Major advances have occurred over the last 50 years in the treatment of children with Wilms' tumor. These advances, made possible by the joint efforts of pediatric oncologists, surgeons, pathologists, radiation oncologists, and support personnel, have led to a dramatic improvement in survival, which currently approaches 90%.
Despite this progress, however, several controversies relating to the diagnosis and management of this intriguing childhood neoplasm remain unresolved. This article explores these controversial issues. As background to the dis-cussion, a brief overview of the epidemiology, etiology, histology, diagnosis, and treatment of this tumor will be presented.
Wilms' tumor is the most common intra-abdominal tumor of childhood, affecting approximately 1 child per 10,000 worldwide. The disease has no sex predilection, and the median age at presentation is approximately 3.5 years. Patients with bilateral tumors have been reported to present at a younger age.[2,3]
Specific congenital anomalies have been associated with Wilms' tumor; these include hemihypertrophy, aniridia, and genitourinary abnormalities. The WAGR syndrome (Wilms' tumor, aniridia, genitourinary malformation, and mental retardation) and the Denys-Drash syndrome (intersexual disorders, nephropathy, and Wilms' tumor) have been linked to a deletion and point mutation, respectively, within chromosome 11p13 (WT1 gene). The Beckwith-Wiedemann syndrome (macroglossia, organomegaly, hemihypertrophy, and omphalocoele) has been linked to the 11p15 locus (WT2 gene) and is thought to result from overexpression of a gene that is normally expressed by one of the paternal alleles. The incidences of Wilms' tumor in the WAGR, Denys Drash, and Beckwith-Wiedemann syndromes have been reported to be more than 30%, more than 90%, and less than 5%, respectively.
Knudson and Strong have proposed a two-hit hypothesis model to explain the earlier age of onset and bilateral presentation in children with a familial history of Wilms' tumor. In this hypothesis, a tumor develops from two mutational events--the first may be prezygotic or postzygotic and the second is always postzygotic. If the first mutation is prezygotic, the tumor would be heritable and may present as multiple tumors, following a Poisson distribution. Wilms' tumor development, however, still depends on a second postzygotic mutation. In contrast, if the first mutation is postzygotic, the tumor is nonhereditary and single.
Wilms' tumor is thought to arise from nephrogenic rests, persistent embryonal remnants in the kidney. The presence of multiple nephrogenic rests (nephroblastomatosis), especially when intralobar, places the child at increased risk for Wilms' tumor formation in the contralateral kidney.
The classic histologic pattern for Wilms' tumor is triphasic, consisting of epithelial, blastemal, and stromal elements. Most neoplasms have a good prognosis and are classified as favorable histology. Unfavorable histologies include focal or diffuse anaplasia and clear cell sarcoma of the kidney. The results of the third National Wilms' Tumor Study (NWTS 3) indicate a survival rate approaching 90% for patients with a favorable histology tumor and 55% to 75% for most patients with anaplasia or clear cell sarcoma. The staging system devised by the NWTS is summarized in Table 1.
The most common presentation is an asymptomatic abdominal mass. Hematuria, hypertension, malaise, and abdominal pain have also been documented. Several paraneoplastic syndromes have been reported; these include erythrocytosis, hypercalcemia, Cushing's syndrome, and acquired von Willebrand's disease.
Ultrasound has replaced the IV pyelogram (IVP) in the work-up of a patient with an abdominal mass. Unlike the IVP, ultrasound does not expose the patient to radiation. Furthermore, ultrasound can aid in determining whether the mass originates from the kidney, the status of the contralateral kidney, and the presence of a tumor thrombus in the renal vein or inferior vena cava.
Abdominal CT can provide detailed information regarding enlarged lymph nodes, tumor thrombi, the contralateral kidney, and the relationship of the tumor to adjacent organs. Liver involvement or invasion identified on the CT scan usually turns out to be nonexistent at surgical exploration.. A chest x-ray, preferably in four projections (posteroanterior, lateral, and two oblique views), is mandatory for determining whether a child has stage IV disease.
