Wilms' tumor pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shanshan Cen, M.D. [2]

Overview

Wilms tumor has a triphasic appearance. It is comprised of 3 types of cells which are stromal, epithelial and blastemal. All the 3 types are not required for the diagnosis of wilms tumor. Primitive tubules and glomeruli are often seen comprised of neoplastic cells. Beckwith and Palmer reported in NWTS the different histopathologic types of wilms tumor to categorize them based on prognosis. Lesions comprising of nephrogenic rests can lead to wilms tumor. Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of at least ten genes. Based on a study wilms tumor is divided into 2 pathologic categories: favorable and anaplastic. Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of at least ten genes. The changes may be somatic or germline. Aberrations in germline or clonal WT1, WT2, and Wnt activation when combined with stage of development of the nephron, characterize different subsets of Wilms tumor that can be differentiated by using gene expression profiling. This genetic/ontogenic categorization describes some of the heterogeneity among wilms tumors.

Pathophysiology

• Wilms tumor has a triphasic appearance.
• It is comprised of 3 types of cells:
  • Stromal
  • Epithelial
  • Blastemal
• All the 3 types are not required for the diagnosis of wilms tumor.
• Primitive tubules and glomeruli are often seen comprised of neoplastic cells.
• Beckwith and Palmer reported in NWTS the different histopathologic types of wilms tumor to categorize them based on prognosis.

• Spindled cell stroma surrounding abortive tubules and glomeruli is characteristic.
• The stroma may include:
  • Striated muscle cartilage
  • bone
  • Fat tissue
  • Fibrous tissue.
• Lesions comprising of nephrogenic rests can lead to wilms tumor.
  • Nephrogenic rests may be be prognostic for a recurrence of wilms tumor.
  • These rests may be:
    • Hyperplastic
    • Schlerotic
• Wilms tumor metastases to the lung is common.
• Based on a study wilms tumor is divided into 2 pathologic categories:
  • Favorable
    • Contains well developed components mentioned above.
  • Anaplastic
    • Contains diffuse anaplasia (poorly developed cells).

Genetics

• Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of at least ten genes.
• The changes may be somatic or germline.
• Aberrations in germline or clonal WT1, WT2, and Wnt activation when combined with stage of development of the nephron, characterize different subsets of Wilms tumor that can be differentiated by using gene expression profiling.
• This genetic/ontogenic categorization describes some of the heterogeneity among wilms tumors.

Wilms tumor 1 gene (WT1)

• The WT1 gene is located on the short arm of chromosome 11 (11p13).
  • The normal function of WT1 is required for normal genitourinary development and is important for differentiation of the renal blastema.
  • When modern molecular genetic techniques are used in testing, the incidence of germline WT1 mutations is about 11%.
• Most of these mutations may be diagnosed, or at least highly suspected, on the basis of clinical syndromic findings at or before diagnosis of wilms tumor.
• In a United Kingdom Children's Cancer Study Group study of patients entered in clinical trials, about 2% of wilms tumor patients had germline mutations in WT1 but no genitourinary abnormalities.
  • These were mostly de novo mutations in children presenting before age 2 years, and the tumors were mostly unilateral with stromal histology.
• The relatively low number of reports of parent and child pairs with wilms tumors and WT1 mutations may be the result of decreased fertility.
  • However, the offspring of a child who has a parent with wilms tumor and WT1 mutation will be at risk for developing wilms tumor.

• Because deletion of WT1 was the first mutation found to be associated with wilms tumor, WT1 was assumed to be a conventional tumor suppressor gene.
  • However, non-inactivating mutations can result in altered WT1 protein function that also results in wilms tumor, such as in Denys-Drash syndrome.

• WT1 mutations are more common in children with wilms tumor and one of the following:
  • WAGR syndrome, Denys-Drash syndrome, or Frasier syndrome.
  • Genitourinary anomalies, including hypospadias and cryptorchidism.
  • Bilateral wilms tumor.
  • Unilateral wilms tumor with nephrogenic rests in the contralateral kidney.
  • Stromal and rhabdomyomatous differentiation.

Imprinting Cluster Regions (ICR) on chromosome 11p15 (WT2) and Beckwith-Wiedemann syndrome

• A second wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5, which, when it is a germline mutation, causes Beckwith-Wiedemann syndrome.
• About 3% of children with wilms tumors have germline epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth.
• Like children with Beckwith-Wiedemann syndrome, these children have an increased incidence of bilateral wilms tumor or familial wilms tumor.
• Approximately 80% of patients with Beckwith-Wiedemann syndrome have a molecular defect of the 11p15 domain.
• Various molecular mechanisms underlying Beckwith-Wiedemann syndrome have been identified.
• Some of these abnormalities are genetic (germline mutations of the maternal allele of CDKNIC, paternal uniparental isodisomy of 11p15 , or duplication of part of the 11p15 domain) but are more frequently epigenetic (loss of methylation of the maternal ICR2/KvDMR1 or gain of methylation of the maternal ICR1).
• Several candidate genes at the WT2 locus comprise the two independent imprinted domains IGF2/H19 and KIP2/LIT1.
• Loss of heterozygosity, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones.
• A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations.
• The overall tumor risk in patients with Beckwith-Wiedemann syndrome has been estimated between 5% and 10%, with a risk between 1% (loss of imprinting at IC2) and 30% (gain of methylation at IC1 and paternal 11p15 isodisomy).
• Patients with IC1 gain of methylation only developed wilms tumor, whereas other tumors such as neuroblastoma or hepatoblastoma could occur in patients with paternal 11p15 isodisomy.
• Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5.
• Interestingly, wilms tumors in Asian children are not associated with either nephrogenic rests or IGF2 loss of imprinting.
• Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.
• The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with wilms tumor reported to the National wilms Tumor Study (NWTS).

Wilms tumor gene on the X chromosome (WTX)

• A third gene, WTX, has been identified on the X chromosome and plays a role in normal kidney development.
  • This gene is inactivated in approximately one-third of wilms tumors, but germline mutations have not been observed in patients with wilms tumor.
  • WTX mutations are equally distributed between males and females.
  • WTX inactivation is a frequent, but late, event in tumorigenesis and has no apparent effect on clinical presentation or prognosis.

Other genes and chromosomal alterations

• Additional genes have been implicated in the pathogenesis and biology of wilms tumor, including the following:
  • 1q:
    • Gain of 1q or overexpression of genes from 1q has been associated with an adverse outcome.
    • In an analysis of 212 patients from NWTS-4 and the Pediatric Oncology Group wilms Biology study, 27% of patients displayed 1q gain.
    • A strong relationship between 1q gain and 1p/16q loss was observed.
    • The 8-year event-free survival (EFS) rate was 76% for patients with 1q gain and 93% for those lacking 1q gain.
    • The 8-year overall survival (OS) rate was 89% for those with 1q gain and 98% for those lacking 1q gain.
    • Gain of 1q was not found to correlate with disease stage.
    • After stratification for stage of disease, 1q gain was associated with a significantly increased risk of disease recurrence.

• 16q and 1p:
  • Additional tumor-suppressor or tumor-progressive genes may lie on chromosomes 16q and 1p as evidenced by loss of heterozygosity for these regions in 17% and 11% of wilms tumors, respectively.

• CACNA1E:
  • Overexpression and amplification of the gene CACNA1E located at 1q25.3, which encodes the ion-conducting alpha-1 subunit of R-type voltage-dependent calcium channels, may be associated with relapse in FH wilms tumor.
• 7p21
• SKCG-1
• TP53 (tumor suppressor gene)
• FBXW7
• PTCH1
• DICER1
• MYCN

References