Introduction

An inclusion in the World Health Organization (WHO) CNS Tumors 2016 classification involves the introduction of a distinctive form of glioblastoma (GBM) recognized as epithelioid glioblastoma (eGBM).1 eGBMs can be recognized by their large epithelioid cells, which have plenty of pinkish cytoplasm, grainy chromatin, noticeable nuclei (sometimes resembling melanoma cells), and occasionally occurring rhabdoid cells.23 The average age of onset for this specific tumor subtype is notably lower in comparison to that of conventional GBM. In some instances, eGBMs have been observed to develop from preexisting pleomorphic xanthoastrocytomas (PXAs).45 A specific genetic mutation, BRAF-V600E (where valine is replaced by glutamic acid at position 600 of the B-Raf protein, which is involved in serine/threonine-specific protein kinase activity),6 has been identified in 50 to 100% of cases of eGBM.7 eGBMs harboring the BRAF V600E mutation have demonstrated a promising response to BRAF and MEK inhibitors.89101112 The utilization of BRAF and MEK inhibitors leads to meaningful clinical changes .

The primary objective of this study was to elucidate the clinicopathological features as well as the subsequent outcomes of a collection of 10 cases of eGBM that underwent treatment at the Apollo Proton Cancer Centre situated in Chennai, Tamil Nadu, India.

Materials and Methods

All cases diagnosed as eGBM over the past 5 years were retrieved from the database of the Department of Neuro-oncology, Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India. Between 2018 and 2023, 10 patients with eGBM were referred for radiation therapy. Of these, five were recurrent eGBMs. Surgical resection was done for all patients and the histopathological confirmation of the diagnosis was obtained. Immunohistochemistry (IHC) was conducted for all patients to analyze specific protein markers and BRAV600E mutation. The degree of surgical resection was assessed qualitatively either during the surgery itself by the surgeon or, if possible, by evaluating contrast-enhanced magnetic resonance imaging (MRI) images after the operation.

All patients received adjuvant radiation to a dose of 59.4 Gy/33 fractions or 60 Gy/30 fractions with concurrent temozolomide (75 mg/m²) followed by adjuvant temozolomide as per protocol until recurrence. One patient was started with dabrafenib and trametinib instead of adjuvant temozolomide after initial radiation due to suspicion of progression. In recurrent settings, patients were considered to redo surgery, reradiation, BRAF with MEK inhibitors, and bevacizumab based on clinical condition, MRI findings, and progression-free survival. All cases were discussed in the Neuro-oncology Clinical Management Team at our institute.

Results

The median patient age at diagnosis was 34 years (range: 22–55 years). The male and female ratio was 1:1. All tumor locations were supratentorial. Among the cohort, a total of five patients were referred for adjuvant treatment after their initial surgical interventions. The other five patients exhibited indications suggesting the possible recurrence of eGBMs. The extent of surgical resection at the point of initial diagnosis consisted of gross total resection (n = 7, 70%), and subtotal resection (n = 3, 30%). All patients were positive for BRAFV600E on IHC.

The median follow-up was 2.3 years and the median time to recurrence was 19 months (range 4–36 months) from the diagnosis of eGBM (Tables 1 and 2). An ependymal nodular lesion in ventricles and spine, lung, and bone metastatic lesions were seen in two patients (Fig. 1). In recurrent situations, three patients underwent reexcision, four patients had reradiation, and four patients received dabrafenib and trametinib. Two patients defaulted after recurrence and died due to disease progression. Bevacizumab was considered based on MRI findings and steroid dependency.

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Fig. 1: (A) Ependymal nodule in ventricle. (B) Ependymal nodule in spine. (C) Distant lung metastasis. (D) Distant bone metastasis.

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One patient who started dabrafenib and trametinib after adjuvant radiation experienced local progression after 33 months, followed by local recurrence with lung and bone metastasis (Fig. 1C, D). One patient died due to multiple subacute hemorrhages, which was a known case of congenital vascular malformations, and two patients remained disease-free later (Fig. 2A and B corresponds to 24 and 12 months of follow-up after BRAFV600E inhibitors, respectively).

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Fig. 2: Response of BRAF + MEK inhibitors. (A) Patient A; A1, local recurrence; A2, postsurgery and reradiation; A-3 and A4, no residual lesion on follow-up. (B) Patient B: B1 and B, local early recurrence; B3 and B4, regression of lesion during follow-up.

