What is the appropriate diagnosis and treatment approach for a child under the age of 5 suspected of having Wilms tumor?

Wilms Tumor: Diagnosis and Treatment in Children Under 5

Initial Diagnostic Approach

For a child under 5 with suspected Wilms tumor, obtain abdominal ultrasound or MRI immediately to characterize the renal mass, followed by chest CT with thin cuts (approximately 1 cm slice thickness) to evaluate for pulmonary metastases, and proceed with genetic testing for predisposition syndromes as part of the comprehensive evaluation. 1, 2

Key Diagnostic Steps

• Imaging sequence: Start with abdominal ultrasound or MRI (preferred for superior soft tissue characterization) to evaluate the primary renal tumor 2, 3
• Metastatic workup: Obtain chest CT with thin cuts (approximately 1 cm slice thickness) rather than standard chest imaging, as small pulmonary nodules may be missed with thicker slices 2, 3
• Genetic testing: Test for predisposition syndromes including TRIM28, REST, CTR9, DIS3L2, WT1, and Beckwith-Wiedemann syndrome, as these influence surveillance and prognosis 1, 4
• Special consideration: All patients with epithelial-predominant histology should undergo TRIM28 testing, as 86% of these tumors harbor TRIM28 pathogenic variants 1, 4

Treatment Approach

The treatment strategy depends on whether you follow North American (Children's Oncology Group) or European (SIOP) protocols—North American protocols prioritize upfront surgery for staging followed by risk-adapted chemotherapy, while SIOP protocols use preoperative chemotherapy followed by delayed surgery. 5, 6, 7

North American Approach (COG Protocol)

• Primary surgery first: Perform nephrectomy upfront for unilateral disease to achieve proper staging, which directs adjuvant therapy 6, 7
• Surgical principles: Meticulous attention to correct staging is crucial—avoid tumor spillage and ensure clear surgical margins 6
• Post-operative chemotherapy: Vincristine-based combination chemotherapy (vincristine is FDA-approved for Wilms tumor) with other oncolytic agents, tailored to stage and histology 8, 5
• Radiation therapy: Reserved for higher-stage disease or unfavorable histology based on surgical staging 7

European Approach (SIOP Protocol)

• Preoperative chemotherapy: Initiate chemotherapy before surgery to reduce tumor size 7
• Response monitoring: Evaluate clinical and radiological response after every 2 cycles of chemotherapy, with maximal tumor response typically occurring after 6-12 months 2, 3
• Critical caveat: Radiographic response does not equal pathologic response—25-40% of patients with complete radiological response harbor viable tumor at resection, and 10-75% of partial responders have no tumor at final pathology 2, 3
• Delayed surgery: Perform nephrectomy after chemotherapy when tumor is resectable with clear surgical margins achievable 2

Special Considerations for Bilateral Disease

• Nephron-sparing surgery: When technically feasible, partial nephrectomy is reasonable for bilateral disease to preserve renal function 7
• Genetic implications: Bilateral tumors often represent genetic predisposition syndromes requiring surveillance of family members 1
• Prognosis: 4-year event-free survival is approximately 43.8% with overall survival of 55.2% for bilateral disease 1

Risk Stratification and Prognosis

Stage I-II favorable histology tumors have excellent outcomes with 4-year overall survival of 98.3% and 92% respectively, while overall survival exceeds 90% for localized disease and 75% for metastatic disease. 1, 5

Prognostic Factors

• Histology: Favorable vs. unfavorable (anaplastic) histology is the most critical prognostic factor 7
• Stage: Proper surgical staging is crucial for directing adjuvant therapy and limiting treatment-related morbidity 6
• Genetic factors: TRIM28-associated epithelial-predominant tumors have better prognosis and are being investigated for reduced-intensity therapy 4
• Age: Median age of diagnosis varies by genetic syndrome—WT1-affected individuals present around 1 year of age, approximately 2-3 years earlier than sporadic cases 4

Surveillance for Genetic Predisposition Syndromes

Children with identified genetic predisposition syndromes require renal ultrasound surveillance every 3 months until 8 years of age, with specific protocols varying by syndrome. 4, 1

Syndrome-Specific Surveillance

• WT1 pathogenic variants (WAGR, Denys-Drash syndrome): Abdominal ultrasound every 3 months from birth through age 7 years, with Wilms tumor risk of approximately 50% in WAGR and >90% in Denys-Drash syndrome 4, 1
• REST pathogenic variants: Surveillance until 8 years of age, as most tumors occur between 6 months and 6 years 4
• CTR9 pathogenic variants: Renal ultrasound every 3 months until 8 years of age, with tumors occurring from ages 7 to 39 months 4
• DIS3L2 heterozygous variants: Surveillance recommended despite undefined penetrance, as most tumors occur before 7 years of age 4
• TRIM28 pathogenic variants: Continued surveillance after treatment completion, as risk of second tumors may be higher than general population 4
• Beckwith-Wiedemann syndrome: Renal ultrasound every 3 months until the 7th birthday 1
• DICER1 syndrome: Biannual abdominal ultrasound until age 8, then annually thereafter 1

Family Screening

• Cascade testing: Recommend genetic testing for all first-degree family members of affected probands with identified pathogenic variants 4
• TRIM28 inheritance: Although predominantly maternally inherited, test all first-degree family members regardless of gender as data are still evolving 4

Common Pitfalls to Avoid

• Do not rely solely on radiographic complete response to defer surgery in metastatic disease, as significant proportions harbor viable tumor requiring resection 2, 3
• Do not delay imaging assessments beyond every 2 cycles in SIOP protocols, as this may result in prolonged chemotherapy for non-responding tumors 3
• Do not miss genetic testing in patients with epithelial-predominant histology, as TRIM28 testing is critical for this subgroup 4, 1
• Do not discontinue surveillance prematurely in genetic predisposition syndromes—continue until at least 8 years of age 4
• Do not assume heterozygous carriers are unaffected—DIS3L2 heterozygotes have increased Wilms tumor risk despite homozygous variants causing Perlman syndrome 4