary renal tumor associated with a significantly higher rate of relapse and death than favorable-histology Wilms tumor. 12 In addition to pulmonary metastases, clear cell sarcoma also spreads to bone, brain, and soft tissue. The classic pattern of clear cell sarcoma of the kidney is defined by nests or cords of cells separated by regularly spaced fibrovascular septa. 12 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. 13 The brain is a frequent site of recurrent disease. 14 15

While little is known about the biology of clear cell sarcoma of the kidney, the t(10;17)(q22;p13) translocation has been reported in clear cell sarcoma of the kidney. As a result of the translocation, the YWHAE-FAM22 fusion transcript is formed; this transcript was detected in 12% of clear cell sarcoma of the kidney cases in one series. 16

Rhabdoid Tumors of the Kidney

Rhabdoid tumors are extremely aggressive malignancies that generally occur in infants and young children. The most common locations are the kidney and central nervous system (CNS) (atypical teratoid/rhabdoid tumor), although rhabdoid tumors 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 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 rhabdoid tumor of the kidney. 17 Approximately two-thirds of patients will present with advanced stage. Bilateral cases have been reported. 18 Rhabdoid tumors of the kidney tend to metastasize to the lungs and the brain. As many as 10% to 15% of patients with rhabdoid tumors of the kidney also have CNS lesions. 19 Relapses occur early (median time from diagnosis is 8 months). 18 20

Rhabdoid tumors in all anatomical locations have a common genetic abnormalitythe 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. 21 22 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. 23 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. 24 25 Approximately 35% of patients with rhabdoid tumors have germline SMARCB1 alterations. 26 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. 27

Rhabdoid predisposition syndrome

Early-onset, multifocal disease and familial cases strongly support the possibility of a rhabdoid predisposition syndrome. This has been confirmed by the presence of constitutional mutations of SMARCB1 in rare familial cases and in a subset of patients with apparently sporadic rhabdoid tumors. In a cohort of 74 rhabdoid tumors, 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 rhabdoid tumors, 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. 28

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 atypical teratoid/rhabdoid tumor 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. 29 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