. 2025 May 15;27(4):1031-1045.

doi: 10.1093/neuonc/noae269.

VGLL fusions define a new class of intraparenchymal central nervous system schwannoma

Simone Schmid^{1

2}, Kanish Mirchia^{3

4

5}, Anna Tietze⁶, Ilon Liu⁷, Christin Siewert², Jakob Nückles², Jens Schittenhelm⁸, Felix Behling^{9

10

11}, Matija Snuderl^{12

13}, Christian Hartmann¹⁴, Sebastian Brandner¹⁵, Simon M L Paine^{16

17}, Andrey Korshunov¹⁸, Martin Hasselblatt¹⁹, Roland Coras^{20

21}, Sridhar Epari²², Christine Stadelmann²³, Sabrina Zechel²³, Michèle Simon²⁴, Yelena Wilson²⁵, Francesca Gianno^{26

27}, Calixto-Hope G Lucas Jr²⁸, Viktor Zherebitskiy²⁹, Vassil B Kaimaktchiev^{30

31}, Lorraina Robinson³², Kenneth Aldape³³, Eelco W Hoving³⁴, Bastiaan B J Tops³⁴, Ashwyn Augustine Perera^{35

36

37

38}, Pauline Göller³⁹, Pablo Hernáiz Driever^{40

41}, Pieter Wesseling^{42

34}, Arend Koch², Arie Perry^{3

4}, Felix Sahm⁴³, David T W Jones^{44

45

46}, David Capper¹

Affiliations

¹ German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institut für Neuropathologie, Berlin, Germany.
³ Department of Pathology, University of California San Francisco, San Francisco, California, USA.
⁴ Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
⁵ Department of Radiation Oncology, University of California San Francisco, San Francisco, California, USA.
⁶ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institut für Neuroradioloie, Berlin, Germany.
⁷ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institut für Neurology, Berlin, Germany.
⁸ Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tübingen, Germany.
⁹ Hertie Institute for Clinical Brain Research, Tübingen, Germany.
¹⁰ Department of Neurosurgery and Neurotechnology, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany.
¹¹ Center for Neuro-Oncology, Comprehensive Cancer Center, Tübingen-Stuttgart, University Hospital Tübingen, Eberhard-Karls University Tübingen, Germany.
¹² Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
¹³ Department of Pathology, NYU Grossman School of Medicine, New York, USA.
¹⁴ Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany.
¹⁵ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology and Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁶ Nottingham University Hospitals NHS Trust, Queen's Medical Centre, Nottingham, UK.
¹⁷ Children's Brain Tumour Research Centre, University of Nottingham Biodiscovery Institute, Nottingham, UK.
¹⁸ Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumour Diseases (NCT), Heidelberg, Germany.
¹⁹ Institute of Neuropathology, University Hospital Münster, Münster, Germany.
²⁰ Partner of the European Reference Network (ERN) EpiCARE, Barcelona, Spain.
²¹ Department of Neuropathology, Universitätsklinikum Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany.
²² Neurooncology Disease Management Group, Tata Memorial Centre, Dr Ernest Borges Marg and Homi Bhabha National Institute, Mumbai, India.
²³ Institute of Neuropathology, University Medical Center Goettingen, Goettingen, Germany.
²⁴ Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German HIT-LOGGIC-Registry for pLGG in children and adolescents, Department of Pediatric Oncology and Hematology, Berlin, Germany.
²⁵ Department of Pathology, Akron Children's, Ohio, USA.
²⁶ Department of Radiological, Oncological and Anatomic Pathology, Sapienza University, Rome, Italy.
²⁷ Department of Laboratory Medicine and Pathobiology-Neuropathology, Hospital for Sick Children (SickKids), Toronto, Ontario, Canada.
²⁸ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁹ Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
³⁰ Providence Hood River Memorial Hospital, Hood River, Oregon, USA.
³¹ Department of Pathology, The Dalles, Oregon, USA.
³² Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
³³ Laboratory of Pathology, National Cancer Institute, Centre for Cancer Research, Bethesda, Maryland, USA.
³⁴ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
³⁵ Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁶ National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³⁷ Heidelberg Medical Faculty, University of Heidelberg, Heidelberg, Germany.
³⁸ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
³⁹ Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
⁴⁰ Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Berlin, Germany.
⁴¹ German HIT-LOGGIC-Registry of low-grade glioma in children and adolescents.
⁴² Department of Pathology, Amsterdam University Medical Centers/VUmc, Amsterdam, The Netherlands.
⁴³ Department of Neuropathology, University Hospital Heidelberg and CCU Neuropathology, German Consortium for Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany.
⁴⁴ German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁵ Division of Pediatric Glioma Research, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
⁴⁶ National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Germany.

