WILMS' TUMOR

Wilms' tumor is the most common embryonic malignancy of renal origin. Approximately 500 new patients are seen annually in the United States.13,14 Although the overall management of children with Wilms' tumor is one of the great success stories in cancer therapy and currently more than 90% of children survive 4 years after their diagnosis, there is still room for improvement.

Genetic considerations

Children susceptible to Wilms' tumor are born with a constitutional DNA mutation in one allele of a gene. One copy of a presumed tumor suppressor gene mutation is inherited from one parent and results from a spontaneous mutation. Under these circumstances, a new genetic event such as deletion of inhibition of the paired allele of the gene would be needed for tumorigenesis to occur. This genetic presentation increases the likelihood of bilateral tumors and earlier age at onset as compared with sporadic cases, in which tumorigenesis requires two independent mutations.2,5,6 Two-event activation of a tumor suppressor gene occurs at two different genetic sites. The first allele is inactivated by mutation of the gene itself; the second allele is inactivated by loss of heterozygosity (a loss of chromosomal material).

Wilms' tumor occurring in children with aniridia, genitourinary abnormalities, and mental retardation is known as the WAGR syndrome.2,13 Wilms' tumor will develop in 30% of these children. The karyotypic analysis of these patients demonstrates a deletion of the short arm (the p arm) of one copy of chromosome 11 at the 11p13 locus. The syndrome actually encompasses a number of contiguous genes, including the aniridia gene PAX6 and the first Wilms' tumor suppressor gene, called WT1. In contrast to WAGR, children with the Denys-Drash syndrome with Wilms' tumor have only point mutations of the WT1 gene.13 These patients account for approximately 1% of all children with Wilms' tumor. In instances of unilateral Wilms' tumor, fewer than 15% will have mutations of the WT1 gene. This suggests that more than one genetic locus is involved in the development of Wilms' tumor.

Children with Beckwith-Wiedemann syndrome have the WT2 gene, characterized by a loss of DNA at the 11p15 locus.15-18 Much interest has been focused on insulin-like growth factor II, which resides in 11p15, because it is subject to genomic imprinting. An additional Wilms' tumor locus is seen on the long arm (the q arm) of chromosome 16 (16q). This occurs in approximately 20% of patients with Wilms' tumor.2,19 Some investigators have suggested that this is a statistically important adverse prognostic factor. These patients have a relapse rate 3 times higher and a mortality rate 12 times higher than Wilms' tumor patients without loss of heterozygosity. Twelve percent of Wilms' tumor patients have loss of heterozygosity at chromosome 1p, and they too have higher relapse and mortality rates. The involvement of genes at 11p13, 11p15, and 16q3 does not play a role in familial cases of Wilms' tumors where a detailed linkage analysis is required. Children with nephrogenic rests in their kidneys are at risk for mutational change and development of Wilms' tumor.20

Clinical presentation

Most patients with Wilms' tumor are between the ages of 1 and 4 years; the mean age is 3 years. Wilms' tumor usually presents as a smooth, round, nontender abdominal flank mass. Hematuria is observed in 20% of patients; hypertension (due to renin-angiotensin release related to compression of the juxtaglomerular apparatus) in 20%; anorexia, fever, and weight loss in approximately 10%; and occasionally polycythemia (due to erythropoietin release) is noted. Approximately 10% of patients are diagnosed after the onset of hematuria or flank pain following trivial renal trauma. Coexisting conditions associated with an increased risk of Wilms' tumor include Beckwith-Wiedemann syndrome, sporadic aniridia, hemihypertrophy, a positive family history, Denys-Drash syndrome, Perlman's syndrome, WAGR syndrome, and Klippel-Trenaunay syndrome.2,13,18 Patients with aniridia having hemihypertrophy and those with Beckwith Wiedemann's syndrome should be screened with a surveillance renal ultrasonographic examination every 3 months until they are 8 to 10 years of age.17 In familial instances, there is a 20% incidence of bilateral Wilms' tumor, which are synchronous in two-thirds of the patients. The incidence of bilateral Wilms' tumor is only 4% to 5% in sporadic cases.18,21