Treatment of a child with Wilms' tumor involves a radical or modified radical nephrectomy. A stage is assigned to the patient based on pathologic findings and imaging studies. The results of three National Wilms' Tumor Studies (NWTS 1-3) have provided guidance for further management.[7,10,11] In patients with stage I or II, favorable histology tumors and those with stage I, anaplastic histology, postoperative radiation is unnecessary if dactinomycin(Drug information on dactinomycin) (Cosmegan) and vincristine are given in combination. The NWTS 2 showed that the duration of dactinomycin and vincristine can be restricted to 10 weeks.
For patients with stage III or IV, favorable histology lesions, the addition of doxorubicin(Drug information on doxorubicin) has been shown to improve outcome. For stage III, favorable histology disease, the administration of fractionated radiation therapy at a dose of 1,000 cGy to the flank or abdomen is as effective as 2,000 cGy. Patients with tumors classified as stage IV, favorable histology who have at least stage III local disease receive the same radiation dose to the flank or abdomen as do those with stage III, favorable histology lesions.
The most common site of hemato-genous metastases is the lungs. For patients with lung metastases, whole-lung radiation therapy is employed and is given in a fractionated fashion to a dose of 1,200 cGy. For stage II-IV anaplastic tumors and all clear cell sarcomas, the renal bed or abdomen is at risk for local recurrence, and radiation therapy is given to reduce this risk.
Overall survival at 4 years ranges from 97% for patients with stage I, favorable histology disease to 54% for those with stage II-IV, anaplastic disease (Table 2). Despite the phenomenal improvement in the prognosis of patients with Wilms' tumor, various aspects of the diagnosis and management of this neoplasm remain controversial. These unresolved issues include the extent of surgery, the role of chemotherapy as an adjuvant and as treatment for recurrence, the optimal dose and timing of radiation therapy, and the approach to managing bilateral tumors.
Using a transverse supraumbilical incision, the abdomen is explored with attention to possible metastasis in the peritoneal cavity. The opposite kidney is visually inspected, and all surfaces are palpated for any lesions. Any suspicious nodules are biopsied. The involved kidney is then handled carefully to avoid tumor rupture and upstaging of the patient, which would require more extensive therapy. The kidney and hilar structures are removed en bloc along with a generous segment of the ureter. The renal vein and inferior vena cava are palpated to detect tumor thrombi prior to vessel ligation. The liver and para-aortic nodes are inspected, and gross nodules or enlarged nodes are biopsed. A random biopsy of the para-aortic nodes is performed if the lymph nodes appear normal.
In some patients, the tumor is found to be extensive, compromising vital structures. These tumors are biopsied and treated with chemotherapy and/or radiation therapy, which reduces the tumor burden and allows for subsequent resection. In NWTS 3, the use of preoperative treatment facilitated surgical resection in 93% of initially unresectable patients.
Should the Contralateral Kidney Be Explored?
Whether the contralateral kidney should be explored surgically is the subject of controversy. This procedure involves opening Gerota's fascia so that the surgeon can inspect and palpate the contralateral kidney. The finding of a contralateral tumor significantly changes patient management, as will be discussed below. Some have argued that exploration of the contralateral kidney adds to possible surgical morbidity and unnecessarily prolongs anesthesia duration, and have suggested that advances in diagnostic imaging obviate the need for this exploration. Table 3 summarizes current data on the pro-portion of patients with bilateral Wilms' tumor detected by preoperative imaging.
In NWTS 2 and 3, approximately one third of patients with bilateral tumors were not detected preoperatively by IVP or CT. Based on these findings, the NWTS surgical committee recommended careful exploration of the contralateral kidney in patients suspected to have Wilms' tumor in order to rule out bilateral involvement.
Recent studies by Koo et al and Goleta Dy et al have challenged this approach.[14,15] Concern has been raised over the potential morbidity caused by handling and mobilizing the opposite kidney, the longer incision, and complete mobilization of the contralateral colon. In both series, all bilateral tumors were diagnosed pre- operatively. In the report by Koo et al, patients had one or more of the following examinations: IVP, ultrasound, CT, and MRI. In Goleta Dy's report, all bilateral tumors were detected by ultrasound and/or CT.
Of the more commonly employed preoperative examinations, CT has identified more bilateral tumors than IVP or ultrasound. In the NWTS 4 report by Ritchey et al, 96% of involved kidneys were detected by CT. Likewise, at St. Jude 97% of patients with bilateral Wilms' tumor were identified preoperatively by CT scanning.
