Diffuse Glial tumours and the new WHO 2016 Classification Prof. Dr. M. Lammens Department of Pathology Antwerp University Hospital University of Antwerp, Antwerp, Belgium Average Annual Age-Adjusted Incidence Ratesa of Primary Brain and CNS Tumors by Age and Behavior, CBTRUS Statistical Report: NPCR and SEER, 2008-2012. Quinn T. Ostrom et al. Neuro Oncol 2015;17:iv1-iv62 © The Centers for Disease Control. Published by Oxford University Press on behalf of the Society for Neuro-Oncology in cooperation with the Central Brain Tumor Registry 2015 Distributiona of Primary Brain and CNS Tumors by Behavior (N = 356,858), CBTRUS Statistical Report: NPCR and SEER, 2008-2012. Quinn T. Ostrom et al. Neuro Oncol 2015;17:iv1-iv62 © The Centers for Disease Control. Published by Oxford University Press on behalf of the Society for Neuro-Oncology in cooperation with the Central Brain Tumor Registry 2015 Distributiona of All Primary Brain and CNS Tumors by CBTRUS Histology Groupings and Histology (N = 356,858), CBTRUS Statistical Report: NPCR and SEER, 2008-2012. Quinn T. Ostrom et al. Neuro Oncol 2015;17:iv1-iv62 © The Centers for Disease Control. Published by Oxford University Press on behalf of the Society for Neuro-Oncology in cooperation with the Central Brain Tumor Registry 2015 Distributiona of Primary Brain and CNS Gliomasb by Histology Subtypes (N = 97,910), CBTRUS Statistical Report: NPCR and SEER, 2008-2012. Quinn T. Ostrom et al. Neuro Oncol 2015;17:iv1-iv62 © The Centers for Disease Control. Published by Oxford University Press on behalf of the Society for Neuro-Oncology in cooperation with the Central Brain Tumor Registry 2015 WHO-2007 classification WHO-2016 classification 4th edition revised 4 th edition WHO-2016 classification Revised 4 th edition Integration Molecular Biologic Markers Glial and Mixed Neuronal-Glial Tumors In the WHO 2007 • Diffuse astrocytic and oligodendroglial tumors • Other astrocytic astrocytoma – Diffuse astrocytoma – Pilocytic astrocytoma • Gemistocytic astrocytoma • Pilomyxoid astrocytoma – Subependymal giant cell astrocytoma • Fibrillary astrocytoma – Pleomorphic xanthoastrocytoma • Proteoplasmic astrocytoma – Anaplastic astrocytoma, IDH mutant • Ependymal tumors – Subependymoma – Glioblastoma – Myxopapillary ependymoma • Giant cell glioblastoma – Ependymoma • Fliosarcoma • Cellular ependymoma • Papillary ependymoma • Clear cell ependymoma – Gliomatosis cerebri • Tanycytotic ependymoma – Anaplastic ependymoma – Oligodendroglioma • Other gliomas – Anaplastic oligodendroglioma – Chordoid glioma of the third ventricle – Angiocentric glioma – Astroblastoma • Mixed neuronal-glial tumors – Oligoastrocytoma – Anaplastic oligoastrocytoma – Ganglioglioma – Anaplastic ganglioglioma – Desmoplastic infantile astrocytoma and ganglioglioma – Papillary glioneural tumor – Rosette-forming glioneuronal tumor Glial and Mixed Neuronal-Glial Tumors In the WHO 2007 and WHO 2016 Classification • Diffuse astrocytic and oligodendroglial tumors • Other astrocytic astrocytoma Diffuse astrocytoma, IDH mutant – Pilocytic astrocytoma Gemistocytic astrocytoma, IDH mutant • Pilomyxoid astrocytoma – Subependymal giant cell astrocytoma Fibrillary astrocytoma – Pleomorphic