Table Of Content

WHO Classification of Tumours of the Central Nervous System David N. Louis, Hiroko Ohgaki, Otmar D. Wiestier, Webster K. Cavenee, David W. Ellison, Dominique Figarella-Branger, Arie Perry, Guido Reifenberger, Andreas von Deimling WHO World Health Organization Classification of Tumours OMS WHO International Agency for Research on Cancer (IARC) Revised 4th Edition WHO Classification of Tumours of the Central Nervous System Edited by David N. Louis Hiroko Ohgaki Otmar D. Wiestler Webster K. Cavenee International Agency for Research on Cancer Lyon, 2016 World Health Organization Classification of Tumours Series Editors Fred T. Bosman, MD PhD Elaine S. Jaffe, MD Sunil R. Lakhani, MD FRCPath Hiroko Ohgaki, PhD WHO Classification of Tumours of the Central Nervous System Revised 4th Edition Editors David N. Louis, MD Hiroko Ohgaki, PhD Otmar D. Wiestler, MD Webster K. Cavenee, PhD Senior Advisors David W. Ellison, MD PhD, Dominique Figarella-Branger, MD Arie Perry, MD Guido Reifenberger, MD Andreas von Deimling, MD Project Coordinator Paul Kleihues, MD Project Assistant Asiedua Asante Technical Editor Jessica Cox Database Kees Kleihues-van Tol Layout Stefanie Brottrager Printed by Maestro 38330 Saint-lsmier, France Publisher International Agency for Research on Cancer (IARC) 69372 Lyon Cedex 08, France This volume was produced with support from and in collaboration with the German Cancer Research Center The WHO Classification of Tumours of the Central Nervous System presented in this book reflects the views of a Working Group that convened for Consensus and Editorial Meeting at the German Cancer Research Center, Heidelberg, 21-24 June 2015. Members of the Working Group are indicated in the list of contributors on pages 342-348. Published by the International Agency for Research on Cancer (IARC) 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France © International Agency for Research on Cancer, 2016 Distributed by WHO Press, World Health Organization, 20 Avenue Appla, 1211 Geneva 27, Switzerland Tel.: +41 22 791 3264; Fax: +41 22 791 4857; email: [email protected] Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of Its authorities, or concerning the delimitation of Its frontiers or boundaries. The mention of specific companies or of certain manufacturers’ products does not Imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The authors alone are responsible for the views expressed In this publication. The copyright of figures and charts remains with the authors. (SeeSources of figures and tables, pages 351-355.) First print run (10 000 copies) Formatforbibliographiccitations; DavidN.Louis,HirokoOhgaki,OtmarD.Wiestler,WebsterK.Cavenee(Eds): WHO Classification of Tumours of the Central Nervous System (Revised 4th edition). IARC; Lyon 2016. IARCLibraryCataloguinginPublicationData WHO classification of tumours of the central nervous system / edited by David N. Louis, Hiroko Ohgaki, Otmar D. Wiestler, Webster K. Cavenee. -Revised 4th edition. (WorldHealthOrganizationclassificationoftumours) 1. CentralNervousSystemNeoplasms-genetics 2. Central Nervous System Neoplasms -pathology I. Louis David N ISBN 978-92-832-4492-9 (NLM Classification: WJ 160) Contents WHO classification 10 Anaplastic ganglioglioma 141 Introduction: WHO classification and grading of tumours Dysplastic cerebellar gangliocytoma of the central nervous system 12 (Lhermitte-Duclos disease) 142 Desmoplastic infantile astrocytoma and ganglioglioma 144 1 Diffuse astrocytic and oligodendroglial tumours 15 Papillary glioneuronal tumour 147 Introduction 16 Rosette-forming glioneuronal tumour 150 Diffuse astrocytoma, IDH-mutant 18 Diffuse leptomeningeal glioneuronal tumour 152 Gemistocytic astrocytoma, IDH-mutant 