Wilms Tumor

• Loss of WT1 tumor suppressor gene function: The WT1 gene (located at chromosome 11p13) encodes a zinc finger transcription factor essential for normal kidney development and urogenital ridge formation. WT1 acts as a transcriptional regulator of multiple genes including PAX8, GDNF, and IGF2. Mutations or deletions in WT1 (present in 30-40% of sporadic Wilms tumors and nearly 100% of WAGR syndrome cases) allow unopposed proliferation of nephrogenic cells. Loss of WT1 also removes normal apoptotic controls, permitting survival of cells that would normally undergo programmed cell death. In bilateral cases, WT1 mutations predispose to diffuse nephrogenic rests—foci of persistent embryonic kidney tissue that serve as precursor lesions for tumor development.

• Alterations in the WT1-regulated IGF2/H19 imprinted locus: The IGF2 (insulin-like growth factor 2) gene normally undergoes parent-of-origin-specific imprinting, with the paternal allele expressed and maternal allele silenced. Beckwith-Wiedemann syndrome (BWS), caused by loss of imprinting (LOI) at chromosome 11p15.5, results in maternal allele activation and overexpression of IGF2, a potent mitogenic growth factor. This produces excessive IGF2-mediated signaling through IGF1 receptor, driving uncontrolled cell proliferation. BWS is present in 1-2% of Wilms tumors and these patients carry a 1000-fold increased risk of Wilms tumor development. The H19 gene, a long non-coding RNA also subject to imprinting disruption, normally acts as an IGF2 antagonist; its downregulation removes this growth restraint.

• Inactivation of the WT2/WTX gene (AMER1): Mutations in AMER1 (which encodes a Wnt pathway antagonist) occur in 15-20% of Wilms tumors and result in constitutive Wnt/β-catenin signaling. This pathway, normally essential only during early nephrogenesis, becomes aberrantly reactivated in tumor cells, promoting cell proliferation and blocking differentiation. β-catenin accumulation in the nucleus permits transcription of proliferation-associated genes. AMER1 mutations are particularly associated with epithelial predominant histology and favorable prognosis.

• TP53 alterations and anaplastic histology: Inactivation of the TP53 tumor suppressor gene (chromosome 17p13.1), either through mutation or deletion, occurs in approximately 5-10% of Wilms tumors but in up to 70% of anaplastic tumors. Loss of p53 function eliminates critical checkpoints in cell cycle progression and apoptosis, permitting survival of cells with additional chromosomal abnormalities. Anaplastic tumors demonstrate marked nuclear enlargement, hyperchromatic nuclei, and abnormal mitotic figures reflecting severe genomic instability. These tumors display dramatically worse prognosis (survival <50%) compared to favorable histology tumors.

• Other genetic alterations: CTNNB1 (β-catenin) mutations (15% of tumors), FBXW7 mutations affecting cell cycle regulation, and alterations in REST/NRSF transcriptional repressor genes contribute to additional signaling pathway dysregulation. Copy number variations and chromosomal aneuploidy (particularly loss of chromosome 16q) occur in approximately 10-15% of cases and correlate with worse outcomes.

• WAGR syndrome (Wilms, Aniridia, Genitourinary anomalies, intellectual disability): Results from contiguous gene deletion at 11p13 affecting not only WT1 but also neighboring genes PAX6 (causing aniridia) and BDNF. Patients carry 30-50% cumulative risk of Wilms tumor development and require aggressive screening (renal ultrasound every 3 months until age 7). Aniridia (iris hypoplasia) is the clinical hallmark and should trigger immediate renal imaging workup in any young child.

• Beckwith-Wiedemann syndrome (BWS): Caused by dysregulation of imprinted genes at chromosome 11p15.5, manifesting as macrosomia, hemihypertrophy, exomphalos, macroglossia, and neonatal hypoglycemia. These patients have 4-5% lifetime risk of Wilms tumor (compared to 1 in 10,000 in general population) and may develop bilateral disease. BWS also predisposes to hepatoblastoma, adrenocortical carcinoma, and rhabdomyosarcoma. Regular ultrasound screening (every 3 months) is standard of care.