xanthoastrocytoma Proteoplasmic astrocytoma – Anaplastic pleomorphic xanthoastrocytoma Diffuse astrocytoma, IDH wild type Diffuse astrocytoma, NOS • Ependymal tumors Anaplastic astrocytoma, IDH mutant – Subependymoma Anaplastic astrocytoma , IDH- wild-type – Myxopapillary ependymoma Anaplastic astrocytoma, NOS – Ependymoma • Cellular ependymoma Glioblastoma, IDH wild-type • Papillary ependymoma • Clear cell ependymoma Giant cell glioblastoma • Tanycytotic ependymoma Gliosarcoma – Ependymoma, RELA fusion-positive Epitheloid glioblastoma – Anaplastic ependymoma Glioblastoma, IDH mutant Glioblastoma, NOS Gliomatosis cerebri • Other gliomas – Chordoid glioma of the third ventricle Diffuse midline glioma, H3-K27M mutant – Angiocentric glioma – Astroblastoma Oligodendroglioma, IDH mutant and 1p/19q codeleted Oligodendroglioma, NOS • Mixed neuronal-glial tumors Anaplastic oligodendroglioma, IDH mutant and &p/19q codeleted – Ganglioglioma – Anaplastic ganglioglioma Anaplastic oligodendroglioma, NOS – Desmoplastic infantile astrocytoma and ganglioglioma – Papillary glioneural tumor Oligoastrocytoma, NOS – Rosette-forming glioneuronal tumor Anaplastic oligoastrocytoma, NOS – Diffuse leptomeningeal glioneuronal tumor Glial and Mixed Neuronal-Glial Tumors In the WHO 2007 and WHO 2016 Classification • Diffuse astrocytic and oligodendroglial tumors • Other astrocytic astrocytoma Diffuse astrocytoma, IDH mutant • Pilocytic astrocytoma Gemistocytic astrocytoma, IDH mutant • Pilomyxoid astrocytoma Fibrillary astrocytoma • Subependymal giant cell astrocytoma Proteoplasmic astrocytoma • Pleomorphic xanthoastrocytoma Diffuse astrocytoma, IDH wild type • Anaplastic pleomorphic xanthoastrocytoma Diffuse astrocytoma, NOS • Ependymal tumors Anaplastic astrocytoma, IDH mutant Anaplastic astrocytoma , IDH- wild-type – Subependymoma Anaplastic astrocytoma, NOS – Myxopapillary ependymoma – Ependymoma • Cellular ependymoma Glioblastoma, IDH wild-type • Papillary ependymoma Giant cell glioblastoma • Clear cell ependymoma Gliosarcoma • Tanycytotic ependymoma Epitheloid glioblastoma – Ependymoma, RELA fusion-positive – Anaplastic ependymoma Glioblastoma, IDH mutant Glioblastoma, NOS Gliomatosis cerebri • Other gliomas – Chordoid glioma of the third ventricle Diffuse midline glioma, H3-K27M mutant – Angiocentric glioma – Astroblastoma Oligodendroglioma, IDH mutant and 1p/19q codeleted Oligodendroglioma, NOS • Mixed neuronal-glial tumors Anaplastic oligodendroglioma, IDH mutant and 1p/19q codeleted – Ganglioglioma Anaplastic oligodendroglioma, NOS – Anaplastic ganglioglioma – Desmoplastic infantile astrocytoma and ganglioglioma Oligoastrocytoma, NOS – Papillary glioneural tumor – Rosette-forming glioneuronal tumor Anaplastic oligoastrocytoma, NOS – Diffuse leptomeningeal glioneuronal tumor 11 Diffuse Glioma excluding Glioblastoma Oligodendroglioma • Male>female • Peak incidence 5-6th decade • Epilepsy most often presenting symptom • Frontal lobe site of preference • Survival 12-14 years (with best therapies) Acta Neuropathol (2015) 129:809–827 Oligodendroglioma Oligodendroglioma • Nuclear features: most important – generally round and uniform with crisp nuclear membranes delicate chromatin and