22 Central neurocytoma 156 Diffuse astrocytoma, IDH-wildtype 23 Extraventricular neurocytoma 159 Diffuse astrocytoma, NOS 23 Cerebellar liponeurocytoma 161 Anaplastic astrocytoma, IDH-mutant 24 Paraganglioma 164 Anaplastic astrocytoma, IDH-wildtype 27 Anaplastic astrocytoma, NOS 27 7 Tumours of the pineal region 169 Glioblastoma, IDH-wildtype 28 Pineocytoma 170 Giant cell glioblastoma 46 Pineal parenchymal tumour of intermediate differentiation 173 Gliosarcoma 48 Pineoblastoma 176 Epithelioid glioblastoma 50 Papillary tumour of the pineal region 180 Glioblastoma, IDH-mutant 52 Glioblastoma, NOS 56 8 Embryonal tumours 183 Diffuse midline glioma, H3 K27M-mutant 57 Medulloblastoma 184 Oligodendroglioma, IDH-mutant and 1p/19q-codeleted 60 Medulloblastoma, NOS 186 Oligodendroglioma, NOS 69 Medulloblastomas, genetically defined 188 Anaplastic oligodendroglioma, IDH-mutant and Medulloblastoma, WNT-activated 188 1p/19q-codeleted 70 Medulloblastoma, SHH-activated and TP53-mutant 190 Anaplastic oligodendroglioma, NOS 74 Medulloblastoma, SHH-activated and TP53-wildtype 190 Oligoastrocytoma, NOS 75 Medulloblastoma, non-WNT/non-SHH 193 Anaplastic oligoastrocytoma, NOS 76 Medulloblastomas, histologically defined 194 Medulloblastoma, classic 194 2 Other astrocytic tumours 79 Desmoplastic/nodular medulloblastoma 195 Pilocytic astrocytoma 80 Medulloblastoma with extensive nodularity 198 Pilomyxoid astrocytoma 88 Large cell / anaplastic medulloblastoma 200 Subependymal giant cell astrocytoma 90 Embryonal tumour with multilayered rosettes, Pleomorphic xanthoastrocytoma 94 C19MC-altered 201 Anaplastic pleomorphic xanthoastrocytoma 98 Embryonal tumour with multilayered rosettes, NOS 205 Other CNS embryonal tumours 206 3 Ependymal tumours 101 Medulloepithelioma 207 Subependymoma 102 CNS neuroblastoma 207 Myxopapillary ependymoma 104 CNS ganglioneuroblastoma 207 Ependymoma 106 CNS embryonal tumour, NOS 208 Papillary ependymoma 111 Atypical teratoid/rhabdoid tumour 209 Clear cell ependymoma 111 CNS embryonal tumour with rhabdoid features 212 Tanycytic ependymoma 111 Ependymoma, RELAfusion-positive 112 9 Tumours of the cranial andparaspinal nerves 213 Anaplastic ependymoma 113 Schwannoma 214 Cellular schwannoma 216 4 Other gliomas 115 Plexiform schwannoma 217 Chordoid glioma of the third ventricle 116 Melanotic schwannoma 218 Angiocentric glioma 119 Neurofibroma 219 Astroblastoma 121 Atypical neurofibroma 220 Plexiform neurofibroma 220 5 Choroid plexus tumours 123 Perineurioma 222 Choroid plexus papilloma 124 Hybrid nerve sheath tumours 224 Atypical choroid plexus papilloma 126 Malignant peripheral nerve sheath tumour (MPNST) 226 Choroid plexus carcinoma MPNST with divergent differentiation 227 128 Epithelioid MPNST 228 6 Neuronal and mixed neuronal-glial tumours 131 MPNST with perineurial differentiation 228 Dysembryoplastic neuroepithelial tumour 132 Gangliocytoma 136 10 Meningiomas 231 Ganglioglioma 138 Meningioma 232 Meningioma variants 237 Intravascular large B-cell lymphoma 276 Meningothelial meningioma 237 Miscellaneous rare lymphomas in the CNS 276 Fibrous meningioma 237 Low-grade B-cell lymphomas 276 Transitional meningioma 238 T-cell and NK/T-cell lymphomas 276 Psammomatous meningioma 238 Anaplastic large cell lymphoma (ALK+/ALK-) 277 Angiomatous meningioma 238 MALT lymphoma of the dura 277 Microcystic meningioma 239 14 Histiocytic tumours 279 Secretory meningioma 239 Lymphoplasmacyte-rich meningioma 240 Langerhans cell histiocytosis 280 Metaplastic meningioma 240 Erdheim-Chester disease 281 Chordoid meningioma 240 Rosai-Dorfman disease 282 Clear cell meningioma 241 Juvenile xanthogranuloma 282 Atypical meningioma 241 Histiocytic sarcoma 283 Papillary meningioma 242 15 Germ cell tumours 285 Rhabdoid