Pleomorphic Xanthoastrocytoma: Symptoms, Treatment, Prognosis

Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor that most often appears in children and young adults, typically causing seizures as its first and most recognizable symptom. Classified by the World Health Organization as either grade 2 or grade 3, PXA generally carries a more favorable outlook than many other brain tumors, with five-year survival above 80% for grade 2 cases. But the picture gets considerably more complicated when tumors show anaplastic (higher-grade) features, when surgery cannot remove the entire mass, or when the tumor recurs. Understanding what to expect from diagnosis through treatment and long-term follow-up matters, because the decisions made early on shape outcomes years down the road.

What PXA Looks Like Under the Microscope

PXA gets its name from its appearance. “Pleomorphic” means the cells come in a wide range of shapes and sizes, and “xanthoastrocytoma” refers to the lipid-laden (fatty, yellowish) astrocytic cells that make up much of the tumor. Under the microscope, pathologists see nests of these xanthomatous cells alongside plump spindle-shaped cells, all wrapped in a network of reticulin fibers. There is often striking cellular variety, including bizarre giant cells and multinucleated cells, which can look alarming but do not automatically signal aggressive behavior.¹ This dramatic-looking microscopic appearance is part of what makes PXA tricky to distinguish from more dangerous tumors. Pathologists rely on specific markers like CD34 expression and low Ki-67 proliferation indices to confirm the diagnosis and separate PXA from aggressive lookalikes such as giant cell glioblastoma.²

Symptoms That Bring People to a Doctor

Seizures dominate the clinical picture. In one series, about 71% of patients presented with seizures as their initial symptom, while headache accounted for roughly 23% and focal neurological deficits or behavioral changes made up the remainder.³ Another study of anaplastic PXA cases found seizures in about half the patients, which still made them the single most common presenting complaint.⁴ The reason seizures are so frequent is location: PXA overwhelmingly grows in the outer layers of the cerebral hemispheres, particularly the temporal lobe.⁵ These superficial, cortical locations are exactly the brain regions most prone to generating seizure activity when irritated by a growing mass.

Because PXA is slow-growing in many cases, patients sometimes live with seizures for months or even years before imaging reveals the tumor. Headaches tend to develop when the tumor is large enough to raise pressure inside the skull or cause significant surrounding brain swelling. Visual changes, weakness on one side, or personality shifts are less common initial symptoms and more often appear with larger or higher-grade tumors.

Where PXA Tends to Grow

The vast majority of PXAs are supratentorial, meaning they sit in the upper portion of the brain rather than the brainstem or cerebellum. In one adult series of 50 patients, 91% had supratentorial tumors, and the temporal lobe was the single most common site at 36%.⁶ The frontal lobe is the next most frequent location, and together the temporal and frontal lobes account for the large majority of cases.⁴ PXA tumors involving the BRAF V600E mutation show a particularly strong association with the temporal lobe.⁷ Rare cases pop up in unusual spots like the cerebellum, spinal cord, or even inside the ventricles, but these are exceptions worth noting mostly because they can make the diagnosis harder to reach.

What MRI Reveals

On MRI, PXA can take a few different forms. The most common pattern is a solid mass, sometimes with cystic (fluid-filled) areas mixed in. The second pattern is a predominantly cystic mass with a solid nodule attached to one wall, often sitting near the brain’s surface close to the meninges. A third, less common pattern is a cystic mass with uneven wall thickness but no obvious nodule. The solid portions typically light up brightly with contrast dye.⁶ In children, most tumors show intense enhancement and about two-thirds have prominent cystic components. A distinctive finding in pediatric cases is scalloping of the inner skull table, seen in about three-quarters of supratentorial tumors, which reflects the slow growth of the tumor pressing against bone over time.⁸

The imaging distinction between grade 2 PXA and the anaplastic (grade 3) variant matters for surgical planning and prognosis. Anaplastic PXA tumors tend to be larger, show more irregular contrast enhancement, have more surrounding brain swelling, and display features on advanced MRI sequences that mimic high-grade gliomas.⁹ These overlapping features are one reason anaplastic PXA is sometimes initially mistaken for glioblastoma, which carries a much worse prognosis and different treatment implications.