• Denys-Drash syndrome: Results from WT1 point mutations (typically in the zinc finger DNA-binding domain), presenting with intersex development or female pseudohermaphroditism, progressive glomerulosclerosis with nephrotic syndrome, and Wilms tumor in approximately 90% of cases. These patients develop progressive renal failure from glomerulosclerosis even independent of tumor development.

• Hemihypertrophy and asymmetric growth disorders: Encompasses isolated hemihypertrophy, trisomy 18, and other asymmetric growth patterns associated with 1-3% risk of Wilms tumor. The mechanism relates to dysregulation of growth-promoting imprinted genes similar to BWS.

• Cryptorchidism and hypospadias: These genitourinary anomalies are present in 5-10% of Wilms tumor cases and suggest shared embryologic defects during urogenital ridge development. They serve as clinical clues to underlying genetic predisposition.

• Sporadic disease without syndromic features (approximately 85-90% of cases): These tumors likely result from acquired mutations in WT1, CTNNB1, or other genes in isolated populations of nephrogenic cells, with no germline predisposition. However, up to 5-10% of apparently sporadic cases demonstrate bilateral disease or multifocal foci suggesting germline mosaicism.

• Horseshoe kidney and renal dysplasia: Developmental renal anomalies are present in 5% of Wilms tumor cases and represent shared disruption of renal development pathways. Patients with horseshoe kidney warrant enhanced surveillance.

• Abdominal mass (40-50% of cases): This is the most common presenting sign, typically detected by parents during diaper changes or bathing as a palpable flank fullness or mass. The mass is characteristically firm, unilateral (in 90% of cases), and non-tender, located in the flank or lower abdomen. Bilateral masses are present in 5-10% of cases at diagnosis and should trigger investigation for syndromic features and germline mutations. The mass represents the expanding tumor within the renal fossa, often with displacement of surrounding structures. Early tumors may be asymptomatic and detected incidentally on imaging obtained for unrelated reasons.

• Abdominal pain or distension (25-30% of cases): Pain results from stretching of the renal capsule and surrounding peritoneum as the tumor expands, producing flank or generalized abdominal discomfort. Rapidly enlarging tumors may cause more acute pain. Abdominal distension occurs from the enlarging mass or, occasionally, from ascites secondary to peritoneal involvement or tumor rupture.

• Gross or microscopic hematuria (15-20% of cases): Blood in the urine results from tumor invasion into the collecting system and renal pelvis, causing mucosal ulceration and bleeding. Hematuria may be visible or detected only on urinalysis. Unlike in adults where hematuria raises concern for renal cell carcinoma, hematuria in a young child with a renal mass is entirely consistent with Wilms tumor. Absence of hematuria should not reduce clinical suspicion.

• Hypertension (10-40% of cases): Elevated blood pressure results from renin secretion by the tumor itself (ectopic renin production), mass effect on the renal artery causing vascular stenosis, or involvement of the juxtaglomerular apparatus. Hypertension may be severe and occasionally precipitate hypertensive emergency or encephalopathy. Blood pressure normalization following nephrectomy confirms the tumor as the causative mechanism. Renin-mediated hypertension can persist months after surgery in some cases due to hypertrophic juxtaglomerular apparatus changes.

• Constitutional symptoms (fever, malaise, weight loss): These nonspecific symptoms are present in a minority of cases and suggest more aggressive disease or systemic effects. Fever may result from tumor necrosis or paraneoplastic effects rather than infection.

• Respiratory symptoms from pulmonary metastases: Because the lungs are the most common site of metastatic spread (present in 10-15% of children at diagnosis), dyspnea, cough, or chest discomfort may be the presenting complaint in advanced disease. Pulmonary involvement may be asymptomatic and detected only on imaging.

