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Neuro-Oncology

XX(XX), 1–21, 2021 | doi:10.1093/neuonc/noab106 | Advance Access date 29 June 2021

© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.

For permissions, please e-mail: journals.permissions@oup.com

The 2021 WHO Classification of Tumors of the Central Nervous System: a summary

David N. Louis, Arie  Perry, Pieter Wesseling , Daniel J. Brat , Ian A. Cree,

Dominique Figarella-Branger, Cynthia Hawkins, H. K. Ng, Stefan M. Pfister, Guido Reifenberger, Riccardo Soffietti, Andreas von Deimling, and David W. Ellison

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA (D.N.L.); Department of Pathology, University of California San Francisco, San Francisco, California, USA (A.P.); Department of Pathology, Amsterdam University Medical Centers/VUmc, Amsterdam, the Netherlands (P.W.); Laboratory for Childhood Cancer Pathology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands (P.W.); Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA (D.J.B.); International Agency for Research on Cancer, World Health Organization, Lyon, France (I.A.C.);

Service d’Anatomie Pathologique et de Neuropathologie, APHM, CNRS, Institut de Neurophysiopathologie, Hôpital de la Timone, Aix-Marseille University, Marseille, France (D.F.B.); Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada (C.H.); Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China (H.K.N.); Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), and Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany (S.M.P.); Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University Düsseldorf, and German Cancer Consortium (DKTK) Partner Site Essen/Düsseldorf, Düsseldorf, Germany (G.R.); Department of Neurology and Neuro-Oncology, University of Turin Medical School, Turin, Italy (R.S.); Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University, Heidelberg, Germany (A.v.D.); Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Heidelberg, Germany (A.v.D.); Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA (D.W.E.)

Corresponding Author: David N. Louis, MD, James Homer Wright Pathology Laboratories, Massachusetts General Hospital, 55 Fruit Street, Warren 225, Boston, MA 02114, USA (dlouis@mgh.harvard.edu).

Abstract

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome pro- filing. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.

Key words

brain tumor | central nervous system | classification | diagnosis | World Health Organization

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The fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5)1 is the sixth version of the international standard for the classification of brain and spinal cord tumors, following the prior publications from 1979, 1993, 2000, 2007, and 2016.2–6 WHO CNS5 builds on the updated fourth edition that appeared in 2016, on the many developments in the field that followed the 2016 clas- sification, and on the recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW).7–16 WHO CNS5 features substan- tial changes by moving further to advance the role of molec- ular diagnostics in CNS tumor classification but remaining rooted in other established approaches to tumor characteri- zation, including histology and immunohistochemistry. WHO CNS5 is presented in Table 1, and the major general and spe- cific changes are summarized in this review.

General Changes

CNS Tumor Taxonomy

CNS tumor classification has long been based on histolog- ical findings supported by ancillary tissue-based tests (eg, immunohistochemical, ultrastructural). More recently, mo- lecular biomarkers have gained importance in providing both ancillary and defining diagnostic information. WHO CNS5 therefore incorporates numerous molecular changes with clinicopathologic utility that are important for the most accurate classification of CNS neoplasms. Table 2 catalogs the key genes and proteins that are analyzed for diagnostic alterations important for integrated CNS tumor classification. WHO CNS5 does not recommend specific methods for molecular assessment of the individual diag- nostic alterations unless a certain method is unequivocally required for the diagnosis of a distinct tumor type or sub- type (see below).

As the use of molecular biomarkers in brain and spinal cord tumor diagnosis has been further elucidated, chal- lenges have arisen in how to organize the classification of tumor types. Some are readily and consistently character- ized by defining molecular features; for some, molecular parameters are not required but may support their clas- sification; yet others are rarely or never diagnosed using molecular approaches. The resulting nosological organ- ization is therefore also mixed. For some tumor families, WHO CNS5 has grouped tumors according to the genetic changes that enable a complete diagnosis (eg, IDH and H3 status); by looser oncogenic associations, such as MAPK pathway alterations; by histological and histogenetic similarities even though molecular signatures vary (eg, see neoplasms listed under Other Gliomas, Glioneuronal Tumors, and Neuronal Tumors); or, for many, by using molecular features to define new types and subtypes (eg, medulloblastoma). This hybrid taxonomy represents the current state of the field but is likely only an interme- diate stage to an even more precise future classification.

Examples of such transitional states include tumor fam- ilies, such as Pediatric-type diffuse low-grade gliomas, in which some tumor types encompass several subtypes with a shared molecular feature while other types are precisely defined by a single feature, with such consensus decisions

being based on the state of the field at the time of final ed- itorial discussions.

To standardize WHO CNS5 with other fifth-edition Blue Books, the term “type” is used instead of “entity”

and “subtype” is used instead of “variant.” Only types are listed in the classification (Table 1), with subtypes listed in the Subtype(s) subsections and described under Histopathology and/or Diagnostic Molecular Pathology of individual sections. For example, as a result of this change and because grading is being applied within types (see below), Meningioma is a single type with only one entry in the classification, but with many histological subtypes and grades further described in the text.

CNS Tumor Nomenclature

For CNS tumor nomenclature, WHO CNS5 follows the recommendations of the 2019 cIMPACT-NOW Utrecht meeting to make nomenclature more consistent and simple.14 In the past, some tumor names had anatomic site modifiers (eg, Chordoid glioma of the third ventricle) whereas others did not, despite occurring in specific loca- tions (eg, Medulloblastoma). Some included genetic modi- fiers (eg, Glioblastoma, IDH-wildtype), whereas others did not, despite having specific genotypes (eg, Atypical teratoid/rhabdoid tumor [AT/RT]). Names have there- fore been simplified as much as possible, and only loca- tion, age, or genetic modifiers with clinical utility have been used (eg, Extraventricular neurocytoma vs Central neurocytoma). Importantly, for tumors with highly char- acteristic features (eg, that chordoid gliomas occur in the third ventricle), these are included in tumor definitions and descriptions, even if they are not part of a tumor name.

In addition, tumor names sometimes reflect morphologic features that are not prominent in all examples of the type; for example, some myxopapillary ependymomas are minimally myxoid, and some may not be overtly pap- illary. Similarly, xanthomatous change may be limited to a small fraction of cells in pleomorphic xanthoastrocytomas.

