GLIOMAS WHO2016 CLASSIFICATION. Pieter Wesseling, M.D., Ph.D., neuropathologist. Depts. of Pathology. VU University Medical Center, Amsterdam
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1 GLIOMAS WHO2016 CLASSIFICATION Pieter Wesseling, M.D., Ph.D., neuropathologist Depts. of Pathology VU University Medical Center, Amsterdam Princess Máxima Center for Pediatric Oncology, Utrecht University Medical Center Utrecht The Netherlands
2 The WHO 2016 Classification of Gliomas Conception The newborn baby Growth potential
3 Traditional view on diagnostic process patient surgery morphological diagnosis Gold standard for (brain) tumor classification Basis for further therapy
4 Decision tree for histologic diagnosis of glial tumors tissue specimen GLIAL TUMOR normal tissue non-neoplastic lesion metastatic neoplasm primary, but non-glial tumor Perry A, Wesseling P, Histologic Classification of Gliomas (Handbook of Clinical Neurology 2016; Berger M, Weller M, eds)
5 Decision tree for histologic diagnosis of glial tumors tissue specimen GLIAL TUMOR normal tissue non-neoplastic lesion metastatic neoplasm primary, but non-glial tumor diffuse glioma other astrocytic tumor ependymal tumor other glioma mixed neuronal-glial tumor astrocytic mixed oligodendroglial Perry A, Wesseling P, Histologic Classification of Gliomas (Handbook of Clinical Neurology 2016; Berger M, Weller M, eds)
6 Decision tree for histologic diagnosis of glial tumors tissue specimen GLIAL TUMOR normal tissue non-neoplastic lesion metastatic neoplasm primary, but non-glial tumor diffuse glioma other astrocytic tumor ependymal tumor other glioma mixed neuronal-glial tumor WHO grade astrocytic mixed oligodendroglial I II III low grade diffuse astrocytoma anaplastic astrocytoma low grade oligoastrocytoma anaplastic oligoastrocytoma low grade oligodendroglioma anaplastic oligodendroglioma pilocytic astrocytoma subependymal giant cell astrocytoma pleiomorphic xanthoastrocytoma anaplastic pleiomorphic xanthoastrocytoma subependymoma myxopapillary ependymoma low grade ependymoma anaplastic ependymoma angiocentric glioma chordoid glioma of the 3rd ventricle astroblastoma ganglioglioma rosette-forming glioneuronal tumor of the fourth ventricle papillary glioneuronal tumor desmoplastic infantile astrocytoma/ganglioglioma diffuse leptomeningeal glioneuronal tumor anaplastic ganglioglioma IV glioblastoma Perry A, Wesseling P, Histologic Classification of Gliomas (Handbook of Clinical Neurology 2016; Berger M, Weller M, eds)
7 Decision tree for histologic diagnosis of glial tumors tissue specimen GLIAL TUMOR normal tissue non-neoplastic lesion metastatic neoplasm primary, but non-glial tumor diffuse glioma WHO grade astrocytic mixed oligodendroglial II low grade diffuse astrocytoma low grade oligoastrocytoma low grade oligodendroglioma III anaplastic astrocytoma anaplastic oligoastrocytoma anaplastic oligodendroglioma IV glioblastoma Ostrom QT et al, Neuro-oncology 2014;16 Suppl 4, iv1-63 (CBTRUS, N = 343,175)
8 1 st edition K.J. Zülch
9 WHO Classification of CNS Tumors 2 nd edition P. Kleihues, P.C. Burger, B.W. Scheithauer
10 WHO Classification of CNS Tumors 3 rd edition P. Kleihues, W.K. Cavenee
11 WHO Classification of CNS Tumors 4 th edition D.N. Louis, H. Ohgaki, O.D. Wiestler, W.K. Cavenee
12 Histopathologic spectrum of diffuse gliomas astrocytic mixed oligodendroglial WHO grade II A OA O WHO grade III AA AOA AO WHO grade IV GBM GBM-O Wesseling P, Van den Bent M, Perry A Acta Neuropathol 2015
