BRAF VE1 Immunoreactivity Patterns in Epithelioid Glioblastomas Positive for BRAF V600E Mutation

Abstract

Background Epithelioid glioblastomas (E-GBMs) manifest BRAF V600E mutation in up to fifty percent of cases, compared to a small percentage of ordinary GBMs, suggesting 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. Design 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 to those in similarly-assessed giant cell GBMs, anaplastic pleomorphic xanthoastrocytomas (A-PXAs). Results 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 A-PXAs tended to manifest strong, diffuse cytoplasmic immunoreactivity, compared to previously-studied GGs which demonstrate more intense immunoreactivity in the ganglion, than 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. Conclusions E-GBMs show good correlation between mutational status and IHC, albeit with limitations to IHC. E-GBMs can respond to targeted therapy.

Rapid Clinical and Radiographic Response With Combined Dabrafenib and Trametinib in Adults With BRAF -Mutated High-Grade Glioma

“…14 Although epithelioid GBMs often lack the common molecular characteristics of adult GBMs, such as EGFR amplification or PTEN loss, the frequency of BRAF V600E mutations in this subgroup is estimated at 50%. 6,[15][16][17][18] Likewise, BRAF V600E mutations are commonly found in LGGs, such as PXA or ganglioglioma, 8,[19][20][21][22] and therefore HGGs arising via malignant transformation from these lesions also possess an increased number of BRAF mutations. [23][24][25][26][27] Interestingly, in some circumstances, the presence of a BRAF mutation may actually drive the transformative process, because BRAF V600E mutations appear to be mutually exclusive with IDH mutations, suggesting that they may be an alternative oncogenic driver in a subset of IDH wild-type LGGs.…”

BRAF‐V600E immunohistochemistry in a large series of glial and glial–neuronal tumors

“…If the presence of BRAF‐V600E mutation is a diagnostic clue to a circumscribed low‐grade glial or glial–neuronal tumor, this mutation is not specific of GNT; it has been reported in rare cases of low‐grade diffuse gliomas in children and in 10% of GB, especially in the epithelioïd variant (which also expresses CD34 more often) (Brastianos et al., 2014; Ichimura et al., 2012; Kleinschmidt‐DeMasters, Aisner, & Foreman, 2015; Kleinschmidt‐DeMasters et al., 2013). The detection of the mutation can still help to distinguish a GG from the cortical infiltration of a diffuse glioma or a GG from an astrocytoma especially in the cerebellum, where PA rarely exhibits BRAF‐V600E mutation (but instead the BRAF‐KIAA1549 fusion in 80% of cases).…”

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

“…BRAF V600E mutation analysis is important not only as a diagnostic tool but also as a possible biomarker for the choice of treatment. Although further studies will be needed, glial tumors that are BRAF V600E positive by immunostaining and Sanger sequencing have shown clinical response with the targeted therapy vemurafinib . A favorable response to targeted therapy is well‐established in patients with BRAF V600E‐mutated metastatic melanoma.…”

“…Although further studies will be needed, glial tumors that are BRAF V600E positive by immunostaining and Sanger sequencing have shown clinical response with the targeted therapy vemurafinib. 15 A favorable response to targeted therapy is well-established in patients with BRAF V600E-mutated metastatic melanoma. Thus, despite the rarity of BRAF V600E-mutated brain tumors, especially E-GBM, the availability of targeted therapies with documented efficacy underscores the importance of genetic analysis.…”