Nonetheless, such names represent characteristic, if not universal, features. The terms may also reflect historical as- sociations that have become embedded in common usage;

for instance, although a medulloblast has not been identi- fied in developmental studies, the term medulloblastoma is deeply ingrained in tumor terminology, and changing the name could be quite disruptive to clinical care and scien- tific experiments that rely on prior data, as well as epidemi- ological studies. Lastly, with the change to grading within tumor type (see below), modifier terms like “anaplastic”

are not routinely included; familiar names like “anaplastic astrocytoma” and “anaplastic oligodendroglioma” do not, therefore, appear in this classification.

Gene and Protein Nomenclature for CNS Tumor Classification

The fifth edition of the WHO Classification of Tumours uses the HUGO Gene Nomenclature Committee (HGNC) system for gene symbols and gene names (https://www.

genenames.org/),17 the Human Genome Variation Society (HGVS) recommendations for sequence variants (http://

Table 1 2021 WHO Classification of Tumors of the Central Nervous System. Provisional Entities are in Italics

World Health Organization Classification of Tumors of the Central Nervous System, fifth edition Gliomas, glioneuronal tumors, and neuronal tumors

Adult-type diffuse gliomas Astrocytoma, IDH-mutant

Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted Glioblastoma, IDH-wildtype

Pediatric-type diffuse low-grade gliomas Diffuse astrocytoma, MYB- or MYBL1-altered Angiocentric glioma

Polymorphous low-grade neuroepithelial tumor of the young Diffuse low-grade glioma, MAPK pathway-altered

Pediatric-type diffuse high-grade gliomas Diffuse midline glioma, H3 K27-altered Diffuse hemispheric glioma, H3 G34-mutant

Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype Infant-type hemispheric glioma

Circumscribed astrocytic gliomas Pilocytic astrocytoma

High-grade astrocytoma with piloid features Pleomorphic xanthoastrocytoma

Subependymal giant cell astrocytoma Chordoid glioma

Astroblastoma, MN1-altered Glioneuronal and neuronal tumors

Ganglioglioma

Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma Dysembryoplastic neuroepithelial tumor

Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters Papillary glioneuronal tumor

Rosette-forming glioneuronal tumor Myxoid glioneuronal tumor

Diffuse leptomeningeal glioneuronal tumor Gangliocytoma

Multinodular and vacuolating neuronal tumor

Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease) Central neurocytoma

Extraventricular neurocytoma Cerebellar liponeurocytoma Ependymal tumors

Supratentorial ependymoma

Supratentorial ependymoma, ZFTA fusion-positive Supratentorial ependymoma, YAP1 fusion-positive Posterior fossa ependymoma

Posterior fossa ependymoma, group PFA Posterior fossa ependymoma, group PFB Spinal ependymoma

Spinal ependymoma, MYCN-amplified Myxopapillary ependymoma

Subependymoma

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Table 1 2021 WHO Classification of Tumors of the Central Nervous System. Provisional Entities are in Italics

World Health Organization Classification of Tumors of the Central Nervous System, fifth edition Gliomas, glioneuronal tumors, and neuronal tumors

Adult-type diffuse gliomas Astrocytoma, IDH-mutant

Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted Glioblastoma, IDH-wildtype

Pediatric-type diffuse low-grade gliomas Diffuse astrocytoma, MYB- or MYBL1-altered

Angiocentric glioma

Polymorphous low-grade neuroepithelial tumor of the young Diffuse low-grade glioma, MAPK pathway-altered

Pediatric-type diffuse high-grade gliomas Diffuse midline glioma, H3 K27-altered Diffuse hemispheric glioma, H3 G34-mutant

Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype Infant-type hemispheric glioma

Circumscribed astrocytic gliomas Pilocytic astrocytoma

High-grade astrocytoma with piloid features Pleomorphic xanthoastrocytoma

Subependymal giant cell astrocytoma Chordoid glioma

Astroblastoma, MN1-altered Glioneuronal and neuronal tumors Ganglioglioma

Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma Dysembryoplastic neuroepithelial tumor

Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters Papillary glioneuronal tumor

Rosette-forming glioneuronal tumor Myxoid glioneuronal tumor

Diffuse leptomeningeal glioneuronal tumor Gangliocytoma

Multinodular and vacuolating neuronal tumor

Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease) Central neurocytoma

Extraventricular neurocytoma Cerebellar liponeurocytoma

Ependymal tumors

Supratentorial ependymoma

Supratentorial ependymoma, ZFTA fusion-positive Supratentorial ependymoma, YAP1 fusion-positive

Posterior fossa ependymoma

Posterior fossa ependymoma, group PFA Posterior fossa ependymoma, group PFB Spinal ependymoma

Spinal ependymoma, MYCN-amplified Myxopapillary ependymoma

Subependymoma

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Table 1 Continued

World Health Organization Classification of Tumors of the Central Nervous System, fifth edition Choroid plexus tumors

Choroid plexus papilloma Atypical choroid plexus papilloma Choroid plexus carcinoma Embryonal tumors

Medulloblastoma

Medulloblastomas, molecularly defined Medulloblastoma, WNT-activated

Medulloblastoma, SHH-activated and TP53-wildtype Medulloblastoma, SHH-activated and TP53-mutant Medulloblastoma, non-WNT/non-SHH

Medulloblastomas, histologically defined Other CNS embryonal tumors

Atypical teratoid/rhabdoid tumor Cribriform neuroepithelial tumor

Embryonal tumor with multilayered rosettes CNS neuroblastoma, FOXR2-activated

CNS tumor with BCOR internal tandem duplication CNS embryonal tumor

Pineal tumors Pineocytoma

Pineal parenchymal tumor of intermediate differentiation Pineoblastoma

Papillary tumor of the pineal region

Desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant Cranial and paraspinal nerve tumors

Schwannoma Neurofibroma Perineurioma

Hybrid nerve sheath tumor

Malignant melanotic nerve sheath tumor Malignant peripheral nerve sheath tumor Paraganglioma

