J.Sales-Llopis

Neurosurgery Department, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Alicante, Spain

Pleomorphic xanthoastrocytoma (PXA) is a astrocytic tumor that occasionally progresses to a higher grade.

see Anaplastic Pleomorphic Xanthoastrocytoma.

see Pigmented variant of pleomorphic xanthoastrocytoma.

Most frequently occurs in children and teenagers.

They usually arise supratentorial > 90 % and superficially from the cerebral hemispheres (upper most sections) of the brain and in contact with the leptomeninges, rarely they arise from the spinal cord.

Histologically, they can be associated with inflammatory cell infiltration and reticulin deposits.

A rich reticulin network surrounds individual cells and small cell nests. Verification of a rich reticulin network is helpful in differentiating PXA from high grade gliomas.

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.

MIB-1 index is usually < 1 %.

The term “PXA with anaplastic features” is reserved for those tumors with > 5 mitoses/10 high power fields, and/or necrosis.

Although histology may not reliably predict aggressive behavior in pleomorphic xanthoastrocytomas, the presence of increased mitosis, necrosis, and increased cell proliferation labeling indices may be indicative of a higher grade tumor ¹⁾

They have certain morphological similarities to fibrous histiocytoma (or fibrous xanthoma) of the meninges and brain, namely the occurrence of lipid-laden neoplastic cells and, frequently, a dense reticulin fiber network. The detection of glial fibrillary acidic (GFA) protein in the tumor cells helped to establish its astrocytic derivation, but it has been advanced that, in spite of this agreed observation, the tumor should still be regarded as a fibrous xanthoma of meningeal origin. Although many patients have a long symptom-free postoperative survival, local recurrences at varying intervals after surgery have been noted in some instances. Weldon-Linne et al. first reported that such a recurrence had the morphology of a small-cell glioblastoma. We are reporting three further examples of locally recurrent neoplasms in patients whose original meningocerebral tumors had the typical features of PXA; the recurrences (developing 7 months, 7 years and 15 years, respectively, after surgery) were small-cell glioblastomas. The rich reticulin network present in the initial tumor was mostly lost in the recurrences. This anaplastic evolution further confirms the astrocytic nature of the PXA ²⁾.

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

They are consistently positive for S100 and GFAP, though the latter may be patchy.

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

CD34 expression is also frequently encountered.

Given their superficial “meningo-cerebral” localization, patients typically present with a history of sudden onset seizures, often of a longstanding nature.a Headaches may also occur.

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.

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

They may rarely show multifocality or leptomeningeal dissemination.

MRI

T1

solid component iso to hypointense c.f. grey matter cystic component low signal leptomeningeal involvement seen in over 70% of cases

T1 C+ (Gd)

solid component usually enhances vividly

T2

solid component iso to hyperintense c.f. grey matter

cystic component high signal

on T2 FLAIR sequence, cystic areas show hyperintensity relative to CSF due to higher protein contents little surrounding vasogenic oedema

Main differential diagnosis is that of other cortical tumours, with helpful distinguishing features including:

Ganglioglioma can look very similar contrast enhancement often less prominent calcification in ~50% of cases no dural tail sign.

The analysis of the methylation profile suggested the diagnosis of an anaplastic pleomorphic xanthoastrocytoma and as a differential diagnosis an anaplastic ganglioglioma ³⁾.

Dysembryoplastic neuroepithelial tumors (DNET) contrast enhancement uncommon 'bubbly appearance' common

Oligodendroglioma calcifications common

Desmoplastic infantile ganglioglioma young children dural involvement prominent large often multiple lesions

Cystic meningioma

Fibrillary astrocytoma

Anaplastic astrocytoma.

