VGLL-fusions define a new class of intraparenchymal CNS schwannoma

Simone Schmid; Kanish Mirchia; Anna Tietze; Ilon Liu; Christin Siewert; Jakob Nückles; Jens Schittenhelm; Felix Behling; Matija Snuderl; Christian Hartmann; Sebastian Brandner; Simon M L Paine; Andrey Korshunov; Martin Hasselblatt; Roland Coras; Sridhar Epari; Christine Stadelmann; Sabrina Zechel; Michèle Simon; Yelena Wilson; Francesca Gianno; G Lucas Calixto-Hope Jr; Viktor Zherebitskiy; Vassil B Kaimaktchiev; Lorraina Robinson; Kenneth Aldape; Eelco W Hoving; Bastiaan B J Tops; Ashwyn Augustine Perera; Pauline Göller; Pablo Hernáiz Driever; Pieter Wesseling; Arend Koch; Arie Perry; Felix Sahm; David T W Jones; David Capper

doi:10.1093/neuonc/noae269

VGLL-fusions define a new class of intraparenchymal CNS schwannoma

Neuro Oncol. 2024 Dec 23:noae269. doi: 10.1093/neuonc/noae269. Online ahead of print.

Authors

Simone Schmid^{1

2}, Kanish Mirchia^{3

4

5}, Anna Tietze⁶, Ilon Liu⁷, Christin Siewert¹, Jakob Nückles¹, 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}, G Lucas Calixto-Hope 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 Driever⁴⁰, Pieter Wesseling^{34

41}, Arend Koch¹, Arie Perry^{4

5}, Felix Sahm⁴², David T W Jones^{43

44

45}, David Capper^{1

2}

Affiliations

¹ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institut für Neuropathologie, Charitéplatz 1, 10117 Berlin, Germany.
² German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³ Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
⁴ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
⁶ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institut für Neuroradioloie, Charitéplatz 1, 10117 Berlin, Germany.
⁷ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institut für Neurology, Charitéplatz 1, 10117 Berlin, Germany.
⁸ Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tübingen, Germany.
⁹ Department of Neurosurgery and Neurotechnology, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany.
¹⁰ Center for Neuro-Oncology, Comprehensive Cancer Center, Tübingen-Stuttgart, University Hospital Tübingen, Eberhard-Karls University Tübingen, Germany.
¹¹ Hertie Institute for Clinical Brain Research, Tübingen, Germany.
¹² Department of Pathology, NYU Grossman School of Medicine, New York, USA.
¹³ Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, 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, UKHopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
¹⁶ Children's Brain Tumour Research Centre, University of Nottingham Biodiscovery Institute, Nottingham, UK.
¹⁷ Nottingham University Hospitals NHS Trust, Queen's Medical Centre, Derby Road, Nottingham NG7 2UH, UK.
¹⁸ Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumour Diseases (NCT), Im Neuenheimer Feld 280, Heidelberg, Germany.
¹⁹ Institute of Neuropathology, University Hospital Münster, Münster, Germany.
²⁰ Department of Neuropathology, Universitätsklinikum Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany.
²¹ Partner of the European Reference Network (ERN) EpiCARE, Barcelona, Spain.
²² Neurooncology Disease Management Group, Tata Memorial Centre, Dr Ernest Borges Marg & Homi Bhabha National Institute, Trombay, Mumbai, India.
²³ Institute of Neuropathology, University Medical Center Goettingen, 37075 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 Laboratory Medicine & Pathobiology - Neuropathology, Hospital for Sick Children (SickKids), Toronto, ON, Canada.
²⁷ Department of Radiological, Oncological and Anatomic Pathology, Sapienza University, Rome, Italy.
²⁸ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁹ Pathology & Laboratory Medicine, University of Saskatchewan, Saskatoon SK, Canada.
³⁰ Department of Pathology, The Dalles, OR, USA.
³¹ Providence Hood River Memorial Hospital, Hood River, Oregon.
³² University of Utah, Department of Pathology, Salt Lake City, UT, USA.
³³ Laboratory of Pathology, National Cancer Institute, Centre for Cancer Research, Bethesda, MD, USA.
³⁴ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
³⁵ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
³⁶ Heidelberg Medical Faculty, University of Heidelberg, Heidelberg, Germany.
³⁷ National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³⁸ Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), 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. German HIT-LOGGIC-Registry of low-grade glioma in children and adolescents.
⁴¹ Department of Pathology, Amsterdam University Medical Centers/VUmc, Amsterdam, The Netherlands.
⁴² Department of Neuropathology, University Hospital Heidelberg and CCU Neuropathology, German Consortium for Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany.
⁴³ Division of Pediatric Glioma Research, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
⁴⁴ National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Germany.
⁴⁵ German Cancer Research Center (DKFZ), Heidelberg, Germany.

PMID: 39713960
DOI: 10.1093/neuonc/noae269

Abstract

Background: Intracerebral schwannomas are rare tumors resembling their peripheral nerve sheath counterparts but localized in the CNS. They are not classified as a separate tumor type in the 2021 WHO 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. 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 GFAP staining. All (n=20) shared DNA-methylation profiles distinct from other CNS tumors, as well as from VGLL-altered peripheral nerve sheath tumors. Most cases (n=14/17) harbored fusions of either VGLL3 or VGLL1 (CHD7::VGLL3 (n=9/17) and EWSR1::VGLL1 (n=5/17)). In two cases the presence of a VGLL3 fusion was also confirmed by CNA 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 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 [email protected] 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 [email protected].