Meningiomas Meningioma

Mesenchymal, non-meningothelial tumors Soft tissue tumors

Fibroblastic and myofibroblastic tumors Solitary fibrous tumor

Vascular tumors

Hemangiomas and vascular malformations Hemangioblastoma

Skeletal muscle tumors Rhabdomyosarcoma Uncertain differentiation

Intracranial mesenchymal tumor, FET-CREB fusion-positive CIC-rearranged sarcoma

Primary intracranial sarcoma, DICER1-mutant Ewing sarcoma

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Table 1 Continued

World Health Organization Classification of Tumors of the Central Nervous System, fifth edition Chondro-osseous tumors

Chondrogenic tumors

Mesenchymal chondrosarcoma Chondrosarcoma

Notochordal tumors

Chordoma (including poorly differentiated chordoma) Melanocytic tumors

Diffuse meningeal melanocytic neoplasms

Meningeal melanocytosis and meningeal melanomatosis Circumscribed meningeal melanocytic neoplasms

Meningeal melanocytoma and meningeal melanoma Hematolymphoid tumors

Lymphomas CNS lymphomas

Primary diffuse large B-cell lymphoma of the CNS Immunodeficiency-associated CNS lymphoma Lymphomatoid granulomatosis

Intravascular large B-cell lymphoma Miscellaneous rare lymphomas in the CNS

MALT lymphoma of the dura

Other low-grade B-cell lymphomas of the CNS Anaplastic large cell lymphoma (ALK+/ALK−) T-cell and NK/T-cell lymphomas

Histiocytic tumors Erdheim-Chester disease Rosai-Dorfman disease Juvenile xanthogranuloma

Langerhans cell histiocytosis Histiocytic sarcoma Germ cell tumors

Mature teratoma Immature teratoma

Teratoma with somatic-type malignancy Germinoma

Embryonal carcinoma Yolk sac tumor Choriocarcinoma

Mixed germ cell tumor Tumors of the sellar region

Adamantinomatous craniopharyngioma Papillary craniopharyngioma

Pituicytoma, granular cell tumor of the sellar region, and spindle cell oncocytoma Pituitary adenoma/PitNET

Pituitary blastoma Metastases to the CNS

Metastases to the brain and spinal cord parenchyma Metastases to the meninges

Abbreviations: CNS, central nervous system; IDH, isocitrate dehydrogenase; NK, natural killer; PitNET, pituitary neuroendocrine tumor; SHH, sonic hedgehog.

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Table 2 Key Diagnostic Genes, Molecules, Pathways, and/or Combinations in Major Primary CNS Tumors

Tumor Type Genes/Molecular Profiles Characteristically Altereda

Astrocytoma, IDH-mutant IDH1, IDH2, ATRX, TP53, CDKN2A/B

Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted IDH1, IDH2, 1p/19q, TERT promoter, CIC, FUBP1, NOTCH1 Glioblastoma, IDH-wildtype IDH-wildtype, TERT promoter, chromosomes 7/10, EGFR Diffuse astrocytoma, MYB- or MYBL1-altered MYB, MYBL1

Angiocentric glioma MYB

Polymorphous low-grade neuroepithelial tumor of the young BRAF, FGFR family Diffuse low-grade glioma, MAPK pathway-altered FGFR1, BRAF

Diffuse midline glioma, H3 K27-altered H3 K27, TP53, ACVR1, PDGFRA, EGFR, EZHIP Diffuse hemispheric glioma, H3 G34-mutant H3 G34, TP53, ATRX

Diffuse pediatric-type high-grade glioma, H3-wildtype,

and IDH-wildtype IDH-wildtype, H3-wildtype, PDGFRA, MYCN, EGFR

(methylome)

Infant-type hemispheric glioma NTRK family, ALK, ROS, MET

Pilocytic astrocytoma KIAA1549-BRAF, BRAF, NF1

High-grade astrocytoma with piloid features BRAF, NF1, ATRX, CDKN2A/B (methylome)

Pleomorphic xanthoastrocytoma BRAF, CDKN2A/B

Subependymal giant cell astrocytoma TSC1, TSC2

Chordoid glioma PRKCA

Astroblastoma, MN1-altered MN1

Ganglion cell tumors BRAF

Dysembryoplastic neuroepithelial tumor FGFR1

Diffuse glioneuronal tumor with oligodendroglioma-like features and

nuclear clusters Chromosome 14, (methylome)

Papillary glioneuronal tumor PRKCA

Rosette-forming glioneuronal tumor FGFR1, PIK3CA, NF1

Myxoid glioneuronal tumor PDFGRA

Diffuse leptomeningeal glioneuronal tumor KIAA1549-BRAF fusion, 1p (methylome) Multinodular and vacuolating neuronal tumor MAPK pathway

Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease) PTEN

Extraventricular neurocytoma FGFR (FGFR1-TACC1 fusion), IDH-wildtype

Supratentorial ependymomas ZFTA, RELA, YAP1, MAML2

Posterior fossa ependymomas H3 K27me3, EZHIP (methylome)

Spinal ependymomas NF2, MYCN

Medulloblastoma, WNT-activated CTNNB1, APC

Medulloblastoma, SHH-activated TP53, PTCH1, SUFU, SMO, MYCN, GLI2 (methylome)

Medulloblastoma, non-WNT/non-SHH MYC, MYCN, PRDM6, KDM6A (methylome)

Atypical teratoid/rhabdoid tumor SMARCB1, SMARCA4

Embryonal tumor with multilayered rosettes C19MC, DICER1

CNS neuroblastoma, FOXR2-activated FOXR2

CNS tumor with BCOR internal tandem duplication BCOR Desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant SMARCB1

Meningiomas NF2, AKT1, TRAF7, SMO, PIK3CA; KLF4, SMARCE1,

BAP1 in subtypes; H3K27me3; TERT promoter, CDKN2A/B in CNS WHO grade 3

Solitary fibrous tumor NAB2-STAT6

Meningeal melanocytic tumors NRAS (diffuse); GNAQ, GNA11, PLCB4, CYSLTR2 (circum- scribed)

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Table 2 Continued

varnomen.hgvs.org/),18 and the reporting guidelines for chromosomal alterations of the International System for Human Cytogenetic Nomenclature 2020.19 Gene symbols are presented in italics, but proteins and gene groups (eg, the family of IDH genes) are not italicized.

