The New WHO Classification of Brain Tumors and Molecular Profiling in the Diagnosis of Gliomas
Aivi Nguyen, MD Neuropathology Fellow Division of Neuropathology Center for Personalized Diagnosis (CPD) Glial neoplasms – infiltrating gliomas
Astrocytic tumors • Diffuse astrocytoma II • Anaplastic astrocytoma III • Glioblastoma • Giant cell glioblastoma IV • Gliosarcoma
Oligodendroglial tumors • Oligodendroglioma II • Anaplastic oligodendroglioma III
Oligoastrocytic tumors • Oligoastrocytoma II • Anaplastic oligoastrocytoma III
Courtesy of Dr. Maria Martinez-Lage 2 2016
3 The 2016 WHO classification of tumours of the central nervous system
Louis et al., Acta Neuropathologica 2016 4 Talk Outline
Genetic, epigenetic and metabolic changes in gliomas • Mechanisms/tumor biology • Incorporation into daily practice and WHO classification Penn’s Center for Personalized Diagnostics • Tests performed • Results and observations to date Summary
5 The 2016 WHO classification of tumours of the central nervous system
Louis et al., Acta Neuropathologica 2016 6 Mechanism of concurrent 1p and 19q chromosome loss in oligodendroglioma lost
FUBP1
CIC
Whole-arm translocation
Griffin et al., Journal of Neuropathology and Experimental Neurology 2006 7 Oligodendroglioma: 1p19q co-deletion
Since the 1990s
Diagnostic Prognostic Predictive
Li et al., Int J Clin Exp Pathol 2014 8 Mutations of Selected Genes in Glioma Subtypes
GBM
Astrocytoma
Oligodendroglioma
Oligoastrocytoma
Killela et al., PNAS 2013 9 Escaping Senescence
Telomerase reverse transcriptase gene Oligodendrogliomas Primary GBMs
Alternative lengthening of telomeres (ALT)/ATRX Astrocytomas Secondary GBMs
Cohesion between sister chromatids provides a template for recombination and repair during and after DNA replication in S and G2 phases of the cell cycle
Reitman et al., Acta Neuropathol 2013, Ramamoorthy & Smith, Cancer Cell 2015 10 Mutations of Selected Genes in Glioma Subtypes
GBM
Astrocytoma
Oligodendroglioma
Oligoastrocytoma
Killela et al., PNAS 2013 11 Association of IDH1 status with PFS
mutated IDH1
Hartmann et al., Acta Neuropathologica 2010 12 Mutations of Selected Genes in Glioma Subtypes
GBM
Astrocytoma
Oligodendroglioma
Oligoastrocytoma
Killela et al., PNAS 2013 13 Diagnosis of GBM
Pseudopalisading necrosis Endothelial proliferation
14 Glioblastoma subtypes – genomic changes
Cell 155, 462–477, October 10, 2013 15
Sturm et al., Cancer Cell 2012 16 IDH
Labussiere et al., 2010 17 IDH mutations result in Glioma- CpG methylation phenotype (G-CIMP) and histone methylation in gliomas
demethylases
Block to differentiation
DNA hydroxylases
Venneti & Thompson, Brain Pathology 2013 18 Simplified algorithm for classification of diffuse gliomas based on histology and genetics
Louis et al., Acta Neuropathologica 2016 19 EGFR p53
mutated IDH1 Ki-67 20 Center for Personalized Diagnostics
David Roth, MD PhD Jennifer Morrissette, PhD Kojo Elanitoba-Johnson, MD Chair of Pathology Clinical Director of the CPD Director of the CPD
21 The CPD gene panel
47 genes targeted (Illumina® TruSeq Cancer Panel) MiSeq instrument In-house algorithms to identify variants
