EPIDEMIOLOGÍA Y CLASIFICACIÓN DE LOS TUMORES DEL SISTEMA NERVIOSO CENTRAL
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1 XI CURSO NACIONAL DE NEURORRADIOLOGÍA Barcelona, 19 de febrero de 2015 Neurorradiología en la patología tumoral cerebral EPIDEMIOLOGÍA Y CLASIFICACIÓN DE LOS TUMORES DEL SISTEMA NERVIOSO CENTRAL Elena Martínez Sáez Servicio de Anatomía Patológica Hospital Universitario Vall d Hebron, Barcelona
2 A MISCELLANEOUS International Society of Neuropathology-Haarlem Consensus Guidelines for Nervous System Tumor Classification and Grading David N. Louis 1 ; Arie Perry 2 ; Peter Burger 3 ; David W. Ellison 4 ; Guido Reifenberger 5,6 ; Andreas von Deimling 6,7 ; Kenneth Aldape 8 ; Daniel Brat 9 ; V. Peter Collins 10 ; Charles Eberhart 3 ; Dominique Figarella-Branger 11 ; Gregory N. Fuller 12 ; Felice Giangaspero 13,14 ; Caterina Giannini 15 ; Cynthia Hawkins 16 ; Paul Kleihues 17 ; Andrey Korshunov 6,18 ; Johan M. Kros 19 ; M. Beatriz Lopes 20 ; Ho-Keung Ng 21 ; Hiroko Ohgaki 22 ; Werner Paulus 23 ; Torsten Pietsch 24 ; Marc Rosenblum 25 ; Elisabeth Rushing 26 ; Figen Soylemezoglu 27 ; Otmar Wiestler 28 ; Pieter Wesseling 29, Brain Pathology 24 (2014) Julio The Authors. Brain Pathology published by John Wiley & Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA
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4 TUMORES ASTROCITARIOS TUMORES OLIGO- ASTROCITARIOS TUMORES OLIGODENDROGLIALES TUMORES EPENDIMARIOS OTROS TUMORES NEUROEPITELIALES TUMORES DE PLEXOS COROIDEOS TUMORES NEURONALES Y MIXTOS NEUROGLIALES TUMORES DE LA REGIÓN PINEAL TUMORES EMBRIONARIOS TUMOURS OF NEUROEPITHELIAL TISSUE WHO classification, 2007
5 XAP (gr. II) Astrocitoma Pilocítico (gr. I/III) A.! Pmx (gr. II) SEGA (gr. I) Tumores bien delimitados TUMORES ASTROCITARIOS TUMORES OLIGO- ASTROCITARIOS TUMORES OLIGODENDROGLIALES Astrocitoma Difuso (gr. II) Tumores difusamente infiltrantes OA (gr. II) O Anapl (gr. III) O (gr. II) Astrocitoma anaplásico (gr. III) Glioblastoma Multiforme (gr. IV) OAA (gr. III)
6 ASTROCITOMAS INFILTRANTES DIFUSOS!!Astrocitomas difusos- grado II % de los astrocitomas - 4ª década años de supervivencia media!!astrocitoma anaplásico- grado III - 45 años - 2 años de supervivencia media!!glioblastoma- grado IV -! Más frecuente: 12-15% tumores intracraneales, 60-75% de astrocitomas. -! 61 años -! 12 meses de supervivencia media
7 ASTROCITOMA DIFUSO-gr II-HIPERCELULARIDAD
8 ASTROCITOMA ANAPLÁSICO-gr. III- MITOSIS
9 GLIOBLASTOMA MULTIFORME-gr. IV NECROSIS Y/O PROLIFERACIÓN VASCULAR
10 DOS FORMAS DE PROLIFERACIÓN VASCULAR!! HIPERPLASIA ENDOTELIAL PROLIFERACIÓN MICROVASCULAR
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12 TÉCNICAS INMUNOHISTOQUÍMICAS Proteína glial fibrilar acídica (GFAP)
13 TÉCNICAS INMUNOHISTOQUÍMICAS GFAP Ki67 Índice de proliferación celular
14 TÉCNICAS INMUNOHISTOQUÍMICAS GFAP Ki67 p53 Gen supresor tumoral. Papel en apoptosis y control del ciclo celular. GBM secundarios
