Combined “Infiltrating Astrocytoma/Pleomorphic Xanthoastrocytoma” Harboring IDH1 R132H and BRAF V600E Mutations

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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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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Comparison of next-generation sequencing and FISH/IHC for molecular classification in glioma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14021 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14021-e14021

Author(s):

Deze Jia ◽

Yi Lu ◽

Xiaomin Li ◽

Tiantian Han ◽

Wanglong Deng ◽

...

Keyword(s):

False Negative ◽

Clinical Pathology ◽

Molecular Classification ◽

Braf V600e ◽

Actual Condition ◽

Idh1 R132h ◽

1P Deletion ◽

Mutation Braf ◽

H3 K27m Mutations

e14021 Background: The updated 2016 edition of the WHO Classification of CNS tumors indicates that IDH1 R132H, H3 K27M mutations, and co-deletion of 1p19q are strong stratification and prognostic markers glioma. FISH/IHC, as the commonly detected methods, present specific false-negative rates in the actual condition. Methods: In our study, IDH1 R132H status of 158 cases was assessed by IHC and NGS, and H3 K27M statuses of 83 patients were evaluated by IHC and NGS. 22 positive cases of 1p/19q co-deletion, all confirmed by FISH, were assessed by NGS. Results: For IDH1 R132H, 2 cases were IHC negative and were positive as confirmed by NGS. Another 10 patients with weakly IHC positive results were negative in NGS. Combined with histologic hallmarks, 6 cases of these samples could be diagnosed as glioblastoma, IDH wildtype; 1 case with POLE could be diagnosed as giant cell glioblastoma; 3 cases with BRAF V600E mutation, BRAF fusion, and ATRX mutation, respectively, could be diagnosed as pilocytic astrocytoma. Towards H3 K27M, 3 cases with IHC weakly positive were negative in NGS. Among these samples, 2 cases were diagnosed as glioblastoma, IDH wildtype by molecular and histologic hallmarks, and 1 case was medulloblastoma, SHH. Using NGS, IDH1 R132H /H3 K27M statues can be distinctly distinguished in which that is unknown by IHC. The results of NGS and FISH showed a 90.9%(20/22) consistent rate for the 1p19q co-deletion. 1 case was 1p deletion and intact 19q by FISH while 1p19q co-deletion by NGS because of the 19p deletion. 1 case was 1p19q co-deletion by FISH but 1p19q wildtype by NGS, diagnosed as glioblastoma, IDH wildtype with chr7+/10-. Conclusions: In our study, the agreement between NGS results and clinical pathology diagnosis was approximately 100%. NGS may act as the primary technology of molecular classification in glioma in the future.

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Extracranial invasion of a recurrent, transformed anaplastic pleomorphic xanthoastrocytoma: a case report

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.40 ◽

2018 ◽

Vol 45 (S1) ◽

pp. S2-S3

Author(s):

K.D. Langdon ◽

D. Krivosheya ◽

M.O. Hebb ◽

B. Wehrli ◽

L.C. Ang

Keyword(s):

Posterior Fossa ◽

Jugular Foramen ◽

Jugular Bulb ◽

Neck Mass ◽

Pleomorphic Xanthoastrocytoma ◽

Braf V600e ◽

Rare Tumour ◽

Who Grade ◽

Original Tumour ◽

The Right

Pleomorphic xanthoastrocytoma (PXA) is a rare tumour comprising <1% of all primary central nervous system tumours and the majority (~98%) occur supratentorially. We report on a 40-year-old female with a past medical history of a rare posterior fossa/cerebellar PXA who presented with a right-sided neck mass, decreased shoulder power and longstanding right tongue deviation with right-sided hemi-atrophy. The patient had prior tumour debulking. Recent MRI demonstrated an enhancing posterior fossa mass extending to the skull base at the jugular foramen and another mass in the upper neck along the jugular bulb with displacement and encasement of the right common carotid artery down to C5. Resection of the neck mass reveals an anaplastic PXA. The tumour has close approximation with adjacent peripheral nerves and is positive in 2 lymph nodes. Comparison with the original tumour molecular and immunohistochemical profiles reveals a conserved BRAF V600E mutation but the transformed malignant glioma now expresses dot-like EMA positivity and ATRX is completely lost (mutated). Transformation of a PXA (WHO Grade II) into an anaplastic PXA (WHO Grade III) has been well documented, but extracranial extension is extraordinarily rare. We report herein the first documented case of a posterior fossa PXA that underwent malignant transformation and extracranial invasion to the parapharyngeal space.

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RARE-31. TREATMENT OUTCOME OF CHILDREN WITH PLEOMORPHIC XANTHOASTROCYTOMA: RETROSPECTIVE ANALYSIS – A SINGLE INSTITUTION EXPERIENCE

Neuro-Oncology ◽

10.1093/neuonc/noz175.954 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi228-vi228

Author(s):

Ossama Maher ◽

Toba Niazi ◽

Ziad Khatib ◽

John Ragheb

Keyword(s):

