AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Wilms tumor, or nephroblastoma, is the most common childhood abdominal malignancy. In the past 3 decades, the multidisciplinary approach to this tumor has become an example for successful cancer treatment. At present, survival rates of children with this neoplasm are approximately 80-90%. This is in contrast to the rate 50 years ago, when only 10% of children survived. The addition of radiation therapy to surgery alone improved survival rates to approximately 40%. Since the use of chemotherapy began, survival rates of 80-90% have been observed.

Under the leadership of the National Wilms Tumor Study Group (NWTSG) and the International Society of Pediatric Oncology (SIOP), several active chemotherapeutic agents have been identified. When used together, these agents lead to a cure in most children with this renal tumor. In addition, the guidelines for surgical treatment and the role of radiation therapy are better defined now than ever before.

With overall survival rates approaching 90%, recent therapeutic trials have been able to focus on limiting treatment-related toxicity. Understanding of the molecular mechanisms that contribute to the development of Wilms tumor has greatly expanded in recent years, making Wilms tumorigenesis a model for the understanding of the development of other tumors.

Pathophysiology

In the early 1970s, Knudson and Strong proposed a genetic model for the development of Wilms tumor. WT1, the first Wilms tumor suppressor gene at chromosomal band 11p13, was identified as a direct result of the study of children with Wilms tumor who also had aniridia, genitourinary anomalies, and mental retardation (WAGR syndrome). Karyotypic analysis revealed constitutional deletions within the short arm of 1 copy of chromosome 11. The 11p13 locus was subsequently demonstrated to encompass 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 renal and gonadal development.

Characterization of this novel tumor suppressor gene has provided insight into the mechanisms underlying normal kidney development and Wilms tumorigenesis. The WT1 gene is the specific target of mutations and deletions in a subset of patients with sporadic Wilms tumors, as well as in the germline of some children (eg, those with Denys-Drash syndrome) with a genetic predisposition to develop this cancer.

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

Results of linkage analyses in large pedigrees with familial transmission of susceptibility to the Wilms tumor suggest the existence of additional genetic loci.

Finally, loci at 16q, 1p, 7p, and 17p have also been implicated in the biology of Wilms tumor, though these loci do not seem to predispose individuals to develop a Wilms tumor. Instead, they seem to be associated with the phenotype or the outcome.

Frequency

United States

Wilms tumor affects approximately 10 children and adolescents per 1 million before the age of 15 years. Therefore, it accounts for 6-7% of all childhood cancers in North America. As a result, about 450-500 new cases are diagnosed each year on this continent. In 5-10% of patients, both kidneys are affected at the same time (synchronous bilateral Wilms tumor) or 1 after the other (metachronous bilateral Wilms tumor).

International

Wilms tumor appears to be most common among African Americans and least common in the East Asian population. The incidence in Europe is similar to that reported in North America.

Mortality/Morbidity

Before the multimodality approach was available, the survival rate of patients was <50%. With the current NWTSG and SIOP strategies, survival rates are approaching 90%. Most survivors of Wilms tumor have good functional outcomes and quality of life. See also Prognosis.

Race

Wilms tumor is more common in African Americans than in Caucasians and is rare in East Asians.

Sex

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

Age

The median age at diagnosis is approximately 3.5 years. The median age is highest for patients with unilateral unicentric disease (36.1 mo) and lowest for those with synchronous bilateral Wilms tumors (25.5 mo).

CLINICAL

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History

The most common manifestation of Wilms tumor is an asymptomatic abdominal mass; an abdominal mass occurs in 80% of children at presentation. Abdominal pain or hematuria occurs in 25%. Urinary tract infection and varicocele are less common findings than these. Hypertension, gross hematuria, and fever are observed in 5-30% of patients. A few patients with hemorrhage into their tumor may present with hypotension, anemia, and fever. Rare patients with advanced disease may present with respiratory symptoms related to lung metastases.

Physical

Examination often reveals a palpable abdominal mass. Pay special attention to features of those syndromes (WAGR syndrome and BWS) associated with Wilms tumor, ie, aniridia, genitourinary malformations, and signs of overgrowth.

The abdominal mass should be examined carefully. Palpating a mass too vigorously could lead to the rupture of a large tumor into the peritoneal cavity.

Causes

Wilms tumor is thought to be caused by alterations of genes responsible for normal genitourinary development. Examples of common congenital anomalies associated with Wilms tumor are cryptorchidism, a double collecting system, horseshoe kidney, and hypospadias. Environmental exposures, though considered, seem relatively unlikely to play a role. See Pathophysiology.

