The incidence of Wilms tumor is 7.1 cases per 1 million children younger than 15 years. Approximately 500 cases of Wilms tumor are diagnosed in the United States each year. The incidence is substantially lower in Asians. The male to female ratio in unilateral cases of Wilms tumor is 0.92:1.00, but in bilateral cases it is 0.60:1.00. The mean age at diagnosis is 44 months in unilateral cases of Wilms tumor and 31 months in bilateral cases.[1,2] About 10% of children with Wilms tumor have an associated congenital malformation syndrome.
Syndromes and Other Conditions Associated With Wilms Tumor
Wilms tumor typically develops in otherwise healthy children; however, approximately 10% of children with Wilms tumor have been reported to have a congenital anomaly.[3,4] Of 295 consecutive patients with Wilms tumors seen at the Institute Curie in Paris, 52 (17.6%) had anomalies or syndromes, 43 of which were considered major, and 14 of which were genetically proven tumor predisposition syndromes. Children with Wilms tumors may have associated hemihypertrophy and urinary tract anomalies, including cryptorchidism and hypospadias. Children may have a recognizable phenotypic syndrome (including overgrowth, aniridia, genetic malformations, and others). These syndromes have provided clues to the genetic basis of the disease. The phenotypic syndromes and other conditions have been grouped into overgrowth and nonovergrowth categories. Overgrowth syndromes and conditions are the result of excessive prenatal and postnatal somatic growth.[6,7]
Table 1. Syndromes and Conditions Associated With Wilms Tumor
|Syndrome/Condition||Gene||Overgrowth Phenotype||Nonovergrowth Phenotype|
|WAGR = Wilms tumor, aniridia, genitourinary anomaly, and mental retardation.|
|9q22.3 microdeletion syndrome||9q22.3||X|
|Familial Wilms tumor||FWT1||X|
|Fanconi anemia with biallelic mutations inBRCA2(FANCD1) orPALB2(FANCN)||BRCA2||X|
For information about the genes associated with Wilms tumor, including Wilms tumor 1 (WT1) and Wilms tumor 2 (WT2), refer to the Genes Associated With Wilms Tumor section of this summary.
Syndromic causes of Wilms tumor
- WT1-related syndromes include the following:
- WAGR syndrome. WAGR syndrome is characterized by Wilms tumor, aniridia, genitourinary anomaly, and mental retardation. The constellation of WAGR syndrome occurs in association with an interstitial deletion on chromosome 11 (del(11p13)) (prevalence is about 0.4% of children with Wilms tumors).[8,9] The incidence of bilateral Wilms tumor in children with WAGR syndrome is about 15%. (Refer to the WT1 deletion and WAGR syndrome section of this summary for more information.)
- Denys-Drash syndrome and Frasier syndrome. Genitourinary anomalies including hypospadias, undescended testis, and others are associated with WT1 deletions (prevalence is about 8%-10% of children with Wilms tumor). Children with pseudo-hermaphroditism and/or renal disease (glomerulonephritis or nephrotic syndrome) who develop Wilms tumor may have Denys-Drash or Frasier syndrome (characterized by male hermaphroditism, primary amenorrhea, chronic renal failure, and other abnormalities), both of which are associated with mutations in the WT1 gene. Specifically, germline missense mutations in the WT1 gene are responsible for most Wilms tumors that occur as part of Denys-Drash syndrome.[13,14] The risk of Wilms tumor is about 90% for children with Denys-Drash syndrome.
- WT2-related syndromes include the following:
- Beckwith-Wiedemann syndrome. Beckwith-Wiedemann syndrome is an overgrowth syndrome characterized by asymmetric growth of one or more parts of the body, large tongue, omphalocele or umbilical hernia at birth, creases or pits in the skin near the ears, hypoglycemia (in infants), and kidney abnormalities. It is also characterized by the development of Wilms tumor, rhabdomyosarcoma, and hepatoblastoma. It is caused by either altered methylation at the imprinted 11p15 region or mutation in that region. The prevalence is about 1% of children with Wilms tumor.[15,16,17,18] Between 20% and 30% of Beckwith-Wiedemann syndrome patients will develop Wilms tumor. (Refer to the WT2 and Beckwith-Wiedemann syndrome section of this summary for more information.)
- Other syndromes include the following:
- Perlman syndrome. Perlman syndrome is characterized by fetal gigantism, renal dysplasia, Wilms tumor, islet cell hypertrophy, multiple congenital anomalies, and mental retardation.[19,20] Germline inactivating mutations in DIS3L2 on chromosome 2q37 are associated with Perlman syndrome.
- Simpson-Golabi-Behemel syndrome. Simpson-Golabi-Behemel syndrome is characterized by macroglossia, macrosomia, renal and skeletal abnormalities, and increased risk of embryonal cancers. It is caused by mutations in GPC3 and is believed to enhance the risk of Wilms tumor.
- Sotos syndrome. Sotos syndrome is characterized by cerebral gigantism and learning disability, ranging from mild to severe. Sotos syndrome is associated with behavioral problems, congenital cardiac anomalies, neonatal jaundice, and renal anomalies such as Wilms tumor, scoliosis, and seizures. NSD1 is the only gene in which mutations are known to cause Sotos syndrome.
- 9q22.3 microdeletion syndrome. 9q22.3 microdeletion syndrome is characterized by craniofacial abnormalities, metopic craniosynostosis, hydrocephalus, macrosomia, and learning disabilities. Three patients presented with Wilms tumor in addition to a constitutional 9q22.3 microdeletion and dysmorphic/overgrowth syndrome. Although the size of the deletions was variable, all encompassed the PTCH1 gene.
- Bloom syndrome. Bloom syndrome is characterized by short stature and being thinner than other family members, sun-sensitive skin changes, and an increased risk of Wilms tumor. BLM is the only gene in which mutations are known to cause Bloom syndrome.
- Li-Fraumeni syndrome. Li-Fraumeni syndrome is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults. The cancers most often associated with Li-Fraumeni syndrome include breast cancer, osteosarcoma, soft tissue sarcoma, brain tumor, leukemia, adrenocortical carcinoma, and Wilms tumor. The TP53 gene mutation is present in most families with Li-Fraumeni syndrome. The CHEK2 gene mutation is also known to cause Li-Fraumeni syndrome.
- Alagille syndrome.
Nonsyndromic causes of Wilms tumor
Nonsyndromic causes of Wilms tumor include the following:
Familial Wilms tumor. Despite the number of genes that appear to be involved in the development of Wilms tumor, familial Wilms tumor is uncommon, with approximately 2% of patients having a positive family history for Wilms tumor. Siblings of children with Wilms tumor have a less than 1% chance of developing Wilms tumor.[28,29,30] The risk of Wilms tumor among offspring of persons who have had unilateral (sporadic) tumors is less than 2%.
Two familial Wilms tumor genes have been localized to FWT1 (17q12-q21) and FWT2 (19q13.4).[32,33,34] There are occasional Wilms tumor families with a germline mutation in WT1. In these families, most, but not all, family members have genitourinary tract malformations.[35,36]
- Sporadic aniridia. Sporadic aniridia may result from small germline deletions of one copy of the PAX6 gene that includes part or all of the adjacent WT1 gene but does not result in genitourinary abnormalities or retardation (i.e., not obviously WAGR syndrome). Therefore, many patients with sporadic aniridia develop Wilms tumors and are candidates for screening. The relative risk of Wilms tumor in sporadic aniridia is 67-fold. About half of individuals with sporadic aniridia and PAX6 and WT1 deletions develop Wilms tumor.
- Isolated hemihypertrophy. Hemihypertrophy is an asymmetric overgrowth of one or more body parts and is associated with Wilms tumor. It can also be associated with other predisposition syndromes such as Beckwith-Wiedemann syndrome. Clinical signs may not be very evident, and hemihypertrophy may be noted after tumor diagnosis. The overall Wilms tumor incidence was 5.9% in a study of 168 patients with isolated hemihypertrophy. The prevalence is about 2.5% of children with Wilms tumor.[15,39]
- Trisomy 18.
