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EPIDEMIOLOGY
Incidence
- Frequency rare in East Asian populations than Whites
- Frequency higher in black children than in whites
- Predominant age: median age of 36.5 months
- Predominant sex: female > male (1.1:1)
- Represents 6 " 7% of all childhood cancers
- >80% are diagnosed before 5 years of age (median age is 3.5 years at diagnosis).
- Wilms tumor makes up 95% of all renal cancers in children <15 years (2).
Prevalence
United States: 0.69/100,000; 7.6 cases/1 million children <15 years old
ETIOLOGY AND PATHOPHYSIOLOGY
- Hereditary or sporadic forms of genetic mutation
- Familial form: autosomal dominant trait with incomplete penetrance (1%)
- Potential of parental occupational exposure (machinists, welders, motor vehicle mechanics, auto body repairmen)
Genetics
- Several congenital anomalies are known to be associated with Wilms tumor. A 2-stage mutational model has been proposed: occurrence in either hereditary form or sporadic form. Patients with aniridia have a deletion of the short arm of chromosome 11 (11p13).
- Abnormalities of chromosome 11 at the 11p15 locus are associated with Beckwith-Wiedemann syndrome. Wilms tumor-suppressor gene (WT1) has been identified as well as additional candidates for another suppressor gene (WT2). Chromosome band 17q12 " 17q21 has been linked to two kindreds with Wilms tumor, and other kindred are associated with a Wilms tumor predisposition gene at 19q13.3 " 19q13.4. Loss of heterozygosity at chromosomes 16q and 1p is associated with adverse outcome (1).
- p53 is associated with anaplastic Wilms tumors (2).
RISK FACTORS
- Familial occurrence (5%) (2)
- These patients tend to have earlier age of onset.
- Familial patients have greater risk of bilateral disease.
- Parental occupation (machinists, welders, motor vehicle mechanics, auto body repairmen)
- Maternal exposure to pesticides prior to child 's birth (3)
- High birth weight or preterm birth (3)
- Compared with firstborn, being a second or later birth may be associated with significantly decreased risk of Wilms tumor (3).
GENERAL PREVENTION
- Routine surveillance in patients with syndromes associated with Wilms tumor
- Routine screening with serial renal US at 3- to 4-month intervals has been recommended in children who have syndromes associated with an incidence of Wilms tumor >5% (4)[C].
- Routine screening with serial renal US is also recommended for infants born to kindreds with familial Wilms (every 3 to 4 months until age 7 years) (4)[C].
COMMONLY ASSOCIATED CONDITIONS
- Aniridia (partial or complete absence of iris) 600 times normal risk
- Hemihypertrophy (100 times normal risk)
- Cryptorchidism
- Hypospadias
- Duplicated renal collecting systems
- Denys-Drash syndrome (nephropathy, renal failure, male pseudohermaphroditism, Wilms tumor)
- Klippel-Trenaunay syndrome
- Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR) complex
- Beckwith-Wiedemann syndrome (visceromegaly, macroglossia, omphalocele, hyperinsulinemic hypoglycemia)
DIAGNOSIS
- Symptoms of pain, anorexia, vomiting, malaise in 30% (1)
- >90% present with asymptomatic abdominal mass (5)
HISTORY
- History of increasing abdominal size
- Usually asymptomatic; may have fever, abdominal pain
PHYSICAL EXAM
- Palpable upper abdominal mass
- Fever, hepatosplenomegaly
- Rarely, signs of acute abdomen with free intraperitoneal rupture
- Cardiac murmur
- Ascites, prominent abdominal wall veins, varicocele
- Gonadal metastases
- Aniridia (present in 1.1% of Wilms tumor patients)
- Hypertension (20 " 65%) (1)
DIFFERENTIAL DIAGNOSIS
- Neuroblastoma
- Hepatic tumor
- Sarcoma
- Rhabdoid tumor
- Cystic nephroma
- Renal cell carcinoma (generally occurs in older children)
- Mesoblastic nephroma: distinguished only by histology. Age usually <6 months, essentially benign, although metastases have been reported; tend to be locally invasive
- Nephroblastomatosis: considered premalignant; may present as nodularity of one or both kidneys
DIAGNOSTIC TESTS & INTERPRETATION
- Urinalysis (occasional hematuria, proteinuria)
- CBC (anemia)
- Lactate dehydrogenase
- Plasma renin (rarely helpful)
- Urine catecholamines
- Serum creatinine and calcium
- Coagulation factors
- Chest radiograph
- Abdominal US (with Doppler imaging): best initial test. Gives best information about tumor and extension into inferior vena cava
- CT scan (with IV and oral contrast material) of chest and abdomen. Allows anatomic visualization and excludes synchronous bilateral disease with a high degree of sensitivity (2)
- CT may have high sensitivity and specificity for atriocaval thrombus and obviate the needs for US (2).
