IDH-mutant astrocytomas with primitive neuronal component have a distinct methylation profile and a higher risk of leptomeningeal spread

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.

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Journal
Acta Neuropathologica
Published
2025-02-03
DOI
https://doi.org/10.1007/s00401-025-02849-8
Citations
6
Primary Topic
Glioma Diagnosis and Treatment
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article
Field-Weighted Citation Impact
9.75

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article

IDH-mutant astrocytomas with primitive neuronal component have a distinct methylation profile and a higher risk of leptomeningeal spread

Sybren L. N. Maas, Eleonora Aronica, Sebastian Brandner, Sandro M. Krieg et al.
6 citations
Acta Neuropathologica
Glioma Diagnosis and Treatment
9.75
article

IDH-mutant astrocytomas with primitive neuronal component have a distinct methylation profile and a higher risk of leptomeningeal spread

Sybren L. N. Maas, Eleonora Aronica, Sebastian Brandner, Sandro M. Krieg, Roman Sankowski, Maximilian Deng, Abigail K. Suwala, Guido Reifenberger, Mathew Ryan Voisin, Marco Prinz, Wolfgang Wick, Pim J. French, Henning B. Boldt, Martin Hasselblatt, Angelika Mühlebner, Vera van Dis, Daniel Schrimpf, Christian Mawrin, Andrey Korshunov, David Capper, Robert M. Verdijk, Rouzbeh Banan, Stefan M. Pfister, Asan Cherkezov, Felix Hinz, Pieter Wesseling, Andreas von Deimling, Pietro Luigi Poliani, Jörg Felsberg, David Reuß, Michael Brodhun, Juergen Hench, Marike L. D. Broekman, Vaidas Dirsė, Felix Sahm, Patricia Kohlhof‐Meinecke, Stephan Frank, Koray Özduman, Eric A. Goold, Dennis Friedel, Matija Snuderl, Henri Bogumil, Franziska M. Ippen, Martin Sill, Kirsten Göbel, Markus J. Riemenschneider, Hildegard Dohmen, Rüdiger Gerlach, Sven R. Kantelhardt, Gillian Morrison
article en
6 citations

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.

Acta NeuropathologicaVol. 149(1)
University Health Network (CA), University College London Hospitals NHS Foundation Trust (GB), University of Freiburg (DE), Vilnius University (LT), University of Southern Denmark (DK), German Cancer Research Center (DE), University of Basel (CH), University of Toronto (CA), Justus-Liebig-Universität Gießen (DE), University of Utah (US), Heidelberg University (DE), Leiden University Medical Center (NL), Odense University Hospital (DK), Erasmus MC (NL), University Hospital Heidelberg (DE), University Hospital of Basel (CH), Princess Margaret Cancer Centre (CA), University Medical Center Utrecht (NL), University Hospital Regensburg (DE), Acıbadem University (TR), Humboldt-Universität zu Berlin (DE), NYU Langone Health (US), Katharinenhospital (DE), Düsseldorf University Hospital (DE), Heidelberger Institut für Radioonkologie (DE), University Hospital Münster (DE), MRC Centre for Regenerative Medicine (GB), Amsterdam Neuroscience (NL), National Center for Tumor Diseases (DE), Hopp Children's Cancer Center Heidelberg (DE), Center for Behavioral Brain Sciences (DE), Princess Máxima Center (NL), Helios Klinikum Erfurt (DE), Erasmus MC Cancer Institute (NL), National Hospital for Neurology and Neurosurgery (GB), Amsterdam University Medical Centers (NL), Klinikum im Friedrichshain (DE), Heinrich Heine University Düsseldorf (DE), University College London (GB), ARUP Laboratories (United States) (US), Freie Universität Berlin (DE), Charité - Universitätsmedizin Berlin (DE), University of Brescia (IT), University of Amsterdam (NL), Otto-von-Guericke-Universität Magdeburg (DE), University of Edinburgh (GB)
Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Albert-Ludwigs-Universität Freiburg, Fritz Thyssen Stiftung, Gottfried Wilhelm Leibniz Universität Hannover, Novo Nordisk, Universitätsklinikum Heidelberg, Roman, Marga und Mareille Sobek Stiftung, Leibniz-Gemeinschaft, Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg
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Openalex Percentile: Top 2%
Glioma Diagnosis and Treatment
9.75
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