PMID: 39713960
PMCID: PMC12083230 (available on 2025-12-23)
DOI: 10.1093/neuonc/noae269

VGLL fusions define a new class of intraparenchymal central nervous system schwannoma

Simone Schmid et al. Neuro Oncol. 2025.

. 2025 May 15;27(4):1031-1045.

doi: 10.1093/neuonc/noae269.

Authors

Affiliations

¹ German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institut für Neuropathologie, Berlin, Germany.
³ Department of Pathology, University of California San Francisco, San Francisco, California, USA.
⁴ Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
⁵ Department of Radiation Oncology, University of California San Francisco, San Francisco, California, USA.
⁶ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institut für Neuroradioloie, Berlin, Germany.
⁷ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institut für Neurology, Berlin, Germany.
⁸ Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tübingen, Germany.
⁹ Hertie Institute for Clinical Brain Research, Tübingen, Germany.
¹⁰ Department of Neurosurgery and Neurotechnology, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany.
¹¹ Center for Neuro-Oncology, Comprehensive Cancer Center, Tübingen-Stuttgart, University Hospital Tübingen, Eberhard-Karls University Tübingen, Germany.
¹² Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York, USA.
¹³ Department of Pathology, NYU Grossman School of Medicine, New York, USA.
¹⁴ Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany.
¹⁵ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology and Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁶ Nottingham University Hospitals NHS Trust, Queen's Medical Centre, Nottingham, UK.
¹⁷ Children's Brain Tumour Research Centre, University of Nottingham Biodiscovery Institute, Nottingham, UK.
¹⁸ Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumour Diseases (NCT), Heidelberg, Germany.
¹⁹ Institute of Neuropathology, University Hospital Münster, Münster, Germany.
²⁰ Partner of the European Reference Network (ERN) EpiCARE, Barcelona, Spain.
²¹ Department of Neuropathology, Universitätsklinikum Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany.
²² Neurooncology Disease Management Group, Tata Memorial Centre, Dr Ernest Borges Marg and Homi Bhabha National Institute, Mumbai, India.
²³ Institute of Neuropathology, University Medical Center Goettingen, Goettingen, Germany.
²⁴ Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German HIT-LOGGIC-Registry for pLGG in children and adolescents, Department of Pediatric Oncology and Hematology, Berlin, Germany.
²⁵ Department of Pathology, Akron Children's, Ohio, USA.
²⁶ Department of Radiological, Oncological and Anatomic Pathology, Sapienza University, Rome, Italy.
²⁷ Department of Laboratory Medicine and Pathobiology-Neuropathology, Hospital for Sick Children (SickKids), Toronto, Ontario, Canada.
²⁸ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁹ Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
³⁰ Providence Hood River Memorial Hospital, Hood River, Oregon, USA.
³¹ Department of Pathology, The Dalles, Oregon, USA.
³² Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
³³ Laboratory of Pathology, National Cancer Institute, Centre for Cancer Research, Bethesda, Maryland, USA.
³⁴ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
³⁵ Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁶ National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³⁷ Heidelberg Medical Faculty, University of Heidelberg, Heidelberg, Germany.
³⁸ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
³⁹ Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
⁴⁰ Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Berlin, Germany.
⁴¹ German HIT-LOGGIC-Registry of low-grade glioma in children and adolescents.
⁴² Department of Pathology, Amsterdam University Medical Centers/VUmc, Amsterdam, The Netherlands.
⁴³ Department of Neuropathology, University Hospital Heidelberg and CCU Neuropathology, German Consortium for Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany.
⁴⁴ German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁵ Division of Pediatric Glioma Research, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
⁴⁶ National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Germany.

PMID: 39713960
PMCID: PMC12083230 (available on 2025-12-23)
DOI: 10.1093/neuonc/noae269

Abstract

Background: Intracerebral schwannomas are rare tumors resembling their peripheral nerve sheath counterparts but localized in the central nervous system (CNS). They are not classified as a separate tumor type in the 2021 World Health Organization classification. This study aimed to compile and characterize these rare neoplasms morphologically and molecularly.

Methods: We analyzed 20 tumor samples by histology, RNA next-generation sequencing, DNA-methylation profiling, copy number analyses, and single-nucleus RNA sequencing (snRNA-seq). Clinical data, including age, sex, and disease progression, were collected. Magnetic resonance imaging (MRI) series were included when available.