Diagnosis

Evaluation of the renal mass is accomplished by obtaining an ultrasound to determine whether the mass is cystic or solid, followed by CT of the abdomen with contrast. The ultrasound usually confirms that the mass is solid, but there is a variant of Wilms' tumor that is cystic and is associated with an improved prognosis. Abdominal ultrasonographic examination may also be helpful in identifying intravascular extension of tumor into the renal vein and vena cava. In selected patients, echocardiography is useful in identifying atrial tumor extension. The CT shows an intrarenal neoplasm that displaces the collecting system medially in most patients.22 Chest radiograph and, in some instances, chest CT are obtained to assess for pulmonary metastases.

Tumor histologic type and the stage of disease at diagnosis are important predictors of survival. Ninety percent of tumors with favorable histology respond well to chemotherapy. Favorable histology includes blastemal epithelial, myxoid, and cystic components.23, 24 Ten percent of the tumors have unfavorable (anaplastic) histology. Three additional pediatric renal tumors include sarcomatous, clear cell, and rhabdoid lesions, which are considered separate entities from Wilms' tumor but are treated as unfavorable variants. Three-fourths of these lesions present as either stage III or stage IV tumors, and patients have a 3-year survival rate of less than 20%. Clear cell tumors metastasize early to the brain and bone; anaplastic tumors often relapse despite more aggressive therapy. Rhabdoid tumors are the least common but most lethal of the pediatric renal tumors. Renal cell carcinoma also can occur in childhood and carries a 50% mortality rate.

A key factor in the management of Wilms' tumor is resection of the primary tumor. This is accomplished through a generous transverse, transperitoneal approach. Early control of the vessels is preferred when possible.25 Evaluating for extension of tumor into the renal vein and vena cava is an important consideration. Great care is taken to remove the tumor without violating the capsule to avoid tumor spillage, which adversely affects outcomes. During the procedure, perirenal and paraaortic lymph nodes are acquired for staging purposes, but a formal retroperitoneal lymph node dissection is unnecessary.26 The contralateral kidney should be evaluated for a second tumor. Intracaval tumor extension that is identified preoperatively by ultrasonographic examination often responds to neoadjuvant chemotherapy.27 Initially unresectable tumors also shrink when treated with chemotherapy and can be excised subsequently at second-look surgical procedures.28 Bilateral Wilms' tumor is usually managed by initial biopsy of both kidneys and chemotherapy. The goal is to salvage the renal parenchyma if possible with delayed second-look resection and bilateral heminephrectomy. This may not be possible in many patients, and complete nephrectomy on one side and partial nephrectomy on the other may be necessary.13,18,25,29 If both kidneys are not amenable to partial resection, additional chemotherapy is administered and a third-look laparotomy is performed. Patients that are unresponsive and require bilateral nephrectomy are managed with peritoneal dialysis and chemotherapy for 1 year before renal transplantation.

Staging

In the National Wilms' Tumor Study-4 (NWTS-4), patients were randomized according to their tumor stage and histologic type and whether they received standard chemotherapy administration or pulse-intensified treatments after tumor resection.2,13,18 The current staging criteria for Wilms' tumor are listed in Table 1. Stage I patients with favorable histology (low-risk category) did not have radiation and received actinomycin D and vincristine for 24 weeks or pulse-intensive actinomycin D and vincristine for 18 weeks. Stage I patients with anaplasia were treated similarly. Stage II patients with favorable histology (low risk) received no radiation and were randomized to receive either actinomycin D or vincristine for 22 weeks or 65 weeks, respectively. They were compared with a similar group of patients who received pulse-intensive actinomycin D and vincristine for either 18 weeks or 60 weeks. Stage III patients with favorable histology (intermediate risk) received radiation therapy (1,080 cGy) and were randomized to receive actinomycin D and vincristine for either 26 or 65 weeks versus pulse-intensive actinomycin D and vincristine for either 24 or 54 weeks. Patients with higher risk tumors, which included clear cell sarcoma of the kidney, and stage IV patients with favorable histology were considered for this arm of the protocol. Any patients with stages II through IV tumors with anaplasia (high risk) received radiotherapy and were randomized to actinomycin D, vincristine, and doxorubicin for 65 weeks or actinomycin D, vincristine, doxorubicin, and cyclophosphamide for 65 weeks.

