eMedicine Specialties > Urology > Cancer, Wilms Tumor and Neuroblastoma

Wilms Tumor

Marc Cendron, MD, Associate Professor of Surgery, Harvard School of Medicine; Consulting Staff, Department of Urological Surgery, Children's Hospital Boston

Updated: May 5, 2009

Introduction

Wilms tumor (WT) is the fifth most common pediatric malignancy and the most common type of renal tumor in children. The treatment used to treat Wilms tumor is an example of success achieved through a multidisciplinary collaboration of the National Wilms' Tumor Study Group (NWTSG) and the Societe Internationale d'Oncologie Pediatrique (SIOP).

History of the Procedure

Fifty years ago, with surgery alone, the survival rate 2 years after nephrectomy was 20%. The introduction of adjuvant radiotherapy raised the survival rate to 50% overall. Owing to the cooperative efforts of oncologists, surgeons, and pathologists and with the introduction of chemotherapy with vincristine, dactinomycin (actinomycin D), and doxorubicin, the overall survival rate has risen to 90% in the last 30 years.

Frequency

The incidence of Wilms tumor is approximately 0.8 cases per 100,000 persons. Approximately 500 new cases are diagnosed each year in the United States, with 6% involving both kidneys.

Etiology

Wilms tumor may arise in 3 clinical settings, the study of which resulted in the discovery of the genetic abnormalities that lead to the disease. Wilms tumors can arise sporadically, can develop in association with genetic syndromes, or can be familial. Although some of the molecular biology of Wilms tumor is coming to light, the exact cellular mechanisms involved in the etiology of the tumor are still being investigated.

Sporadic Wilms tumor

Most cases of Wilms tumor are not part of a genetic malformation syndrome and occur in the absence of a family history of the malignancy; however, familial Wilms tumor is very common in certain families. Genetic syndromes that predispose to and may include Wilms tumor include the following:

• Beckwith-Wiedemann syndrome (macroglossia, gigantism, and umbilical hernia)
• Hemihypertrophy
• Congenital aniridia
• Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR syndrome)
• Denys-Drash syndrome (Wilms tumor, pseudohermaphroditism, and glomerulopathy)
• Trisomy 18 mutation

These clinical observations have led to genetic and molecular studies that have enhanced discovery of the genetic mechanism that promotes Wilms tumor genesis. In addition, the molecular genetic characterization of Wilms tumor plays a major role in the understanding of the genetic aspects of carcinogenesis in general.

Molecular genetics

Based on the model developed originally for retinoblastoma, Knudson and Strong proposed that Wilms tumor results from 2 mutational events based on loss of function of tumor suppressor genes.

The first mutation, the inactivation of the first allele of the specific tumor suppressor gene, involves prezygotic and postzygotic aspects. Prezygotic (constitutional or germline) mutations are inherited or result from a de novo germline mutation. This mutation is present in all body cells and predisposes the patient to familial and/or multiple Wilms tumor. Postzygotic mutations occur only in specific cells, and they predispose to single tumors and sporadic cases of Wilms tumor.

The second mutation is inactivation of the second allele of the specific tumor suppressor gene.

Although the model of the retinoblastoma suppressor gene has been used to explain the genetics, clinical characteristics of Wilms tumor suggest that the molecular genetic mechanism in the second type of mutation depends on more than one tumor suppressor gene.

The WT1 gene (at chromosome 11p13) is a tissue-specific gene for renal blastemal cells and glomerular epithelium, with both renal precursor cells thought to harbor sites of origin of Wilms tumor. The expression of WT1 peaks around birth. As the kidney matures, the expression declines. It is also a dominant oncogene; hence, a certain mutation in only 1 of the 2 alleles is enough to promote changes that may lead to the formation of Wilms tumor. The WT2 gene (at chromosome 11p15) remains isolated.

In addition, several genetic factors have been identified as possible prognostic factors in individuals with Wilms tumor. One such factor is loss of heterozygosity at chromosomes 1p and 16q. Children with loss of heterozygosity at 16q appear to be at greater risk of relapse and mortality than children without this genetic change. According to the latest NWTS-5 study, tumor-specific loss of heterozygosity for both chromosomes 1p and 16q, identified in about 5% of patients with favorable-histology Wilms tumor, was shown to be associated with a significantly increased risk of relapse and death.

