2. Seven new cases per 1 million children per year in North America (450 cases per year)

b. Eighty percent of all genitourinary (GU) cancers in children younger than 15 years

c. Seventy-five percent in children between 1 and 5 years of age; peak incidence 3 to 4 years of age, 90% before 7 years of age

d. Male-to-female ratio equal, 1% familial, slightly higher rates in black population and lower in Asian children

b. Usually solitary

c. Frequently hemorrhagic or necrotic

d. True cyst formation rare

e. Pelvis invasion rare, venous invasion 20%

f. Extrarenal sites (retroperitoneum, inguinal, mediastinal, sacrococcygeal) rare

2. Microscopic features — wide spectrum

b. Unfavorable histology (UH) in 10% of cases; two types:

2) Rhabdoid: Uniform large cells with large nuclei, prominent nucleoli, and eosinophilic cytoplasmic inclusions (fibrils), metastasizes to brain, is probably not metanephric. Rhabdoid tumor of the kidney and clear-cell sarcoma of the kidney have been reclassified and are now considered distinct entities from Wilms tumor sarcoma.

3) Clear cell sarcoma, “bone metastasizing tumors of childhood”: Vasocentric spindle cell pattern, may be malignant version of congenital mesoblastic nephroma (pure blastemal origin) and not a true form of Wilms tumor

c. Favorable histology (FH) consists of all other types, tubular predominance perhaps being most favorable of all.

d. Cystic nephroma (CN) and cystic, partially differentiated nephroblastoma (CPDN) are benign neoplasms currently considered by many experts to be part of the spectrum of nephroblastoma; tumors occur in both adults and children and are generally asymptomatic but may cause hematuria. CNs are all cystic, without solid component, with septa purely stromal without blastemal elements. CPDN is also cystic, but septae contain blastemal elements (or nephrogenic rests). It is important to note that nephroblastomas, clear-cell sarcomas, and mesoblastic nephromas may also be predominantly cystic.

e. Congenital mesoblastic nephroma occurs in early infancy. It is associated with polyhydramnios, resembles leiomyoma grossly, and histologically exhibits sheets of spindle-shape uniform cells that appear to be fibroblasts. There is no capsule but when completely excised, it follows a benign course; it may be a hamartoma. The spindle-cell variant may behave with a more malignant potential.

3. Genetics and associated anomalies

b. 11p deletion common in tumor genotype, 12q also reported

c. Trisomy 8 and 18, 45 XO (Turner), and XX/XY mosaicism associated

d. Loss of heterozygosity for portion of chromosome 16q may portend poorer outcome.

e. Sporadic (nonfamilial) aniridia associated; full syndrome includes early tumor (less than 3 years) and other GU anomalies; external ear deformities, retardation, facial dysmorphism, hernias, and hypotonia.

f. Hemihypertrophy (1 in 14,000 general population, 1 in 32 in Wilms patients) along with other malignancies (i.e., adrenal carcinoma, hepatoblastoma), and pigmented nevi and hemangiomas

g. Beckwith-Wiedemann syndrome: Visceromegaly involving adrenal, kidney, liver, pancreas, often with hypoglycemia; gonads with omphalocele, hemihypertrophy, microcephaly, retardation, macroglossia; 10% develop a neoplasm of liver, adrenal, or kidney.

h. Musculoskeletal deformities exhibited in 2.9% with 30-fold increase in neurofibromatosis incidence.

i. GU anomalies exhibited in 4.4%, including renal hypoplasia, ectopia or fusion, duplications, cystic disease, hypospadias, cryptorchidism, and pseudohermaphroditism.

4. The nephroblastomatosis complex appears to be a precursor of Wilms tumor and consists of persistent primitive metanephric elements beyond 36 weeks of gestation; it occurs in three forms.

b. Multifocal juvenile form or nodular renal blastema (NRB) consists of gross or microscopic NRB nodules that may be sclerotic or glomerulocystic and papillary, usually in the subcapsular region or along the columns of Bertin.

c. Wilms tumorlet exhibits triphasic histology and nodules between 1 and 3.5 cm.

d. Some component of nephroblastomatosis is present in 100% of bilateral Wilms patients and in at least 40% of unilateral cases.

e. May represent Wilms tumor precursor in the “two-hit” theory of oncogenesis of Knudson and Strong

f. NRB should be sought, mobilizing and inspecting the contralateral kidney carefully. Any area of abnormal color or a cleft should be biopsied; it does respond to chemotherapy, but the best program and full therapeutic implications remain to be demonstrated.

