BRAF VE1 immunoreactivity patterns in epithelioid glioblastomas positive for BRAF V600E mutation.

Abstract

Epithelioid glioblastomas (E-GBMs) manifest BRAF V600E mutation in up to 50% of cases, compared with a small percentage of ordinary GBMs, suggesting that they are best considered variants rather than a different pattern of GBM. Availability of a targeted therapy, vemurafenib, may make testing BRAF status important for treatment. It is unclear whether BRAF VE1 immunohistochemistry (IHC) can substitute for Sanger sequencing in these tumors. BRAF VE1 IHC was correlated with Sanger sequencing results on our original cohort of E-GBMs, and then new E-GBM cases were tested with both techniques (n=20). Results were compared with those in similarly assessed giant cell GBMs, anaplastic pleomorphic xanthoastrocytomas. All tumors tested showed 1:1 correlation between BRAF V600E mutational results and IHC. However, heavy background immunostaining in some negatively mutated cases resulted in equivocal results that required repeat IHC testing and additional mutation testing using a different methodology to confirm lack of detectable BRAF mutation. Mutated/BRAF VE1 IHC E-GBMs and anaplastic pleomorphic xanthoastrocytomas tended to manifest strong, diffuse cytoplasmic immunoreactivity, compared with previously studied gangliogliomas, which demonstrate more intense immunoreactivity in the ganglion than in the glial tumor component. One of our E-GBM patients with initial gross total resection quickly recurred within 4 months, required a second resection, and then was placed on vemurafenib; she remains tumor free 21 months after second resection without neuroimaging evidence of residual disease, adding to the growing number of reports of successful treatment of BRAF-mutated glial tumors with drug. E-GBMs show good correlation between mutational status and IHC, albeit with limitations to IHC. E-GBMs can respond to targeted therapy.