- Fanconi anemia with biallelic mutations in BRCA2 (FANCD1) or PALB2 (FANCN). BRCA2 and PALB2 play central roles in homologous recombination DNA repair. Biallelic mutations in either BRCA2 or PALB2 lead to Fanconi anemia and to increased risks of selected childhood cancers, including Wilms tumor.[41,42,43]
Genes Associated With Wilms Tumor
Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of at least ten genes. The changes may be somatic or germline. Several genes, but not all, will be discussed here.
Aberrations in germline or clonal WT1, WT2, and Wnt activation, when combined with stage of development of the nephron, characterize different subsets of Wilms tumor that can be differentiated by using gene expression profiling. This genetic/ontogenic categorization describes some of the heterogeneity among Wilms tumors.
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.
When modern molecular genetic techniques are used in testing, the incidence of germline WT1 mutations is about 11%. Most of these mutations may be diagnosed, or at least highly suspected, on the basis of clinical syndromic findings at or before diagnosis of Wilms tumor. In a United Kingdom Children's Cancer Study Group study of patients entered in clinical trials, about 2% of Wilms tumor patients had germline mutations in WT1 but no genitourinary abnormalities, as detected by WT1 heteroduplex DNA screen followed by sequencing. These were mostly de novo mutations in children presenting before age 2 years, and the tumors were mostly unilateral with stromal histology. The relatively low number of reports of parent and child pairs with Wilms tumors and WT1 mutations may be the result of decreased fertility. However, the offspring of a child who has a parent with Wilms tumor and WT1 mutation will be at risk for developing Wilms tumor.
Germline WT1 mutations in children with Wilms tumors do not confer poor prognoses per se.
Because deletion of WT1 was the first mutation found to be associated with Wilms tumor, WT1 was assumed to be a conventional tumor suppressor gene. However, non-inactivating mutations can result in altered WT1 protein function that also results in Wilms tumor, such as in Denys-Drash syndrome.
WT1 mutations are more common in children with Wilms tumor and one of the following:
WT1deletion and WAGR syndrome
The observation that led to the discovery of WT1 was that children with WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) were at high risk (>30%) for developing Wilms tumor. Germline mutations were then identified at chromosome 11p13 in children with WAGR syndrome. Deletions involved a set of contiguous genes that included WT1 and the PAX6 gene.
Inactivating mutations or deletions in the PAX6 gene lead to aniridia, while deletion of WT1 confers the increased risk of Wilms tumor. Some of the sporadic cases of aniridia are caused by large chromosomal deletions that also include WT1. This results in a 67-fold increased relative risk (95% confidence interval [CI], 8.1-241) of developing Wilms tumor in children with sporadic aniridia. The incidence of Wilms tumor in children with sporadic aniridia is estimated to be about 5%. Seventy-seven percent of aniridia patients with submicroscopic WT1 deletions detectable by high-resolution fluorescence in situ hybridization (FISH) analysis presented with Wilms tumor compared with 42.5% of aniridia patients with visible deletions detected by microscopy. Patients with sporadic aniridia and a normal WT1 gene, however, are not at increased risk of developing Wilms tumor. Children with familial aniridia, generally occurring for many generations, and without renal abnormalities, have a normal WT1 gene and are not at an increased risk of Wilms tumor.[15,46]
Children with WAGR syndrome or other germline WT1 mutations are at increased risk of developing hypertension, nephropathy, and renal failure and are monitored throughout their lives. Patients with Wilms tumor and aniridia without genitourinary abnormalities are at less risk but are monitored for nephropathy or renal failure. Children with Wilms tumor and any genitourinary anomalies are also at increased risk for late renal failure and are monitored. Features associated with germline WT1 mutations that increase the risk of developing renal failure include the following:
- Stromal predominant histology.
- Bilateral disease.
- Intralobar nephrogenic rests.
- Wilms tumor diagnosed before age 2 years.
Age at tumor diagnosis, frequency of bilaterality, and risk of late-onset renal compromise may vary with the type of mutation.
WT1 mutations and 11p15 loss of heterozygosity were associated with relapse in patients with very low-risk Wilms tumor in one study of 56 patients who did not receive chemotherapy. These findings await validation but may provide biomarkers by which to stratify patients in the future.
WT1interaction with beta-catenin
Activating mutations of the beta-catenin gene (CTNNB1) have been reported to occur in 15% of Wilms tumor patients. In one study, all but one tumor with a beta-catenin mutation had a WT1 mutation, and at least 50% of the tumors with WT1 mutations had a beta-catenin mutation.[51,52] Activation of beta-catenin in the presence of intact WT1 protein appears to be inadequate to promote tumor development because CTNNB1 mutations are rarely found in the absence of a WT1 or WTX mutation.[53,54] About one-third of Wilms tumors have a somatic mutation in WT1, WTX, and/or CTNNB1.
Wilms tumor 2locus (WT2)
When modern molecular genetic techniques are used in testing, the incidence of germline WT2 aberrations is about 8%. Most of these aberrations may be diagnosed, or at least highly suspected, on the basis of clinical syndromic findings at or before diagnosis of Wilms tumor. However, when 437 children with nonsyndromic Wilms tumor were screened for germline mutations in the WT2 locus, 13 mutations (3% of patients) were found. None of these children had signs of Beckwith-Wiedemann syndrome, although they did have a higher frequency of bilateral tumors and perilobar nephrogenic rests. All were de novo abnormalities, except one novel microdeletion in one child, and their mother was not affected. A similar mutation at the WT2 locus was found in 1 of 22 familial Wilms tumor families tested.
WT2and Beckwith-Wiedemann syndrome
A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5, which, when it is a germline mutation, causes the Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumors have germline epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. Like children with Beckwith-Wiedemann syndrome, these children have an increased incidence of bilateral Wilms tumor or familial Wilms tumor.
Several candidate genes at the WT2 locus comprise the two independent imprinted domains IGF2/H19 and KIP2/LIT1. Loss of heterozygosity, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations. A study of 35 sporadic primary Wilms tumors suggests that more than 80% have somatic loss of heterozygosity or loss of imprinting at 11p15.5. The mechanism resulting in loss of imprinting can be either genetic mutation or epigenetic change of methylation.[49,56] Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5. Interestingly, Wilms tumors in Asian children are not associated with either nephrogenic rests or IGF2 loss of imprinting.
Beckwith-Wiedemann syndrome results from loss of imprinting or heterozygosity of WT2 germline mutations. Observations suggest genetic heterogeneity in the etiology of Beckwith-Wiedemann syndrome, with differing levels of association with risk of tumor formation. Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[15,16,17] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the National Wilms Tumor Study (NWTS).[1,17]
A relationship between epigenotype and phenotype has been shown in Beckwith-Wiedemann syndrome, with a different rate of cancer in Beckwith-Wiedemann syndrome according to the type of alteration of the 11p15 region. The overall tumor risk in Beckwith-Wiedemann syndrome was estimated between 5% and 10%, with a risk between 1% (loss of imprinting at IC2) and 30% (gain of methylation at IC1 and paternal 11p15 isodisomy). Patients with IC1 gain of methylation only developed Wilms tumor, whereas other tumors such as neuroblastoma or hepatoblastoma could occur in patients with paternal 11p15 isodisomy.
Wilms tumor gene on the X chromosome(WTX)
A third gene, WTX, has been identified on the X chromosome and plays a role in normal kidney development. This gene is inactivated in approximately one-third of Wilms tumors, but germline mutations have not been observed in patients with Wilms tumor.WTX mutations are equally distributed between males and females. WTX inactivation is a frequent, but late, event in tumorigenesis and has no apparent effect on clinical presentation or prognosis.
Other genes and chromosomal alterations
Additional genes have been implicated in the pathogenesis and biology of Wilms tumor, including the following:
1q: Gain of 1q or overexpression of genes from 1q has been associated with an adverse outcome.
