Presentation, diagnosis, and staging of Wilms tumor

INTRODUCTION — Wilms tumor is the most common renal malignancy in children, with approximately 500 new cases diagnosed in the United States each year [1]. The epidemiology, presentation, diagnosis, and staging of Wilms tumor will be reviewed here. The treatment and outcome of Wilms tumor are discussed separately. (See "Treatment and prognosis of Wilms tumor".)

EPIDEMIOLOGY — In the United States, the annual incidence of renal tumors is approximately 7 cases per 1 million children younger than 15 years, accounting for 5 percent of all childhood malignancies (table 1) and approximately 500 new cases per year [1-4]. Wilms tumor is the most common renal malignancy in children <15 years old, accounting for approximately 95 percent of all cases. In the United States, two-thirds of cases of Wilms tumor are diagnosed before five years of age and 95 percent before 10 years of age [5]. In contrast, renal cell carcinoma (RCC) is more common in the 15- to 19-year-old age group [5].

Most patients have solitary Wilms tumor, 5 to 7 percent have bilateral kidney involvement, and 10 percent have multifocal loci within a single kidney [6]. In patients with unilateral involvement, the median age at diagnosis is 43 months in girls and 37 months in boys [7]. Children with bilateral disease are diagnosed at an earlier age (median age 31 months for girls and 24 months for boys) [7]. Patients with associated congenital anomalies, such as aniridia or genitourinary abnormalities, are also diagnosed at an earlier age [7].

The risk of developing Wilms tumor varies among ethnic groups, with a greater risk in African Americans and a lower risk in the Asian population [3,7-9]. Epigenetic differences may contribute to the lower rate of disease in Asian children, as demonstrated by a study that reported infrequent loss of insulin-like growth factor 2 (IGF-2) imprinting in tumors from Asian patients [10]. (See 'Genetics' below.)

ASSOCIATED CONGENITAL SYNDROMES — Wilms tumor is primarily a sporadic disease, and only 1 to 2 percent of individuals with Wilms tumor have a relative with the disease [11]. In approximately 10 percent of cases, Wilms tumor occurs as a part of a multiple malformation syndrome, including WAGR, Denys-Drash, and Beckwith-Wiedemann syndrome (BWS) [12].

WAGR syndrome — WAGR syndrome refers to the syndrome of Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability (mental retardation) [13]. In children with WAGR syndrome, the risk of developing Wilms tumor is approximately 50 percent [12,14]. Children with this syndrome have a constitutional chromosomal deletion of the WT1 gene located at 11p13. The WT1 gene product is a transcription factor involved in both gonadal and renal development. (See 'Genetics' below.)

In a retrospective study of 54 children with WAGR syndrome, the following clinical findings were noted [15]:

●Aniridia – 53 patients

●Genitourinary abnormalities (eg, cryptorchidism, ambiguous genitalia) – 41 patients

●Intellectual disability – 39 patients

●Wilms tumor – 31 patients

●Renal impairment (defined as glomerular filtration rate <80 mL/min) and proteinuria developed in 14 patients

In another case series of 64 patients with WAGR syndrome, all patients had tumors with favorable histology [16]. Eleven (7 percent) had bilateral disease. Chronic renal disease developed in approximately one-half of the cohort at a 20-year follow-up, including end-stage kidney disease in four patients who subsequently underwent renal transplantation.

Denys-Drash syndrome — The Denys-Drash syndrome (also called simply Drash syndrome) is a triad of progressive renal disease, male pseudohermaphroditism, and Wilms tumor. Affected individuals have a germline point mutation in the eighth or ninth exon of the WT1 gene, which results in an amino acid substitution, and almost all patients (90 percent) will develop Wilms tumor. (See 'Genetics' below.)

The underlying renal pathology is diffuse mesangial sclerosis, which presents in infancy with proteinuria and progresses to nephrotic syndrome and renal failure. (See "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis with Denys-Drash syndrome'.)

Beckwith-Wiedemann syndrome — Patients with BWS have a 5 to 10 percent chance of developing Wilms tumors [17]. This disorder is caused by microduplication mutations in the 11p15.5 region, a site of a cluster of imprinting genes [18]. (See 'Genetics' below.)

