Diffuse & Anaplastic Overview Astrocytoma and Classification Midline Glioma WHO 2016 Reclassification MR TA Yousry Institute of Neurology MR characteristics National Hospital for Neurology and Neurosurgery Treatment Queen Square

WHO 2007 Classification

Classification based on histogenetic Original cell type concepts; using Light & Electron  Astrocytoma microscopy & Immunohistochemistry  Oligodendroglioma  Putative cells of origin  Oligo-astrocytoma  Developmental differentiation states

 + Supplementary information: Genetic status

Astrocytoma Astrocytoma  Pilocytic  Pilomyxoid 75% of glial tumours  Subendymal giant cell Classification  Pleomorphic xantoastrocytoma  Diffuse infiltrating astrocytoma (WHO grade II)  Low grade Diffuse  Anaplastic astrocytoma (WHO grade III)  High grade Anaplastic  Glioblastoma multiforme (WHO grade IV)  GBM  Gliosarcoma  Gliomatosis cerebri Astrocytoma Grading

Astrocytomas of distinctive pathology, slow WHO Classification growing & well circumscribed Based on cellular atypia, mitosis, vascular,  Juvenile pilocytic astrocytoma proliferation, necrosis  Pleomorphic xanthoastrocytoma Grade II Cellular atypia  Subependymal giant-cell astrocytoma Grade III Cellular atypia + mitosis Grade IV Cellular atypia + mitosis + Vascular proliferation / necrosis

MRI Diffuse Infiltrating Astrocytoma Diffuse infiltrating astrocytoma (LGG) WHO II  Focal or diffuse WM mass  Can extend into the cortex  T1 hypointense - T2 hyperintense  Usually non-enhancing  Calcium, Cysts, haemorrhage rare FLAIR volume T2 multi-slice

Diffuse Infiltrating Astrocytoma MRI Anaplastic Astrocytoma WHO III  Focal or diffuse WM mass  Can extend into the cortex  T1 iso-hypointense  T2 heterogenous hyperintense  Variable enhancement  Calcium, Cysts, haemorrhage rare MRI WHO 2016 Anaplastic astrocytoma (LGG) Classification based on histogenetic concepts; using Light & Electron microscopy, Immunohistochemistry, and molecular parameters (genotype)  Putative cells of origin  Developmental differentiation states  Genetic parameters (Genotype) Courtesy S Bisdas

WHO 2016 Changes New family trees! Previously All astrocytomas together Now All diffuse gliomas together  Astrocytoma II/III  Oligodendroglioma II/III  Oligoastrocytoma II/III  GBM IV  Diffuse midline glioma (e.g. those of childhood)

Diffuse Astrocytoma Diffuse Astrocytoma Vast majority IDH Mutant (1 or 2); IDH-wildtype TP53; ATRX Rare WHO grade II (Don’t use LGG; fibrillary) Less favourable outcome Proportion 11-15% of Astrocytomas Usually reclassified (provisional diagnosis) 59%-90% of all AII Gliomatosis cerebri Incidence 0.55-0.75/100.000 ≥ 3 lobes Presentation Seizures NOS IDH status not assessed Anaplastic Astrocytoma Anaplastic Astrocytoma Vast majority IDH-Mutant (1 or 2); TP53; IDH-wildtype ATRX  20% of anaplastic Astrocytomas WHO grade III (Don’t use HGG)  Highest incidence of wildtype in diffuse glioma Distribution 11-15% of all Astrocytomas II/III 52-78% of AIII  Clinical course more similar to GBM Incidence 0.37/100.000 NOS Mean age 38y  IDH status not assessed Survival 9-10y

Gliomatosis Cerebri Diffuse Midline Glioma Predominant astrocytic differentiation  ≥ 3 lobes Mutation H3 K27M  No unique molecular signature WHO grade IV  IDH mutation when distinct solid component  Children> adults Median age 5-11y  Initial manifestation of diffuse gliomas  Incidence 0.55-0.75/100.000  Most common in anaplastic astrocytoma  2y survival rate <10%  Now simply a widespread pattern of  Wildtype better outcome involvement

IDH IDH Effect of IDH classification on Diffuse Astrocyt  AII & AIII Similar age (38y) & survival Age distribution Age related survival  GBM Distinct

Reuss Acta Neuropath 2015 Reuss Acta Neuropath 2015 IDH IDH-wt Subdivision of 160 IDHwt astrocytomas IDH-mutant AII ̴ AIII

IDH-wt AII < AIII Reuss Acta Neuropath 2015 Reuss Acta Neuropath 2015

IDH-wt IDH-wt AII AIII Total  GBM 70% 80% 78%  GBM-H3 7% 10% 9%  Midline HGG 10% 8% 8%  Lower grade 17% 1% 5% pilocytic pleomorphic DNTs or gangliogliomas Reuss Acta Neuropath 2015 Reuss Acta Neuropath 2015

