Wilms Tumor

Overview

Epidemiology

• Most common renal malignancy in children
• Accounts for 6%–7% of all childhood malignancies
• 500 new cases per year in the United States
• Incidence of approximately 7 cases/million children age < 15 years in the United States:
  • ⅔ of cases diagnosed before 5 years of age.
  • 95% of cases diagnosed before 10 years of age.
• Median age at diagnosis for:
  • Unilateral disease:
    • Boys: 37 months
    • Girls: 43 months
  • Bilateral disease:
    • Boys: 24 months
    • Girls: 31 months
• Associated congenital anomaly is diagnosed at an earlier age.
• African Americans have a greater risk of developing disease.
• Asians have a significantly lower risk of developing disease.

Etiology

• Generally occurs sporadically
• Approximately 10% have a multiple malformation syndrome:
  • WAGR syndrome: chromosomal deletion of WT1 gene at 11p13
    • Wilms tumor
    • Aniridia
    • Genitourinary abnormalities
    • Intellectual disability (mental Retardation)
  • Beckwith–Wiedemann syndrome (BWS): microduplication mutations at WT2 gene at 11p15
    • Wilms’ tumor (in 5%–10%)
    • Macrosomia
    • Macroglossia
    • Hemihypertrophy
    • Omphalocele
    • Prominent eyes
    • Ear creases
    • Enlarged kidneys
    • Pancreatic hyperplasia
    • Neonatal hypoglycemia
  • Denys–Drash syndrome: germline point mutation in the 8th or 9th exon in the WT1 gene
    • Wilms tumor
    • Male pseudohermaphroditism: may have undescended testes owing to gonadal dysgenesis
    • Diffuse mesangial sclerosis in kidneys: proteinuria in infancy, which progresses to nephrotic syndrome and renal failure

Pathophysiology

• Associated with aberrant renal development:
  • Abnormal glomerular or tubular development in metanephric blastema proliferation
  • Believed to arise from nephrogenic rests or nephroblastomatosis (which are foci of persistent immature or embryonal cells):
    • Present in 1% of newborn kidneys and regress in early childhood
    • Present in 35% of unilateral and almost 100% of bilateral Wilms tumor
• Tumorigenesis:
  •  Thought to be from genetic changes triggering these nephrogenic rests
  • Associated with loss-of-function mutation in a number of tumor suppressor and transcription genes:
    • WT1
    • WT2
    • p53
    • FWT1
    • FWT2
• Some tumors do not have any of the above genetic mutations, suggesting that other, unknown genes may be involved in Wilms tumor.

Clinical Presentation

Manifestations

• Most present with only a firm, painless smooth mass that does not cross the midline.
• Other less common symptoms:
  • Abdominal pain
  • Hematuria
  • Fever
  • Hypertension
• Subset of patients presents with subcapsular hemorrhage:
  • Rapid abdominal enlargement
  • Anemia
  • Hypertension
  • Fever

Physical examination

• General abdominal exam with patient in supine position: 
  • Visually inspect abdomen and flank.
  • Assess for palpable mass.
  • Careful exam required if Wilms tumor suspected (vigorous palpation increases risk of rupture and tumor spillage).
• General genitourinary exam assessing for syndromic conditions
• Eye exam to assess for aniridia
• Assess for hemihypertrophy of limbs.

Diagnosis

Screening

Serial abdominal ultrasonography for those at risk for Wilms tumor:

• Children with BWS or isolated hemihyperplasia: every 3 months until 7 years old
• Children with WAGR and WT1-associated syndromes: every 3 months until 5 years old
• Siblings of patient with familial Wilms tumor: every 3 months until 8 years old
• Children of survivors of bilateral Wilms tumor: every 3 months until 8 years old

Diagnostic imaging and laboratory studies

• Abdominal (renal) ultrasonography: detects hydronephrosis and a multicystic renal mass
• CT with contrast or MRI of abdomen: to further evaluate nature or extent of disease
• CT of chest:
  • To determine if there is lung metastasis
  • Biopsy if there is a suspicious nodule
• Definitive diagnosis is via biopsy:
  • Tumor is a mixed pattern of 3 types of cells:
    • Blastemal cells
    • Stromal cells
    • Epithelial cells
  • Proportions vary, leading to multiple appearances.
  • Anaplastic Wilms tumor:
    • Large, distorted nuclei + multipolar polypoid mitotic figures noted
    • More common in older age
    • Indicative of adverse outcome
• Laboratory tests:
  • Urinalysis:
    • Hematuria
    • Proteinuria in Denys–Drash syndrome
  • CMP for baseline creatinine
  • CBC for baseline hemoglobin (may have polycythemia)
  • Abnormal liver function tests if there is liver metastasis

Staging

From National Wilms Tumor Study (NWTS)/Children’s Oncology Group (COG):