A sequence alteration relative to a transcript reference sequence is reported using a “c.” prefix for the coding DNA sequence, followed by the nucleotide number and nucleotide change. The predicted protein sequence change then follows a “p.” prefix with the reference amino acid, the amino acid number, and the variant amino acid resulting from the mutation. For example, the most common BRAF variant is BRAF:c.1799T>A p.Val600Glu (or BRAF:c.1799T>A p.V600E if single-letter amino acid codes are preferred). Notably, this example assumes that a par- ticular BRAF transcript reference sequence accession and version have previously been defined, eg, NM_004333.5.

For some genes, such as those in the H3 histone group, there is potential for confusion with amino acid numbering.

Histone amino acid positions are typically described in the context of the protein sequence lacking the initiating methionine, resulting in a single amino acid difference in numbering compared with the predicted sequence derived from the corresponding gene transcript. The description of histone sequence alterations in many cancers has there- fore differed to date from the HGVS numbering by omitting the first amino acid. Next-generation sequencing reports, however, follow HGVS guidelines. The coexistence of these 2 nomenclatures may lead to confusion for pathologists, oncologists, and researchers. To address this issue, the fifth edition uses the legacy protein numbering system in parentheses after the protein-level variant description, eg, H3-3A:c.103G>A p.Gly35Arg (G34R), or H3-3A:c.83A>T p.Lys28Met (K27M). In these examples, as noted above, prior definition of the accession and version of the refer- ence transcript is required.

CNS Tumor Grading

CNS tumor grading has for many decades differed from the grading of other, non-CNS neoplasms, since brain and spinal cord tumors have had grades applied across different entities.20 As discussed below, WHO CNS5 has moved CNS tumor grading closer to how grading is done for non-CNS

neoplasms but has retained some key aspects of tradi- tional CNS tumor grading because of how embedded such grading has been in neuro-oncology practice. Two spe- cific aspects of CNS tumor grading have changed for WHO CNS5: Arabic numerals are employed (rather than Roman numerals) and neoplasms are graded within types (rather than across different tumor types).14 Nonetheless, because CNS tumor grading still differs from other tumor grading systems, WHO CNS5 endorses use of the term “CNS WHO grade” when assigning grade (eg, see Tables 3–6).

Arabic vs Roman numerals. —Traditionally, CNS WHO tumor grades were written as Roman numerals. However, the fifth-edition WHO Blue Books have emphasized more uniform approaches to tumor classification and grading and have favored the use of Arabic numerals for grading, as is currently done for all the other organ sys- tems. Furthermore, a danger of using Roman numerals in a within-tumor grading system is that a “II” and a “III”

or a “III” and a “IV” can be mistaken for one another and an uncaught typographical error could have clinical con- sequences. This was less likely when each tumor type had a different name, eg, “anaplastic” was present in addition to grade “III.” Given these considerations, WHO CNS5 has changed all CNS WHO tumor grades to Arabic numerals (Table 3).

Grading within types.—As outlined above, CNS tumors have traditionally had a grade assigned to each entity, and grades were applied across different entities.20 For ex- ample, in prior WHO classifications, if a tumor had been classified as an anaplastic astrocytoma, it was automat- ically assigned to WHO grade III (Roman numerals were used for CNS tumor grading in past classifications); there was no option to grade an anaplastic astrocytoma as WHO grade I, II, or IV. Notably, an anaplastic (malignant) menin- gioma was also assigned to WHO grade III. Even though tumors like meningiomas and astrocytomas are biolog- ically unrelated, WHO grade III tumors in these different categories were expected to have roughly similar survival times. But these were only roughly similar, with the clinical course of an anaplastic astrocytoma often quite different from that of an anaplastic (malignant) meningioma. This

Tumor Type Genes/Molecular Profiles Characteristically Altereda

Adamantinomatous craniopharyngioma CTNNB1

Papillary craniopharyngioma BRAF

Abbreviations: CNS, central nervous system; C19MC, chromosome 19 microRNA cluster; IDH, isocitrate dehydrogenase; SHH, sonic hedgehog.

Some of these are definitional for specific diagnoses, while others are not definitional but are characteristically altered or not altered. For each tumor type, these distinctions are specified in the Diagnostic Molecular Pathology as well as the Essential and Desirable Criteria sections of the Blue Book chapters.

aIn this column, molecules that are definitional (including for those that are wildtype) are listed before others; for those tumor types without specific definitional changes, more commonly altered genes and molecules are listed before others. Most types have characteristic methylome patterns, but

“(methylome)” is only listed for those types for which methylome testing offers particular diagnostic guidance, including for designating subtypes (as for Medulloblastoma, SHH-activated; Medulloblastoma, non-WNT/non-SHH; and Diffuse leptomeningeal glioneuronal tumor). H3 is a gene family (eg, H3F3A, HIST1H3B).

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approach thus correlated grade to an idealized clinical- biological behavior; for instance, WHO grade I tumors were curable if they could be surgically removed; at the other end of the spectrum, WHO grade IV tumors were highly malignant, leading to death in relatively short periods of time in the absence of effective therapy.

This entity-specific and clinical approach to tumor grading was different from the grading used in other, non- CNS tumor types.20 Most tumors in other organ systems are graded within tumor types, eg, a breast or prostate cancer is graded according to its particular grading system.

In the 2016 CNS WHO classification, solitary fibrous tumor/

hemangiopericytoma was graded in this manner, using a single name but with the option of 3 grades. In WHO CNS5, the shift to within-tumor-type grading has been extended to many categories (eg, see Tables 3 and 5). This change was done for several reasons: (1) to provide more flexibility in using grade relative to the tumor type, (2) to emphasize biological similarities within tumor types rather than ap- proximate clinical behavior, and (3) to conform with WHO grading in non-CNS tumor types.

