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Summary Table

Domain	Detail
Risk Factors	Age 3 to 4 years (peak incidence), associated syndromes: WAGR syndrome, Denys-Drash syndrome, Beckwith-Wiedemann syndrome, hemihypertrophy, sporadic aniridia, family history of Wilms tumor
Etiology	Embryonal renal neoplasm arising from persistent metanephric blastema; linked to WT1 gene deletion/mutation (chromosome 11p13) or WT2 locus abnormality (chromosome 11p15); loss of tumor suppressor function
Patient Presentation	A parent notices a large, painless abdominal mass in a toddler, often discovered incidentally during bathing or dressing; may present with abdominal distension, hematuria, hypertension, or low-grade fever
Classic Physical Exam	Large, smooth, firm, unilateral flank mass that does not cross the midline; hypertension (due to renin secretion by tumor); occasionally acquired varicocele (left-sided, from renal vein compression)
Key Diagnostic Results	Abdominal ultrasound showing intrarenal solid mass; CT abdomen/pelvis for staging reveals well-circumscribed renal mass with contrast enhancement; chest CT for pulmonary metastases
Management	Radical nephrectomy followed by stage-based chemotherapy (vincristine + dactinomycin +/- doxorubicin); radiation therapy added for Stage III and above; bilateral disease (Stage V) receives neoadjuvant chemotherapy before nephron-sparing surgery
Keywords	"Painless abdominal mass in a child," "does not cross midline," "large flank mass found by parent," "aniridia + genitourinary anomalies," "do not biopsy"

1. Pathophysiology

Wilms tumor originates from persistent metanephric blastema, the embryonic precursor tissue of the kidney that normally differentiates and involutes during fetal development. When this tissue fails to mature, it persists as nephrogenic rests, which serve as the precursor lesions for nephroblastoma. These rests can undergo malignant transformation, producing a triphasic tumor composed of blastemal, stromal, and epithelial elements.

The genetic basis centers on the WT1 tumor suppressor gene located on chromosome 11p13. WT1 encodes a transcription factor essential for normal kidney and gonadal development. When both copies are lost or mutated (following the Knudson two-hit hypothesis), the metanephric blastema escapes normal growth regulation and proliferates uncontrollably. A second locus, WT2 on chromosome 11p15, is associated with Beckwith-Wiedemann syndrome and involves loss of imprinting at the IGF-2 gene, leading to overexpression of this growth factor and consequent organomegaly and tumor predisposition.

The tumor's hypertension is explained by direct renin secretion from the neoplastic cells or by compression of the renal vasculature, activating the renin-angiotensin-aldosterone system. Hematuria results from tumor invasion into the collecting system. The mass itself grows within the renal parenchyma, displacing and compressing surrounding structures but typically maintaining a well-defined pseudocapsule, which explains why it appears smooth on exam and does not cross the midline (unlike neuroblastoma, which arises from the adrenal medulla or sympathetic chain and grows irregularly across the midline).

The histologic classification into favorable histology (no anaplasia) and unfavorable histology (diffuse anaplasia) is the single most important prognostic factor. Anaplasia is defined by the presence of markedly enlarged and hyperchromatic nuclei with abnormal mitotic figures. Diffuse anaplasia confers treatment resistance and a significantly worse prognosis compared to focal anaplasia or favorable histology.

2. Classification and Clinical Manifestation

Staging (National Wilms Tumor Study / Children's Oncology Group)

Staging is determined after surgical resection, not before. This is a commonly tested distinction.

Stage	Definition
I	Tumor limited to the kidney and completely resected; renal capsule intact; no rupture or spillage
II	Tumor extends beyond the kidney (through the renal capsule or into renal sinus vessels) but is completely resected with negative margins
III	Residual tumor confined to the abdomen after surgery: positive margins, lymph node metastases, peritoneal contamination, tumor spillage during operation, or biopsy performed prior to resection
IV	Hematogenous metastases to distant organs (lungs, liver, bone, brain)
V	Bilateral renal involvement at time of diagnosis

Histologic Classification

Category	Features	Prognosis
Favorable histology	Well-differentiated triphasic pattern (blastemal, epithelial, stromal) without anaplasia	Excellent; >90% survival in early stages
Focal anaplasia	Anaplastic cells confined to one or a few discrete foci within the tumor	Intermediate; treated similarly to favorable histology in Stage I
Diffuse anaplasia	Anaplastic cells distributed throughout the tumor	Poor; requires intensified chemotherapy; most important adverse prognostic indicator

