Clinical manifestations

Presentation and course

Pleomorphic xanthoastrocytomas are tumors most often found in supratentorial cortical regions (60; 25), often with a cystic component on imaging, which can make it difficult to distinguish them from pilocytic astrocytomas (25) or higher-grade infiltrating astrocytomas. Most frequently, temporal lobe is affected in up to 65% of cases, the parietal lobe being next in frequency, and the occipital and frontal lobes are less commonly involved (58; 76; 17). They can rarely occur within deeper structures, such as the thalamus, brainstem, and cerebellum (39; 80; 60; 69; 01; 21). Rare primary occurrence in the spinal cord has been reported (08; 83; 22; 09), and even an extramedullary intradural tumor has been observed (34). There have also been occasional reports of multicentric tumor occurrence (53; 70; 83). Pleomorphic xanthoastrocytoma primarily arises in children and young adults, with a median age in the early 20s, but it can also arise in children less than 1 year of age and adults reaching their ninth decade of life (60). There is no significant gender predilection.

Patients most commonly present with seizures, often harboring epilepsy for some time prior to diagnosis, given the relatively indolent nature of pleomorphic xanthoastrocytoma. Patients may also present with signs of increased intracranial pressure (nausea, vomiting, papilledema), focal neurologic deficits, or both (45; 25; 69).

Prognosis and complications

The prognosis for pleomorphic xanthoastrocytoma is generally more favorable than what is observed in patients with high-grade infiltrating gliomas. In a reported series of 408 pleomorphic xanthoastrocytomas, a substantially inferior survival was observed for patients with grade 3 pleomorphic xanthoastrocytoma compared to patients with grade 2 pleomorphic xanthoastrocytoma (median survival: 51 months vs. not reached) (66). In another series of 67 pleomorphic xanthoastrocytomas reported in the prior year, grade 2 tumors had a 60% 5-year progression-free survival and 81% overall survival rates, whereas its grade 3 counterparts had a 40% 5-year progression-free survival and 48% overall survival rates, corroborating the data from prior studies (18; 60; 14; 55; 25; 78). Tumor grade (grade 2 pleomorphic xanthoastrocytoma vs. grade 3 pleomorphic xanthoastrocytoma) has been implicated in the prediction of overall survival, with extent of resection and age also proving significant in a number of studies (60; 14; 25; 69; 78). Subsequent work that differentiates grade 3 pleomorphic xanthoastrocytoma from conventional grade 2 pleomorphic xanthoastrocytoma revealed that the anaplastic variant more closely resembles higher grade gliomas with less favorable outcomes, even following gross total resection (25; 72; 06; 69). Conventional grade 2 pleomorphic xanthoastrocytoma is also known to undergo late recurrences. Kepes’s original report of 12 patients included one patient who suffered her first recurrence 18 years after initial resection and subsequently died of a second recurrence 25 years after her original diagnosis. Other studies have reported primary recurrences and survival greater than 25 years following initial diagnosis (60; 25). It has been consistently shown 5-year and overall survival rates are significantly different between grade 2 and grade 3 tumors (79; 78).

More recent work has shown that the majority of pleomorphic xanthoastrocytomas harbor MAPK alterations, the majority of which involve BRAF. Further investigation of BRAF alterations shows that they comprise three classes: class I includes V600E mutations resulting in low RAS activity; class II consists of BRAF fusions and non-V600E mutations, which lead to increased ERK activation with decreased RAS activity; and class III has impaired and/or absent kinase activity. The most common alteration is the BRAF V600E mutation, generally estimated to occur in up to 80% of tumors and associated with a favorable overall prognosis (11; 35; 25; 72; 69; 77; 78). BRAF mutations have been shown to promote cell proliferation, differentiation, and survival via the RAS/RAF/MEK/ERK kinase pathway (71). This represents an exciting avenue for further research given the development of targeted BRAF inhibitors, such as dabrafenib and vemurafenib, and other MAPK pathway inhibitors that may augment surgical resection. It may be warranted to subclassify the tumors that are histopathologically consistent with pleomorphic xanthoastrocytoma into two groups, those with MAPK pathway aberrancies and those without, as this may underlie differences in clinical response to treatments.

