Neurosurgery notes/Tumours/Mesenchymal non meningothelial tumours/Soft tissue tumors/CIC-rearranged sarcoma

CIC-rearranged sarcoma

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Soft tissue tumors

General

  • CIC-rearranged sarcoma of the neural axis is a high-grade, poorly differentiated sarcoma.
  • It is defined by an oncogenic gene fusion involving the CIC transcriptional repressor and various partner genes.

Definition

  • Essential criteria
    • Evidence of a CIC gene fusion is an essential diagnostic requirement.
    • Neoplasms must show a predominant round cell phenotype.
    • The tumour cells typically exhibit only mild nuclear pleomorphism.
    • There is often a variable admixture of epithelioid and spindle cells.
    • The presence of a variably myxoid stroma is required.
    • Immunophenotypic criteria include variable CD99 expression alongside frequent expression of ETV4 and WT1.
  • Desirable criteria
    • A DNA methylation profile that aligns with CIC-rearranged sarcoma is a desirable criterion.

Epidemiology

  • 0.44 per cent of newly diagnosed CNS tumours in patients aged 21 years or younger.
  • There is a clinical preference for adolescents and young adults, though older patients can also be affected by this disease.

Grade

  • CNS WHO grade of 4.

Histopathology

Macroscopic

  • The tumours are typically well-circumscribed, solid masses that appear white or tan in colour.
  • Haemorrhage and necrosis are frequently observed on the cut surface.

Microscopic

  • Neoplasms consist of sheets of highly undifferentiated small round cells.
  • They often display a variably lobulated growth pattern and desmoplastic stroma.
  • Foci of necrosis are commonly interspersed within the cellular sheets.
  • The predominant round cell component may be interspersed with areas showing spindle or epithelioid morphology.
  • Myxoid change is a common finding.
  • Neoplastic cells exhibit eosinophilic cytoplasm and variably prominent nucleoli.
A: A primary tumour in the cerebrum showing a well-circumscribed nodule in the brain parenchyma. B: There is a diffuse proliferation of small round cells with minimally pleomorphic nuclei and variably prominent nucleoli.
A: A primary tumour in the cerebrum showing a well-circumscribed nodule in the brain parenchyma.
B: There is a diffuse proliferation of small round cells with minimally pleomorphic nuclei and variably prominent nucleoli.
 

Immunophenotype

  • CD99 expression is typically weak and patchy.
  • The tumour cells frequently show positivity for ETV4 and WT1.
  • NKX2-2 expression is typically negative, which helps distinguish this tumour from Ewing sarcoma.
  • Variants involving a CIC::NUTM1 fusion express the NUT protein in the nucleus.
  • Nuclear expression of SMARCB1 and SMARCA4 is preserved, ruling out atypical teratoid/rhabdoid tumour.
  • Scattered expression has been reported for cytokeratin AE1/AE3, calretinin, alpha-SMA, and neurofilament.

Pathogenesis

  • The tumour is defined by an oncogenic gene fusion involving the CIC transcriptional repressor → Changes the normal repressor function of CIC into an activating one. → Pathological upregulation of normal target genes, including the PEA3 family genes ETV4 and ETV5, as well as CCND2 and MUC5AC.
    • Common fusion partners include
      • DUX4
        • DUX4 fusion is the most frequent partner in peripheral tumours
      • FOXO4
      • LEUTX
      • NUTM1
        • NUTM1 fusions is the most frequent partner in primary central nervous system cases
      • NUTM2A

Localisation

  • These tumours occur in both intra-axial and extra-axial compartments of the central nervous system.
  • Primary cases have been identified in the cerebrum and as spinal intramedullary or intraspinal intra-axial masses.
  • The central nervous system can also be involved through metastatic spread.

Clinical features

  • Symptoms depend on the specific location of the tumour and are typically due to mass effect.
  • Presentation can include focal neurological deficits or signs of globally raised intracranial pressure.

Radiological features

  • Tumours can appear as solid masses or as cystic lesions.
  • Magnetic resonance imaging may demonstrate a large cystic tumour with several mural nodules.
  • Enhancement of the capsule and solid components is typically observed.
Axial FLAIR (A, D), T2‐weighted (G, J), postcontrast T1‐weighted (B, E, H, K), and Susceptibility‐weighted (C, I, L) or echo‐planar (F) images of cases #1 (A, B, C), #3 (D, E, F), #5 (G, H, I) and #6 (J, K, L). The tumors were located supratentorially, and had partially cystic content, intense contrast enhancement, intra‐tumoral hemorrhage, and large peritumoral edema. Most of the tumors had pachymeningeal contact
Axial FLAIR (A, D), T2‐weighted (G, J), postcontrast T1‐weighted (B, E, H, K), and Susceptibility‐weighted (C, I, L) or echo‐planar (F) images of cases #1 (A, B, C), #3 (D, E, F), #5 (G, H, I) and #6 (J, K, L). The tumors were located supratentorially, and had partially cystic content, intense contrast enhancement, intra‐tumoral hemorrhage, and large peritumoral edema. Most of the tumors had pachymeningeal contact

Management

Work up

  • Suspected cases require positive confirmation of a CIC gene fusion event.
    • Molecular diagnostic techniques include next-generation sequencing of the transcriptome (RNA sequencing), anchored multiplex PCR, or RT-PCR.
      • Break-apart FISH is a simple approach but does not inform on the binding partner and is affected by false negative results.
  • Staging should include a radiological survey and evaluation of the cerebrospinal fluid for the presence of tumour cells.

Surgical Intervention

  • Extent of Resection: The primary goal is Gross Total Resection (GTR).
  • Re-excision: If initial surgery results in positive margins, re-excision is often pursued if safely possible before starting adjuvant therapy.

Adjuvant Radiotherapy

  • Because these tumors carry a high risk for local recurrence, radiation is a standard component of management.
  • Targeting: Radiation is typically delivered to the surgical bed (focal RT)
  • Dosage: Common dose ranges reported in literature are 54 to 60 Gy, typically delivered in 28 to 30 fractions.
  • Leptomeningeal Coverage: While focal RT is standard, craniospinal irradiation (CSI) may be considered in cases where there is evidence or high risk of leptomeningeal seeding.

Systemic Chemotherapy

  • Chemotherapy is used to manage potential micrometastatic disease, although CIC-rearranged sarcomas are noted for being relatively chemo-insensitive compared to classic Ewing sarcoma.5
  • Common Regimens: Most patients are treated with Ewing-based multi-agent protocols:
    • VDC/IE: Vincristine, Doxorubicin (Adriamycin), and Cyclophosphamide alternating with Ifosfamide and Etoposide.
    • ICE: Ifosfamide, Carboplatin, and Etoposide—particularly used in pediatric CNS series with encouraging results.
  • Treatment Resistance: Rapid development of chemotherapy resistance is a hallmark of this disease, leading to poor overall survival.

Reference

Prognosis

  • Specific clinical data for central nervous system cases are limited, but the tumour follows a highly aggressive clinical course.
    • 5-year overall survival rate estimated between 34% and 43%.
  • The prognosis is markedly worse than that associated with Ewing sarcoma.
  • These tumours typically show an inferior response to the chemotherapy regimens used as standard for Ewing sarcoma.
  • Metastasis: There is a high frequency of systemic metastasis, particularly to the lungs, necessitating frequent surveillance imaging of the chest in addition to the brain and spine.9
  • Molecular Heterogeneity: Recent studies highlight that different fusion partners (e.g., CIC::DUX4, CIC::NUTM1, or CIC::LEUTX) may have slightly different clinical behaviors, reinforcing the need for precise molecular diagnosis.