What are the characteristic histological features and treatment approaches for pleomorphic xanthoastrocytoma (PXA) of the brain?

Pleomorphic Xanthoastrocytoma: Histological Features and Treatment

Characteristic Histological Features

PXA is characterized by distinctive cellular pleomorphism with large, frequently multinucleated cells, spindle cells, lipidized (xanthomatous) cells, dense pericellular reticulin network, and numerous eosinophilic granular bodies. 1, 2

Key Microscopic Features:

• Pleomorphic cells: Large, bizarre-appearing cells with marked nuclear atypia 1
• Lipidized (xanthomatous) cells: Cells with foamy, lipid-laden cytoplasm giving the tumor its characteristic appearance 1
• Eosinophilic granular bodies: Distinctive intracellular and extracellular hyaline structures 1, 2
• Dense pericellular reticulin network: Demonstrated on reticulin staining 2
• Spindle cells: Elongated cells intermixed with pleomorphic elements 2
• Leptomeningeal involvement: Frequent attachment to meninges 1
• Desmoplasia: Fibrous tissue proliferation 1

Immunohistochemical Profile:

• GFAP positivity: Confirms astrocytic lineage, though expression may be focal or faint 3
  • Critical pitfall: Complete absence of GFAP on initial staining can occur; use both monoclonal and polyclonal antibodies with prolonged tissue pretreatment to enhance sensitivity 3
• BRAF V600E mutation: Present in majority of cases 2, 4
• CDKN2A/B homozygous deletion: Frequently observed 4

Anaplastic Features (Grade III):

• Mitotic activity: Elevated mitotic index (MI) is the strongest predictor of recurrence and survival 1
• Atypical mitoses: Associated with worse outcomes 1
• Necrosis: Indicates anaplastic transformation 1, 2
• Microvascular proliferation: Suggests high-grade behavior 2
• Ki-67 labeling index >21%: Indicates aggressive biology 2

Treatment Approach

Optimal surgical resection should be undertaken in all patients with PXA as the primary treatment. 5

Surgical Management Algorithm:

Complete Resection Achieved (Confirmed on MRI):

• Standard: Postoperative MRI evaluation to confirm extent of resection 5
• If WHO Grade II (typical PXA): Simple clinical follow-up with serial MRI 5
• If WHO Grade III (anaplastic features present): Postoperative external-beam radiotherapy should be undertaken, irrespective of complete resection 5

Incomplete Resection:

• Standard: Annual follow-up over many years with clinical examination and MRI 5
• If tumor progression occurs: Surgery and/or external-beam radiotherapy can be considered 5
• Options: Radiotherapy and/or chemotherapy, though optimal modalities remain uncertain 5

Prognostic Factors Affecting Treatment Decisions:

The extent of surgical resection and mitotic index are the two most important independent predictors of recurrence-free survival and overall survival. 1

Favorable Prognostic Factors:

• Gross total resection (GTR): Disease progression occurred in 21% with GTR versus 57% without GTR 6
• Low mitotic index: Strongest predictor of both recurrence-free and overall survival 1
• Typical tumor location: Temporal lobe involvement 6, 1
• Absence of peritumoral edema: Significantly correlated with better outcomes 6
• Small tumor size: Associated with reduced disease progression 6

Poor Prognostic Factors:

• Atypical tumor location: Significantly correlated with disease progression 6
• Large tumor size: Associated with worse outcomes 6
• Peritumoral edema: Predicts disease progression 6
• Elevated mitotic index: Independent predictor of recurrence and death 1
• Atypical mitoses: Associated with worse survival 1

Adjuvant Therapy Considerations:

Radiotherapy is mandatory for anaplastic PXA (WHO Grade III) regardless of resection extent. 5

• For typical PXA (Grade II): Adjuvant radiotherapy may provide benefit in cases of incomplete resection or tumor progression, though evidence is limited 6
• Chemotherapy: Can be considered for progressive disease, though optimal regimens are uncertain 5
• Targeted therapy: BRAF V600E inhibitors may be considered given the high frequency of this mutation, particularly in recurrent or anaplastic cases 2, 4

Long-Term Surveillance:

Clinical follow-up should include MRI monitoring, as PXA can recur years after initial treatment and undergo malignant transformation. 5

• Overall survival: 81% at 5 years, 70% at 10 years 1
• Recurrence-free survival: 72% at 5 years, 61% at 10 years 1
• Malignant transformation risk: PXA can transform to anaplastic PXA or glioblastoma, even after prolonged disease-free intervals 2, 4
• Distant metastasis: Rare but documented, including spinal cord and bone metastases 4

Critical Pitfalls to Avoid:

• Do not rely on single GFAP staining protocol: Use multiple antibodies and prolonged pretreatment to avoid missing diagnosis 3
• Do not underestimate recurrence potential: Even after complete resection, long-term surveillance is essential as recurrence can occur after 9+ years 4
• Do not overlook molecular testing: BRAF V600E mutation status and CDKN2A/B deletion should be assessed to guide targeted therapy and predict aggressive behavior 2, 4
• Do not confuse with other entities: Differential diagnosis includes glioblastoma, malignant fibrous histiocytoma, and amelanotic melanoma, particularly when GFAP is negative 3