• Varicocele (2-5% of cases): Presentation of a new varicocele in a young child is unusual and should raise suspicion for renal vein or inferior vena cava (IVC) involvement by tumor thrombus. The thrombus mechanically obstructs testicular venous drainage. This finding suggests advanced disease with vascular invasion.

• Inferior vena cava (IVC) thrombosis: Tumor thrombus extending into the renal vein and IVC occurs in 5-10% of cases and may present with hepatomegaly, ascites, lower extremity edema, or acute cardiovascular collapse if the thrombus extends to the right atrium. Cardiac thrombus is a surgical emergency requiring careful perioperative management.

• Clinical history and examination: Careful history from parents regarding the time of mass detection, associated symptoms (hematuria, pain, fever), constitutional symptoms, and developmental milestones is essential. Family history of cancer, consanguinity, or hereditary syndromes should be elicited. Physical examination focuses on palpation of both flanks and abdominal quadrants for masses, assessment of blood pressure (hypertension present in up to 40% of cases), evaluation for syndromic features (aniridia, hemihypertrophy, exomphalos, macroglossia in BWS), and examination for lymphadenopathy suggesting metastatic disease. The presence of aniridia is a critical finding mandating urgent renal imaging and WT1 genetic testing.

• Renal ultrasound: This is typically the first imaging modality, offering excellent visualization of renal anatomy without radiation and high sensitivity (>95%) for detecting solid renal masses in children. Ultrasound characterizes the mass as solid or cystic, assesses echogenicity (typically heterogeneous due to areas of necrosis and hemorrhage), evaluates for vascular invasion by Doppler ultrasound to assess renal vein patency, and screens the contralateral kidney for metachronous disease or nephrogenic rests. The presence of a cystic component does not exclude malignancy. Color Doppler interrogation of the renal vein and IVC is essential to assess for thrombus, which dramatically affects surgical planning.

• CT scan of abdomen and pelvis with contrast: CT provides superior definition of tumor extent, local invasion into surrounding structures (perirenal fat, psoas muscle, peritoneal surface), ipsilateral renal vein and IVC involvement, regional lymph node involvement, and presence of distant metastases. CT with IV contrast (arterial and portal venous phases) evaluates the relationship of tumor thrombus to the heart (critical for surgical planning) and identifies hepatic metastases. The tumor typically appears as a heterogeneous mass with areas of necrosis, cystic change, and hemorrhage. Sensitivity for detecting nodal involvement is limited; negative imaging does not exclude microscopic disease.

• Chest CT: Lung metastases are present at diagnosis in 10-15% of patients and are the most common site of metastatic disease. High-resolution chest CT with thin sections has sensitivity >95% for nodules as small as 3-5 mm and is superior to chest radiographs for detecting metastatic disease. Bilateral pulmonary involvement may be present. Pulmonary staging significantly impacts treatment intensity.

• Renal vein and IVC ultrasound or CT/MRI: When tumor thrombus is suspected from initial imaging, venography or MRI is performed to precisely define the superior extent of thrombus (extending only into renal vein, IVC below hepatic veins, or into right atrium). This is critical information for surgical planning, as atrial involvement requires special perioperative monitoring (possible bypass, positioning) and carries increased morbidity.

• Laboratory studies: CBC assesses baseline hemoglobin and platelet count (thrombocytosis may be paraneoplastic). Comprehensive metabolic panel evaluates renal function, electrolytes, and liver function. Plasma renin activity (PRA) and aldosterone levels may be measured if hypertension is present; markedly elevated PRA supports renin-secreting tumor. Urinalysis documents hematuria. Coagulation studies (PT/INR, PTT) are obtained preoperatively given risk of IVC involvement with potential for thromboembolism.

• Genetic testing: WT1 sequencing and deletion/duplication analysis is indicated in all cases with bilateral disease, any patient with syndromic features (WAGR, DDS, BWS), family history of Wilms tumor, or aniridia. Chromosome 11p15 imprinting analysis (assessing for loss of imprinting at IGF2/H19 locus) confirms BWS. Testing identifies germline mutations (present in 20-25% of unilateral cases without syndromic features) that have implications for screening of contralateral kidney, cancer surveillance in relatives, and reproductive counseling.