Does the morbidity from exploration of the contralateral kidney warrant elimination of this added procedure? In an NWTS 3 report of 1,910 children, 19.8% had some form of surgical complication, but none of these complications was attributable to contralateral kidney exploration. Likewise, in the study by Koo et al, 52 patients underwent contralateral kidney exploration without added morbidity.
Furthermore, the argument that exploration of the contralateral kidney necessitates a longer incision also is questionable. Patients who undergo surgery for Wilms' tumor almost always require a long incision to avoid rupture or spillage from a large tumor.
Finally, it should be noted that those who argue against performing contralateral kidney exploration have made their recommendations based on a combined total of 12 children with bilateral tumors. This contrasts with the more favorable experiences with this procedure in the 322 children from the NWTS and St. Jude. At present, therefore, formal inspection and palpation of the contralateral kidney are still necessary.
Can Partial Nephrectomy Be Used for Unilateral Tumors?
Concern has been raised regarding the potential for significant long-term renal dysfunction in patients with Wilms' tumor who have undergone unilateral nephrectomy.[19,20] Focal segmental glomerulosclerosis has been reported in patients with a unilateral kidney after nephrectomy for nephroblastoma.[21,22] The mechanisms of renal failure or dysfunction may include radiation nephritis, chemotherapy-related nephrotoxicity, and hyperfiltration of remaining nephrons secondary to removal of a significant amount of renal tissue. Theoretically, biopsy of the tumor, followed by chemotherapy and subsequent partial nephrectomy after tumor shrinkage, should preserve renal tissue and result in less morbidity for the patient.
Several authors have addressed the role of renal-sparing procedures in children with Wilms' tumors. At the Hospital for Sick Children in Toronto, 37 patients with a histologic diagnosis of Wilms' tumor after percutaneous biopsy were treated with a 4- to 6-week course of combination chemotherapy. Nine patients (four with a unilateral tumor and five with bilateral disease) underwent partial nephrectomy; of these, two patients had an intra-abdominal recurrence 18 months and 24 months, respectively, after partial nephrectomy. After preoperative chemotherapy, only 4 (13.3%) of 30 patients with unilateral tumors were amenable to partial nephrectomy.
The abdominal CT scans of 43 children with nonmetastatic unilateral Wilms' tumor at St. Jude Children's Research Hospital were reviewed retrospectively. Criteria for partial nephrectomy included tumor involving only one pole and less than one-third of the kidney, a functioning kidney, no invasion of the collecting system or renal vein, and clear margins between the tumor, kidney, and surrounding structures. Preoperative CT scans met these criteria in only 2 (4.7%) of 43 cases.
In a report by the Austrian/Hungarian Wilms' Tumor Study, 3 of 21 patients with a stage I Wilms' tumor underwent partial nephrectomy after preoperative chemotherapy, allowing renal preservation. Selection criteria for renal preservation included tumor involving only one pole, without collecting system or renal vein involvement; less than 25% residual tumor at week 4 after preoperative chemotherapy; normal excretion of tumor-involved kidney; more than 50% remaining renal parenchyma to be preserved after partial nephrectomy; and absence of Wilms' tumor nodules. These three patients remain disease-free 26 to 60 months after partial nephrectomy.
Other authors also have advocated partial nephrectomy for unilateral Wilms' tumor.
In a report by Ritchey et al from NWTS 1-4, 55 children developed renal failure after undergoing treatment for Wilms' tumor. Patients who had a nephrectomy for a unilateral Wilms' tumor and had a normal contralateral kidney had a .25% incidence of renal failure. The authors concluded that parenchymal-sparing procedures, such as partial nephrectomy, may not benefit this subset of patients because of their low risk of renal failure. They also concluded that children with bilateral Wilms' tumor or tumor in a solitary kidney should be considered for renal parenchymal-sparing operations because of their significant risk of renal dysfunction.
In summary, partial nephrectomy, either before or after chemotherapy, remains experimental for unilateral Wilms' tumor. Additional trials are needed to determine the role of partial nephrectomy in a disease for which cure rates approach 90% and the risk of renal failure is lesas than 1%. Because of the small numbers of patients who may be amenable to partial nephrectomy, it may be impossible to conduct such trials.