Teaching pack: Wilms tumour (nephroblastoma)

Wilms tumour is an embryonal kidney cancer arising from nephrogenic rests, associated with WT1, CTNNB1, WTX, TP53 (anaplastic), and microRNA-processing gene (DROSHA, DGCR8) mutations, and with predisposition syndromes (WAGR, Denys-Drash, Beckwith-Wiedemann). Two cooperative-group philosophies coexist: COG (upfront nephrectomy, then risk-stratified chemotherapy using stage, histology, 1p/16q loss of heterozygosity and 1q gain) and SIOP (pre-operative vincristine-actinomycin then nephrectomy, with post-operative therapy by histologic response and stage; UMBRELLA protocol).

Favourable-histology stage I-II disease is treated with vincristine and actinomycin D (EE-4A) or, for very low-risk stage I tumours in children under 2 with tumours <550 g, surgery alone; stage III-IV adds doxorubicin and flank/whole-lung radiotherapy, with lung irradiation omitted in rapid complete responders without 1p/16q LOH (AREN0533). Diffuse anaplastic tumours need intensive regimen UH-1/UH-2 with carboplatin, cyclophosphamide and etoposide; bilateral tumours receive neoadjuvant chemotherapy and nephron-sparing surgery. Relapse is treated by risk group (ICE regimens, high-dose chemotherapy in some). Survivorship issues include cardiotoxicity, renal function, second cancers and fertility (radiation).

• Survival ~90% with steadily less therapy: surgery-only for the youngest lowest-risk children, radiation omitted for lung responders.
• Molecular markers (1p/16q LOH, 1q gain) already stratify therapy, a rare achievement in paediatric solid tumours.
• Two cooperative strategies (COG vs SIOP) reach similar outcomes, giving the field a natural experiment.
• The largest gap is geographic: mortality in sub-Saharan Africa is several-fold higher, driven by late presentation, abandonment and supportive-care shortfalls (SIOP PODC adapted regimens).

1. 1899Max Wilms's monograph on mixed tumours of the kidney
2. 1956Actinomycin D active in Wilms tumour (Farber)
3. 1969National Wilms Tumor Study (NWTS-1) begins
4. 1990WT1 cloned (Call, Gessler)
5. 20051p/16q LOH predicts relapse (NWTS-5, Grundy)
6. 2018AREN0533: lung radiotherapy omitted for rapid complete responders
7. 2019AREN0532: surgery alone confirmed for very-low-risk stage I

• Vincristine (treatment)
• Dactinomycin (actinomycin D) (treatment)

• COG AREN0533 (phase 3, n=395): 4-year event-free survival (all lung-metastasis patients): 85.4% vs 72.5%
• COG AREN0532 (phase 3, n=808): Event-free survival at 4 years by risk group (registry results): 88% vs 87% vs 88%
• Childhood Cancer Survivor Study (CCSS) (observational study, n=50,000): 15-year cumulative all-cause mortality by treatment era: 12.4% vs 6%

• Diffuse anaplastic and relapsed disease: survival ~50% or lower.
• Global inequity: Wilms is curable, yet most children with it worldwide lack access to the treatment that cures it; adapted regimens (SIOP PODC) are the response.
• Late effects of doxorubicin and radiation in 90% survivors.
• Bilateral disease: preserving kidney function.

• NCI PDQ: Wilms tumour: https://www.cancer.gov/types/kidney/patient/wilms-treatment-pdq
• SIOP-RTSG UMBRELLA protocol (Nat Rev Urol 2017): https://doi.org/10.1038/nrurol.2017.163
• Children's Oncology Group: https://childrensoncologygroup.org/
• Wikipedia: https://en.wikipedia.org/wiki/Wilms%27_tumor
• Guideline: https://doi.org/10.1200/JCO.18.02102