WHO 2016 CNS TUMOR CLASSIFICATION UPDATE. Arie Perry, M.D. Director, Neuropathology
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1 WHO 2016 CNS TUMOR CLASSIFICATION UPDATE Arie Perry, M.D. Director, Neuropathology
2 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 School of Medicine
3 School of Medicine PATTERN RECOGNITION
4 School of Medicine IMPERSONATORS
5 PATTERN RECOGNITION
6
7 Sturm et al., Cancer Cell 2012 ; 22: Prognostic Diagnostic Both
8
9 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)
10 layered diagnosis format I II III IV ISN-Haarlem
11
12
13 cimpact-now Ken Aldape Dan Brat David Capper David W. Ellison Dominique Figarella-Branger Cynthia Hawkins David N. Louis Werner Paulus Arie Perry cimpact-now (cont.) Andreas von Deimling Pieter Wesseling cimpact-now Clinical Advisory Panel Tracy Batchelor J. Gregory Cairncross Stefan Pfister School of Medicine
14 To Guido Reifenberger Stefan Rutkowski provide a forum to evaluate Michael Weller and recommend Wolfgang Wick proposed changes to future CNS tumor classifications, cimpact- NOW will at regular intervals facilitate input and consensus review of novel diagnostically relevant data and determine how such information can be practically incorporated into CNS tumor classifications. While it is understood that the major impact on international brain tumor classification comes about through the WHO classification update process, it is anticipated that this additional process will see impact in selected tumor types and in time periods between the WHO classification updates. The cimpact-now updates are not intended to supplant the existing WHO classification, but to provide possible guidelines for practicing diagnosticians and future WHO classification updates.
15 BIOMARKER CONCEPTS Types Diagnostic Prognostic Predictive Practicality issues Cost and ease of implementation IHC vs. FISH vs. PCR vs. genomics Reimbursement School of Medicine
16 GBM BIOMARKERS: EGFR/PTEN (+ 7 / - 10 ) School of Medicine CEP 7 EGFR PTEN DMBT 1
17 OLIGODENDROGLIOMA 1 p 19 q FISH 1 p 32 1 q p q 13 School of Medicine
18 321 ( 5897 ): , 2008
19 IDH - 1 R 132 H IHC School of Medicine
20 DIAGNOSTIC EXAMPLE OF HISTOLOGIC MIMICRY: ELVIS IMPERSONATOR AO (IDHm and 1p/19q codeletion) Average survival 15 years 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 School of Medicine
21 REFLEX TO IDH 1 / 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 School of Medicine
22 CANCER CELLS ESCAPING SENESCENCE
23 School of Medicine Shay JW et al. Science 15: , 2012
24 Reitman et al. Acta Neuropathol ( 2013 ) 126:
25
26 Killela et al. PNAS 2013; 110:
27 ATRX/H 3.3 alterations ALT
28 ATRX IHC
29 Brain Pathol 25 ; , 2015
30 IDH - mutant astrocytomas IDH 1 p 53 ATRX
31 IDHm + 1 p/ 19 q - codel oligodendrogliomas IDH 1 p 53 ATRX
32 *Combine with m orphology and p 53 IHC *
33 DIFFUSE MIDLINE GLIOMA (DIPG, THAL, SC) H 3 K 27 me 3 H 3 K 27 M p 53 ATRX
34 Sturm et al., Cancer Cell 2012 ; 22:
35
36 HGG, H 3 G 34 R/V - mutant H 3 G 34 R/V p 53 ATRX
37 Astro, IDHm AA, IDHm IDHm 9 p (CDKN 2 A/B) LOH TP 53 m ATRXm Preneoplastic Cell IDHm TERTm 1 p 19 q - codel Oligo, IDHm, 1 p 19 q - codel CICm FUBP 1 m IDHwt EGFR - amp TERTm ( H 3 G 34 R/V) GBM, IDHwt Diffuse midline glioma, K27Mm PIK 3 R 1 /PIK 3 CAm 4 q LOH? PIK 3 CAm?
