Neurosurgery notes/Tumours/Gliomas, Glioneuronal Tumors, and Neuronal Tumors/Ependymoma/Supratentorial ependymoma (STE)/Supratentorial ependymoma, ZFTA fusion-positive

Supratentorial ependymoma, ZFTA fusion-positive

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Supratentorial ependymoma (STE)

General

  • Used to be called Ependymoma RELA fusion positive in WHO CNS 2016 but changed now
    • ZFTA is the principal gene involved in fusion events in supratentorial ependymomas.
    • RELA is one common fusion partner but not the only one.
    • The 2021 WHO classification uses "ZFTA fusion-positive" to include both RELA and non-RELA fusion variants under one entity.

Definition

  • Essential:
    • Supratentorial tumour with morphological and immunohistochemical features of ependymoma AND
    • Gene fusion involving ZFTA (C11orf95)
  • Desirable:
    • DNA methylation profile aligned with supratentorial ependymoma, ZFTA fusion positive
    • Immunoreactivity for p65 (RELA) or L1CAM

Numbers

  • Can occur in adults and children
  • Accounts for 75% of supratentorial ependymomas in children

CNS WHO grading

  • Grade 2 or 3
    • Depending on degrees of anaplasia

Location

  • Common
    • Frontal lobe
    • Parietal lobe
  • Less common
    • Thalamus
    • Hypothalamus
    • 3rd ventricle

Molecular pathology

  • Fusion of the ZFTA (Zinc Finger Translocation Associated) gene with partner genes, mainly RELA (@Chr 11) → Pathological activation of NF-кВ signalling.
  • Some tumours have Homozygous deletions of CDKN2A → disruption of cell-cycle control.

Pathology

Macroscopic

  • Sharply demarcated tumours of soft consistency
  • Dystrophic calcification and necrotic areas are common findings.

Microscopic

  • Composed of cells characterized mainly by round uniform nuclei with speckled chromatin and poorly defined fibrillary cytoplasm.
  • Pseudorosettes are not prominent in most cases,
    • True ependymal rosettes are rare.
  • Tumours often have a network of branching capillary blood vessels and a clear cell phenotype.
Supratentorial ependymoma, ZFTA fusion-positive. Tumour cells with round nuclei set in a fibrillary matrix. Branching capillary blood vessels (A) or branching blood vessels and dystrophic calcification (B) can be seen.
Supratentorial ependymoma, ZFTA fusion-positive. Tumour cells with round nuclei set in a fibrillary matrix. Branching capillary blood vessels (A) or branching blood vessels and dystrophic calcification (B) can be seen.
  • C11orf95-RELA fusion
      • Form from chromothripsis: a shattering and reassembly of the genome that rearranges genes and produces oncogenic gene products
        • Simultaneous fragmentation of distinct chromosomal regions (breakpoints show a non-random distribution) and then subsequent imperfect reassembly by DNA repair pathways or aberrant DNA replication mechanisms.
      • Constitutive activation of the NF-kappaB pathway
       
      Fig. 3.16 RELA Interphase FISH with fusion-positive ependymoma. break-apart probes RELA gene. Overlapping probes (yellow) intact RELA gene, but probe separation occurs with rearrangement of the RELA gene. around the indicate an (red/green)
      RELA fusion-positive ependymoma. Interphase FISH with break-apart probes around the RELA gene. Overlapping probes (yellow) indicate and intact RELA gene, but probe separation (red/green) occurs with rearrangement of the RELA gene.

Clinical features

  • Focal neurological deficits
  • Seizures
  • Raised intracranial pressure

Radiology

  • MRI
      • Diffusion restriction:
        • High DWI signals with concomitant low signals in ADC
      • Most tumours show strong, but often inhomogeneous, enhancement in their solid components after intravenous gadolinium injection
       
      Supratentorial ependymoma, ZFTA fusion-positive. A, T1-weighted axial MRI with gadolinium, showing a well-demarcated left frontal lesion with heterogeneous contrast enhancement and areas of necrosis. B, Coronal FLAIR MRI showing conspicuous surrounding oedema.
      Supratentorial ependymoma, ZFTA fusion-positive. A, T1-weighted axial MRI with gadolinium, showing a well-demarcated left frontal lesion with heterogeneous contrast enhancement and areas of necrosis. B, Coronal FLAIR MRI showing conspicuous surrounding oedema.

Outcomes

  • Poor prognostication
    • ZFTA fusion-positive poorer survival vs YAP1 fusion-positive supratentorial ependymomas
    • Homozygous deletion of CDKN2A/B an independent poor prognostic indicator