Associated Syndromes

Syndrome	Genetic Basis	Key Features Beyond Wilms Tumor
WAGR	WT1 deletion at 11p13 (contiguous gene deletion)	Wilms tumor, Aniridia, Genitourinary anomalies (cryptorchidism, hypospadias), intellectual disability (formerly mental Retardation)
Denys-Drash	WT1 point mutation at 11p13	Diffuse mesangial sclerosis (early-onset nephrotic syndrome leading to renal failure), male pseudohermaphroditism, very high Wilms tumor risk
Beckwith-Wiedemann	WT2 abnormality at 11p15 (loss of imprinting of IGF-2)	Macroglossia, organomegaly (visceromegaly), omphalocele/umbilical hernia, hemihypertrophy, neonatal hypoglycemia, ear pits/creases

3. Diagnostic Workup

Test	Role	Key Findings
Abdominal ultrasound	Best initial test	Solid intrarenal mass, often with areas of necrosis or hemorrhage; evaluates for IVC or renal vein tumor thrombus; distinguishes solid from cystic masses
CT abdomen and pelvis with contrast	Staging and surgical planning	Well-circumscribed intrarenal mass with heterogeneous enhancement; assesses contralateral kidney, lymph nodes, liver involvement; identifies tumor extension into renal vein or IVC
Chest CT	Metastatic workup	Pulmonary nodules (lungs are the most common site of distant metastasis)
Urinalysis	Supportive	Hematuria (microscopic or gross)
Complete blood count	Baseline	May show anemia from intratumoral hemorrhage; acquired von Willebrand disease is a rare association
Serum creatinine and BUN	Renal function baseline	Important for chemotherapy planning and to assess contralateral kidney function
Histopathology after nephrectomy	Confirmatory (gold standard)	Triphasic pattern; favorable vs. unfavorable histology determined; stage finalized

The best initial test when a child presents with a painless abdominal mass is abdominal ultrasound. This is noninvasive, avoids radiation, and reliably distinguishes a solid intrarenal mass from hydronephrosis, polycystic kidney disease, or a cystic lesion. Ultrasound also evaluates the renal vein and inferior vena cava for tumor thrombus extension, which directly affects the surgical approach.

Once ultrasound confirms a solid renal mass, CT abdomen and pelvis with IV contrast is obtained for staging and preoperative planning. CT delineates the tumor's relationship to surrounding structures, assesses the contralateral kidney for synchronous disease or nephrogenic rests, evaluates regional lymph nodes, and identifies liver metastases. Chest CT is included in the initial workup because the lungs are the most common site of hematogenous spread.

A critical exam concept: percutaneous biopsy is contraindicated in suspected Wilms tumor. Needle biopsy risks tumor rupture, spillage into the peritoneum, and upstaging the disease from Stage I/II to Stage III. The diagnosis is confirmed on pathology after surgical nephrectomy. This is the gold standard and the point at which histologic subtype and surgical stage are definitively assigned.

Urine catecholamines (vanillylmandelic acid [VMA] and homovanillic acid [HVA]) are not elevated in Wilms tumor. If they are elevated, the diagnosis shifts to neuroblastoma. This distinction is frequently tested.

4. Management and Treatment

Stage / Situation	Treatment Protocol
Stage I and II, favorable histology	Radical nephrectomy + vincristine + dactinomycin (Regimen EE-4A); no radiation; approximately 18 weeks of chemotherapy
Stage III, favorable histology	Radical nephrectomy + vincristine + dactinomycin + doxorubicin (Regimen DD-4A) + abdominal radiation therapy (10.8 Gy); approximately 24 weeks
Stage IV, favorable histology	Same as Stage III + whole-lung irradiation (12 Gy) if pulmonary metastases are present; intensified chemotherapy
Stage V (bilateral)	Neoadjuvant chemotherapy (vincristine + dactinomycin for 6 weeks) to shrink tumors bilaterally, followed by bilateral nephron-sparing surgery (partial nephrectomy)
Unfavorable histology (diffuse anaplasia)	Intensified regimen: vincristine + dactinomycin + doxorubicin + cyclophosphamide + etoposide; radiation therapy included regardless of stage

Surgical resection by radical nephrectomy is the cornerstone of management for unilateral Wilms tumor. The approach includes removal of the entire affected kidney, perirenal fat, ipsilateral adrenal gland (if involved), and regional lymph node sampling. Lymph node sampling is mandatory because omission can lead to understaging and inadequate adjuvant therapy.

Chemotherapy is stage-dependent. The backbone agents are vincristine (given IV weekly) and dactinomycin (also known as actinomycin D, given IV in pulses). For Stage I and II with favorable histology, this two-drug regimen alone achieves cure rates exceeding 90%. Doxorubicin is added beginning at Stage III because the residual disease burden warrants a more aggressive cytotoxic approach. Awareness of doxorubicin's cumulative cardiotoxicity (dilated cardiomyopathy) is important, especially in pediatric patients with a long life expectancy.