15 Astrocito o célula precursora ALTERACIONES MOLECULARES EN ASTROCITOMAS ASTROCITOMA DE BAJO GRADO Mutación TP53 (59%) Sobreexpresión PDGFR Grado II OMS GLIOBLASTOMA PRIMARIO LOH 10q (70%) Amplificación EGFR (36%) Deleción p16 (31%) Mutación TP53 (28%) Mutación PTEN (25%) Grado IV OMS ASTROCITOMA ANAPLÁSICO Mutación TP53 (53%) Sobreexpresión PDGFR Grado III OMS GLIOBLASTOMA SECUNDARIO LOH 10q (63%) Amplificación EGFR (8%) Deleción p16 (19%) Mutación TP53 (65%) Mutación PTEN (4%) Grado IV OMS Ohgaki H and Kleihues P. Genetic Pathways to Primary and Secondary Glioblastoma. Am J Pathol 2007, 150:
16 GLIOBLASTOMAS PRIMARIOS VS SECUNDARIOS +! +!! % #! $! $! $ $ $ EGFR fi TP53"! PTEN"! ) " IDH1/2"! 0!! TP53 "!! $ ATRX"!! $ * //"! #! $ #!! #! $ $ # ' CIC ""!!!! $ $ ( FUBP1 ""!!!! $ $ II! WHO grade III Amplificación EGFR Mutación IDH Mutación p53 Mutación ATRX Primary glioblastoma Secondary glioblastoma IV, " & & # & "!! fi - "!! fi #! #!! # 1! / ) Ohgaki H and Kleihues P. The definition of Primary and Secondary Glioblastomas. Clin Can Res 2013, 19(4).
17 Epidermal Growth Factor Receptor (EGFR) Amplificado en el 35% de GBMs primarios. Ayuda en el diagnóstico diferencial.
18 Isocitrato DesHidrogenasa 1&2 -!Parsons DW et al, 2008: 12% IDH mutado (An integrated genomic analysis of human glioblastoma multiforme. Science 321: ). - Balss et al, 2008 (Analysis of the IDH1 codon 132 mutation in brain tumours. Acta Neuropathol 116: ): 685 tumores neurogliales, -! 68% astrocitomas difusos -! 69% oligodendrogliomas -! 78% oligoastroctomas -! 88% GBM secundarios Mejor pronóstico en GBM
19 IDH R132H
20 Metilación del promotor de MGMT O6-MethylGuanine-DNAMethylTransferase Proteína reparadora de DNA que protege a las células del GBM de agentes alquilantes (TMZ). Metilación del promotor >silenciación epigenética de MGMT >predictivo de mayor supervivencia tras TMZ+RT. Excesiva variabilidad intra e interlaboratorios en el método de detección >pirosecuenciación.
21 ATRX (Alpha-Thalassemia/Mental Retardation syndrome X-linked) 2011: mutaciones en 30-40% GBM pediátricos. 2012: mutaciones en 25,6% de 363 gliomas: -! 67% astrocitomas grado II -! 73% astrocitomas grado III -! 57% GBMs secundarios -! 68% oligoastrocitomas mixtos -! 14% oligodendrogliomas puros -! 4% GBMs primarios La mutación de ATRX y la codeleción de 1p/19q son casi excluyentes.
22 ATRX (Alpha-Thalassemia/Mental Retardation syndrome X-linked) Clinical Neuropathology, Vol. 33 No. 2/2014 ( )
23 OLIGODENDROGLIOMAS!! Gliomas infiltrantes!! Mejor pronóstico que los astrocitomas infiltrantes: supervivencia media de 11a.!! años.!! Grados II (oligodendroglioma) y III (oligodendroglioma anaplásico)!!codeleción 1p/19q: factor diagnóstico y pronóstico
24 Oligodendroglioma, gr. II: Núcleos redondos, halo perinuclear Capilares finos ramificados
25
26 Oligodendroglioma anaplásico, gr. III: Hipercelularidad, atipia, abundantes mitosis, proliferación microvascular y necrosis
27 +! +! ) " IDH1/2"! 0!!! % # TP53 "!! $ ATRX"!! $ * //"! #! ' CIC "!! $ ( FUBP1 "!! $ WHO grade II Mutación IDH Codeleción 1p/19q $ #! $! $! $ $ $ EGFR fi TP53"! PTEN"!!! #! $ $ #! III Primary glioblastoma Secondary glioblastoma IV, " & & # & "!! fi - "!! fi #! #!! # 1! / ) Ohgaki H and Kleihues P. The definition of Primary and Secondary Glioblastomas. Clin Can Res 2013, 19(4).
