The evolution of pleomorphic xanthoastrocytoma: from genesis to molecular alterations and mimics

Pleomorphic xanthoastrocytomas (PXAs) are rare tumors accounting for less than 1% of astrocytomas. They commonly occur in young patients and have relatively favorable prognosis. However, they are well known to have heterogenous morphology and biological behavior with the potential to recur and disseminate throughout the central nervous system, especially their anaplastic counterparts. Recent advances in the molecular characterization have discovered BRAFp.V600E mutations in conjunction with CDKN2A/B deletions and TERTp mutations to be the most frequent alterations in PXAs. These tumors can present a diagnostic challenge as they share overlapping histopathological, genomic as well as methylation profile with various other tumor types, particularly epithelioid glioblastomas (eGBs). This review provides the spectrum of evolution of PXAs from their genesis to recent molecular insights and attempts to review pathogenesis and relationship to other tumors that they mimic especially eGB. It is postulated based on evidence from literature that PXA and eGB are possibly related and not distinct entities, being two ends of a continuous spectrum of malignant progression (grade 2-grade 4) with anaplastic PXA (grade 3) lying in between. Future WHO classifications will have to possibly redefine these tumors using more confirmatory data from larger studies.