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Wilms Tumor Overview

, MD, PhD and , PhD.

Author Information
, MD, PhD
Children’s National Medical Center
Washington, DC
, PhD
Department of Genetics
University of Texas MD Anderson Cancer Center
Houston, Texas

Initial Posting: ; Last Update: September 19, 2013.

Summary

Disease characteristics. Wilms tumor (nephroblastoma), an embryonal malignancy of the kidney, is the most common renal tumor of childhood. Wilms tumor usually presents as an abdominal mass in an otherwise apparently healthy child. Wilms tumor has the potential for both local and distant spread. Approximately 5%-10% of children with Wilms tumor have bilateral or multicentric tumors. 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.

Current models of Wilms tumor development propose that a genetic mutation predisposes to nephrogenic rests (benign foci of embryonal kidney cells that persist abnormally into postnatal life). Nephrogenic rests are characterized as intralobar or perilobar. In general, intralobar rests (usually single lesions within the renal lobe, renal sinus, or calyceal walls) are associated with the WAGR (Wilms tumor-aniridia-genital anomalies-retardation) syndrome and Denys-Drash syndrome (DDS). In general, perilobar rests (usually multiple lesions in the periphery of the renal lobe) are associated with Beckwith-Wiedemann syndrome (BWS) and hemi-hyperplasia. However, the association between type of nephrogenic rest and predisposition syndrome is not absolute.

Diagnosis/testing. The evaluation of a child with suspected Wilms tumor begins with appropriate diagnostic imaging studies. Ultrasonography is the recommended first-line test because it provides a panoramic view of the abdomen. Computed tomography (CT) can also visualize pelvic and abdominal structures as well as lymph nodes. Magnetic resonance imaging (MRI) may facilitate the distinction between Wilms tumor and nephrogenic rests. The definitive diagnosis of Wilms tumor can be made only by surgical resection or biopsy.

Causes. A germline mutation is thought to be the cause of about 10%-15% of Wilms tumor. WT1 germline mutations give rise to WAGR syndrome, DDS, Frasier syndrome, and isolated Wilms tumor (i.e., Wilms tumor with no evidence of an underlying syndrome). Epigenetic and genomic alterations of chromosome 11p15 give rise to BWS. Approximately 1%-2% of individuals with Wilms tumor have at least one relative also diagnosed with Wilms tumor; however, the underlying genetic mechanisms are usually not known. Linkage analysis has mapped Wilms tumor predisposition genes to 17q (locus name FWT1) and 19q (locus name FWT2). Because in some families the Wilms tumor phenotype does not show linkage to WT1, FWT1, or FWT2, the existence of one or more other genes in which mutation causes familial Wilms tumor is likely.

Genetic counseling. If a proband has syndromic Wilms tumor, genetic counseling for the specific syndrome is appropriate. Nonsyndromic Wilms tumor most frequently occurs as a simplex case (i.e., a single occurrence in a family). Empiric risks to the sibs of a proband who represents a simplex case are unknown but likely low; empiric risks to the offspring of a proband who represents a simplex case are not increased. Prenatal diagnosis for pregnancies at 50% risk of inheriting a WT1 or 11p15 genomic alteration from a parent is possible when the pathogenic variant and/or genetic mechanism in the family is known.

Management. Treatment of manifestations: Includes surgery, chemotherapy, and for some individuals, radiation therapy. Surgery, a cornerstone of treatment, is performed at the time of diagnosis or after 4-8 weeks of preoperative chemotherapy. Because Wilms tumor can spread to the lungs, preoperative chest radiography or chest CT scans are imperative. Nephron-sparing surgery is routinely advocated for those with bilateral Wilms tumor. Chemotherapy includes: vincristine and dactinomycin for stage I and II favorable histology Wilms tumor; and vincristine, dactinomycin, and doxorubicin for stage III or IV favorable histology disease. Treatment for anaplastic Wilms tumor includes vincristine, doxorubicin, cyclophosphamide or ifosfamide, etoposide, and carboplatin. After surgery children with advanced disease (stage III or IV) undergo radiation therapy. End-stage renal disease (ESRD), which occurs in fewer than 1% of individuals with unilateral Wilms tumor, is treated initially with dialysis, followed by renal transplantation when possible.