28 Codeleción 1p/19q!! Mejor pronóstico. Mejor respuesta a tratamiento. Woehrer, Sander, Haberler et al. Clinical Neuropathology, Vol. 30 No. 2/2011 (47-55)
29 MISCELLANEOUS International Society of Neuropathology-Haarlem Consensus Guidelines for Nervous System Tumor Classification and Grading David N. Louis 1 ; Arie Perry 2 ; Peter Burger 3 ; David W. Ellison 4 ; Guido Reifenberger 5,6 ; Andreas von Deimling 6,7 ; Kenneth Aldape 8 ; Daniel Brat 9 ; V. Peter Collins 10 ; Charles Eberhart 3 ; Dominique Figarella-Branger 11 ; Gregory N. Fuller 12 ; Felice Giangaspero 13,14 ; Caterina Giannini 15 ; Cynthia Hawkins 16 ; Paul Kleihues 17 ; Andrey Korshunov 6,18 ; Johan M. Kros 19 ; M. Beatriz Lopes 20 ; Ho-Keung Ng 21 ; Hiroko Ohgaki 22 ; Werner Paulus 23 ; Torsten Pietsch 24 ; Marc Rosenblum 25 ; Elisabeth Rushing 26 ; Figen Soylemezoglu 27 ; Otmar Wiestler 28 ; Pieter Wesseling 29,30 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA Julio 2014 Brain Pathology 24 (2014) The Authors. Brain Pathology published by John Wiley & Table 2. Report format. Layer 1: Integrated diagnosis (incorporating all tissue-based information) Layer 2: Histological classification Layer 3: WHO grade (reflecting natural history) Layer 4: Molecular information
30 Table 5. Example: integrated diagnoses for WHO grade II adult diffuse gliomas. # Histologic classification Diffuse astrocytoma Oligodendroglioma Oligoastrocytoma or ambiguous histology Molecular information IDH-mut, 1p/19q-nondel, ATRX loss IDH-mut, 1p/19q-codel, ATRX intact Diffuse astrocytoma, ATRX loss of expression Diffuse glioma (astrocytoma phenotype), 1p/19q-codeleted Diffuse glioma* (oligodendroglioma phenotype), 1p/19q non-deleted, ATRX loss of expression Oligodendroglioma, 1p/19q-codeleted IDH wild type Diffuse astrocytoma, IDH wild type* Diffuse glioma* (oligodendroglioma phenotype), IDH wild type* Diffuse astrocytoma, ATRX loss of expression Oligodendroglioma, 1p/19qcodeleted Diffuse astrocytoma, IDH wild type* Testing not performed Diffuse astrocytoma, NOS Oligodendroglioma, NOS Diffuse glioma, NOS This example shows how the integrated diagnostic terms for adult WHO grade II diffuse gliomas (names in italics in boxes) could involve a Brain Pathology 24 (2014) The Authors. Brain Pathology published by John Wiley &
31 Acta Neuropathol (2015) 129: DOI /s ORIGINAL PAPER ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an integrated diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma David E. Reuss Felix Sahm Daniel Schrimpf Benedikt Wiestler David Capper Christian Koelsche Leonille Schweizer Andrey Korshunov David T. W. Jones Volker Hovestadt Michel Mittelbronn Jens Schittenhelm Christel Herold-Mende Andreas Unterberg Michael O Platten Michael A Weller A Wolfgang Wick Stefan M. Pfister Andreas von Deimling ini al diagnosis O GBM GBMo GBMs gcgbm GS casos O A-IDHmut A-IDHwt GBM GBM-IDHmut gcgbm GS integrated diagnosis