Clinical vignette

An 8-year-old girl presented to the clinic with a 3.5-year history of medically refractory partial complex seizures. She had a febrile convulsion at the age of 2, but she developed spontaneous seizures at 4.5 years of age, consisting of 20 to 40 seconds of staring with bilateral arm twitching, sometimes accompanied by chewing movements or picking at her clothes. These occurred daily despite concurrent treatment with four anticonvulsants. Neurologic examination was normal. MRI scan demonstrated a 1.5 cm lesion centered in the right superior temporal gyrus, which was felt to be consistent with a cavernous hemangioma. In retrospect, this lesion was thought to have been present on a scan done at 2 years of age, albeit without the dense calcification seen subsequently.

On video-EEG monitoring, her seizures were not well localized. Right temporal resection was performed 6 months after the MRI diagnosis, with pathology demonstrating a pleomorphic xanthoastrocytoma. She was tapered to a single anticonvulsant and remained seizure-free. Eighteen months after her initial resection, a routine follow-up MRI revealed recurrent tumor, which was gross totally resected and pathologically confirmed. The recurrent mass was partially cystic. One year after her second resection she was well and without recurrent seizures.

Comment. This case illustrates the typical age, location, and presentation of this tumor in a patient. If her initial febrile seizure is considered symptomatic, the interval between initial symptom and diagnosis was 6 years. It also illustrates the potential for recurrence even with benign histology and no symptoms.

Biological basis

Etiology and pathogenesis

The etiology of this tumor is unknown.

Pleomorphic xanthoastrocytoma is pathologically distinct from other astrocytomas and is now classified in the category of circumscribed astrocytic gliomas (46).

Grossly, the tumor is firm and yellow, often with a prominent cystic component filled with golden or xanthochromic fluid (42). Leptomeningeal involvement can be prominent. Histologically, it is moderately cellular, consisting of astrocytes with pleomorphic nuclei, bizarre multinucleated giant cells, and fascicles of elongated or polygonal cells. Lipid droplets are present in many cells (hence, the prefix "xantho-") and are sometimes large enough to force the cytoplasm into a thin rim around the droplet. The nonlipidized portion of the cytoplasm stains positive for GFAP, a glial immunohistochemical marker (32; 84). In addition to nuclear pleomorphism, GFAP positivity, and lipidization, the fourth cardinal histologic feature is the presence of reticulin fibers surrounding many of the cells.

This feature led to its initial misclassification as a mesenchymal tumor, as pure gliomas are reticulin-negative. Notably, lipidization and reticulin staining may each be present focally. A less-appreciated finding is that of eosinophilic granular bodies, which are often present (17). A variable amount of lymphoplasmacytic infiltrate may also be present.

Mitoses are rare, and necrosis is generally absent in a classic pleomorphic xanthoastrocytoma. Electron microscopic studies demonstrate basal laminae, an ultrastructural correlate of positive immunohistochemical staining for reticulin, between the cells. Importantly, these tumors do not demonstrate the extensive parenchymal brain infiltration observed with diffuse gliomas.

A number of cases that have all the cardinal features of classic pleomorphic xanthoastrocytoma, and additionally exhibit anaplastic features such as frequent mitoses, necrosis, nuclear pseudopalisading, microvascular proliferation, and hypercellularity, have been described (48; 02; 25; 06; 72; 69).

Although the original description of this tumor expressly excludes such features, an apparent consensus stipulates that the remarkable pathologic and clinical similarity to more typical xanthoastrocytomas justifies the labeling of these tumors as grade 3 pleomorphic xanthoastrocytoma (25; 72; 06; 69).

