A case of an epithelioid glioblastoma with the BRAF V600E mutation colocalized with BRAF intact low-grade diffuse astrocytoma

Abstract BACKGROUND Biological features of pediatric glioma differ significantly from those of adult glioma, and limited data are available on those of AYA patients. Here, we focused on AYA patients with glioma, especially those harboring BRAF V600E mutation, and investigated their clinical and genetic features. METHOD: We retrospectively analyzed AYA patients with brain tumors harboring BRAF V600E, who were treated in two hospitals in Japan. RESULTS Clinical information was available for 14 patients. The median age at diagnosis was 25 years (range: 15–38). Five patients were diagnosed with glioblastoma (GBM), including one epithelioid type. These patients were over 25. Although one patient with GBM died of the disease 6.9 years after initial diagnosis, the remaining patients were alive. Two patients were alive without recurrence at 38 and 51 months after the treatment. The patient with epithelioid glioblastoma experienced early recurrence. The remaining nine patients (64%) were diagnosed with low-grade glioma, including ganglioglioma, pilocytic astrocytoma, diffuse astrocytoma, oligodendroglioma, pleomorphic xanthoastrocytoma, and polymorphous low-grade neuroepithelial tumor of the young. No patients died of the disease, and four patients are alive without recurrence after initial operation without adjuvant treatment. Two patients are (epithelioid glioblastoma and ganglioglioma) currently undergoing treatment with a BRAF inhibitor for recurrent tumors. DISCUSSION Although the number of this study is limited, our study suggested that the prognosis of AYA patients with BRAF-V600E positive GBM may not be as dismal as that of children or adults.

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Concurrent TERT promoter and BRAF V600E mutation in epithelioid glioblastoma and concomitant low-grade astrocytoma

Neuropathology ◽

10.1111/neup.12318 ◽

2016 ◽

Vol 37 (1) ◽

pp. 58-63 ◽

Cited By ~ 26

Author(s):

Nozomi Matsumura ◽

Nozomi Nakajima ◽

Tatsuya Yamazaki ◽

Takuro Nagano ◽

Kaie Kagoshima ◽

...

Keyword(s):

Braf V600e Mutation ◽

Braf V600e ◽

Low Grade ◽

Tert Promoter ◽

Epithelioid Glioblastoma

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LGG-23. EXCELLENT CLINICAL / RADIOLOGICAL RESPONSE TO BRAF INHIBITION IN A YOUNG CHILD WITH IN-OPERABLE SUPRA-SELLAR PILOCYTIC ASTROCYTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.405 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii370-iii371

Author(s):

Stacy Chapman ◽

Demitre Serletis ◽

Colin Kazina ◽

Mubeen Rafay ◽

Sherry Krawitz ◽

...

Keyword(s):

Targeted Therapy ◽

Pilocytic Astrocytoma ◽

Clinical Symptoms ◽

Obstructive Hydrocephalus ◽

Braf V600e Mutation ◽

Braf V600e ◽

Low Grade ◽

Dramatic Improvement ◽

Chemotherapeutic Regimen ◽

Response To Chemotherapy

Abstract In-operable low grade gliomas (LGG) in the pediatric population continue to present a treatment dilemma. Due to the low-grade nature of these tumors, and variable response to chemotherapy / radiation, the choice of adjuvant treatment is difficult. Overall survival is directly related to the degree of surgical resection, adding complexity to these inoperable tumors. Current chemotherapeutic regimen for these inoperable tumors includes vincristine (VCR) and carboplatin (Carbo). With advancements in the molecular characterization of gliomas, the role of targeted therapy has come into question. We present a 2-year-old female with biopsy proven Pilocytic Astrocytoma (positive BRAF-V600E mutation) involving the hypothalamic/optic chiasm region. She presented with ataxic gait, bi-temporal hemianopia, obstructive hydrocephalus and central hypothyroidism, which progressed to altered consciousness, and right hemiparesis due to location/mass effect of the tumor. She was initially treated with chemotherapy (VCR/Carbo) but her tumor progressed at 6 weeks of treatment. As her tumor was positive for BRAF-V600E mutation, she was started on Dabrafenib monotherapy, resulting in dramatic improvement in her clinical symptoms (able to stand, improved vision), and a 60% reduction in tumor size at 3-months. At 6-months, follow up MRI showed slight increase in the solid portion of the tumor, with no clinical symptoms. We plan to add MEK inhibitor (Trametinib) and continue with Dabrafenib. Our experience and literature review suggests that LGG with BRAF-V600E mutations may benefit from upfront targeted therapy. Prospective clinical trials comparing the efficacy of BRAF inhibitors versus standard chemotherapy in LGG with BRAF mutations are urgently needed.

