MGMT Promoter Methylation and BRAF V600E Mutations Are Helpful Markers to Discriminate Pleomorphic Xanthoastrocytoma from Giant Cell Glioblastoma

Abstract

Giant Cell Glioblastoma (gcGBM) and Pleomorphic Xanthoastrocytoma (PXA) are rare astroglial tumors of the central nervous system. Although they share certain histomorphological and immunohistochemical features, they are characterized by different clinical behavior and prognosis. Nevertheless, few cases remain uncertain, as their histomorphological hallmarks and immunophenotypes do correspond to the typical pattern neither of gcGBM nor PXA. Therefore, in addition to the routinely used diagnostic histochemical and immunohistochemical markers like Gömöri, p53 and CD34, we analyzed if genetic variations like MGMT promoter methylation, mutations in the IDH1/2 genes, or BRAF mutations, which are actually used as diagnostic, prognostic and predictive molecular markers in anaplastic glial tumors, could be helpful in the differential diagnostic of both tumor entities. We analyzed 34 gcGBM and 20 PXA for genetic variations in the above-named genes and found distinct distributions between both groups. MGMT promoter hypermethylation was observed in 3 out of 20 PXA compared to 14 out of 34 gcGBM (15% vs. 41.2%, p-value 0.09). BRAF V600E mutations were detected in 50% of the PXA but not in any of the gcGBM (50% vs. 0%, p-value < 0.001). IDH1 R132 and IDH R172 mutations were not present in any of the PXA and gcGBM cases. Our data indicate, that in addition to the histological and immunohistochemical evaluation, investigation of MGMT promoter methylation and in particular BRAF V600E mutations represent reliable additional tools to sustain differentiation of gcGBM from PXA on a molecular basis. Based on these data specific BRAF kinase inhibitors could represent a promising agent in the therapy of PXA and their use should be emphasized.

Whole‐exome sequencing revealed mutational profiles of giant cell glioblastomas

“…Four gcGBM samples (40%) were positive for MGMT methylation as revealed by MSP. Similar prevalence of MGMT methylation was reported by Lohkamp et al . MGMT methylation was not associated with age, sex or overall survival.…”

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway

“…In fact, it was this immunohistochemical observation, along with the consistent failure of the tumors in this series to manifest labeling for IDH1 R132H or chromosome 1p/19q codeletion, despite their oligodendrogliomatous appearances, that prompted us to consider these as distinct from the infiltrating gliomas of later life and to initiate additional molecular studies. While the immunohistochemical labeling of some glioblastomas for CD34 is recognized [ 19 , 25 ], this phenomenon is generally foreign to infiltrating astrocytomas of lower grade and to neoplasms of the oligodendroglioma group [ 2 , 5 , 6 , 10 , 13 – 15 , 28 , 29 , 32 , 36 , 43 , 45 – 47 ]. Only one of the many studies that have examined CD34 expression in gliomas found tumoral (as opposed to endothelial) immunoreactivity in lesions classified as WHO grade II or III astrocytomas, oligodendrogliomas or oligoastrocytomas [ 8 ].…”

Association between giant cell glioblastoma and glioblastoma multiforme in the United States: A retrospective cohort study

“…Importantly, several small series and case reports have suggested that the prognosis of GCG is significantly better than that observed for GBM (Akslen et al, 1988;Becker et al, 1967;Burger & Vollmer, 1980;Chang, Kuwana, Ito, Koike, & Kitamura, 2001;Deb, Sharma, Chander, Mahapatra, & Sarkar, 2006;Gullotta, Casentini, & Neumann, 1980;Klein, Molenkamp, Sorensen, & Roggendorf, 1998;Kroh, Matyja, Marchel, & Bojarski, 2004;Margetts & Kalyan-Raman, 1989;Sabel, Reifenberger, Weber, Reifenberger, & Schmitt, 2001;Shinojima et al, 2004). The development of GBG is highly related to mutations of the TP53 gene (Kleihues & Glioblastoma,) MGMT promoter methylation, mutations in the IDH1/2 genes, or BRAF mutations, which are actually used as diagnostic, prognostic, and predictive molecular markers in anaplastic glial tumors (Lohkamp et al, 2016).…”