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Discussion

Due to the rarity of eGBM, there are limited published studies that focus on assessing outcomes specifically for individuals with this condition. This particular tumor tends to manifest in young adult group, as evidenced by a median age of 34 years observed in our case series. eGBMs are commonly found as tumors located in the diencephalon or, less frequently, as superficial masses within the cerebral hemispheres.13 These tumors have apparent enhancement after contrast injection and show significantly restricted hyperintensive signals with mild perilesional edema (Fig. 3). Hemorrhage and the dissemination of tumor cells into the leptomeninges are likely to be frequently observed during the time of diagnosis.141516

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Fig. 3: The tumor in left temporal lobe showing hyperintensity on T2-weighted image (T2WI) with edema (A). Intratumoral hemorrhage on gradient echo (GRE) (B) and enhancement on T1W (C).

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The tumor exhibited characteristics of an astrocytic glioma, featuring high mitotic activity, microvascular proliferation, and necrosis. It primarily consisted of cohesive sheets of epithelioid or melanoma-like cells that displayed loose cohesion, ample cytoplasm, eccentric nuclei, and occasional presence of fibrillar or globular cytoplasmic inclusions, resembling rhabdoid cytology717181920 (Fig. 4). A minority of cases of extremely aggressive GBM also displayed limited areas that resembled the morphological characteristics of PXA.2122 Analysis of the genetic profile uncovered the presence of BRAF V600E mutations in a range of 50 to 93% within the subset of eGBMs.2324 Additionally, TERT promoter mutations were detected in 70% of cases, while homozygous deletions affecting CDKN2A/2B were observed in 79% of instances.225 In our series, all patients were positive for BRAFV600E on IHC.

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Fig. 4: (A) Hematoxylin and eosin (H&E) staining displayed abundant eosinophilic cytoplasm with rhabdoid features in the tumor cells. (B) BRAFV600E mutation on immunohistochemistry.

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In contrast to the typical GBM, eGBM exhibits a distinct tendency to metastasize to extracranial organs and spread via cerebrospinal fluid dissemination. One patient had ependymal nodular spread in the ventricles and spine, while another patient developed distant lung with bone metastasis in this series (Fig. 1). As a highly invasive brain tumor, the median survival time is only a few months (ranging from 6 to 31 months).1526 Our series showed the same (Tables 1 and 2).

BRAF V600E mutation was detected in neuroepithelial tumors, including astrocytomas of WHO grade II and a gliosarcoma of WHO grade IV, as well as on GBMs with epithelioid histopathological features.2728 One of the extensively investigated focal points pertains to the proto-oncogene B-Raf (BRAF), which encodes a serine/threonine protein kinase situated within the RAS-RAF-MEK-ERK-MAP kinase pathway.6 Within this context, the BRAF V600E mutation has garnered significant attention, manifesting itself in up to 7% of diverse human malignancies. This mutation triggers a substitution wherein valine is replaced by glutamine at position 600 within the amino acid sequence of the protein kinase. Directly addressing this genetic aberration, B-Raf kinase inhibitors such as vemurafenib or dabrafenib have emerged as notably efficacious therapeutic avenues. Particularly, these inhibitors have garnered approval for the treatment of advanced malignant melanomas that bear the BRAF V600E mutation.29 Vemurafenib, an inhibitor targeting BRAF, has exhibited noteworthy clinical effectiveness among patients who harbor BRAF V600E-mutant melanoma brain metastases.30 Moreover, its positive impact has extended beyond melanoma, demonstrating favorable outcomes in the context of various other malignancies.

Numerous case reports have documented promising outcomes in the context of targeted therapy for brain tumors characterized by the presence of the BRAF V600E mutation.103132 Examples of such tumors include ganglioglioma, PXA, and papillary craniopharyngioma.293334 Likewise, in mice carrying BRAFV600E gliomas, a combination therapy involving both BRAFV600E and MEK inhibitors resulted in diminished tumor growth when compared to the effects of solely inhibiting BRAFV600E.35 The investigator-assessed objective response rate was 33% in high-grade glioma (32% in GBM) and 69% in low-grade glioma which is shown in an ongoing ROAR study.36

Within the scope of our investigation, a total of four patients received the BRAF inhibitor (dabrafenib) and the MEK inhibitor (trametinib). Our experiences are summarized in Table 2. The concurrent administration of dabrafenib and trametinib yielded a notable therapeutic response in a patient afflicted by eGBM multiforme harboring the BRAF V600E mutation. This treatment combination exhibited substantial efficacy while causing minimal adverse effects and preserving a favorable quality of life. Notably, three patients demonstrated sustained local control (Fig. 2).

Conclusion

eGBM multiforme is a notably infrequent yet extensively documented entity. As a result, meticulous preoperative imaging, histomorphology, and molecular assessment are imperative to ensure precise diagnosis. Furthermore, multi-institutional prospective study is essential for additional insights through the utilization of BRAF + MEK inhibitors, to gather a more comprehensive understanding of treatment outcomes over an extended period.