Results: All cases with tissue available for histology review (n = 13) were morphologically consistent with intracerebral schwannoma, but differed in their extent of glial fibrillary acidic protein staining. All (n = 20) shared DNA-methylation profiles distinct from other CNS tumors, as well as from Vestigial-like family (VGLL)-altered peripheral nerve sheath tumors. Most cases (n = 14/17) harbored fusions of either Vestigial-like family member 3 (VGLL3) or Vestigial-like Family member 1 (VGLL1) (CHD7::VGLL3 [n = 9/17] and EWSR1::VGLL1 [n = 5/17]). In 2 cases, the presence of a VGLL3 fusion was also confirmed by copy number analyses (n = 2/17). MRI (n = 4) showed well-defined, nodular tumors with strong, homogeneous enhancement and no diffusion restriction. Tumors were located throughout the neuroaxis (supratentorial [n = 15], infratentorial [n = 4], and spinal [n = 1]). snRNA-seq of a VGLL1-fused tumor indicated VGLL1 upregulation in 28.6% of tumor cells (n = 1). During a median follow-up of 1.8 years (range 3 months-9 years), none of the tumors recurred (n = 10).

Conclusions: We identify and define a new benign tumor class, designated VGLL-altered intraparenchymal CNS schwannomas. These tumors feature VGLL alterations and a specific DNA-methylation profile, with schwannoma-like histopathology and CNS localization, akin to previously classified intracerebral schwannomas.

Keywords: VGLL; gliofibroma; glioma; schwannoma; tumor.

© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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Conflict of interest statement

F.S., D.C., D.T.W.J., and M.S. are co-founders and shareholders of Heidelberg Epignostix GmbH. D.C.’s work was supported by the Everest Centre for Research into Paediatric Low-Grade Brain Tumours (GN-000707, The Brain Tumour Charity, UK) and the PLGA Fund at the Paediatric Brain Tumour Foundation. He serves as Vice President of the International Society of Neuropathology (ISN) and as MDEB Speaker of the German Cancer Consortium. He holds a pending patent for DNA-methylation–based tumor classification. The position of S.S. is partially funded by GN-000707. C.H. provided study materials and holds a royalty/license for the IDH1 R132H-specific antibody via Dianova GmbH through DKFZ. I.L. participates in the BIH Charité Digital Clinician Scientist Program. P.H.D. received funding for a registry from Deutsche Kinderkrebsstiftung (DKS 2019.06, 2021.03, 2023.08) and consulting fees from Alexion, AstraZeneca, and Bayer. He also serves on the Advisory Board of AstraZeneca. F.B. received travel reimbursement for attending the Annual Meeting of the German Society of Senology 2024 (Dresden) and the Neuro-oncology Masterclass 2024. He has various roles in the YoungNOA (junior group of the Neuro-oncology Working Group of the German Cancer Society). He also received a Scholarship for Interdisciplinary Oncology (SIO) sponsored by MEDAC. F.S.’s work is supported by a grant from DFG, UNIT1389. He has licenses and receives royalties for methylation classification. Additionally, he has received honoraria from Illumina and has patents planned, issued, or pending for methylation classification and tumor classification. He serves in various roles within SC EORTC-BTG, WB and QM Committee of DGNN, SC ITCC Brain, and SC EANO. K.A. has patents planned, issued, or pending on DNA-methylation–based cancer diagnostics. M.S.’s work was supported by a research grant from Loxo/Lilly Oncology (NYU Langone Health). He received consultation fees from Veracyte and Servier Pharmaceuticals and holds stock or stock options in Arima Genomics, InnoSIGN, HaloDx, and Heidelberg Epignostix. D.T.W.J. has patents planned or pending for a DNA-methylation-based method for classifying tumor species and a pending patent for a method for cancer classification. He is Co-chair of ITCC Brain and holds stock or stock options in Heidelberg Epignostix GmbH. He is also Co-founder and CSO of Heidelberg Epignostix GmbH. E.W.H., A.P., A.T., F.G., J.S., S.Z., B.T., V.K., A.K., M.H., J.N., C.S., C.S., R.C., M.S., P.C.G., K.M., L.R., C.-H.G.L., P.W., V.Z., Y.W., S.B., A.K., S.P., A.P., and E.S. declare no conflicts of interest.

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VGLL fusions define a new class of intraparenchymal central nervous system schwannoma

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VGLL fusions define a new class of intraparenchymal central nervous system schwannoma

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