13 Conclusions 1 pathologist: a diagnosis 2 pathologists: a debate 3 pathologists: chaos
14 Limitations of histopathological diagnosis of gliomas patient surgery morphological diagnosis suboptimal tissue quantity and/or quality imprecise criteria for typing and grading morphology doesn t fully represent biology
15 Genetic hallmark of oligodendrogliomas: Co-deletion of chromosome arms 1p & 19q -1p A OA O AA AOA AO GBM GBM+O 1994: Reifenberger J, Reifenberger G -19q et al
16 Science, Sept Feb. 2009
17 IDH1 IDH2 IDH1/IDH2 (IDH = Isocitrate Dehydroxygenase)
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19 Simplified scheme of key (epi)genetic findings in six GBM subgroups Sturm D et al, Cancer Cell 2012
20 June 2015
21 June 2015
22 The future of (neuro)pathology Smart synthesis of morphological and molecular information! TCGA Research Network et al. Nature Genetics 2013;45:1113
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25 Major question How can non-histological, esp. molecular criteria be used to enhance typing and grading of human brain tumors? International collaboration of 117 contributors from 20 countries June 2015 Most controversial issues discussed by 35 colleagues from 10 countries
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27 The WHO 2016 Classification of Gliomas Conception The newborn baby Growth potential
28 DOB May 9 th 2016
29 DOB May 9 th 2016
30 WHO Classification of CNS Tumors Revised/updated 4 th edition! D.N. Louis, H. Ohgaki, O.D. Wiestler, W.K. Cavenee, D.W. Ellison, D. Figarella-Branger, A. Perry, G. Reifenberger, A. von Deimling
31 The WHO 2016 Classification of CNS Tumors
32 Glial and Mixed Neuronal-Glial Tumors in the WHO 2007 Classification Diffuse astrocytic and oligodendroglial tumors Diffuse astrocytoma, IDH mutant Gemistocytic astrocytoma, IDH mutant Fibrillary astrocytoma Protoplasmic astrocytoma Diffuse astrocytoma, IDH wild-type Diffuse astrocytoma, NOS Anaplastic astrocytoma, IDH mutant Anaplastic astrocytoma, IDH wild-type Anaplastic astrocytoma, NOS Glioblastoma, IDH wild-type Giant cell glioblastoma Gliosarcoma Epitheloid glioblastoma Glioblastoma, IDH mutant Glioblastoma, NOS Gliomatosis cerebri Diffuse midline glioma, H3-K27M mutant Oligodendroglioma, IDH mutant and 1p/19q codeleted Oligodendroglioma, NOS Anaplastic oligodendroglioma, IDH mutant and 1p/19q codeleted Anaplastic oligodendroglioma, NOS Oligoastrocytoma, NOS Anaplastic oligoastrocytoma, NOS Other astrocytic tumors Pilocytic astrocytoma Pilomyxoid astrocytoma Subependymal giant cell astrocytoma Pleomorphic xanthoastrocytoma Anaplastic pleomorphic xanthoastrocytoma Ependymal tumors Subependymoma Myxopapillary ependymoma Ependymoma Cellular ependymoma Papillary ependymoma Clear cell ependymoma Tanycytic ependymoma Ependymoma, RELA fusion-positive Anaplastic ependymoma Other gliomas Chordoid glioma of the third ventricle Angiocentric glioma Astroblastoma Mixed neuronal-glial tumors Ganglioglioma Anaplastic ganglioglioma Desmoplastic infantile astrocytoma and ganglioglioma Papillary glioneuronal tumor Rosette-forming glioneuronal tumor Diffuse leptomeningeal glioneuronal tumor
