Jonathan S. Karpelowsky, MD, PhD
Grahame H.H. Smith, MBBS
BASICS
DESCRIPTION
• Wilms tumor (nephroblastoma) is the most common primary malignant renal tumor in childhood
• Represents 6% of all childhood cancers
• Most present in children with abdominal mass
• Symptoms may include pain, hypertension, or hematuria
• Wilms tumor is considered a pediatric renal tumor, but does rarely occur in adults
EPIDEMIOLOGY
Incidence
• 6% of all childhood tumors
• 80% of cases occur in age <5
• 7% bilateral (present at mean age 2.5)
• 12% multifocal within a single kidney
• Rare >10 yr and <6 mo
• Median age 3.5 yr
Prevalence
8 per million children every year
RISK FACTORS
• Increased frequency in children with:
– Beckwith–Wiedemann syndrome: 1 in 10 children develop a tumor of the liver, adrenal cortex, or kidney
– Hemihypertrophy (2% risk)
– Denys–Drash syndrome
– WAGR syndrome (Wilms tumor/aniridia/genitourinary anomalies/mental retardation syndrome), (30% risk)
– Perlman syndrome
– Sotos syndrome (2–3% risk)
• Presence of nephrogenic rests:
– 1% of kidneys on infant postmortems
– 35% of unilateral Wilms
– Almost 100% of bilateral Wilms
• Higher risk in African American compared to Caucasians for Wilms tumor
• Lower risk in Asians compared to Caucasians
Genetics
• WT1 (11p13): Denys–Drash and WAGR syndromes
• WT2 (11p15): Beckwith–Wiedemann syndrome
• FWT1 (17q), FWT2 (19q): Familial; 1–2% of cases
• 16q, loss of long arm in 20% of cases
• 1p, loss of short arm in 10% of cases
PATHOPHYSIOLOGY
• An embryonal tumor marked by proliferation of metanephric blastema composed of 3 cell types: Blastemal, stromal, epithelial
• Histology: Favorable vs. unfavorable (ie, anaplasia pre- or postchemotherapy and blastemal predominant histology postchemotherapy)
• Anaplasia seen in 5%
ASSOCIATED CONDITIONS
• Congenital anomalies in 15% of Wilms tumors
• GU anomalies: Renal anomalies, cryptorchidism, hypospadias, ureteral duplication, ambiguous genitalia (4%)
• Hemihypertrophy (3%)
• Aniridia (1%)
• Denys–Drash syndrome (male pseudohermaphroditism, renal mesangial sclerosis, renal failure)
• WAGR syndrome
• Beckwith–Wiedemann syndrome (macroglossia, organomegaly, hemihypertrophy)
• Other: Perlman syndrome, Sotos syndrome, Simpson–Golabi–Behmel syndrome
GENERAL PREVENTION
N/A
DIAGNOSIS
HISTORY
• Abdominal mass
• Fever, anorexia, weight loss
• Hematuria
PHYSICAL EXAM
• Most common presentation is abdominal mass
• HTN: 20–25% from activation of RAAS (renin-angiotensin-aldosterone system)
• Occasionally present as acute abdomen or with hypotension from tumor rupture
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• CBC: Anemia, polycythemia
• Liver function tests
• BUN, creatinine
• Serum calcium
• Urine analysis: 25% with microhematuria
• Coagulation studies to assess for an acquired von Willebrand disease
Imaging
• Abdominal US: Initial study and if there is any concern about intravascular extension
• CT of abdomen and chest: To detect smaller lesions in either renal unit not detected by US; chest imaging to evaluate for pulmonary metastasis
• Bone scan: If history of bone pain or elevated alkaline phosphatase or serum Ca
Diagnostic Procedures/Surgery
• National Wilms Tumor Study Group (NWTSG)/Children’s Oncology Group (COG), recommends surgical excision or biopsy, followed by adjuvant treatment
• SIOP (International Society of Pediatric Oncology) treatment involves preoperative chemotherapy followed by surgery. Histology and staging are potentially altered but the tumor response to chemotherapy is noted and aids in risk stratification
• Percutaneous biopsy is not recommended
Pathologic Findings
• Gross: Tan or grayish, fleshy tumor with a pseudocapsule
• Microscopic (3 features): Stromal (immature spindle cells and can have muscle cartilage or fat), epithelial (recapitulates kidney with glomeruli and tubules), and blastemal (undifferentiated cells)