The major clinical features of BWS include macrosomia, macroglossia, omphalocele, prominent eyes, ear creases, large kidneys, pancreatic hyperplasia, and hemihypertrophy. (See "Beckwith-Wiedemann syndrome".)

Other congenital anomalies — Patients with other congenital syndromes and isolated congenital anomalies are also at risk for developing Wilms tumors. These include:

●Perlman syndrome – Perlman syndrome is an autosomal recessive overgrowth syndrome due to a germline mutation of the DIS3L2 gene [19,20]. It is characterized by fetal gigantism, visceromegaly, unusual face, bilateral renal hamartomas with nephroblastomatosis, and Wilms tumor [21].

●Sotos syndrome – There is a 2 to 3 percent risk of Wilms tumor in children with Sotos syndrome (also referred to as cerebral gigantism). Sotos syndrome is an overgrowth syndrome associated with facial, extremity, and cognitive abnormalities [21]. (See "The child with tall stature and/or abnormally rapid growth", section on 'Cerebral gigantism'.)

●Simpson-Golabi-Behmel syndrome – Simpson-Golabi-Behmel syndrome is an X-linked genetic disorder caused by mutations in the gene encoding glypican-3, which maps to chromosome Xq26 [22]. It is characterized with pre- and postnatal overgrowth with organomegaly, a distinctive coarse facial appearance described as a bulldog appearance, congenital heart disease, polydactyly, and a 7.5 percent chance of developing Wilms tumor [23].

●Isolated hemihypertrophy – The estimated risk for developing Wilms tumor in children with isolated hemihypertrophy is 3 to 4 percent [24].

●Isolated genitourinary abnormalities – Boys with Wilms tumor may have cryptorchidism or hypospadias, while 10 percent of girls with Wilms tumor have congenital uterine anomalies [25]. Other kidney abnormalities, such as renal ectopia or duplicated collecting systems, can also be seen.

●Familial Wilms tumor is rare and is associated with mutations in the BRCA2 or TP53 genes (Li-Fraumeni syndrome). (See "Li-Fraumeni syndrome".)

PATHOGENESIS — Wilms tumor appears to be caused by abnormal renal development, resulting in proliferation of the metanephric blastema without normal tubular and glomerular differentiation. Wilms tumor is thought to arise from foci of persistent metanephric cells referred to as nephrogenic rests or nephroblastomatosis [26]. Nephrogenic rests normally occur in 1 percent of newborn kidneys and regress early in childhood. In contrast, they are present in 35 percent of kidneys with unilateral Wilms tumor and almost 100 percent of kidneys with bilateral disease [27].

Genetics — Wilms tumor has been associated with loss-of-function mutations of a number of tumor suppressor and transcription genes. These include mutations of the WT1, p53, FWT1, and FWT2 genes and at the 11p15.5 locus [28]. The role of these gene mutations in the pathogenesis of Wilms tumor remains unknown.

●WT1 gene – The WT1 gene is located on chromosome 11p13. The WT1 gene product is expressed in the developing kidney, testis, and ovary. It appears to play a role in the development and differentiation of genitourinary tissues. Mutations of the WT1 gene were the first identified genetic abnormalities in children with Wilms tumor and were discovered in karyotypic analysis of children with WAGR syndrome [29]. The 11p13 deletion in WAGR syndrome encompasses several contiguous genes, including the WT1 and PAX6 (associated with aniridia) genes. In contrast, patients with Denys-Drash syndrome have a point mutation in the eighth or ninth exon of the WT1 gene, resulting in their clinical findings. Less than 10 percent of patients with sporadic Wilms tumor have a WT1 gene mutation, suggesting that other mechanisms are involved [30]. (See 'WAGR syndrome' above and 'Denys-Drash syndrome' above.)

●11p15.5 – The 11p15.5 locus (also referred to as the WT2 gene locus) contains a cluster of imprinted genes. Mutations at this locus have been identified in a number of syndromes characterized by either growth retardation or overgrowth, including Beckwith-Wiedemann syndrome (BWS) [12,18,31]. Imprinted genes are those that demonstrate selective gene expression based upon parental origin, such that either the paternal- or maternal-inherited gene copy is expressed, but not both. As an example, in patients with BWS, the maternal copy of the Beckwith-Wiedemann gene is silenced during gametogenesis and only the paternal copy is expressed. As a result, offspring with BWS receive a mutation passed from their father and those who inherit a Beckwith-Wiedemann gene mutation from their mother are asymptomatic carriers, who can pass the mutation to their offspring. Patients with BWS and 11p15 gene mutations are at increased risk for Wilms tumor [12,31]. (See "Principles of epigenetics" and "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)' and 'Beckwith-Wiedemann syndrome' above.)