Pathophysiology

The pathophysiology of Wilms tumor is characterized by an abnormal proliferation of the metanephric blastema cells, which are believed to be primitive embryologic cells of the kidney.

Presentation

Wilms tumor is diagnosed at a mean age of 3.5 years. The most common feature at presentation is an abdominal mass. Abdominal pain occurs in 30%-40% of cases. Other signs and symptoms of Wilms tumor include hypertension, fever caused by tumor necrosis, hematuria, and anemia.

Major congenital anomalies include genitourinary anomalies (WAGR and Denys-Drash syndromes, 5% of cases), ectopic solitary horseshoe kidney, hypospadias and cryptorchidism, hemihypertrophy and organomegaly (Beckwith-Wiedemann syndrome, 2% of cases); and aniridia (1% of cases). Children with such syndrome anomalies should undergo periodic testing for Wilms tumor. Ultrasonography of the kidneys (once or twice per year) is a good screening tool.

Indications

Indications for primary surgical excision of a Wilms tumor (WT) include tumors confined to the kidney, extending beyond the kidney but not crossing the midline, and with or without vascular extension. Postchemotherapy excision of the tumor is indicated in patients with bilateral tumors, tumors that extended beyond the midline and have shrunk, and tumors with vascular extension. Surgery alone is not recommended for Wilms tumor based on the results of the NWTS-5 study.

Relevant Anatomy

Wilms tumor (WT) arises from the primitive embryonal renal tissue. Grossly, Wilms tumor is typically an intrarenal solid or cystic mass, which may displace and, in rare cases, invade the renal collecting system. The tumor extends into the renal vein in 40% of cases. In very rare cases, it extends into the ureter and down to the bladder, where it may cause hematuria. Wilms tumor is bilateral in 6% of cases. Local invasion is rare and tumor spread is usually through lymphatic and vascular routes.

Contraindications

Contraindications to primary surgery for Wilms tumor (WT) include bilateral tumors and documented metastatic disease. Large tumors that extend beyond the midline, have vascular extension, or both are relative contraindications since some surgeons elect to obtain tissue via surgical excision, but this may expose patients to increased surgical risks.

Workup

Laboratory Studies

• Complete blood count
• Basic metabolic panel, including serum calcium levels
• Coagulation abnormalities (to rule out acquired von Willebrand disease, which is coincident in up to 8% of individuals with Wilms tumor)
• Liver function tests
• Renal function tests
• Urinalysis and urine culture

Imaging Studies

• Ultrasonography
  • Initial diagnosis of a renal or abdominal mass, possible renal vein or inferior vena cava (IVC) thrombus (Doppler flow study may be helpful in the setting of vascular invasion.)
  • Information regarding liver and other kidney
• CT scanning of the chest and abdomen
  • Differential diagnosis of a kidney tumor versus adrenal tumor (neuroblastoma)
  • Liver metastases
  • Status of opposite kidney
  • Lymph node assessment
  • Status of chest with respect to metastases
• Chest radiography - As a baseline for pulmonary metastases
• Bone scan - Necessary for children with clear cell sarcoma of the kidney
• Magnetic resonance imaging
  • Typically, these tumors appear inhomogeneous on gadolinium-enhanced MRI, while the nephrogenic rests (which sometimes are precursors of Wilms tumor [WT]) appear as homogeneous masses.
  • MRI is also useful for magnetic resonance venography to aid in the diagnosis of thrombus of the renal vein of the IVC.
  • MRI scanning of the head is recommended in patients with suspected rhabdoid and clear cell carcinoma of the kidney.

Other Tests

• Chromosomal analysis and gene mapping
• Analysis for LOH on chromosomes 1p and 16q

Histologic Findings

Wilms tumor arises from the primitive embryonal renal tissue and contains epithelial, stromal, and blastemal elements.

Favorable histology (90% of cases) is characterized by all 3 histological elements, without any anaplastic features. The cure rate in these cases is close to 90%. Occasionally, foci of cartilaginous, adipose, or muscle tissue may appear (ie, teratoid Wilms tumor).

