Pleomorphic Xanthoastrocytoma: Prognosis and Treatments

Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor primarily affecting children and young adults. While typically considered a low-grade glioma, some cases exhibit aggressive behavior, leading to variations in prognosis. Early diagnosis and appropriate intervention are crucial for managing symptoms and improving outcomes.

Understanding its pathological characteristics, molecular markers, and treatment options helps guide clinical decisions.

Histopathological Features

PXA has a distinctive histopathological profile, characterized by pronounced cellular pleomorphism. It contains large, bizarre astrocytes with irregular nuclei and abundant eosinophilic cytoplasm. In WHO grade II PXAs, mitotic activity is generally low, whereas anaplastic variants (WHO grade III) show increased mitotic figures, necrosis, and microvascular proliferation, indicating a more aggressive phenotype. Lipid-laden astrocytes, known as xanthomatous cells, contribute to its unique histological appearance.

The tumor architecture is often loosely cohesive, with reticulin fiber deposition surrounding individual cells, distinguishing it from diffuse gliomas. Perivascular lymphocytic infiltration is frequently observed, suggesting immune interaction. While necrosis is typically absent in lower-grade PXAs, its presence in anaplastic cases correlates with a more aggressive clinical course.

Immunohistochemically, PXA cells strongly express glial fibrillary acidic protein (GFAP), confirming their astrocytic lineage. Other markers, such as S-100 protein and vimentin, are also commonly positive. A defining molecular feature is the frequent presence of the BRAF V600E mutation in 60–80% of cases, which plays a role in tumor pathogenesis and has therapeutic implications, especially in progressive or recurrent cases.

Molecular Insights

PXA is defined by distinct molecular alterations that influence tumor behavior and treatment strategies. The BRAF V600E mutation, present in most cases, results in MAPK/ERK pathway activation, driving tumor growth. BRAF-mutant PXAs tend to progress more slowly than their wild-type counterparts, though anaplastic transformation can still occur. This mutation has enabled targeted therapies, particularly BRAF and MEK inhibitors, which have shown efficacy in recurrent cases.

Other genetic changes contribute to PXA’s heterogeneity. CDKN2A/B deletions are linked to a more aggressive course and a higher risk of anaplastic transformation, as they impair tumor suppressor function and disrupt cell cycle regulation. TERT promoter mutations, found in some anaplastic PXAs, are associated with increased aggressiveness and poorer prognosis.

Epigenetic modifications also shape PXA’s molecular profile. DNA methylation studies show a distinct signature differentiating it from other gliomas. Transcriptomic analyses highlight altered gene expression in pathways related to cell adhesion, extracellular matrix remodeling, and immune regulation, which may influence tumor progression and treatment response.

Neurological Manifestations

PXA presents with neurological symptoms that depend on tumor location and growth rate. Seizures are the most common initial symptom, occurring in up to 75% of cases and often preceding diagnosis by months or years. Many patients experience drug-resistant seizures, necessitating adjustments to antiepileptic therapy. The strong epileptogenic nature of PXA is likely due to frequent cortical involvement, particularly in the temporal and frontal lobes.

As the tumor progresses, additional neurological deficits may emerge due to mass effect and peritumoral edema. Temporal lobe tumors can cause memory disturbances, language difficulties, or behavioral changes, while frontal lobe involvement may lead to executive dysfunction, personality shifts, or motor impairments. Parietal lobe tumors can result in sensory deficits or spatial disorientation. Larger or rapidly growing tumors may increase intracranial pressure, causing headaches, nausea, vomiting, and papilledema.

Symptom progression varies widely. Some tumors remain stable for years, while others undergo anaplastic transformation, leading to rapid clinical decline. Focal neurological deficits such as hemiparesis or visual field defects may develop if the tumor encroaches on motor or occipital cortices. Cognitive decline can occur in cases of extensive infiltration, particularly in younger patients.

Diagnostic Imaging Techniques

Magnetic resonance imaging (MRI) is the primary tool for evaluating PXA, providing detailed visualization of tumor morphology, location, and extent. PXAs typically appear as well-circumscribed, supratentorial masses involving the cerebral cortex and leptomeninges. They often exhibit a solid-cystic structure, with an enhancing mural nodule that avidly takes up contrast. The cystic component, when present, usually has a thin, non-enhancing wall, distinguishing PXA from other cystic gliomas. On T2-weighted imaging, the solid portion appears hyperintense, with variable surrounding vasogenic edema.