Somatic 11p15 defects have been found in Wilms tumor cells, perilobar nephrogenic rests associated with Wilms tumors, and some normal renal cells surrounding Wilms tumors, suggesting 11p15 mutations may play an early role in nonsyndromic Wilms tumorigenesis [32]. In addition, one study demonstrated germline (constitutional) mutations in genes from this locus in the lymphocytes of 3 percent of nonsyndromic Wilms tumor patients (13 of 437 patients) and in one family with Wilms tumors [33]. No 11p15 defect was detected in the 220 controls. Patients with constitutional 11p15 defects were more likely to have bilateral tumor involvement compared with those without 11p15 mutations.

●p53 gene – The p53 tumor suppressor gene is located on chromosome 17p13.1. It encodes a nuclear protein, which acts as a transcription factor and blocks the progression of the cell cycle late in the G1 phase. p53 is the most commonly mutated gene in human cancer and is associated with a variety of malignancies including colorectal cancer, non-small cell lung cancer, osteosarcoma, and Ewing sarcoma. The p53 gene mutation is seen infrequently in patients with favorable histology tumors, but it is seen in approximately 75 percent of Wilms tumors with anaplastic histology [34]. In one study, p53 mutational status in patients with diffuse anaplasia was associated with increased risk of tumor recurrence and mortality [35].

●Familial WT genes – Familial Wilms tumor accounts for 1 to 2 percent of cases. The mode of inheritance appears to be autosomal dominant with variable penetrance. In these families, there is no association with the WT1 gene mutations. Linkages have been demonstrated to the FWT1 gene locus at 17q12-21 [36,37], the FWT2 gene locus at 19q13.3-q13.4, and the 11p15.5 locus [38].

●Other potential gene mutations:

•A genome-wide association study of 757 patients with Wilms tumor and 1879 controls identified 2p24 and 11q14 as genetic loci related with Wilms tumorigenesis [39]. Additional candidate predisposition loci included 5q14, 22q12, and Xp22.

•Genes identified as being mutated in Wilms tumor include WTX (classic oncogene) on the X chromosome and B-catenin (CTNNB1), although they occur either singly or in combination in only one-third of tumors [11].

•Mutations identified through whole-genome and whole-exome sequencing include those in microRNA processing genes, SIX1 and SIX2 homeodomain genes, and the MLLT1 gene [40,41].

•Though the incidence of Wilms tumor is low in DICER1 syndrome, it has been reported [42].

It remains unknown whether the presence of any of the above genes associated with Wilms tumor affect response to therapy or are predictive of outcome.

Limited data suggest that patients with WT1 germline mutations have a poorer outcome. This was illustrated in one study from the International Society of Pediatric Oncology that demonstrated that patients with WT1 germline mutations had an increased risk for bilateral involvement, second tumor events, and poor response to initial chemotherapy [43]. The poor response correlated with stromal predominant tumors with rhabdomyomatous changes. However, further studies are needed before treatment stratification should be considered based upon the presence or absence of a WT1 germline mutation [44].

In addition, patients with 11p15.5 constitutional defects appear to be more likely to have bilateral involvement [33].

PATHOLOGY — Most Wilms tumors are solitary lesions. However, 5 to 7 percent of patients have bilateral renal involvement and 10 percent have multifocal loci within a single kidney [6].

Wilms tumor may include cysts, hemorrhage, or necrosis. The tumor is typically surrounded by a pseudocapsule, which may help distinguish it from other renal tumors (which have an infiltrative border) [6]. (See 'Differential diagnosis' below.)

Histologically, the classic favorable histology Wilms tumor is comprised of three cell types (picture 1):

●Blastemal cells – Undifferentiated cells

●Stromal cells – Immature spindle cells and heterologous skeletal muscle, cartilage, osteoid, or fat

●Epithelial cells – Glomeruli and tubules

Some Wilms tumors contain only one or two cell types. In tumors with only one cell type, it is often difficult to make the diagnosis of Wilms tumor.