• Stage I:
  • Tumor confined to the kidney and completely excised
  • Renal capsule is intact.
  • No biopsy was performed or tumor spillage
  • No renal vessel involvement
  • No positive surgical margins
  • All sampled lymph nodes negative
• Stage II:
  • Tumor has grown beyond the kidney but is completely excised.
  • May have regional extension of tumor (penetration of renal capsule or invasion of renal sinus).
  • Blood vessels outside the renal parenchyma may contain tumor.
  • All lymph nodes sampled are negative.
• Stage III:
  • Residual tumor remains (incomplete surgical excision)
  • Tumor penetrating through the peritoneum
  • Positive tumor spillage or biopsy
  • Positive regional lymph nodes (not in distant lymph nodes)
• Stage IV:
  • Hematogenous metastasis
  • Lymph node metastases outside the abdominopelvic region
  • Tumor within the adrenal gland
• Stage V: bilateral renal involvement

Management

Treatment

Recommendations based on the NWTS/COG trials:

• Depends on the stage and histology
• Stages I and II:
  • Primary surgical resection
  • 19 weeks of vincristine and dactinomycin after surgery
  • If patient has high-risk molecular markers (loss of heterozygosity at chromosomes 1p and 16q): 
    • Add doxorubicin.
    • Extend chemotherapy regimen to 25 weeks.
  • If patient has stage I anaplasia or stage II focal anaplasia:
    • Add doxorubicin.
    • Extend chemotherapy regimen to 25 weeks.
    • Add radiation therapy.
  • If patient has stage II + diffuse anaplasia: 
    • Add carboplatin, cyclophosphamide, and etoposide.
    • Remove dactinomycin.
    • Add radiation therapy.
    • Extend chemotherapy regimen to 30 weeks.
• Stage III:
  • Primary surgical resection with lymph node sampling
  • 25 weeks of vincristine, dactinomycin, and doxorubicin after surgery
  • Radiation therapy
  • If patient has high-risk molecular markers:
    • Add cyclophosphamide and etoposide.
    • Extend chemotherapy regimen to 31 weeks.
  • If patient has diffuse anaplasia:
    • Add carboplatin, cyclophosphamide, and etoposide.
    • Remove dactinomycin.
    • Extend chemotherapy regimen to 30 weeks.
• Stage IV:
  • Primary surgical resection with lymph node sampling
  • 25 weeks of vincristine, dactinomycin, and doxorubicin after surgery
  • Radiation therapy
  • If patient has high-risk molecular markers and/or lung nodule with incomplete response in 6 weeks:
    • Add cyclophosphamide and etoposide.
    • Extend chemotherapy regimen to 31 weeks.
  • If patient has focal anaplasia:
    • Add carboplatin, cyclophosphamide, and etoposide.
    • Remove dactinomycin.
    • Extend chemotherapy regimen to 30 weeks.
  • If patient has diffuse anaplasia:
    • Add carboplatin, cyclophosphamide, and irinotecan.
    • Remove dactinomycin.
    • Extend chemotherapy regimen to 36 weeks.
• Stage V (bilateral):
  • Preoperative vincristine, actinomycin, and doxorubicin for 6 weeks
  • Surgery
  • Postoperative chemotherapy and radiotherapy (decision based on histopathology of the tumor and lymph node involvement)

Prognosis

• 5-year survival rate > 90%
• Depends on tumor stage at diagnosis
• Patients with diffuse anaplasia have the worst prognosis.
• Age influences prognosis:
  • Older age at diagnosis is associated with a worse prognosis.
  • Adults: higher rate of treatment-associated toxicity
  • < 2 years of age: lower relapse rate
• Cause of death:
  • Tumor-related: 86%
  • Late effects of therapy: 9%
  • Not related to disease or effects of therapy: 5%
  • Unknown: 1%

Differential Diagnosis

• Clear cell sarcoma of the kidney: second most common pediatric malignancy of the kidney: This condition has higher relapse and mortality rates than Wilms’ tumor. Bone is a common site of metastasis. Pathology shows cords and nests of pale-stained tumor cells with significant extracellular matrix that is separated by a network of vascular arcades. Diagnosis is via imaging ultrasonography or CT, and treatment consists of surgery and chemotherapy.
• Rhabdoid tumor of the kidney: highly malignant renal tumor that commonly involves children < 2 years old. At diagnosis, the tumor is often advanced, with metastasis to the lungs, lymph nodes, abdomen, brain, liver, and bone. Mortality rate is high (> 80%) within a year of diagnosis. Abdominal imaging: ultrasonography versus CT with biopsy are utilized for diagnosis, and treatment is with chemotherapy.
• Congenital mesoblastic nephroma: benign renal mass diagnosed during first year of life or via prenatal ultrasonography: Congenital mesoblastic nephroma associated with hypertension and elevated renin and calcium. The mass is usually infiltrative and requires surgical excision.
• Renal cell carcinoma (RCC): Rare in childhood, but at presentation the disease is usually already advanced in children as compared with in adults. Neuroblastoma survivors who had renally directed radiotherapy and platinum-based chemotherapy may be at increased risk of RCC. Diagnosis is with abdominal imaging, and treatment is surgical excision.
• Renal medullary carcinoma: highly invasive, rare renal malignancy: Disease is essentially seen in patients with sickle cell hemoglobinopathy, particularly sickle cell trait. Tumor is aggressive and is noted with early metastasis. Treatment is with surgical excision and chemotherapy.