“Clinicopathological” grading.—Nonetheless, because CNS tumor grading has for decades been linked to overall expected clinical-biological behaviors (see above), WHO CNS5 has generally retained the ranges of grades used for tumor types in prior editions. In this context, IDH- mutant astrocytomas extend from CNS WHO grade 2-4 and meningiomas from CNS WHO grade 1-3. In other words, at least for now, there is neither a CNS WHO grade 1 IDH-mutant astrocytoma nor a CNS WHO grade 4 me- ningioma. Moreover, given that tumors are graded on the basis of their expected natural history, certain malig- nant tumors (eg, medulloblastoma, germinoma) can be assigned a CNS WHO grade 4 designation in WHO CNS5 even if they now have effective treatments associated

with favorable survival times, particularly in the case of certain molecularly defined types like WNT-activated medulloblastoma.

The above approach to grading is a compromise since the original underlying prognostic correlations were based on natural history, at a time when few effective therapies were available. Today, estimating natural history is nearly impossible, since practically all patients receive ther- apies that often affect overall survival.21 In the context of modern therapies that can dramatically affect patient sur- vival, the necessity of grading every tumor type is ques- tionable. In fact, in editorial discussions for WHO CNS5, it was argued that grades should not be assigned if desig- nation of a grade could confuse clinical care (eg, see Table 6). For instance, WNT-activated medulloblastoma is an embryonal tumor that has an aggressive behavior if left untreated but that is responsive to current therapeutic regi- mens such that nearly all patients have long-term survival.

Designating this tumor as CNS WHO grade 4, and therefore equivalent to many untreatable pediatric brain tumors with a dismal outcome, potentially risks giving a false sense of prognosis when therapeutic options are discussed in the clinic. Conversely, designating this tumor as CNS WHO grade 1 on the basis of its good outcome, and therefore equivalent to neoplasms with a similar prognosis on the basis of surgery alone, certainly gives a false sense that the tumor is biologically benign.

Combined histological and molecular grading.— Traditionally, CNS tumor grading has been based ex- clusively on histological features, but certain molecular markers can now provide powerful prognostic informa- tion. For this reason, molecular parameters have now been added as biomarkers of grading and for further estimating prognosis within multiple tumor types. Examples in WHO CNS5 include CDKN2A/B homozygous deletion in Table 3 CNS WHO Grades of Selected Types, Covering Entities for Which There Is a New Approach to Grading, an Updated Grade, or a Newly Recognized Tumor That Has an Accepted Grade

CNS WHO Grades of Selected Types

Astrocytoma, IDH-mutant 2, 3, 4

Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted 2, 3

Glioblastoma, IDH-wildtype 4

Diffuse astrocytoma, MYB- or MYBL1-altered 1

Polymorphous low-grade neuroepithelial tumor of the young 1

Diffuse hemispheric glioma, H3 G34-mutant 4

Pleomorphic xanthoastrocytoma 2, 3

Multinodular and vacuolating neuronal tumor 1

Supratentorial ependymomaa 2, 3

Posterior fossa ependymomaa 2, 3

Myxopapillary ependymoma 2

Meningioma 1, 2, 3

Solitary fibrous tumor 1, 2, 3

Grade is based on natural history and for some tumor types, definite grading criteria and understanding of natural history are not yet known. Note the use of Arabic numerals.

aFor morphologically defined ependymomas.

Table 4 Layered Report Structure

Integrated diagnosis (combined tissue-based histological and molecular diagnosis)

Histological diagnosis CNS WHO grade

Molecular information (listed)

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IDH-mutant astrocytomas, as well as TERT promoter muta- tion, EGFR amplification, and +7/−10 copy number changes in IDH-wildtype diffuse astrocytomas (allowing a glioblas- toma, IDH-wildtype CNS WHO grade 4 designation even in cases that otherwise appear histologically lower grade). In other words, a molecular parameter can sometimes add value to histological findings in assigning a grade. Specific instances are discussed for the relevant tumor types (see below). It is also important to note that CNS WHO grade is therefore no longer restricted to being a histological grade, as was previously recommended.22

NOS (Not Otherwise Specified) and NEC (Not Elsewhere Classified) Diagnoses

As detailed elsewhere,12,13 use of the suffixes NOS and NEC allow the ready separation of standard, well-characterized WHO diagnoses from those diagnoses that result from ei- ther (1) a lack of necessary diagnostic (eg, molecular) in- formation or (2) nondiagnostic (ie, for a WHO diagnosis) or negative results. Adding an NOS suffix indicates that the diagnostic information (histological or molecular) necessary to assign a specific WHO diagnosis is not avail- able, providing an alert to the oncologist that a molecular work-up has not been undertaken or failed technically. An NEC suffix, on the other hand, indicates that the necessary diagnostic testing has been successfully performed but that the results do not readily allow for a WHO diagnosis; for ex- ample, if there is a mismatch between clinical, histological, immunohistochemical, and/or genetic features. NEC diag- noses are what pathologists have termed “descriptive diag- noses,” in which the pathologist uses a non-WHO diagnosis to categorize the tumor. In this regard, an NEC designation provides an alert to the oncologist that, despite an ade- quate pathological work-up, the tumor does not conform to a standard WHO diagnosis. Like WHO diagnoses, NEC and NOS diagnoses are facilitated by the use of layered inte- grated reports22 (see below and Tables 4-6).

Novel Diagnostic Technologies

Over the past century, many novel technologies have im- pacted tumor classification. These have included light microscopy, histochemical stains, electron microscopy, immunohistochemistry, molecular genetics, and most re- cently, a variety of broad molecular profiling approaches.

Each burst on the scene as a method that promised to change classification completely and each then eventually found a specific niche alongside the others, rather than

replacing them. Over the past couple of decades, nucleic acid-based methodologies (eg, DNA and RNA sequencing, DNA fluorescence in situ hybridization, RNA expression profiling) have clearly shown their abilities to contribute to tumor diagnosis and classification, as evidenced by the changes in the updated fourth edition (2016) and in WHO CNS5. The availability of such technologies was increasing throughout the world as the 2016 classification was being prepared,23,24 and the last few years have witnessed further expansion of availability as well as skillful ways to adapt to molecular classification recommendations.25,26 WHO CNS5 thus incorporates more molecular approaches for the clas- sification of CNS tumors.