In an analysis of 212 patients from NWTS-4 and the Pediatric Oncology Group Wilms Biology study, 27% of patients displayed 1q gain. A strong relationship between 1q gain and 1p/16q loss was observed. The 8-year event-free survival (EFS) rate was 76% (95% CI, 63%-85%) for patients with 1q gain and 93% (95% CI, 87%-96%) for those lacking 1q gain (P = .0024). The 8-year overall survival (OS) rate was 89% (95% CI, 78%-94%) for those with 1q gain and 98% (95% CI, 94-99%) for those lacking 1q gain (P = .0075). Gain of 1q was not found to correlate with disease stage. After stratification for stage of disease, 1q gain was associated with a significantly increased risk of disease recurrence (risk ratio estimate, 2.72; P = .0089).
Similar results have been reported by European investigators.
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.
- In large NWTS studies, patients with tumor-specific loss of these loci had significantly worse relapse-free survival (RFS) and OS rates. Combined loss of 1p and 16q are used to select favorable-histology (FH) Wilms tumor patients for more aggressive therapy in the current COG study. However, a U.K. study of more than 400 patients found no significant association between 1p deletion and poor prognosis, but a poor prognosis was associated with 16q loss of heterozygosity.
- An Italian study of 125 patients, using treatment quite similar to that in the COG study, found significantly worse prognosis in those with 1p deletions but not 16q deletions.
These conflicting results may arise from the greater prognostic significance of 1q gain described above. The loss of heterozygosity of 16q and 1p appear to arise from complex chromosomal events that result in 1q loss of heterozygosity or 1q gain. The change in 1q appears to be the critical tumorigenic genetic event.
- CACNA1E: Overexpression and amplification of the gene CACNA1E located at 1q25.3, which encodes the ion-conducting alpha-1 subunit of R-type voltage-dependent calcium channels, may be associated with relapse in FH Wilms tumor.
- 7p21: A consensus region of loss of heterozygosity has been identified in 7p21 containing ten known genes, including two candidate tumor suppressor genes (Mesenchyme homeobox 2 [MEOX2] and Sclerostin domain containing 1 [SOSTDC1]).
- SKCG-1: Somatic loss of a growth regulatory gene, SKCG-1, located at 11q23.2, was found in 38% of examined sporadic Wilms tumors, particularly the highly proliferative Wilms tumors. Additional studies of siRNA silencing of the SKCG-1 gene in human embryonic kidney epithelial cells resulted in a 40% increase in cell growth, suggesting that this gene may be involved in loss of growth regulation and Wilms tumorigenesis.
- TP53 (tumor suppressor gene): Most anaplastic Wilms tumors show mutations in the p53 tumor suppressor gene. It may be useful as an unfavorable prognostic marker.[73,74] Microdissection of focally anaplastic Wilms tumors demonstrated TP53 mutation in anaplastic but not nonanaplastic areas of the tumor, suggesting that acquisition of TP53 mutation may be inherent in the process of becoming anaplastic.
- 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.
- PTCH1: Patients with germline 9q22.3 microdeletion syndrome have an increased risk of Wilms tumor. PTCH1 has a role in the pathogenesis of nephroblastoma. This is supported by the germline deletion of one copy of the PTCH1 gene in all described patients, as well as the presence of a nonsense mutation in the remaining allele in a Wilms tumor of one of the patients.
DICER1: Germline mutations in DICER1 have been associated with a pleiotropic tumor predisposition syndrome, and Wilms tumor is a rare manifestation of this syndrome. A subset of Wilms tumors have been reported to exhibit two "hits" in DICER1, suggesting that these mutations could be key events in the pathogenesis of these tumors.
The pathology of WT1-associated and DICER1-associated Wilms tumors appears to differ. WT1-associated Wilms tumors are often stromal rich, with rhabdomyomatous differentiation and intralobar nephrogenic rests that are thought to occur early in renal development, while DICER1-associated Wilms tumors are triphasic with abundant blastema and are not associated with nephrogenic rests.
- MYCN: Genomic gain or amplification of MYCN is relatively common in Wilms tumors and associated with diffuse anaplastic histology.
Bilateral Wilms Tumor
Approximately 5% to 10% of individuals with Wilms tumor have bilateral or multicentric tumors. The prevalence of bilateral involvement is higher in individuals with genetic predisposition syndromes than in those without predisposition syndromes; however, 85% of individuals with WAGR or Beckwith-Wiedemann syndrome have unilateral tumors.[18,78]
Only 16% of persons with bilateral Wilms tumor have a WT1 germline mutation, and only 3% of persons with bilateral Wilms tumors have affected family members. Bilateral Wilms tumor with WT1 mutations are associated with early presentation in pediatric patients (age 10 months vs. age 39 months for those without a mutation) and a high frequency of WT1 nonsense mutations in exon 8. The presence of bilateral or multifocal disease implies that a patient has a genetic predisposition for Wilms tumor.
Screening Children Predisposed to Wilms Tumor
Children with a significantly increased predisposition to develop Wilms tumor (e.g., most children with Beckwith-Wiedemann syndrome or other overgrowth syndromes, WAGR syndrome, Denys-Drash syndrome, sporadic aniridia, or isolated hemihypertrophy) are usually screened with ultrasound every 3 months at least until they reach age 8 years.[6,7,15,46] Early-stage, asymptomatic, small Wilms tumors may be discovered and potentially removed with renal-sparing surgery.
Tumor screening programs for each overgrowth syndrome have been suggested, based on published age and incidence of tumor type. Approximately 10% of patients with Beckwith-Wiedemann syndrome will develop a malignancy, with the most common being either Wilms tumor or hepatoblastoma, although adrenal tumors can also occur. Children with hemihypertrophy are also at risk for developing liver and adrenal tumors. Screening with abdominal ultrasound and serum alpha-fetoprotein is suggested until age 4 years. After age 4 years, most hepatoblastomas will have occurred, and imaging may be limited to renal ultrasound, which is quicker and does not require fasting before the exam.
Newborns born with sporadic aniridia should undergo molecular testing for deletion analysis of PAX 6 and WT1. If a deletion of WT1 is observed, the child should be screened with ultrasound every 3 months until age 8 years, and the parents should be educated about the need to identify and treat early Wilms tumor.[45,46,82]
Although the risk for Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown and likely varies with the gene in which the mutation occurred, some experts recommend screening such children with serial ultrasound examinations every 3 months until age 8 years.
The risk of Wilms tumor in children with Klippel-Trénaunay syndrome (a unilateral limb overgrowth syndrome) was no different than the risk in the general population when assessed using the NWTS database. Routine ultrasound surveillance is not recommended.
The frequency of malformations observed in patients with Wilms tumor underlines the need for genetic counseling, molecular and genetic explorations, and follow-up.
A French study  concluded that patients need to be referred for genetic counseling if they have one of the following:
- One major abnormality such as:
- Beckwith-Wiedemann symptoms (macroglossia, neonatal or postnatal macrosomia, abdominal wall defects, or visceromegaly); or
- One condition such as:
- Overgrowth syndrome or mental retardation.
- Diffuse mesangial sclerosis.
- Two or more minor malformations such as:
- Inguinal or umbilical hernia.
- Renal abnormalities.
- Ectopic testis.
Simple oncological follow-up is indicated when there is no malformation or when there is only one minor malformation.
After genetic counseling takes place, a search for WT1 mutations should be considered for patients who have the following:
- Bilateral Wilms tumor.
- Familial Wilms tumor.
- Wilms tumor and age younger than 6 months.
- Genitourinary abnormality.
- Mental retardation association.
A search for an 11p15 abnormality should be considered for patients exhibiting any symptoms of Beckwith-Wiedemann syndrome, hemihypertrophy, or bilateral or familial Wilms tumor.
The following symptoms may be caused by Wilms or other childhood kidney tumors:
- A lump, swelling, or pain in the abdomen. Most children present with an asymptomatic mass that is noted when they are bathed or dressed. Abdominal pain is present in 40% of children.
- Fever. Fever is occasionally noted.
- Blood in the urine. Although gross hematuria occurs in about 25% of children with Wilms tumor, most children with gross hematuria do not have Wilms tumor.
- Hypertension. About 25% of children have hypertension at presentation, which is caused by excessive renin excretion and responds to angiotensin-converting enzyme (ACE) inhibitors or surgical removal of the tumor.