Table 1. Staging Criteria: National Wilms' Tumor Study 5

Stage	Criteria
I	A tumor limited to the kidney and completely resected. The renal capsule must be intact without rupture or violation. The vessels of the renal sinus are free of disease.
II	A tumor that extends beyond the kidney but is completely resected. There may be regional extension of tumor related to penetration of the capsule or invasion of the renal sinus. Blood vessels outside the renal sinus may contain tumor. The tumor may be violated by a biopsy or sustain spillage of tumor that is confined to the flank area. When the resection is completed, there should be no microscopic evidence of tumor at or beyond the margins of resection.
III	There is residual tumor confined to the abdomen or lymph nodes in the renal hilum or pelvis, penetration of tumor through the peritoneal surface, tumor implants on the peritoneal surface, either gross or microscopic tumor at or beyond the margin of the surgical resection, or an incomplete resection because of local infiltration into vital structures; finally, there may be generalized tumor spread that is not confined to the flank area.
IV	Hematogenous metastatic disease to lung, liver, bone, or brain or lymph node metastases outside the abdomen or pelvis. Pulmonary nodules observed on chest CT must be biopsied for definitive diagnosis of stage IV disease.
V	Bilateral renal involvement at diagnosis. The tumors on each side must be staged individually according to the above noted criteria .

The results of NWTS-4 are listed in Table 2. For children with tumors with favorable histology with either stage I or II disease, there were no significant differences in survival according to the various arms of the protocols. Approximately 98.6% of patients with stage I disease survived and 89% of patients with stage II disease survived using standard therapy, compared with 98% with pulse-intensive therapy with stage I disease and 85% with stage II disease. Slightly lower survival was seen in the children older than 4 years. For stage I anaplastic tumors, survival was better with standard therapy than with pulse-intensive therapy (92.3% versus 85.7%). In patients with stage III tumors and favorable histology, there were no significant advantages to pulse-intensive therapy. Survival was achieved in 98.6% of patients after pulse-intensive therapy versus 99.3% of patients given standard therapy in the first 2 years of life. In patients with stage IV disease with favorable histology (three-quarters had lung metastases), similar outcomes were obtained with standard versus pulse-intensive therapy.13,30 All patients with stages II to IV disease with unfavorable histology demonstrated a higher survival with pulse-intensive therapy (90.9%) than with standard therapy (71.4%). In instances of clear cell sarcoma, the relapse-free rate was similar among patients receiving pulse-intensive versus standard therapy, but the survival was slightly better in the pulse-intensive group.

Table 2. Results of National Wilms' Tumor Study 4

		Standard Rx		Pulse-intensive Rx
Stage	Age (y)	Relapse free (%)	Survival (%)	Relapse free (%)	Survival (%)
I/FH	2	92.5	99.6	94.3	98.6
	4	91.0	98.5	92.3	97.3
I/ana	2	93.8	92.3	87.5	85.7
	4	93.8	9.3	87.5	85.7
II/FH	2	89.0		85.4
	4	84.0		82.8
III/FH	2	95.2	99.3	90.8	98.6
	4	91.5	93.8	88.9	94.4
IV/FH	2	79.5	89.2	78.5	88.0
	4	77.5	89.1	74.5	80.0
IV/FH, lung met	2	71.4	71.4	90.9	90.9
	4	71.4	71.4	90.9	90.9
Clear cell	2	82.4	95.5	83.4	100.0
	4	66.0	88.6	79.0	95.0

Ana, anaplasia; FH, favorable histology; lung met, lung metastases; Rx, treatment.