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Molecular Alterations in Pediatric Low-Grade Gliomas That Led to Death

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab097 ◽

2021 ◽

Author(s):

Jared T Ahrendsen ◽

Claire Sinai ◽

David M Meredith ◽

Seth W Malinowski ◽

Tabitha M Cooney ◽

...

Keyword(s):

Braf V600e ◽

Molecular Characteristics ◽

Low Grade ◽

Diffuse Astrocytoma ◽

Term Survival ◽

Pten Loss ◽

Low Grade Gliomas ◽

Molecular Alterations ◽

Idh1 R132h ◽

Poor Outcomes

Abstract Pediatric low-grade gliomas (PLGGs) have excellent long-term survival, but death can occasionally occur. We reviewed all PLGG-related deaths between 1975 and 2019 at our institution: 48 patients were identified; clinical data and histology were reviewed; targeted exome sequencing was performed on available material. The median age at diagnosis was 5.2 years (0.4–23.4 years), at death was 13.0 years (1.9–43.2 years), and the overall survival was 7.2 years (0.0–33.3 years). Tumors were located throughout CNS, but predominantly in the diencephalon. Diagnoses included low-grade glioma, not otherwise specified (n = 25), pilocytic astrocytoma (n = 15), diffuse astrocytoma (n = 3), ganglioglioma (n = 3), and pilomyxoid astrocytoma (n = 2). Recurrence occurred in 42/48 cases, whereas progression occurred in 10. The cause of death was direct tumor involvement in 31/48 cases. Recurrent drivers included KIAA1549-BRAF (n = 13), BRAF(V600E) (n = 3), NF1 mutation (n = 3), EGFR mutation (n = 3), and FGFR1-TACC1 fusion (n = 2). Single cases were identified with IDH1(R132H), FGFR1(K656E), FGFR1 ITD, FGFR3 gain, PDGFRA amplification, and mismatch repair alteration. CDKN2A/B, CDKN2C, and PTEN loss was recurrent. Patients who received only chemotherapy had worse survival compared with patients who received radiation and chemotherapy. This study demonstrates that PLGG that led to death have diverse molecular characteristics. Location and co-occurring molecular alterations with malignant potential can predict poor outcomes.

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Radiological characteristics study on epithelioid glioblastoma, a rare subtype of GBM

10.21203/rs.2.10915/v1 ◽

2019 ◽

Author(s):

Xiaojuan Deng ◽

Qingya Luo ◽

Xiaolin Tang ◽

Youqiang Chen ◽

Chengyi Mao ◽

...

Keyword(s):

Cerebral Cortex ◽

Diffusion Weighted Imaging ◽

Braf V600e ◽

Diffuse Astrocytoma ◽

Peritumoral Edema ◽

1H Mrs ◽

Radiological Features ◽

Epithelioid Glioblastoma ◽

Intracerebral Tumor ◽

Immunohistological Staining

Abstract Purpose Epithelioid glioblastoma (eGBM) is rare and a newly recognized subtype of GBM. Given the short of studies focusing on radiological characteristics of these tumors, we aimed to report the radiological features of eGBM deriving from six patients. Methods Six patients with pathologically diagnosed as eGBM were enrolled in this retrospective study. CT and pre-operative MR examinations with conventional and advanced sequences, such as diffusion weighted imaging and so on were analyzed. Immunohistological staining and mutation analysis of BRAF V600E was also explored. Results Only case 6 showed a co-locating tumor which was verified to be a diffuse astrocytoma (WHO II), other cases demonstrated single intracerebral tumor. Majority of the tumors originated in cerebral cortex, two cases involved corpus callosum. Tumors demonstrated iso-, hypo- or mixed intensity on T1WI, hyper- or mixed intensity on T2WI and FLAIR, heterogeneous enhancement on post-contrasted imaging. Involvement of leptomeninge, which appeared as leptomenigeal thickening and abnormal enhancing was discovered in 4 cases. Peritumoral edema (4/6) and hemorrhage (3/6) was common, calcium was only seen in case 5. Notable restrictive diffusion and consequently decreased rADC was found in solid component in 5 cases. Most cases demonstrated increased Cho and Lac/Lip value on 1H-MRS, and promoted rCBV value on PWI. The cases with CT examination showed an ill-defined mass with mixed density. Conclusions Although there are some overlaps between typical GBM and eGBM, some radiological characteristics, such as location (often in cerebral cortex), involvement of leptomeninge and intratumoral calcium, may support the diagnosis of eGBM.

