Wilms Tumor Overview

Clinical Manifestations

Wilms tumor usually presents as an abdominal mass in an otherwise well-appearing child. Abdominal pain, fever, anemia, hematuria, and hypertension are seen in 25-30% of affected children [Green 1985].

Approximately 5-10% of individuals with Wilms tumor have bilateral or multicentric tumors. Although the prevalence of bilateral involvement is higher in individuals with genetic predisposition syndromes as compared to individuals without predisposition syndromes, 85% of individuals with WAGR (see Aniridia) or BWS have unilateral tumors [Huff 1998, Porteus et al 2000].

The average age at presentation is 42-47 months for children with unilateral Wilms tumor and 30-33 months for those with bilateral Wilms tumor [Breslow et al 1993]. Wilms tumor occasionally occurs in adults. Several studies have shown that adults with Wilms tumor have worse outcomes compared to children, but under treatment is a likely contributory factor [Terenziani et al 2004]. When treated with regimens similar to those used for children, most adults with Wilms tumor can be cured [Kalapurakal et al 2004, Reinhard et al 2004].

Girls have a slightly increased risk of Wilms tumor, with a male-to-female ratio of 0.92 to 1.00.

Establishing the Diagnosis

Imaging. The workup of a child with suspected Wilms tumor begins with appropriate diagnostic imaging studies to define the extent of disease and to help plan the surgical intervention.

• Ultrasonography is the recommended first-line test for children suspected of having Wilms tumor because it provides a panoramic view of the abdomen, including the patency of the inferior vena cava.

• Computed tomography (CT) can also visualize the pelvic and abdominal structures, as well as lymph nodes.

• Magnetic resonance imaging (MRI) is not a routine component of the evaluation of Wilms tumor, although MRI may facilitate the distinction between Wilms tumor and nephrogenic rests.

Surgical resection or biopsy. Although imaging studies may suggest a diagnosis of Wilms tumor, the definitive diagnosis can be made only upon histologic assessment of the tumor.

• The COG recommends performing nephrectomy/tumor resection and regional lymph node sampling before chemotherapy to obtain the most accurate staging information. If the tumor is deemed unresectable, a biopsy is recommended to confirm the diagnosis [Green 2004, Metzger & Dome 2005].

• The International Society of Pediatric Oncology (SIOP) recommends administering pre-operative chemotherapy to all individuals (with or without a biopsy, depending on the individual's age) to shrink the tumor with the aim of facilitating surgery [de Kraker & Jones 2005].

Differential Diagnosis

The differential diagnosis of Wilms tumor includes other primary renal malignancies of childhood such as clear cell sarcoma and malignant rhabdoid tumor. These two tumors, once considered variants of Wilms tumor, are now recognized to be distinct entities. Other renal neoplasms that occur in children include congenital mesoblastic nephroma, renal sarcoma, and renal cell carcinoma.

Benign renal processes that may be confused with Wilms tumor include nephrogenic rests, autosomal recessive polycystic kidney disease (ARPKD) and occasionally autosomal dominant polycystic kidney disease (ADPKD), hydronephrosis, renal carbuncles, and hemorrhage.

Neuroblastoma, an embryonal malignancy of the adrenal gland, may be confused with Wilms tumor because these two tumors affect the same age group and commonly arise in the same general region of the abdomen.

Prevalence

Wilms tumor affects approximately one of every 8,000-10,000 children in North America [Breslow et al 1993]. It is the most common pediatric kidney cancer and comprises 6.3% of malignancies in children younger than 15 years of age [Miller et al 1995].

Heritable Causes

In individuals with Wilms tumor, 10-15% are considered to have a heritable cause. These may or may not be associated with known syndromes. A heritable cause of Wilms tumor may be suggested by clinical features of genetic predisposition syndromes such as hypospadias or undescended testes (6%); hemihypertrophy and other features of Beckwith-Wiedemann syndrome (BWS) (4%); or aniridia (1%) [Breslow et al 1993]. In the absence of syndromic features, a heritable cause may also be implied by the existence of other family members with a history of Wilms tumor.