Over the past decade, methylome profiling—the use of ar- rays to determine DNA methylation patterns across the ge- nome—has emerged as a powerful approach to CNS tumor classification, as detailed in a variety of publications over the past few years.27–30 Most CNS tumor types can be reli- ably identified by their methylome profile, although caveats remain that optimal methodologic approaches and regula- tory issues for methylome profiling have yet to be resolved and that the technology is currently not widely available.14 Copy number profiles can also be derived from methyla- tion data, eg, 1p/19q codeletion, the +7/−10 signature, amp- lifications, homozygous deletions, and profiles suggestive of fusion events. At this time, methylome profiling is an effective ancillary method for brain and spinal cord tumor classification when used alongside other, standard tech- nologies, including histology. Indeed, the great majority of tumor types and subtypes can also be reliably identified by other techniques, eg, from a combination of morpholog- ical features and defining genetic alteration. On the other hand, methylome profiling may be the most effective way to characterize some tumors with unusual morphological features and may be the only current way to identify some rare tumor types and subtypes. The method also has utility when small biopsy samples are limiting for standard tech- nologies. Methylome profiling may also be used as a sur- rogate marker for genetic events, for instance when a methylome signature is characteristic of an IDH-wildtype glioblastoma in the absence of IDH mutation testing—but methylome profiling cannot serve as a surrogate when tar- geted therapies and clinical trials require the demonstra- tion of specific mutations prior to patient treatment. For methylome profiling results, careful attention must be paid to the common calibrated score threshold; as discussed in detail elsewhere,28 thresholds may be set at 0.84 or 0.90, and pathologists should be wary about endorsing sug- gested diagnoses with scores below 0.84 and should prob- ably discard recommendations if scores are below 0.50. As with other diagnostic tests, the pathologist must take into account histological features (eg, tumor cell amount and pu- rity) when interpreting results; for example, methylome pro- filing can struggle with classification of low-grade diffuse gliomas. For the WHO CNS5, therefore, it is assumed that nearly all (but not all) tumor types are aligned to a distinct methylation signature27 and these are not specified in every Definition; however, information about diagnostic methyla- tion profiling is included in those Definitions and Essential and Desirable Diagnostic Criteria sections for which the method can provide more critical guidance for diagnosis.

Table 4 Layered Report Structure

Integrated diagnosis (combined tissue-based histological and molecular diagnosis)

Histological diagnosis CNS WHO grade

Molecular information (listed)

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Integrated and Layered Diagnoses

Because of the growing importance of molecular informa- tion in CNS tumor classification, diagnoses and diagnostic reports need to combine different data types into a single,

“integrated” diagnosis. Such integrated diagnoses are im- plicit in the use of WHO CNS5. Even diagnostic terms that do not incorporate a molecular term may require a mo- lecular characteristic for diagnosis (eg, AT/RT). Thus, to display the full range of diagnostic information available, the use of layered (or tiered) diagnostic reports is strongly encouraged, as endorsed by the International Society of Neuropathology—Haarlem consensus guidelines22 and the International Collaboration on Cancer Reporting.31 Such re- ports feature an integrated diagnosis at the top, followed by layers that display histological, molecular, and other key types of information (Table 4).

For some tumor types in WHO CNS5, the listed diag- nostic terms are general ones (eg, Diffuse high-grade pediatric-type glioma, H3-wildtype and IDH-wildtype and Diffuse low-grade glioma, MAPK pathway-altered); for these types, a combination of diagnostic features drawn from a matrix of relevant histological and molecular abnor- malities is necessary to arrive at a specific integrated di- agnosis. These approaches are described for each of these tumor groups and are similar to how the 2016 CNS WHO classified medulloblastomas22 and what cIMPACT-NOW Update 4 recommended for pediatric low-grade diffuse gliomas10: an integrated diagnosis optimally combines a term from a histologically defined list of tumors and a ge- netically defined list of tumors (Tables 4–6). Even though each list may contain many items, some combinations

are more common than others. The resulting number of routinely used integrated diagnoses is typically man- ageable, and common diagnoses are included as tumor subtypes in the case of Diffuse low-grade glioma, MAPK pathway-altered.

In WHO CNS5, Essential and Desirable Diagnostic Criteria are given for each tumor type, mostly in tabular form, in the hope that such a format makes it easier for the user to evaluate whether key diagnostic criteria are present and whether the combinations of such criteria are suffi- cient for diagnosis. Essential Diagnostic Criteria are con- sidered “must have” features, but there may be different combinations that allow a diagnosis, ie, not all criteria are needed for a diagnosis. For these diagnostic types, the user should pay close attention to the use of “AND” vs

“OR” designations in the Essential Diagnostic Criteria ta- bles. On the other hand, Desirable Diagnostic Criteria are

“nice to have” features, ie, they clearly support a diagnosis but are not needed per se.

Newly Recognized Entities and Revised Nomenclature

The major specific changes to the classification are dis- cussed in sections relating to families of tumors below.

Multiple newly recognized types (see Table 7) have been accepted into WHO CNS5, and some of the more distinct microscopic features are illustrated in Figures 1–8. In ad- dition, changes were made to the nomenclature of some entities, both to clarify molecular alterations and to follow the nomenclature guidelines in cIMPACT-NOW Update 614

Table 6 Layered Report Example Illustrating: (1) A Tumor Type With a Subtype; (2) Lack of a Definite Grade; and (3) That the Integrated Diagnosis Does Not Necessarily Have the Histological Designation Included

Cerebrum

Integrated diagnosis Diffuse low-grade glioma, MAPK pathway-altered

Subtype: Diffuse low-grade glioma, FGFR1 TKD-duplicated Histopathological classification Oligodendroglioma

CNS WHO grade Not assigned

Molecular information Duplication of the FGFR1 tyrosine kinase domain (next-generation sequencing) Table 5 Layered Report Example Illustrating: (1) Use of Site in the Diagnosis; (2) Use of a Histological Diagnosis That Does Not Designate

“Anaplasia” But the Report Still Assigns a Grade; (3) Use of the NOS Designation (Here Because the Case Could Not Be Worked up Adequately at a Molecular Level)

Cerebrum

Integrated diagnosis Supratentorial ependymoma, NOS

Histopathological classification Ependymoma

CNS WHO grade 3

Molecular information Derivatives extracted from FFPE tissue were of insufficient quality for sequencing and insufficient tissue remained for FISH studies Abbreviations: CNS, central nervous system; FFPE, formalin-fixed paraffin-embedded; FISH, fluorescence in situ hybridization; NOS, not otherwise specified.

