Pathophysiology: Knudson and Strong proposed a genetic model for the development of Wilms tumor in the early 1970s. WT1, the first Wilms tumor suppressor gene at chromosome 11p13, was identified as a direct result of the study of children with Wilms tumor that also had aniridia, mental retardation and genitourinary anomalies (WAGR syndrome). Karyotypic analysis of these children revealed constitutional deletions within the short arm of one copy of chromosome 11. Subsequently, it was shown that the 11p13 locus encompasses a number of contiguous genes, including the aniridia gene Pax6 and the Wilms tumor suppressor gene WT1, which was cloned in 1990. WT1 encodes a transcription factor critical to normal kidney and gonadal development. The characterization of this novel tumor suppressor gene has provided insight into the mechanisms underlying normal kidney development and Wilms tumorigenesis. The WT1 gene has now been shown to be the specific target of mutations and deletion events in a subset of sporadic Wilms tumors, as well
as in the germline of some children (those with Denys-Drash syndrome for example) with genetic predisposition to this cancer.

A second Wilms tumor predisposing gene has been identified, but not yet cloned, telomeric of WT1, at 11p15. This locus has been proposed based on studies of patients with both Wilms tumor and Beckwith-Wiedemann syndrome (BWS), another congenital Wilms tumor predisposition syndrome, linked to chromosome 11p15. BWS is an overgrowth syndrome characterized by visceromegaly, macroglossia, and hyperinsulinemic hypoglycemia. In addition, patients with BWS are predisposed to several embryonal neoplasms including Wilms tumor. Thus far a few candidate loci for Wilms tumor and BWS have been proposed. These include the insulin-like growth factor II gene (IGFII), H19 (an untranslated RNA) and p57kip2.

The existence of additional genetic loci involved in the development of Wilms tumor is suggested by linkage analyses in large pedigrees with familial transmission of susceptibility to Wilms tumor. Finally, loci at 16q, 1p, 7p and 17p have also been evoked in the biology of Wilms tumor, although these loci do not seem to predispose to Wilms tumor, but rather seem to be associated with phenotype or outcome.

Frequency:

• In the US: Wilms tumor affects approximately 10 children per one million before the age of 15 years, and therefore accounts for 6-7% of all childhood cancers in North America. As a result, about 450-500 new cases are diagnosed each year in this continent. In 5-10% of cases both kidneys are affected either at the same time (synchronous bilateral Wilms tumor) or one after the other (metachronous bilateral Wilms tumor).

• Internationally: Wilms tumor appears to be more common among certain ethnic groups (Black population) while less common among others (East Asian population). The incidence in Europe is similar to that reported in North America.

Mortality/Morbidity: Prior to the multimodality approach, the survival of patients was less than 50%. With current strategies employed by the NWTSG and SIOP, survival rates are approaching 90%. Most survivors of Wilms tumor have good functional outcome and quality of life.

Race: Wilms tumor is relatively more common in Blacks than Caucasians and is less common in East Asians.

Sex: Among patients with unilateral Wilms tumor enrolled in all NWTSG protocols, the male-to-female ratio was 0.92 to 1.00. For patients with bilateral disease, the male-to-female ratio was 0.60 to 1.00.

History: The most common presentation of Wilms tumor is the presence of an asymptomatic abdominal mass. Hypertension, gross hematuria, and fever are seen in 5-30% of patients. A small number of patients who have hemorrhaged into their tumor may present with signs of hypotension, anemia, and fever. Rarely, patients with advanced stage disease may present with respiratory symptoms related to the presences of lung metastases.

Physical: Examination often reveals a palpable abdominal mass. One should pay special attention to features of those syndromes (WAGR and BWS) associated with Wilms tumor, i.e. aniridia, genitourinary malformations, and signs of overgrowth.

Exam of the abdominal mass should be performed carefully. There has been concern that palpating a mass too vigorously could lead to rupture of a large tumor into the peritoneal cavity.

