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A.M. Adesina et al. (eds.), Atlas of Pediatric Brain Tumors, DOI 10.1007/978-1-4419-1062-2_2, © Springer Science + Business Media, LLC 2010

Keywords Pleomorphic xanthoastrocytoma; Pleomorphic xanthoastrocytoma with anaplastic features

2.1 Overview

• Pleomorphic xanthoastrocytoma (PXA) is an uncommon astrocytic lesion that despite its significant histologic pleo-morphism, generally behaves in a less aggressive fashion than similarly pleomorphic infiltrative gliomas; the latter affords it a WHO grade II designation.

• The vast majority are sporadic, with only rare examples described in association with neurofibromatosis type I (NF1).

• Previously referred to as fibroxanthoma and xanthosar-coma, they have also been misclassified as forms of giant cell glioblastoma or monstrocellular sarcoma.

• Postulated to originate from subpial astrocytes, multipotential neuroectodermal precursor cells, or pre-existing hamartoma-tous lesions, PXAs represent distinctive astrocytic neoplasms with a variable degree of neuronal differentiation demonstra-ble by immunohistochemistry and electron microscopy.

2.2 CliniCal Features

• Representing <1% of all astrocytic tumors, PXAs most fre-quently arise within the first three decades of life. No gender predilection is apparent, and occasional cases have been reported in the elderly.

• Given their superficial “meningo-cerebral” localization, patients typically present with a history of seizures, often of a longstanding nature.

• Headaches may also occur.

2.3 neurOimaging

• PXAs are almost always supratentorial and superficially-situated within the cerebral hemispheres (most commonly the temporal or parietal lobe) with involvement of the leptomeninges.

• Rare sites include the cerebellum, spinal cord, thalamus, and cerebellopontine angle.

• 70% arise as a cyst with solid mural nodule, the remainder being predominantly solid with variable small cystic areas.

• Their solid component is iso to hypodense on CT, isoin-tense on T1-weighted MR imaging, mildly hyperintense on T2-weighted imaging, and strongly enhances following gad-olinium administration (Fig. 2.1a and b).

• Intratumoral hemorrhage or calcifications are uncommon; peritumoral edema may be present, but is typically minimal.

• They may rarely show multifocality or leptomeningeal dissemination.

2.4 PathOlOgy

• Gross pathology: Operative sampling of PXAs yield solid firm tissue (+/- cystic component) with variable coloration ranging from tan to yellow, the latter areas corresponding to xanthoma-tous histology.

• Leptomeninges are usually present in the sample, incorpo-rated into the solid portion of the tumor.

• Intraoperative cytologic imprints / smears: Cytologic sam-ples are polymorphous, containing cells with quite variable cytomorphology; fibrillary astrocytic, spindled, and giant pleomorphic forms with abundant sometimes vacuolated cytoplasm may all be present. (Fig. 2.2a and b).

• Eosinophilic granular bodies and scattered lymphocytes are often identifiable.

• Histology: – PXAs as a group are quite heterogeneous in their histo-

logic appearance, however several key features are con-sistently present in all:

– They are composed of spindle cells arranged in fasci-cles, intersecting bundles, or a storiform pattern, together with an admixture of variably pleomorphic giant cells, the nuclei of which may be singular, mul-tilobated, or multiple. Nuclear hyperchromasia is typical, and intranuclear cytoplasmic invaginations are often present. (Fig. 2.3a and b)

– Large xanthomatous cells with abundant intracytoplas-mic lipid droplets are a helpful diagnostic feature when present, (Fig. 2.3c) though these may be quite inconspic-uous in some cases.

– A rich reticulin network surrounds individual cells and small cell nests. (Fig. 2.3d)

– Though not a diagnostic requirement, eosinophilic granular bodies (EGBs) are almost always present. (Fig. 2.3c).

– Perivascular and intratumoral collections of small lymphocytes are also frequent. (Fig. 2.3e)

– Similar to pilocytic astrocytoma and ganglion cell tumors, PXAs display a solid growth pattern, particu-larly those examples situated predominantly in the suba-rachnoid space.

– The interface with underlying / surrounding brain parenchyma is however variable, and infiltrative areas resembling diffuse astrocytoma may be encountered.

– Typical PXAs have a negligible mitotic rate and are devoid of necrosis and vascular proliferation.

– The term “PXA with anaplastic features” is reserved for those tumors with ³ 5 mitoses/10 high power fields, and/or necrosis. (Fig. 2.3f)

Pleomorphic Xanthoastrocytoma

Christine e. Fuller

20 PleOmOrPhiC XanthOastrOCytOma

– Composite PXA/ganglioglioma, replete with identifi-able ganglion cell component, may be occasionally encountered, and PXAs with clear cell change, pig-mentation, and papillary structures have been reported.

– Features of cortical dysplasia may be seen in cortex adja-cent to PXA in some cases.