Syndromic Causes

WT1-related. To date, only one Wilms tumor gene, WT1, has been identified (Table 2). WT1 encodes a zinc finger transcription factor that is critical to normal development of the kidneys and gonads [Pelletier et al 1991, Kreidberg et al 1993]. Numerous studies have identified putative transcriptional targets of the WT1 protein, many of which are involved in cell growth, differentiation, and apoptosis. The biologically relevant precise targets that are involved in Wilms tumorigenesis remain to be determined.

Table 2. Molecular Genetics of Syndromic Wilms Tumor

Gene Symbol	Locus	Protein	Test Availability
WT1	11p13	Wilms tumor protein	Clinical

The following are syndromes in which germline WT1 mutations occur:

• WAGR syndrome (Wilms tumor, aniridia, genital anomalies, retardation) is caused by deletions of chromosome 11p13 that include both PAX6 and WT1. Aniridia arises from deletion of the PAX6 gene, which lies adjacent to the WT1 gene. The risk of Wilms tumor in simplex cases (i.e., a single occurrence of aniridia ina family) (so-called "sporadic" aniridia) is 40-50% if the individual has a 11p13 deletion that encompasses WT1. If a WT1 deletion is not detected by FISH in a simplex case of aniridia, the risk of Wilms tumor is low [Gronskov et al 2001, Muto et al 2002].

  
  As shown in Table 3, affected individuals have an earlier age of Wilms tumor diagnosis and more frequent occurrence of bilateral disease than individuals without WAGR. Interestingly they also have a high incidence of intralobar nephrogenic rests and their tumors invariably exhibit a favorable histology. Individuals with WAGR generally respond well to treatment for WT [Breslow et al 2003] and have short-term survival comparable to non-WAGR persons. However, individuals with WAGR often develop end-stage renal disease (ESRD) around adolescence, resulting in declining survival. In studies employing the NWTS patient population, 34-40% of individuals with WAGR who survived WT subsequently developed ESRD, and a 48% (±17%) survival rate at 27 years from diagnosis of WT was estimated for this group [Breslow et al 2000, Breslow et al 2003, Breslow et al 2005].

• Denys-Drash syndrome (DDS) (undermasculinized external genitalia in an individual with a 46,XX karyotype that can range from ambiguous to normal-appearing female, diffuse mesangial sclerosis leading to early-onset renal failure, and Wilms tumor) is caused by WT1 mutations. The risk for Wilms tumor in individuals with DDS is estimated to be greater than 90%. As shown in Table 4, the genotype/phenotype relationship is strong such that most individuals with DDS have germline missense mutations in exons 8 and 9 [Huff 1996, Royer-Pokora et al 2004]. The observation of other types of WT1 mutations in a small number of affected individuals is likely due, at least in part, to the diagnosis of "DDS" in the absence of renal failure [Royer-Pokora et al 2004] along with variable expressivity of these missense mutations. In contrast to the renal failure associated with WAGR syndrome, the renal failure associated with DDS tends to be early-onset. The NWTSG recently reported that the cumulative incidence of renal failure in those with DDS 20 years after Wilms tumor diagnosis was 74% [Breslow et al 2005]. However, not all individuals in this series had WT1 molecular genetic testing, so it is possible that some designated as having DDS did not have the typical exon 8 and 9 mutations.

• Frasier syndrome (undermasculinized external genitalia in an individual with a 46,XY karyotype that can range from ambiguous to normal-appearing female, focal segmental glomerulosclerosis, gonadoblastoma) is caused by point mutations in the WT1 intron 9 donor splice site [Barbaux et al 1997]. Although Frasier syndrome is not typically associated with Wilms tumor, several cases have been reported.

• Genitourinary (GU) anomalies without renal failure. Some individuals with germline WT1 point mutations have GU anomalies and Wilms tumor, but do not have early renal failure. As shown in Table 4, these findings are predominantly associated with WT1 gene deletions and nonsense and frameshift mutations.

