Definition
- Primary intracranial sarcoma, DICER1-mutant is a primary intracranial sarcoma composed of spindled or pleomorphic tumour cells.
- These tumours are genetically defined by mutations in the DICER1 gene, occurring either somatically or as part of the germline DICER1 syndrome.
Diagnostic criteria
- Essential criteria
- A primary intracranial sarcoma AND
- A pathogenic DICER1 mutation, which may be either germline or somatic. AND
- For unresolved lesions, a DNA methylation profile aligned with primary intracranial sarcoma, DICER1-mutant is also an essential criterion.
Numbers
- The median age at diagnosis is 6 years, with a reported range from 2 to 76 years.
- The sex distribution is reported to be almost equal.
- This is an exceptionally rare tumour with limited clinical data available.
WHO grade
- This tumour type is assigned a CNS WHO grade of 4.
Histopathology
Macroscopic
- These tumours are typically unifocal and relatively circumscribed.
- They tend to be firm and frequently feature haemorrhage.
Microscopic
- The tumours are malignant neoplasms composed of pleomorphic or spindle cells arranged in fascicles or disorganized sheets.
- Characteristic features include cytoplasmic eosinophilic globules and a myxoid stroma.
- Foci of myogenic or cartilaginous differentiation may be present, with some tumours showing frank malignant cartilage.
- There is typically abundant intercellular basement membrane deposition.
Immunophenotype
- The tumours usually show immunophenotypic evidence of myogenic differentiation, most frequently with desmin and SMA expression.
- Expression of myogenin is typically limited or absent, which serves as a feature to distinguish the entity from rhabdomyosarcoma.
- The tumours frequently demonstrate nuclear positivity for TLE1 and loss of H3 p.K28me3.
- They are generally negative for GFAP, OLIG2, cytokeratins, EMA, S100, SOX10, and SOX2.
- Loss of ATRX expression or aberrant p53 accumulation resulting from TP53 mutation may be seen.
Pathogenesis
- Genetic disruption of the DICER1 gene, which encodes a microRNA-processing enzyme → allows aberrant oncofetal transcriptional programmes to persist beyond fetal development.
- Mutations are most often a hotspot missense mutation in the RNase IIIb domain on one allele combined with a truncating mutation occurring in trans on the other allele.
- Most tumours also show disruption of p53 signalling via inactivating mutations in the TP53 gene and ATRX mutation or deletion.
- Activation of the MAPK signalling pathway is common through mutations in KRAS, NF1, or PDGFRA.
Localisation
- The characteristic localisation is intracranial, frequently in supratentorial forebrain regions.
- There is typically involvement of the leptomeninges and sometimes the dura.
Clinical features
- Symptoms depend on the specific brain region involved and include headaches, seizures, or focal neurological signs.
Radiological features
- Imaging typically reveals a heterogeneously enhancing mass with dural involvement and marked mass effect.
- The tumours are iso- to hyperintense on T1-weighted images and hyperintense on T2-weighted images.
Management
- Management generally relies on radical operative resection
- Spinal imaging and sampling of the cerebrospinal fluid should be considered for staging.
Prognosis
- The prognosis for patients with this tumour remains unknown due to the limited clinical data available.
- An aggressive clinical course is suspected, though long-term follow-up data are not yet sufficient for reliable conclusions.
- No specific prognostic or predictive factors have been reported to date.
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