These reports have fueled speculation about the cellular origin of this tumor. The cells of a xanthoastrocytoma are GFAP-positive and have basal laminae between them. Thus, the prevailing hypothesis has been that this tumor derives from the subpial astrocyte, as these are the only astrocytes that possess a basal lamina (30). The fact that these tumors are nearly always superficial and frequently involve the leptomeninges has supported this hypothesis. The observed association of gangliogliomas and dysplasias, as well as the finding of tumor cells that stain with both glial and neuronal markers has led some to hypothesize that the xanthoastrocytoma derives from a primitive neuroectodermal precursor that can differentiate along either neuronal or glial lines with a marked tendency toward the latter. The formation of the tumor may then be associated with abnormal neuronal migration and a tendency for the dysplastic cells to become neoplastic. Such a hypothesis places pleomorphic xanthoastrocytoma in close relationship to other indolent, mixed glioneuronal tumors associated with epilepsy such as ganglioglioma, dysembryoplastic neuroepithelial tumor, and the subependymal giant-cell astrocytoma of tuberous sclerosis (SEGA) (41; 63).

In the last decade, more has become known about the molecular biology of this neoplasm. Earlier studies failed to consistently reveal aberrations commonly found in other glioma types (29), and in the following years some of those were elucidated. Mutations of the oncogene p53 were found in two of eight (25%) patients in one study (59), but a different group describing 55 tumors demonstrated that only 2% had a high degree of p53 immunostaining (16). Only a single grade 3 pleomorphic xanthoastrocytoma case with a p53 mutation was reported in a cohort of low- and high-grade pleomorphic xanthoastrocytomas (78). A group of 50 xanthoastrocytomas was studied using comparative genomic hybridization, revealing loss of material from chromosome 9 in 50% of cases; this genetic abnormality was not seen in any of a control group of more typical astrocytomas (81). A genetic study of several types of grade I gliomas found a consistent pattern of subtelomeric duplications and deletions among three different xanthoastrocytoma cases, involving 10 different chromosomes, that was not seen in any material from pilocytic astrocytomas (19). Finally, a unifying mutation in the BRAF gene, a component of the MAPK pathway, was found and confirmed in the majority (up to 80%) of xanthoastrocytomas (11; 25; 72; 69; 77), including 96% of tumors arising in the temporal lobe (11; 35). Both low- and high-grade pleomorphic xanthoastrocytomas were noted to harbor it. However, its presence was much less frequent in grade 3 pleomorphic xanthoastrocytoma compared to classic grade 2 pleomorphic xanthoastrocytoma. Significantly longer overall survival has been reported in the V600E-mutant tumors (25). The observation that the BRAF V600E mutations occur frequently in several other glial and glioneuronal tumors, including gangliogliomas, pilocytic astrocytomas, chordoid gliomas, and astroblastomas, further supports the hypothesis that pleomorphic xanthoastrocytoma shares a common cell of origin with them (07; 44). Pleomorphic xanthoastrocytomas without the canonical V600E mutation have been shown to harbor other MAPK/ERK signaling pathway alterations, such as mutations and fusions in the RAF family of kinases (09; 78). Another recurrent alteration found in pleomorphic xanthoastrocytomas is homozygous deletion of CDKN2A/B, which is reported in 60% to 94% of cases (81; 77; 61). Interestingly, concurrent MAPK alterations and CDKN2A/B deletions are frequent in epithelioid glioblastoma, pediatric secondary high-grade glioma types, and a recently defined high-grade astrocytoma with piloid features (65). Some studies also reported TERT promoter mutations and amplifications, which are more prevalent in recurrent grade 3 pleomorphic xanthoastrocytoma, suggesting that it may be a late genetic event associated with anaplastic transformation and recurrence and less favorable overall prognosis (61; 78; 12; 82). The definitive prognostic significance of some of these alterations in pleomorphic xanthoastrocytoma still remains to be elucidated in larger studies.

An epigenetic study examined methylation in a group of 10 both grade 2 (n=8) and grade 3 pleomorphic xanthoastrocytomas (n=2) and found that the two anaplastic cases had increased methylation of five different genes (CD81, HCK, HOXA5, ASCL2, and TES) that have been described in glioblastomas (50). The most recent genome-wide methylation profiling study of 46 cases performed against a comprehensive reference data set assigned 40 of them to the pleomorphic xanthoastrocytoma methylation class, with the remaining six cases grouped with the methylation classes of ganglioglioma, pilocytic astrocytoma, anaplastic pilocytic astrocytoma, or control tissue (78). No prognostic difference was reported in association with the methylation class with the advent of DNA methylation; systemic metastases of pleomorphic xanthoastrocytoma can now be diagnosed using methylation profiling (27).