DIFFERENTIALS

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Other Problems to be Considered

Mesoblastic nephroma
Renal cell carcinoma
Clear cell sarcoma of the kidney (CCSK)
Rhabdoid tumor of the kidney (RTK)
Nonmalignant mass
Hydronephrosis
Multicystic kidney disease
Renal cyst
Renal thrombosis
Dysplastic kidney
Renal hemorrhage

WORKUP

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Lab Studies

• CBC count
• Chemistry profile, including kidney function tests and routine measurements of electrolytes and calcium
• Urinalysis
• Coagulation studies
• Cytogenetics studies
• • Results may reveal an 11p13 deletion as in WAGR syndrome.
  • Studies may show a duplication of the paternal allele 11p15, as in BWS.
  • Mutational analysis of the WT1 gene may be indicated when Denys-Drash syndrome (intersexual disorders, nephropathy, Wilms tumor) is suspected.

Imaging Studies

• Renal ultrasonography: Include dynamic imaging of the renal vein and interior vena cava.
• CT scanning
• • Abdominal CT scanning helps in determining the origin of the tumor, involvement of the lymph nodes, bilateral kidney involvement, invasion into major vessels (eg, inferior vena cava), and liver metastases.
  • If findings on chest CT are positive while chest radiographic findings are negative, diagnostic biopsy of the lesions noted on the chest CT scan is recommended.
• Four-field chest radiography: Images may depict lung metastases. Patients with lung lesions on chest radiography are given whole-lung radiation therapy.

Procedures

• Histopathologic confirmation of disease is essential.
• • In North America, patients with suspected Wilms tumor undergo nephrectomy immediately. During this procedure, the contralateral kidney is explored to ensure that the disease is indeed unilateral, and lymph-node biopsy samples are obtained for staging purposes. Lymph node dissection is not indicated.
  • In contrast to immediate surgery, most European centers make a presumptive diagnosis of Wilms tumor based on imaging findings alone. Clinicians at SIOP centers prefer to administer chemotherapy before nephrectomy.
  • In North America, immediate nephrectomy is not performed in patients with bilateral disease at presentation, when sparing of the renal tissue becomes important.
  • Transcutaneous biopsy is not indicated and may in fact complicate treatment.
• Patients with negative findings on chest radiography and positive findings on CT of the lungs require tissue diagnosis of the lung nodules because several conditions (eg, histoplasmosis, atelectasis, pseudotumor, intrapulmonary lymph node, pneumonia) can mimic pulmonary metastases.

Histologic Findings

The classic histologic pattern is triphasic and composed of epithelial, blastemal, and stromal elements. Approximately 90% of all renal tumors have favorable histology. About 3-7% of Wilms tumors are characterized by anaplastic changes. If these changes are present diffusely throughout the tumor, they are predictive of a poor outcome. Wilms tumors with anaplastic changes have unfavorable histology. Finally, 2 tumor types previously included in the category with unfavorable histology are, in fact, clearly separate malignant entities. These types are CCSK and 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 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 kidneys affected by Wilms tumors. The relationship between the pathology of the nephrogenic rests, the tumor, and the congenital disorders is of particular interest. These associations have been helpful in evaluating a potential correlation between a Wilms tumor phenotype in one regard and molecular genetic events leading to the development of that same tumor in another.

TREATMENT

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Medical Care

The usual approach in most patients is nephrectomy followed by chemotherapy with or without postoperative radiotherapy. Table 1 summarizes the current approach to patients with Wilms tumor according to the fifth NWTSG report (NWTS-5) (Dome, 2006).

Table 1. Current Approach to Wilms Tumor by Stage and Histology

^*The current dose for radiation therapy is approximately 1080 cGy for the abdomen and 1200 cGy for the lung. Only patients with stage IV with lung metastases receive whole-lung radiation therapy.

Consultations

The patient should be referred to a pediatric surgeon, a pediatric oncologist, and, in some cases, a radiation oncologist.

Diet

No special diet is recommended.

Activity

No precautions regarding activity are advised, though the patient and his or her parents should be aware that the patient has only 1 kidney after therapy. Activities that carry an inherent risk of kidney injury, such as boxing and hockey, should be avoided.

MEDICATION

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Drug Category: Antineoplastic agents

Chemotherapy agents used to treat patients with Wilms tumor depend on the stage and histology of disease. Commonly used agents include dactinomycin, vincristine, doxorubicin, cyclophosphamide, etoposide, and carboplatin. The dosage depends on the particular stage of disease and on the child.