Table 3. Findings in WAGR and Non-WAGR Wilms Tumor

	WAGR	Non-WAGR 1
Mutation type	Contiguous gene deletion	Mutation status not determined
Population frequency	0.75%	99.25%
Birth weight	2.94 kg	3.45 kg
Median age at diagnosis	22 months	39 months
Bilateral	17%	6%
Metastatic disease	2%	13%
Favorable histology	100%	92%
ILNR	77%	22%
4-yr survival	95±3%	92±0.3%
27-yr survival	48±17% 2	486±1%
Observed ESRD 2
Unilateral WT	11/37 (29.7%)	44/5489 (0.8%)
Bilateral WT	5/10 (50%)	55/440 (12.5%)

Breslow et al 2003
WAGR = Wilms tumor, aniridia, genital anomalies, retardation
WT = Wilms tumor
ILNR = Intralobar nephrogenic rests
ESRD = End-stage renal disease
1. Includes individuals with DDS
2. Mean follow-up 12.6 years following WT diagnosis

Table 4. Genotype/Phenotype Correlations

	Gene Deletion 1 (n=21)	Missense: Exon 8 or 9 (n=25)	Missense: Other Exons (n=5)	Truncation, Frameshift, Nonsense (n=63)
Clinical Phenotype
WAGR	9 (43%)
WT/AN/GU	5 (24%)
WT/AN 2	5 (24%)
WT/GU	1 (5%)			32 (51%)
DDS diagnosis	1 (5%)	23 (92%)		5 (8%) 3
WT, early-onset renal disease		1 (4%)
WT only		1 (4%)	5 (100%)	26 (41%)
Laterality
Bilateral	5 (24%)	4 (16%)	1	33 (52%)
Unilateral	16 (76%)	21 (84%)	4	30 (48%)
Age at Diagnosis
Average	31.4 mo	17.0 mo	27.6 mo	14.8 mo
Range	12-87 mo	4-36 mo	8-55 mo	3-41 mo

Data taken with slight modification from Royer-Pokora et al 2004
WAGR = Wilms tumor, aniridia, genital anomalies, retardation
WT = Wilms tumor
AN = Aniridia
GU = Genitourinary abnormalities
DDS = Denys-Drash syndrome
1. Most are large contiguous gene deletions at 11p13.
2. Includes three females in whom GU phenotype is less penetrant
3. Includes cases reported as DDS, but ESRD (end-stage renal disease) may not have been noted

11p15 locus-related. The 11p15 locus is often referred to as "WT2," although a distinct Wilms tumor gene has not been isolated. The existence of a gene(s) at 11p15 that plays a role in Wilms tumorigenesis is inferred from two lines of evidence:

• Wilms tumor is observed in a small (<5%) but significant percentage of children with the Beckwith-Wiedemann syndrome, which has been mapped to chromosome 11p15.5, a region containing several imprinted genes [Koufos et al 1989, Ping et al 1989, DeBaun et al 1998].

• Loss of heterozygosity (LOH) or loss of imprinting (LOI) at 11p15 is observed in approximately 40% of Wilms tumors [Koufos et al 1985, Ogawa et al 1993, Moulton et al 1996]. Candidate genes in this region include IGF2 and H19 (telomeric) and CDKN1C/p57^kip2 and KCNQ1OT1/LIT1 (centromeric). Research on genotype-phenotype relationships is ongoing, but accumulating evidence indicates that uniparental isodisomy of 11p15 and hypermethylation of H19 are associated with development of Wilms tumor, whereas alterations of KCNQ1OT1 are associated with other tumors, macrosomia, and abdominal wall defects [Engel et al 2000, Tycko 2000, Bliek et al 2001, Weksberg et al 2001, DeBaun et al 2002]. Inherited microdeletions within the H19/IGF2 imprinting control region have been identified in two children with BWS and one family with BWS/WT, further strengthening the association between aberrant expression of IGF2 with WT development [Sparago et al 2004, Prawitt et al 2005].