The Molecular Fingerprint

Two molecular changes define PXA more than any others. The first is a mutation in the BRAF gene called V600E, found in roughly 60% to 78% of cases depending on the study.¹⁰ ⁷ The second is a deletion of genes called CDKN2A and CDKN2B, which normally act as brakes on cell growth. This deletion shows up in about 87% of PXA cases and appears equally in both grade 2 and grade 3 tumors, as well as in both BRAF-mutant and BRAF-wildtype tumors.¹⁰

Why do these molecular details matter to you as a patient or caregiver? The BRAF V600E mutation is directly targetable with drugs already approved for other cancers. If your tumor carries this mutation, it opens a door to targeted therapy that would not otherwise be available. CDKN2A/B deletion appears to be a fundamental feature of PXA biology rather than something that predicts worse outcomes on its own. However, when additional mutations are present, particularly a TERT promoter mutation, tumors may behave more aggressively, with higher risk of early recurrence and spread beyond the original site.¹¹

Surgery as the Cornerstone of Treatment

Complete surgical removal remains the single most important treatment for PXA. In a multivariate analysis of long-term outcomes, the extent of resection was one of only three independent factors predicting both overall survival and progression-free survival, alongside tumor grade and patient age at diagnosis. Younger patients with grade 2 tumors who underwent complete resection had the longest survival.¹² One institutional series found that complete resection roughly doubled progression-free survival compared with partial removal at both two and five years, though the small sample size limited the statistical certainty of that finding.¹³

The practical reality is that complete removal is not always possible. PXA can involve eloquent brain areas that control speech, movement, or vision, where aggressive resection would cause unacceptable neurological deficits. In these situations, surgeons aim for the maximum safe resection and then weigh additional treatments based on what remains.

When Radiation and Chemotherapy Enter the Picture

The role of radiation therapy for PXA has been debated for years, largely because no study has conclusively shown a survival benefit. No randomized trial exists, and the retrospective data are mixed. What the evidence does suggest is that radiation tends to be used in specific circumstances: recurrent tumors, tumors that could not be fully removed, anaplastic histology, or cases where the disease has spread. Several reports describe reasonable disease control in anaplastic PXA patients treated with radiation after surgery, sometimes combined with chemotherapy.¹⁴ For a newly diagnosed grade 2 PXA that has been completely removed, most centers would observe rather than irradiate. The calculus changes when the tumor comes back or when the pathology is grade 3.

Standard chemotherapy agents like temozolomide and bevacizumab have shown activity against PXA in preclinical models, slowing tumor growth and prolonging survival regardless of whether the tumor carries the BRAF V600E mutation.¹⁵ In practice, chemotherapy is typically reserved for recurrent disease or situations where targeted therapy is not an option.

Targeted Therapy for BRAF-Mutant Tumors

The emergence of BRAF and MEK inhibitors has been one of the more encouraging developments in PXA treatment. For tumors carrying the BRAF V600E mutation, the combination of dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) can produce rapid and dramatic responses. In one reported case of a metastatic anaplastic PXA, this combination led to a deep partial response within weeks, with the mutant DNA becoming undetectable in the bloodstream by six weeks. Near-complete metabolic remission was documented on PET scan three months after starting treatment.¹⁶ Additional cases confirm that this dual blockade can achieve meaningful tumor shrinkage on imaging in BRAF V600E-mutant anaplastic PXA.¹⁷

The evidence so far comes from case reports and small series rather than large trials, which is inevitable for a tumor this rare. Still, the responses have been striking enough that BRAF/MEK inhibitor therapy is now a standard consideration for BRAF V600E-mutant PXA that has recurred, progressed, or cannot be controlled with surgery alone. For tumors without the BRAF mutation, targeted therapy options are much more limited, and treatment relies on conventional chemotherapy or radiation.

Grade 2 Versus Grade 3 and What It Means for Survival

Tumor grade is the single strongest predictor of how PXA will behave over time. Grade 2 PXA has a five-year overall survival rate in the range of 80% to 91%, depending on the study, while grade 3 (anaplastic) PXA drops to roughly 48% to 65%.¹⁸ ¹⁹ Progression-free survival tells a similar story: about 76% at five years for grade 2 compared with 37% for grade 3.¹⁹ Recurrence rates also differ starkly. In one series, about 28% of grade 2 patients experienced recurrence compared with 78% of grade 3 patients.¹⁹

Besides grade, other factors that affect outlook include the extent of surgical resection, patient age (younger tends to be better), and whether the tumor has infiltrative margins rather than well-defined borders. WHO grade and infiltrative margins both independently predicted overall survival in at least one analysis.¹⁹ This matters for prognosis discussions because two patients with PXA can have very different trajectories. A young person with a completely resected grade 2 tumor has an excellent long-term outlook. An older adult with a partially resected grade 3 tumor faces a much steeper road.