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(see Table 8). Other nomenclature changes were made to standardize type names with those in other Blue Books, eg, for peripheral nerve and other soft tissue tumors.

Some proposed tumor types were discussed and pro- visionally accepted as types because they appeared to be clinicopathologically distinct, but additional pub- lished studies are needed for full acceptance. The 3 provi- sional entities are designated in italics in the table: Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC); Cribriform neuroepithelial tumor (CRINET); and Intracranial mesenchymal tumor, FET- CREB fusion-positive. Others were discussed during the edi- torial process, but the published literature still left questions about the nature of the proposed entity. An example of this was Neuroepithelial tumor, PATZ1 fusion-positive, for which there are only a few cases described in the literature.32–34 While unpublished data suggest that these lesions have dis- tinct molecular alterations, there is marked heterogeneity in their histopathological appearances and clinical courses, and therefore more published data are needed to evaluate whether these cases form a distinct tumor type.

Specific Changes

Gliomas, Glioneuronal Tumors, and Neuronal Tumors

WHO CNS5 has taken a new approach to classify the Gliomas, Glioneuronal Tumors, and Neuronal Tumors,

and dividing them into 6 different families: (1) Adult-type diffuse gliomas (the majority of primary brain tumors in neuro-oncology practice of adults, eg, glioblastoma, IDH- wildtype); (2) Pediatric-type diffuse low-grade gliomas (expected to have good prognoses); (3) Pediatric-type diffuse high-grade gliomas (expected to behave aggres- sively); (4) Circumscribed astrocytic gliomas (“circum- scribed” referring to their more solid growth pattern, as opposed to the inherently “diffuse” tumors in groups 1, 2, and 3); (5) Glioneuronal and neuronal tumors (a diverse group of tumors, featuring neuronal differentiation); and (6) Ependymomas (now classified by site as well as his- tological and molecular features). Choroid Plexus Tumors, with their marked epithelial characteristics, are separated from the category of Gliomas, Glioneuronal Tumors, and Neuronal Tumors.

Fourteen newly recognized types have been added to the classification of Gliomas, Glioneuronal Tumors, and Neuronal Tumors (see Table 7). For some of these types—especially for Diffuse high-grade pediatric-type, H3-wildtype and IDH-wildtype, and for Diffuse low-grade glioma, MAPK pathway-altered—integrating histological appearances and molecular features is required to arrive at a diagnosis, and such data are most effectively dis- played as tiers of information. There have also been some nomenclature changes to existing entities. For example, the diffuse midline glioma is now designated as “H3 K27- altered” rather than “H3 K27M-mutant” in order to rec- ognize alternative mechanisms by which the pathogenic pathway can be altered in these tumors.35 Astroblastoma Table 7 Newly Recognized Tumor Types in the 2021 WHO Classification of Tumors of the Central Nervous System

Newly Recognized Tumor Types

Diffuse astrocytoma, MYB- or MYBL1-altered

Polymorphous low-grade neuroepithelial tumor of the young Diffuse low-grade glioma, MAPK pathway-altered

Diffuse hemispheric glioma, H3 G34-mutant

Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype Infant-type hemispheric glioma

High-grade astrocytoma with piloid features

Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (provisional type) Myxoid glioneuronal tumor

Multinodular and vacuolating neuronal tumor Supratentorial ependymoma, YAP1 fusion-positive Posterior fossa ependymoma, group PFA

Posterior fossa ependymoma, group PFB Spinal ependymoma, MYCN-amplified

Cribriform neuroepithelial tumor (provisional type) CNS neuroblastoma, FOXR2-activated

CNS tumor with BCOR internal tandem duplication

Desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant Intracranial mesenchymal tumor, FET-CREB fusion positive (provisional type) CIC-rearranged sarcoma

Primary intracranial sarcoma, DICER1-mutant Pituitary blastoma

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has been specified as “MN1-altered” to provide more diag- nostic focus for this entity, even though future work will be needed to establish clear histopathological and molecular parameters by which astroblastomas with MN1 alterations

can be distinguished from morphologically comparable neuroepithelial tumors with similar genetic alterations. For other tumor types, changes in nomenclature regarding the inclusion of genetic and anatomical site modifiers have

A B

Fig. 2 Diffuse hemispheric glioma, H3 G34-mutant, is a malignant, infiltrative glioma, typically of the cerebral hemispheres and with a missense mutation in the H3F3A gene that results in a G34R/V substitution of histone H3. (A) High-grade anaplastic features, sometimes with an embryonal appearance (H&E, ×200) and (B) positive nuclear staining with H3 G34R/V immunohistochemistry (×100).

A

C D

B

Fig. 1 Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a glial neoplasm associated with a history of epilepsy in young people, diffuse growth patterns, frequent presence of oligodendroglioma-like components, calcification, CD34 immunoreactivity, and MAPK pathway-activating genetic abnormalities. (A) Common oligodendroglioma-like appearance (H&E, ×200), but (B) histological appearances can vary greatly within tumors (H&E, ×400). (C) CD34 immunostaining is typically strong and diffuse in the tumor (×100); and (D) is often found in the peritumoral cortex (×200).

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followed the recommendations of cIMPACT-NOW Update 614 and cIMPACT-NOW Update 7.16 Nearly all of these newly recognized types can be diagnosed on the basis of standard histological, immunohistochemical, and molec- ular analyses.

Division of diffuse gliomas into adult-type and pediatric- type.—Importantly, WHO CNS5 recognizes the clinical and molecular distinctions between those diffuse gliomas that primarily occur in adults (termed “adult-type”) and those that occur primarily in children (termed “pediatric-type”).

Note the use of the word “primarily” in the last sentence, since pediatric-type tumors may sometimes occur in adults, particularly young adults, and adult-type tumors may more rarely occur in children. Nonetheless, the divi- sion of the classification into adult-type and pediatric-type

diffuse gliomas should be a step forward in clearly separ- ating these prognostically and biologically distinct groups of tumors. The need to do so has been considered for a long time, but the elucidation of molecular differences has now made this possible. It is hoped that this distinction will enable improved care for both children and adults with CNS tumors.