small-to- inconspicuous nucleoli – Anaplastic: nuclei a more vesicular chromatin pattern and more prominent nucleoli, maintain an overall sense of regularity and nuclear roundness • Cytoplasm: clear perinuclear halo (=artefact) Acta Neuropathol (2015) 129:809–827 a: honeycomb growth b: mucin filled cysts c,d: microgemistocytes e: anaplastic (left) f: epitheloid cell g: red crunchy cell h: microvascular proliferation i: necrosis j: GFAP: reactive cells k: GFAP: positive tumor l: NF: diffuse growth m: synaptophysin n: IDH1 + o: p53 p: ATRX wt Acta Neuropathol (2015) 129:809–827 Oligodendroglioma • Secondary structures (diffuse growth pattern) – Perineuronal satellitosis – Subpial aggregates – Perivascular aggregates • Chicken wire vessels (often seen, not specific) • Calcifications (often seen, not specific) • Sometimes pleiomorphic, minigemistocytes, signet ring cells,… Acta Neuropathol (2015) 129:809–827 a: lobular growth b: cd56 c: synaptophysin d: IDH1 e: spindle cells f: neurocytic rosettes g/h ganglioglionic Acta Neuropathol (2015) 129:809–827 Oligodendroglioma Immunohistochemistry • NO SPECIFIC ANTIBODY • GFAP: negative, but may be positive (microgemistocytes, more diffuse) • Olig2: not helpful in distinguishing astro and oligo • Synaptophysine: may be positive in oligo • EMA: negative Acta Neuropathol (2015) 129:809–827 Genetic hallmark of oligodendrogliomas: Co-deletion of chromosome arms 1p & 19q -1p WHO 2007 A OA O AA AOA AO GBM GBM+O -19q Combined 1p/19q loss in glioma OligodendrogliomaOligoastrocytoma Astrocytoma 60% - 80%40% - 60% 5% - 15% oligodendrogliomas WHO III radiotherapy vs. radiotherapy+ adjuvant PCV randomized phase III trial; EORTC 26951; 368 patients progression free overallsurvival survival 1p/19q loss predictive! van den Bent et al. JCO 2006 Oligodendroglial tumors WHO grade Oligodendroglioma II Anaplastic oligodendroglioma III Oligoastrocytic tumors WHO grade Oligoastrocytoma II Anaplastic oligoastrocytoma III Most frequently used: LOH or FISH 1p36 n - T LOH LOH N N T -1p Loss of WHOLE arms of 1p and 19q: FISH not the best method Pediatric Oligodendrogliomas no 1p 19q codeletion WHO 2007 A OA O AA AOA AO GBM GBM+O Wesseling P, Van den Bent M, Perry A Acta Neuropathol 2015 isocitrate dehydrogenases IDH2 IDH1 mitochondrial cytosolic NADP + specific NADP + specific IDH3A / IDH3B / IDH3G mitochondrial NAD + specific IDH1 - R132H COO - COO - NADPH NADP + CH 2 CH 2 CH 2 CH 2 CO H C OH COO - COO - ααα-ketoglutarate 2-hydroxyglutarate (2-oxoglutarate) wt mut % mut Pilocytic astrocytoma WHO grade I (PA I) 41 40 1 2% Subependymal giant cell astrocytoma WHO grade I (SEGA I) 12 12 0 0% Pleomorphic xanthoastrocytoma WHO grade II (PXA II) 7 7 0 0% IDH1 Astrocytoma WHO grade II (A II) 46 13 34 74% 685 tumors Anaplastic astrocytoma WHO grade III (A III) 47 18 29 62% Primary Glioblastoma WHO grade IV (prGBM) 99 92 7 7% Secondary glioblastoma WHO grade IV (secGBM) 8 1 7 88% Giant cell glioblastoma WHO grade IV (gcGBM) 8 6 2 25% Pediatric Glioblastoma WHO grade IV (pedGBM) 14 13 1 7% Gliosarcoma WHO grade IV (GS) 5 5 0 - Oligodendroglioma WHO grade II (O II) 51 15 36 71% Anaplastic oligodendroglioma
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