Unfavorable histology (10% of cases): Clear cell carcinoma of the kidney (bone-metastasizing renal tumor of childhood) and rhabdoid tumor of the kidney are now considered distinct type tumors and should not be included.

Anaplasia is defined by nuclear enlargement, nuclear hyperchromasia, and abnormal mitoses. Focal anaplasia is defined as less than 10% anaplastic features in a specimen, whereas more than 10% is considered diffuse anaplasia. Nephrogenic rests are foci of abnormally present nephrogenic renal blastemal cells (metanephric blastema). These are considered precursors of Wilms tumor. Nephroblastomatosis is the diffuse presence of nephrogenic rests. It may be perilobar; intralobar (usually the more primitive elements are situated intralobarly), which has been associated more frequently with the development of Wilms tumor than the perilobar blastemal rests; or panlobular.

Grossly, Wilms tumor is typically an intrarenal solid or cystic mass that displaces the collecting system. It usually has a pseudocapsule and may contain hemorrhage and necrosis. The tumor extends into the renal vein in 40% of cases. It rarely extends into the ureter and bladder.

The partially differentiated cystic nephroblastoma (ie, multilocular cystic nephroma) with possible Wilms elements is generally considered a benign lesion.

Staging

NWTSG recommends surgical staging in every case. In addition, recent data have suggested that patients with Wilms tumor undergo an individual risk assessment based on biological determinants or markers.

• Stage I: The tumor is limited to the kidney and is excised completely.
• Stage II: The tumor extends beyond the kidney but is excised completely. Capsular penetration, renal vein involvement, and renal sinus involvement may also be found. A biopsy of the tumor is performed, and local spillage occurs.
• Stage III: Residual intra-abdominal tumor (nonhematogenous) exists after the completion of surgery. Lymph node findings are positive, or peritoneal implants are found. The resected specimen has histologically positive margins, or the tumor has been spilled into the abdominal cavity.
• Stage IV: Hematogenous or lymph node metastasis has occurred outside the abdomen or pelvis.
• Stage V: Synchronous bilateral involvement has occurred. Each side is assigned a stage from I to III, and histology is based on biopsy findings.

Treatment

Medical Therapy

Chemotherapy is essential in the treatment of Wilms tumor (WT). Refinements in the combination, length, and mode of administration of the various chemotherapeutic agents have resulted from the successive NWTS trials and have helped to optimize survival rates while minimizing acute and chronic toxicities.

Chemotherapy protocols vary from study to study; however, the main agents administered include vincristine, dactinomycin, and doxorubicin.

In the SIOP trials, chemotherapy is administered up front to reduce tumor volume, thereby decreasing the risk of surgical spillage of tumor.

Radiation therapy is restricted to treatment of higher-stage (III and IV) disease.

Surgical Therapy

According to the NWTSG protocol, the first step in the treatment of Wilms tumor is surgical staging followed by radical nephrectomy, if possible.

Make a transverse abdominal incision and begin abdominal exploration. Exploration should include the contralateral kidney by mobilizing the ipsilateral colon and opening the Gerota fascia. Exploration of the contralateral kidney is currently not recommended because of the improvement in imaging techniques (CT scan, MRI). If bilateral disease is diagnosed, nephrectomy is not performed, but biopsy specimens are obtained. New protocols in the management of bilateral Wilms tumor are being explored. If the disease is unilateral, radical nephrectomy and regional lymph node dissection or sampling are performed.

If the tumor is unresectable, biopsies are performed and the nephrectomy is deferred until after chemotherapy, which, in most cases, will shrink the tumor. Contiguous involvement of adjacent organs is frequently overdiagnosed. The overall surgical complication rate for Wilms tumor is approximately 20%. If IVC thrombus is present, preoperative chemotherapy will reduce the cavotomy rate by 50%.

