Wilms Tumor – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

  • An embryonal renal neoplasm containing blastema, stromal, or epithelial cell types, usually affecting children <5 years of age
  • Staging: In US, National Wilms Tumor Study Group (NWTSG) staging is done pretreatment based on radiographic imaging and surgery, whereas in Europe/Asia, Société Internationale d’Oncologie Pédiatrique (SIOP) staging is done after neoadjuvant chemotherapy is administered (1):
    • I: Tumor limited to kidney; completely excised
    • II: Tumor extends beyond kidney; completely excised
    • III: Residual nonhematogenous tumor confined to abdomen (lymph nodes positive, spillage of tumor, peritoneal implants, extension beyond resection region)
    • IV: Hematogenous metastases
    • V: Bilateral renal involvement
  • System(s) affected: Renal/Urologic
  • Synonym(s): Nephroblastoma

Pediatric Considerations

  • Occurs only in children
  • Most common renal malignancy in childhood

Epidemiology

Incidence

  • Frequency rarer 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:
    • More than 80% are diagnosed before 5 years of age (median age is 3.5 yr at diagnosis).

Prevalence

US: 0.69/100,000; 7.6 cases/1 million children <15 years

Risk Factors

  • Familial occurrence (1–2%):
    • These patients tend to have earlier age of onset.
    • Familial patients have greater risk of bilateral disease.
  • Paternal occupation (see Etiology)

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 17q12–21 has been linked to 2 kindreds with Wilms tumor, and other kindreds are associated with a Wilms tumor predisposition gene at 19q13.3–q13.4.
  • Loss of heterozygosity at chromosomes 16q and 1p is associated with adverse outcome (1)[C].

General Prevention

Routine surveillance in patients with syndromes associated with Wilms tumor (see Commonly Associated Conditions)

Etiology

  • Hereditary or sporadic forms of genetic mutation
  • Familial form: Autosomal dominant trait with incomplete penetrance (1%)
  • Potential of paternal occupational exposure (machinists, welders, motor vehicle mechanics, auto body repairmen)

Commonly Associated Conditions

  • Aniridia (partial or complete absence of iris) 600× > normal risk
  • Hemihypertrophy (100× > normal risk)
  • Cryptorchidism
  • Hypospadias
  • Duplicated renal collecting systems
  • Wiedemann-Beckwith syndrome
  • Denys-Drash syndrome (nephropathy, renal failure, male pseudohermaphroditism, Wilms tumor)
  • Klippel-Trénaunay syndrome
  • WAGR complex (Wilms tumor, aniridia, genitourinary malformations, and mental retardation)
  • Beckwith-Wiedemann syndrome (visceromegaly, macroglossia, omphalocele, hyperinsulinemic hypoglycemia)

Diagnosis

  • Symptoms of pain, anorexia, vomiting, malaise in 30% (1)[C]
  • Over 90% present with asymptomatic abdominal mass (2)[B].

History

  • History of increasing abdominal size
  • Usually asymptomatic

Physical Exam

  • Palpable upper abdominal mass
  • Abdominal pain
  • Fever
  • Anemia
  • Rarely, signs of acute abdomen with free intraperitoneal rupture
  • Cardiac murmur
  • Hepatosplenomegaly
  • Ascites
  • Prominent abdominal wall veins
  • Varicocele
  • Gonadal metastases
  • Aniridia (present in 1.1% of Wilm’s tumor patients)
  • Hypertension (20–65%) (1)[C]

Diagnostic Tests & Interpretation

Lab

  • Urinalysis (occasional hematuria, proteinuria)
  • Complete blood count (CBC) (anemia)
  • Lactate dehydrogenase
  • Plasma renin (rarely helpful)
  • Urine catecholamines
  • Serum creatinine and calcium
  • Coagulation factors

Imaging

  • Chest radiograph
  • Kidney, ureter, and bladder (presence of linear calcifications)
  • Abdominal ultrasound (with Doppler imaging): Gives best information about tumor extension into inferior vena cava
  • Computed tomography (CT) scan (with IV and oral contrast material) of chest and abdomen (12–15% have lung metastases at diagnosis) (1)
  • IV pyelogram rarely helpful

Diagnostic Procedures/Surgery

Occasionally, bone marrow aspiration necessary to distinguish from neuroblastoma

Pathological Findings

  • Favorable findings (mortality of 7%):
    • Bulky lesion, well encapsulated
    • Focal areas of hemorrhage and necrosis
    • Absence of anaplasia and sarcomatous cell types
    • Presence of blastema, stomal, and epithelial elements (2)[B]:
      • 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 (2)[B]:
    • These are precursor lesions found in 25–40% of Wilms
    • Found in 1% of infants at autopsy, but most do not develop into malignancy

Differential Diagnosis

  • Neuroblastoma
  • Hepatic tumor
  • Sarcoma
  • Rhabdoid tumor
  • Cystic nephroma
  • Mesoblastic nephroma
  • Renal cell carcinoma (generally occurs in older children)

