Molecular Profiling Reclassifies Adult Astroblastoma into Known and Clinically Distinct Tumor Entities with Frequent Mitogen-Activated Protein Kinase Pathway Alterations

Abstract

Background: Astroblastoma (ABM) is a rare glial brain tumor. Recurrent meningioma 1 (MN1) alterations have been recently identified in most pediatric cases. Adolescent and adult cases, however, remain molecularly poorly defined.

Materials and methods: We performed clinical and molecular characterization of a retrospective cohort of 14 adult and 1 adolescent ABM.

Results: Strikingly, we found that MN1 fusions are a rare event in this age group (1/15). Using methylation profiling and targeted sequencing, most cases were reclassified as either pleomorphic xanthoastrocytomas (PXA)-like or high-grade glioma (HGG)-like. PXA-like ABM show BRAF mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and CD34 expression. Conversely, HGG-like ABM harbored specific alterations of diffuse midline glioma (2/5) or glioblastoma (GBM; 3/5). These latter patients showed an unfavorable clinical course with significantly shorter overall survival (p = .021). Mitogen-activated protein kinase pathway alterations (including FGFR fusion, BRAF and NF1 mutations) were present in 10 of 15 patients and overrepresented in the HGG-like group (3/5) compared with previously reported prevalence of these alterations in GBM and diffuse midline glioma.

Conclusion: We suggest that gliomas with astroblastic features include a variety of molecularly sharply defined entities. Adult ABM harboring molecular features of PXA and HGG should be reclassified. Central nervous system high-grade neuroepithelial tumors with MN1 alterations and histology of ABM appear to be uncommon in adults. Astroblastic morphology in adults should thus prompt thorough molecular investigation aiming at a clear histomolecular diagnosis and identifying actionable drug targets, especially in the mitogen-activated protein kinase pathway.

Implications for practice: Astroblastoma (ABM) remains a poorly defined and controversial entity. Although meningioma 1 alterations seem to define a large subset of pediatric cases, adult cases remain molecularly poorly defined. This comprehensive molecular characterization of 1 adolescent and 14 adult ABM revealed that adult ABM histology comprises several molecularly defined entities, which explains clinical diversity and identifies actionable targets. Namely, pleomorphic xanthoastrocytoma-like ABM cases show a favorable prognosis whereas high-grade glioma (glioblastoma and diffuse midline gliome)-like ABM show significantly worse clinical courses. These results call for in-depth molecular analysis of adult gliomas with astroblastic features for diagnostic and therapeutic purposes.

Keywords: Astroblastoma; BRAF mutation; MN1‐BEND2; Next‐generation sequencing.

Figure 1.

Summary of genetic alterations (A), age distribution (B), and overall survival (C) by subgroups. Abbreviations: CN, copy number; EGFR, epidermal growth factor receptor; GBM, glioblastoma; HGG, high‐grade glioma; HGNET, high grade neuroepithelial tumor; IHC, immunohistochemistry; MN1, meningioma 1; N/A, not available; PXA, pleomorphic xanthoastrocytoma; qPCR, quantitative real‐time polymerase chain reaction; RT‐PCR, reverse transcription polymerase chain reaction; SNV, single nucleotid variant.

Figure 2.

Representative histological (A) and magnetic resonance imaging (MRI) (B) features of subgroups. (A): H&E staining shows large astroblastic pseudorosettes in all cases (upper panel). Unlike HGG and HGNET‐MN1, PXA‐like astroblastoma (ABM) demonstrate an intense cytoplasmic and pericellular expression of CD34 (lower panel). (B): Representative MRI features of subgroups. Axial post‐contrast T1‐weighted magnetic resonance images demonstrate a solid component in all cases (upper panel). Unlike the other subgroups, HGG‐like ABM show moderate‐to‐extensive perifocal edema on FLAIR sequences (lower panel). Abbreviations: FLAIR, T2‐weighted fluid‐attenuated inversion recovery; H&E, hematoxylin and eosin; HGG, high‐grade glioma; HGNET, high grade neuroepithelial tumor; MN1, meningioma 1; PXA, pleomorphic xanthoastrocytoma; T1w, T1‐weighted.