Glioblastoma

Epithelioid glioblastoma (eGBM) and pleomorphic xanthoastrocytoma (PXA) with anaplastically transformed foci (ePXA) show overlapping features. Eleven eGBMs and 5 ePXAs were reviewed and studied immunohistochemically. Fluorescence in situ hybridization for EGFR amplification, PTEN deletion and ODZ3 deletion was also performed, with Ilumina 450 methylome analysis obtained in five cases. The average age for eGBM was 30.9 (range 2-79) years, including five pediatric cases and a M : F ratio of 4.5. The ePXA patients had a M : F ratio of 4 and averaged 21.2 (range 10-38) years in age, including two pediatric cases. Six eGBMs and two ePXAs recurred (median recurrence interval of 12 and 3.3 months, respectively). All tumors were composed of solid sheets of loosely cohesive, “melanoma-like” cells with only limited infiltration. ePXAs showed lower grade foci with classic features of PXA. Both tumor types showed focal expression of epithelial and glial markers, retained INI1 and BRG1 expression, occasional CD34 positivity, and lack of mutant IDH1 (R132H) immunoreactivity. BRAF V600E mutation was present in four eGBMs and four ePXAs. ODZ3 deletion was detected in seven eGBMs and two ePXAs. EGFR amplification was absent. Methylome analysis showed that one ePXA and one eGBM clustered with PXAs, one eGBM clustered with low-grade gliomas, and two eGBMs clustered with pediatric-type glioblastomas. Common histologic, immunohistochemical, molecular and clinical features found in eGBM and ePXA suggest that they are closely related or the same entity. If the latter is true, the nomenclature and WHO grading remains to be resolved ⁴⁾.

The primary treatment of PXA is surgical resection, and the outcome is generally favorable. Pathology is notable for anaplasia in ∼15% of PXAs, but there is no consensus regarding any advantage of adjuvant postsurgical therapy ⁵⁾.

Pleomorphic xanthoastrocytoma (PXA) has characteristic histologic features and is regarded as a WHO grade II lesion. Overall survival is reported to be >60%, but published series usually consist of a range of ages and treatment modalities. Gross total resection is associated with superior survival but recurrence rates after gross total resection are not well described, particularly in a pediatric population.

Perioperative neurological complications are relatively common, but do not affect long-term functional outcome or mortality.

Pleomorphic xanthoastrocytomas (PXA) may recur and demonstrate aggressive clinical behavior with a mortality rate between 15% and 20%, and a new concept of anaplastic PXA has been proposed.

No histopathologic features currently are known to reliably predict recurrence or tumor progression.

Malignant PXAs are higher risk for perioperative complications and, ultimately, death from tumor progression, despite increased use of adjuvant radiation and chemotherapy.

Gross total resection without adjuvant therapy provides prolonged disease control, as seen in 6 of 7 patients (85%) in the series of Fouladi et al. ⁶⁾.

Extent of resection, mitotic index, and necrosis appear to be the best predictors of outcome ^{7) 8)}.

BRAF mutation may potentially identify specific subgroups with distinct prognoses ⁹⁾.

Both pediatric and adult PXAs may be resected with good functional outcomes. Perioperative neurological complications are relatively common, but do not affect long-term functional outcome or mortality. Malignant PXAs are higher risk for perioperative complications and, ultimately, death from tumor progression, despite increased use of adjuvant radiation and chemotherapy ¹⁰⁾.

A literature review of 79 patients with PXAs is described and confirms a favorable prognosis in 80% of patients. The sex ratio in the reported cases was almost equal, and the median age at time of diagnosis was 14 years. Seventy-nine percent of the patients presented with seizures. Nine of the 15 deaths from PXA are associated with histological evidence of necrosis at initial presentation or in a recurrent tumor, confirming the poor prognosis associated with the presence of necrosis in these neoplasms. Survival curves confirm that the optimal treatment for PXAs without necrosis is primary surgical resection with subsequent operation for recurrent tumor. The roles of surgery or radiotherapy in necrotic PXA are not clear from the literature ¹¹⁾.

Pleomorphic xanthoastrocytoma case series.

Pleomorphic Xanthoastrocytoma case reports.