Epidemiology

Due to the extreme rarity of this tumor, no precise information regarding its incidence or prevalence is available. It is estimated to account for less than 1% of astrocytic tumors (42), and it represented 1.5% of all pediatric low-grade gliomas in one Canadian based population study (38). In the setting of epilepsy referral centers, chronic epilepsy is found to be due to pleomorphic xanthoastrocytoma in roughly one out of every 650 cases (54).

Prevention

No means of preventing these tumors is available. Pleomorphic xanthoastrocytoma is not associated with any other disorders, nor is any particular group (besides the young) known to be at risk. Several case reports of xanthoastrocytomas occurring in patients with Sturge-Weber syndrome or neurofibromatosis are available, but whether these are chance occurrences or harbingers of a population at risk has yet to be determined (57; 40; 68; 33; 70; 73).

Differential diagnosis

Confusing conditions

The differential diagnosis for this lesion consists of all the other glioma subtypes, including pilocytic, diffuse, and anaplastic astrocytomas, glioblastoma, oligodendroglioma, chordoid glioma and ganglioglioma (20). Leptomeningeal involvement is uncommon in all of these except pilocytic astrocytoma. Dysembryoplastic neuroepithelial tumor may also arise in this location. Meningioma is an important diagnostic consideration as well because of the superficial location of these lesions, which may even produce a "dural tail" on imaging (62). Cavernous hemangioma is another important consideration in an enhancing temporal lobe lesion that fails to change over time. Unusual primary intradural extramedullary location of pleomorphic xanthoastrocytoma has been described at the cervical spinal cord level (34). Metastases may produce a similar appearance but are usually not a consideration in the younger age group in which these tumors most frequently arise. Two cases of pleomorphic xanthoastrocytoma mimicking an inflammatory granuloma were reported (10). As there is no pathognomonic feature of pleomorphic xanthoastrocytomas, the diagnosis can often be difficult in clinical practice.

Associated or underlying disorders

Pleomorphic xanthoastrocytomas are frequently associated with seizures. Epilepsy is the most common presenting sign, likely due to the tumor predilection for the temporal lobes, particularly the cortical (as opposed to subcortical) involvement. It is also possible that the tumor biology and the tumor cell-microenvironment interactions facilitate the epileptogenicity of the tumor.

Diagnostic workup

As with all brain neoplasms, the diagnosis of pleomorphic xanthoastrocytoma generally requires cerebral imaging for identification and localization, followed by surgical resection (or biopsy) for pathologic examination. MRI, the imaging modality of choice, often demonstrates a cyst with a mural nodule. The nodule is usually hyperintense on T2-weighted images and hypo- or isointense on T1-weighted images, with gadolinium enhancement in almost all cases (25). CT scan reveals a superficial cortical tumor with a cyst visible in 50% to 60% of cases (58; 76; 17). The tumor itself frequently appears as a solid mural nodule and may be hypodense or isodense to the surrounding brain. Calcification is rare, as is bony erosion. Contrast enhancement is an almost invariable feature, but the pattern of enhancement is variable (45). Edema is not prominent. Angiography is usually normal, though occasional tumors are hypovascular (58).

Analysis of imaging characteristics has shown that the BRAF V600E-wildtype grade 2 pleomorphic xanthoastrocytoma presented with more aggressive conventional and advanced MR imaging features than the V600E-mutant grade 2 pleomorphic xanthoastrocytoma (23). However, no significant differences were detected between the wildtype and mutant grade 3 tumors. A study of positron emission tomography with fluorodeoxyglucose (FDG-PET), though it included only 3 tumors, showed a strong correlation between the degree of metabolism and the tumor grade (13). The clinical utility of this, however, is unclear.

Management

The mainstay of treatment for this tumor is surgical resection (78). In one reported study, all grades underwent surgical resection at high rates: 95.1% (n = 329) of patients with grade 2 pleomorphic xanthoastrocytoma and 98.4% (n=61) of patients with anaplastic pleomorphic xanthoastrocytoma (p=0.332) (66). Most evidence supports more favorable outcomes with greater extent of resection (60; 14; 55; 25; 69). Several large case series and reviews have found 5-year progression-free survival and overall survival rates of 28% to 71% and 48% to 81%, respectively, for pleomorphic xanthoastrocytoma of all grades (60; 14; 55; 25), and extent of resection proved significant in a number of studies (60; 14; 25; 78).

