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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 <jats:italic>CDKN2A\/B<\/jats:italic> locus has recently been implemented as a molecular marker for grade 4 IDH-mutant astrocytomas. Here, we describe a subgroup of high-grade <jats:italic>IDH<\/jats:italic>-mutant astrocytomas characterised by a primitive neuronal component based on histology and a distinct DNA methylation profile (n\u2009=\u200951, 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 <jats:italic>IDH1<\/jats:italic>, <jats:italic>TP53<\/jats:italic>, and <jats:italic>ATRX<\/jats:italic>, we observed enrichment for alterations in <jats:italic>RB1<\/jats:italic> (n\u2009=\u200919\/51, 37%) and <jats:italic>MYCN<\/jats:italic> (n\u2009=\u200914\/51, 27%). Homozygous <jats:italic>CDKN2A\/B<\/jats:italic> deletion (n\u2009=\u20091\/51, 2%) and <jats:italic>CDK4<\/jats:italic> amplification (n\u2009=\u20093\/51, 6%) were relatively rare events. Clinical (n\u2009=\u200931 patients) and survival data (n\u2009=\u200923 patients) indicate a clinical behaviour similar to other CNS WHO grade 4 IDH-mutant astrocytomas, however with an increased risk for leptomeningeal (n\u2009=\u20097) and extra-axial (n\u2009=\u20092) 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.<\/jats:p>","DOI":"10.1007\/s00401-025-02849-8","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T10:00:51Z","timestamp":1738576851000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["IDH-mutant astrocytomas with primitive neuronal component have a distinct methylation profile and a higher risk of leptomeningeal spread"],"prefix":"10.1007","volume":"149","author":[{"given":"Felix","family":"Hinz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Friedel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey","family":"Korshunov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska M.","family":"Ippen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henri","family":"Bogumil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rouzbeh","family":"Banan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Brandner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Hasselblatt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning B.","family":"Boldt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaidas","family":"Dirse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hildegard","family":"Dohmen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Aronica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Brodhun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marike L. 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DC, SMP, DS, AvD and FS are shareholders of Heidelberg Epignostix.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Collection and analysis of corresponding tissue samples and clinical data was performed in accordance with local ethics regulations (local ethics vote S-318\/2022) and in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"12"}}