Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival

Abstract

Pleomorphic xanthoastrocytoma (PXA) in its classic manifestation exhibits distinct morphological features and is assigned to CNS WHO grade 2 or grade 3. Distinction from glioblastoma variants and lower grade glial and glioneuronal tumors is a common diagnostic challenge. We compared a morphologically defined set of PXA (histPXA) with an independent set, defined by DNA methylation analysis (mcPXA). HistPXA encompassed 144 tumors all subjected to DNA methylation array analysis. Sixty-two histPXA matched to the methylation class mcPXA. These were combined with the cases that showed the mcPXA signature but had received a histopathological diagnosis other than PXA. This cohort constituted a set of 220 mcPXA. Molecular and clinical parameters were analyzed in these groups. Morphological parameters were analyzed in a subset of tumors with FFPE tissue available. HistPXA revealed considerable heterogeneity in regard to methylation classes, with methylation classes glioblastoma and ganglioglioma being the most frequent mismatches. Similarly, the mcPXA cohort contained tumors of diverse histological diagnoses, with glioblastoma constituting the most frequent mismatch. Subsequent analyses demonstrated the presence of canonical pTERT mutations to be associated with unfavorable prognosis among mcPXA. Based on these data, we consider the tumor type PXA to be histologically more varied than previously assumed. Histological approach to diagnosis will predominantly identify cases with the established archetypical morphology. DNA methylation analysis includes additional tumors in the tumor class PXA that share similar DNA methylation profile but lack the typical morphology of a PXA. DNA methylation analysis also assist in separating other tumor types with morphologic overlap to PXA. Our data suggest the presence of canonical pTERT mutations as a robust indicator for poor prognosis in methylation class PXA.

Pleomorphic xanthoastrocytoma in the multiverse of epigenomics: is it time to recognize the variants?

“…This implies that, using the current CNS WHO definition, more than half of PXA cases would be missed by a lack of histopathological consideration of this differential diagnosis. In addition, more than half of histPXA cases did not fall into the mcPXA, reinforcing several other tumor entities may show PXA-like histological features [ 10 ].…”

“…In a recent paper by Ebrahimi et al published in this journal, the authors discussed the challenges associated with the diagnosis and grading of PXA using morphologic and molecular criteria, especially including methylation profiling [ 10 ]. Their investigation of histologically defined PXA (histPXA) and PXA defined by DNA methylation analysis (mcPXA) highlights the wide spectrum of morphological patterns that fall under mcPXA and further explores its distinction from aggressive entities with similar morphology, such as Glioblastoma, IDH-wildtype (GBM, IDH-wt) using methylation profiling studies.…”

The Neoplastic Tonnage-Pleomorphic Xanthoastrocytoma

“…Children and young adults are commonly incriminated although most neoplasms appear within 10 years to 30 years. No age of disease emergence is exempt [2,3]. Pleomorphic xanthoastrocytoma constitutes <1% of the primary astrocytic neoplasms.…”

“…The unique pleomorphic xanthoastrocytoma is predominantly situated within the superficial cerebral cortex or supra-tentorial region and adheres to superimposed leptomeninges wherein infiltration of the dura is exceptional. Commonly, the temporal lobe is implicated followed in frequency by the frontal lobe or parietal lobe [2,3]. Besides, the neoplasm may be located within the cerebellum, spinal cord, retina, thalamus, pineal gland or sellar region [2,3].…”

Establishment and characterization of patient-derived xenograft from leptomeningeal spread of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion

“…Speci cally, epithelioid glioblastoma shares both morphological as well as molecular features with APXA including a high incidence of BRAF V600E mutations 16 . On the benign end of the disease spectrum, PXA can also harbor morphologic and molecular similarities to lower grade tumors such as ganglioglioma and pilocytic astrocytoma 20,21 . Gangliogliomas carry the BRAF V600E mutation in most cases and have been reported occasionally to contain CDKN2A/B homozygous deletions 22 .…”