FOLLOW-UP

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Further Inpatient Care

• As many as one third of patients with Wilms tumor present with hypertension. Their blood pressure usually normalizes after nephrectomy, but they occasionally require prolonged therapeutic intervention.
• About 5-10% of patients present with acquired von Willebrand disease at the time of diagnosis. Several hypothesis have been postulated to explain acquired von Willebrand disease, including absorption of the von Willebrand factor (vWF) by tumor cells, hyperviscosity caused by elevated serum levels of hyaluronic acid, and an immunoglobulin G (IgG)–type antibody that prevents aggregation of normal platelet cells (immunologic inactivation).
• If present, excessive bleeding during surgery should be expected and prenephrectomy therapy should be started. Whenever possible, the use of blood derivatives should be avoided because of the potential to transmit viral infections. Instead, an initial trial of desmopressin (DDAVP), a drug that promotes the release of vWF from storage sites, is recommended. DDAVP has been effective in most patients with type I von Willebrand disease and in some with type II disease. If DDAVP is administered, fluid and electrolyte balance should be monitored carefully. If DDAVP is ineffective, cryoprecipitator (a specific vWF concentrate) should be administered.

Further Outpatient Care

• The patient must be examined at the follow-up clinic after he or she completes all therapy. The purpose of follow-up care is to check for recurrence and for late effects of therapy.
• Table 2 outlines the types and frequency of radiographic studies during follow-up according to the NWTSG.

  Table 2. Recommended Follow-Up Imaging Studies in Children with Wilms Tumor Without Metastasis at Diagnosis^*

  Stage and Type of Wilms Tumor	Imaging Studies	Off-Treatment Schedule
  Stages I, II, and III with favorable histology Stages I, II, and III with anaplastic histology	Chest radiography	6 wk and 3 mo after surgery Then every 3 mo (5 times) Then every 6 mo (3 times) Then yearly (2 times)
  All stages in patients aged <48 mo at diagnosis with nephrogenic rests	Abdominal ultrasonography	Every 3 mo for 6 y
  All stages in patients aged >48 mo at diagnosis with nephrogenic rests	Abdominal ultrasonography	Every 3 mo for 4 y
  Stages I and II with favorable histology	Abdominal ultrasonography	Yearly (6 times)
  Stage III with favorable histology	Abdominal ultrasonography	6 wk and 3 mo after surgery Then every 3 mo (5 times) Then every 6 mo (3 times) Then yearly (2 times)
  All stages with unfavorable histology	Abdominal ultrasonography	Every 3 mo (4 times) Then every 6 mo (4 times)

  ^*Subsequent imaging studies should be performed as clinically indicated.

In/Out Patient Meds

• Inpatient and outpatient drugs depend on the patient's specific circumstances.