meningioma 243 Anaplastic (malignant) meningioma 244 Germinoma 288 Embryonal carcinoma 289 11 Mesenchymal, non-meningothelial tumours 247 Yolk sac tumour 290 Solitary fibrous tumour /haemangiopericytoma 249 Choriocarcinoma 290 Haemangioblastoma 254 Teratoma 291 Haemangioma 258 Mature teratoma 291 Epithelioid haemangioendothelioma 258 Immature teratoma 291 Angiosarcoma 259 Teratoma with malignant transformation 291 Kaposi sarcoma 259 Mixed germ cell tumour 291 Ewing sarcoma / peripheral primitive 16 Familial tumour syndromes 293 neuroectodermal tumour 259 Lipoma 260 Neurofibromatosis type 1 294 Angiolipoma 260 Neurofibromatosis type 2 297 Hibernoma 260 Schwannomatosis 301 Liposarcoma 260 Von Hippel-Lindau disease 304 Desmoid-type fibromatosis 260 Tuberous sclerosis 306 Myofibroblastoma 260 Li-Fraumeni syndrome 310 Inflammatory myofibroblastic tumour 261 Cowden syndrome 314 Benign fibrous histiocytoma 261 Turcot syndrome 317 Fibrosarcoma 261 Mismatch repair cancer syndrome 317 Undifferentiated pleomorphic sarcoma / malignant Familial adenomatous polyposis 318 fibrous histiocytoma 261 Naevoid basal cell carcinoma syndrome 319 Leiomyoma 262 Rhabdoid tumour predisposition syndrome 321 Leiomyosarcoma 262 17 Tumours of thesellarregion 323 Rhabdomyoma 262 Rhabdomyosarcoma 262 Craniopharyngioma 324 Chondroma 262 Adamantinomatous craniopharyngioma 327 Chondrosarcoma 263 Papillary craniopharyngioma 328 Osteoma 264 Granular cell tumour of thesellar region 329 Osteochondroma 264 Pituicytoma 332 Osteosarcoma 264 Spindle cell oncocytoma 334 18 Metastatic tumours 337 12 Melanocytic tumours 265 Meningeal melanocytosis 267 Contributors 342 Meningeal melanomatosis 267 Meningeal melanocytoma 268 Declaration of interest statements 349 Meningeal melanoma 269 IARC/WHO Committee for ICD-0 350 Sources of figures and tables 351 13 Lymphomas 271 References 356 Diffuse large B-cell lymphoma of the CNS 272 Subject index 402 Corticoid-mitigated lymphoma 275 Lisit of abbreviations 408 Sentinel lesions 275 Immunodeficiency-associated CNS lymphomas 275 AIDS-related diffuse large B-cell lymphoma 275 EBV+ diffuse large B-cell lymphoma, NOS 276 Lymphomatoid granulomatosis 276 WHO classification of tumours of the central nervous system Diffuse astrocytic and oligodendroglial Neuronal and mixed neuronal-glial tumours tumours Diffuse astrocytoma, IDH-mutant 9400/3 Dysembryoplasticneuroepithelialtumour 9413/0 Gemistocyticastrocytoma, IDH-mutant 9411/3 Gangliocytoma 9492/0 Diffuse astrocytoma, IDH-wildtype 9400/3 Ganglioglioma 9505/1 Diffuse astrocytoma, NOS 9400/3 Anaplastic ganglioglioma 9505/3 Dysplastic cerebellar gangliocytoma Anaplastic astrocytoma, IDH-mutant 9401/3 (Lhermitte-Duclos disease) 9493/0 Anaplastic astrocytoma, IDH-wildtype 9401/3 Desmoplastic infantile astrocytoma and Anaplastic astrocytoma, NOS 9401/3 ganglioglioma 9412/1 Papillary glioneuronal tumour 9509/1 Glioblastoma, IDH-wildtype 9440/3 Rosette-forming glioneuronal tumour 9509/1 Giant cell glioblastoma 9441/3 Diffuse leptomeningeal glioneuronal tumour Gliosarcoma 9442/3 Central neurocytoma 9506/1 Epithelioid glioblastoma 9440/3 Extraventricular neurocytoma 9506/1 Glioblastoma, IDH-mutant 9445/3* Cerebellar liponeurocytoma 9506/1 Glioblastoma, NOS 9440/3 Paraganglioma 8693/1 Diffuse midline glioma, H3 K27M-mutant 9385/3* Tumours of the pineal region Pineocytoma 9361/1 Oligodendroglioma, IDH-mutant and Pineal parenchymal tumour of intermediate 1p/19q-codeleted 9450/3 differentiation 9362/3 Oligodendroglioma, NOS 9450/3 Pineoblastoma 9362/3 Papillary tumour of the pineal region 9395/3 Anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted 9451/3 Embryonal tumours Anaplastic oligodendroglioma, NOS 9451/3 Medulloblastomas, genetically defined