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| Home > Publications database > IDH-mutant astrocytomas with primitive neuronal component have a distinct methylation profile and a higher risk of leptomeningeal spread. |
| Journal Article | DKFZ-2025-00283 |
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2025
Springer
Heidelberg
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Please use a persistent id in citations: doi:10.1007/s00401-025-02849-8
Abstract: IDH-mutant astrocytomas are diffuse gliomas that are defined by characteristic mutations in IDH1 or IDH2 and do not have complete 1p/19q co-deletion. The established grading criteria include histological features of brisk mitotic activity (grade 3) and necrosis and/or microvascular proliferation (grade 4). In addition, homozygous deletion of the CDKN2A/B locus has recently been implemented as a molecular marker for grade 4 IDH-mutant astrocytomas. Here, we describe a subgroup of high-grade IDH-mutant astrocytomas characterised by a primitive neuronal component based on histology and a distinct DNA methylation profile (n = 51, ASTRO PNC). Misinterpretation as carcinoma metastasis was common, since GFAP expression was absent in the primitive neuronal component, whereas TTF-1 expression was detected in 15/19 cases (79%) based on immunohistochemistry. Apart from mutations in IDH1, TP53, and ATRX, we observed enrichment for alterations in RB1 (n = 19/51, 37%) and MYCN (n = 14/51, 27%). Homozygous CDKN2A/B deletion (n = 1/51, 2%) and CDK4 amplification (n = 3/51, 6%) were relatively rare events. Clinical (n = 31 patients) and survival data (n = 23 patients) indicate a clinical behaviour similar to other CNS WHO grade 4 IDH-mutant astrocytomas, however with an increased risk for leptomeningeal (n = 7) and extra-axial (n = 2) spread. Taken together, ASTRO PNC is defined by a distinct molecular and histological appearance that can mimic metastatic disease and typically follows an aggressive clinical course.
Keyword(s): Humans (MeSH) ; Astrocytoma: genetics (MeSH) ; Astrocytoma: pathology (MeSH) ; Isocitrate Dehydrogenase: genetics (MeSH) ; Brain Neoplasms: genetics (MeSH) ; Brain Neoplasms: pathology (MeSH) ; Male (MeSH) ; Mutation (MeSH) ; Female (MeSH) ; Middle Aged (MeSH) ; DNA Methylation (MeSH) ; Adult (MeSH) ; Aged (MeSH) ; Meningeal Neoplasms: genetics (MeSH) ; Meningeal Neoplasms: pathology (MeSH) ; Young Adult (MeSH) ; MYCN ; RB1 ; Astrocytoma ; DNA methylation ; IDH-mutant ; Primitive neuronal component ; Isocitrate Dehydrogenase ; IDH1 protein, human ; IDH2 protein, human
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