Advanced imaging techniques offer further insights. Diffusion-weighted imaging (DWI) typically shows facilitated diffusion in low-grade PXAs, while anaplastic variants may exhibit restricted diffusion due to increased cellularity. Perfusion MRI often reveals moderate perfusion in grade II PXAs, while anaplastic cases may show elevated relative cerebral blood volume (rCBV), indicating higher angiogenic activity. MR spectroscopy can detect metabolic changes, such as increased choline-to-N-acetylaspartate (NAA) ratios, which suggest active tumor proliferation. Lipid and lactate peaks may indicate necrotic changes in high-grade lesions.

Medical Interventions

Effective PXA management combines surgical, radiotherapeutic, and pharmacological approaches, tailored to tumor grade and progression risk. Given its circumscribed nature and frequent cortical involvement, surgical resection is the primary treatment. When complete resection is not possible or anaplastic features are present, adjunct therapies help reduce recurrence and control progression.

Surgical Methods

Gross total resection (GTR) is the primary surgical goal, as it significantly improves progression-free survival. When achieved, recurrence rates are lower, with some studies reporting five-year progression-free survival exceeding 80%. Subtotal resection (STR) may be necessary when the tumor is near eloquent brain regions to avoid permanent deficits. Intraoperative neuronavigation, awake craniotomy, and cortical mapping help maximize safe tumor removal.

Some PXAs, particularly anaplastic variants, exhibit infiltrative growth that complicates GTR. Leptomeningeal involvement can increase recurrence risk even after aggressive resection. Postoperative MRI within 48 hours is essential to assess residual tumor burden and guide further treatment. In cases with residual disease or anaplastic features, adjuvant therapies are considered to improve disease control.

Radiotherapy

Radiotherapy is typically used for incompletely resected PXAs or those with anaplastic transformation. Conventional fractionated radiotherapy delivers doses of 54 to 60 Gy in 1.8–2 Gy fractions. While low-grade PXAs are often managed without radiation after complete resection, anaplastic cases frequently benefit from adjuvant radiotherapy.

Advancements in radiation techniques, such as intensity-modulated radiotherapy (IMRT) and proton beam therapy, allow high-dose delivery while minimizing damage to healthy brain tissue. Proton therapy is particularly beneficial for pediatric and young adult patients, reducing long-term neurocognitive side effects. Stereotactic radiosurgery (SRS) may be considered for smaller residual or recurrent tumors, offering a highly focal treatment option, though its role in PXA remains less defined.

Pharmacological Options

Targeted therapy has emerged as a promising approach, particularly for tumors with the BRAF V600E mutation. BRAF inhibitors such as vemurafenib and dabrafenib have shown efficacy in recurrent or progressive cases, often leading to tumor regression and symptom relief. Combining these agents with MEK inhibitors like trametinib enhances clinical benefit by reducing resistance.

For cases without actionable genetic targets, conventional chemotherapy has been explored with limited success. Temozolomide, commonly used in gliomas, has been utilized in select cases but with inconsistent efficacy. Bevacizumab, an anti-VEGF monoclonal antibody, has been investigated for recurrent anaplastic PXAs due to its anti-angiogenic properties, though its role remains experimental. As molecular profiling advances, personalized treatments integrating novel targeted agents may improve outcomes for high-risk cases.

Prognostic Considerations

PXA prognosis varies based on tumor grade, extent of resection, and molecular characteristics. WHO grade II PXAs generally have favorable outcomes, with five-year overall survival exceeding 80% when gross total resection is achieved. Anaplastic PXAs (WHO grade III) exhibit a more aggressive course, with higher recurrence rates and reduced survival, often requiring multimodal therapy.

Molecular markers refine prognostic stratification. The BRAF V600E mutation is associated with better response to targeted therapy, potentially improving long-term outcomes in recurrent cases. In contrast, CDKN2A/B deletions and TERT promoter mutations correlate with shorter progression-free survival and increased malignant transformation risk. These genetic alterations underscore the need for individualized treatment strategies based on tumor biology.