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
IMPERSONATORS Sturm et al., Cancer Cell 2012;22:425-437 Prognostic Diagnostic Both
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
Courtesy of Dr. Pieter Wesseling Brain Pathology 24: 429-435, 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
BIOMARKER CONCEPTS Types Diagnostic Prognostic Predictive Practicality issues Cost and ease of implementation IHC vs. FISH vs. PCR vs. genomics Reimbursement
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
321(5897):1807-12, 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
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 15:1388-1390, 2012 Reitman et al. Acta Neuropathol (2013) 126:789 792
Killela et al. PNAS 2013; 110: 6021 6026 ATRX/H3.3 alterations ALT ATRX IHC
ADULT GLIOMAS TERT ATRX IDH1/2 TP53 Killela et al. PNAS 2013; 110: 6021 6026 TERT IDH 1p/19q-del ADULT TYPE ASTROCYTOMA IDH1 p53 ATRX ADULT TYPE OLIGODENDROGLIOMA IDH1 p53 ATRX
DIFFUSE MIDLINE GLIOMA (DIPG, THAL, SC) H3 K27M p53 ATRX 26-yo M
H3 K27M H3 K27M Different Case H3 K27M H3K27me3
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!
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)
IS IT VALID TO COMBINE TRADITIONAL GLIOMA GRADING CRITERIA WITH NEW MOLECULAR DEFINITIONS FOR CELL TYPE (e.g. IDHm)? IDHwt
372: 2499-2508, 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 )
WNT MOL SUBTYPE β-catenin- β-catenin+ SHH MOL SUBTYPE YAP-1 GAB-1 SHH MOL SUBTYPE GAB-1
SHH-ACTIVATED, TP53-MUTANT p53 NON-WNT/NON-SHH MOL SUBTYPE YAP1
CEP17 17q11.2 CEP8 c-myc Mol Groups 3 and 4 Mol Group 3 (mostly) UCSF500 NGS: SHH Medulloblastoma WNT Medulloblastoma Scatter Plot
AT/RT Ho et al. Acta Neuropathol 99:482, 2000 ATYPICAL TERATOID/RHABDOID TUMOR AT/RT BRG1 INI1
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
Brain Pathology 22:689-97, 2012 WHO 2016 = ETMR, C19MC-altered CNS WHO 2016 = Embryonal Tumors EXAMPLES
CASE 1 46 yo man New onset seizures MRI: non-enhancing L frontotemporal mass Resection performed
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
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 (https://www.youtube.com/watch?v=ffp4htuu6v)