- Hypercalcemia. Symptomatic hypercalcemia can sometimes be seen at presentation of rhabdoid tumors.
Children with Wilms tumors or other renal malignancies may also come to medical attention as a result of the following:
- Vascular obstruction or metastasis, including pulmonary symptoms due to lung metastasis.
- Abdominal pain due to liver metastasis, prominent abdominal wall vessels, or varicocele due to inferior vena cava obstruction.
- Pulmonary embolus (rare).
Diagnostic and Staging Evaluation
About 5% of renal masses thought to be Wilms tumor on the basis of clinical and radiological findings are diagnosed as another condition.[87,88] The German Pediatric Oncology study group entered 188 patients on the SIOP-9 trial from 1988 to 1991. However, only 136 patients received preoperative chemotherapy because imaging was regarded as atypical on central review. Nine of the 188 patients (5%) had other diagnoses, including benign tumors and renal cell carcinoma.
Tests and procedures used to evaluate and stage Wilms tumor and other childhood kidney tumors include the following:
- Physical exam and history.
- Complete blood count (CBC).
- Liver function test.
- Renal function test.
- Abdominal imaging.
- Abdominal X-ray.
- Computed tomography (CT) scan with contrast or magnetic resonance imaging (MRI) of abdomen.
- Ultrasound exam of the abdomen. Ultrasound exam of the abdomen is often performed before a more definitive CT scan with contrast or MRI with contrast of the abdomen is done. This procedure is unnecessary after the definitive diagnostic study has been performed.
- CT scan of chest.
- X-ray of the chest and bones.
- Bone scan.
- 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT. Wilms tumor is 18F-FDG avid, and 18F-FDG-PET-CT imaging adds clinically applicable information to conventional imaging, which may be particularly helpful in patients with bilateral disease or those receiving preoperative chemotherapy. 18F-FDG-PET-CT highlights FDG-avid areas in the tumor and metastases, which corresponds to histologically confirmed active disease.
- von Willebrand disease work-up. About 1% to 8% of patients presenting with Wilms tumor have acquired von Willebrand disease, although many are asymptomatic. von Willebrand multimers bind to Wilms tumor, reducing the plasma concentration to low levels. Some clinicians recommend evaluation for von Willebrand disease before surgery.
Biopsy or resection. In children with a renal mass that clinically appears to be stage I or stage II Wilms tumor, biopsy is not performed so that tumor cells are not spread during the biopsy. A biopsy would upstage such a patient to stage III. Nephrectomy (in North America) or chemotherapy (in Europe) is performed instead. Therefore, the diagnostic pathology is first seen when the nephrectomy specimen is examined.
Biopsy of a renal mass may be indicated if the mass is atypical by radiographic appearance for Wilms tumor, and the patient is not going to undergo immediate nephrectomy. Biopsy tissue from inoperable Wilms tumor obtained before chemotherapy may be used for histologic review and initial treatment decisions. The use of biopsy to determine histology in an inoperable tumor remains controversial because biopsy may cause local tumor spread. It is important to recognize that data from NWTS-4 and NWTS-5 have shown conclusively that, because of histologic heterogeneity of Wilms tumor, a significant number of patients have unfavorable histology that is missed during an upfront biopsy but revealed at the time of definitive surgery following chemotherapy.
If the initial imaging studies suggested a possible lesion on the contralateral kidney, the contralateral kidney is formally explored to rule out bilateral involvement. This is done before nephrectomy to exclude bilateral Wilms tumor.
Biopsy is also controversial in patients with bilateral tumors because biopsy rarely detects anaplasia in bilateral Wilms tumor, and the incidence of bilateral tumors being other than Wilms is very low. The current COG study of bilateral Wilms tumor and of patients with unilateral Wilms tumor predisposed to developing bilateral tumors tries to avoid initial biopsy and mandates biopsy after 6 weeks of three-drug chemotherapy.
- Lymph node sampling is required to stage all Wilms tumor patients, except those with stage 5.
Children with a renal mass are carefully assessed for signs of associated syndromes such as aniridia, developmental delay, hypospadias, cryptorchidism, pseudohermaphrodism, overgrowth, and hemihypertrophy.
For patients with suspected Wilms tumor, preoperative staging studies include a CT or MRI scan of the abdomen/pelvis and chest to assess intravascular extension or rupture of Wilms tumor.
- Intravascular extension of the Wilms tumor. Preoperative assessment of intravascular extension of Wilms tumor is essential to guide management. The presence of intravenous tumor thrombus in the lumen of the renal vein, inferior vena cava, and right atrium has been reported in up to 11.3% of Wilms tumor patients and may lead to differences in management.
In North America, local staging of Wilms tumor is performed with CT or MRI of the abdomen and pelvis. Contrast-enhanced CT for Wilms tumor patients has high sensitivity and specificity for detection of cavoatrial tumor thrombus that may impact surgical approach. Routine Doppler evaluation after CT has been performed but is not necessarily required. Large tumor thrombi need to be controlled before surgical approach to the renal mass.
- Wilms tumor rupture. CT has moderate specificity but relatively low sensitivity in the detection of preoperative Wilms tumor rupture. Ascites beyond the cul-de-sac is most predictive of preoperative Wilms tumor rupture, irrespective of attenuation. In the presence of ascites, fat stranding around the tumor and the presence of retroperitoneal fluid are highly predictive of rupture.
Prognosis and Prognostic Factors
Wilms tumor is a curable disease in most affected children. Since the 1980s, the 5-year survival rate for Wilms tumor with FH has been consistently above 90%. 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.
- Stage of disease at diagnosis.
- Tumor size.
- Histopathologic features of the tumor (FH vs. anaplastic histology). (Refer to the Histologic Findings in Wilms Tumor section of this summary for more information.)
- Molecular features of the tumor. B7-H1, an immune costimulatory molecule, has been found to be associated with an increased risk of tumor recurrence in favorable histology Wilms tumor.
- Patient age (adolescents and young adults).
Adolescents and young adults with Wilms tumor
In an analysis of Wilms tumor patients in the Surveillance, Epidemiology, and End Results (SEER) database, adults (n = 152) had a statistically worse OS (69% vs. 88%, P < .001) than did pediatric patients (n = 2,190), despite previous studies showing comparable outcome with treatment on protocol.[104,105] The inferior outcome of the adult patients on this study may be the result of differences in tumor biology between children and adults, incorrect diagnosis, inadequate staging (e.g., more likely to be staged as localized disease or to not receive lymph node sampling), or undertreatment (e.g., not receiving radiation therapy). Additional factors in this SEER report that may have contributed to a worse OS in adult patients include the size of the study and lack of central review of pathology. Adolescent and young adult patients up to age 30 years are now eligible for treatment on the COG Wilms tumor protocols.
The inferior outcome of older patients is not explained entirely by inadequate treatment or not being treated according to the pediatric Wilms tumor protocol. In a U.K. study looking at the outcome of patients aged 10 to 16 years (N = 50) registered on the U.K. Wilms Tumor 3 and SIOP 2001 Wilms tumor trials, patients in this age group had a higher percentage of diffuse anaplastic tumors. The overall 5-year survival was 63% for patients aged 10 to 16 years (43% for anaplastic tumors), which is significantly lower than the outcome for younger patients with Wilms tumor. However, SEER 5-year relative survival of nephroblastoma between 2003 and 2009 did not show differences among age groups from younger than 1 year to age 10 to 14 years.
Histologic Findings in Wilms Tumor
Although most patients with a histologic diagnosis of Wilms tumor do well with current treatment, approximately 10% of patients have histopathologic features that are associated with a worse prognosis, and in some types, with a high incidence of relapse and death. Wilms tumor can be separated into the following two prognostic groups on the basis of tumor and kidney histopathology:
- Favorable histology (FH).
- Anaplastic histology.
Favorable histology (FH)
Histologically, Wilms tumor mimics the triphasic development of a normal kidney consisting of blastemal, epithelial (tubules), and stromal cell types. Not all tumors are triphasic, and monophasic patterns may present diagnostic difficulties.
While associations between histologic features and prognosis or responsiveness to therapy have been suggested, with the exception of anaplasia, none of these features have reached statistical significance in North American treatment algorithms, and therefore, do not direct the initial therapy.
