WHO 2016 CNS Tumor Classification Update. DISCLOSURES (Arie Perry, MD) PATTERN RECOGNITION. Arie Perry, M.D. Director, Neuropathology
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1 WHO 2016 CNS Tumor Classification Update Arie Perry, M.D. Director, Neuropathology DISCLOSURES (Arie Perry, MD) I have no financial relationships to disclose. - and - I will not discuss off label use or investigational use in my presentation PATTERN RECOGNITION
2 IMPERSONATORS Sturm et al., Cancer Cell 2012;22: Prognostic Diagnostic Both
3 Challenge: balancing desires and needs Incorporate the latest molecular signatures Utilize the most accurate, cutting-edge techniques Do not disrupt current clinical diagnosis and patient management Weigh the availability and cost of novel diagnostic techniques Preserve the ability for long-term clinical, experimental and etiological correlations Courtesy of Dr. David Louis Earliest record from Narrenbeschwörung (Appeal to Fools) by Thomas Murner, 1512 Don t throw the baby out with the bathwater : Das Kind mit dem Bade ausschütten Baby = roughly a century of clinicopathologic experience, tight correlations with outcome, and cost efficiency of light microscopy Bathwater = subjectivity, diagnostic pitfalls, histologic mimicry, lack of sufficient reproducibility
4 Courtesy of Dr. Pieter Wesseling Brain Pathology 24: , 2014 ISN-Haarlem format of layered diagnoses Integrated Diagnosis (incorporating all aspects of tissue diagnosis) Histological Classification WHO Grade (natural history) Molecular information (see parameters from previous slide) ISN-Haarlem layered diagnosis format I II III IV
5 BIOMARKER CONCEPTS Types Diagnostic Prognostic Predictive Practicality issues Cost and ease of implementation IHC vs. FISH vs. PCR vs. genomics Reimbursement
6 OLIGODENDROGLIOMA 1p19q FISH 1p32 1q42 19p13 19q13 OLIGODENDROGLIOMA NGS SCATTER PLOT UCSF500 Gene Panel GBM BIOMARKER: MGMT METHYLATION Hegi ME et al., NEJM 352;10:997, 2005
7 321(5897): , 2008 IDH1 R132H IHC DIAGNOSTIC EXAMPLE OF HISTOLOGIC MIMICRY: ELVIS IMPERSONATOR AO (IDHm and 1p/19q codeletion) Average survival 15 years with 1p/19q loss if treated with combined PCV chemo and radiation What about chemo alone up front? SC-GBM (IDHwt, EGFR-AMP 70%, -10q 95%) Average survival 1 year Typically treated with combined radiochemotherapy Different set of clinical trials than the high-grade oligodendrogliomas
8 REFLEX TO IDH1/2 SEQUENCING Young patient (<55 years old) Long clinical history Prior history of WHO grade II or III glioma Non-enhancing cerebral hemispheric mass on MR imaging Looks low-grade and/or classic oligo on histopathology Loss of ATRX expression on IHC CANCER CELLS ESCAPING SENESCENCE Shay JW et al. Science 15: , 2012 Reitman et al. Acta Neuropathol (2013) 126:
9 Killela et al. PNAS 2013; 110: ATRX/H3.3 alterations ALT ATRX IHC
10 ADULT GLIOMAS TERT ATRX IDH1/2 TP53 Killela et al. PNAS 2013; 110: TERT IDH 1p/19q-del ADULT TYPE ASTROCYTOMA IDH1 p53 ATRX ADULT TYPE OLIGODENDROGLIOMA IDH1 p53 ATRX
11 DIFFUSE MIDLINE GLIOMA (DIPG, THAL, SC) H3 K27M p53 ATRX 26-yo M
12 H3 K27M H3 K27M Different Case H3 K27M H3K27me3
13 IDH-wildtype Astrocytomas/GBMs New Stain: H3 G34R/V Astro, IDHm AA, IDHm 9p (CDKN2A/B) LOH IDHm TP53m ATRXm Preneoplastic Cell IDHm TERTm 1p19q codel Oligo, IDHm, 1p19q codel CICm FUBP1m IDHwt EGFR amp TERTm (H3 G34R/V) GBM, IDHwt Diffuse midline glioma, H3 K27Mm PIK3R1/PIK3CAm 4q LOH? PIK3CAm? GBM, IDHm AO, IDHm, 1p19q codel Note: no oligoastro!