22 Solid Tumor Panel Version 2: 153 genes
ABL1 BAP1 CDK6 EPHA3 FGFR3 JAK1 MAP2K2 MRE11A NOTCH1 PTPN11 SETD2 TERT
AKT1 BRAF CDKN2A ERBB2 FGFR4 JAK2 MAP2K4 MSH2 NOTCH2 RAB35 SF3B1 TET2
AKT2 BRCA1 CHEK2 ERBB3 FLT3 JAK3 MAPK1 MSH6 NOTCH3 RAC1 SLIT2 TGFBR2
AKT3 BRCA2 CIC ERBB4 FUBP1 KCNG1 MAPK3 MTOR NRAS RAD50 SMAD4 TP53
ALK BRIP1 CRKL ERCC2 GATA3 KDM5A MAX MYC PAK1 RAD51 SMARCA4 TRAF7
APC BTK CSF1R ERG GNA11 KDM5C MCL1 MYCN PALB2 RAD51B SMO TSC1
AR CREBBP CTNNB1 ESR1 GNAQ KDM6A MDM2 NBN PBRM1 RAD51C SPOP TSC2
ARAF CCND1 DAXX ESR2 GNAS KDR MDM4 NF1 PDGFRA RAD51D SRC
ARID1A CCND2 DDR2 EZH2 HRAS KIT MED12 NF2 PIK3CA RAF1 STAG2 U2AF1
ARID2 CCND3 DNMT3A FBXW7 H3F3A KMT2C MEN1 NTRK1 PIK3CB RB1 STK11 VHL
ATM CCNE1 EGFR FGF3 IDH1 KRAS MET NTRK2 PIK3R1 RET SUFU WT1
ATRX CDH1 FGFR1 IDH2 LRRK2 MITF NTRK3 PTCH1 RHOA SUZ12 XRCC2
AURKA CDK4 EP300 FGFR2 IGF1R MAP2K1 MLH1 NKX2-1 PTEN RNF43 SYK
23 Penn Precision Panel
AKT1 ERBB2 KRAS PDGFRA ALK HRAS MAP2K1 PTEN BRAF IDH1 MET PIK3CA CSF1R IDH2 NOTCH1 RET EGFR KIT NRAS TP53
24 WHO 2016:
“Layered Diagnosis”
Integrated Diagnosis • incorporating all aspects of tissue diagnosis Histological Classification WHO Grade • reflects natural history, based on histology Molecular information
Louis et al., Brain Pathology 2014 25 Example: initial diagnosis 1. Integrated Diagnosis: pending 2. Histologic diagnosis: diffuse glioma with atypia, mitoses, microvascular proliferation and necrosis 3. WHO grade: at least III 4. Molecular studies: pending
26 1. Integrated Diagnosis: pending 2. Histologic diagnosis: diffuse glioma with atypia, mitoses, microvascular proliferation and necrosis 3. WHO grade: at least III 4. Molecular studies: pending
Final Diagnosis Integrated Diagnosis: GBM (primary type), WHO IV, IDH wildtype, 1p19q intact, ATRX intact, +/- EGFR-AMP
27 1. Integrated Diagnosis: pending 2. Histologic diagnosis: diffuse glioma with atypia, mitoses, microvascular proliferation and necrosis 3. WHO grade: at least III 4. Molecular studies: pending
Final Diagnosis Integrated Diagnosis: GBM (secondary type), WHO IV, IDH-mutated, 1p19q intact, ATRX loss
28 1. Integrated Diagnosis: pending 2. Histologic diagnosis: diffuse glioma with atypia, mitoses, microvascular proliferation and necrosis 3. WHO grade: at least III 4. Molecular studies: pending
Final Diagnosis Integrated Diagnosis: Anaplastic Oligodendroglioma, WHO III, IDH- mutated, 1p19q codeleted, ATRX intact
29
Three different possible final diagnoses
GBM (primary type), WHO IV, IDH intact, 1p19q intact, ATRX intact, +/- EGFR-AMP
GBM (secondary type), WHO IV, IDH mutated, 1p19q intact, ATRX loss
Anaplastic Oligodendroglioma, WHO III, IDH mutated, 1p19q codeleted, ATRX intact
30 Do we need a microscope? Yes! Must make histological diagnosis of glioma first WHO grade is based mainly on histology Some gliomas do not have these diagnostic genetic changes
31 Simplified algorithm for classification of diffuse gliomas based on histology and genetics
More genetic changes will be found.
Louis et al., Acta Neuropathologica 2016 32