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Diffuse Glial Tumours and the New WHO 2016 Classification

Diffuse Glial Tumours and the New WHO 2016 Classification

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- in cooperation with the Central 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 – Diffuse astrocytoma – • Gemistocytic astrocytoma • Pilomyxoid astrocytoma – Subependymal giant cell astrocytoma • – Pleomorphic xanthoastrocytoma • Proteoplasmic astrocytoma

– , IDH mutant • Ependymal tumors

– – – Myxopapillary • Giant cell glioblastoma – Ependymoma • Fliosarcoma • Cellular ependymoma • Papillary ependymoma • Clear cell ependymoma – • Tanycytotic ependymoma – Anaplastic ependymoma

– • Other

– Anaplastic oligodendroglioma – Chordoid of the third ventricle – Angiocentric glioma – Astroblastoma

• Mixed neuronal-glial tumors – – Anaplastic oligoastrocytoma – – 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 – 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: 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 :

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 WHO grade III (O III) 54 18 36 67% Oligoastrocytoma WHO grade II (OA II) 46 10 36 78% Anaplastic oligoastrocytoma WHO grade III (OA III) 37 8 29 78% Myxopapillary ependymoma WHO grade I (E myx I) 6 5 0 - Ependymoma WHO grade II (E II) 15 15 0 0% Anaplastic ependymoma WHO grade III (E III) 10 10 0 0% WHO grade IV (MB IV) 58 58 0 0% Primitive neuroectodermal tumor WHO grade IV (PNET) 9 6 3 33 % WHO grade I (S I) 17 17 0 0% WHO grade I (M I) 38 38 0 0% Atypical meningioma WHO grade II (M II) 17 17 0 0% Anaplastic meningioma WHO grade III (M III) 17 17 0 0% Pituitary adenoma WHO grade I (PIAD) 23 23 0 0%

Balss et al., Acta Neuropathologica, 2008 Gene Nucleotide Amino acid N (%) IDH1 change change

1010 IDH1 G395A R132H 664 (92.7%) diffuse C394T R132C 29 (4.2%) gliomas C394A R132S 11 (1.5%)

C394G R132G 10 (1.4%)

G395T R132L 2 (0.2%)

IDH2 G515A R172K 20 (64.5%)

G515T R172M 6 (19.3%)

A514T R172W 5 (16.2%)

Hartmann et al., Acta Neuropathologica, 2009 12 3 4 51 2 3 4 5

72 kD

55 kD

36 kD

mIDH1R132H rIDH1 H09

Capper et al., Acta Neuropathologica, 2009 Oligodendroglioma WHO grade II H09 +: 88%

Anaplastic oligodendroglioma WHO grade III H09 +: 88% Central WHO grade II H09 +: 0% (n = 34)

DNT WHO grade I H09 +: 0% (n = 20) Clear cell ependymoma WHO grade II H09 +: 0% (n = 6)

Pilocytic astrocytoma (with focal oligodendroglial differentiation) WHO grade I H09 +: 0% (n = 5) WHO 2016

IDHmut

WHO 2007

A OA O

AA AOA AO

GBM GBM+O

After Wesseling P, Van den Bent M, Perry A Acta Neuropathol 2015 Oligodendroglioma, IDH mutant and 1p/19q codeleted (WHO Grade 2)

Anaplastic oligodendroglioma, IDH mutant and 1p/19q codeleted (WHO Grade 3) Oligodendroglioma Grading

• Grade 2 • Grade 3: one of – marked mitotic activity ( >5 /10 HPF?) – Florid microvascular activity – Necrosis (subjective…) • (Grade 4: GBM with Oligo-features) not in WHO 2016 anymore – Oligoastrocytoma with necrosis? Oligodendroglioma, IDH mutant and 1p/19q codeleted (WHO Grade 2)

Anaplastic oligodendroglioma, IDH mutant and 1p/19q codeleted (WHO Grade 3)

A diffusely infiltrating glioma with classic oligodendroglial histology, in which molecular testing for combined IDH mutation and 1p19q codeletion could not be completed or was inconclusive: Oligodendroglioma, NOS Anaplastic oligodendroglioma, NOS Oligoastrocytoma, NOS Anaplastic oligoastrocytoma, NOS Diffuse astrocytoma(DA) anaplastic astrocytoma (AA)