With bilateral Wilms tumor (6% of cases), surgical exploration, biopsies from both sides, and accurate surgical staging (including lymph node biopsy of both sides) are performed. This is followed by 6 weeks of chemotherapy that is appropriate to the stage and histology of the tumor. Then, reassessment is performed using imaging studies, followed by definitive surgery with (1) unilateral radical nephrectomy and partial nephrectomy on the contralateral side; (2) bilateral partial nephrectomy; and (3) unilateral nephrectomy only, if the response was complete on the opposite side. This approach dramatically reduces the renal failure rate following bilateral Wilms tumor therapy.

The overall 2-year survival rate is higher than 80% with this approach, and the nephrectomy rate drops by 50% in patients with bilateral Wilms tumor. Bilateral partial nephrectomy is possible after chemotherapy or, if the tumor on one side responds completely to chemotherapy, with no subsequent need for nephrectomy.

Tumor biomarkers, histology, and stage are the most important prognostic factors in cases of unilateral disease. Bilateral high-stage tumors with unfavorable histology are associated with a poor prognosis in spite of the multimodal therapy.

Preoperative Details

Multimodal therapy (ie, surgery, radiation, chemotherapy) is the key to success when treating Wilms tumor.

The NWTSG recommends preoperative chemotherapy (after initial exploratory laparotomy and biopsy) in the following situations:

• Intracaval tumor extension: This occurs in 5% of cases of Wilms tumor. It is associated with a 40% rate of surgical complications, even in experienced hands. Upfront chemotherapy after staging and biopsy reduces tumor and thrombus size, which account for 25% of surgical complications.
• Inoperable tumors: Large tumors that involve vital structures make resection difficult. The complication rate is high, and the incidence of tumor spill soilage is also high. Upfront chemotherapy reduces soilage by 50%.
• Bilateral Wilms tumor

SIOP advocates upfront chemotherapy without previous laparotomy and biopsy. The NWTSG suggests that this approach comprises a 1%-5% risk of treating a benign disease.

Chemotherapy without proper surgical staging (eg, staging by means of imaging studies only) may alter the actual initial stage of the disease by the time of surgery and may subsequently alter decisions regarding the adjuvant chemotherapy and radiation therapy, which is based on the surgical staging.

Intraoperative Details

Enter the Gerota (perinephric fascia) fascia to examine the kidney. In cases of unilateral tumor, perform a nephrectomy if the opposite side is normal. In cases of bilateral disease, excisional biopsy of visible tumor is indicated, followed by re-resection with nephron preservation after chemotherapy. Identify the involved nodes with clips to facilitate postoperative radiation therapy.

Postoperative Details

Postoperative chemotherapy and radiotherapy protocols are based on the surgical staging and follow the guidelines of the NWTSG.

• Stage I favorable histology and unfavorable histology or stage II favorable histology
  • Nephrectomy
  • Postoperative vincristine and actinomycin D (18 wk)
• Stage II focal anaplasia or stage III favorable histology and focal anaplasia
  • Nephrectomy
  • Abdominal radiation (1000 cGy)
  • Vincristine, actinomycin D, and doxorubicin (24 wk)
• Stage IV favorable histology or focal anaplasia
  • Nephrectomy
  • Abdominal irradiation according to local stage
  • Bilateral pulmonary irradiation (1200 cGy) with sulfamethoxazole and trimethoprim (Bactrim) prophylaxis for Pneumocystis carinii
  • Chemotherapy with vincristine, actinomycin D, and doxorubicin
• Stage II and stage IV diffuse anaplasia
  • Nephrectomy
  • Abdominal irradiation
  • Whole lung irradiation for stage IV
  • Chemotherapy for 24 months with vincristine, actinomycin D, doxorubicin, etoposide, and cyclophosphamide

Follow-up

Follow-up care after treatment must be long (if possible, lifelong) because Wilms tumor may recur after several years. Follow-up consists of chest radiography and abdominal ultrasonography, CT scan, or MRI every 3 months for the first 2 years, every 6 months for another 2 years, and once every 2 years thereafter.