The role for adjuvant radiation and chemotherapy remains less clear, with multiple studies unable to reconcile the risks and benefits (48; 58; 74; 05; 51; 36; 56; 64; 52; 60). Chemotherapy traditionally did not have a definitive role in treatment (17; 60; 79), though some early reports noted success with carboplatin and vincristine (47; 56). In one study of 408 pleomorphic xanthoastrocytomas, chemotherapy (regimen not specified) was administered to about 52% of patients with anaplastic pleomorphic xanthoastrocytoma and only about 11% of patients with grade 2 pleomorphic xanthoastrocytoma (66). In pediatric patients, where radiation therapy is limited, the use of adjuvant chemoradiotherapy in the treatment of grade 3 pleomorphic xanthoastrocytoma has been supported empirically (67). Currently, the use of systemic therapy continues to be an active area of investigation in the treatment of anaplastic pleomorphic xanthoastrocytoma. The same study reported that about 70% of grade 3 tumors were irradiated; however, only about 18% of grade 2 tumors received radiation. It appears that pleomorphic xanthoastrocytoma does not frequently possess MGMT methylation, raising doubts about the benefits of temozolomide, despite the scattered attempts to use it reported in the literature.

The use of targeted therapies has been an active area of investigation, particularly in the BRAF V600E-mutant pleomorphic xanthoastrocytoma. The overall survival of patients with V600E-mutant tumors was significantly higher than of those with wildtype tumors, which included 74 pleomorphic xanthoastrocytoma of all grades, 35 of which were treated with adjuvant therapies after recurrence or progression (25). This could be confounded by the increased prevalence of the mutation in the grade 2 pleomorphic xanthoastrocytoma group compared to grade 3 cases. Case reports and case series have demonstrated radiographic stability of disease and partial responses in some patients treated with BRAF inhibitors vemurafenib and dabrafenib, which appear to be tolerable in this patient population (04; 24; 75; 43; 03). The VE-BASKET study reported the highest response rate to vemurafenib in low-grade tumors, particularly pleomorphic xanthoastrocytoma (n=7), with promising efficacy data (26). One significant challenge that emerged during the medical management of the affected patients is resistance to BRAF inhibitors, leading to consideration of additional treatment options. An increasing number of reports support the concurrent use of BRAF and MEK inhibitors in treating pleomorphic xanthoastrocytoma. BRAF/MEK dual-drug inhibitor therapy has been reported to delay tumor progression without unexpected adverse events (28). Although the mechanism is not entirely elucidated, this may be attributed, in part, to a synergistic potential of combining both inhibitors and their specific effects depending on the specific class of the BRAF alteration harbored by each tumor. Dual BRAF and MEK inhibition with dabrafenib and trametinib has received histology agnostic regulatory approval for patients with tumors harboring the V600E BRAF mutation.

Seizures in patients with pleomorphic xanthoastrocytoma are managed with standard anticonvulsant medications and resection of the lesion. Most case reports indicate that these patients’ epilepsy responds well to tumor resection.

Outcomes

The most common adverse event associated with BRAF or MEK inhibitor treatment is grade 1–2 fatigue and skin rash. Dual BRAF and MEK inhibitors were reported to be well tolerated, with reversible grade 1–2 adverse events, including transient skin rash, fatigue, abdominal discomfort, neutropenia, and diarrhea. No grade 3–4 adverse events were detected (28).

Special considerations

Pregnancy

Malignant transformation within a 6-month period of a grade 3 pleomorphic xanthoastrocytoma initially diagnosed in a pregnant patient to a glioblastoma postpartum was reported (49). Another patient was reported as having delivered a normal child 4 years after gross total resection and whole-brain radiation for xanthoastrocytoma (37).

Anesthesia

No information is available regarding the use of various types of anesthesia in patients with this tumor.