Local Recurrence ◽

Retrospective Analysis ◽

Malignant Transformation ◽

Cranial Nerve ◽

Pleomorphic Xanthoastrocytoma ◽

Braf V600e ◽

Biological Behavior ◽

High Local Recurrence Rate ◽

Cranial Nerve Palsies

Abstract BACKGROUND Pleomorphic xanthoastrocytoma (PXA) and anaplastic pleomorphic xanthoastrocytoma (APXA) are two types of rare astrocytomas in pediatrics. There is limited literature reporting their outcomes. METHODS A retrospective analysis of pediatric patients with diagnosis of PXA and APXA treated at Nicklaus Children’s Hospital was conducted using descriptive measures. RESULTS A chart review of patients with brain tumors from 2001 to 2019 revealed that 13 patients (median age 6 years, range 2–17 years) were diagnosed with non-metastatic PXA (n=12) and APXA (n=1). Six patients (46%) were male. Clinical presentation included seizures (n=8), headaches (n=2) cranial nerve palsies (n=2). Diagnostic imaging showed tumor in the temporal lobe (n=5), parietal lobe (n=2), temporoparietal lobe (n=2), frontal lobe (n=1), occipital lobe (n=1), others (n=2). BRAF V600E mutation were identified in three of five analyzed tumors including PXA (n=4) and APXA (n=1). Surgical intervention consisted of gross total resection (n=8) and near/subtotal resection (n=5). Ten patients (76%) required a second surgery (median 2; range 1–4) due to local recurrence. The median time to recurrence was 3 years (range 6 months - 7 years). Three patients (23%) had malignant transformation of PXA, which occurred three to eight years from the initial surgery; one of them also had extensive spinal metastasis. Focal radiation was given to six patients (46%) due to multiple recurrence (n=2), malignant transformation (n=3), APXA (n=1). At a median follow up of 8 years (range 3 to 20 years), eight patients remain alive, three patients had lost to follow up, two patients died from progressive disease. Long-term sequelae varied as follows; seizures (n=5), motor weakness (n=4), cranial nerve palsies (n=2), and learning disability (n=1). CONCLUSION PXA is associated with high local recurrence rate and uncommonly malignant transformation to APXA in pediatrics, which requires close follow-up due to unpredictable biological behavior of these tumors.

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NTRK2 Fusion Driven Pediatric Glioblastoma: Identification of key molecular drivers by personalized oncology

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.266 ◽

2019 ◽

Vol 46 (s2) ◽

pp. S64

Author(s):

Levine ◽

Y Shen ◽

K Mungall ◽

J Serrano ◽

M Snuderl ◽

...

Keyword(s):

Clinical Trials ◽

Checkpoint Inhibitors ◽

Braf V600e ◽

Current Status ◽

Driver Mutations ◽

List Type ◽

Idh1 R132h ◽

Tyrosine Kinase 2 ◽

Cerebellar Glioblastoma ◽

Molecular Landscape

We describe the case of an 11-month-old girl with a rare cerebellar glioblastoma driven by a NACC2-NTRK2 (Nucleus Accumbens Associated Protein 2-Neurotrophic Receptor Tyrosine Kinase 2) fusion. Initial workup of our case demonstrated homozygous CDKN2A deletion, but immunohistochemistry for other driver mutations, including IDH1 R132H, BRAF V600E, and H3F3A K27M were negative, and ATRX was retained. Tissue was subsequently submitted for personalized oncogenomic analysis, including whole genome and whole transcriptome sequencing, which demonstrated an activating NTRK2 fusion, as well as high PD-L1 expression, which was subsequently confirmed by immunohistochemistry. Furthermore, H3 and IDH demonstrated wildtype status. These findings suggested the possibility of treatment with either NTRK- or immune checkpoint- inhibitors through active clinical trials. Ultimately, the family pursued standard treatment that involved Head Start III chemotherapy and proton radiotherapy. Notably, at most recent follow upapproximately two years from initial diagnosis, the patient is in disease remission and thriving, suggesting favorable biology despite histologic malignancy. This case illustrates the value of personalized oncogenomics, as the molecular profiling revealed two actionable changes that would not have been apparent through routine diagnostics. NTRK fusions are known oncogenic drivers in a range of cancer types, but this is the first report of a NACC2-NTRK2 fusion in a glioblastoma.LEARNING OBJECTIVESThis presentation will enable the learner to:1.Explore the current molecular landscape of pediatric high grade gliomas2.Recognize the value of personalized oncogenomic analysis, particularly in rare and/or aggressive tumors3.Discuss the current status of NTRK inhibitor clinical trials

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BRAF V600E mutation: A treatable driver mutation in pleomorphic xanthoastrocytoma (PXA)

Acta Oncologica ◽

10.3109/0284186x.2015.1021428 ◽

2015 ◽

Vol 55 (1) ◽

pp. 122-123 ◽

Cited By ~ 10

Author(s):

Silvia Hofer ◽

Grégoire Berthod ◽

Christian Riklin ◽

Elisabeth Rushing ◽

Jonas Feilchenfeldt

Keyword(s):

Pleomorphic Xanthoastrocytoma ◽

Braf V600e Mutation ◽

Driver Mutation ◽

Braf V600e

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Combined pleomorphic xanthoastrocytoma-ganglioglioma with BRAF V600E mutation: case report

Journal of Neurosurgery Pediatrics ◽

10.3171/2016.1.peds15558 ◽

2016 ◽

Vol 18 (1) ◽

pp. 53-57 ◽

Cited By ~ 5

Author(s):

Marta Cicuendez ◽

Elena Martinez-Saez ◽

Francisco Martinez-Ricarte ◽

Esteban Cordero Asanza ◽

Juan Sahuquillo

Keyword(s):

Case Report ◽

Tumor Recurrence ◽

Pleomorphic Xanthoastrocytoma ◽

Braf V600e Mutation ◽

Braf V600e ◽

Rare Tumor ◽

Total Resection ◽

Cell Lineages ◽

Cellular Origin ◽

History Of

Combined pleomorphic xanthoastrocytoma (PXA) and ganglioglioma (GG) is an extremely rare tumor, with fewer than 20 cases reported. The authors report a case of combined PXA-GG in an 18-year-old man with a history of seizures. The tumor showed necrosis and the BRAF V600E mutation on histological examination, with no evidence of tumor recurrence 1 year after gross-total resection. The BRAF V600E mutation was present, which suggests that both cell lineages may share a common cellular origin.

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