Tumor histology is linked to patient outcome. Anaplasia, defined as the presence of multipolar polypoid mitotic figures and marked nuclear enlargement with hyperchromasia (picture 2), is associated with poor outcome [45]. (See "Treatment and prognosis of Wilms tumor", section on 'Anaplastic histology'.)

Blastemal type histology, assessed after preoperative chemotherapy (as performed in protocols of the International Society of Paediatric Oncology [SIOP]), also appears to be associated with poor outcome; however, blastemal content has less prognostic significance when histologic categorization is performed before chemotherapy (as in National Wilms Tumor Study protocols). (See "Treatment and prognosis of Wilms tumor", section on 'Blastemal type histology'.)

CLINICAL PRESENTATION — Most children with Wilms tumor present with an abdominal mass or swelling, without other signs or symptoms. Other symptoms can include abdominal pain (30 to 40 percent of patients), hematuria (12 to 25 percent), fever, and hypertension (25 percent) [6,46].

A subset of patients with subcapsular hemorrhage can present with rapid abdominal enlargement, anemia, hypertension, and, sometimes, fever. Although the lung is the most common metastatic site, children rarely present with respiratory symptoms.

Physical examination reveals a firm, nontender, smooth mass that is eccentrically located and rarely crosses the midline [6].

Once a Wilms tumor is suspected, subsequent abdominal examinations should be performed carefully. Vigorous palpation may rupture the renal capsule, resulting in tumor spillage, which increases the tumor stage and the need for more intensive therapy. (See 'Staging' below and "Treatment and prognosis of Wilms tumor", section on 'Management'.)

As noted above, Wilms tumor may be associated with congenital anomalies and syndromes. Thus, the examination should include assessment for associated anomalies, such as aniridia, hemihypertrophy, and genitourinary anomalies. (See 'Associated congenital syndromes' above.)

Although Wilms tumor is rarely diagnosed in the neonate [47], there are a few reported cases of prenatal detection of a renal mass with postnatal confirmation of Wilms tumor [47-51]. All of these prenatal cases were unilateral, and none was associated with multiple malformation syndrome or nephrogenic rests. One neonate presented with nonimmune hydrops with rapid growth of the tumor [51].

SCREENING — Patients with Wilms tumor may also be identified through screening of high-risk patients (eg, children with Beckwith-Wiedemann syndrome [BWS] or WAGR syndrome) [14,52-57]. Surveillance with serial abdominal ultrasonography is recommended, as follows [14,57]:

●Children with BWS or isolated hemihyperplasia – Every three months until age seven years

●Children with WAGR and WT1-related syndromes – Every three months until age five years

●Siblings of an individual with familial Wilms tumor and offspring of survivors of bilateral Wilms tumor – Every three months until age eight years

DIAGNOSTIC EVALUATION — The definitive diagnosis of Wilms tumor is made by histologic confirmation at the time of either surgical excision or biopsy. Children who are suspected of having Wilms tumor should be referred to a pediatric cancer center for evaluation and diagnosis.

Abdominal imaging — Imaging is useful to differentiate Wilms tumor from other causes of abdominal masses. The first goal of imaging is to establish the presence of a renal tumor [6]. Imaging studies also guide management decisions prior to confirmation of a histologic diagnosis, such as surgical approach and need for preoperative chemotherapy. Important information includes confirming the presence and function of the contralateral kidney as well as determining whether there is also tumor in the contralateral kidney, the size and extent of the tumor, and the presence of lung metastases. (See 'Chest imaging' below.)

Abdominal ultrasonography is typically the initial study performed for evaluation of abdominal mass (see "Overview of common presenting signs and symptoms of childhood cancer", section on 'Abdominal masses'). Ultrasonography detects hydronephrosis and multicystic kidney disease, which may present as abdominal masses or swelling. In patients with a suspected renal tumor, Doppler ultrasonography can be performed to detect tumor infiltration of the renal vein and inferior vena cava and to assess patency of blood flow. This information can also be clarified with computed tomography (CT).