Surveillance:

  • For children with BWS or isolated hemihyperplasia: abdominal ultrasound examination every three months until age eight years.
  • For children with WAGR and WT1-related syndromes: abdominal ultrasound examination every three months until age five years.
  • For sibs of an individual with familial Wilms tumor and offspring of survivors of bilateral Wilms tumor: abdominal ultrasound examination every three months until age eight years.
  • For those who have completed therapy for Wilms tumor and have features consistent with genetic predisposition, such as bilateral Wilms tumor: renal ultrasound examination every three months for metachronous tumors during the risk period for that particular syndrome (5 years for WT1-related syndromes; 8 years for BWS).
  • For ESRD: in individuals with WAGR syndrome, DDS, and genitourinary (GU) anomalies: at least annual urinalysis, blood pressure measurement, and serum chemistries (including BUN and creatinine).

Definition of Wilms Tumor

The classic Wilms tumor (nephroblastoma) is an embryonal malignancy of the kidney that consists of blastemal, epithelial, and stromal cells; however, not all Wilms tumors have all three cell types.

Tumor stage and histology are the most important prognostic factors used to direct therapy. Molecular classification, patient age, and tumor size are used for certain populations of affected individuals [Green et al 1994, Pritchard et al 1995, Hill et al 2003, Grundy et al 2005].

  • Approximately 8% of Wilms tumors contain anaplasia, a term that refers to nuclear enlargement and atypia with irregular mitotic figures [Beckwith & Palmer 1978, Dome et al 2006]. Several large studies have demonstrated that the presence of anaplasia is associated with adverse outcome.
  • Wilms tumors without anaplasia are designated as tumors of "favorable histology."
  • Some Wilms tumors display a high degree of maturation into mature skeletal muscle elements, a variant sometimes called "fetal rhabdomyomatous nephroblastoma (FRN)." Such Wilms tumors typically do not respond to chemotherapy by shrinking; instead, they differentiate and occasionally grow [Anderson et al 2003]. The lack of tumor shrinkage does not necessarily portend an adverse prognosis because FRN has low metastatic potential. The incidence of FRN is higher in bilateral tumors than in unilateral tumors. FRN has been associated with mutation of WT1 [Schumacher et al 1997, Miyagawa et al 1998].
  • Loss of heterozygosity for 1p and 16q markers (observed in ~5% of tumors) or gain of chromosome 1q (observed in ~30% of tumors) are associated with relapse [Grundy et al 2005, Gratias et al 2013].

Current models of Wilms tumor development propose that a genetic mutation predisposes to nephrogenic rests, benign foci of embryonal kidney cells that persist abnormally into postnatal life. Nephrogenic rests are found in approximately 1% of newborn kidneys and usually regress or differentiate by early childhood [Beckwith et al 1990]. Some nephrogenic rests persist into childhood. These rests are considered to be Wilms tumor precursors [Gylys-Morin et al 1993]; nephrogenic rests that sustain additional mutations transform into a Wilms tumor [Dome & Coppes 2002].

Nephrogenic rests are characterized as intralobar or perilobar:

  • Intralobar rests are usually solitary and randomly distributed throughout the kidney, although they tend to be situated centrally within the renal lobe. Intralobar rests are associated with two syndromes related to mutation of WT1: WAGR (Wilms tumor-aniridia-genital anomalies-retardation) syndrome (see Aniridia) and Denys-Drash syndrome (DDS) [Breslow et al 2006].
  • Perilobar rests tend to be located at the periphery of the kidney and are often multiple. Perilobar rests are associated with Beckwith-Wiedemann syndrome (BWS) and hemihyperplasia [Breslow et al 2006].

The association between type of nephrogenic rest and predisposition syndrome is not absolute (Table 1).

The term nephroblastomatosis is used to describe the presence of multiple nephrogenic rests. Nephroblastomatosis may be manifest as a diffuse overgrowth of rests (producing a rim that enlarges the kidney) or as multiple distinct rests [Perlman et al 2006]. It is sometimes challenging to distinguish nephrogenic rests from Wilms tumors, even with biopsies. Although nephrogenic rests are considered benign, chemotherapy has been advocated if the rests are growing or if a child becomes symptomatic. Some evidence indicates that chemotherapy may decrease the risk for subsequent Wilms tumor development in children with nephrogenic rests [Coppes et al 1999].