Medulloblastoma, WNT-activated 9475/3* Oligoastrocytoma, NOS 9382/3 Medulloblastoma, SHH-activated and Anaplastic oligoastrocytoma, NOS 9382/3 TP53-mutant 9476/3* Medulloblastoma, SHH-activated and Other astrocytic tumours TP53-wildtype 9471/3 Pilocytic astrocytoma 9421/1 Medulloblastoma, non-WNT/non-SHH 9477/3* Pilomyxoid astrocytoma 9425/3 Medulloblastoma, group 3 Subependymal giant cell astrocytoma 9384/1 Medulloblastoma, group 4 Pleomorphic xanthoastrocytoma 9424/3 Medulloblastomas, histologically defined Anaplastic pleomorphic xanthoastrocytoma 9424/3 Medulloblastoma, classic 9470/3 Medulloblastoma, desmoplastic/nodular 9471/3 Ependymal tumours Medulloblastoma with extensive nodularity 9471/3 Subependymoma 9383/1 Medulloblastoma, large cell / anaplastic 9474/3 Myxopapillary ependymoma 9394/1 Medulloblastoma, NOS 9470/3 Ependymoma 9391/3 Papillary ependymoma 9393/3 Embryonal tumour with multilayered rosettes, Clear cell ependymoma 9391/3 C19MC-altered 9478/3* Tanycytic ependymoma 9391/3 Embryonal tumour with multilayered Ependymoma,RELAfusion-positive 9396/3* rosettes, NOS 9478/3 Anaplastic ependymoma 9392/3 Medulloepithelioma 9501/3 CNS neuroblastoma 9500/3 Other gliomas CNS ganglioneuroblastoma 9490/3 Chordoid glioma of the third ventricle 9444/1 CNS embryonal tumour, NOS 9473/3 Angiocentric glioma 9431/1 Atypical teratoid/rhabdoid tumour 9508/3 Astroblastoma 9430/3 CNS embryonal tumour with rhabdoid features 9508/3 Choroid plexus tumours Tumours of the cranial and paraspinalnerves Choroid plexus papilloma 9390/0 Schwannoma 9560/0 Atypical choroid plexus papilloma 9390/1 Cellular schwannoma 9560/0 Choroid plexus carcinoma 9390/3 Plexiform schwannoma 9560/0 10 WHO classification of tumours of the central nervous system Melanoticschwannoma 9560/1 Osteochondroma 9210/0 Neurofibroma 9540/0 Osteosarcoma 9180/3 Atypical neurofibroma 9540/0 Melanocytic tumours Plexiform neurofibroma 9550/0 Perineurioma 9571/0 Meningeal melanocytosis 8728/0 Hybrid nerve sheath tumours 9540/3 Meningealmelanocytoma 8728/1 Malignant peripheral nerve sheath tumour Meningeal melanoma 8720/3 Epithelioid MPNST 9540/3 Meningealmelanomatosis 8728/3 MPNST with perineurialdifferentiation 9540/3 Lymphomas Meningiomas 9530/0 Diffuse large B-cell lymphoma of the CNS 9680/3 Meningioma Immunodeficiency-associated CNS lymphomas Meningothelialmeningioma 9531/0 AIDS-related diffuse large B-cell lymphoma Fibrous meningioma 9532/0 EBV-positivediffuselargeB-celllymphoma, Transitional meningioma 9537/0 NOS Psammomatousmeningioma 9533/0 Lymphomatoidgranulomatosis 9766/1 Angiomatous meningioma 9534/0 Intravascular large B-cell lymphoma 9712/3 Microcysticmeningioma 9530/0 Low-grade B-cell lymphomas of the CNS T-cell 9714/3 Secretory meningioma 9530/0 and NK/T-cell lymphomas of the CNS Anaplastic Lymphoplasmacyte-rich meningioma 9530/0 large cell lymphoma, ALK-positive Metaplastic meningioma 9530/0 Anaplastic large cell lymphoma, ALK-negative 9702/3 Chordoidmeningioma 9538/1 MALT lymphoma of the dura 9699/3 Clear cell meningioma 9538/1 Histiocytic tumours Atypical meningioma 9539/1 Langerhans cellhistiocytosis 9751/3 Papillary meningioma 9538/3 Erdheim-Chester disease 9750/1 Rhabdoidmeningioma 9538/3 Rosai-Dorfmandisease 9755/3 Anaplastic (malignant) meningioma 9530/3 Juvenilexanthogranuloma Mesenchymal, non-meningothelialtumours 8815/0 Histiocytic sarcoma Solitary fibrous tumour /haemangiopericytoma** Germ cell tumours Grade 1 Grade 2 8815/1 Germinoma 9064/3 Grade 3 8815/3 Embryonal carcinoma 9070/3 Haemangioblastoma 9161/1 Yolk sac tumour 9071/3 Haemangioma 9120/0 Choriocarcinoma 9100/3 Epithelioidhaemangioendothelioma 9133/3 Teratoma 9080/1 Angiosarcoma 9120/3 Mature teratoma 9080/0 Kaposi sarcoma 9140/3 Immature teratoma 9080/3 Ewing sarcoma / PNET 9364/3 Teratomawith malignant transformation 9084/3 Lipoma 8850/0 Mixed germ cell tumour 9085/3 Angiolipoma 8861/0 Tumours of thesellarregion Hibernoma 8880/0 Liposarcoma 8850/3 Craniopharyngioma 9350/1 Desmoid-type fibromatosis 8821/1 Adamantinomatouscraniopharyngioma 9351/1 Myofibroblastoma 8825/0 Papillary craniopharyngioma 9352/1 Inflammatorymyofibroblastictumour 8825/1 Granular cell tumour of thesellarregion 9582/0 Benign fibrous histiocytoma 8830/0 Pituicytoma 9432/1 Fibrosarcoma 8810/3 Spindle celloncocytoma 8290/0 Undifferentiated pleomorphic sarcoma / malignant8802/3 fibrous histiocytoma Metastatic tumours Leiomyoma 8890/0 The morphology codes are from the International Classification of Diseases for Leiomyosarcoma 8890/3 Oncology (ICD-O) {742A}. Behaviouris coded /0for benign tumours; Rhabdomyoma 8900/0 /1 for unspecified, borderline, or uncertain behaviour; /2for carcinoma in situ and grade III intraepithelial neoplasia; and /3for malignant tumours. The classification Rhabdomyosarcoma 8900/3 is modified from the previous WHO classification, taking into account changes in Chondroma 9220/0 our understanding of these lesions. Chondrosarcoma 9220/3 'These new codes were approved by the IARC/WHO Committee for ICD-O.Italics: Provisional tumour entities. "Grading according to the 2013WHO Classification of Osteoma 9180/0 Tumours of Soft Tissue and Bone. WHO classification of tumours of the central nervous system 11 WHO classification and grading of Louis D.N. tumours of the central nervous system Combined histological-molecular molecular genetic alterations suggest a genetic finding is present, leaving that classification that such challenges will be readily over- to individual practitioners and institutions, For nearly a century, the classification of come in the near future {2105}. Many of but the commentary sections do clarify brain tumours has been based on con- the genetic parameters included in the theimplicationofcertaingeneticfeatures; cepts of histogenesis, hingingontheidea 2016 WHO classification can be as- forexample,inwhatsituationsIDHstatus that tumours can be classified according sessed using immunohistochemistry canbedesignatedaswildtype. to their microscopic similarities with puta- or FISH, but it is recognized that some Histologicalgrading tivecellsoforiginandtheirdevelopmental centres may not have the ability to carry Histological grading is a means of pre- differentiation states. These histological out molecular analyses and that some dicting the biological behaviour of a similarities have been characterized pri- molecular results may not be conclusive. neoplasm. In the clinical setting, tumour marilyonthebasisofthelightmicroscop- Withthisinmind,anNOSdiagnosticdes- grade is a key factor influencing the ic appearance of H&E-stained sections, ignation has been included in the 2016 choice of therapies. Since its first pub- the immunohistochemical expression of WHO classification wherever such issues lication in 1979, the WHO classification proteins, and the electron microscopic may apply. The NOS designation indi- of tumours ofthe central nervous system assessment of ultrastructural features. cates that there is insufficient informa- has included a grading scheme that es- The 2000 and 2007 WHO classifications tion to assign a more specific code. In sentially constitutes a malignancy scale considered histological features along this context, the NOS category includes (ranging across a wide variety of neo- with the rapidly increasing knowledge both tumours that have not been tested plasms) rather than a strict histological of the genetic changes that underlie the for the genetic parameter(s) and tumours grading system {1290,1291,2878}. WHO tumorigenesis of CNS