IDH-wt Astrocytomas 2007 Survival

Reuss Acta Neuropath Reuss Acta 2015 Neuropath 2015 Major Difference NOS Diffuse Glioma Not otherwise specified WHO 2007 WHO 2016 Mean Age/Survival Mean Age/Survival IDH IDHIDH mut Mut  LG Diffuse A  Diffuse Wild type 38y / 6-8y 38y / 10.9y Co-deletion Mutation TP53  HG Anaplastic A  Anaplastic A 1p 19q Loss ATRX Diffuse Astrocytoma 45-53y / 2-3y IDH +ve 38y / 9.3y Oligodendroglioma Diffuse Astrocytoma IDH Wild type IDH mutation, 1p 19q co-deletion IDH mutation Grade II Grade II Grade II IDH -ve Courtesy A Ramos

Cimino Acta Neuropath Comm 2017 Diffuse Astrocytomas

MR suggestions for IDH status  Contrast enhancement  T2-FLAIR  DWI-ADC  Perfusion  Spectroscopy

Diffuse Astrocytomas Lower Grade Gliomas

• “O” Molec oligodendroglial IDH & TERTp mutations & 1p/19q co-deletions • “A” Molec astrocytic IDH mutation & TP53/ATRX inactivation, or absence of 1p/19q co- deletions and/or TERTp mutations • “Glioblastoma- like” No IDH mutation

Smits Radiology 2017 Juratli J Neuro-Oncology 2019 Lower Grade Gliomas Contrast Enhancement

Juratli J Neuro-Oncology 2019 Juratli J Neuro-Oncology 2019

Contrast Enhancement T2-FLAIR Mismatch N-CE IDH-m (non-codeleted) High prevalence in “G”  T2 homogenous & Does not correlate with prognosis or hyperintense  FLAIR hypointense core survival in hyperintense rim Gliomas & subgroups  PPV 100% Not in IDH-m & 1p/19q codeleted oligodendroglioma Juratli J Neuro-Oncology 2019 Broen Neuro-Oncology 2018

T2-FLAIR Mismatch T2-FLAIR Mismatch

Juratli J Neuro-Oncology 2019 Juratli J Neuro-Oncology 2019 “A” Probability  Age <40y Size >6cm

 T2-FLAIR mismatch Juratli J Neuro-Oncology 2019

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Juratli J Neuro- Oncology 2019

GII Diffuse Astrocytomas GII Diffuse Astrocytomas  DWI-ADC

Villanueva-Meyer AJR Villanueva-Meyer AJR 2018 2018

IDH-wt GII DGs Non-Enhancing Gliomas Thust ER 2018 Independent predictors ADC Older age  wt < mut  Volumetric Multifocal cut-off 1.65 Brainstem Sens 80% No cystic changes Spec 92%  Single slice Low ADC Sens 80-86%

NOT CE Villanueva-Meyer AJR 2018 Spec 91-96%

Perfusion Perfusion  Grade II diffuse  The limited available evidence precludes reliable gliomas estimation of the performance of DSC MR perfusion-derived rCBV for the identification of grade in untreated solid and non-enhancing LGG from that of HGG (1990 – 11/2016)  Wide range of estimates for  Sensitivity 66-93% for LGGs detection 7-34% misclassified as HGG  Specificity 9-90% for HGGs detection Villanueva-Meyer AJR 2018 Abrigo Cochrane Database of Systematic Reviews 2019

IDH MRI IDH1 functions as tumor suppressor; mutations 2HG in IDH gliomas  Associated with alterations in DNA methylation of isocitrate  Overproduction and accumulation of oncometabolite2-  Primarily derived from glutamine hydroxyglutarate (2-HG)  Contribute to tumorigenesis partially through induction of the angiogenesis pathway

Young Nat Med 2012

MRI IDH – 2HG Effect of technique IDH-MT, short TE IDH-MT, long TE

IDH-WT, short TE IDH-WT, long TE

Natsumeda Acta Neuropath Comm 2016 Kim KJR 2016 MRI IDH – 2HG Glioma WHO II/III Effect of technique  2HG 100% IDH-m 37% IDH-wt

Natsumeda Acta Neuropath Comm 2016 Kim KJR 2016

2HG 2HG Cut off value 2- mM  False positive (GBM)  Sensitivity 89.5%  Specificity 81.3%  PPV 89.5%  NPD 87.5%  False negative (AIII/II)

Tietze JNS 2017 Tietze JNS 2017

MR-IDH status Location  MR Multifocal, No cystic changes  T2-FLAIR Mismatch  DWI-ADC Low ADC  Perfusion  Spectroscopy 2HG  Size >6cm  Older age (>40)

 Brainstem Paleocortex Archicortex Periarchicortex Yasargil MRI Limbic/Paralimbic Tumours Neocortex Limbic tumours (Allocortex) Paleocortex & Archicortex (Transional) Amygdala Hippocampus Subcallosal G Septal areas Limbic Tumours (Allocortex) Substantia innominata Paralimbic tumours (Mesocortex) Paralimbic tumours (Mesocortex) Central Grey matter Temporal pole Fronto orbital G BG Central nuclei Insula Cingulate G Brainstem G Yasargil Parahippocamus

Treatment LGG (3-4M Post op) • Extent of resection Residual tumour

Lus JNS 2012

Treatment Conclusion

Oligo Astro IDH-m WHO 2016  Importance of IDH MR Characteristics

 FLAIR-T2 mismatch  Low ADC  2HG

Wijnenga Neuro-oncology 2018