Treatment

Medication

First Line

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  • Dactinomycin (Actinomycin-D)
  • Vincristine
  • Doxorubicin
  • Cyclophosphamide (Cytoxan)
  • Iphosphamide
  • Etoposide

Second Line

  • Doxorubicin (Adriamycin)
  • Cyclophosphamide

Additional Treatment

General Measures

  • Appropriate health care: Inpatient workup and treatment until stable postoperative and induction chemotherapy completed
  • Chemotherapy
  • Radiation therapy in stage II (unfavorable histology), stage III, and stage IV

Issues for Referral

Surgical complications have been found to be significantly higher if the radical nephrectomy is done by a general surgeon rather than a pediatric surgeon or a pediatric urologist (3)[B].

Complementary and Alternative Medicine

SIOP recommends pretreatment with neoadjuvant chemotherapy based on radiographic studies and, on occasion, needle biopsy (1):

  • May decrease incidence of intraoperative tumor rupture (this is debated)
  • 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

Surgery/Other Procedures

  • Exam (visual and manual) of contralateral kidney
  • Radical nephroureterectomy and biopsies as needed to provide precise staging information
  • Sampling of any enlarged lymph nodes (absence of any lymph nodes in the surgical specimen mandates treatment as stage III disease) (2)[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 present (possible use of cardiopulmonary bypass)
  • Bilateral Wilms tumors (represent 4–6% of Wilms) (2)[B]:
    • Preoperative chemotherapy with reevaluation by CT or magnetic resonance imaging 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 preferred but only if it does not compromise tumor resection
      • Kidney with lowest tumor burden is addressed first. If successful resection 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.

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

  • Multidrug chemotherapy every 3–4 weeks for 16 weeks–15 months depending on stage
  • Every 4 months for 1 year, every 6 months for 2nd–3rd 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 ultrasound (US) every 3–4 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 (4)[C].

Patient Education

  • Patient and family teaching regarding long-term outlook
  • Possibility of 2nd malignancy (up to 12% by age 50)
  • 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 1–3 studies
    • Children with stage III, favorable histology tumor: Overall survival of 89% in NWTSG 3–4 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

Complications

  • Complication rate of 9.8% in NWTSG-5 study group (2)[B]:
    • Complication rate of 6.4% reported from SIOP (patients all pretreated with 4–8 weeks of chemotherapy)
  • 1–2% will develop 2nd 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 2nd malignant neoplasms in 2% of patients 7–34 years after treatment:
    • Bone and soft tissue sarcomas, breast cancer, hepatocellular carcinoma, lymphoma, gastrointestinal tract tumors, melanoma, leukemias
  • Surgical complications (3)[B]:
    • Postoperative hemorrhage
    • 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 (5)[B]. Incidence of tumor spillage is reported as 2.2% by SIOP following preoperative neoadjuvant chemotherapy (2)[B].
  • Local tumor recurrence
  • Renal failure
  • Cardiomyopathy (usually related to doxorubicin and radiation therapy)
  • Impaired pulmonary function (radiation therapy)

References

1. Sonn G, Shortliffe LM. Management of Wilms tumor: current standard of care. Nat Clin Pract Urol. 2008;5:551–60.

2. Ko EY, Ritchey ML, et al. Current management of Wilms’ tumor in children. Journal of pediatric urology. 2009;5:56–65.

3. Ritchey ML, et al. Surgical complications after primary nephrectomy for Wilms tumor: Report from the national Wilms tumor study group. J Am Coll Surg. 2001;192:63–8.

4. Scott RH, et al. Surveillance for Wilms Tumour in at-risk children: Pragmatic recommendations for best practice. Arch Dis Child. 2006;91:995–9.

5. Ehrlich PF, et al. Quality assessment for Wilms tumor: A report from the national Wilms study-5. J Ped Surg. 2005;40:208–10.

Codes

ICD9

189.0 Malignant neoplasm of kidney, except pelvis

Snomed

302849000 nephroblastoma (disorder)

Clinical Pearls

  • Nephrectomy typically is performed as soon as possible after completing the radiographic evaluation. This is important because it is 1 of the major components in staging the tumor.
  • To treat bilateral tumors, staging is completed with open surgical biopsies, followed by adjuvant chemotherapy. After several cycles, surgical treatment is completed with bilateral partial nephrectomy or unilateral radical nephrectomy combined with contralateral partial nephrectomy, depending on the anatomy. New protocols are evaluating primary chemotherapy, followed by nephron-sparing resection.
  • Mesoblastic nephroma:
    • Distinguished only by histology
    • Age usually <6 months
    • Essentially benign, although metastases have been reported; tends to be locally invasive
    • Operative spillage may lead to recurrence.
    • No chemotherapy or radiotherapy is needed with complete excision.
  • Nephroblastomatosis: Considered premalignant; may present as nodularity of 1 or both kidneys; treated with biopsy and local excision (renal tissue sparing)

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