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. In bilateral tumors, 12% to 14% have been reported to have anaplastic histology in one kidney.[109,110]
The following two histologic criteria must be present for the diagnosis of anaplasia:
- Presence of multipolar polyploid mitotic figures with marked nuclear enlargement.
Changes on 17p consistent with mutations in the p53 gene have been associated with foci of anaplastic histology. Focal anaplasia is defined as the presence of one or more sharply localized regions of anaplasia in a primary tumor. All of these factors lend support to the hypothesis that anaplasia evolves as a late event from a subpopulation of Wilms tumor cells that have acquired additional genomic lesions. Focal anaplasia does not confer as poor a prognosis as does diffuse anaplasia.[100,112,113]
Anaplasia correlates best with responsiveness to therapy rather than to tumor aggressiveness. It is most consistently associated with poor prognosis when it is diffusely distributed and when identified at advanced stages. These tumors are more resistant to the chemotherapy traditionally used in children with FH Wilms tumor.
Nephrogenic rests are abnormally retained embryonic kidney precursor cells arranged in clusters. Nephrogenic rests are found in about 1% of unselected pediatric autopsies, 35% of kidneys with unilateral Wilms tumors, and nearly 100% of kidneys with bilateral Wilms tumors.[114,115]
The term nephroblastomatosis is defined as the presence of diffuse or multifocal nephrogenic rests. There are two types: intralobar nephrogenic rests and perilobar nephrogenic rests. Diffuse hyperplastic perilobar nephroblastomatosis is defined as nephroblastomatosis forming a thick rind around one or both kidneys and is considered a preneoplastic condition.
The type and percentage of nephrogenic rests vary in patients with unilateral or bilateral disease. Patients with bilateral Wilms tumor have a higher proportion of perilobar rests (52%) than of intralobar or combined rests (32%) and higher relative proportions of rests, compared with patients with unilateral tumors (18% perilobar and 20% intralobar or both).
Patients with any type of nephrogenic rest in a kidney removed for nephroblastoma are considered at increased risk for tumor formation in the remaining kidney. This risk decreases with patient age.
Extrarenal nephrogenic rests are rare and may develop into extrarenal Wilms tumor.
Stage Information for Wilms Tumor
Both the results of the imaging studies and the surgical and pathologic findings at nephrectomy are used to determine the stage of disease. The stage is the same for tumors with FH or anaplastic histology. Thus, the stage information is characterized by a statement of both criteria (for example, stage II, FH or stage II, anaplastic histology).[108,117]
The staging system was originally developed by the NWTS Group and is still used by the COG. The staging system and incidence by stage are outlined below.
In stage I Wilms tumor (43% of patients), all of the following criteria must be met:
- Tumor is limited to the kidney and is completely resected.
- The renal capsule is intact.
- The tumor is not ruptured or biopsied before being removed.
- No involvement of renal sinus vessels.
- No evidence of the tumor at or beyond the margins of resection.
- All lymph nodes sampled are negative.
For a tumor to qualify for certain therapeutic protocols such as very low-risk stage I, regional lymph nodes must be examined microscopically. Lymph node sampling is recommended for all patients.
In stage II Wilms tumor (20% of patients), the tumor is completely resected, and there is no evidence of tumor at or beyond the margins of resection. The tumor extends beyond the kidney as evidenced by any one of the following criteria:
- There is regional extension of the tumor (i.e., penetration of the renal sinus capsule, or extensive invasion of the soft tissue of the renal sinus, as discussed below).
- Blood vessels in the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor cells.
- Vascular extension of tumor is considered stage II only if it is completely removed en bloc in the nephrectomy specimen.
- All lymph nodes sampled are negative.
Rupture or spillage confined to the flank, including biopsy of the tumor, is now included in stage III by the COG Renal Tumor Committee; however, data to support this approach are controversial.
In stage III Wilms tumor (21% of patients), there is postsurgical residual nonhematogenous tumor that is confined to the abdomen. Any one of the following may occur:
- Lymph nodes in the abdomen or pelvis are involved by tumor. (Lymph node involvement in the thorax or other extra-abdominal sites is a criterion for stage IV.)
- The tumor has penetrated through the peritoneal surface.
- Tumor implants are found on the peritoneal surface.
- Gross or microscopic tumor remains postoperatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination).
- The tumor is not completely resectable because of local infiltration into vital structures.
- Tumor spillage occurs either before or during surgery.
- Any biopsy is performed, regardless of type-Tru-cut biopsy, open biopsy, or fine-needle aspiration-before the tumor is removed.
- The tumor is removed in more than one piece (e.g., tumor cells are found in a separately excised adrenal gland; a tumor thrombus in the renal vein is removed separately from the nephrectomy specimen). Extension of the primary tumor in the vena cava into the thoracic vena cava and heart is considered stage III, rather than stage IV, even though outside the abdomen-and it can even be stage II if completely resected en bloc with the nephrectomy specimen.
Lymph node involvement and microscopic residual disease are highly predictive of outcome in patients with stage III FH Wilms tumor.
In stage IV Wilms tumor (11% of patients), hematogenous metastases (lung, liver, bone, brain) or lymph node metastases outside the abdominopelvic region are present. The presence of tumor within the adrenal gland is not interpreted as metastasis and staging depends on all other staging parameters present. According to the criteria described above, the primary tumor is assigned a local stage, which determines local therapy. For example, a patient may have stage IV, local stage III disease.
In stage V Wilms tumor (5% of patients), bilateral involvement by tumor is present at diagnosis. A previous attempt was made to stage each side according to the above criteria on the basis of the extent of disease. The ongoing COG-AREN0534 protocol is testing the approach of preoperative chemotherapy without local biopsy in hopes of reducing tumor size to allow renal-sparing surgical procedures. In these patients, renal failure rates approach 15% at 15 years posttreatment, making renal-sparing treatment important.
Treatment for Wilms Tumor
Because of the relative rarity of Wilms tumor, all patients with this tumor should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon and/or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) who have experience treating Wilms tumor is necessary to determine and implement optimal treatment.
Most randomized clinical studies for treatment of children with Wilms tumor have been conducted by two large clinical groups. There are differences between the two groups that affect staging and classification.
- The COG (includes the previous NWTS Group): The NWTS Group established standard treatment for Wilms tumor in North America, consisting of initial nephrectomy followed by chemotherapy and, in some patients, radiation therapy.[121,122,123]
- Société Internationale d'Oncologie Pédiatrique (SIOP): The SIOP is a European consortium, and their trials provide preoperative chemotherapy before definitive resection for patients with renal tumors.
This summary focuses on the NWTS (now COG Renal Tumor Committee) results and studies.
The major treatment and study conclusions of NWTS-1 through NWTS-5 are as follows:
- 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.
- The prognosis for patients with stage III FH is best when treatment includes either (a) dactinomycin, vincristine, doxorubicin, and 10.8 Gy of radiation therapy to the flank; or (b) dactinomycin, vincristine, and 20 Gy of radiation therapy to the flank. Whole abdominal radiation is indicated for extensive intraperitoneal disease or widespread intraperitoneal tumor spill.
- The addition of cyclophosphamide at the protocol dose (10 mg/kg/d for 3 days every 6 weeks) to the combination of vincristine, dactinomycin, and doxorubicin does not improve prognosis for patients with stage IV FH tumors.
- A single dose of dactinomycin per course (stages I-II FH, stage I anaplastic, stage III FH, stages III-IV, or stages I-IV clear cell sarcoma of the kidney) is equivalent to the divided-dose courses, results in the same EFS, achieves greater dose intensity, and is associated with less toxicity and expense.
- Eighteen weeks of therapy is adequate for patients with stage I and II FH, whereas other patients can be treated with 6 months of therapy instead of 15 months.[97,121,124,125,126]
- Tumor-specific loss of heterozygosity for combined 1p and 16q predicts recurrence of FH Wilms tumor.