33 Glial and Mixed Neuronal-Glial Tumors in the WHO 2007 (in black and blue) and WHO 2016 Classification Diffuse astrocytic and oligodendroglial tumors Diffuse astrocytoma, IDH mutant Gemistocytic astrocytoma, IDH mutant Fibrillary astrocytoma Protoplasmic astrocytoma Diffuse astrocytoma, IDH wild-type Diffuse astrocytoma, NOS Anaplastic astrocytoma, IDH mutant Anaplastic astrocytoma, IDH wild-type Anaplastic astrocytoma, NOS Glioblastoma, IDH wild-type Giant cell glioblastoma Gliosarcoma Epitheloid glioblastoma Glioblastoma, IDH mutant Glioblastoma, NOS Gliomatosis cerebri Diffuse midline glioma, H3-K27M mutant Oligodendroglioma, IDH mutant and 1p/19q codeleted Oligodendroglioma, NOS Anaplastic oligodendroglioma, IDH mutant and 1p/19q codeleted Anaplastic oligodendroglioma, NOS Oligoastrocytoma, NOS Anaplastic oligoastrocytoma, NOS Other astrocytic tumors Pilocytic astrocytoma Pilomyxoid astrocytoma Subependymal giant cell astrocytoma Pleomorphic xanthoastrocytoma Anaplastic pleomorphic xanthoastrocytoma Ependymal tumors Subependymoma Myxopapillary ependymoma Ependymoma Cellular ependymoma Papillary ependymoma Clear cell ependymoma Tanycytic ependymoma Ependymoma, RELA fusion-positive Anaplastic ependymoma Other gliomas Chordoid glioma of the third ventricle Angiocentric glioma Astroblastoma Mixed neuronal-glial tumors Ganglioglioma Anaplastic ganglioglioma Desmoplastic infantile astrocytoma and ganglioglioma Papillary glioneuronal tumor Rosette-forming glioneuronal tumor Diffuse leptomeningeal glioneuronal tumor
34 Glial and Mixed Neuronal-Glial Tumors in the WHO 2007 (in black and blue) and WHO 2016 (in black and red) Classification Diffuse astrocytic and oligodendroglial tumors Diffuse astrocytoma, IDH mutant Gemistocytic astrocytoma, IDH mutant Fibrillary astrocytoma Protoplasmic astrocytoma Diffuse astrocytoma, IDH wild-type Diffuse astrocytoma, NOS Anaplastic astrocytoma, IDH mutant Anaplastic astrocytoma, IDH wild-type Anaplastic astrocytoma, NOS Glioblastoma, IDH wild-type Giant cell glioblastoma Gliosarcoma Epitheloid glioblastoma Glioblastoma, IDH mutant Glioblastoma, NOS Gliomatosis cerebri Diffuse midline glioma, H3-K27M mutant Oligodendroglioma, IDH mutant and 1p/19q codeleted Oligodendroglioma, NOS Anaplastic oligodendroglioma, IDH mutant and 1p/19q codeleted Anaplastic oligodendroglioma, NOS Oligoastrocytoma, NOS Anaplastic oligoastrocytoma, NOS Other astrocytic tumors Pilocytic astrocytoma Pilomyxoid astrocytoma Subependymal giant cell astrocytoma Pleomorphic xanthoastrocytoma Anaplastic pleomorphic xanthoastrocytoma Ependymal tumors Subependymoma Myxopapillary ependymoma Ependymoma Cellular ependymoma Papillary ependymoma Clear cell ependymoma Tanycytic ependymoma Ependymoma, RELA fusion-positive Anaplastic ependymoma Other gliomas Chordoid glioma of the third ventricle Angiocentric glioma Astroblastoma Mixed neuronal-glial tumors Ganglioglioma Anaplastic ganglioglioma Desmoplastic infantile astrocytoma and ganglioglioma Papillary glioneuronal tumor Rosette-forming glioneuronal tumor Diffuse leptomeningeal glioneuronal tumor
35 The WHO 2016 Classification of Gliomas Molecular parameters incorporated into classification of entities! Diffuse astrocytic and oligodendroglial tumors Diffuse astrocytoma, IDH mutant Gemistocytic astrocytoma, IDH mutant Fibrillary astrocytoma Protoplasmic astrocytoma Diffuse astrocytoma, IDH wild-type Diffuse astrocytoma, NOS Anaplastic astrocytoma, IDH mutant Anaplastic astrocytoma, IDH wild-type Anaplastic astrocytoma, NOS Glioblastoma, IDH wild-type Giant cell glioblastoma Gliosarcoma Epitheloid glioblastoma Glioblastoma, IDH mutant Glioblastoma, NOS Gliomatosis cerebri Diffuse midline glioma, H3-K27M