Table 1. Association of Nephrogenic Rests with Wilms Tumor Predisposition Syndromes and Congenital Anomalies

Clinical Phenotype+ ILNR
− PLNR
− ILNR
+ PLNR
+ ILNR
+ PLNR
− ILNR
− PLNR
Denys-Drash59%0%4%37%
WAGR73%4%4%18%
Beckwith-Wiedemann syndrome18%35%27%20%
Male GU anomalies43%9%5%44%

Breslow et al [2006]

ILNR = intralobar nephrogenic rests

PLNR = perilobar nephrogenic rests

WAGR = Wilms tumor-aniridia-genital anomalies-retardation

GU = genitourinary

The National Wilms Tumor Study Group (NWTSG) designated five tumor stages; higher stages are associated with greater recurrence risk. These staging criteria were recently modified by the Children's Oncology Group (COG), which now conducts Wilms tumor clinical trials in North America [Metzger & Dome 2005] (Table 2).

Table 2. Children's Oncology Group Clinicopathologic Staging of Wilms Tumor

StageDescription
ITumor limited to kidney and completely excised
No penetration of the renal capsule or involvement of renal sinus vessels
IITumor extending beyond the kidney but completely excised
No residual tumor apparent at or beyond the margins of excision
Tumor thrombus in vessels outside the kidney is stage II if the thrombus is removed en bloc with the tumor. 1
IIIGross or microscopic residual tumor remaining postoperatively, including:
• Inoperable tumor
• Positive surgical margins
• Diffuse tumor spillage or biopsy
• Regional lymph node metastases, or
• Transected tumor thrombus
IVHematogenous metastases (lung, liver, bone, brain) or lymph node metastases outside the abdominal or pelvic cavities
VBilateral renal tumors at diagnosis

1. Note: Tumor biopsy or local spillage confined to the flank was considered stage II by the NWTSG in the past; such events are considered stage III on current COG studies.

Clinical Manifestations of Wilms Tumor

Wilms tumor usually presents as an abdominal mass in an otherwise apparently healthy 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. 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 (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 than do 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].

Wilms tumor has the potential for both local and distant spread. Local spread typically occurs into the renal hilar structures and may penetrate the renal capsule. The tumors have a propensity to invade the renal vein and to form thrombi in the inferior vena cava, sometimes progressing into the heart. Local and distant lymph node involvement can also occur. The most common sites of distant metastases are the lungs and liver, with rare instances of spread to bone and brain.

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

Establishing the Diagnosis of Wilms Tumor

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. Ultrasonography carries no risk for radiation exposure.
  • Computed tomography (CT) produces a higher-resolution image of the pelvic and abdominal structures as well as lymph nodes than does ultrasonography.
  • Magnetic resonance imaging (MRI) is not a routine component of the evaluation of Wilms tumor, although MRI is being used with increasing frequency because unlike CT scans, it does not involve radiation exposure. MRI may facilitate the distinction between Wilms tumor and nephrogenic rests.
  • Positron emission tomography (PET) is not a routine component of the initial evaluation of Wilms tumor, though most Wilms tumors take up the radiotracer fluoro-deoxyglucose. PET may play a role in the detection of occult metastatic sites at recurrence [Moinul Hossain et al 2010].

Surgical resection or biopsy. Although imaging studies may suggest a diagnosis of Wilms tumor, the definitive diagnosis can be made only on 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 preoperative 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 of Wilms Tumor

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. (See ALK-Related Neuroblastoma Susceptibility.)

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Prevalence of Wilms Tumor

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 age 15 years [Miller et al 1995].

Causes

In 10%-15% of individuals with Wilms tumor, the cause is considered to be heritable. It may or may not be associated with a known syndrome.

Syndromic Causes

WT1-related. Germline WT1 mutations predispose to Wilms tumor (Table 3). 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 targets that are involved in Wilms tumorigenesis largely remain to be determined.

Table 3. Molecular Genetics of Syndromic Wilms Tumor

Gene SymbolLocusProtein
WT1 11p13Wilms tumor protein

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 PAX6, which lies within approximately 0.6 Mb of WT1. The risk for Wilms tumor in simplex cases (i.e., a single occurrence of aniridia in a family) (so-called "sporadic" aniridia) is 40%-50% if the individual has an 11p13 deletion that encompasses WT1. If a WT1 deletion is not detected by FISH in a simplex case of aniridia, the risk for Wilms tumor is low [Gronskov et al 2001, Muto et al 2002].