The following operative principles have also evolved from NWTS trials:
- The most important role for the surgeon is to ensure complete tumor removal without rupture and assess the extent of disease. Radical nephrectomy and lymph node sampling via a transabdominal or thoracoabdominal incision is the procedure of choice. A flank incision is not performed because it provides limited exposure to the kidney. For patients with resectable tumors, preoperative or intraoperative biopsy is not performed because it potentially upstages the tumor.
- Routine exploration of the contralateral kidney is not necessary if technically adequate imaging studies do not suggest a bilateral process. If the initial imaging studies are suggestive of bilateral kidney involvement, treatment approaches should facilitate renal-sparing surgery.
- About 2% of Wilms tumors have ureteral involvement. The presence of gross hematuria, nonfunctioning kidney, or hydronephrosis suggests the tumor may extend into the ureter, and cystoscopy is recommended. En bloc resection to avoid tumor spill is recommended.
- The surgeon needs to be aware of the risk of intraoperative spill, especially in patients who have right-sided and large tumors.
- Predisposition to bilateral tumors. Some children who are predisposed to bilateral tumors and who have very small tumors detected by ultrasound screening may be considered for renal-sparing surgery to preserve renal tissue.
- A solitary kidney.
- Horseshoe kidney. Wilms tumor arising in a horseshoe kidney is rare, and accurate preoperative diagnosis is important for planning the operative approach. Primary resection is possible in most cases. Inoperable cases can usually be resected after chemotherapy.
- Wilms tumor in infants with Denys-Drash or Frasier syndrome (to delay the need for dialysis).
The use of renal-sparing surgery for bilateral tumors is under investigation.
Renal-sparing surgery does not appear to be feasible in most patients at the time of diagnosis because of the location of the tumor within the kidney, even in those with very low risk. In North America, renal-sparing surgery (partial nephrectomy) of unilateral Wilms tumor following administration of chemotherapy to shrink the tumor mass is considered investigational.[134,135]
Hilar and periaortic lymph node sampling is appropriate even if the nodes appear normal.[127,136] Furthermore, any suspicious node basin is sampled. Margins of resection, residual tumor, and any suspicious node basins are marked with titanium clips.
Wilms tumor rarely invades adjacent organs; therefore, resection of contiguous organs is rarely indicated. There is an increased incidence of complications occurring in more extensive resections that involve removal of additional organs beyond the diaphragm and adrenal gland. This has led to the recommendation in current COG protocols that these patients should be considered for initial biopsy, neoadjuvant chemotherapy, and then secondary resection. Primary resection of liver metastasis is not recommended.
- Synchronous bilateral Wilms tumor.
- Wilms tumor in a solitary kidney.
- Extension of tumor thrombus in the inferior vena cava above the level of the hepatic veins.
- Tumor involves contiguous structures whereby the only means of removing the kidney tumor requires removal of the other structures (e.g., spleen, pancreas, or colon but excluding the adrenal gland).
- Inoperable Wilms tumor.
- Pulmonary compromise due to extensive pulmonary metastases.
Preoperative chemotherapy follows a biopsy unless the patient is being treated on COG-AREN0534. The biopsy may be performed through a flank approach.[143,144,145,146,147,148] Preoperative chemotherapy includes doxorubicin in addition to vincristine and dactinomycin unless anaplastic histology is present; in such cases, then chemotherapy includes treatment with regimen I (refer to Table 2 below). The chemotherapy generally makes tumor removal easier by decreasing the size and vascular supply of the tumor; it may also reduce the frequency of surgical complications.[91,137,139,148,149]
In North America, the use of preoperative chemotherapy in patients with evidence of a contained preoperative rupture has been suggested to avoid intraoperative spill, but this is controversial. The preoperative diagnosis of a contained retroperitoneal rupture on CT is difficult, even for experienced pediatric radiologists. The routine use of preoperative chemotherapy would lead to overtreatment in a significant number of these children.
Newborns and all infants younger than 12 months who will be treated with chemotherapy require a 50% reduction in chemotherapy dose compared with the dose given to older children. This reduction diminishes the toxic effects reported in children in this age group enrolled in NWTS studies while maintaining an excellent overall outcome.
Liver function tests in children with Wilms tumor are monitored closely during the early course of therapy because hepatic toxic effects (sinusoidal obstructive syndrome, previously called veno-occlusive disease) have been reported in these patients.[153,154] Dactinomycin or doxorubicin should not be administered during radiation therapy. Patients who develop renal failure while undergoing therapy can continue receiving chemotherapy with vincristine, dactinomycin, and doxorubicin. Vincristine and doxorubicin can be given at full doses; however, dactinomycin is associated with severe neutropenia. Reductions in dosing these agents may not be necessary, but accurate pharmacologic and pharmacokinetic studies are needed while the patient is receiving therapy.[155,156]
Postoperative radiation therapy to the tumor bed is required when a biopsy is performed or in the setting of local tumor stage III.
Table 2 describes the standard chemotherapy regimens used to treat Wilms tumor.
Table 2. Standard Chemotherapy Regimens for Wilms Tumor
|Regimen Name||Regimen Description|
|Regimen EE-4A||Vincristine, dactinomycin × 18 weeks postnephrectomy|
|Regimen DD-4A||Vincristine, dactinomycin, doxorubicin × 24 weeks; baseline nephrectomy or biopsy with subsequent nephrectomy|
|Regimen I||Vincristine, doxorubicin, cyclophosphamide, etoposide × 24 weeks postnephrectomy|
Standard treatment options for stage I Wilms tumor
Table 3 provides an overview of the standard treatment and survival data for stage I Wilms tumor, based on published results.
Table 3. Overview of Standard Treatment for Stage I Wilms Tumor
|Stage||Histology||4-Year RFS or EFS||4-Year OS||Treatment (refer toTable 2for chemotherapy regimen descriptions)|
|DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.|
|a Fewer than five patients have survived 4 years; therefore, results should be interpreted with caution.|
|Stage I[67,100,101]||FH <24 mo/tumor weight <550g||85%||98%||Surgery only (not standard treatment; should be done only in the context of a clinical trial)|
|FH >24 mo/tumor weight >550g||94% RFS||98%||Nephrectomy + lymph node sampling followed by regimen EE-4A|
|FA||68%a||89%||Nephrectomy + lymph node sampling followed by regimen EE-4A and XRT|
|DA||68% EFS||79% (n = 10)||Nephrectomy + lymph node sampling followed by regimen EE-4A and XRT|
The COG addressed the question of whether a subset of stage I Wilms tumor patients could be treated with surgery alone. The NWTS-5 (COG-Q9401/NCT00002611) trial investigated this approach for children younger than 2 years at diagnosis with stage I FH Wilms tumors that weigh less than 550 g.
Evidence (surgery only for children younger than 24 months at diagnosis with stage I FH tumor that weighed <550 g):
- In the NWTS-5 (NCT00002611) study, the omission of adjuvant chemotherapy was tested for children younger than 2 years at diagnosis with stage I FH Wilms tumors that weighed less than 550 g. Stringent stopping rules were designed to ensure closure of the study if the 2-year RFS rate was 90% or lower. The expectation was that approximately 50% of the surgery-only children would be salvaged after recurrence, thus attaining the 95% predicted survival of children with very low-risk Wilms tumor treated with standard chemotherapy according to regimen EE-4A.
- The study was discontinued in 1998 when the predicted 2-year EFS fell below 90%.
- Long-term follow-up of this study's surgery-only cohort and the EE-4A group with a median follow-up of 8.2 years reported the estimated 5-year EFS for surgery-only patients was 84% (95% CI, 73%-91%); for the EE-4A patients, it was 97% (95% CI, 92%-99%, P = .002). One death was observed in each treatment group. The estimated 5-year OS was 98% (95% CI, 87%-99%) for surgery only and 99% (95% CI, 94%-99%) for EE-4A (P = .70).
- Investigators observed that the children who relapsed were more successfully retreated than prior stage I/FH children, probably because they were naive to both radiation therapy and chemotherapy.
Standard treatment options for stage II Wilms tumor
Table 4 provides an overview of the standard treatment and survival data for stage II Wilms tumor, based on published results.