• Peak incidence 38-48 (DA), 49-53 (AA) • Epilepsy most often presenting symptom in DA (48%), subjective symptoms in AA (44 %) • Frontal lobe site of preference ( ca 40 %) • Rare in (4 %) • Radiological contrast enhancement: 10% in DA, 29-44% in AA • 5y Overall Survival 47-75% in DA, 25-41% in AA • 20y Overall Survival 10-20% in DA, very low in AA Diffuse astrocytoma(DA) anaplastic astrocytoma (AA)

• Ill defined mass  enlargement and distorsion • Hypercellular regions, tumor cells intermixed with normal cells • Secundary structures “of Scherer” • Angular, elongated nuclei • Eosinophilic fibrillary cytoplasm • AA: frank mitotic activity (>2/10 HPF ?) (WHO 3) (microvascular proliferation and necrosis = Grade 4) Astrocytic phenotype: diverse! low grade (fibrillary) gemistocytic anaplastic

giant cell small cell gliosarcoma Diffuse astrocytoma (WHO grade II)

Claes A, Idema B, Wesseling P. Diffuse glioma growth: A guerilla war. Acta Neuropathol (2007). Anaplastic astrocytoma (WHO grade III)

Claes A, Idema B, Wesseling P. Diffuse glioma growth: A guerilla war. Acta Neuropathol (2007). IDH1 Man 23 year, epilepsy, temporal process

IDH1 IDH1/2 mutation

• about 90 % found with IHC (R132H IDH1 mutation) • On further examination:5-10% PCR IDH1 or IDH2 Diffuse astrocytoma, IDH mutant (WHO Grade 2)

Anaplastic astrocytoma, IDH mutant (WHO Grade 3) ATRX

• ATRX mutations: α-thalassemia/mental retardation X-linked syndrome • ATRX part of a multiprotein complex that includes DAXX and plays a role in regulating chromatin remodeling, nucleosome assembly, telomere maintenance and deposition of histone H3.3 at transcriptionally silent regions of the genome. • ATRX mutation: 36% of diffuse adult gliomas • Mostly together with IDH1/IDH2 mutation • Not seen in 19p 1q co-deletion ATRX-mutations in adult gliomas

Liu et al. Acta Neuropathol (2012) 124:615–625 Diffuse glioma dd oligodendroglioma/astrocytoma Diffuse glioma dd oligodendroglioma/astrocytoma

IDH1 Diffuse astrocytoma IDH mutant

ATRX

No Co-deletion 1p19q ATRX mutations in adult gliomas

Liu et al. Acta Neuropathol (2012) 124:615–625 TP53 mutations p53 expression (by immunohistochemistry) no independent marker for outcome in gliomas

Zolota et al; Neuropathology 2008 P53 positivity: strong in >10 % nuclei of tumor cells predicted the presence of TP53 missense mutations with a high accuracy. Gillet et al. J. Neurooncology 2014 ATRX alterations are associated with TP53 mutations in IDH1/2-mutant gliomas Xiao-Yang et al; Neuropathology 2012 TP53 mutation (by sequencing) indicative for poorer outcome In astrocytoma WHO grade II Xiao-Yang et al; Neuropathology 2012 Diffuse adult gliomas

• IDH1/2-mutant and 1p19q-deleted gliomas (best prognosis)

• IDH1/2 and TP53 mutant group of gliomas (intermediate prognosis)

• IDH1/2, TP53 and 1p19q wild-type gliomas (worst prognosis)

Xiao-Yang et al; Neuropathology 2012 Diffuse low grade glioma adults

• 3 primary lower-grade glioma disease classes that were best represented by IDH and 1p/19q status • lower-grade gliomas with an IDH mutation had either 1p/19q codeletion or a TP53 mutation in a mutually exclusive fashion • the majority of lower-grade gliomas with wild-type IDH showed remarkable genomic and clinical similarity to primary (wild-type IDH) glioblastoma Oligoastrocytoma

• Mixture oligodendroglial, astrocytic cells • Diffusely mixed • Separated (rarely) • Existence???: “The WHO classification discourages the diagnosis of tumours as oligoastrocytoma or mixed glioma” (page 75) Diffuse astrocytoma Grading

• Grade 2 • Grade 3: – Focal or dispersed anaplasia – Significant mitotic activity: (not specified in WHO: >2 /10 HPF? ) • Grade 4: GBM – nuclear atypia – Cellular pleomorphism (in most cases) – Mitotic activity – microvascular proliferation and/or necrosis Diffuse astrocytoma, IDH-wildtype (WHO II)