As shown in Table 4, individuals with WAGR 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 Wilms tumor [Breslow et al 2003] and have short-term survival comparable to persons who do not have WAGR. 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. 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].

Table 4. Findings in WAGR and Non-WAGR Wilms Tumor

WAGRNon-WAGR 1
Mutation type Contiguous gene deletionMutation status not determined
Population frequency 0.75%99.25%
Birth weight 2.94 kg3.45 kg
Median age at diagnosis 22 months39 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 86% ± 1%
Observed ESRD 2Unilateral WT11/37 (29.7%)44/5489 (0.8%)
Bilateral WT5/10 (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

Denys-Drash syndrome (DDS) (undermasculinized external genitalia in an individual with a 46,XY 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 mutation of WT1. The risk for Wilms tumor in individuals with DDS is estimated at greater than 90%. As shown in Table 5, the genotype/phenotype correlation is very strong: most individuals with DDS have a germline missense mutation in exon 8 or 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 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; thus 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, and gonadoblastoma) is caused by point mutations in the WT1 intron 9 donor splice site [Barbaux et al 1997]. Although Frasier syndrome (FS) is not typically associated with Wilms tumor, several cases have been reported. This, in addition to case reports of gonadoblastoma in persons with DDS, has led to the suggestion that DDS and FS represent two ends of a phenotypic spectrum [Koziell et al 2000].

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 5, these findings are predominantly associated with WT1 deletions and nonsense and frameshift mutations.

Table 5. Genotype/Phenotype Correlations

WT1 Deletion 1 (n=21)Missense: Exon 8 or 9 (n=25)Missense: Other Exons (n=5)Truncation, Frameshift, Nonsense (n=63)
Clinical Phenotype
WAGR9 (43%)
WT/AN/GU5 (24%)
WT/AN 2 5 (24%)
WT/GU1 (5%)32 (51%)
DDS diagnosis1 (5%)23 (92%)5 (8%) 3
WT, early-onset renal disease1 (4%)
WT only1 (4%)5 (100%)26 (41%)
Laterality
Bilateral5 (24%)4 (16%)133 (52%)
Unilateral16 (76%)21 (84%)430 (48%)
Age at Diagnosis
Average31.4 mo17.0 mo27.6 mo14.8 mo
Range12-87 mo4-36 mo8-55 mo3-41 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. Several observations suggest that a gene or genes at 11p15 play a role in Wilms tumorigenesis:

Other disorders associated with Wilms tumor include:

Nonsyndromic Causes

Familial Wilms tumor. Of individuals with Wilms tumor, 1%-2% have at least one relative also diagnosed with Wilms tumor. Most often the affected relative(s) is a sib, parent, aunt/uncle, or close cousin [Breslow et al 1996]. Because of the very low incidence of Wilms tumor in the population and the lack of a strong environmental risk factor, the occurrence of more than one individual with Wilms tumor in a family is thought to be the result of a germline genetic alteration that predisposes to Wilms tumor development. Analyses of large families with many affected individuals have indicated that such predisposition is due to an autosomal dominant mutation with incomplete penetrance, although multigene models cannot be excluded. In general, a higher frequency of bilateral tumors and an earlier age of diagnosis are observed in families with Wilms tumor, although exceptions occur. The following genes/loci have been implicated in familial Wilms tumor:

  • FWT1 and FWT2 loci. Genetic linkage analyses of families with Wilms tumor have mapped familial predisposition genes to a locus on 17q (called FWT1) and 19q (called FWT2) [Rahman et al 1996, McDonald et al 1998]. Additionally, some families are linked to neither WT1, 17q, nor 19q, implying the existence of one or more other familial Wilms tumor genes [McDonald et al 1998].
  • WT1. Mutations in WT1 are not implicated in most families with Wilms tumor predisposition; however, a small number of families that have germline WT1 mutations have been identified [Grundy et al 1988, Huff et al 1988, Diller et al 1998, Huff 1998].
  • BRCA2. Two siblings with Wilms tumor and brain tumors (glioblastoma multiforme in one and medulloblastoma in the other) have biallelic BRCA2 mutations. Of 23 individuals with biallelic BRCA2 mutations reported in the literature, five have had Wilms tumor [Reid et al 2005].