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Transformation of ganglioglioma to epithelioid glioblastoma, both with BRAF V600E mutation

Histopathology ◽

10.1111/his.14516 ◽

2021 ◽

Vol 79 (S1) ◽

pp. 29-30

Keyword(s):

Braf V600e Mutation ◽

Braf V600e ◽

Epithelioid Glioblastoma

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Polymorphous Low-Grade Neuroepithelial Tumor of the Young (PLNTY): Molecular Profiling Confirms Frequent MAPK Pathway Activation

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab075 ◽

2021 ◽

Author(s):

Cristiane M Ida ◽

Derek R Johnson ◽

Asha A Nair ◽

Jaime Davila ◽

Thomas M Kollmeyer ◽

...

Keyword(s):

Copy Number ◽

Mapk Pathway ◽

Braf V600e Mutation ◽

Mitogen Activated Protein Kinase ◽

Braf V600e ◽

Low Grade ◽

Pathway Activation ◽

Mitogen Activated Protein ◽

Copy Number Changes ◽

Cd34 Expression

Abstract Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and frequent mitogen-activated protein kinase (MAPK) pathway activation. We molecularly profiled 13 cases with diagnostic histopathological features of PLNTY (10 female; median age, 16 years; range, 5–52). Patients frequently presented with seizures (9 of 12 with available history) and temporal lobe tumors (9 of 13). MAPK pathway activating alterations were identified in all 13 cases. Fusions were present in the 7 youngest patients: FGFR2-CTNNA3 (n = 2), FGFR2-KIAA1598 (FGFR2-SHTN1) (n = 1), FGFR2-INA (n = 1), FGFR2-MPRIP (n = 1), QKI-NTRK2 (n = 1), and KIAA1549-BRAF (n = 1). BRAF V600E mutation was present in 6 patients (17 years or older). Two fusion-positive cases additionally harbored TP53/RB1 abnormalities suggesting biallelic inactivation. Copy number changes predominantly involving whole chromosomes were observed in all 10 evaluated cases, with losses of chromosome 10q occurring with FGFR2-KIAA1598 (SHTN1)/CTNNA3 fusions. The KIAA1549-BRAF and QKI-NTRK2 fusions were associated respectively with a 7q34 deletion and 9q21 duplication. This study shows that despite its name, PLNTY also occurs in older adults, who frequently show BRAF V600E mutation. It also expands the spectrum of the MAPK pathway activating alterations associated with PLNTY and demonstrates recurrent chromosomal copy number changes consistent with chromosomal instability.

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A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): A Pediatric Brain Tumor Consortium (PBTC) study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.10504 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 10504-10504 ◽

Cited By ~ 7

Author(s):

Jason R. Fangusaro ◽

Arzu Onar-Thomas ◽

Tina Young-Poussaint ◽

Shengjie Wu ◽

Azra H Ligon ◽

...

Keyword(s):

Phase Ii ◽

Pediatric Brain Tumor ◽

Braf V600e Mutation ◽

Low Grade Glioma ◽

Braf V600e ◽

Low Grade ◽

Optic Pathway ◽

Grade 3 ◽

Molecular Aberrations

10504 Background: A greater understanding of the Ras-MAP kinase-signaling pathway in pediatric low-grade glioma (LGG) paired with the availability of potent selective inhibitors has enhanced the ability to target this pathway with therapeutic intent. Methods: The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata and treated at 25 mg/m2/dose PO BID for up to two years. Here we present the data from three of these strata. The remaining strata are still accruing patients. Results: Stratum I included children with non-NF-1 and non-optic pathway recurrent/refractory pilocytic astrocytoma (PA) harboring BRAF aberrations (BRAF V600e mutation or the BRAF-KIAA 1549 fusion). Eight of 25 (32%) patients achieved a partial response (PR) with 2-year PFS of 66+/-11%. Two of 7 (29%) patient tumors with a BRAF V600e mutation and 6/18 (33%) with a BRAF KIAA-1549 fusion had a PR. Stratum 3 enrolled NF-1-associated LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Ten of 25 (40%) achieved PR with a 2-year PFS of 96+/-4%. Only one patient progressed while on treatment. Stratum 4 included children with non-NF-1 optic pathway/hypothalamic LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Two of 16 (12.5%) had a PR with a 2-year PFS of 65+/-13%. The BRAF aberration status of the responders in strata 3 and 4 is mostly unknown. All responses were confirmed centrally and seven patients remain on treatment. The most common toxicities were grade 1/2 CPK elevation, diarrhea, hypoalbuminemia, elevated AST and rash. Rare grade 3/4 toxicities included elevated CPK, rash, neutropenia, emesis and paronychia. Conclusions: Selumetinib was effective in treating children with recurrent/refractory LGG, including those with NF-1 associated LGG and PA harboring BRAF V600e mutation or BRAF-KIAA 1549 fusion. Larger prospective studies are necessary to determine the future, specific role of this agent in treating children with LGG harboring specific molecular aberrations. Clinical trial information: NCT01089101.

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