b. One third present with abdominal pain, often associated with minor trauma and hemorrhage within tumor.

c. Hypertension accompanies 25% to 60% of cases.

d. Differential diagnosis includes other tumors and hydronephrosis or cystic disease.

e. Abdominal ultrasound will diagnose most Wilms tumors and evaluate the retroperitoneum, liver, and vena cava for extension of disease.

f. Screening serial renal ultrasounds are needed for patients with aniridia, hemihypertrophy, and Beckwith-Wiedemann syndrome at an interval of every 3 to 4 months.

g. Four-view chest x-ray completes the metastatic workup.

h. Angiography and cavography are rarely indicated; computed tomography (CT) may be helpful with very extensive lesions, detecting bilateral disease, and providing functional assessment of contralateral kidney.

2. Surgical treatment

b. Transverse abdominal incision provides adequate exposure in most cases, from the tip of the twelfth rib on the involved side to the lateral rectus border on the opposite side.

c. Exploration of the contralateral kidney with biopsy as needed should be carried out first; reflection of colon and complete mobilization of kidney are required for adequate visualization and manual inspection of front and back surfaces of the kidney.

d. Resectability depends largely on the degree of attachment to the liver, duodenum, pancreas, spleen, diaphragm, abdominal wall, or major vascular invasion into the vena cava. Heroic extirpation involving major resection of these organs or cardiopulmonary bypass to remove high caval or atrial tumors is not warranted.

e. Unresectable lesions should be treated with chemotherapy and reexplored; usually the tumor may then be removed. Pretreatment of large tumors reduces the rate of intraoperative rupture but does not influence and may alter histology (FH versus UH distinction). Because the preoperative diagnostic error rate has been 5% in the United States, routine pretreatment has not been recommended.

f. Beginning the dissection along the posterior abdominal wall inferiorly and the great vessels medially, with early ureteral ligation, allows early exposure and ligation of renal vessels prior to mobilization of the mass.

g. Biopsy of the tumor or localized operative spill does not upstage the tumor unless it is massive, in which case, whole abdomen irradiation is needed to avoid an increased incidence of abdominal recurrence. Largest relative risk for local recurrence in National Wilms Tumor Study (NWTS)-4 was observed in patients with stage III disease, those with UH (especially diffuse anaplasia), and those reported to have major tumor spillage during surgery.

h. The adrenal is taken if the tumor involves the upper pole.

i. Gross assessment of nodes has a 40% false-positive and 0% false-negative rate, and thus routine biopsy of hilar and periaortic nodes is warranted; radical node dissection does not influence survival but does improve staging. The absence of lymph node biopsy is associated with an increased relative risk of recurrence, which was largest in children with presumed stage I disease because of understaging.

j. Remaining tumor in nodes or other organs should be marked with surgical clips to facilitate direction of radiation therapy.

k. NWTS investigators found a 20% incidence of surgical complications, with the most common being intestinal obstruction and hemorrhage.

b. In NWTS-3, the distribution by stage of FH tumors was stage I, 47%; stage II, 22%; stage III, 22%; and stage IV, 9%. Both the surgeon and pathologist have responsibility for determining local tumor stage.

b. The use of single-dose (pulse-intensive) treatment with dactinomycin has an equivalent 2-year RFS to those treated with a standard 5-day regimen. Pulse-intensive drug administration provides for equal efficacy, greater administration dose intensity, and less severe hematologic toxicity.

c. Patients with bilateral Wilms tumor (BWT) and/or nephrogenic rests should be managed with a nephron-sparing approach following primary chemotherapy. Those patients with anaplasia are at much greater risk for recurrence, so for them a renal-sparing approach is not beneficial.

d. NWTS-4 included 5.6% of patients with bilateral Wilms tumor. The 8-year event-free survival for BWT with FH was 74%, and overall survival was 89%; the event-free survival for BWT with UH was 40%, and overall survival was 45%. Preservation of renal parenchyma is possible in many patients after initial preoperative chemotherapy. The incidence of end-stage renal disease remains significantly higher in children with BWT.

b. Risk of tumor relapse in NWTS-3 at 3 years was 9.6%, 11.8%, 22%, and 22%, respectively, for stages I through IV. Relapses occurred in 36% of stage I through III and 45% of stage IV patients with UH.

c. Adriamycin, dacarbazine, cisplatin, or higher doses of vincristine and/or cyclophosphamide (Cytoxan) are used to treat relapses.

6. Complications of therapy

b. Secondary neoplasms are reported in 3% to 17% in 20- to 25-year survivors, especially in radiation fields.

7. Cooperative group trials