Molecular, histologic, and clinical characterization of methylation class pleomorphic xanthoastrocytoma: An analysis of 469 tumors

Christopher H Dampier¹, Niharika Shah¹, Kristyn Galbraith², Azadeh Ebrahimi³, Osorio Lopes Abath Neto⁴, Zied Abdullaev¹, Sanda Alexandrescu⁵, Felipe Andreiuolo^{6

7

8}, Terri Armstrong⁹, Tiffany Baker¹⁰, Sahara Cathcart¹¹, Hye-Jung Chung¹, Patrick J Cimino¹², Kyle S Conway¹³, Jennifer Cotter¹⁴, Felipe D'Almeida Costa¹⁵, Karen Dazelle¹, Nima Etminam¹⁶, Sima Esther Ferman¹⁷, Igor Fernandes¹⁸, Christina K Ferrone¹, Ahmed Gilani¹⁹, Mark Gilbert⁹, Jason Gregory²⁰, Courtney Ketchum¹, Han Sung Lee²¹, Ina Lee¹, Maria Beatriz S Lopes²², Qinwen Mao²³, Michael S Marshall²⁴, Matthew McCord²⁵, Stewart G Neill²⁶, Jeffrey J Nirschl²⁷, Byram H Ozer⁹, Werner Paulus²⁸, Marta Penas-Prado⁹, Marco Prinz^{29

30}, Peter Pytel³¹, Martha Quezado¹, Mark Raffeld¹, Sharika Rajan¹, Miriam Ratliff¹⁶, Guido Reifenberger³², Lorraina Robinson²³, Jens Schittenhelm³, Daniel Schrimpf³³, Omkar Singh¹, Christian Thomas²⁸, Diana Thomas³⁴, Jaiyeola Thomas-Ogunniyi³⁵, Angus Toland¹⁹, Rust Turakulov¹, Rachael Vaubel³⁶, Nitin Wadhwani³⁷, Jing Wu⁹, Caterina Giannini^{36

38}, Matija Snuderl², Sebastian Brandner³⁹, Andreas von Deimling³³, Kenneth Aldape¹

Affiliations

¹ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
² Department of Pathology, NYU Langone Health, New York, New York 10016, USA.
³ Institute for Neuropathology, Department of Pathology and Neuropathology, University of Tuebingen, Tuebingen, Germany.
⁴ Department of Pathology, University of Iowa, Iowa City, Iowa, USA.
⁵ Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA.
⁶ Department of Pathology, Instituto Estadual do Cerebro Paulo Niemeyer, Rio de Janeiro, Brazil.
⁷ Department of Pathology, Rede D'Or, Estr. dos Tres Rios, Rio de Janeiro, Brazil.
⁸ D'Or Institute for Research and Education, Rua Diniz Cordeiro, Rio de Janeiro, Brazil.
⁹ Neuro-Oncology Branch, National Cancer Institute and National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
¹⁰ Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
¹¹ Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
¹² Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
¹³ Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan, USA.
¹⁴ Department of Pathology, Children's Hospital Los Angeles, Los Angeles, California, USA.
¹⁵ Department of Pathology, AC Camargo Cancer Center, R. Prof. Antonio Prudente, Sao Paulo, Brazil.
¹⁶ Department of Neurosurgery, University Medical Center Mannheim, Mannheim, Germany.
¹⁷ Department of Pediatric Oncology, Instituto Nacional de Cancer (INCA), Praca Cruz Vermelha, Rio de Janeiro, Brazil.
¹⁸ Laboratorio Bacchi, R. Maj. Leonidas Cardoso, Botucatu, Brazil.
¹⁹ Department of Pathology, Children's Hospital of Colorado, Aurora, Colorado, USA.
²⁰ Department of Pathology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
²¹ Department of Pathology, University of California Davis, Sacramento, California, USA.
²² Department of Pathology, University of Virginia Health System, Charlottesville, Virginia, USA.
²³ Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
²⁴ Department of Pathology, Rush University Medical Center, Chicago, Illinois, USA.
²⁵ Department of Pathology, Northwestern University, Chicago, Illinois, USA.
²⁶ Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁷ Department of Pathology, Stanford University, Stanford, California, USA.
²⁸ Institute for Neuropathology, University Hospital Muenster, Muenster, Germany.
²⁹ Institute of Neuropathology, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
³⁰ Signaling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.
³¹ Department of Pathology, University of Chicago, Goldblatt Pavilion, Chicago, Illinois, USA.
³² Institute for Neuropathology, Heinrich Heine University, Medical Faculty and University Hospital Duesseldorf, Duesseldorf, Germany.
³³ Department of Neuropathology, Institute of Pathology, University Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁴ Department of Pathology, Nationwide Children's Hospital, Columbus, Ohio, USA.
³⁵ Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas , USA.
³⁶ Department of Pathology, Mayo Clinic Laboratories, Rochester, Minnesota, USA.
³⁷ Department of Pathology, Lurie Children's Hospital, Chicago, Illinois, USA.
³⁸ Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy.
³⁹ Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.