Other disorders associated with Wilms tumor include:

• Autosomal dominant disorders: Li-Fraumeni syndrome, Sotos syndrome, hyperparathyroid-jaw tumor syndrome, and neurofibromatosis type 1

• Autosomal recessive disorders: Fanconi anemia syndrome (specifically the D1 subtype that is associated with biallelic BRCA2 mutations), mosaic variegated aneuploidy, and Bloom's syndrome

• X-linked disorder: Simpson-Golabi-Behmel syndrome

• Perlman syndrome

• Trisomy 18

Non-Heritable Causes

Some somatic mutations that have been detected in Wilms tumor samples presumably contribute to the pathogenesis of the tumor. The following genes/loci have been implicated in either the initiation or progression of Wilms tumor:

• CTNNB1 (β-catenin) gene. Mutations in the CTNNB1 gene have been identified in approximately 15% of Wilms tumors, but, as in other tumor types, mutations of this gene are tumor specific. CTNNB1 mutations are almost invariantly coincident with WT1 mutations [Koesters et al 1999, Maiti et al 2000, Li et al 2004].

• Chromosome 7p. Cytogenetic studies have detected both germline and acquired rearrangements of chromosome 7 in a subset of individuals with Wilms tumor. LOH studies have identified at least three regions at the 7p locus that may contain Wilms tumor-related genes [Grundy et al 1998, Powlesland et al 2000, Perotti et al 2001]. A candidate tumor suppressor gene at 7p14 called POU6F2 has been identified; further work is underway to determine whether this candidate plays a role in Wilms tumor development [Perotti et al 2004].

• Regions of LOH. LOH and cytogenetic analyses of tumors have also implicated other genes at other loci, most notably at 16q and 1p [Maw et al 1992]; the genes have yet to be identified. A recent study from the NWTSG demonstrated that LOH at 1p and 16q is associated with adverse prognosis in individuals with favorable histology Wilms tumor [Grundy et al 2005]. Linkage studies of families with Wilms tumor have not provided any evidence for Wilms tumor predisposition genes in these regions [McDonald et al 1998].

Mode of Inheritance

Wilms tumor may occur as a part of a syndrome (syndromic Wilms tumor) or as an isolated finding (i.e., not in association with any other medical findings) (nonsyndromic Wilms tumor).

Syndromic Wilms tumor. If a proband is found to have syndromic Wilms tumor (e.g., WAGR, a WT1-related syndrome, Beckwith-Wiedemann syndrome), genetic counseling for the specific syndrome is appropriate.

Nonsyndromic Wilms tumor. This most frequently occurs in a single individual of a family; however, nonsyndromic Wilms tumor may occur in more than one family member (familial Wilms tumor) and may be inherited in an autosomal dominant manner with reduced penetrance. In both of these situations, Wilms tumor predisposition is usually not due to a germline WT1 mutation.

Individuals with a known WT1 germline mutation

• WT1 germline mutations are inherited in an autosomal dominant manner with variable expressivity and reduced penetrance.

• The majority of individuals with a WT1 germline mutation have a de novo mutation; their parents are unlikely to have had Wilms tumor or to have the WT1 mutation.

• When the WT1 disease-causing mutation identified in the proband cannot be detected in the DNA of either parent, the risk to the sibs of a proband is likely to be low; however, the rate of parental germline mosaicism is unknown [Huff 1994 & unpublished data].

• Offspring of an individual with a known WT1 mutation have a 50% risk of inheriting the mutation. The risk of Wilms tumor developing in a child with a known WT1 alteration depends on the penetrance of the specific mutation.

Familial Wilms tumor

• Most individuals diagnosed with nonsyndromic Wilms tumor do not have an affected parent; some may have another affected family member (familial Wilms tumor).

