You are in: eMedicine Specialties > Urology > Cancer, Wilms Tumor and Neuroblastoma Wilms TumorArticle Last Updated: Jun 29, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Marc Cendron, MD, Associate Professor of Surgery, Harvard School of Medicine; Consulting Staff, Department of Urological Surgery, Children's Hospital Boston Marc Cendron 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 Editors: Leonard Gabriel Gomella, MD, FACS, Director of Urologic Oncology, Bernard W Godwin Associate Professor of Prostate Cancer, Department of Urology, Kimmel Cancer Center, Thomas Jefferson University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Dan Theodorescu, MD, PhD, Paul Mellon Professor of Urologic Oncology, Department of Urology, University of Virginia Health Sciences Center; J Stuart Wolf, Jr, MD, FACS, David A Bloom Professor of Urology, Director, Division of Minimally Invasive Urology, Department of Urology, University of Michigan Medical Center; William J Cromie, MD, MBA, President and Chief Executive Officer, Health Care, Capital District Physicians' Health Plan Author and Editor Disclosure Synonyms and related keywords: 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 INTRODUCTIONSection 2 of 11
  Wilms tumor (WT) is the fifth most common pediatric malignancy and the most common renal tumor in children. Treatment is a living 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 ProcedureFifty years ago, with surgery alone, the survival rate 2 years after nephrectomy was 20%. The introduction of adjuvant radiation raised the survival rate to 50% overall. Due 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 (OS) rate has risen to 90% in the last 30 years. FrequencyIncidence is approximately 0.8 cases per 100,000 persons. Approximately 500 new cases are diagnosed each year in the United States, with 6% of cases involving both kidneys. EtiologyThe tumor may arise in 3 clinical settings, the study of which resulted in the discovery of the genetic abnormalities that lead to the disease. The settings for Wilms tumor are (1) sporadic, (2) in association with genetic syndromes, and (3) familial. Although some of the molecular biology of WT is coming to light, the exact cellular mechanisms involved in the etiology of the tumor are still being investigated. Sporadic Wilms tumor Most cases are not part of a genetic malformation syndrome and have no familial history; however, familial Wilms tumor arises with high frequency in certain families. Genetic syndromes that predispose to and may include Wilms tumor include the following:
These clinical observations lead to genetic and molecular studies that enhance 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, Knudsen 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 they 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 patients 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 being thought to harbor sites of origin of Wilms tumor. The expression of WT1 peaks around birth. As the kidney matures, the expression declines. It also is 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 to be 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 (LOH) at chromosomes 1p and 16q. Children with LOH at 16q appear to be at greater risk of relapse and mortality than children without this genetic change. According to the latest NWTS-5, tumor-specific LOH 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. PathophysiologyThe pathophysiology of Wilms tumor is characterized by an abnormal proliferation of the metanephric blastema cells, which are felt to be primitive embryologic cells of the kidney. ClinicalThe mean age at diagnosis is 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 include hypertension, fever from 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 these syndrome anomalies should be checked periodically for Wilms tumor. Ultrasonography of the kidneys (once or twice per year) is a good screening tool. INDICATIONSSection 3 of 11
Indications for primary surgical excision of a Wilms tumor 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 ANATOMYSection 4 of 11
Wilms tumor arises from the primitive embryonal renal tissue. Grossly, Wilms tumor typically is an intrarenal solid or cystic mass, which displaces the collecting system. The tumor extends into the renal vein in 40% of cases. It rarely extends into the ureter and down to the bladder. It is bilateral in 6% of cases. Local invasion is rare and tumor spread is usually through lymphatic and vascular routes. CONTRAINDICATIONSSection 5 of 11
Contraindications to primary surgery 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. WORKUPSection 6 of 11
Lab Studies
Imaging Studies
Other Tests
Histologic FindingsWilms tumor arises from the primitive embryonal renal tissue and contains epithelial, stromal, and blastemal elements. Favorable histology (FH): This is present in 90% of cases. All 3 histological elements are present without any anaplastic features. The cure rate is close to 90%. Occasionally, foci of cartilaginous, adipose, or muscle tissue may appear (ie, teratoid Wilms tumor). Unfavorable histology (UH): This is present in 10% of the 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 present if less than 10% of the specimen has anaplastic features. Diffuse anaplasia is present if more than 10% of the specimen has anaplastic features. 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 typically is an intrarenal solid or cystic mass, which 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 generally is considered a benign lesion. StagingNWTSG recommends surgical staging in every case.
TREATMENTSection 7 of 11
Medical therapyThe role of chemotherapy is essential in the treatment of Wilms tumor. Refinements in the combination, length, and mode of administration of the various chemotherapeutic agents result from the successive NWTS trials and have helped to optimize survival rates while minimizing acute and long-term 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 for treatment of higher-stage (III and IV) disease. Surgical therapyAccording 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 being questioned because of the improvement in imaging techniques (CT scan, MRI) and may be dropped in the next NWTS protocol. If bilateral disease is diagnosed, nephrectomy is not performed but biopsy specimens are obtained. 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 will shrink the tumor in most cases. Contiguous involvement of adjacent organs frequently is 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 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 detailsMultimodal therapy (ie, surgery, radiation, and 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.
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 detailsEnter the Gerota (perinephric fascia) fascia to examine both kidneys. 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 detailsPostoperative chemotherapy and radiotherapy protocols are based on the surgical staging and follow the guidelines of the NWTSG.
Follow-upFollow-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. COMPLICATIONSSection 8 of 11
Surgical complications
Long-term complications
OUTCOME AND PROGNOSISSection 9 of 11
With the advent of multimodal therapy, the prognosis of Wilms tumor 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 CONTROVERSIESSection 10 of 11
The purpose of NWTSG-5, which is now closed for patient accrual, was to increase the cure rate for 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. Clinical outcomes may further be 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. REFERENCESSection 11 of 11
Article Last Updated: Jun 29, 2006 |