Table 4. Overview of Standard Treatment for Stage II Wilms Tumor
|Stage||Histology||4-Year RFS or EFS||4-Year OS||Treatment (refer toTable 2for chemotherapy regimen descriptions)|
|DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.|
|Stage II[67,100]||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|
On NWTS-3 through NWTS-5, patients with intraoperative spill were divided into two groups: (1) those with diffuse spillage involving the whole abdominal cavity; and (2) those with local spillage confined to the flank. Patients with diffuse spillage were treated with radiation therapy to the entire abdomen and three-drug chemotherapy (vincristine, dactinomycin, and doxorubicin), whereas patients with local spillage were treated with vincristine and dactinomycin only. On the basis of an analysis of patients treated on NWTS-3 and NWTS-4 indicating that patients with stage II disease and local spillage had inferior OS compared with patients with stage II disease without local spillage, ongoing COG studies treat patients with local spillage with doxorubicin and flank radiation. This approach is controversial and has not been tested; therefore, it should not be considered standard.
In a review of 499 patients from NWTS-4 with stage II, FH Wilms tumor, 95 of the patients experienced tumor spill. The 8-year RFS and OS for patients who experienced tumor spill and were treated with vincristine and dactinomycin without flank radiation therapy was lower, at 75.7% and 90.3%, than the 85% and 95.6% rates for those who did not experience tumor spill. None of these differences achieved statistical significance.
Standard treatment options for stage III Wilms tumor
Table 5 provides an overview of the standard treatment and survival data for stage III Wilms tumor, based on published results.
Table 5. Overview of Standard Treatment for Stage III Wilms Tumor
|Stage||Histology||4-Year RFS or EFS||4-Year OS||Treatment (refer toTable 2for chemotherapy regimen descriptions)|
|DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.|
|Stage III[67,100]||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|
The outcome of patients with peritoneal implants treated with gross resection, three-drug chemotherapy, and total-abdominal radiation (10.5 Gy) is similar to that of other stage III patients.[Level of evidence: 2A]
For patients classified as stage III purely on the basis of local spill, refer to the Standard treatment options for stage II Wilms tumor section of this summary.
Standard treatment options for stage IV Wilms tumor
Table 6 provides an overview of the standard treatment and survival data for stage IV Wilms tumor, based on published results.
Table 6. Overview of Standard Treatment for Stage IV Wilms Tumor
|Stage||Histology||4-Year RFS or EFS||4-Year OS||Treatment (refer toTable 2for chemotherapy regimen descriptions)|
|DA = diffuse anaplasia; EFS = event-free survival; FA = focal anaplasia; 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/chest CT evidence of pulmonary metastases.|
|Stage IV[67,100]||FH||76% RFS||86%||Nephrectomy + lymph node sampling, followed by abdominal XRT,a radiation to sites of metastases, bilateral pulmonary XRT,b and regimen DD-4A|
|FA||61% EFS||72% (n = 11)||Nephrectomy + lymph node sampling, followed by abdominal XRT,a radiation to sites of metastases, bilateral pulmonary XRT,b and regimen DD-4A|
|DA||33% EFS||33% (n = 15)||Immediate nephrectomy + lymph node sampling followed by abdominal XRT,a radiation to sites of metastases, whole-lung XRT,b and regimen I|
|DA (preoperative treatment)||31% EFS||44% (n = 13)||Preoperative treatment with regimen I followed by nephrectomy + lymph node sampling, followed by abdominal XRT,a radiation to sites of metastases, and whole-lung XRTb|
Stage IV disease is defined by the presence of hematogenous metastases to the lung, liver, bone, brain, or other sites, with the lung being the most common site. Historically, chest X-rays were used to detect pulmonary metastases. The introduction of CT created controversy because many patients had lung nodules detected by chest CT scans that were not seen on chest X-rays. Management of newly diagnosed patients with FH Wilms tumor who have lung nodules detected only by CT scans (with negative chest X-ray) has elicited controversy as to whether they need to be treated with additional intensive treatment that is accompanied by acute and late toxicities.
Evidence (treatment of pulmonary nodules detected by chest CT scan only):
- A retrospective review of 186 patients from NWTS-4 and NWTS-5 (COG-Q9401/NCT00002611) with CT-only-detected lung nodules reported on the use of doxorubicin, vincristine, and dactinomycin with or without lung radiation versus the use of two drugs.
- Patients who received doxorubicin, vincristine, and dactinomycin with or without lung radiation had a 5-year EFS of 80% versus an EFS of 56% for patients receiving only two drugs (P = .004).
- There was no difference in the 5-year OS (87% vs. 86%).
The issue of whether radiation can be omitted in patients with FH Wilms tumor and pulmonary metastases (identified by chest CT scans) has been studied prospectively in North America in the COG-AREN0533 trial. COG-AREN0533 patients underwent 6 weeks of chemotherapy consisting of vincristine, dactinomycin, and doxorubicin and were reevaluated to assess the response of their pulmonary metastases. Patients whose pulmonary metastases had completely resolved were spared pulmonary irradiation and continued with the same chemotherapy. If the pulmonary metastases were still present at that time, patients were treated with chemotherapy in which cyclophosphamide and etoposide were added, and they also underwent pulmonary irradiation. The trial is closed, and results are pending.
Retrospective studies from Europe have examined the impact of omitting pulmonary radiation in patients with pulmonary metastases diagnosed by chest X-ray. European investigators omitted radiation from the treatment of most patients with Wilms tumor and pulmonary metastases as identified on chest X-ray who were treated on the SIOP-93-01 (NCT00003804) trial. The European approach to renal tumors differs from the approach used in North America. All patients who were shown to have a renal tumor by imaging underwent 9 weeks of prenephrectomy chemotherapy consisting of vincristine, dactinomycin, and doxorubicin.
Evidence (treatment of pulmonary nodules detected by chest X-ray):
- In a retrospective study, 234 newly diagnosed patients with Wilms tumor presenting with pulmonary metastases were treated according to the response of the pulmonary metastases to the prenephrectomy chemotherapy.
- Patients who were in complete remission after 9 weeks of therapy continued with the same chemotherapy and did not require radiation to their lungs.
- The 5-year EFS was 77%, and the OS was 88%.
- Patients who had residual pulmonary metastases were evaluated for metastasectomy; 37 patients obtained complete remission with surgery, and their outcome was similar to that of the group of patients who were treated with chemotherapy. Tumor viability in the resected pulmonary metastases was not a factor for omitting radiation therapy.
- The 5-year EFS was 84%, and the OS was 92%.
- Patients with residual pulmonary metastases that were incompletely resected or inoperable received more aggressive chemotherapy consisting of ifosfamide/anthracycline alternating with carboplatin/etoposide for 9 weeks.
- Patients showing a complete remission at that time were spared pulmonary radiation and continued with chemotherapy, whereas patients with residual pulmonary metastases continued with additional chemotherapy (to complete 34 weeks) and pulmonary irradiation. The 5-year OS was 48%, compared with the OS for patients who responded to chemotherapy alone (88%) and those who underwent metastasectomy (92%) (P < .001).
- Patients with high-risk histologies, such as anaplastic Wilms tumor, were treated with more aggressive chemotherapy but had a poorer outcome, compared with that of patients with nonanaplastic histologies (5-year OS, 87% vs. 33%; P < .001).
It is important to note that patients in Europe receive higher cumulative doses of dactinomycin and doxorubicin before their pulmonary metastases are reevaluated than do patients in North America. The European experience cannot be directly applied to North America, although it suggests that for patients with nonanaplastic histology who are in a complete remission with chemotherapy, radiation may be omitted without impacting outcome.
- Patients who were in complete remission after 9 weeks of therapy continued with the same chemotherapy and did not require radiation to their lungs.
The presence of liver metastases at diagnosis is not an independent adverse prognostic factor in patients with stage IV Wilms tumor.
Treatment options for stage V and those predisposed to developing bilateral Wilms tumor
Currently, there is not a standard approach for the treatment of stage V Wilms tumor (bilateral Wilms tumor at diagnosis) and those predisposed to developing Wilms tumor.
Management of a child with bilateral Wilms tumor is very challenging. The goals of therapy are to eradicate all tumor and to preserve as much normal renal tissue as possible, with the hope of decreasing the risk of chronic renal failure among these children.