• Familial Wilms tumor may be caused by a WT1 germline mutation that is inherited in an autosomal dominant manner with variable expressivity and reduced penetrance [Zirn et al 2005]; however, in most families, Wilms tumor predisposition is not caused by a WT1 mutation [Huff 1998].

• Empiric risks to the sibs of a proband who does not have an identified WT1 mutation to develop Wilms tumor are unknown.

Nonsyndromic Wilms tumor in a single individual in a family

• The vast majority of individuals with Wilms tumor have no family history of Wilms tumor nor do they have associated congenital anomalies.

• Empiric risks to the sibs of a proband who is the only affected family member are unknown but likely low.

• Empiric risks to the offspring of a proband who is the only affected family member are not increased.

  • No Wilms tumor was observed in the 179 offspring of 96 long-term survivors who had been diagnosed with unilateral, non-familial Wilms tumor [Li et al 1988].

  • In the absence of an identified WT1 mutation in the proband, molecular genetic testing or ultrasound screening of the offspring of such individuals is not warranted.

Related Genetic Counseling Issues

Genetic cancer risk assessment and counseling. For comprehensive descriptions of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see:

• Genetic Cancer Risk Assessment and Counseling: Recommendations of the National Society of Genetic Counselors

• Elements of Cancer Genetics Risk Assessment and Counseling (part of PDQ^®, National Cancer Institute)

DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal diagnosis for pregnancies at 50% risk for inheriting a WT1 mutation from a parent is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. The WT1 mutation in the parent must be identified before prenatal testing can be performed. The risk of Wilms tumor developing in a child with a known WT1 alteration depends on the penetrance of the specific mutation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Evaluations at Initial Diagnosis to Establish the Extent of Disease

Because Wilms tumor can spread to the lungs, pre-operative chest radiography is imperative. Although plain films of the chest have been recommended on past National Wilms Tumor Studies, many physicians in North America favor chest CT scans because they provide increased sensitivity. However, the prognostic significance of small pulmonary nodules detected by CT scan and not chest x-ray is unclear and is a subject of active investigation [Green et al 1991, Meisel et al 1999].

Treatment of Manifestations

The management of Wilms tumor involves multi-modal therapy including surgery, chemotherapy, and, for selected individuals, radiation therapy [Metzger & Dome 2005, Wu et al 2005].

Surgery is a cornerstone of Wilms tumor treatment, though there is disagreement about the optimal timing of tumor resection summarized below. Either approach yields excellent results.

• The NWTSG in North America advocates performing surgery at the time of diagnosis to achieve the most accurate staging information.

• The International Society of Pediatric Oncology (SIOP) in Europe administers 4-8 weeks of pre-operative chemotherapy to shrink the tumor and facilitate surgical resection.

• Nephron-sparing surgery is advocated for individuals with bilateral Wilms tumor but not routinely recommended for those with unilateral Wilms tumor. In persons with unilateral Wilms tumor, the risk of renal failure is less than 1% after nephrectomy, so nephron-sparing surgery should be considered only if the tumor is very small and can be resected with clean margins [Ritchey 2005].

Chemotherapy. Serial studies starting in the 1960s by the NWTSG, SIOP, and other groups have led to the development of the modern Wilms tumor chemotherapy regimens.

• In North America, individuals with stage I and II favorable histology Wilms tumor are treated with vincristine and dactinomycin.

• Individuals with stage III or IV favorable histology disease are treated with vincristine, dactinomycin, and doxorubicin.

Note: All chemotherapy for favorable histology Wilms tumors may be given on an outpatient basis.

Treatment of anaplastic Wilms tumor requires more intensive therapy. Although the optimal regimen has not been established, treatment for anaplastic Wilms tumor typically includes the agents vincristine, doxorubicin, cyclophosphamide or ifosfamide, etoposide, and carboplatin.

Radiation therapy. After surgery, radiation therapy is administered to individuals with advanced disease (stage III or IV).

