CNS UPDATE 2: DIFFUSE GLIOMAS AND PA. Arie Perry, M.D. Director, Neuropathology
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1 CNS UPDATE 2: DIFFUSE GLIOMAS AND PA Arie Perry, M.D. Director, Neuropathology
2 Distribution of Childhood Primary Brain and CNS Tumors by Histology and Age (Ages 0-14) (N = 15,398), CBTRUS Statistical Report: NPCR and SEER, Ostrom Q T et al. Neuro Oncol 2013;15:ii1-ii56 The Centers for Disease Control and Prevention. Published by Oxford University Press on behalf of the Society for Neuro-Oncology in cooperation with the Central Brain Tumor Registry 2013.
3
4 ISN-Haarlem conclusions (1) Disease entities should be defined as narrowly as possible in order to establish highly biologically uniform groups (i.e., as previously undertaken by the hematopathology community) Molecular information will be incorporated into the definitions of some diagnostic entities For some diagnostic entities, histology will remain the basis for definition and diagnosis
5 ISN-Haarlem conclusions (2) Grade will reflect natural history and will be based on histological findings; for some diagnoses, avoiding a histological grade may be preferable Some pediatric tumor types will require the creation of entities independent of their adult histological look-alikes 1. Pediatric GBM 2. Pediatric oligodendroglioma
6 ASTROCYTOMAS Diffuse Fibrillary Gemistocytic Giant Cell Small Cell Granular Cell Others Circumscribed / Favorable Pilocytic PXA SEGA DIA School of Medicine
7 School of Medicine DIFFUSE ASTROCYTOMAS
8 DIFFUSE ASTROCYTOMA GRADING Atypia Mitoses Endothelial Proliferation (MVP, EH) Necrosis WHO II=A; III=A+M; IV=A+M+(E or N) School of Medicine
9 School of Medicine ASTROCYTOMA (WHO GRADE II)
10
11 School of Medicine ANAPLASTIC ASTROCYTOMA, WHO III
12 School of Medicine GEMISTOCYTIC ASTROCYTOMAS
13 p53
14 GLIOBLASTOMA (GBM), WHO GRADE IV WHO dropped multiforme in 2000 Rapid onset and progression Rim (or ring)-enhancing, but can be less clear in kids Survival ~1-year, but highly variable More often brainstem and thalamus in kids, but also cerebral hemispheres School of Medicine
15 School of Medicine GBM, WHO IV
16
17 School of Medicine BRAINSTEM GLIOMA
18 BRAINSTEM GLIOMA Diffuse intrinsic pontine glioma (DIPG): malignant Dorsal, exophytic cervicomedullary astrocytoma (pilocytic) Focal tectal glioma (pilocytic) NF1-associated (pilocytic) School of Medicine
19
20
21
22 H3.3 K27M
23 Brain Pathology 23 (2013)
24 PDGFRα CEP4
25 IDH1R132H mutant GBM maybe further subdivided based upon PDGFRA amplification Log-rank test, p<0.05
26 Nat Genet 46: , 2014
27 GBM VARIANTS / PATTERNS School of Medicine Fibrillary (Classic) Gemistocytic Giant Cell Gliosarcoma Adenoid / Epithelioid / Metaplastic Lipidized Inflammation-rich Granular Cell Small Cell GBM with an oligodendroglial component GBM with PNET-like foci Rhabdoid / Epithelioid
28 School of Medicine GIANT CELL GBM
29 GFAP
30 GIANT CELL GBM 19p13 19q14 School of Medicine
31 GIANT CELL GBM/GS ~1-5% of GBMs and gliosarcomas Clinical DDx: Meningioma, pleomorphic sarcoma, or metastasis Pathology DDx: PXA (EGBs; BRAF V600E) Less infiltrative Clinically a primary GBM, but younger patients, TP53 mutations common and EGFR-AMP rare; Mostly IDH1-R132H-neg Small subset with better prognosis May be overrepresented in Turcot disease School of Medicine
32 19: 81-90, 2009
33
34 GFAP NSE SYN Neu-N
35 MIB-1 p53
36 GBM with PNET-like Features School of Medicine PTEN DMBT1
37 GBM with PNET-like Features School of Medicine CEP2 N-myc
38
39
40 GBM/GS WITH A PNET COMPONENT <1% of diffuse gliomas DDx: CNS PNET, lymphoma, metastatic small cell carcinoma Behaves locally like a GBM, but many develop CSF dissemination Can be either a primary or secondary GBM: PTEN-del in most cases, MYCN-AMP or MYCC-AMP in PNET-like area in >40%; IDH1-R132H in 16% Misdiagnosed CNS PNETs in kids? School of Medicine
41 AJSP 2010; 34: AJSP 2013; 37:658-98
42
43
44 GFAP SOX2
45 BRAF-V600E