Anaplastic astrocytoma, IDH-wildtype (WHO III)

Diffuse astrocytoma, NOS (WHO II)

Anaplastic astrocytoma, NOS (WHO III)

Oligoastrocytoma, NOS (WHO II)

Anaplastic Oligoastrocytoma, NOS (WHO III) Wesseling P, Van den Bent M, Perry A Acta Neuropathol 2015 • Diffuse astrocytic and oligodendroglial tumors

Diffuse astrocytoma, IDH mutant Gemistocytic astrocytoma, IDH mutant Fibrillary astrocytoma Proteoplasmic astrocytoma Diffuse astrocytoma, IDH-wildtype Diffuse astrocytoma, NOS

Anaplastic astrocytoma, IDH mutant Anaplastic astrocytoma , IDH-wildtype 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 Brandner and von Deimling 2015 Astrocytoma

Oligodendroglioma

IDH1R132H

ATRX

IDH1, 2 Sequencing Mut Mut wt 1p/19q test codeleted retained H3 sequencing H3 wt H3 wt H3 mut OII AII GBM infiltration, GBM(?)-H3 OIII AIII other tumours Essential Recommended Not essential / not required Reuss et al. 2015 “Anaplastic oligodendroglioma” Molecular analysis

• 139 cases, 6 uninformative • Type 1: oligodendroglioma 1p19q codeletion: 49 • Type 2: astrocytoma: IDH1m 1p19q no codeletion: 20 • Type 3: glioblastoma 7+/10q- or TERTmut and 1p/19q intact: 55 • Type 4: childhood glioblastoma (H3F3Amut): 2

• 7 unclassified Neuro Oncol. 2015 Sep 9. pii: nov182 Diffuse astrocytic low grade diffuse astrocytoma glioblastoma Examples of radiology GBM

“ring-enhancing lesion” “butterfly” glioma

Glioblastoma, IDH-mutant

• “A high grade glioma with predominantly astrocytic differentiation; featuring nuclear atypia, cellular pleiomorphism (in most cases), mitotic activity, and typically a diffuse growth pattern, as well as microvascular proliferation and/or necrosis, with a mutation in either the IDH& or IDH2 gene” • Can be so-called “secondary” glioblastoma – Astrocytoma GII  Astrocytoma GIII  Glioblastoma Glioblastoma, IDH-mutant

• About 10 % of glioblastoma • “Younger” patients than wild type (mean 48 years) • Predominance frontal lobe • Focal oligodendroglial differentiation more common than in IDH wt glioblastoma; 50 % show areas of necrosis (90% in IDHwt glioblastoma) • Often also p53 and ATRX mutation, very rarely EGFR overexpression

Glioblastoma, IDH-wildtype

• “A high grade glioma with predominantly astrocytic differentiation; featuring nuclear atypia, cellular pleiomorphism (in most cases), mitotic activity, and typically a diffuse growth pattern, as well as microvascular proliferation and/or necrosis, and which lacks mutations in the IDH genes. • > parietal lobe > frontal lobe > occipital lobe • Older adults (peak 55-85 years) Glioblastoma, IDH-wildtype

• “A high grade glioma with predominantly astrocytic differentiation; featuring nuclear atypia, cellular pleiomorphism (in most cases), mitotic activity, and typically a diffuse growth pattern, as well as microvascular proliferation and/or necrosis, and which lacks mutations in the IDH genes. • Temporal lobe > parietal lobe > frontal lobe > occipital lobe • Older adults (peak 55-85 years) Glioblastoma, IDH-wildtype: variants

• Giant cell glioblastoma – Numerous multinucleated giant cells,… – Frequent PTEN mutations, frequent p53 mutations • Gliosarcoma – 2 components: glial and mesenchymal • Epitheloid glioblastoma – +_ uniform epitheloid cell population – 50 % BRAF V600E mutation (DD)

Diffuse midline glioma, H3 K27M-mutant

• “An infiltrative midline high-grade glioma with predominantly astrocytic differentiation and a K27M mutation in either H3F3A or HIST1H3B/C” • Predominates in children, can be seen in adults • Brain stem, thalamus, spinal cord • (“brain stem glioma”, “diffuse intrinsic pontine glioma”) • Diffuse astrocytic and oligodendroglial tumors

Diffuse astrocytoma, IDH mutant Gemistocytic astrocytoma, IDH mutant Fibrillary astrocytoma Proteoplasmic 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 MGMT methylation in GBM O6-methylguanine-DNA methyltransferase