Isolated, simplex Wilms tumor

  • Germline WT1 mutations. WT1 mutations are present in the germline of fewer than 5% of individuals with Wilms tumor. Some individuals with germline mutations do not exhibit features of any of the above syndromes [Huff et al 1991, Diller et al 1998, Huff 1998, Royer-Pokora et al 2004]. These are more likely to be individuals with a 46, XX karyotype. For example, 25 of the 32 (78%) individuals with "WT only" in Table 5 are female, consistent with the notion that germline WT1 mutations have a greater effect on sex determination and genital tract development in males than females. Compared to individuals with sporadic Wilms tumor, those with germline WT1 mutations are more likely to have bilateral or multicentric tumors and to develop tumors at an early age, although not all children with bilateral disease at an early age have WT1 mutations [Huff 1998, Perotti et al 2005]. In the absence of GU anomalies, renal mesangial sclerosis, or bilateral tumors, the likelihood that a child with Wilms tumor has a WT1 germline mutation is low, with reported frequencies of 2%-5% [Huff 1998, Little et al 2004].
  • Somatic WT1 mutations. In individuals without GU anomalies or DDS, WT1 mutations have been reported in 10%-20% of Wilms tumors. More than 70% of these mutations are somatic [Gessler et al 1994, Varanasi et al 1994, Huff 1998].

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 an appreciable subset (>1%) of Wilms tumor:

Evaluation Strategy

Family history. A three-generation pedigree should be obtained with attention to individuals with Wilms tumor, renal abnormalities that may be nephrogenic rests, GU anomalies, and/or early-onset renal failure.

In the absence of syndromic features, a heritable cause of Wilms tumor may be implied by the existence of other family members with a history of Wilms tumor.

Clinical examination should focus on those congenital anomalies suggestive of BWS (macroglossia, macrosomia, hemihyperplasia, omphalocele) or findings of a WT1 mutation (aniridia, genital anomalies, evidence of early-onset renal failure). Clinical features that suggest a genetic predisposition syndrome include hypospadias, undescended testes or other congenital genitourinary anomalies; hemihyperplasia and other features of Beckwith-Wiedemann syndrome (BWS); or aniridia [Breslow et al 1993].

Testing

  • Individuals with familial Wilms tumor. Although several families with a germline WT1 mutation have been reported, most families with Wilms tumor do not have a WT1 germline mutation. Molecular genetic testing for a germline WT1 mutation in individuals with familial Wilms tumor is possible and can be considered, although the yield will be low.
  • Individuals with bilateral Wilms tumor
  • Individuals with unilateral Wilms tumor. Individuals with unilateral Wilms tumor and no congenital anomalies are unlikely to have a germline WT1 mutation; in three large studies, the frequency of germline WT1 mutation in such individuals was 0%, 1.3%, and 1.4% [Diller et al 1998, Huff 1998, Little et al 2004].
  • Individuals with known or suspected Denys-Drash syndrome (DDS) or Frasier syndrome. Sequence analysis of WT1 to detect an intragenic germline mutation can be considered. Germline WT1 mutations identified to date are predominantly missense mutations in exons 8 or 9 (DDS) or IVS9 mutations that affect splicing (Frasier syndrome).
  • Individuals with aniridia. (See Aniridia for testing issues.)
  • Individuals with BWS or hemihyperplasia. (See Beckwith-Wiedemann Syndrome for testing issues.)

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 has syndromic Wilms tumor (e.g., WAGR, a WT1-related syndrome, or Beckwith-Wiedemann syndrome), genetic counseling for the specific syndrome is appropriate.

Nonsyndromic Wilms tumor. This most frequently occurs in a single individual in 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 the result of a germline WT1 mutation.

Individuals with a known WT1 germline mutation

Familial Wilms tumor

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 unknown but likely low.
  • 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 germline mutation in the proband, molecular genetic testing or ultrasound screening of the offspring of such individuals is not warranted.

Nonsyndromic Wilms tumor in an individual with bilateral or multifocal Wilms tumor

  • Only 16% of persons with bilateral Wilms tumor have a WT1 germline mutation and only 3% of persons with bilateral Wilms tumor have affected family members. However, the presence of bilateral or multifocal disease in the proband implies that the proband has a genetic predisposition.
  • The risk to offspring of the proband is unknown and likely varies with the gene in which the mutation occurred. Ultrasound screening of the offspring for Wilms tumor in childhood should be considered.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the WT1 germline mutation in the parent has been identified, prenatal diagnosis for pregnancies at 50% risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation). The risk of Wilms tumor developing in a child with a known WT1 germline mutation 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.