In the NWTS-4 trial, bilateral Wilms tumor patients had a lower EFS and OS than did patients with localized Wilms tumor (including anaplastic histology), except for stage IV disease, in which OS was higher for patients with bilateral Wilms. The NWTS-4 study reported that the 8-year EFS for patients with bilateral FH Wilms tumor was 74% and the OS was 89%; for patients with anaplastic histology, the EFS was 40% and the OS was 45%. The NWTS-5 (COG-Q9401/NCT00002611) study reported the 4-year EFS for bilateral Wilms tumor patients was 61% and the OS was 81%; for patients with anaplastic histology, the EFS was 44% and the OS was 55%.[100,162] Similar outcomes for patients with bilateral Wilms tumor have been reported in Europe.[109,109,163] In a single-institution experience in the Netherlands (N = 41), there was significant morbidity in terms of renal failure (32%) and secondary tumors (20%). The incidence of end-stage renal failure in the Dutch study may be a reflection of a longer follow-up period.
Therapy for stage V Wilms tumor is being studied by the COG. Traditionally, patients have undergone bilateral renal biopsies, with staging of each kidney followed by preoperative chemotherapy. Currently on COG trials, pretreatment biopsies are not required if results of imaging tests are consistent with Wilms tumor. In the past the surgical approach varied according to the size of the tumor, with small tumors being resected and larger tumors being biopsied followed by prenephrectomy chemotherapy. The COG-AREN0534 trial is expected to provide data on whether using vincristine, dactinomycin, and doxorubicin initially is appropriate; in previous studies, approximately 40% of stage V patients did not require anthracyclines.
Preoperative chemotherapy and resection
In the first COG trial to formally study bilateral Wilms tumors (COG-AREN0534), the treatment approach consists of preoperative chemotherapy with vincristine, dactinomycin, and doxorubicin to attempt to shrink the tumor and spare renal parenchyma. As part of this trial, an initial biopsy, laparotomy, or primary tumor excision is not recommended.
Evidence (preoperative chemotherapy):
- In a series of 49 patients with Wilms tumor who received preoperative therapy according to the SIOP-93-01 (NCT00003804) guidelines, the timing of surgery was determined when there was no longer imaging evidence of tumor regression. The mean treatment duration was 80 days before renal-sparing surgery.
- The 5-year EFS rate was 83.4% and the OS rate was 89.5%.
- All but one of the patients had renal-sparing surgery in at least one kidney.
- Despite the good survival, 14% of the patients developed end-stage renal disease.
- In a retrospective review from St. Jude Children's Research Hospital, investigators described their experience with preoperative chemotherapy followed by renal-sparing procedures in children with bilateral FH Wilms tumor.
- In a series, nine out of ten patients with bilateral FH Wilms tumors underwent successful bilateral renal-sparing procedures after receiving preoperative chemotherapy.
- One patient in the series developed renal failure after bilateral renal-sparing surgery. Two patients with anaplastic histology died, although one patient died from complications of treatment rather than tumor. The OS for this group of patients was 83%.
- The authors concluded that bilateral renal-sparing surgery should be considered for all patients who have bilateral Wilms tumor, even if preoperative imaging studies suggest that the lesions are unresectable.
For patients who are treated with preoperative chemotherapy, the tumor pathology needs to be evaluated after 4 to 8 weeks. For patients not treated on a clinical trial, the ideal time to perform a biopsy or resection is unknown because minimal shrinkage may reflect chemotherapy-induced differentiation or anaplastic histology. A planned attempt at resection or biopsy of apparently unresectable tumor is undertaken no later than 12 weeks from diagnosis. Continuing therapy without evaluating tumor pathology in a patient with bilateral Wilms tumor may miss anaplastic histology or chemotherapy-induced differentiation (including rhabdomyomatous differentiation) and thus increase toxicity for the patient without providing additional benefit for tumor control. Anaplastic histology occurs in 10% of patients with bilateral Wilms tumor, and these tumors respond poorly to chemotherapy.
Once the diagnosis is confirmed, a complete resection is performed. Histologic confirmation of the diagnosis is not straightforward. In a series of 27 patients from NWTS-4, discordant pathology was seen in 20 cases, which highlights the need to obtain tissue from both kidneys. Seven children who were later diagnosed with diffuse anaplastic tumors had core biopsies performed to establish the diagnosis; however, anaplasia was not found. Anaplasia was identified in only three of the nine patients when an open-wedge biopsy was performed and in seven of nine patients who had a partial or complete nephrectomy.
The decision to administer chemotherapy and/or radiation therapy following biopsy or second-look operation is dependent on the tumor's response to initial therapy. More aggressive therapy is required for patients with inadequate response to initial therapy observed at the second procedure or in the setting of anaplasia.[117,162,166,167,168,169,170]
Renal transplantation for children with stage V Wilms tumor is usually delayed until 1 to 2 years have passed without evidence of malignancy. Similarly, renal transplantation for children with Denys-Drash syndrome and Wilms tumor, all of whom require bilateral nephrectomy, is generally delayed 1 to 2 years after completion of initial treatment.
Treatment options under clinical evaluation
Stage V and those predisposed to developing bilateral Wilms tumor
The following treatment option is currently under investigation in COG clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Patients with multicentric tumors, patients with high-risk bilateral tumors, and patients with diffuse hyperplastic nephrogenic rests are being treated on the following protocol:
COG-AREN0534 (Combination Chemotherapy and Surgery in Treating Young Patients With Wilms Tumor): Children with bilateral tumors are eligible for COG-AREN0534, which is the first protocol to prospectively study bilateral tumors. The goals of therapy are to eradicate all tumor and to preserve as much normal renal tissue as possible, with the hope of decreasing the risk of chronic renal failure among these children.[48,172] When children are identified with bilateral tumors by CT or MRI, central radiologic review will be performed to exclude tumor extension, invasion, rupture, metastases, or thrombus. Central review will also assess characteristics of nephrogenic rests versus tumor and differentiate active from sclerotic rests or tumors. Biopsy will not be mandated.
Upfront intensification with three drugs (vincristine, doxorubicin, and dactinomycin) will be used in large part to move patients to definitive surgery earlier. Repeat imaging will be mandated at 6 weeks. On the basis of patient response to treatment, surgery, definitive surgery, biopsy, or continued chemotherapy will be performed. If biopsy or surgery is performed, chemotherapy or radiation therapy will be given on the basis of histology. Patients undergoing biopsy or continued chemotherapy will have repeat imaging performed at 12 weeks, with definitive surgery performed if results of imaging studies are at all positive.
This approach will identify patients with anaplasia, rhabdomyomatous differentiation, complete necrosis, or stromal differentiation; select them for early surgery; and define the intensity of chemotherapy to be administered.[165,167,173] The decision to administer chemotherapy and/or radiation therapy following the second-look operation is dependent on the response to initial therapy, with more aggressive therapy required for patients with inadequate response to initial therapy observed at the second procedure.[117,166,167,168,169,170]
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I Wilms tumor, stage II Wilms tumor, stage III Wilms tumor, stage IV Wilms tumor and stage V Wilms tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Follow-up after treatment
For patients who have completed therapy for Wilms tumor and exhibit features consistent with genetic predisposition, such as bilateral Wilms tumor, screening involves renal ultrasound examination every 3 months for metachronous tumors during the risk period for that particular syndrome (5 years for WT1-related syndromes; 8 years for Beckwith-Wiedemann syndrome).
Late effects following Wilms tumor therapy
Children treated for Wilms tumor are at increased risk of developing the following:
- Second malignant neoplasms.[174,175]
- Congestive heart failure (influenced by dose of doxorubicin received, radiation to the heart, and female gender).[175,176]
- Complications of pregnancy.
The cumulative incidence of end-stage renal disease due to chronic renal failure at 20 years from diagnosis of Wilms tumor is low at 3.1% for patients with bilateral Wilms tumor and less than 1% for those with unilateral Wilms tumor. Efforts, therefore, have been aimed toward reducing the intensity of therapy when possible.
(Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)
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