mutant Oligodendroglioma, IDH mutant and 1p/19q codeleted Oligodendroglioma, NOS Anaplastic oligodendroglioma, IDH mutant and 1p/19q codeleted Anaplastic oligodendroglioma, NOS Oligoastrocytoma, NOS Anaplastic oligoastrocytoma, NOS Other astrocytic tumors Pilocytic astrocytoma Pilomyxoid astrocytoma Subependymal giant cell astrocytoma Pleomorphic xanthoastrocytoma Anaplastic pleomorphic xanthoastrocytoma Ependymal tumors Subependymoma Myxopapillary ependymoma Ependymoma Cellular ependymoma Papillary ependymoma Clear cell ependymoma Tanycytic ependymoma Ependymoma, RELA fusion-positive Anaplastic ependymoma Other gliomas Chordoid glioma of the third ventricle Angiocentric glioma Astroblastoma Mixed neuronal-glial tumors Ganglioglioma Anaplastic ganglioglioma Desmoplastic infantile astrocytoma and ganglioglioma Papillary glioneuronal tumor Rosette-forming glioneuronal tumor Diffuse leptomeningeal glioneuronal tumor
36 Histopathologic spectrum of diffuse gliomas astrocytic mixed oligodendroglial WHO grade II A OA O WHO grade III AA AOA AO WHO grade IV GBM GBM-O Wesseling P, Van den Bent M, Perry A Acta Neuropathol 2015
37 Molecular subgroups of diffuse gliomas astrocytic mixed oligodendroglial WHO grade II 1p/19q intact IDH mut 1p/19q codel IDH mutx x xxx WHO grade III WHO grade IV 1p/19q intact IDH wt Wesseling P, Van den Bent M, Perry A Acta Neuropathol 2015
38 Molecular subgroups of diffuse gliomas WHO grade II WHO grade III astrocytic 1p/19q intact IDH mut ATRX IHC- TERT wt TP53 mut oligodendroglial 1p/19q codel IDH mutxxxxx ATRX IHC+xxxx TERT mutxxxxxx TP53 wtxxxxxxxxx WHO grade IV 1p/19q intact IDH wt ATRX IHC+ TERT mut TP53 wt or mut Wesseling P, Van den Bent M, Perry A Acta Neuropathol 2015
39 Percentage of centers performing A Global View on the Availability of Methods and Information in the Neuropathological Diagnostics of CNS Tumors: Results of an International Survey Among Neuropathological Units (via ISN) Andreiuolo F, Mazeraud A, Chrétien F, Pietsch T; Brain Pathol 2016 Immunohistochemistry Molecular exams Techniques
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41 Immunohistochemistry (very) helpful! IDH1 R132H ATRX H3 K27M
42 Molecular techniques for 1p/19q analysis n - T T LOH N N LOH T LOH -1p -19q MLPA FISH Array-CGH
43 The WHO 2016 Classification of Gliomas Diagnoses that (still) can be made without molecular testing Diffuse astrocytic and oligodendroglial tumors Diffuse astrocytoma, IDH mutant Gemistocytic astrocytoma, IDH mutant Fibrillary astrocytoma Protoplasmic astrocytoma Diffuse astrocytoma, IDH wild-type Diffuse astrocytoma, NOS Anaplastic astrocytoma, IDH mutant Anaplastic astrocytoma, IDH wild-type Anaplastic astrocytoma, NOS Glioblastoma, IDH wild-type Giant cell glioblastoma Gliosarcoma Epitheloid glioblastoma Glioblastoma, IDH mutant Glioblastoma, NOS Gliomatosis cerebri Diffuse midline glioma, H3-K27M mutant Oligodendroglioma, IDH mutant and 1p/19q codeleted Oligodendroglioma, NOS Anaplastic oligodendroglioma, IDH mutant and 1p/19q codeleted Anaplastic oligodendroglioma, NOS Oligoastrocytoma, NOS Anaplastic oligoastrocytoma, NOS Other astrocytic tumors Pilocytic astrocytoma Pilomyxoid astrocytoma Subependymal giant cell astrocytoma Pleomorphic xanthoastrocytoma Anaplastic pleomorphic xanthoastrocytoma Ependymal tumors Subependymoma Myxopapillary ependymoma Ependymoma Cellular ependymoma Papillary ependymoma Clear cell ependymoma Tanycytic ependymoma Ependymoma, RELA fusion-positive Anaplastic ependymoma Other gliomas Chordoid glioma of the third ventricle Angiocentric glioma Astroblastoma Mixed neuronal-glial tumors Ganglioglioma Anaplastic ganglioglioma Desmoplastic infantile astrocytoma and ganglioglioma Papillary glioneuronal tumor Rosette-forming glioneuronal tumor Diffuse leptomeningeal glioneuronal tumor