Complications

• Nephrectomy leaves the child with 1 functional kidney. In almost all patients, the remaining kidney can compensate and maintain adequate renal function. Additional treatment modalities after nephrectomy may damage several organs, such as the heart, lungs, liver, bones, and gonads. In addition, both chemotherapy and radiation therapy can induce second malignant neoplasms.
• Specific complications are described below.
• • Impaired renal function: Children with Wilms tumor have a minimal risk for impaired renal function primarily related to nephrectomy. In selected patients, ie, those who receive radiation therapy, function of the remaining kidney can be further endangered. The development of compensatory postnephrectomy hypertrophy of the remaining kidney is 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 comparison, renal function can be impaired in those with bilateral disease. The most common cause of renal failure in patients with bilateral Wilms tumor is bilateral nephrectomy. Treatment-related injury (eg, radiation-induced damage, surgical complications) of the remaining kidney is the second leading cause of renal insufficiency.
  • Impaired cardiac function: Congestive heart failure is a well-known complication of the administration of anthracyclines. Therefore, patients with Wilms tumor who receive anthracyclines, most commonly doxorubicin, should be monitored for cardiac dysfunction.
  • Impaired pulmonary function: Because radiation therapy can affect pulmonary function, monitoring of pulmonary function is required in patients with metastatic Wilms tumors to the lung who are treated with bilateral pulmonary irradiation. The total lung capacity and vital capacity of patients receiving bilateral irradiation can be expected to decrease by 50-70% of the predicted values.
  • Impaired hepatic function
    • Several cytotoxic agents may damage the liver of patients treated for Wilms tumor, including dactinomycin, and irradiation. Most early reports suggest that hepatic irradiation is the major etiologic factor in hepatic injury. However, recent reports have documented hepatic toxicity with the combination of vincristine and dactinomycin in nonirradiated children with Wilms tumor, suggesting that the chemotherapeutic agents themselves can also damage the liver. In the fourth NWTSG report, the incidence of hepatotoxicity was 2.8-14.3% in patients who did not receive irradiation. The fact that patients who received less dactinomycin than others (ie, those with relatively low-stage disease) had a low incidence of 2.8% suggests a dose-related toxicity for dactinomycin.
    • Some patients with Wilms tumor have developed hepatic veno-occlusive disease (VOD). VOD is primarily a clinical diagnosis characterized by hepatomegaly or pain in the right upper quadrant, jaundice, ascites, and unexplained weight gain. The syndrome occurs both in patients with Wilms tumor undergoing nephrectomy first and in those receiving combination chemotherapy before surgery, the standard approach the SIOP recommends. Although treatment for VOD is primarily supportive, the administration of chemotherapeutic agents can be resumed after the signs of VOD have disappeared.
    • With the use of currently accepted radiotherapy techniques, radiation-induced hepatitis is rare in survivors of Wilms tumor.
  • Impaired gonadal function: Women who received whole-abdomen irradiation in childhood can develop ovarian failure. Recent data clearly suggest that a high risk of adverse pregnancy outcomes should be considered in the counseling and prenatal care of women who received abdominal radiation therapy to treat a Wilms tumor. Male patients are at risk for testicular failure after whole-abdomen radiation therapy or certain types of chemotherapy, most notably that involving alkylating agents.
  • Impaired musculoskeletal function: The effect of radiation therapy to the skeletal system is often predictable. Although 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 in the dose delivered. Most patients who received doses >24 Gy with megavoltage beams developed asymptomatic scoliosis. Patients receiving current doses of 10-12 Gy may have a much reduced likelihood of developing scoliosis.
  • Second malignant neoplasms
    • Patients who survive Wilms tumor are at risk because both inherited disposition and treatment (eg, chemotherapy, irradiation) can induce second malignant neoplasms. Most secondary malignant neoplasms reported (eg, 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 secondary malignancies.
    • Fifteen years after initial diagnosis, the cumulative incidence of a secondary malignant neoplasm in patients registered with the NWTSG was 1.6% and increasing. According to NWTSG investigators, abdominal irradiation increases the risk of a secondary malignant neoplasm and doxorubicin potentiates the radiation effect. Treatment for relapse further increased the risk for a secondary malignant neoplasm by a factor of 4-5.
  • Relapses: The lungs are the most common site of relapse. This site is affected in more than two thirds of children who have a relapse. The tumor bed is the site of relapse only in about one fourth of patients. The brain and the bones are not usual sites of relapse for Wilms tumors with favorable histology.

Prognosis

• Approximately 80-90% of children with a diagnosis of Wilms tumor survive with current multimodality therapy.
• Patients who have tumors with favorable histology have an overall survival rate of at least 80% at 4 years after the initial diagnosis, even in patients with stage IV disease.
• The 4-year relapse-free and overall survival rates in patients with favorable-histology Wilms tumor are shown in Table 3.

  Table 3. Survival Rates in Patients with Favorable-Histology Wilms Tumor

  Stage	Relapse-Free Survival, %	Overall Survival, %
  I	92	98
  II	85	96
  III	90	95
  IV	80	90

• Patients with synchronous bilateral tumors have a 70-80% survival rate, whereas those with metachronous tumors have a 45-50% survival rate.
• The prognosis for patients who have a relapse is not good, with only 30-40% expected to survive after retrieval therapy.

Patient Education

• The parents and patient must know that long-term follow-up care is essential because of the late effects of treatment.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Informed consent is necessary before treatment. Discuss potential late effects of treatment, including, but not limited to, bony and soft-tissue abnormalities, second malignancy, interstitial pneumonitis, VOD, congestive heart failure, ovarian failure, and bowel obstruction.
• For primary care physicians, the failure to diagnose an abdominal mass in a timely fashion has become a legal issue.

Special Concerns

• Whether patients younger than 6 years who have stage III disease should receive radiation therapy is controversial. In the NWTS-5 protocol, physicians were required to call an NWTS-5 radiation oncologist to discuss guidelines. The late toxicity of irradiating young children has been a concern for many, even with relatively low doses of radiation.
• Female patients have an increased risk of giving birth prematurely. Possible explanations include loss of elasticity of the uterine wall, surgical adhesions, and a high incidence of uterine anomalies.