Survival. The treatment results from the most recently reported National Wilms Tumor Studies (NWTS) are summarized in Table 5. Children with BWS and Wilms tumor have an excellent prognosis with modern treatment regimens [Porteus et al 2000]. Individuals with WAGR syndrome are usually cured of Wilms tumor, but have decreased long-term survival rates due to the risk of end-stage renal disease (Table 3) [Breslow et al 2003].

Bilateral Wilms tumor. The aim of therapy is to eradicate the tumors while preserving as much kidney tissue as possible. The modern approach is to perform pre-operative chemotherapy to shrink the tumors followed by nephron-sparing surgery [Horwitz et al 1996].

Relapsed Wilms tumor. Only 10-15% of individuals with Wilms tumor experience recurrence, the majority of which occur within two years of diagnosis. Although the survival after Wilms tumor recurrence historically has been only 20-30% [Wilimas et al 1985, Grundy et al 1989], modern intensive treatment regimens, with or without autologous transplantation, have improved survival to the 50-60% range [Garaventa et al 1994, Pein et al 1998, Dome et al 2002, Kremens et al 2002, Campbell et al 2004].

Renal transplantation. Individuals with bilateral Wilms tumor or Denys-Drash Syndrome are at risk for renal failure. Individuals with renal failure are treated initially with dialysis and are candidates for renal transplantation. Most oncologists and transplant surgeons recommend performing the renal transplant one to two years following the end of chemotherapy treatment, which is the time period during which most Wilms tumor relapses occur. A recent study from the North American Pediatric Renal Transplant Cooperative Study demonstrated that the outcomes of renal transplantation in individuals with Wilms tumor or DDS are comparable to outcomes in children with other renal disorders [Kist-van Holthe et al 2005].

Surveillance

For relapse of Wilms tumor. See Table 6.

• Individuals with Beckwith-Wiedemann syndrome or isolated hemihypertrophy. Individuals with BWS or isolated hemihypertrophy have a 5% to 7.5% risk of developing Wilms tumor or other malignancies (mainly hepatoblastoma, adrenocortical carcinoma, neuroblastoma, and rhabodmyosarcoma). It is generally accepted that screening every three months with abdominal ultrasound examination is warranted until the child is eight years old. Among individuals with BWS and Wilms tumor, 81% develop the tumor by age five years and 93% develop the tumor by age eight years [Beckwith 1998a].

• Individuals with WAGR. Because the risk of Wilms tumor is high, regular screening by abdominal ultrasound examination is recommended until age five to seven years. Among individuals with Wilms tumor and WAGR syndrome, 90% develop a tumor by age four years and 98% by age seven years [Beckwith 1998b]. Because Wilms tumors can double in size every week [Beckwith 1998a], evaluation every three months is optimal.

• Familial Wilms tumor. Screening siblings of the affected individual with renal ultrasound examination until the age of five to seven years is recommended.

• Bilateral Wilms tumor. After completion of therapy for Wilms tumor, individuals with bilateral or multifocal Wilms tumors should be screened by renal ultrasound examination every three months for metachronous tumors until they are seven years old. It is assumed that most individuals with bilateral Wilms tumor have a germline mutation in a gene predisposing to Wilms tumor. Although the risk of Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown, the authors recommend screening such children with serial ultrasound examinations until the age of five to seven years.

For end-stage renal disease (ESRD). Individuals with DDS, WAGR syndrome, and GU anomalies are at increased risk for ESRD [Breslow et al 2005]. Guidelines for surveillance of ESRD have not been published, but it is prudent to perform urinalysis, blood pressure measurement, and serum chemistries (including BUN and creatinine) at least annually in such individuals. If abnormalities or changes are detected, further testing of renal function should be pursued.

Testing of Relatives at Risk

Although the risk of Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown, the authors recommend screening such children with serial ultrasound examinations until the age of five to seven years.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Readings

Revision History

• 10 April 2006 (me) Comprehensive update posted to live Web site

• 24 May 2004 (cd) Revision: Genetic Counseling

• 19 December 2003 (me) Overview posted to live Web site

• 14 July 2003 (jsd) Original submission