Preimplantation genetic diagnosis may be an option for some families in which the disease-causing germline mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International WAGR Syndrome Association
    Email: Reachingout@wagr.org
  • Medline Plus
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • American Childhood Cancer Organization (ACCO)
    PO Box 498
    Kensington MD 20895-0498
    Phone: 800-366-2223 (toll-free); 301-962-3520
    Fax: 301-962-3521
    Email: staff@acco.org
  • Kidney Cancer Association
    PO Box 96503
    Washington DC 20090
    Phone: 800-850-9132 (toll-free); 312-436-1455
    Fax: 847-332-2978
    Email: kidney.cancer@hotmail.com
  • Childhood Cancer Research Network (CCRN) Registry
    A pediatric cancer research registry established by the Children's Oncology Group for all COG member institutions in the United States and Canada.

Management

Evaluations Following Initial Diagnosis

Because Wilms tumor can spread to the lungs, preoperative chest imaging is imperative. Although plain films of the chest have been recommended on past National Wilms Tumor Studies (NWTS), many physicians in North America favor chest CT scans because they provide increased sensitivity.

  • On NWTS-4 and -5, clinicians were given the option to disregard lung nodules detected by CT scan but not chest x-ray. A study from the Children’s Oncology Group indicated that affected individuals with so-called “CT-only” nodules had a higher relapse rate when they received two-drug therapy (vincristine/dactinomycin) versus three-drug therapy (vincristine/dactinomycin/doxorubicin) [Grundy et al 2012].
  • Therefore, CT scans may add prognostic value and may help direct therapy for Wilms tumor. CT scans have become a standard part of the diagnostic workup in North America.

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 disagreement exists as to the optimal timing of tumor resection summarized below. Either approach yields excellent results.

  • The Children’s Oncology Group (COG) 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 four to eight weeks of preoperative 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 for renal failure is less than 1% after nephrectomy; thus, 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 6. 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 4) [Breslow et al 2003].

Table 6. Outcomes from NWTS-5

HistologyStageRelapse-Free Survival (%) 1Overall Survival (%) 1
Favorable 2I (age ≥24 mos; tumor weight ≥550 g)94.298.4
II86.297.7
III86.594.4
IV76.486.1
374 (8-year)89 (8-year)
Anaplastic4 69.582.6
II82.181.2
III68.372.0
IV37.537.5
V43.855.2

Grundy et al [2005], Dome et al [2006], Hamilton et al [2011]

1. Four-year survival unless otherwise noted

2. Results are for tumors without LOH at 1p (shown to be an adverse prognostic factor).

3. Results from NWTS-4

4. Individuals with stage I anaplastic Wilms tumor received less therapy than those in the other stages.

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 preoperative chemotherapy to shrink the tumors followed by nephron-sparing surgery [Horwitz et al 1996, Davidoff et al 2008].

Relapsed Wilms tumor. Only 10%-15% of individuals with Wilms tumor experience recurrence, the majority of which occurs within two years of diagnosis. Although the survival after Wilms tumor recurrence historically has been only 20%-30% [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]. The main prognostic factor for patients with relapsed Wilms tumor is the initial therapy that the patient received. Patients treated initially with vincristine/dactinomycin had a four-year overall survival rate after relapse of 82% [Green et al 2007]. Patients treated initially with vincristine/dactinomycin/doxorubicin had a four-year overall survival rate after relapse of 48% [Malogolowkin et al 2008].

Renal transplantation. Individuals with bilateral Wilms tumor or Denys-Drash syndrome are at risk for renal failure; end-stage renal disease (ESRD) occurs in fewer than 1% of individuals with unilateral Wilms tumor. 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 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. The guidelines for surveillance of relapse of Wilms tumor are evolving. Current COG studies alternate CT scans with chest x-ray and abdominal ultrasound examination after the completion of therapy, but the value of CT imaging is under review. Table 7 shows the guidelines from NWTS-5.