• Histopathologic classification: Following nephrectomy, histologic examination categorizes tumor as favorable histology (FH) or unfavorable histology (UH). Favorable histology tumors (90% of cases) demonstrate epithelial, stromal, or mixed differentiation with normal mitotic rates and nuclear morphology, conveying excellent prognosis (90-95% 4-year event-free survival for stage I-II). Anaplastic histology (UH, 5% of cases) demonstrates significant nuclear enlargement (>3-fold nuclear enlargement), hyperchromasia, and abnormal mitotic figures, conferring poor prognosis (50-60% survival) requiring more intensive chemotherapy. Blastemal predominance affects treatment intensity. Clear cell sarcoma and rhabdoid tumor variants are rare (<1%) with intermediate prognosis requiring different chemotherapy regimens (see Treatment section).

• Staging system: The COG (Children's Oncology Group) staging system is used in North America. Stage I: tumor limited to kidney, completely excised (40% of cases). Stage II: tumor extends beyond kidney but completely excised (20% of cases). Stage III: incomplete excision or positive margins, regional node involvement, tumor rupture, positive lymph nodes, or positive peritoneal cytology (40% of cases). Stage IV: hematogenous metastases (lung, liver, bone) or distant lymph node metastases (8% of cases). Stage V: bilateral renal involvement (10% of cases). The COG risk stratification combines stage with

Initial stabilisation

• Handle the abdomen gently: avoid deep or repeated palpation once a renal mass is suspected — capsular disruption with intraperitoneal tumor spill upstages disease and mandates whole-abdomen radiation.
• Blood pressure control: renin-mediated hypertension is treated preoperatively; a hypertensive emergency is managed with a titratable IV agent (e.g., nicardipine) in the ICU.
• Coagulation screen before surgery: acquired von Willebrand disease occurs in a small subset and causes perioperative hemorrhage; it responds to desmopressin or factor concentrate.

Definitive surgery (North American standard)

• Upfront radical nephroureterectomy with lymph node sampling: the Children's Oncology Group (COG) renal tumor protocols favor immediate resection through a transabdominal approach, with mandatory regional node sampling (unsampled nodes cannot be staged and force higher-intensity therapy) and inspection of the contralateral kidney and liver. This differs from the SIOP (European) approach of preoperative chemotherapy then delayed nephrectomy.
• Preoperative chemotherapy is preferred by COG for bilateral (stage V) disease, tumor in a solitary kidney, extensive IVC/atrial thrombus, or unresectable tumor — shrinkage permits nephron-sparing partial nephrectomy and preserves renal mass.

Chemotherapy by risk group

• Vincristine plus dactinomycin (regimen EE-4A): stage I–II favorable histology.
• Add doxorubicin and flank/abdominal radiotherapy (regimen DD-4A): stage III–IV favorable histology.
• Intensified multiagent therapy (adding alkylating agents such as cyclophosphamide plus etoposide, with carboplatin for diffuse anaplasia) plus radiotherapy: anaplastic histology and other high-risk renal tumors, per COG.
• Loss of heterozygosity at 1p/16q augments therapy in COG protocols — a molecular result that changes treatment, not just prognosis.

Avoid

• Routine pretreatment biopsy of a resectable unilateral mass — under COG staging it risks upstaging and added therapy.
• Cumulative anthracycline excess; dose is capped for cardiotoxicity, and radiation fields are minimized in young children.