Complications

Surgical complications

• Small-bowel obstruction (7%)
• Hemorrhage (6%)
• Wound infection, hernia (4%)
• Vascular complications (2%)
• Splenic and intestinal injury (1.5%)

Long-term complications

• Renal function: The rate of chronic renal failure is 1% overall. Of these cases, 70% are children with bilateral Wilms tumor (WT). In unilateral Wilms tumor, the rate is 0.25%. Bilateral nephrectomy is the most common cause of chronic renal failure, followed by treatment-related causes such as radiation or surgical complications. Unrecognized renal disease, such as Denys-Drash syndrome, is rare but should be kept in mind. The damage produced by radiation is dose-dependent, and the rate of impairment in creatinine clearance is approximately 20% with total abdomen irradiation with less than 1200 rads.
• Cardiac function: Anthracyclines such as doxorubicin produce cardiac muscle impairment in 5% of those receiving a cumulative of 400 mg/m². The overall incidence rate of some form of cardiac damage is 25% in those treated with anthracycline. The overall incidence of cardiac failure is 1.7%. The mean time to the onset of cardiac failure is 8 years (according to NWTSG-2 and NWTSG-3). If lung irradiation is added, the rate of cardiac failure is 5.4%.
• Pulmonary function: Radiation pneumonitis is encountered in 20% of the cases receiving total pulmonary radiation. The rate of diffuse interstitial pneumonitis with varicella and Pneumocystis infection is 13%.
• Hepatic function: Actinomycin D and radiation may damage the liver, with an overall incidence rate of 10%. Hepatic venoocclusive disease (VOD) is a clinical syndrome of hepatotoxicity and consists of jaundice, ascites, hepatomegaly, and weight gain. The incidence rate is 8%. Patients younger than 1 year have double the incidence of VOD.
• Gonadal function: Chemotherapy may affect gonadal function in boys but rarely affects the function of ovaries. Abdominal irradiation may induce ovarian failure if ovaries were in the target field.
• Musculoskeletal function: Clinical rickets is possible due to renal tubular Fanconi syndrome caused by drugs that are too cytotoxic. Skeletal sequelae of radiation, including scoliosis or kyphosis, result from uneven growth when the radiation was unilaterally targeted to the vertebral bodies and the dose was higher than 2000 rads.
• Second malignant neoplasm: These may result from inherited disposition and treatment, bone tumors, breast cancer, and thyroid cancer. The rate after a medium follow-up of 15 years is 1.6%, which is 5 times the expected rate. Second malignant neoplasm can possibly be limited by limiting the intensive chemotherapy and radiotherapy and reserving the intensive treatment regimens only for the high stages and the cases with unfavorable histology.

Outcome and Prognosis

With the advent of multimodal therapy, the prognosis of Wilms tumor (WT) is good, and it is considered an example of success in cancer therapy. The overall survival rate of Wilms tumor is 90%. Cases that involve diffuse anaplasia and stage III or IV disease that recur despite complex therapy have a much poorer prognosis. However, the addition of newer chemotherapeutic agents such as cyclophosphamide, ifosfamide, cisplatin, carboplatin, and etoposide, especially the ICE combination (ifosfamide, carboplatin, etoposide), have contributed to significantly increased postrelapse survival rates to 50%-60%.

Future and Controversies

The purpose of NWTSG-5, which is now closed for patient accrual, was to increase the cure rate in patients with unfavorable histology by using chemotherapy regimens based also on cyclophosphamide and etoposide (VP-16). Another goal of NWTSG is to reduce the rate of adverse effects of treatment by modifying the radiotherapy delivery technique to the abdomen and lung.

In addition, using risk stratification based on tumor molecular profile may allow treatment to be tailored for each patient individually.

Clinical outcomes may be further improved through promising new cytotoxic agents such as the camptothecin analogue topotecan. Another promising class of chemotherapeutic agents are the antiangiogenesis agents, which target the vascular endothelial growth factor (VEGF) pathway.

References

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2. Davies-Johns T, Chidel M, Macklis RM. The role of radiation therapy in the management of Wilms' tumor. Semin Urol Oncol. Feb 1999;17(1):46-54. [Medline].

3. de Kraker J, Jones KP. Treatment of Wilms tumor: an international perspective. J Clin Oncol. May 1 2005;23(13):3156-7; author reply 3157-8. [Medline].

4. Egeler RM, Wolff JE, Anderson RA, Coppes MJ. Long-term complications and post-treatment follow-up of patients with Wilms' tumor. Semin Urol Oncol. Feb 1999;17(1):55-61. [Medline].