Contrast-enhanced CT or magnetic resonance imaging (MRI) is recommended to further evaluate the nature and extent of the mass, including evidence of preoperative rupture or ascites. CT or MRI also may detect small lesions of tumor or nephrogenic rests in the opposite kidney that were not detected by ultrasonography. The Children's Oncology Group (COG) evaluated the diagnostic performance of CT and MRI for local staging of pediatric renal tumors and found that they have similar abilities to detect lymph node metastasis and capsular penetration [58]. MRI detected more contralateral synchronous lesions; however, these were rare. The investigators concluded that either modality can be used for initial locoregional staging of pediatric renal tumors based on institutional expertise, need for anesthesia, risks of radiation exposure, and cost concerns. At the authors' institution, we typically use CT at the time of initial diagnosis; MRI or CT may be used for follow-up imaging depending on the patient's specific circumstances.

In a separate study, the COG investigated the role of preoperative CT scans in detecting tumor rupture and found that ascites beyond the cul-de-sac was the best indicator of rupture; however, the sensitivity of CT to detect tumor rupture was poor (54 to 70 percent) [59].

Preoperative imaging helps the surgeon determine whether the tumor is operable at diagnosis. Patients with any of the following findings or circumstances generally undergo an upfront biopsy and receive prenephrectomy chemotherapy rather than initial primary nephrectomy [60]:

●Tumor thrombus above the level of the hepatic veins

●Pulmonary compromise from massive tumor or extensive pulmonary metastases

●Resection requiring removal of contiguous structures (other than adrenal gland)

●Surgeon judges that attempting nephrectomy would result in significant morbidity, tumor spill, or residual tumor

Chest imaging — Imaging of the chest is needed to determine whether there are lung metastases. At the authors' institution, we routinely perform CT of the chest. If there is a suspicious nodule, a biopsy is performed at diagnosis or after six weeks of therapy to determine whether it represents metastatic disease.

An alternate approach (used by the International Society of Paediatric Oncology [SIOP]) is to perform the initial evaluation for pulmonary metastases with chest radiography in two planes [61]. A patient with normal chest radiographs is considered to be free of metastatic lung disease. CT is performed in cases of suspicious or positive chest radiography. In addition, chest CT is used to assess the response of the pulmonary nodules to chemotherapy. The management of children with Wilms tumor with lung metastases is discussed separately. (See "Treatment and prognosis of Wilms tumor", section on 'Lung metastases'.)

Laboratory testing — Laboratory studies include tests for renal function including urinalysis, liver function, serum calcium, complete blood count, and coagulation studies.

●Serum creatinine is obtained to detect any reduction in glomerular filtration rate prior to surgical intervention. A urinalysis is sent to detect proteinuria, a finding that can occur in patients with Denys-Drash syndrome and mesangial sclerosis. (See 'Denys-Drash syndrome' above.)

●Liver function tests may be abnormal with liver metastases.

●Elevated serum calcium can be seen in children with rhabdoid tumor of the kidney or congenital mesoblastic nephroma [62]. (See 'Differential diagnosis' below.)

●Coagulation studies, including von Willebrand assay for acquired von Willebrand disease, should be obtained in children who have a history of bleeding or hypervascular tumors because acquired von Willebrand disease occurs in 4 to 8 percent of patients with Wilms tumors at diagnosis [63,64]. Although this abnormality usually has minimal clinical significance [65], there are case reports of severe bleeding requiring intensive intervention [66,67]. As a result, patients with a history of excessive bleeding should be screened for coagulopathy and any abnormality should be corrected perioperatively [65,66]. (See "Acquired von Willebrand syndrome".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of Wilms tumor includes neuroblastoma and other renal tumors. Imaging studies and tissue histology differentiate Wilms tumor from these other disorders.

Neuroblastoma can be differentiated from Wilms tumor by contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), and/or ultrasonography, which distinguish renal and nonrenal tissue. Final diagnostic confirmation is based upon tissue histology at the time of either biopsy or surgical excision. (See "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma", section on 'Diagnostic criteria'.)