MULTIMEDIA

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Media file 1:  CT scan in a patient with a right-sided Wilms tumor with favorable histology.
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Media type:  CT

Media file 2:  CT scan of child with a stage IV Wilms tumor with favorable histology. Note the bilateral pulmonary metastases.
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Media type:  CT

Media file 3:  Gross nephrectomy specimen shows a Wilms tumor pushing the normal renal parenchyma to the side.
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Media type:  Photo

REFERENCES

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• Breslow N, Olshan A, Beckwith JB, Green DM. Epidemiology of Wilms tumor. Med Pediatr Oncol. 1993;21(3):172-81. [Medline].
• Coppes MJ, Huff V, Pelletier J. Denys-Drash syndrome: relating a clinical disorder to genetic alterations in the tumor suppressor gene WT1. J Pediatr. Nov 1993;123(5):673-8. [Medline].
• Coppes MJ, Haber DA, Grundy PE. Genetic events in the development of Wilms'' tumor. N Engl J Med. Sep 1 1994;331(9):586-90. [Medline].
• Coppes MJ, Ritchey ML, D''Angio GJ. The path to progress in medical science: a Wilms tumor conspectus. Hematol Oncol Clin North Am. Dec 1995;9(6):xiii-xviii. [Medline].
• Coppes MJ, Arnold M, Beckwith JB, et al. Factors affecting the risk of contralateral Wilms tumor development: a report from the National Wilms Tumor Study Group. Cancer. Apr 1 1999;85(7):1616-25. [Medline].
• Coppes MJ, Pritchard-Jones K. Principles of Wilms'' tumor biology. Urol Clin North Am. Aug 2000;27(3):423-33, viii. [Medline].
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• D''Angio GJ, Rosenberg H, Sharples K, et al. Position paper: imaging methods for primary renal tumors of childhood: costs versus benefits [published erratum appears in Med Pediatr Oncol 1993;21(9):695]. Med Pediatr Oncol. 1993;21(3):205-12. [Medline].
• Dome JS, Cotton CA, Perlman EJ, et al. Treatment of anaplastic histology Wilms' tumor: results from the fifth National Wilms' Tumor Study. J Clin Oncol. May 20 2006;24(15):2352-8. [Medline].
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• Evans AE, Norkool P, Evans I, et al. Late effects of treatment for Wilms'' tumor. A report from the National Wilms'' Tumor Study Group. Cancer. Jan 15 1991;67(2):331-6. [Medline].
• Green DM, Breslow NE, Beckwith JB, et al. Effect of duration of treatment on treatment outcome and cost of treatment for Wilms'' tumor: a report from the National Wilms'' Tumor Study Group. J Clin Oncol. Dec 1998;16(12):3744-51. [Medline].
• Green DM, Donckerwolcke R, Evans AE, D''Angio GJ. Late effects of treatment for Wilms tumor. Hematol Oncol Clin North Am. Dec 1995;9(6):1317-27. [Medline].
• Green DM, Breslow NE, Beckwith JB, et al. 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. Jan 1998;16(1):237-45. [Medline].
• Knudson AG, Strong LC. Mutation and cancer: a model for Wilms' tumor of the kidney. J Natl Cancer Inst. Feb 1972;48(2):313-24. [Medline].
• Leisenring WM, Breslow NE, Evans IE, et al. Increased birth weights of National Wilms'' Tumor Study patients suggest a growth factor excess. Cancer Res. Sep 1 1994;54(17):4680-3. [Medline].
• Paulino AC. Current issues in the diagnosis and management of Wilms'' tumor. Oncology (Williston Park). Oct 1996;10(10):1553-65; discussion 1565-71. [Medline].
• Paulino AC, Thakkar B, Henderson WG. Metachronous bilateral Wilms'' tumor: the importance of time interval to the development of a second tumor. Cancer. Jan 15 1998;82(2):415-20. [Medline].
• Paulino AC, Wilimas J, Marina N, et al. Local control in synchronous bilateral Wilms tumor. Int J Radiat Oncol Biol Phys. Oct 1 1996;36(3):541-8. [Medline].
• Paulino AC, Wen BC, Brown CK, et al. Late effects in children treated with radiation therapy for Wilms'' tumor. Int J Radiat Oncol Biol Phys. Mar 15 2000;46(5):1239-46. [Medline].

Article Last Updated: Dec 19, 2006