- Chest lesions only identified on CT have improved event-free survival with three drug treatment regimens (6)[B].
Diagnostic Procedures/Other
Occasionally, bone marrow aspiration is necessary to distinguish from neuroblastoma.
Test Interpretation
- Favorable findings (mortality of 7%)
- Bulky lesion, well encapsulated
- Focal areas of hemorrhage and necrosis
- Absence of anaplasia and sarcomatous cell types
- Presence of blastemal, stromal, and epithelial elements (5)
- Predominance of epithelial elements usually are less aggressive when diagnosed early but tend to be resistant to treatment when diagnosed late.
- Predominance of blastemal elements indicate more aggressive tumors.
- Unfavorable histology (mortality rate of 57%)
- Anaplasia: markedly enlarged and multipolar mitotic figures, 3-fold enlargement of nuclei in comparison with adjacent similar nuclei, hyperchromasia of enlarged nuclei; anaplasia may be diffuse or focal.
- Sarcomatous changes: now considered to be separate from Wilms, not subtypes (mortality 64%)
- Rhabdoid tumor of the kidney: now considered to be separate tumor from Wilms
- Nephroblastomatosis: considered premalignant
- Nephrogenic rests (5): These are precursor lesions found in 25 " 40% of Wilms; found in 1% of infants at autopsy, but most do not develop into malignancy.
TREATMENT
GENERAL MEASURES
- Appropriate health care: inpatient workup and treatment until stable postoperatively and induction chemotherapy completed
- Chemotherapy; some recommend pretreatment with neoadjuvant chemotherapy (1).
- May decrease incidence of intraoperative tumor rupture (debatable)
- May result in inappropriate treatment with chemotherapeutic agents of non-Wilms tumors (5%) or benign lesions (1.6%)
- Results in the inability to directly compare treatment results worldwide
- Radiation therapy in stage II (unfavorable histology), stage III, and stage IV
MEDICATION
First Line
- Children typically treated with protocols based on staging, histology, and other variables as part of a multimodal therapy approach (chemotherapy, radiation, surgery). The following medications may be used as part of a protocol:
- Dactinomycin (Actinomycin-D)
- Vincristine
- Doxorubicin
- Cyclophosphamide (Cytoxan)
- Ifosfamide
- Etoposide
- Topotecan
- Irinotecan
Second Line
- Doxorubicin (Adriamycin)
- Cyclophosphamide
SURGERY/OTHER PROCEDURES
- Exploration of contralateral kidney no longer required if adequate CT done preoperatively
- Radical nephroureterectomy and lymph node sampling is needed to provide precise staging information.
- Renal-sparing resection
- Tumors are usually too large, but 10 " 15% may be amenable to partial nephrectomy if given preoperative chemotherapy (4)[C].
- May be recommended for patients with high risk of bilateral disease or renal failure (4)[C]
- Sampling of any enlarged lymph nodes (absence of any lymph nodes in the surgical specimen mandates treatment as stage III disease) (5)[B]
- Identification of any retained tumor with titanium clips
- Tumor should be given to pathologist fresh, not in formalin.
- Vertical midline incision if tumor extension to right atrium " increased morbidity (2)
- Bilateral Wilms tumors (represent 4 " 6% of Wilms) (5)[B]
- Preoperative chemotherapy with reevaluation by CT or MRI after 6 weeks (some are biopsied prior to chemotherapy)
- Renal-sparing operation at 6 weeks if good response to chemotherapy:
- Partial nephrectomy or wedge excision of tumor is preferred but only if it does not compromise tumor resection.
- Kidney with lowest tumor burden is addressed first. If successful resection is accomplished, radical nephrectomy can be done on the contralateral kidney. Bilateral partial nephrectomy may be possible in some cases.
- Preoperative treatment also generally is accepted in a solitary kidney, horseshoe kidneys, intravascular extension of tumor above the intrahepatic vena cava, and in the case of respiratory distress from extensive metastatic tumor.
- Treatment of patients with relapsed Wilms (7)[B]: Current treatment is either with chemotherapy with or without radiation therapy alone or high-dose chemotherapy followed by autologous stem cell rescue.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Multidrug chemotherapy every 3 to 4 weeks for 16 weeks to 15 months depending on stage
- Every 4 months for 1 year, every 6 months for second to third year; yearly after that
- CBC, CT of chest and abdomen with each visit
- Patients at high risk for developing Wilms tumor should be monitored with renal US every 3 to 4 months until 5 years of age. Patients with Beckwith-Wiedemann syndrome or Simpson-Golabi-Behmel syndrome should have yearly US until 7 years of age (8)[C].
