Pleomorphic Xanthoastrocytoma
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1 Pleomorphic Xanthoastrocytoma Christine E. Fuller Keywords Pleomorphic xanthoastrocytoma; Pleomorphic xanthoastrocytoma with anaplastic features 2.1 Overview Pleomorphic xanthoastrocytoma (PXA) is an uncommon astrocytic lesion that despite its significant histologic pleomorphism, 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 xanthosarcoma, 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 hamartomatous lesions, PXAs represent distinctive astrocytic neoplasms with a variable degree of neuronal differentiation demonstrable by immunohistochemistry and electron microscopy. 2.2 Clinical Features Representing <1% of all astrocytic tumors, PXAs most frequently 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 superficiallysituated 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, isointense on T1-weighted MR imaging, mildly hyperintense on T2-weighted imaging, and strongly enhances following gadolinium 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 xanthomatous histology. Leptomeninges are usually present in the sample, incorporated into the solid portion of the tumor. Intraoperative cytologic imprints / smears: Cytologic samples 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 histologic appearance, however several key features are consistently present in all: They are composed of spindle cells arranged in fascicles, intersecting bundles, or a storiform pattern, together with an admixture of variably pleomorphic giant cells, the nuclei of which may be singular, multilobated, or multiple. Nuclear hyperchromasia is typical, and intranuclear cytoplasmic invaginations are often present. (Fig. 2.3a and b) Large xanthomatous cells with abundant intracytoplasmic lipid droplets are a helpful diagnostic feature when present, (Fig. 2.3c) though these may be quite inconspicuous 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, particularly those examples situated predominantly in the subarachnoid 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) A.M. Adesina et al. (eds.), Atlas of Pediatric Brain Tumors, DOI / _2, Springer Science + Business Media, LLC
2 20 Pleomorphic Xanthoastrocytoma Composite PXA/ganglioglioma, replete with identifiable ganglion cell component, may be occasionally encountered, and PXAs with clear cell change, pigmentation, and papillary structures have been reported. Features of cortical dysplasia may be seen in cortex adjacent 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 microtubules, dense core granules and/or clear vesicles. Intercellular basement membrane and aggregates of secondary 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 homozygous deletion involving CDKN2A/p14 ARF /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 nodule 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 demonstrating positivity for neuronal markers and CD34, both of which would be unexpected in glioblastoma. Immunopositivity for S-100 and GFAP effectively differentiates PXA from the occasional pleomorphic leptomeningeal-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 survival, whereas elevated mitotic rate (>5 mitoses / 10 HPF) and necrosis are significantly associated with poor overall survival. suggested reading Hirose T, Ishizawa K, Sugiyama K, Kageji T, Ueki K, Kannuki S. (2008) Pleomorphic xanthoastrocytoma: a comparative pathological study between conventional and anaplastic types. Histopathology 52: Crespo-Rodriguez AM, Smirniotopoulos JG, Rushing EJ. (2007) MR and CT imaging of 24 pleomorphic xanthoastrocytomas (PXA) and a review of the literature. Neuroradiology 49: Weber RG, Hoischen A, Ehrler M, Zipper P, Kaulich K, Blaschke B et al. (2007) Frequent loss of chromosome 9, homozygous CDKN2A/p14(ARF)/ CDKN2B deletion and low TSC1 mrna expression in pleomorphic xanthoastrocytoma. Oncogene 26(7): Hirose T, Giannini C, Scheithauer BW. (2001) Ultrastructural features of pleomorphic xanthoastrocytoma: a comparative study with glioblastoma multiforme. Ultrastruct Pathol 25(6): Kepes JJ, Rubinstein LJ, Eng LF. (1979) Pleomorphic xanthoastrocytoma: a distinctive meningocereberal glioma of young subjects with relatively favorable prognosis. A study of 12 cases. Cancer 44: Tien RD, Cardenas CA, Rajagopalan S. (1992) Pleomorphic xanthoastrocytoma of the brain: MR findings in six patients. AJR Am J Roentgenol 159(6): Davies KG, Maxwell RE, Seljeskog E, Sung JH. (1994) Pleomorphic xanthoastrocytoma: report of four cases, with MRI scan appearances and literature review. Br J Neurosurg 8(6): Fouladi M, Jenkins JJ, Burger PC, Langston J, Merchant T, Heideman R et al. (2001) Pleomorphic xanthoastrocytoma: favorable outcome after complete surgical resection. Neuro-oncol 3(3): Giannini C, Hebrink D, Scheithauer BW, Dei Tos AP, James CD. (2001) Analysis of p53 mutation and expression in pleomorphic xanthoastrocytoma. Neurogenetics 3(3): Giannini C, Scheithauer BW, Lopes MB, Hirose T, Kros JM, VandenBerg SR. (2002) Immunophenotype of pleomorphic xanthoastrocytoma. Am J Surg Pathol 26(4): Bucciero A, De Caro M, De Stefano V, Tedeschi E, Monticelli A, Siciliano A et al. (1997) Pleomorphic xanthoastrocytoma: clinical, imaging and pathological features of four cases. Clin Neurol Neurosurg 99:40 45 Giannini C, Scheithauer BW, Burger PC, Brat D, Wollan PC, Lach B et al. (1999) Pleomorphic xanthoastrocytoma. Cancer 85:
3 Pleomorphic Xanthoastrocytoma 21 Fig 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 Intraoperative cytologic smear preparations are quite polymorphous, containing a mixture of cells with (a) fibrillary astrocytic, spindled, and (b) giant pleomorphic morphologies.
4 22 Pleomorphic Xanthoastrocytoma Fig (a and b) PXAs, though notable for their heterogeneous histologic appearance, fairly consistently contain spindle cells arranged in fascicles or intersecting bundles, together with an admixture of pleomorphic giant cells, the nuclei of which may be singular, multilobated, or multiple. 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.
5 Pleomorphic Xanthoastrocytoma 23 Fig (a) GFAP is likewise consistently positive in PXAs. (b) Not uncommonly, scattered individual tumor cells will express neuronal markers, such as synaptophysin shown here.
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Pleomorphic Xanthoastrocytoma
Pleomorphic Xanthoastrocytoma Christine E. Fuller Keywords Pleomorphic xanthoastrocytoma; Pleomorphic xanthoastrocytoma with anaplastic features 2.1 OVERVIEW Pleomorphic xanthoastrocytoma (PXA) is an uncommon
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