PMID: 40735274
PMCID: PMC12305539
DOI: 10.1093/noajnl/vdaf089

Molecular, histologic, and clinical characterization of methylation class pleomorphic xanthoastrocytoma: An analysis of 469 tumors

Christopher H Dampier et al. Neurooncol Adv. 2025.

. 2025 Jul 19;7(1):vdaf089.

doi: 10.1093/noajnl/vdaf089. eCollection 2025 Jan-Dec.

Authors

Affiliations

¹ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
² Department of Pathology, NYU Langone Health, New York, New York 10016, USA.
³ Institute for Neuropathology, Department of Pathology and Neuropathology, University of Tuebingen, Tuebingen, Germany.
⁴ Department of Pathology, University of Iowa, Iowa City, Iowa, USA.
⁵ Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA.
⁶ Department of Pathology, Instituto Estadual do Cerebro Paulo Niemeyer, Rio de Janeiro, Brazil.
⁷ Department of Pathology, Rede D'Or, Estr. dos Tres Rios, Rio de Janeiro, Brazil.
⁸ D'Or Institute for Research and Education, Rua Diniz Cordeiro, Rio de Janeiro, Brazil.
⁹ Neuro-Oncology Branch, National Cancer Institute and National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
¹⁰ Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
¹¹ Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
¹² Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
¹³ Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan, USA.
¹⁴ Department of Pathology, Children's Hospital Los Angeles, Los Angeles, California, USA.
¹⁵ Department of Pathology, AC Camargo Cancer Center, R. Prof. Antonio Prudente, Sao Paulo, Brazil.
¹⁶ Department of Neurosurgery, University Medical Center Mannheim, Mannheim, Germany.
¹⁷ Department of Pediatric Oncology, Instituto Nacional de Cancer (INCA), Praca Cruz Vermelha, Rio de Janeiro, Brazil.
¹⁸ Laboratorio Bacchi, R. Maj. Leonidas Cardoso, Botucatu, Brazil.
¹⁹ Department of Pathology, Children's Hospital of Colorado, Aurora, Colorado, USA.
²⁰ Department of Pathology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
²¹ Department of Pathology, University of California Davis, Sacramento, California, USA.
²² Department of Pathology, University of Virginia Health System, Charlottesville, Virginia, USA.
²³ Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
²⁴ Department of Pathology, Rush University Medical Center, Chicago, Illinois, USA.
²⁵ Department of Pathology, Northwestern University, Chicago, Illinois, USA.
²⁶ Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁷ Department of Pathology, Stanford University, Stanford, California, USA.
²⁸ Institute for Neuropathology, University Hospital Muenster, Muenster, Germany.
²⁹ Institute of Neuropathology, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
³⁰ Signaling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.
³¹ Department of Pathology, University of Chicago, Goldblatt Pavilion, Chicago, Illinois, USA.
³² Institute for Neuropathology, Heinrich Heine University, Medical Faculty and University Hospital Duesseldorf, Duesseldorf, Germany.
³³ Department of Neuropathology, Institute of Pathology, University Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁴ Department of Pathology, Nationwide Children's Hospital, Columbus, Ohio, USA.
³⁵ Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas , USA.
³⁶ Department of Pathology, Mayo Clinic Laboratories, Rochester, Minnesota, USA.
³⁷ Department of Pathology, Lurie Children's Hospital, Chicago, Illinois, USA.
³⁸ Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy.
³⁹ Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.