Radiation therapy is introduced at Stage III and above for favorable histology. The flank or whole abdomen receives targeted irradiation to address residual microscopic disease. For Stage IV with pulmonary metastases, whole-lung irradiation is added. Radiation is used regardless of stage in cases of diffuse anaplasia because of the inherent chemoresistance of anaplastic cells.

Bilateral Wilms tumor (Stage V) represents a unique management challenge. The goal is to preserve as much functional renal parenchyma as possible. The approach begins with neoadjuvant chemotherapy (preoperative tumor shrinkage), followed by bilateral nephron-sparing partial nephrectomy. Complete nephrectomy of both kidneys resulting in dialysis dependency is avoided whenever surgically feasible.

Contraindications and considerations:

Doxorubicin requires echocardiographic monitoring; cumulative doses above 300 to 450 $\text{mg/m}^2$ carry elevated risk of irreversible cardiomyopathy.
Radiation to the flank in young children increases long-term risk of musculoskeletal growth disturbance, secondary malignancies, and gonadal toxicity (if pelvic fields are involved).
In cases of IVC tumor thrombus extension, preoperative chemotherapy or careful surgical extraction of the thrombus under cardiopulmonary bypass may be required.

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Neuroblastoma	Also presents as an abdominal mass in a young child; similar age group; can arise near the kidney (adrenal medulla)	Neuroblastoma crosses the midline, is irregular and calcified on imaging, and has elevated urine catecholamines (VMA/HVA); Wilms tumor is smooth, intrarenal, does not cross midline, and has normal catecholamines
Polycystic kidney disease (autosomal recessive)	Can present with bilateral flank masses in an infant or child	Ultrasound shows bilateral enlarged kidneys with multiple cysts, not a solid mass; associated with hepatic fibrosis and Potter sequence in severe cases
Hydronephrosis	Palpable flank mass in a child; can be unilateral	Ultrasound shows dilated renal pelvis and calyces (fluid-filled), not a solid tumor; often caused by ureteropelvic junction obstruction
Renal cell carcinoma	Solid renal mass with hematuria	Occurs in adults (peak 60 to 70 years), not young children; associated with smoking, VHL syndrome; classic triad of hematuria, flank pain, palpable mass is more common in adults
Mesoblastic nephroma	Most common renal tumor in neonates (age < 3 months); solid renal mass on imaging	Benign; occurs in the first few months of life (much younger than typical Wilms); cured by nephrectomy alone without chemotherapy
Clear cell sarcoma of the kidney	Renal tumor in children; similar age group	Bone metastases are characteristic (unlike Wilms, which metastasizes to lungs); requires more aggressive treatment with doxorubicin and radiation
Rhabdoid tumor of the kidney	Renal tumor in very young children (< 2 years)	Extremely aggressive; associated with brain tumors (posterior fossa ATRT); INI1/SMARCB1 gene mutation; worst prognosis of all pediatric renal tumors

6. Traps and High-Yield Pearls

The most common way students lose points on Wilms tumor questions is by confusing it with neuroblastoma. Both are pediatric abdominal masses, but the vignette will contain clues that distinguish them. A smooth, unilateral flank mass that does not cross the midline with normal catecholamines points to Wilms tumor. An irregular, calcified mass crossing the midline with elevated VMA/HVA and opsoclonus-myoclonus points to neuroblastoma. If the vignette mentions "a mass was incidentally noted during bathing," this is nearly always Wilms tumor.

Another frequent trap involves the question: "What is the next step in management?" When a child has a suspected renal mass, students are tempted to select biopsy. Do not biopsy. The answer is abdominal ultrasound (if not yet done) or CT for staging, followed by surgical nephrectomy for tissue diagnosis. Biopsy causes tumor spillage and upstages the disease.

Watch for syndrome associations in the vignette stem. A child with aniridia (absent iris) who has an abdominal mass is essentially being handed the diagnosis of WAGR syndrome with Wilms tumor. A macrosomic infant with macroglossia, an omphalocele, and hemihypertrophy points to Beckwith-Wiedemann syndrome, and the question will likely ask about screening for Wilms tumor (serial renal ultrasounds every 3 months until age 7 to 8).

Finally, remember that staging is surgical, not clinical. Unlike many adult cancers staged by imaging, Wilms tumor staging is finalized only after the pathologist examines the nephrectomy specimen and sampled lymph nodes. A question asking "What determines the stage?" expects you to choose the surgical and pathologic findings, not the CT report.

The core competency being tested is the ability to recognize a classic pediatric renal mass presentation, avoid dangerous interventions (biopsy), sequence the workup correctly (ultrasound first, then CT, then surgery), and match the treatment intensity to the surgical stage and histologic subtype.

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