32 OS for 2007 reference histology ini al diagnosis O OA A Anaplastic oligodendroglioma (WHO grade III) Anaplastic oligoastrocytoma (WHO grade III) Anaplastic astrocytoma (WHO grade III) ! Mejor correlación Time con (days) supervivencia -! Menor variabilidad intra e interobservador OS for integrated diagnosis O A-IDHmut A-IDHwt GBM integrated diagnosis Anaplastic oligodendroglioma (WHO grade III) Anaplastic astrocytoma (WHO grade III) IDH mutated Anaplastic astrocytoma (WHO grade III) Glioblastoma (WHO grade IV) Acta Neuropathol (2015) 129: Time (days) Prediction Error for OS
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34 Raf quinasas: A-Raf, B-Raf, C-Raf Vía de señalización celular Ras, Raf, MAPK Proliferación celular Nature Reviews Cancer 4,
35 MUTACIÓN V600E BRAF FUSIÓN BRAF-KIAA
36 ESTUDIO DE MUTACIÓN DE BRAF V600E Muestra WT Muestra Mutada (V600E) GTG>GAG Valina>glutamato
37 Mutación BRAF V600E descrita en: -! Melanoma -! Carcinoma de colon -! Carcinoma papilar de tiroides Acta Neuropathol (2011) 121: DOI /s ORIGINAL PAPER Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma!! Xantoastrocitomas pleomórficos: 66%!! XAP con rasgos anaplásicos: 65%!! Gangliogliomas: 18%!! Gangliogliomas anaplásicos (3/6) Astrocitomas pilocíticos: 9%!! DIENCEFÁLICOS!! EXTRA-CEREBELOSOS
38 K0/,+?%!!%=L3)3.-%:0:.6('-%*+6+%+%*)3J6)/3'.&.-;% /L3)3.-%M.6(+*.(+-.-%N3>70&+-% %
39 XANTOASTROCITOMA PLEOMÓRFICO Con MUTACIÓN BRAF V600E: -! Localización TEMPORAL -! Mayor trama de reticulina -! Mayor expresión de CD34 -! Mayor supervivencia global RESEARCH ARTICLE BRAF-Mutated Pleomorphic Xanthoastrocytoma is Associated with Temporal Location, Reticulin Fiber Deposition and CD34 Expression Christian Koelsche 1,2 ; Felix Sahm 1,2 ; Adelheid Wöhrer 3 ; Astrid Jeibmann 4 ; Jens Schittenh Brain Pathology 24 (2014) Pleomorphic Xanthoastrocytoma What Do We Really Know about It? CANCER May 1, 1999 / Volume 85 / Number 9 Pleomorphic Xanthoastrocytoma: Natural History and Long-term Follow-up. Brain Pathol Oct 16. doi: /bpa J Neurooncol (2013) 114: DOI /s ! Futuros tratamientos con inhibidores de BRAF: Vemurafenib CLINICAL STUDY Salvage therapy with BRAF inhibitors for recurrent pleomorphic xanthoastrocytoma: a retrospective case series Marc C. Chamberlain Successful Treatment of a Progressive BRAF V600E Mutated Anaplastic Pleomorphic Xanthoastrocytoma With Vemurafenib Monotherapy Introduction Journal of Clinical Oncology, Vol 32, 2014 Downloaded from j
40 ASTROCITOMA PILOCÍTICO FUSIÓN BRAF-KIAA 1549!! A30+*.%*C-%9,'/)'6('%'6%60P+-%NQ#$%R.-(.%3+-%#S%.;%#T$%&'%#E%.%#U%.O1%!! 2'-056%<0'6%&'30*0(.&.;%Z)>-J/.%/+6%65&)3+%*),.31%%!! [-(,+/0(+*.%703+/>J/+%.6.73C-0/+;%:,%BBB;%/.-+-%.0-3.&+-1%
41 ASTROCITOMA PILOCÍTICO FUSIÓN BRAF-KIAA 1549 " 1A> ; < -@4; 8 D< " 1A> ; 8 ; < E> 534@Ó. 9 1> 5/ -:?? ; / 5-@5; : ; 2" 1A> ; < -@4; 8; : / ) ; 8 " ; -: A-> E < < Y % ) * % ' > -53 ; >. 5:? 75! $ 4 Centrómero cr 7 Gen de BRAF Porción kinasa )75,1
42 #! #! # " "! "!,; 9/54 $,; 9/54 $ : 2+ ' 9: 54+. ' 2, 5, ' 22659: + 8/58,599' /4,8' : + 4: 58/' 2' 4* 56: /) 4+ 8< + 25= - 8' * + - 2/53 ' 9. ' < + ',; 9/54 = ' 9 542? 54+ :. /8* 5, ' 229; 68' : + 4: 58/' Niños> adultos Infratentorial>supratentorial 03, 4 * / ( & -* Mejor pronóstico (?) Ayuda en dignóstico diferencial % 5 7* * ( 56( ' / ( 6+ 1' 1),0& 14214$ 6,0* 6( 56,0*,0
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