Lab Studies:
 

• Complete blood count

• Chemistry profile including kidney function tests and routine electrolytes with calcium

• Urinalysis

• Coagulation studies

• Cytogenetics studies

• An 11p13 deletion as in the WAGR syndrome (Wilms, aniridia, genitourinary abnormalities, mental retardation)

• A duplication of the paternal allele 11p15 as in Beckwith-Wiedemann syndrome

• Mutational analysis of the WT1 gene in cases where Denys-Drash syndrome (intersexual disorders, nephropathy, Wilms) is suspected

Imaging Studies:

• Renal ultrasound with dynamic imaging of the renal vein and interior vena cava

• CT Scan

• Abdominal CT scan helps determine the tumor's origin, lymph node involvement, bilateral kidney involvement, and invasion into major vessels (eg, inferior vena cava or liver metastases).

• Chest CT scan. If positive while chest radiographs are negative, diagnostic biopsy of the lesions noted on CT chest is recommended.

• Chest radiograph (4-field) detects lung metastases. Patient with chest radiograph proven lung lesions receive whole lung radiotherapy.

Procedures:

• Histopathologic confirmation of disease is essential. Consequently in North America, patients with suspected Wilms tumor undergo nephrectomy upfront. During this procedure, the contralateral kidney is explored to ensure that the disease is indeed unilateral, and lymph nodes are biopsied for staging purposes. Lymph node dissection is not indicated. By contrast to surgery upfront, most European centers make a presumptive diagnosis of Wilms tumor based on imaging studies alone. The SIOP centers prefer to administer pre-nephrectomy chemotherapy. In North America, nephrectomy upfront is not performed in bilateral disease at presentation, when sparing of renal tissue becomes important. Transcutaneous biopsy is not indicated and may in fact complicate treatment.

• Patients with a negative chest radiograph and positive CT scan of the lungs need tissue diagnosis of the lung nodule(s) as several conditions such as histoplasma, atelectasis, pseudotumor, intrapulmonary lymph node, and pneumonia can mimic pulmonary metastases.

Histologic Findings: The classic histologic pattern is composed of epithelial, blastemal, and stromal elements (triphasic). Approximately 90% of all renal tumors have the so called favorable histology. Three to 7% of Wilms tumors are characterized by anaplastic changes, a feature that if present diffusely throughout the tumor predicts for poor outcome. Wilms tumors with anaplastic changes are called unfavorable histology Wilms tumors. Finally, it has been clear that two tumor types previously included in the unfavorable histology Wilms tumor category are in fact separate malignant entities. This includes clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RTK).

The improved histopathologic classification of childhood renal tumors has not only helped to define appropriate treatment strategies for these patients, but has also contributed to the understanding of the molecular genetic events underlying the development of Wilms tumor. For instance, nephrogenic rests, dysplastic lesions of metanephric origin, are now believed to represent precursor lesions. These lesions are observed in approximately one third of Wilms tumor kidneys. The relationship between the pathology of the nephrogenic rests, the tumor and congenital disorders is of particular interest. These associations have been helpful in evaluating a potential correlation between a Wilms tumor phenotype on the one hand and molecular genetic events leading to the development of that same tumor on the other.

Medical Care: The usual approach in most patients is nephrectomy followed by chemotherapy with or without postoperative radiotherapy. The following table summarizes the current approach to patients with Wilms tumor according to the NWTS-5.

Table 1. Current approach to Wilms Tumor

*FH = favorable histology, CCSK = clear cell sarcoma of the kidney, RTK = rhabdoid tumor of the kidney

**Current radiotherapy dosage is approximately 1080 cGy for abdomen and 1200 cGy for lung. Only stage IV patients with lung metastases receive whole lung radiotherapy.

Consultations: The patient needs a pediatric surgeon, pediatric oncologist, and, in some cases, a radiation oncologist.

Diet: No special diet is recommended.

• Complete blood count

• Chemistry profile including kidney function tests and routine electrolytes with calcium

• Urinalysis

• Coagulation studies

• Cytogenetics studies

• An 11p13 deletion as in the WAGR syndrome (Wilms, aniridia, genitourinary abnormalities, mental retardation)

• A duplication of the paternal allele 11p15 as in Beckwith-Wiedemann syndrome

• Mutational analysis of the WT1 gene in cases where Denys-Drash syndrome (intersexual disorders, nephropathy, Wilms) is suspected

Imaging Studies:

• Renal ultrasound with dynamic imaging of the renal vein and interior vena cava

• CT Scan

• Abdominal CT scan helps determine the tumor's origin, lymph node involvement, bilateral kidney involvement, and invasion into major vessels (eg, inferior vena cava or liver metastases).