• Venous invasion in up to 20%; usually single tumor; 7% bilateral and 12% multifocal
• Histology relates to final outcome:
– Favorable (95%)
– Unfavorable (Anaplasia) (5%): Nuclear enlargement (>3-fold), hyperchromasia, abnormal mitoses. Unfavorable marker of chemoresistance
DIFFERENTIAL DIAGNOSIS
• Clear cell sarcoma
• Rhabdoid tumor
• Neuroblastoma
• Multilocular cystic nephroma
• Mesoblastic nephroma
• Multicystic dysplastic kidney
• Renal cell carcinoma
• Renal medullary carcinoma
TREATMENT
GENERAL MEASURES
• Multimodality therapy combining surgery, chemotherapy, and radiation
• Treatment decisions based on staging
• Staging relies on anatomic extent of tumor (no genetic, histologic, or biomarkers); higher stages have worse prognosis and require more aggressive therapy
• 2 systems currently used, the NWTSG/COG and SIOP; they are difficult to compare directly due to the fact that NWTSG/COG is a prechemotherapy staging and SIOP post-neoadjuvant therapy:
– NWTSG/COG: Commonly used in USA and Canada; based on surgical evaluation prior to chemotherapy
– SIOP: Commonly used in Europe, based on surgical findings following chemotherapy
MEDICATION
First Line
• SIOP studies favor preoperative chemotherapy for 6 wk with dactinomycin plus vincristine following which surgery is undertaken and the tumor response to chemotherapy and the residual histology, ie, if is blastemal predominant will risk stratify further therapy
• Chemotherapy recommendations based on NWTSG/COG, which is given adjuvantly postoperatively
• Children <24 mo and with a specimen weight of <550 g and favorable histology are being considered under study for surgery only and no chemotherapy
• Pulse-intensive dactinomycin plus vincristine (18 wk) for:
– Stage I: Favorable histology, age >2 yr, or tumor <550 g
– Stage I: Anaplasia
– Stage II: Favorable histology
• Pulse-intensive dactinomycin, vincristine, and doxorubicin (24 wk) for:
– Stages III–IV: Favorable histology
– Stages II–IV: Focal anaplasia
– Stage V: Doxorubicin, vincristine, cyclophosphamide, etoposide
– Stages II–IV: Diffuse anaplasia (1)
Second Line
The optimal salvage chemotherapy regimen is unknown. Recurrent/persistent tumors have been treated with cyclophosphamide, ifosfamide, carboplatin, etoposide, and cisplatin combinations
SURGERY/OTHER PROCEDURES
• Choose incision that provides adequate exposure: Transabdominal, thoracoabdominal, chevron
• Unilateral tumor:
– Radical nephrectomy
– Contralateral exploration not needed if not seen on adequate preoperative imaging
– Lymph node: Sample perihilar, pericaval, and para-aortic nodes; excise suspicious nodes minimum of 3–5 nodes
• Bilateral tumor:
– Biopsy not initially required
– Reimage 6 wk after chemotherapy; if <50% response consider open bilateral biopsy, if >50% response then continue therapy to 12 wk and then aim for nephron sparing surgery
– Renal preservation is key to avoid renal failure; important for patient with syndromes at high risk for metachronous disease
• Tumor spillage:
– Local: Percutaneous anterior/posterior percutaneous biopsy; open incisional biopsy (stage III)
– Peritoneal spillage or tumor thrombus spillage is more extensive (stage III)
• Local invasion: Usually can be resected en masse; if not, biopsy and treat with chemotherapy
ADDITIONAL TREATMENT
Radiation Therapy
• Stage III favorable histology and stages II–III focal or diffuse anaplasia:
– Abdominal/flank irradiation 10.8 Gy
• Stage IV favorable histology and stage IV focal or diffuse anaplasia:
– Abdominal/flank irradiation 10.8 Gy
– Lung radiation 12 Gy with lung metastasis on chest x-ray or CT only metastasis not responding to therapy (CT only metastasis that respond to chemotherapy and have no loss of heterozygosity can have pulmonary radiotherapy omitted)