44 The WORLD Health Organization Classification of (CNS) Tumors
45 The WHO 2016 Classification of Gliomas Conception The newborn baby Growth potential
46 Olar A et al, Acta Neuropathol 2015
47 IDH mutant gliomas
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51 Glial and Mixed Neuronal-Glial Tumors in the WHO 2007 (in black and blue) and WHO 2016 (in black and red) Classification Diffuse astrocytic and oligodendroglial tumors Diffuse astrocytoma, IDH mutant Gemistocytic astrocytoma, IDH mutant Fibrillary astrocytoma Protoplasmic astrocytoma Diffuse astrocytoma, IDH wild-type Diffuse astrocytoma, NOS Anaplastic astrocytoma, IDH mutant Anaplastic astrocytoma, IDH wild-type Anaplastic astrocytoma, NOS Glioblastoma, IDH wild-type Giant cell glioblastoma Gliosarcoma Epitheloid glioblastoma Glioblastoma, IDH mutant Glioblastoma, NOS Gliomatosis cerebri Diffuse midline glioma, H3-K27M mutant Oligodendroglioma, IDH mutant and 1p/19q codeleted Oligodendroglioma, NOS Anaplastic oligodendroglioma, IDH mutant and 1p/19q codeleted Anaplastic oligodendroglioma, NOS Oligoastrocytoma, NOS Anaplastic oligoastrocytoma, NOS Other astrocytic tumors Pilocytic astrocytoma Pilomyxoid astrocytoma Subependymal giant cell astrocytoma Pleomorphic xanthoastrocytoma Anaplastic pleomorphic xanthoastrocytoma Ependymal tumors Subependymoma Myxopapillary ependymoma Ependymoma Cellular ependymoma Papillary ependymoma Clear cell ependymoma Tanycytic ependymoma Ependymoma, RELA fusion-positive Anaplastic ependymoma Other gliomas Chordoid glioma of the third ventricle Angiocentric glioma Astroblastoma Mixed neuronal-glial tumors Ganglioglioma Anaplastic ganglioglioma Desmoplastic infantile astrocytoma and ganglioglioma Papillary glioneuronal tumor Rosette-forming glioneuronal tumor Diffuse leptomeningeal glioneuronal tumor
52 WHO 2016 d
53 And what about good old microscopy? patient surgery morphological diagnosis
54 Old-fashioned and too simple?
55 End result of interaction of thousands of genes! + information on non-neoplastic elements
56 The truth, the whole truth, and nothing but the truth? Rather a(nother) reflection of the truth!
57 Challenge: balancing desires and needs Stay connected Most accurate diagnosis Provide the best possible diagnosis Utilize the most accurate, cuttingedge techniques Incorporate the latest molecular signatures Do not disrupt current clinical diagnosis and patient management Weigh the availability and cost of novel diagnostic techniques Preserve the ability for longterm clinical, experimental and etiological correlations Courtesy of Dr. David Louis
58 Classification of CNS Tumors WHOrk in progress cimpact-now Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (Not Official WHO)
59 THE (NEURO)PATHOLOGIST A knowledgeable, reliable, responsible TISSUE PROFESSIONAL integrating and communicating (clinically) relevant information obtained by all sorts of cell & tissue analyses.
60 Exciting times Enjoy! Wright KD, Gilbertson RJ, Cancer Cell 2010;17: Waalbridge at sunset, Nijmegen, The Netherlands
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