tumours. Many that have been tested but did not show grading is widely used, and it has incor- of the canonical genetic alterations had the diagnostic genetic alterations. In porated or largely replaced other previ- been identified by the time the 2007 other words, the NOS designation does ously published grading systems for WHO classification was published, but at not refer to a specific entity; instead, it brain tumours. Although grading is not the time the consensus opinion was that designates the lesions that cannot be a requirement for the application of the such changes could not yet be used to classified into any of the more precisely WHO classification for some tumours, define neoplasms; instead, genetic sta- definedgroups. including gliomas and meningiomas, tus served as supplementary information Definitions, disease summaries, and numerical WHO grades are useful addi- within the framework of diagnostic cat- commentaries tions to the diagnoses. The WHO Work- egories established by standard, histolo- Each entity-specific section in the 2016 ing Group responsible for this update of gy-based means. In contrast, the present WHO classification begins with a short the 4th editionhas expanded the classifi- update (the 2016 classification) breaks disease definition that describes the es- cation to include additional entities; how- with this nearly century-old tradition and sential diagnostic criteria. This initial ever, since thenumber of cases of some incorporates well-established molecular definition is followed by a description of of these newly defined entities is limited, parameters into the classification of dif- characteristic associated findings; for theassignment of grades tosuch entities fusegliomas. example, although a delicate branching is still provisional, pending publication of Changing the classification to include vasculature and calcospherites are not additionaldataandlong-termfollow-up. diagnostic categories that depend on essential for the diagnosis of oligoden- genotype may create certain challenges Histological grading across tumour droglioma, they are highly characteristic. with respect to testing and reporting. entities The diagnostic criteria and characteris- These challenges include the availability Grade I lesions are generally tumours tic features are then followed by the rest and choice of genotyping and surrogate with low proliferative potential and the of the disease summary, in which other genotyping assays, the approaches that possibility of cure after surgical resec- notable clinical, pathological, and mo- may need to be taken by centres without tion alone. Grade II lesions are usually lecular findings are described. Finally, genotyping (or surrogate genotyping) ca- infiltrative in nature and often recur, de- for some entities, there is also additional pabilities, and the actual formats used to spite having low levels of proliferative commentary that provides information on report these integrated diagnoses {1535}. activity. Some grade II entities tend to classification, clarifying the nature of the However, an important consideration for progress to higher grades of malignancy; genetic parameters to be evaluated and the 2016WHO classification was thatthe for example, grade II diffuse astrocytoma providing genotyping information on pos- implementation of combined phenotyp- tends to transform to grade III anaplas- sibly overlapping histological entities. The ic-genotypic diagnostics in some large tic astrocytoma and glioblastoma. The classification does not specify the type centres and the increasing availability gradeIIIdesignationisappliedtolesions oftestingrequiredtoestablishwhether ofimmunohistochemicalsurrogatesfor 12 WHO classification and grading