Table 7. NWTS-5 Guidelines for Surveillance of Relapse in Individuals with Wilms Tumor after the Completion of Therapy

HistologyImaging StudySchedule
Favorable or anaplasticChest x-ray Every 3 months x 5, then
Every 6 months x 3, then
Every 12 months x 2
Abdominal ultrasound Stage I and II: yearly x 3
Stage III:
Every 3 months x 5, then
Every 6 months x 3, then
Every 12 months x 2

Recommendations from the COG Renal Tumors Committee [Dome et al 2005]

  • Individuals with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. Individuals with BWS or isolated hemihyperplasia 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 age eight years. 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 and WT1-related syndrome. Because the risk of Wilms tumor is high, screening by abdominal ultrasound examination every three months is recommended until age five 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 of siblings of the affected individual with renal ultrasound examination every three months until age eight years is recommended.
  • Bilateral Wilms tumor or individuals with a history of Wilms tumor consistent with a genetic predisposition. 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 during the risk period for that particular syndrome (5 years for WT1-related syndromes; 8 years for BWS). It is assumed that most individuals with bilateral Wilms tumor have a germline mutation in a gene predisposing to Wilms tumor. Although the risk for Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown, the authors recommend screening such children with serial ultrasound examinations every three months until age eight 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. Referral to a nephrologist is recommended.

Evaluation of Relatives at Risk

The risk for Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown; however, the authors recommend screening such children with serial ultrasound examinations every three months until age eight years.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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Suggested Reading

  1. Breslow NE, Ou SS, Beckwith JB, Haase GM, Kalapurakal JA, Ritchey ML, Shamberger RC, Thomas PR, D'Angio GJ, Green DM. Doxorubicin for favorable histology, Stage II-III Wilms tumor: results from the National Wilms Tumor Studies. Cancer. 2004;101:1072–80. [PubMed: 15329918]
  2. DeBaun MR, Niemitz EL, McNeil DE, Brandenburg SA, Lee MP, Feinberg AP. Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects. Am J Hum Genet. 2002;70:604–11. [PMC free article: PMC384940] [PubMed: 11813134]
  3. Dome JS, Roberts CWM, Argani P. Pediatric renal tumors. In: Orkin SH, Ginsburg D, Nathan DG, Look AT, Fisher DE, Lux SE, eds. Oncology of Infancy and Childhood. Amsterdam, Netherlands: Elsevier Academic Publishers; 2009:541-73.
  4. Engel JR, Smallwood A, Harper A, Higgins MJ, Oshimura M, Reik W, Schofield PN, Maher ER. Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome. J Med Genet. 2000;37:921–6. [PMC free article: PMC1734494] [PubMed: 11106355]
  5. Fernandez C, Geller JI, Ehrlich PF, Hill DA, Kalapurakal JA, Grundy PE, Dome JS. Renal tumors. In: Pizzo P, Poplack D, eds. Principles and Practice of Pediatric Oncology. 6 ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2011:861-85.
  6. Green DM, Breslow NE, Beckwith JB, Finklestein JZ, Grundy PE, Thomas PR, Kim T, Shochat SJ, Haase GM, Ritchey ML, Kelalis PP, D'Angio GJ. Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms' tumor: A report from the National Wilms' Tumor Study Group. J Clin Oncol. 1998;16:237–45. [PubMed: 9440748]
  7. Grundy RG, Pritchard J, Scambler P, Cowell JK. Loss of heterozygosity for the short arm of chromosome 7 in sporadic Wilms tumour. Oncogene. 1998;17:395–400. [PubMed: 9690521]
  8. Trepanier A, Ahrens M, McKinnon W, Peters J, Stopfer J, Grumet SC, Manley S, Culver JO, Acton R, Larsen-Haidle J, Correia LA, Bennett R, Pettersen B, Ferlita TD, Costalas JW, Hunt K, Donlon S, Skrzynia C, Farrell C, Callif-Daley F, Vockley CW. Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. J Genet Couns. 2004;13:83–114. [PubMed: 15604628]
  9. Tycko B. Epigenetic gene silencing in cancer. J Clin Invest. 2000;105:401–7. [PMC free article: PMC289180] [PubMed: 10683367]
  10. Weksberg R, Nishikawa J, Caluseriu O, Fei YL, Shuman C, Wei C, Steele L, Cameron J, Smith A, Ambus I, Li M, Ray PN, Sadowski P, Squire J. Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum Mol Genet. 2001;10:2989–3000. [PubMed: 11751681]

Chapter Notes

Revision History

  • 19 September 2013 (me) Comprehensive update posted live
  • 14 June 2011 (me) Comprehensive update posted live
  • 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
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