40% - 60% MGMT Repairs methylation induced by

CH 3 O

N N SH Cys 145 MGMT

N N NH 2

P

O6-Methyl-Guanin

O

N NH

CH S Cys 145 N 3 N NH 2

P Guanin O⁶-methylguanine-DNA methyltransferase promoter degradation hypermethylation

MGMT and Prognosis in GBM

Hegi et al. N Engl J Med, 2005 Management of diffusely infiltrating glioma in the elderly. Wirsching, Hans-Georg; Happold, Caroline; Roth, Patrick; Weller, Michael

Current Opinion in Oncology. 27(6):502-509, November 2015. DOI: 10.1097/CCO.0000000000000236

FIGURE 1 . Therapeutic approach to diffusely infiltrating gliomas in elderly patients. IDH, isocitrate dehydrogenase; MGMT, O6-methylguanine-DNA methyltransferase; PCV, polychemotherapy with procarbazine, CCNU (lomustine) and ; RT, radiotherapy; TMZ, . TMZ/RT, 30 x 2 = 60 Gray (Gy) with daily concomitant temozolomide at 75 mg/m2.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Published by Lippincott Williams & Wilkins, Inc.

Prospective trials (Noa08, Nordic trial en RTOG 0525): MGMT promotor methylation is a useful predictive marker to stratifie older GBM patients for radiotherapy or temozolamide therapy 2 • MGMT methylation status in non-GBM – MGMT promoter methylation is a predictive biomarker for benefit from alkylating agent chemotherapy in patients with IDH1–wild-type, but not IDH1-mutant, malignant gliomas (WHO grade 3) (Wick et al Neurology 2013;81:1515–1522) Other

• EGFR amplification (28 % van GBM IDHwt) (especially in small cell glioblastoma) • ROS translocation (FISH) • TERT promotor mutaties in 74% GBM, in GBM mutually exclusive with IDH1, but not in oligodendroglioma. • …. (Decision table taking into account RIZIV/INAMI regulations in Belgium)

• 1. Decision: Diffuse glial tumor or variant? – Morphology, age, radiology, evt. BRAF, BRAFKIAA1549, IDH1 IHC, NeuN IHC, IHC, p53 IHC

• 2. If diffuse glioma and no GBM – IDH1 immuunhistochemistry (IHC) – ATRX immuunhistochemistry (IHC) – If IDH1 IHC+ and ATRX wt  1p19q (FISH, other method) – If IDH1 IHC - : IDH1 and IDH2 mutation? (PCR or NGS) – If IDH1 or IDH2 mutatie + and ATRXwt: 1p19q codeletion? (no RIZIV/INAM payment anymore: clinician should decide after information of the patient, but for definite diagnosis it should be done) (evt. morphology may be taken into account)

• 3. If GBM: IDH1 IHC, and MGMT methylation (certainly if > 60 yrs) – IF IDH1 is negative and patient < 55 years: IDH1 and IDH2 PRC or NGS, (if >=55yr not necessary). No RIZIV/INAM payment anymore for MGMT methylation, but not strictly indicated when younger than 60)

• (4. If Astro G3, IDH1wt: MGMT methylation ) (but no RIZIV/INAMI

indication for TMZ) , not completely evidence based yet. Example conclusion report according to ISN-Haarlem guidelines 2014

• Resection left temporal process.

(according to ISN-Haarlem guidelines in Brain Pathology 24 (2014) 429–435 )

• Integrated diagnosis: anaplastic astrocytoma WHO gr 3, IDH1m, no co- deletion 1p19q , ATRXm.

• Histological classification: anaplastic oligoastrocytoma

• WHO graad (4 th . edn (2007)): 3

• Molecular information: IDH1m(IHC), ATRXm (IHC), 1p19q no codeletion (FISH), MGMTmethylation not performed, may be performed on demand. Childhood gliomas

Mutatie Pilocytic Astrocytoma Ganglioglioma Pilomyxoid astrocytoma DNET PXA Diffuse astrocytoma Child

BRAFV600E 5% 20-25 % 0 (30%) 60-80 % 10-15%

BRAF-KIAA1549 70% (90% infratentorial 66% 0

BRAF-other fusions 5%

NF1 7%()

FGFR1 5%

1p19q co-deletion 0-1% IDH1 0-1% 0 0 0 0 15%

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