Wilms Tumor

Wilms tumor is a malignancy caused by proliferation of metanephric blastema in the kidneys and is the most common renal malignancy in children. Wilms tumor usually arises sporadically, but it can also occur as a result of a specific congenital anomaly like WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation) syndrome, Denys–Drash syndrome, or Beckwith–Wiedemann syndrome. Wilms tumor commonly presents as a firm, nontender, smooth mass that does not cross the midline. Wilms tumor can also rarely present with abdominal pain, hematuria, and/or hypertension. The malignancy is diagnosed with abdominal ultrasonography and histopathologic studies (from biopsy or resection). Wilms tumor is treated with multimodal therapy (surgery, chemotherapy, radiation). Influenced by patient age, molecular markers, and pathologic findings, prognosis is favorable overall, with 5-year survival rates approaching 90%.

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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

Wilms tumor:
Note the prominent septa subdividing the sectioned surface and the protrusion of tumor into the renal pelvis, resembling botryoid rhabdomyosarcoma.

Image: “Wilms tumor” by The Armed Forces Institute of Pathology. License: Public Domain

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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.

References

  1. American Cancer Society. (2012). Key Statistics for Wilms Tumors. Retrieved November 2, 2020, from https://www.cancer.org/cancer/wilms-tumor/about/key-statistics.html
  2. Chintagumpala, M. (2019). Presentation, diagnosis, and staging of Wilms tumor. UpToDate. Retrieved February 20, 2021, from https://www.uptodate.com/contents/presentation-diagnosis-and-staging-of-wilms-tumor
  3. Chintagumpula, M. (2019). Treatment and prognosis of Wilms tumor. UpToDate. Retrieved February 20, 2021, from https://www.uptodate.com/contents/treatment-and-prognosis-of-wilms-tumor
  4. Kumar, V., Abbas, A.K., Aster, J.C. (2015). Robbins & Cotran Pathologic Basis of Disease. Philadelphia, PA: Elsevier Saunders.
  5. National Cancer Institute (2021). Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®)–Health Professional Version. Retrieved February 20, 2021, from https://www.cancer.gov/types/kidney/hp/wilms-treatment-pdq#_723_toc
  6. Popov, S.D., Sebire, N.J., Vujanic, G.M. (2016). Wilms’ tumour — histology and differential diagnosis. Wilms Tumor. Codon Publications. https://www.ncbi.nlm.nih.gov/books/NBK373364/
  7. Popov, S.D., Sebire, N.J., Vujanic, G.M. (2016). Wilms’ tumour — histology and differential diagnosis. In: van den Heuvel-Eibrink MM, ed. Wilms Tumor. Brisbane, Australia: Codon Publications. https://www.ncbi.nlm.nih.gov/books/NBK373364/table/tab1_4/

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