2.5 immunOhistOChemistry

• PXAs are notable for their biphenotypic glial and neuronal staining pattern.

– They are consistently positive for S-100 and GFAP, though the latter may be patchy. (Fig. 2.4a)

– Expression of neuronal markers, including synaptophysin, neurofilament, MAP2, and Class III b-tubulin, may be detected in individual pleomorphic cells; (Fig. 2.4b) these markers will also highlight any true ganglion cell component.

– CD34 expression is also frequently encountered.

2.6 eleCtrOn miCrOsCOPy

• Ultrastructural features include cells containing numerous intermediate filaments, lipid droplets, and lysosomes.

• Neuronal features present in some cells include microtu-bules, dense core granules and/or clear vesicles.

• Intercellular basement membrane and aggregates of sec-ondary lysosomes (corresponding to EGBs) are common.

2.7 mOleCular PathOlOgy

• PXAs appear to be molecularly distinct from infiltrative astrocytomas, exhibiting a low incidence of p53 mutations.

• Amplifications of EGFR, CDK4, and MDM2 have not been detected.

• Multiple chromosomal abnormalities have been documented via cytogenetics and comparative genomic hybridization, though only chromosome 9p loss with coincident homozy-gous deletion involving CDKN2A/p14ARF/CDKN2B loci has been encountered with significant frequency in 50% of cases.

2.8 DiFFerential DiagnOsis

• For PXA, the main alternate diagnostic consideration is glioblastoma, especially the giant cell variant; both of these cellular gliomas contain variable numbers of pleomorphic astrocytes, though have significantly different therapeutic and prognostic implications.

• Radioimaging findings of a cyst with enhancing mural nod-ule strongly favors PXA, as do the histologic findings of xanthomatous change, EGBs, a paucity of mitoses, and lack of necrosis and vascular proliferation.

• Immunohistochemistry may be of assistance in demon-strating positivity for neuronal markers and CD34, both of which would be unexpected in glioblastoma.

• Immunopositivity for S-100 and GFAP effectively dif-ferentiates PXA from the occasional pleomorphic lep-tomeningeal-based sarcoma such as malignant fibrous histiocytoma.

• Ganglioglioma and pilocytic astrocytoma are two other entities that arise in the young and may present as a cyst with mural nodule on radioimaging studies.

– The former contains abundant dysmorphic ganglion cells and lacks the prominent pleomorphism and lipidized cells of PXA.

– Pilocytic astrocytomas also tend not to display the extent of pleomorphism or reticulin network found in PXA, and are usually less compact in their architecture, frequently exhibiting loose microcystic areas containing cells with typical piloid processes.

2.9 PrOgnOsis

• Although PXAs afford a relatively favorable prognosis, with 5 year recurrence-free and overall survival rates of 70 and 80% respectively, a significant proportion will recur, undergo anaplastic progression, or both.

• Completeness of initial resection and low mitotic rate are both independent predictors of prolonged recurrence-free sur-vival, whereas elevated mitotic rate (>5 mitoses / 10 HPF) and necrosis are significantly associated with poor overall survival.

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Fig. 2.1. Axial MR imaging (a) T2-w showing a large solid mildly hyperintense well-circumscribed nodule with associated fluid-filled cyst arising within the outer aspects of the right temporoparietal region. Peritumoral edema is fairly prominent in this case, and there is noticeable mass effect. (b) Axial TI-w post-Gd imaging shows intense homogeneous enhancement of the solid nodule with rim enhancement of the cyst wall.

Fig. 2.2. Intraoperative cytologic smear preparations are quite polymorphous, containing a mixture of cells with (a) fibrillary astrocytic, spindled, and (b) giant pleomorphic morphologies.

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Fig. 2.3. (a and b) PXAs, though notable for their heterogeneous histologic appearance, fairly consistently contain spindle cells arranged in fas-cicles or intersecting bundles, together with an admixture of pleomorphic giant cells, the nuclei of which may be singular, multilobated, or multi-ple. Nuclei are often hyperchromatic, though some cells may exhibit nuclear features similar to those seen in ganglion cells, containing more open chromatin and singular prominent nucleoli (b). Eosinophilic granular bodies are another consistent feature (a-c). Cytoplasmic vacuolization may be extensive as in this example (c), though in some PXAs may be exceedingly difficult to identify. (d) Verification of a rich reticulin network is helpful in differentiating PXA from higher grade gliomas. (e) Similar to gangliogliomas, PXAs also frequently contain interspersed collections of lymphocytes. (f) This PXA with anaplastic features was notable for brisk mitotic activity; necrosis was present elsewhere in the tumor.

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Fig. 2.4. (a) GFAP is likewise consistently positive in PXAs. (b) Not uncommonly, scattered individual tumor cells will express neuronal mark-ers, such as synaptophysin shown here.