Nephroblastoma (Wilms’ tumour)

Clinical features

  • Malignant embryonal tumour
  • Common type of paediatric cancer (63% of paediatric cancers)
  • 95% of all paediatric renal tumours
  • 5-10% are bilateral
  • Rarely as an extrarenal tumour
  • 1-2% have familial origin
  • Uncommon in neonates; peak of incidence between three and four years; usually diagnosed before 6 years of age.
  • Female predominance (unlike the majority of childhood cancers)
  • Palpable abdominal mass with pain (generally due to necrosis) is the most common presentation
  • Hypertension and haematuria
  • Associated with hereditary conditions such as WAGR syndrome (Complete deletion of WT1 gene), Beckwith-Wiedemann syndrome (loss heterozygoty of chromosome 11p), hemi hypertrophy, Denys-Drash syndrome (point mutation of WT1 gene).

 

Fig 4a - Wilms ‘tumor-Blastema cells- Loose small round cells with fine chromatin and inconspicuous nucleoli a)-Giemsa- remark nuclei moulding ,  given the scarcity of cytoplasm
Fig 4b - Wilms ‘tumor-Blastema cells- Loose small round cells with fine chromatin and inconspicuous nucleoli; H&E
Fig 5 - Wilms ‘tumor- Short spindled cells in branching tissue fragments in a loose myxoid matrix. Presence of scarce blastema cells with round pale nuclei, and scant cytoplasm (H&E)
Fig 6a - Wilms ‘tumor- Stromal component, rhabdomyoblastic differentiation (H&E)
Fig 6b - Sheet of cohesive epithelial cells is present in a background of spindle (stromal) cells and small round cells (blastema) (H&E)

 

 

Classically, a triphasic morphologic pattern may be present in differing proportions:

  • Blastemal cells  (Fig 4a, Fig 4b)
    • The most common cells in smears (due to looser cohesiveness they are easy to aspirate).
    • Small round blue cells, either singly or in diffuse sheets or rosettes
    • Nuclear moulding
    • Monotonous pale nuclei with very fine chromatin
  • Stromal component(Fig 5)
    • Primitive fibromyxoid stroma
    • Rhabdomyoblastic differentiation (Fig 6), chondroid tissue, or any other type of mesenchymal differentiation
  • Epithelial cells(.Fig 6)
    • Three-dimensional cellular groups, simulating tubules, papillary structures or poorly formed glomeruli
    • Cells with high N/C ratio difficult to differentiate from blastemal cells
    • Squamous metaplastic cells
  • Anaplasia – three criteria must be present:
  1. Nuclear enlargement (greater than three times the size of other nuclei )
  2. Hyperchromasia
  3. Atypical mitotic features
  • Present in any of the tumour components
  • When present in cytology, it should be considered to be representative of diffuse anaplasia and should be reported

 

Immunocytochemistry

  • Vimentin: positive in blastemal cells
  • Wt1: Positive in immature cells (mesenchyma or blastema)
  • Bcl2: Positive
  • p53: intense and extensive positivity suggests anaplasia
  • Cytokeratin: positive in epithelial component
  • NSE, synaptophysin, NB84, CD56 N-CAM: in both blastema, mesenchymal and epithelial immature cells)* ,
  • Actin and desmin may be positive and are generally of no use in differential diagnosis

 

Genetic studies:

  • 1-2% familial
  • 5-10% associated with syndromes and congenital anomalies
  • 11p, 1p and 16q deletion/LOH- prognostic relevance
  • Two main ways of tumorigenesis have been advanced:
  • I- Wnt Pathway
    • CTNNB1 and WT1 mutations appear to coexist in some cases of WT (6-20%),
    • Association with intralobular nephrogenic rests
    • Predominantly stromal type Wilms´ tumours
    • Early age onset (1-2 years old)
    • Association to WARG or Denys-Drash syndromes
    • A novel gene, WTX located at chromosome Xq11.1, is also reported to be mutated in Wilms´ tumours. WTX operates in the AXINAPC complex, down-regulating the activity of beta-catenin
    • LOI of IGF2 can be present
  • II- IGF2 LOH
    • Loss of heterozygoty/imprint of IGF2,
    • Associated with perilobular nephrogenic rests
    • Association with  non-stromal Wilms´ tumours
    • Association with Beckwith –Wiedemann syndrome
    • Affecting older children (3-4 years old)
  • Anaplastic nephroblastoma
    • Aneuploidy Mutation of P53

Differential diagnosis

  • Neuroblastoma vs blastema
    • Monotonous population with small round blue cells
    • Neuroblasts in different stages of maturation
    • Nuclei with typical salt-and-pepper chromatin
    • Fibrillary matrix
    • Rosettes with central fibrillary matrix
    • Vimentin:  usually negative
    • Neuroendocrine markers: positive
    • Cytokeratin: negative
  • Renal PNET vs blastema
    • Most common in young adults
    • True rosettes
    • Nuclei with finely stippled chromatin
    • Dark and light nuclei (low power magnification ),(dark nuclei are probably due to apoptosis)
    • Nuclei more evenly spaced than blastemal Wilms´ tumour
    • Tigroid background (Giemsa stain)
    • CD99: positive - (membranous and strong) – (attention must be paid to blastemal cells of Wilms´ tumour that can be positive, even though less strong).
    • FLI-1: Positive*- in 90% of the cases
    • WT1:Negative ( in most cases)
    • *t (11:22) (q24; q12)
  • Lymphoma (Burkitt) vs blastema
    • Monomorphic population with dispersed cells
    • Lipidic cytoplasmic vacuoles
    • Typical coarse chromatin
    • High number of mitosis and numerous cells in apoptosis
    • CD45: positive
    • CD10: Positive
    • CD38: Positive
    • Bcl2: Negative
    • Ki-67: 100% positive
  • Rhabdomyosarcoma
    • Lacks triphasic pattern
    • Eccentric cytoplasm
    • Differential diagnosis difficult in primitive tumours
    • CD56(NCAM): Positive
    • Myogenin: positive
  • Rhabdoid tumour
    • Monomorphous population of large cells with a rhabdoid-like pattern
    • Stripped bare nuclei
    • Vesicular nuclei with prominent eosinophilic nucleoli
    • Eosinophilic Para nuclear cytoplasmic inclusions
    • Cytokeratin: positive (dot)
    • Vimentin: positive (dot)
    • CD10: Positive
    • CD56(NCAM): Negative
    •  INI 1- Loss of expression
  • Clear cell sarcoma
    • Background with metachromatic mucoid-like material rich in glycoproteins, seen in Giemsa-stained slides
    • Stripped cells can simulate blastema
    •  Neoplastic cells organized in a perivascular pattern (when present, may be helpful)
    • Vesicular nuclei with grooving
    • WT1: Negative

Main points

  • Embryonic neoplasm derived from nephrogenic blastemal cells
  • Less than 10% harbour a WT1 mutation
  • Constitutional WT1 mutation and Constitutional epigenetic mutation IGF 2 locus are predisponent factors
  • It is the only renal tumour of childhood that may be bilateral (5% of the cases) and/or multifocal
  • It is the only renal tumour of childhood associated with the presence of nephrogenic residues (30%)
  • Diffuse anaplasia
    • Present in 5% of the cases
    • Not described in children younger than 6 months of age
    • More likely in patients older than five years of age
    • Represents a more resistant cell line
    • Association with extensive and strong immunoreactivity to p53 (p53 mutations)
  • Metastasizes to lymph nodes in 15%, or to the lungs, liver or peritoneum
  • Rarely metastasizes to the bone (1%)
  • Recurrences are more frequent during the first two years after diagnosis
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