5. Goske MJ, Mitchell C, Reslan WA. Imaging of patients with Wilms' tumor. Semin Urol Oncol. Feb 1999;17(1):11-20. [Medline].

6. Green DM. The treatment of stages I-IV favorable histology Wilms' tumor. J Clin Oncol. Apr 15 2004;22(8):1366-72. [Medline].

7. Levien MG, Bringelsen KA. Postoperative chemotherapy in the National Wilms' Tumor Studies. Semin Urol Oncol. Feb 1999;17(1):40-5. [Medline].

8. Li W, Kessler P, Yeger H, Alami J, Reeve AE, Heathcott R. A gene expression signature for relapse of primary wilms tumors. Cancer Res. Apr 1 2005;65(7):2592-601. [Medline].

9. Metzger ML, Dome JS. Current therapy for Wilms' tumor. Oncologist. Nov-Dec 2005;10(10):815-26. [Medline].

10. Ritchey ML. The role of preoperative chemotherapy for Wilms' tumor: the NWTSG perspective. National Wilms' Tumor Study Group. Semin Urol Oncol. Feb 1999;17(1):21-7. [Medline].

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12. Vujanic GM, Sandstedt B, Harms D, Kelsey A, Leuschner I, de Kraker J. Revised International Society of Paediatric Oncology (SIOP) working classification of renal tumors of childhood. Med Pediatr Oncol. Feb 2002;38(2):79-82. [Medline].

Keywords

Wilms tumor, nephroblastoma, WT, embryoma of the kidney, mixed tumor of the kidney, sporadic Wilms tumor, familial Wilms tumor, bilateral Wilms tumor, Beckwith-Wiedemann syndrome, hemihypertrophy, congenital aniridia, WAGR syndrome, Denys-Drash syndrome, trisomy 18 mutation, teratoid Wilms tumor

Contributor Information and Disclosures

Author

Marc Cendron, MD, Associate Professor of Surgery, Harvard School of Medicine; Consulting Staff, Department of Urological Surgery, Children's Hospital Boston
Marc Cendron, MD is a member of the following medical societies: American Academy of Pediatrics, American Urological Association, European Society for Paediatric Urology, Johns Hopkins Medical and Surgical Association, New Hampshire Medical Society, Society for Fetal Urology, and Society for Pediatric Urology
Disclosure: Nothing to disclose.

Medical Editor

Leonard Gabriel Gomella, MD, FACS, The Bernard W Godwin Professor of Prostate Cancer Chairman, Department of Urology, Associate Director of Clinical Affairs, Kimmel Cancer Center, Thomas Jefferson University
Leonard Gabriel Gomella, MD, FACS is a member of the following medical societies: American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Laser Medicine and Surgery, American Urological Association, Sigma Xi, Society for Basic Urologic Research, Society of University Urologists, and Society of Urologic Oncology
Disclosure: GSK Consulting fee Consulting; Astra Zeneca Honoraria Speaking and teaching; Watson Pharmaceuticals Consulting fee Consulting

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Dan Theodorescu, MD, PhD, Paul Mellon Professor of Urologic Oncology, Department of Urology, University of Virginia Health Sciences Center
Dan Theodorescu, MD, PhD is a member of the following medical societies: American Cancer Society, American College of Surgeons, American Urological Association, Medical Society of Virginia, Society for Basic Urologic Research, and Society of Urologic Oncology
Disclosure: Nothing to disclose.

CME Editor

J Stuart Wolf Jr, MD, FACS, David A Bloom Professor of Urology, Director of Division of Minimally Invasive Urology, Department of Urology, University of Michigan
J Stuart Wolf Jr, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Catholic Medical Association, Endourological Society, Society for Urology and Engineering, Society of Laparoendoscopic Surgeons, Society of University Urologists, and Society of Urologic Oncology
Disclosure: Terumo Corporation Consulting fee Consulting; Omeros Corporation Consulting fee Consulting

Chief Editor

Bradley Fields Schwartz, DO, FACS, Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine
Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoendoscopic Surgeons, and Society of University Urologists
Disclosure: Nothing to disclose.

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