Clinicopathological and genetic association between epithelioid glioblastoma and pleomorphic xanthoastrocytoma

Abstract

Epithelioid glioblastoma (eGBM) is a rare variant of GBM which was adopted in the 2016 WHO classification. eGBM and pleomorphic xanthoastrocytoma (PXA) sometimes show overlapping features histologically and genetically, such as epithelioid pattern and a highly frequent V600E mutation in the gene for vRAF murine sarcoma viral oncogene homolog B1 (BRAF), respectively. Accurate diagnosis of these rare tumors is challenging according to the new criteria in the revised 2016 WHO classification. It is an urgent task to elucidate the biological properties of the tumors and to select appropriate treatment. Twenty consecutive cases diagnosed as PXA or eGBM histologically were investigated. Twelve of the 20 cases were PXAs and eight were eGBMs. Morphologically, mitotic activity, necrosis and degenerative changes such as intracellular lipid accumulation, eosinophilic granular bodies and reticulin fiber deposits were scored. Immunohistochemical and molecular biological assessment for isocitrate dehydrogenases 1 and 2 (IDH1/2), α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX), p53, BRAF, telomere reverse transcriptase promoter (TERT-p), H3F3A, and integrase interactor 1 (INI1) were performed. eGBM tended to lack the degenerative changes characteristic for PXA. Of the 20 cases tested, Sanger technique showed no mutation in IDH1/2. BRAF mutation at T1799 > A (V600E) was detected in 4/12 (33.3%) PXA and 4/8 (50.0%) eGBM, while TERT-p mutation was detected at C228 > T in 2/12 (16.7%) PXA and at C250 > T in 1/8 (12.5%) eGBM. Retained nuclear ATRX was observed in 12/12 (100%) PXA and 6/7 (85.7%) eGBM while p53 mutation was observed in 2/10 (20%) PXA and 7/7 (100%) eGBM. All tumors retained INI1 expression in their nuclei. None of the tumors harbored H3F3A mutation. One PXA without BRAF mutation acquired TERT-p mutation at recurrence and one eGBM harbored both BRAF and TERT-p mutation. Molecular biological similarity between eGBM and PXA was suggested in our series, while degenerative changes reflected the features of PXA. It was speculated that the common genetic alterations for development and progression of eGBM and PXA might include BRAF and TERT-p mutations.

Pediatric low-grade glioma in the era of molecular diagnostics

“…Further, BRAF p.V600E pLGG, especially in the context of co-occurring CDKN2A deletions (discussed further below), are significantly more likely to transform into HGG; an event which may occur 10-20 years after the initial diagnosis [142]. While not exclusive to this entity, transformation has been most commonly describe for pleomorphic xanthoastrocytoma which has been suggested to be within the same family as epithelioid GBM [4,63,210]. These "pleomorphic xanthoastrocytomalike" GBM carry a better prognosis compared to other GBM, but are still significantly worse when compared to pLGG [117].…”

A rare case of BRAF V600E‐mutated epithelioid glioblastoma with a sarcomatous component

“…Next, we considered the possibility that our case may be PXA or GG. Several reports have assumed that E‐GBM and PXA are the same entity because of the similarity in the results of histologic and genetic analyses . Moreover, some studies have suggested that BRAF mutations might be related to the epithelioid features of high‐grade gliomas .…”

“…Several reports have assumed that E-GBM and PXA are the same entity because of the similarity in the results of histologic and genetic analyses. 10,11 Moreover, some studies have suggested that BRAF mutations might be related to the epithelioid features of high-grade gliomas. 12 Thus, it is necessary to make these differential diagnoses based on both histopathologic and genetic analyses.…”

Oncogenic BRAF Alterations and Their Role in Brain Tumors

“…The similar high frequency of BRAF V600E in epithelioid glioblastomas and PXAs suggests that both tumors may belong to one family with divergent morphologic features [95,96]. In this context one interesting clinical case should be noted that reported an eGBM recurrence after the initial diagnosis of a PXA [97].…”