Anaplastic Transformation

One of the more sobering aspects of PXA is that grade 2 tumors can transform into grade 3 over time. When this happens, the tumor acquires features associated with more aggressive behavior: increased cell division, new blood vessel formation within the tumor, and sometimes areas of necrosis (tissue death). The five-year survival rate for grade 3 PXA has been reported around 57%.²⁰ This is why long-term surveillance with regular MRI scans is standard even after seemingly successful treatment of a grade 2 tumor. A tumor that looks completely removed can recur years later, sometimes at a higher grade than the original.

Seizure Outcomes After Treatment

Since seizures are the most common symptom, how well surgery controls them is a practical question that looms large for patients. The news is generally encouraging. In one series, about 65% of patients with tumor-related epilepsy became seizure-free after their first resection, and 67% were seizure-free after their most recent surgery.²¹ A separate institutional study found even higher initial seizure freedom rates at about 79% after the first resection.²²

But there are important caveats. Most patients remain on at least one anti-seizure medication even after achieving seizure freedom; only about 9% in one cohort were able to fully discontinue medication.²¹ And there is a meaningful connection between seizure recurrence and tumor recurrence. In one analysis, the vast majority of patients whose seizures returned had evidence of tumor regrowth on MRI within a month of the breakthrough seizure.²² In other words, a new seizure in someone previously seizure-free after PXA surgery should prompt an urgent scan. It is often the tumor announcing its return before anything else on imaging is scheduled.

Telling PXA Apart from More Aggressive Tumors

Getting the diagnosis right matters enormously because PXA and glioblastoma share some microscopic features but have very different outcomes and treatment approaches. Under the microscope, both can show dramatic cellular pleomorphism and bizarre-looking giant cells. One pathology case report detailed how large portions of a tumor displayed classic PXA features including xanthomatous cells with foamy cytoplasm, positive reticulin staining, and very low proliferative activity, while other areas resembled high-grade glioma.²³ Molecular markers help resolve the ambiguity. CD34 expression tends to be more pronounced in PXA, while p53 overexpression is more characteristic of giant cell glioblastoma and anaplastic PXA, providing a useful discriminatory tool.² The BRAF V600E mutation, common in PXA but rare in glioblastoma, adds another molecular handle for distinguishing the two.

How Age Shapes the Experience

PXA is classically described as a tumor of children and young adults, and younger age at diagnosis is associated with better outcomes. But PXA does occur in older adults, and the experience differs in some clinically relevant ways. In one study examining predictors of survival separately in pediatric and adult populations, several prognostic factors showed up only in adults: tumor size of 30 mm or more and treatment with postoperative radiation were associated with worse outcomes, while female sex and temporal lobe location were linked to better survival. None of these associations reached significance in the pediatric population.²⁴ One interpretation is that children generally do well enough that individual risk factors get washed out, while adults have more variable outcomes where these factors start to matter.

Anaplastic PXA in adults also seems to carry a particular risk. Recurrence-free survival was significantly shorter for adult patients with anaplastic features in at least one long-term follow-up study.²⁵ This does not mean adults with PXA should assume the worst, but it does reinforce why complete resection and close follow-up matter even more in older patients.

Immunotherapy on the Horizon

One area of active research interest involves whether PXA might respond to immune checkpoint inhibitors, the class of drugs that has transformed treatment for melanoma and lung cancer. The rationale comes from studies of the tumor’s immune environment. PXA tumors, both grade 2 and grade 3, show relatively high expression of immune checkpoint molecules like PD-L1 and CTLA-4, and they tend to have abundant immune cells infiltrating the tumor tissue. In one analysis, PD-L1 expression was found in about 60% of grade 2 PXA and 67% of grade 3 PXA, with high rates of tumor-infiltrating lymphocytes in 90% to 100% of cases.²⁶ These features suggest the immune system is already trying to fight the tumor but is being held in check. Whether releasing those brakes with checkpoint inhibitors will translate into clinical benefit remains to be tested in trials, but the biological rationale is stronger here than for many other brain tumors.

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