46 RHABDOID/EPITHELIOID GBM School of Medicine Younger patients Superficial and circumscribed -22 in more rhabdoid cases? Focal INI1 loss? IDH1-neg BRAF V600E in more epithelioid cases Subset with better survival
47 Sturm et al., Cancer Cell 2012;22:
48 OLIGODENDROGLIOMA Rare in kids (2-3% of gliomas) Oligo mimics more common: DNT, pilocytic astrocytoma, central neurocytoma, clear cell ependymoma Series with long followup rare since often transfer care as adults Same biology as adults? Genetics appear to be different School of Medicine
49 School of Medicine OLIGODENDROGLIOMA, WHO GRADE II
50 GFAP
51 GFAP
52 School of Medicine ANAPLASTIC OLIGODENDROGLIOMA
53 SYN
54 ADULT TYPE OLIGODENDROGLIOMA IDH1-R132H
55 ADULT TYPE OLIGODENDROGLIOMA 1p32 1q42 19p13 19q13 School of Medicine
56
57 School of Medicine Raghavan et al. JNEN 62:530, 2003
58 Adult (some teenagers) Diffuse Glioma Histologic diagnosis Oligodendroglioma phenotype Astrocytoma phenotype Glioblastoma phenotype Diffuse glioma, indeterminate, mixed or ambiguous phenotype Grade II, III, IV, ungraded IDH, ATRX, 1p/19q Molecular information IDH, ATRX, 1p/19q Grade II, III, IV, ungraded Integrated Diagnosis 1) Histology and molecular concordant: Diagnosis, grade, molecular findings 2) Indeterminate or mixed histology: Diagnose and grade based on molecular profile 3) Histology and molecular discordant: Diffuse glioma, histologic phenotype, molecular profile 4) Molecular testing not performed: Histologic diagnosis, NOS
59 ADULT TYPE ASTROCYTOMA IDH1 p53 ATRX
60 Integrated diagnosis: Oligodendroglioma, WHO grade II, IDHmut, 1p/19q codeleted Histological classification: Diffuse glioma, oligodendroglioma phenotype WHO grade: Adult Type Oligodendroglioma Grade II Molecular information: IDH-mut, 1p/19q codel, ATRX intact
61 Molecular information Histologic classification Diffuse astrocytoma Oligodendroglioma Oligoastrocytoma or ambiguous histology IDH-mut, 1p/19qnondel, ATRX loss Diffuse astrocytoma, ATRX loss of expression Diffuse glioma (oligodendroglioma phenotype), 1p/19q non-deleted, ATRX loss of expression Diffuse astrocytoma, ATRX loss of expression IDH-mut, 1p/19q-codel, ATRX intact Diffuse glioma (astrocytoma phenotype), 1p/19q-codeleted Oligodendroglioma, 1p/19qcodeleted Oligodendroglioma, 1p/19q-codeleted IDH wild type Diffuse astrocytoma, IDH wild type* Diffuse glioma (oligodendroglioma phenotype), IDH wild type Diffuse astrocytoma, IDH wild type* Testing not performed Diffuse astrocytoma, NOS Oligodendroglioma, NOS Diffuse glioma, NOS
62 Pediatric AA/GBM H3F3A, DAXX TP53, ATRX Primary GBM EGFR, PDGFRA PTEN, TP53 CDKN2A/B, NF1 TERT promoter TP53 ATRX Diffuse astrocytoma Neural Progenitor Cell IDH1,2 IDH1-mutated infiltrating adult gliomas BRAF 1p/19q CIC, FUBP1 TERT promoter Oligodendroglioma Pilocytic astrocytoma PXA Anaplastic astrocytoma, GBM RB1,CDK4 CDKN2A, MDM2, PTEN RB1,CDK4 CDKN2A Anaplastic oligodendroglioma Courtesy of Dr. Dan Brat
63 PILOCYTIC ASTROCYTOMA Child / young adult Cerebellum, hypothalamus/3rd v., optic pathway, spinal cord NF1-associated OPG Insidious onset / slow growth Surgically curable (WHO I) 20-year survival = 80%
64 PILOCYTIC ASTROCYTOMA
65 PILOCYTIC ASTROCYTOMA
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67
68
69
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71 OPG-JPA
72
73 MAPK pathway Nat Genet 45: , 2013
74 BRAF KIAA1549
75 LOWER-GRADE GLIOMA GENETICS BRAF-KIAA1549 duplication/fusion pilocytic astrocytomas (~70% in cerebellum; less in other locations) PMA (1/3 rd to ½) MEK inhibitors? BRAF V600E mutation: PXA (~67%), GG (20-50%), DNET (20-30%), PA (~10%), GBM (5-10%) BRAF inhibitors, especially in recurrent or disseminated cases?
76 VIRTUALLY ALL PEDIATRIC BRAIN TUMORS Did you order BRAF testing? On this??? Really?? Pediatric Neuro-Oncologist Pediatric Pathologist/Neuropathologist
77
78 PILOMYXOID ASTROCYTOMA, WHO II
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80 School of Medicine Komotar et al. Neurosurgery 54:72, 2004
81
82 QUESTIONS?
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