PMID: 40735274
PMCID: PMC12305539
DOI: 10.1093/noajnl/vdaf089

Abstract

Background: Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM).

Methods: To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated.

Results: Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10- pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations.

Conclusion: Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.

Keywords: BRAF p.V600E; CDKN2A/B deletion; DNA methylation classification; epithelioid glioblastoma; pleomorphic xanthoastrocytoma.

Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology 2025.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1.**
Pre-methylation diagnosis and molecular features of the mcPXA cohort. (A) Distribution of common pre-methylation working diagnoses ordered by frequency, with GBM-like working diagnoses grouped together. PXA = pleomorphic xanthoastrocytoma; GBM = glioblastoma; HGG = high-grade glioma; NOS = not otherwise specified; GG = ganglioglioma; EPN = ependymoma; MNG = meningioma. (B) Summary of molecular features including copy number alterations and point mutations. Samples are ordered by patient age (when available) and grouped by GBM-like pre-methylation diagnosis. Pre-Me Dx = pre-DNA methylation diagnosis; CDKN2A/B DEL = *CDKN2A/B* homozygous deletion; MGMT METH = *MGMT* promoter methylation status; AMP = amplification; TERT MUT = *TERT* promoter mutation status.

**Figure 2.**
Histologic features of tumors in the mcPXA cohort. (A) Classical features including epithelioid and spindle-shaped cells intermixed with lymphocytes and frequent eosinophilic granular bodies. Scale bar = 100 micrometers. (B, C) GBM-like features including palisading necrosis (B) and microvascular proliferation (C). Scale bars = 100 micrometers. (D) Summary of histologic features with samples ordered by patient age (when available) and grouped by GBM-like pre-methylation diagnosis. MVP = microvascular proliferation, EGB = eosinophilic granular bodies.

**Figure 3.**
Histologic correlates of patient survival in the mcPXA cohort. (A) Kaplan-Meier (KM) plot demonstrating OS stratified by presence of palisading necrosis. (B) KM plot demonstrating OS stratified by presence of microvascular proliferation. (C) KM plot demonstrating PFS stratified by presence of palisading necrosis. (D) KM plot demonstrating OS stratified by methylation class with mcPXA substratified by GBM-like pre-methylation diagnosis. (E) KM plot demonstrating OS stratified by mitotic activity level. (F) KM plot demonstrating PFS stratified by mitotic activity level. A-IDH = IDH-mutant astrocytoma, low grade; GBM = glioblastoma classes including mesenchymal and RTK1/2, MC = methylation class.

**Figure 4.**
Molecular and histologic features of GBM with *BRAF* p.V600E mutation. (A) Summary of molecular features in *BRAF*-altered GBM cohort, including copy number alterations and point mutations. Samples are ordered by patient age. CDKN2A/B DEL = *CDKN2A/B* homozygous deletion; MGMT METH = *MGMT* promoter methylation status; AMP = amplification; TERT MUT = *TERT* promoter mutation status. (B) Summary of histologic features in *BRAF*-altered GBM cohort, with samples order by patient age. MVP = microvascular proliferation, EGB = eosinophilic granular bodies.

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Molecular, histologic, and clinical characterization of methylation class pleomorphic xanthoastrocytoma: An analysis of 469 tumors

Affiliations

Molecular, histologic, and clinical characterization of methylation class pleomorphic xanthoastrocytoma: An analysis of 469 tumors

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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