PATIENT EDUCATION
- Possibility of second malignancy (up to 12% by age 50 years)
- Side effects of chemotherapy, radiation therapy
PROGNOSIS
- With favorable histology (1)
- Children <2 years of age and stage I, favorable histology: 98% survival in NWTSG 1 to 3 studies
- Children with stage III, favorable histology tumor: overall survival of 89% in NWTSG 3 to 4 studies
- With diffuse anaplasia (1)
- Children with stage I, diffuse or focal anaplasia: overall survival 82.6%
- Stage II tumors with anaplasia: overall survival 81.5%
- Stage III tumors with anaplasia: overall survival 66.7%
- Stage IV tumors with anaplasia: overall survival 33.3%
- With bilateral involvement (stage V): 4-year survival 81.7% (1)
- With rhabdoid features: 19% 3-year survival
- Survival of patients with relapsed Wilms tumor is 40 " 70% (8)[B]:
- Patients with pulmonary relapse only had higher 4-year survival rate (77.7%) compared to other sites (41.6%).
COMPLICATIONS
- Complication rate of 6 " 10%
- 1 " 2% will develop second malignant neoplasms (leukemia, lymphoma, hepatocellular carcinoma, soft tissue sarcoma): 12.2% by 50 years of age
- High risk of delivering low-birth-weight infants, perinatal mortality in offspring of female survivors of Wilms tumor
- Chest is usual site of recurrence.
- Occurrence of second malignant neoplasms in 2% of patients 7 to 34 years after treatment
- Bone and soft tissue sarcomas, breast cancer, hepatocellular carcinoma, lymphoma, gastrointestinal tract tumors, melanoma, leukemias
- Surgical complications
- Postoperative small bowel obstruction (5 " 7%)
- Tumor rupture with spillage in 15.3% according to NWTSG-5; this may be spontaneous or surgical and results in upstaging the tumor. Only 2.7% of spills are considered avoidable. Incidence of tumor spillage is reported at 2.2% by SIOP following preoperative neoadjuvant chemotherapy (5)[B].
- Local tumor recurrence
- Abdominal tumor recurrence after tumor spillage is reduced by radiation therapy (10 or 20 Gy).
- Renal failure
- Cardiomyopathy (usually related to doxorubicin and radiation therapy)
- Impaired pulmonary function (radiation therapy)
REFERENCES
11 Sonn G, Shortliffe LM. Management of Wilms tumor: current standard of care. Nat Clin Pract Urol. 2008;5(10):551 " 560.22 Davidoff AM. Wilms tumor. Adv Pediatr. 2012;59(1):247 " 267.33 Chu A, Heck JE, Ribeiro KB, et al. Wilms ' tumour: a systematic review of risk factors and meta-analysis. Paediatr Perinat Epidemiol. 2010;24(5):449 " 469.44 Nakamura L, Ritchey M. Current management of Wilms ' tumor. Curr Urol Rep. 2010;11(1):58 " 65.55 Ko EY, Ritchey ML. Current management of Wilms ' tumor in children. J Pediatr Urol. 2009;5(1):56 " 65.66 Grundy PE, Green DM, Dirks AC, et al. Clinical significance of pulmonary nodules detected by CT and not CXR in patients treated for favorable histology Wilms tumor on national Wilms tumor studies-4 and -5: a report from the Children 's Oncology Group. Pediatr Blood Cancer. 2012;59(4):631 " 635.77 Presson A, Moore TB, Kempert P. Efficacy of high-dose chemotherapy and autologous stem cell transplant for recurrent Wilms ' tumor: a meta-analysis. J Pediatr Hematol Oncol. 2010;32(6):454 " 461.88 Scott RH, Walker L, Olsen E, et al. Surveillance for Wilms tumor in at-risk children: pragmatic recommendations for best practice. Arch Dis Child. 2006;91(12):995 " 999.
CODES
ICD10
- C64.9 Malignant neoplasm of unsp kidney, except renal pelvis
- C64.1 Malignant neoplasm of right kidney, except renal pelvis
- C64.2 Malignant neoplasm of left kidney, except renal pelvis
ICD9
189.0 Malignant neoplasm of kidney, except pelvis
SNOMED
- 302849000 Nephroblastoma (disorder)
- 4135001 11p partial monosomy syndrome (disorder)
CLINICAL PEARLS
- Wilms is the most common renal tumor in children; it is an embryonal renal neoplasm containing blastemal, stromal, or epithelial cell types, usually affecting children <5 years of age.
- Nephrectomy performed as soon as possible after completing radiographic evaluation is the major component in tumor staging.
- Sampling regional lymph nodes or specifically mentioning "No nodes present " in the operative report is necessary or the tumor will automatically be considered stage III.