• Chest CT scan. If positive while chest radiographs are negative, diagnostic biopsy of the lesions noted on CT chest is recommended.

• Chest radiograph (4-field) detects lung metastases. Patient with chest radiograph proven lung lesions receive whole lung radiotherapy.

Procedures:

• Histopathologic confirmation of disease is essential. Consequently in North America, patients with suspected Wilms tumor undergo nephrectomy upfront. During this procedure, the contralateral kidney is explored to ensure that the disease is indeed unilateral, and lymph nodes are biopsied for staging purposes. Lymph node dissection is not indicated. By contrast to surgery upfront, most European centers make a presumptive diagnosis of Wilms tumor based on imaging studies alone. The SIOP centers prefer to administer pre-nephrectomy chemotherapy. In North America, nephrectomy upfront is not performed in bilateral disease at presentation, when sparing of renal tissue becomes important. Transcutaneous biopsy is not indicated and may in fact complicate treatment.

• Patients with a negative chest radiograph and positive CT scan of the lungs need tissue diagnosis of the lung nodule(s) as several conditions such as histoplasma, atelectasis, pseudotumor, intrapulmonary lymph node, and pneumonia can mimic pulmonary metastases.

Histologic Findings: The classic histologic pattern is composed of epithelial, blastemal, and stromal elements (triphasic). Approximately 90% of all renal tumors have the so called favorable histology. Three to 7% of Wilms tumors are characterized by anaplastic changes, a feature that if present diffusely throughout the tumor predicts for poor outcome. Wilms tumors with anaplastic changes are called unfavorable histology Wilms tumors. Finally, it has been clear that two tumor types previously included in the unfavorable histology Wilms tumor category are in fact separate malignant entities. This includes clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RTK).

Further Outpatient Care:

• The patient needs to be seen at the follow-up clinic after completing all therapy. The purpose of follow-up care is to check for recurrence and also late effects. The following table outlines the types and frequency of radiographic studies during the follow-up period according to the NWTSG.

  Table 2. Imaging studies recommended for follow-up of children with Wilms tumor free of metastasis at diagnosis
  

  Wilms Tumor	Imaging studies	Off treatment schedule
  Favorable histology, stages I, II, and III Anaplastic histology, stages I, II, and III	Chest films	After 6 weeks and 3 months postoperatively; then every 3 months (5x), followed by every 6 months (3x), followed by yearly (2x)
  Patients <48 months of age at diagnosis, with nephrogenic rests (all stages)	Abdominal ultrasound	Every 3 months for 6 years
  Patients >48 months of age at diagnosis, with nephrogenic rests (all stages)	Abdominal ultrasound	Every 3 months for 4 years
  Stage I and II favorable histology	Abdominal ultrasound	Yearly times 6
  Stage III favorable histology	Abdominal ultrasound	After 6 weeks and 3 months postoperatively; then every 3 months (5x), followed by every 6 months (3x), followed by yearly (2x)
  All stages unfavorable histology	Abdominal ultrasound	Every 3 months (4x), followed by every 6 months (4x)

  Subsequent imaging studies should be performed as clinically indicated.

In/Out Patient Meds:

• Patient dependent

Complications:

• The primary treatment, nephrectomy, may damage kidney function. Additional treatment modalities, however, may cause damage to several organs such as the heart, lungs, liver, bones and gonads. In addition, both chemotherapeutic agents and radiation therapy can induce second malignant neoplasms.

• Renal Function:
  Children with Wilms tumor are at risk for impaired renal function primarily due to the nephrectomy performed as part of treatment. In selected patients, i.e. those that receive radiation therapy, the function of the remaining kidney can be further endangered. The development of compensatory post-nephrectomy hypertrophy of the remaining kidney has been well documented in patients with Wilms tumor. NWTSG data suggest that most patients with unilateral Wilms tumor do not develop serious long-term renal complications. By contrast, renal function can be impaired for those with bilateral disease. The most common cause for renal failure in patients with bilateral Wilms tumor is bilateral nephrectomy. Treatment related injury (radiation-induced damage, surgical complications) of the remaining kidney is the second leading cause of renal insufficiency.