In children, other renal cell tumors are rare [68]. They are differentiated from Wilms tumor by tissue histology:

●Clear cell sarcoma of the kidney – Clear cell sarcoma is the second most common pediatric renal tumor. It has a less favorable prognosis than Wilms tumor, with increased rate of relapse and mortality. Bone is a common metastatic site, giving this tumor the alternate name of bone-metastasizing renal tumor of childhood [69]. The histologic appearance is generally distinctive, with cords and nests of pale-stained tumor cells with abundant extracellular matrix separated by a network of fine capillary arcades. However, in some cases, histologic variation can make it difficult to distinguish this tumor from Wilms tumor. As a result, clear cell sarcoma is the most frequently misdiagnosed pediatric renal tumor [6].

●Rhabdoid tumor of the kidney – Rhabdoid tumor of the kidney is a highly malignant renal tumor that occurs most frequently in children less than two years of age and almost never in those older than five years of age [70]. At presentation, the tumor is often metastatic and involving the lungs, abdomen, lymph nodes, liver, bone, and brain [71]. The prognosis is poor, with a reported mortality rate of greater than 80 percent within the first year of diagnosis [70,71].

●Congenital mesoblastic nephroma – Congenital mesoblastic nephroma is usually detected within the first year of life or by prenatal ultrasonography and can be divided into the classic and cellular subtypes [72]. It has been associated with hypertension and elevated concentrations of calcium and renin [73].

●Renal cell carcinoma (RCC) – RCC is rare in childhood. Children and adolescents with RCC present with more advanced disease than do adults [74,75]. There is a subset of affected adolescent males with a unique chromosomal translocation at Xp11.2, which appears to have a poorer prognosis than non-Xp11.2 translocation RCC [76,77]. In addition, survivors of neuroblastoma who received renal-directed radiation therapy and platinum-based chemotherapy appear to be at risk of developing RCC [78]. Factors associated with increased risk of mortality in children with RCC include advanced disease (ie, stage 4), histologic subtype (ie, non-chromophobe), and nonsurgical treatment as first-line therapy [74]. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma" and "Clinical manifestations, evaluation, and staging of renal cell carcinoma".)

●Renal medullary carcinoma – Renal medullary carcinoma is a highly lethal tumor that is virtually restricted to patients with sickle cell hemoglobinopathy, most commonly sickle cell trait. It is a highly invasive tumor with early metastases. (See "Sickle cell disease effects on the kidney", section on 'Renal medullary carcinoma'.)

STAGING — Staging criteria for Wilms tumor are based upon the anatomic extent of the tumor without consideration for genetic, histologic, or biologic markers [79]. Higher stages represent more extensive disease with a worse prognosis. As a result, more aggressive therapeutic regimens are generally administered to patients with higher tumor stages. (See "Treatment and prognosis of Wilms tumor".)

There are two major systems currently in use (table 2) [79]:

●Children's Oncology Group (COG) – The COG staging system is based upon surgical evaluation prior to the administration of chemotherapy. It is used throughout the United States and Canada.

●International Society of Paediatric Oncology (SIOP) – The SIOP system is based upon post-chemotherapy surgical evaluation and is used extensively in Europe.

Direct comparisons of trials using the two systems are difficult due to the difference in the timing of chemotherapy relative to surgical evaluation [80,81].

Children's Oncology Group system — The COG staging system is used throughout the United States and Canada and is based upon surgical evaluation prior to the administration of chemotherapy. The first four stages are confined to unilateral involvement:

●Stage I – Tumor is limited to the kidney. The tumor is completely resected with an intact capsule without evidence of renal sinus vessel involvement or tumor at or beyond the margins of resection. There is no previous rupture or biopsy. For a tumor to qualify for certain therapeutic protocols as stage I, regional lymph nodes must be examined microscopically.

●Stage II – Tumor extends beyond the kidney but is completely resected without evidence of tumor at or beyond the margins of resection. Extension includes penetration beyond the renal capsule, invasion of the soft tissue of the renal sinus, or blood vessel involvement beyond the renal parenchyma but within the resected specimen. Rupture of spillage confined to the flank, including biopsy of the tumor, is no longer included in stage II and is now included in stage III.

●Stage III – After surgery, residual tumor remains but is confined to the abdomen. This includes regional lymph node involvement, peritoneal surface involvement, incomplete resection of the tumor, tumor at or beyond the margin of the resection, tumor spillage, previous biopsy, or preoperative chemotherapy before removal of the tumor.