Disease-related — emergencies flagged

• Tumor rupture with intraperitoneal hemorrhage (EMERGENCY): spontaneous or trauma/palpation-induced capsular breach; signals as sudden abdominal pain, distension, pallor, and hemodynamic instability. Spill upstages to stage III and commits the child to abdominal irradiation.
• IVC/right atrial tumor thrombus with pulmonary embolism (EMERGENCY): mechanical extension along the renal vein; suggested by new varicocele, lower-extremity edema, hepatomegaly, or acute cardiorespiratory collapse. Requires cardiac imaging and, if atrial, cardiopulmonary bypass planning.
• Hypertensive emergency/encephalopathy (EMERGENCY): ectopic renin secretion or renal artery compression; seizures or altered mental status with markedly elevated blood pressure.
• Acquired von Willebrand disease: adsorption/clearance of vWF multimers; prolonged aPTT with mucocutaneous or intraoperative bleeding.
• Metastatic disease: lung is the dominant site; liver and regional nodes follow.

Treatment-related

• Hepatic sinusoidal obstruction syndrome (veno-occlusive disease): classically after dactinomycin; presents with tender hepatomegaly, rapid weight gain/ascites, jaundice, and refractory thrombocytopenia — potentially fatal, treat as an emergency.
• Anthracycline cardiomyopathy: *doxorubicin*-induced free-radical myocyte injury; falling ejection fraction, sometimes years later. The Children's Oncology Group Long-Term Follow-Up Guidelines mandate lifelong echocardiographic surveillance.
• Vincristine neurotoxicity: microtubule disruption in axons; areflexia, foot drop, jaw pain, and constipation/ileus; SIADH can occur.
• Febrile neutropenia (EMERGENCY): myelosuppression; fever in a neutropenic child demands immediate cultures and empiric antipseudomonal beta-lactam therapy.
• Radiation late effects: scoliosis and soft-tissue hypoplasia in the field, radiation nephritis, and second malignancies (breast cancer after whole-lung irradiation, sarcoma in-field).
• Renal insufficiency after nephrectomy: hyperfiltration injury in the remaining kidney, with proteinuria and rising creatinine; the risk is greatest in bilateral disease and *WT1*-mutation syndromes such as Denys-Drash, where glomerulosclerosis progresses independently.

• The classic stem: a healthy 2–4-year-old with a smooth, firm flank mass that does not cross the midline, found by a parent during bathing, plus hematuria and hypertension. Single best next step: abdominal/renal ultrasound with Doppler — not biopsy, not CT first.
• Neuroblastoma is the distractor: it crosses the midline, is irregular and calcified, encases (rather than displaces) vessels, causes elevated urine HVA/VMA, and may show opsoclonus-myoclonus or raccoon-eye periorbital ecchymoses. Wilms displaces structures, rarely calcifies, and arises within the kidney.
• Aniridia in an infant is the association examiners love: it signals WAGR (contiguous 11p13 deletion of WT1 and PAX6) and mandates WT1 testing plus serial renal ultrasound. Do not confuse 11p13 (WT1, WAGR/Denys-Drash) with 11p15 (IGF2/H19 imprinting, Beckwith-Wiedemann).
• Denys-Drash = Wilms + nephrotic-range proteinuria/diffuse mesangial sclerosis + disorder of sex development; the nephropathy progresses to ESRD regardless of tumor therapy.
• Surveillance: predisposition syndromes (BWS, WAGR, hemihypertrophy) get renal ultrasound roughly every 3 months through early childhood — the intervention that actually improves stage at diagnosis.
• Do not palpate deeply and do not biopsy a resectable unilateral mass; rupture or spill upstages to stage III and adds abdominal radiation.
• **Chemotherapy backbone is vincristine plus dactinomycin, with doxorubicin added for higher stage**, per Children's Oncology Group protocols. Dactinomycin → hepatic veno-occlusive disease; doxorubicin → cardiomyopathy.
• Age matters for the differential: a renal mass in a neonate is more likely congenital mesoblastic nephroma; hypercalcemia with a renal mass and a synchronous brain tumor suggests rhabdoid tumor (SMARCB1/INI1 loss), not Wilms.
• Prognosis is excellent — over 90% survival in localized favorable-histology disease; anaplasia and 1p/16q loss are what worsen it.