14 World map by quartiles of Human Development Index in 2013 (WHO NOS = Not Otherwise Specified) DIFFUSE ASTROCYTOMA GRADING Atypia Mitoses Endothelial Proliferation (MVP, EH) Necrosis WHO II=A; III=A+M; IV=A+M+(E or N)
15 IS IT VALID TO COMBINE TRADITIONAL GLIOMA GRADING CRITERIA WITH NEW MOLECULAR DEFINITIONS FOR CELL TYPE (e.g. IDHm)? IDHwt
16 372: , 2015 Oligos Astros 1 0 GBMs? IDHm ~90% 2 0 GBMs IDHm ~10% 1 0 GBMs EMBRYONAL CNS TUMORS WHO 2016 SCHEME Medulloblastomas WNT-activated SHH-activated and TP53-mutant SHH-activated and TP53-wildtype Large cell / anaplastic ET c multilayered rosettes, C19MC-altered Medulloepithelioma CNS Neuroblastoma / Ganglioneuroblastoma Non-WNT/non-SHH Classic CNS ET, NOS Desmoplastic/nodular AT/RT MB c extensive nodularity (no PNETs )
17 WNT MOL SUBTYPE β-catenin- β-catenin+ SHH MOL SUBTYPE YAP-1 GAB-1 SHH MOL SUBTYPE GAB-1
18 SHH-ACTIVATED, TP53-MUTANT p53 NON-WNT/NON-SHH MOL SUBTYPE YAP1
19 CEP17 17q11.2 CEP8 c-myc Mol Groups 3 and 4 Mol Group 3 (mostly) UCSF500 NGS: SHH Medulloblastoma WNT Medulloblastoma Scatter Plot
20 AT/RT Ho et al. Acta Neuropathol 99:482, 2000 ATYPICAL TERATOID/RHABDOID TUMOR AT/RT BRG1 INI1
21 Haarlem and WHO rules for ATRT A dx of ATRT requires typical pathological features and INI1 or BRG1 loss Tumors with typical pathology but no INI1 or BRG1 loss should be called Embryonal tumor with rhabdoid features A center without BRG1 and /or INI1 testing needs to send the case out ETMR
22 Brain Pathology 22:689-97, 2012 WHO 2016 = ETMR, C19MC-altered CNS WHO 2016 = Embryonal Tumors EXAMPLES
23 CASE 1 46 yo man New onset seizures MRI: non-enhancing L frontotemporal mass Resection performed
24 POSSIBLE INITIAL REPORT 1. Integrated Diagnosis: pending 2. Histologic diagnosis: oligoastrocytoma (or ambiguous diffuse glioma) with scattered mitoses, but no MVP or necrosis 3. WHO grade: II 4. Molecular studies: pending POSSIBLE FINAL REPORT 1. Integrated Diagnosis: Oligodendroglioma, WHO grade II, IDH-mutant and 1p/19q codeleted 2. Histologic diagnosis: oligoastrocytoma (or ambiguous diffuse glioma) with scattered mitoses, but no MVP or necrosis 3. WHO grade: II 4. Molecular studies: IDH1 R132H mutant protein positive by IHC, 1p/19q codeletion by FISH ACTUAL FINAL REPORT 1. Integrated Diagnosis: Diffuse astrocytoma, IDHmutant, WHO grade II 2. Histologic diagnosis: oligoastrocytoma (or ambiguous diffuse glioma) with scattered mitoses, but no MVP or necrosis 3. WHO grade: II 4. Molecular studies: 1p/19q intact, IDH1 R132H mutant on sequencing and IHC, ATRX loss of expression by IHC, p53 overexpression by IHC
25 CASE 2: POSSIBLE INITIAL REPORT 1. Integrated Diagnosis: pending 2. Histologic diagnosis: oligoastrocytoma (or ambiguous diffuse glioma) with atypia, mitoses, MVP, and necrosis 3. WHO grade: at least III 4. Molecular studies: pending POSSIBLE FINAL REPORT 1. Integrated Diagnosis: AO, WHO III, IDH-mutant, 1p19q codeleted, ATRX intact 2. Integrated Diagnosis: GBM (secondary type), WHO IV, IDH-mutant, 1p/19q intact, ATRX loss 3. Integrated Diagnosis: GBM (primary type), WHO IV, IDH-wildtype, 1p/19q intact, ATRX intact, +/- EGFR-AMP 4. Diagnosis: GBM-O, NOS, WHO grade IV (molecular studies not performed) Performance of Brain Tumor Rhapsody by Musaic (
26
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