38 GBM, IDHm AO, IDHm, 1p19qcodel Note: no oligoastro!
39
40 (WHO NOS = Not Otherwise Specified)
41 DIFFUSE ASTROCYTOMA GRADING A typia M itoses E ndothelial Proliferation (MVP, EH) N ecrosis WHO II=A; III=A+M; IV=A+M+(E or N) School of Medicine
42
43 IDHwt
44 372 : , 2015 Oligos Astros 1 0 GBMs? IDHm ~ 90 % 2 0 GBMs IDHm ~ 10 % 1 0 GBMs
45 OTHER GLIOMA BIOMARKERS BRAF-KIAA1549 duplication/fusion pilocytic astrocytomas (~70% in cerebellum; less in other locations) Diagnostic and predictive (MEK inhibitors?) FISH or PCR: No IHC surrogates BRAF V600E mutation PXA (~67%), GG (20-60%), PA (~10%), HGG/GBM (5%), E-GBM (50%)
46 Predictive only: BRAF inhibitors, especially in recurrent or disseminated cases?
47 Ganglioglioma BRAF V 600 E
48 UCSF 500 LGG of unknown type post-rx (PXA-like signature)
49 MAPK pathway Nat Genet 45 : , 2013
50 BRAF
51 KIAA1549
52 Pajtler et al., 2015, Cancer Cell 27,
53 Clear cell ependymoma
54 Clear cell (RELA fusion+) ependymoma L 1 CAM
55 UCSF 500 NGS
56
57 PF - A Ependymoma PF - B Ependymoma H 3 K 27 me 3
58 School of Medicine EMBRYONAL NEOPLASMS
59 Taylor et al., Acta Neuropathol 2012 ; 123: School of Medicine
60 + p 53 LEF 1, ALK?
61 WNT MOL SUBTYPE β - catenin - β - catenin+
62 WNT MOL SUBTYPE ALK LEF 1
63 SHH MOL SUBTYPE YAP - 1 GAB - 1
64
65 SHH - ACTIVATED, TP 53 - MUTANT p 53
66 NON - WNT/NON - SHH MOL SUBTYPE YAP 1
67 UCSF500 NGS: SHH Medulloblastoma
68 School of Medicine WNT Medulloblastoma Scatter Plot
69 2017 ; 31:737-53
70 AT/RT Ho et al. Acta Neuropathol 99:482, 2000 School of Medicine
71 ATYPICAL TERATOID/RHABDOID TUMOR
72 AT/RT BRG 1 INI 1
73 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
74 Embryonal Tumor with Multilayered Rosettes (ETMR), C 19 MC - altered
75
76 ETMR CD 99 LIN 28 A
77 CNS School of Medicine WHO 2016 = Embryonal Tumors
78 CASE 1 34 yo man Presents with confusion MRI: 6 - cm hypodense left frontal mass with patchy enhancement Resection performed School of Medicine
79
80
81 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
82 POSSIBLE FINAL REPORT 1. Integrated Diagnosis: AO, IDH-mutant and 1p/19q codeleted, WHO III (ATRX intact) 2. Integrated Diagnosis: GBM, IDH-mutant, WHO grade IV (1p/19q intact, ATRX loss) 3. Integrated Diagnosis: GBM, IDH-wildtype, WHO grade IV (1p/19q intact, ATRX intact, +/- EGFRAMP, +7/-10, ptert-mut)
83 4. Diagnosis: GBM, NOS, WHO grade IV or AOA, NOS, WHO grade III (molecular not performed) POSSIBLE FINAL REPORT 1. Integrated Diagnosis: AO, IDH-mutant and 1p/19q codeleted, WHO III (ATRX intact) 2. Integrated Diagnosis: GBM, IDH-mutant, WHO grade IV (1p/19q intact, ATRX loss)
84 3. Integrated Diagnosis: GBM, IDH-wildtype, WHO grade IV (1p/19q intact, ATRX intact, +/- EGFRAMP, +7/-10, ptert-mut) 4. Diagnosis: GBM, NOS, WHO grade IV or AOA, NOS, WHO grade III (molecular not performed)
85 CASE yo girl 10 day hx of headaches followed by N/V, increasing tiredness, sleepiness and ataxia MRI: a well - demarcated posterior fossa mass School of Medicine
86
87
88
89
90
91 SYN GFAP
92 NFP NeuN
93 OLIG 2 p 53
94 INI 1 LIN 28
95 UCSF500 NGS
96
97 DX: High - grade Neuroepithelial Tumor, BCOR - altered (new entity that s not part of WHO 2016 ; o/w diagnosed as CNS ET, NOS ) School of Medicine
98
99
100 CNS HGNET - BCOR BCOR
101 Performance of Brain Tumor Rhapsody by Musaic (
102
103
WHO 2016 CNS Tumor Classification Update. DISCLOSURES (Arie Perry, MD) PATTERN RECOGNITION. Arie Perry, M.D. Director, Neuropathology
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