Additional Therapies
Ongoing studies of NWTSG/COG to assess modifying treatment based on risk stratification
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• 5-yr overall survival: 90%
• 4-yr postnephrectomy overall survival:
– Favorable histology:
Stage I: 98%
Stage II: 96%
Stage III: 95%
Stage IV: 90%
– Unfavorable histology:
Stage I: 83%
Stage II: 81%
Stage III: 72%
Stage IV: 37%
Stage V: 55%
• Unfavorable histology: 12% of patients, but 50% of deaths
• Prognostic factors: Histology, stage, patient age (younger better prognosis, but less significant today due to improved treatments)
• Future treatment will include 1p and 16q loss of heterozygosity in the risk and treatment stratification
COMPLICATIONS
• Surgical:
– Bowel obstruction (5.1%)
– Hemorrhage (1.9%)
– Wound infection (1.9%)
– Vascular injuries (1.4%)
– Injuries to other visceral organs (1%)
• Medical:
– Renal impairment
1% chance from surgical, chemotherapy, and/or radiation
Increased in bilateral disease with radiation
Unilateral disease risk in Denys–Drash
– Cardiotoxicity
Congestive heart failure in patients treated with doxorubicin; dose dependent
– Hepatotoxicity
Vincristine and dactinomycin; dose related
– Secondary malignancies
Highest risk in patients treated with both doxorubicin and radiation; occur in radiation field; mean 16.1-yr post therapy
• Radiation:
– Short stature, muscle atrophy, scoliosis
– Highest risk in age <1
– Thyroid disease and mammary tissue damage in chest radiation
– Pregnancy complications increased in females receiving high-dose abdominal radiation
FOLLOW-UP
Patient Monitoring
• Screen patients with aniridia, hemihypertrophy, and Beckmann–Wiedemann syndrome with abdominal US every 3–4 mo to age 7
• 1% of children develop contralateral Wilms within 6 yr of 1st diagnosis
• Majority of Wilms tumor recurrence occurs within 2 yr of nephrectomy
• Favorable histology, <24 mo, and tumor weight <550 g
– Chest x-ray, abdominal US every 3 mo for 1st 2 yr after diagnosis, then every 6 mo for 1 yr, then yearly for 2 yr
• All others:
– Chest x-ray 6 wk and 3 mo after surgery; then every 3 mo for 15 mo, every 6 mo for 18 mo, and yearly for 2 yr
– Abdominal US every 3 mo for 2 yr, then every 6 mo for 3 yr
Patient Resources
National Wilms Tumor Study. www.nwtsg.org
REFERENCE
1. Dome JS, Cotton CA, Perlman EJ, et al. Treatment of anaplastic histology Wilms’ tumor: Results from the fifth Wilms’ tumor study. J Clin Oncol. 2008;24:2352–2358.
ADDITIONAL READING
• Ahmed HU, Arya M, Tsiouris A, et al. An update on the management of Wilms’ tumour. Eur J Surg Oncol. 2007;33:824–831.
• Dome JS, Fernandez CV, Mullen EA, et al. Children’s oncology group’s 2013 blueprint for research: Renal tumors. Pediatr Blood Cancer. 2013;60:994–1000.
• Ehrlich PF. Wilms tumor: Progress and considerations for the surgeon. Surg Oncol. 2007;16(3):157–171.
• Hamilton TE, Shamberger RC. Wilms tumor: Recent advances in clinical care and biology. Semin Pediatr Surg. 2012;21(1):15–20.
See Also (Topic, Algorithm, Media)
• Abdominal Mass, Newborn/Child, Urologic Considerations
• Renal Mass
• Wilms Tumor (Nephroblastoma) Image 
• Wilms Tumor Staging System National Wilms Tumor Study Group (NWTSG Now COG)
• Wilms Tumor Staging System: International Society of Pediatric Oncology (SIOP)
CODES
ICD9
• 189.0 Malignant neoplasm of kidney, except pelvis
• 253.0 Acromegaly and gigantism
• 759.89 Other specified congenital anomalies
ICD10
• C64.9 Malignant neoplasm of unsp kidney, except renal pelvis
• E22.0 Acromegaly and pituitary gigantism
• Q87.3 Congenital malformation syndromes involving early overgrowth
CLINICAL/SURGICAL PEARLS
An asymptomatic abdominal mass is the most common manifestation of Wilms tumor.