This cancer treatment information summary provides an overview of the prognosis, diagnosis, classification, staging, and treatment of Wilms tumor and other childhood kidney tumors (clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, neuroepithelial tumor of the kidney, cystic partially-differentiated nephroblastoma, mesoblastic nephroma, and renal cell carcinoma).

The National Cancer Institute 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. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology specialists.

Cancer in children and adolescents is rare. 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 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.[1] 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 have been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. 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 Late Effects of Treatment for Childhood Cancer summary for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Wilms tumor is a curable disease in the majority of affected children. Approximately 500 cases are diagnosed in the United States annually. More than 90% of patients survive 4 years after diagnosis, which is an improvement over the 80% survival observed from 1975 to 1984.[2] The prognosis 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 to each patient by the pediatric surgeon, radiation oncologist, and pediatric oncologist.[2-5] Previous clinical trials have, in part, evaluated with some success whether reduced therapy is sufficient to control disease in patients with early-stage, favorable-histology Wilms tumor.[6-8]

Wilms tumor normally develops in otherwise healthy children; however, 10% of cases occur in individuals with recognized malformations. Children with Wilms tumor may have associated anomalies, including hemihypertrophy, cryptorchidism, and hypospadias. Approximately 10% of patients with Wilms tumor 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 are the result of excessive prenatal and postnatal somatic growth, and result in macroglossia, nephromegaly, and hemihypertrophy. Examples of overgrowth syndromes are Beckwith-Wiedemann syndrome (10% to 20% of Wilms tumor incidence), isolated hemihypertrophy (3% to 5% of Wilms tumor incidence), Perlman syndrome (characterized by fetal gigantism, renal dysplasia, Wilms tumor, islet cell hypertrophy, multiple congenital anomalies, and mental retardation),[9] Sotos' syndrome (characterized by cerebral gigantism), and Simpson-Golabi-Behemel syndrome (characterized by macroglossia, macrosomia, renal and skeletal abnormalities, and increased risk of embryonal cancers).[10-14] Klippel-Trénaunay syndrome, a unilateral limb overgrowth syndrome, is not associated with Wilms tumor.[15] Examples of nonovergrowth syndromes associated with Wilms tumor (42% of Wilms tumor incidence) are isolated aniridia; trisomy 18; Wilms tumor, aniridia, ambiguous genitalia, and mental retardation (WAGR) syndrome; Bloom's syndrome, and Denys-Drash syndrome (characterized by intersexual disorders, nephropathy, and Wilms tumor).[16] The constellation of WAGR syndrome occurs in association with an interstitial deletion on chromosome 11 (del [11p13]).[17,18] 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),[19] both of which are associated with mutations in the WT1 gene at chromosome 11p13.[20,21] Children with a predisposition to develop Wilms tumor (e.g., Beckwith-Wiedemann syndrome, WAGR, hemihypertrophy, or aniridia) should be screened with ultrasound every 3 months until they reach age 8 years.[10-14,22-24]

Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of several genes. The Wilms tumor gene-1 (WT1) 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 WT1 mutations are associated with cryptorchidism and hypospadias.[25] Germline mutations in WT1, however, have also been found in about 2% of phenotypically normal children with Wilms tumor.[26] The offspring of such patients may also be at increased risk of developing Wilms tumor. A gene that causes aniridia (PAX-6) is located near the WT1 gene on chromosome 11p13, and deletions encompassing the WT1 and aniridia genes explain the association between aniridia and Wilms tumor. PAX-6 also affects brain development, and children with WAGR syndrome have a variety of central nervous system development disorders.[18] Patients with aniridia or hemihypertrophy should be screened with ultrasound every 3 months until they reach age 8 years.[10] For patients with WAGR syndrome, the risk of developing Wilms tumor is as high as 45%.[27] Children with WAGR syndrome are found to have small, favorable-histology tumors with low stage at diagnosis and a high incidence of intralobar nephrogenic rests. The incidence of bilateral Wilms tumor in WAGR children is high (about 15%).[28] Treatment outcome at 4 years is similar to that of non-WAGR patients.[28] Children with WAGR syndrome are at increased risk of eventually developing renal failure and should be monitored.[29] Patients with Wilms tumor and aniridia without genitourinary abnormalities are at lesser risk but should be monitored for nephropathy or renal failure.[30] Children with Wilms tumor and any genitourinary anomalies are also at increased risk for late renal failure and should be monitored.[29] The incidence of Wilms tumor in children with sporadic aniridia is estimated to be about 5%.[28] A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5 in association with Beckwith-Wiedemann syndrome. There are several candidates for WT2, including insulin-like growth factors (IGF-2), H19, and LIT1, some of which are paternally imprinted (maternally active) and some maternally imprinted.[31] Loss of heterozygosity (LOH), which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes 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 either LOH or loss of imprinting at 11p15.5.[32] Recent observations suggest genetic heterogeneity in the etiology of Beckwith-Wiedemann syndrome with differing levels of association with risk of tumor formation.[33] Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, though metachronous bilateral disease is also observed.[10-12] A third gene, WTX, has been identified on the X chromosome and plays a role in normal kidney development. This gene is inactivated in approximately one third of Wilms tumors.[34]

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.[35,36] 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.[37] Overexpression and gene amplification of CACNA1E, which encodes the ion-conducting alpha-1 subunit of R-type voltage-dependent calcium channels, is associated with favorable histology in Wilms tumor relapse.[38] Many Wilms tumors appear to arise from abnormally retained embryonic kidney precursor cells arranged in clusters termed nephrogenic rests. The different genetic lesions are associated with different subtypes of nephrogenic rests.[39] Wilms tumors that develop from intralobar nephrogenic rests generally contain heterologous elements such as smooth muscle, cartilage, and fat cells, and are associated with loss of DNA on the short arm of chromosome 11p and occasionally with WT1 gene mutation. In contrast, Wilms tumors that develop from perilobar nephrogenic rests, which appear to reflect a slightly later stage in renal embryonic development and are generally found in older children, are associated with loss of imprinting of the IGF2 gene, which stimulates cell proliferation.[40] Perilobar rests are also associated with Wilms tumors in children with Beckwith-Wiedemann syndrome.[41] Diffuse hyperplastic perilobar nephroblastomatosis is discussed in the Cellular Classification section of this summary. Remarkably, Wilms tumor in Asian children is not associated with either nephrogenic rests or IGF2 loss of imprinting.[42]

Despite the number of genes that appear to be involved in the development of Wilms tumor, hereditary Wilms tumor is uncommon, with 1% to 2% of patients having a positive family history for Wilms tumor.[43,44] The risk of Wilms tumor among offspring of persons who have had unilateral (sporadic) tumors is quite low (<2%).[45] Siblings of children with Wilms tumor have a low likelihood of developing Wilms tumor.[43] About 4% to 5% of patients have bilateral Wilms tumors, but these are not usually hereditary.[43,44] 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: 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 6 months for 2 years, then yearly for an additional 1 to 3 years.[46,47]

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. (Refer to the Cellular Classification section of this summary for more information.) Because of their renal location, they have been treated on clinical trials developed by the National Wilms Tumor Study Group. The approach to their treatment, however, is distinctive from that of Wilms tumor, and requires timely and accurate diagnosis by a pathologist with experience with these types of renal tumors.

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