Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course.
Journal article

Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course.

  • Wefers AK Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. annika.wefers@med.uni-heidelberg.de.
  • Stichel D Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Schrimpf D Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Coras R Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany.
  • Pages M Department of Neuropathology, Sainte-Anne Hospital, Descartes University, Paris, France.
  • Tauziède-Espariat A Department of Neuropathology, Sainte-Anne Hospital, Descartes University, Paris, France.
  • Varlet P Department of Neuropathology, Sainte-Anne Hospital, Descartes University, Paris, France.
  • Schwarz D Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany.
  • Söylemezoglu F Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
  • Pohl U Department of Cellular Pathology, Queen's Hospital BHRUT, Romford, UK.
  • Pimentel J Department of Neurosciences and Mental Health, Laboratory of Neuropathology, Hospital de Santa Maria (CHULN, EPE), Lisbon, Portugal.
  • Meyer J Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Hewer E Institute of Pathology, University of Bern, Bern, Switzerland.
  • Japp A Department of Neuropathology, University of Bonn, Bonn, Germany.
  • Joshi A Department of Neuropathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
  • Reuss DE Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Reinhardt A Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Sievers P Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Casalini MB Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Ebrahimi A Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Huang K Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Koelsche C Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Low HL Department of Neurosurgery, Queen's Hospital BHRUT, Romford, UK.
  • Rebelo O Neuropathology Unit, Centro Hospitalar de Universidades de Coimbra, Coimbra, Portugal.
  • Marnoto D Neuropathology Unit, Centro Hospitalar de Universidades de Coimbra, Coimbra, Portugal.
  • Becker AJ Department of Neuropathology, University of Bonn, Bonn, Germany.
  • Staszewski O Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
  • Mittelbronn M Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt, Germany.
  • Hasselblatt M Institute of Neuropathology, University Hospital Münster, Münster, Germany.
  • Schittenhelm J Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany.
  • Cheesman E Department of Paediatric Histopathology, Royal Manchester Children's Hospital Manchester, Manchester, UK.
  • de Oliveira RS Division of Pediatric Neurosurgery, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
  • Queiroz RGP Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
  • Valera ET Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
  • Hans VH Abteilung Neuropathologie, Institut für klinische Pathologie, Dietrich-Bonhoeffer-Klinikum, Neubrandenburg, Germany.
  • Korshunov A Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Olar A Departments of Pathology and Laboratory Medicine and Neurosurgery, Medical University of South Carolina, Charleston, SC, USA.
  • Ligon KL Department of Oncologic Pathology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Pfister SM Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Jaunmuktane Z Division of Neuropathology, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK.
  • Brandner S Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, London, UK.
  • Tatevossian RG Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Ellison DW Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Jacques TS Developmental Biology and Cancer Section, UCL Great Ormond Street Institute of Child Health, London, UK.
  • Honavar M Department of Pathology, Hospital Pedro Hispano, Matosinhos, Portugal.
  • Aronica E Amsterdam UMC, Department of (Neuro)Pathology, University of Amsterdam, Amsterdam and Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands.
  • Thom M Division of Neuropathology, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK.
  • Sahm F Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • von Deimling A Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Jones DTW Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Blumcke I Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany.
  • Capper D Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. david.capper@charite.de.
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  • 2019-09-30
Published in:
  • Acta neuropathologica. - 2020
English The "isomorphic subtype of diffuse astrocytoma" was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proliferation was low. All 24 cases sequenced were IDH-wildtype. In cluster analyses of DNA methylation data, isomorphic diffuse gliomas formed a group clearly distinct from other glial/glio-neuronal brain tumours and normal hemispheric tissue, most closely related to paediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%). Gene fusions of MYBL1 or MYB with various gene partners were identified in 11/22 (50%) and were associated with an increased RNA-expression of the respective MYB-family gene. Integrating copy number alterations and available RNA sequencing data, 20/26 (77%) of isomorphic diffuse gliomas demonstrated MYBL1 (54%) or MYB (23%) alterations. Clinically, 89% of patients were seizure-free after surgery and all had a good outcome. In summary, we here define a distinct benign tumour class belonging to the family of MYB/MYBL1-altered gliomas. Isomorphic diffuse glioma occurs both in children and adults, has a concise morphology, frequent MYBL1 and MYB alterations and a specific DNA methylation profile. As an exclusively histological diagnosis may be very challenging and as paediatric MYB/MYBL1-altered diffuse astrocytomas may have the same gene fusions, we consider DNA methylation profiling very helpful for their identification.
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