• Cardiac Function:
  Congestive heart failure is a well-known complication following the administration of anthracyclines. Therefore, patients with Wilms tumor who receive anthracyclines, most commonly doxorubicin, should be monitored for cardiac dysfunction.

• Pulmonary Function:
  Because radiation therapy can affect pulmonary function, patients with Wilms tumor metastatic to the lung, who are treated with bilateral pulmonary irradiation, require pulmonary function monitoring. The total lung capacity (TLC) and vital capacity (VC) of patients receiving bilateral irradiation can be expected to decrease by 50-70% of predicted.

• Hepatic Function:
  The liver of patients treated for Wilms tumor may be damaged by several cytotoxic agents, including dactinomycin, and irradiation. Most early reports suggest that hepatic irradiation is the major etiologic factor in hepatic injury. Recent publications however, have documented hepatic toxicity with the combination of vincristine and dactinomycin in non-irradiated children with Wilms tumor, suggesting that the chemotherapeutic agents themselves can also result in damage to the liver. Data obtained from the fourth NWTSG study report a hepatotoxicity incidence of 2.8 to 14.3% in patients that did not receive irradiation. The fact that patients who received less dactinomycin (i.e. those with lower stage disease) had the lower incidence of 2.8%, suggests a dose related toxicity for dactinomycin.

  Some patients with Wilms tumor have been reported to develop hepatic veno-occlusive disease (VOD). This is primarily a clinical diagnosis characterized by hepatomegaly or right upper quadrant pain, jaundice, ascites and unexplained weight gain. The syndrome occurs both in patients with Wilms tumor undergoing upfront nephrectomy as well as in those receiving combination chemotherapy prior to surgery, the standard approach recommended by the SIOP. While treatment for VOD is primarily supportive, the administration of chemotherapeutic agents can be resumed once the signs of VOD have disappeared.

  Using the currently accepted radiotherapy techniques, radiation-induced hepatitis is rare in survivors of Wilms' tumor.

• Gonadal Function:
  It has been known that women who received whole abdominal irradiation in childhood can develop ovarian failure. Recent data clearly suggest that a high risk of adverse pregnancy outcome should be considered in the counseling and prenatal care of women who have received abdominal radiotherapy for Wilms tumor.
  Male patients are at risk for testicular failure after the administration of radiation therapy (whole abdomen) or certain chemotherapeutic agents, most notably alkylating agents.

• Musculoskeletal Function:
  The effect of radiation therapy to the skeletal system is often predictable. While radiation therapy may affect the growth of any given bone, the spine is most notably affected at doses of 20 Gy. A recent study from the University of Iowa showed a dose-response relationship in the induction of scoliosis and dose delivered. The majority of patients who received dose of > 24 Gy with megavoltage beams develop asymptomatic scoliosis. There is also a suggestion that patient receiving current doses of 10 to 12 Gy have a much smaller chances of scoliosis.

• Second Malignant Neoplasms:
  As both inherited disposition and treatment such as chemotherapy and radiotherapy can induce second malignant neoplasms (SMN), Wilms tumor survivors are at risk. Most of the SMNs reported, such as bone tumors, breast and thyroid cancers have occurred in irradiated areas. Nevertheless, certain chemotherapeutic agents, including doxorubicin, dactinomycin and vincristine may contribute to an increased risk for developing SMNs. Fifteen years after initial diagnosis, the cumulative incidence of a SMN in patients registered with the NWTSG is 1.6% and increasing. According to NWTSG investigators, abdominal irradiation increases the risk of a SMN and doxorubicin potentiates the radiation effect. Treatment for relapse further increased the risk for a SMN by a factor of 4 to 5.

Prognosis:

• Approximately 80-90% of diagnosed children survive with current multimodality therapy.

• Favorable histology tumors have at least an 80% overall survival rate at 4 years after initial diagnosis, even in patients with stage IV.

• Synchronous bilateral cases have a 70-80% survival rate, while those with metachronous tumors have a 45-50% survival rate.

• The prognosis for patients who relapse is not good, with only 30-40% expected to survive after retrieval therapy.

Patient Education:

• It is important for the parent and patient to know that long-term follow-up care is essential because of the late-effects of treatment.