●Stage IV – Hematogenous metastasis (eg, lung, liver, bone, brain) or lymph node involvement beyond the abdominopelvic region.

●Stage V – Bilateral renal involvement is present at the time of diagnosis. Each side is then staged separately to guide further management decisions [79].

International Society of Paediatric Oncology staging — SIOP staging is used extensively in Europe and is based upon surgical evaluation after administration of chemotherapy to reduce the size of the tumor (table 2).

●Stage 1 – Tumor is fully resected and is limited to the kidney, or, if outside the kidney, it is surrounded with a fibrous pseudocapsule. Tumor may be found in the renal capsule, pelvic system (but not involving the ureter walls), and intrarenal vessels. There is no evidence of renal sinus vessel involvement or tumor at or beyond the margins of resection.

●Stage 2 – Tumor extends beyond the kidney or fibrous pseudocapsule but is completely resected without evidence of tumor at or beyond the margins of resection. Tumor infiltrates, which are completely resected, can extend into the renal sinus, blood vessels and lymph nodes beyond the renal parenchyma, adjacent organs, or vena cava.

●Stage 3 – After surgery, residual tumor remains but is confined to the abdomen. This includes regional lymph node involvement, incomplete resection of the tumor, tumor penetration of the peritoneal surface, tumor thrombi of vessels at resection margins, tumor spillage, or previous biopsy. There is no evidence of hematogenous metastasis.

●Stage 4 – Hematogenous metastasis (eg, lung, liver, bone, brain) or lymph node involvement beyond the abdominopelvic region.

●Stage 5 – Bilateral renal involvement is present at the time of diagnosis.

SUMMARY

●General principles – Wilms tumor is the most common renal malignancy in children and is one of the most common cancers in early childhood (table 1).

•Almost all cases are diagnosed before 10 years of age and two-thirds before five years of age.

•Most patients have solitary Wilms tumor, 5 to 7 percent have bilateral kidney involvement, and 10 percent have multifocal loci within a single kidney. (See 'Epidemiology' above.)

●Associated congenital syndromes – Wilms tumor may occur as a part of a multiple malformation syndrome including WAGR syndrome, Denys-Drash syndrome, and Beckwith-Wiedemann syndrome (BWS). (See 'Associated congenital syndromes' above.)

●Genetics – Wilms tumor is associated with mutations of a number of genes, including the WT1, p53, FWT1, and FWT2 genes, as well as mutations at the 11p15.5 loci. (See 'Genetics' above.)

●Histopathology – Tumor histology is linked to patient outcome. The classic favorable histology Wilms tumor is comprised of three cell types (blastemal, stromal, and epithelial cells) (picture 1). Anaplasia is associated with poor outcome (picture 2). (See 'Pathology' above and "Treatment and prognosis of Wilms tumor", section on 'Tumor histology'.)

●Clinical presentation – The most common presentation is detection of an abdominal mass or swelling without other signs or symptoms. Symptoms or signs, when present, may include abdominal pain (30 percent of patients), hematuria (12 to 25 percent), and hypertension (25 percent). (See 'Clinical presentation' above.)

●Screening – Screening for Wilms tumor with serial abdominal ultrasonography is performed in high-risk patients (eg, children with BWS or WAGR syndrome). (See 'Screening' above.)

●Diagnostic evaluation – Children who are suspected of having Wilms tumor should be referred to a pediatric cancer center for evaluation and treatment. (See 'Diagnostic evaluation' above.)

•The initial imaging study is typically an abdominal ultrasound, which can differentiate Wilms tumor from other causes of abdominal masses. (See 'Abdominal imaging' above.)

•Contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) is obtained to evaluate the nature and extent of the mass.

●Diagnosis – The diagnosis of Wilms tumor is made by histologic confirmation, either at the time of surgical excision or by biopsy. (See 'Diagnostic evaluation' above.)

●Staging – Staging of Wilms tumor is based upon the anatomic extent of the tumor without consideration for genetic, histologic, or biologic markers (table 2). Treatment decisions and evaluation of long-term outcome are based upon the Wilms tumor stage. (See 'Staging' above and "Treatment and prognosis of Wilms tumor".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jodi A Muscal, MD, who contributed to an earlier version of this topic review.