Summary Table

01Pathophysiology

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.

02Classification 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.

Histologic Classification

Associated Syndromes

03Diagnostic Workup

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.

04Management and Treatment

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 ${\text{mg/m}}^2\backslash text\{mg/m\}^2$ 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.

05Differential Diagnosis and Distractors

06Traps 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.