Current protocols

In the current National Wilms' Tumor Study (NWTS-5), patients are randomized for treatment according to their risk assessment. Low-risk patients include those with stage I favorable histology who are less than 24 months old and with tumors less than 500 g, stage I with tumors greater than 500 g, more than 24 months old with favorable histology or focal or diffuse anaplasia, and stage II with favorable histology. These patients are managed by nephrectomy and receive actinomycin D and vincristine for 18 weeks. Intermediate-risk patients include those with stage III and stage IV tumors with favorable histology, stages II to IV with focal anaplasia, and stage IV with favorable histology and CT-documented lung metastases (Table 3). These patients are treated by nephrectomy and receive actinomycin D, vincristine, and doxorubicin for 24 weeks; plus radiotherapy to the tumor bed (1,080 cGy) and to the lung (1,080 cGy) in instances of CT-detected lung metastases. High-risk patients include those with stages II to IV disease with diffuse anaplasia and stages I to IV clear cell renal tumors. After nephrectomy, these children receive four chemotherapy agents (doxorubicin, vincristine, cyclophosphamide, and etoposide) for 24 weeks and 1,080 cGy of radiotherapy within 9 days of resection. Nephrectomy and three-drug chemotherapy, including carboplatinum, etoposide, and cyclophosphamide for 24 weeks, are used to treat children with rhabdoid tumors in stages I to IV.

Table 3. Risk Categories and Treatment from National Wilms' Tumor Study 5

Risk	Stage	Characteristics	Treatment
Low	I	Favorable histology, focal or diffuse anaplasia	Nephrectomy, actinomycin D, vincristine (18 wk)
	II	Favorable histology	Nephrectomy, actinomycin D, vincristine (18 wk)
Intermediate	III, IV	Favorable histology	Nephrectomy, actinomycin D, vincristine, doxorubicin (24 wk). Radiotherapy: 1,080 cGy to tumor bed, 1,200 cGy to lung metastases
	II-IV	Focal anaplasia	Nephrectomy, actinomycin D, vincristine, doxorubicin (24 wk). Radiotherapy: 1,080 cGy to tumor bed, 1,200 cGy to lung metastases
	IV	Favorable histology plus lung metastases on chest CT	Nephrectomy, actinomycin D, vincristine, doxorubicin (24 wk). Radiotherapy: 1,080 cGy to tumor bed, 1,200 cGy to lung metastases
High	II-IV	Diffuse anaplasia	Nephrectomy, doxorubicin, vincristine, actinomycin D, and etoposide (24 wk). Radiotherapy: 1,080 cGy to tumor bed, 1,200 cGy to lung metastases
	I-IV	Clear cell renal tumors	Nephrectomy, doxorubicin, vincristine, actinomycin D, and etoposide (24 wk). Radiotherapy: 1,080 cGy to tumor bed, 1,200 cGy to lung metastases
	I-IV	Rhabdoid tumors	Nephrectomy, carboplatinum, etoposide, and cyclophosphamide (24 wk)

The main objective of NWTS-5 is to determine whether loss of heterozygosity of chromosome 16q and 1p is associated with worse outcomes. NWTS-5 will also evaluate whether DNA ploidy (diploid status) is associated with worse outcomes in children who have favorable histology. Additional goals of the study are to decrease the acute and longterm morbidity of treatment in children with Wilms' tumor by limiting the intensity and duration of initial treatment and to use a more consistent chemotherapy retrieval program for patients who relapse. Another goal is to improve the disease-free interval of patients with unfavorable histology, including those with diffuse anaplasia and clear cell sarcoma of the kidney, by using new chemotherapy programs that include etoposide and cyclophosphamide and treating rhabdoid tumors of the kidney with carboplatin, etoposide, and cyclophosphamide. Further study of the biologic nature of Wilms' tumor and particularly its biology and pathology in instances of bilateral tumor is planned. The search to identify a specific tumor marker for Wilms' tumor is also a priority, but has remained elusive.