Simplification of the classification of common, adult- type, diffuse gliomas.—In the updated fourth edition CNS classification from 2016, the common diffuse gliomas of adults were divided into 15 entities, largely because different grades were assigned to different entities (eg, Anaplastic oligodendroglioma was considered a dif- ferent type from Oligodendroglioma) and because NOS designations were assigned to distinct entities (eg,

A

A

L

P R

B

Fig. 3 Myxoid glioneuronal tumor is a tumor typically arising in the septal region and involving the lateral ventricle. It is characterized by a prolif- eration of oligodendrocyte-like tumor cells embedded in a prominent myxoid stroma, often including admixed floating neurons, neurocytic rosettes, and/or perivascular neuropil, and by a dinucleotide mutation in the PDGFRA gene. (A) Common septal location (magnetic resonance imaging, T1 with contrast) and (B) characteristic histological features with small round cells and myxoid stroma (H&E, ×200).

A B

Fig. 4 Multinodular and vacuolating neuronal tumor is a benign tumor comprising monomorphous neuronal elements in discrete and coalescent nodules, with vacuolar changes both in tumor cells and the neuropil. (A) Multinodular appearance (H&E, ×40). (B) Vacuolar change in tumor cells and in neuropil (H&E, ×200).

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Diffuse astrocytoma, NOS). WHO CNS5, on the other hand, includes only 3 types: Astrocytoma, IDH-mutant;

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted;

and Glioblastoma, IDH-wildtype.

This focusing of the classification has resulted from (1) more ecumenical use of NOS and NEC terminology, as dis- cussed above and in cIMPACT-NOW Update 112; (2) recogni- tion of the value of molecular diagnostics to assign poorly defined entities (eg, oligoastrocytomas or IDH-wildtype diffuse astrocytic tumors) to more objectively defined types; and (3) use of grades within types14,15 rather than re- quiring each grade to have a different name (see above). In addition, in the fifth edition WHO Blue Books, subtypes (eg, Gliosarcoma and Giant cell glioblastoma) are not listed in the classification, but these classic variants are discussed in their respective chapters.

Nomenclature and grading of common, adult-type, dif- fuse astrocytic gliomas.—In the 2016 WHO classification, IDH-mutant diffuse astrocytic tumors were assigned to 3 different tumor types (Diffuse astrocytoma, Anaplastic astrocytoma, and Glioblastoma) depending on histological parameters. In the current classification, however, all IDH- mutant diffuse astrocytic tumors are considered a single type (Astrocytoma, IDH-mutant) and are then graded as CNS WHO grade 2, 3, or 4. Moreover, grading is no longer entirely histological, since the presence of CDKN2A/B ho- mozygous deletion results in a CNS WHO grade of 4, even in the absence of microvascular proliferation or necrosis.

For IDH-wildtype diffuse astrocytic (NB: diffuse and astrocytic) tumors in adults, a number of papers have shown that the presence of 1 or more of 3 genetic param- eters (TERT promoter mutation, EGFR gene amplification,

A B

Fig. 5 CNS tumor with BCOR internal tandem duplication is a neoplasm with a mostly solid growth pattern, uniform oval or spindle-shaped cells, a dense capillary network, focal pseudorosette formation, and an internal tandem duplication (ITD) in exon 15 of the BCOR gene. (A) High-grade neo- plasm with perivascular rosettes (H&E, ×200) and (B) strong, diffuse nuclear staining on BCOR immunohistochemistry (×100).

A B

Fig. 6 Desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant is a rare pineal-region tumor that features desmoplasia and myxoid changes (H&E, ×200) (A) as well as loss of INI1 staining (×200) (B).

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combined gain of entire chromosome 7 and loss of entire chromosome 10 [+7/−10]) appears sufficient to assign the highest WHO grade.11,36 WHO CNS5 therefore incorporates

these 3 genetic parameters as criteria for a diagnosis of Glioblastoma, IDH-wildtype. As a result, Glioblastoma, IDH-wildtype should be diagnosed in the setting of an

A

C D

B

Fig. 7 Newly recognized mesenchymal, non-meningothelial tumors of uncertain histogenesis. (A) Intracranial mesenchymal tumor, FET-CREB fusion-positive (H&E, ×200); these tumors have variable morphology and a fusion of an FET RNA-binding protein family gene and a member of the CREB family of transcription factors. (B, C) CIC-rearranged sarcoma, with (B) poorly differentiated cells (H&E, ×200) and (C) with ETV4 frequently being upregulated in these tumors (×200). (D) Primary intracranial sarcoma, DICER1-mutant with characteristic eosinophilic cytoplasmic droplets (H&E, ×200).

A B

Fig. 8 Pituitary blastoma is a malignant embryonal sellar neoplasm composed of primitive blastemal cells, neuroendocrine cells, and Rathke ep- ithelium, typically occurring in young children and linked to germline or somatic variants in the DICER1 gene. (A) Neuroendocrine cells arranged in lobules, rosettes, and glands, interspersed with small undifferentiated, blastemal cells (H&E, ×100) and with (B) ACTH immunoreactivity in some cells (×200).

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Table 8 Tumor Types With Revised Nomenclature or Revised Placement in the 2021 WHO Classification of Tumors of the Central Nervous System

Tumor Types With Revised Nomenclature or Revised Placement

Astrocytoma, IDH-mutant (covers grades 2-4; eliminates the term “Glioblastoma, IDH-mutant”) Diffuse midline glioma, H3 K27-altered (changes “mutant” to “altered” given multiple mechanisms) Chordoid glioma (removes site designation)

Astroblastoma, MN1-altered (adds genetic modifier)

Supratentorial ependymoma, ZFTA fusion-positive (reflects changes in fusion partner and gene nomenclature; see text) Embryonal tumor with multilayered rosettes (removes genetic modifier to allow for genetic subtypes)

Malignant melanotic nerve sheath tumor (conforms to terminology in soft tissue pathology literature)

Solitary fibrous tumor (removes the term “hemangiopericytoma” to conform fully with soft tissue pathology nomenclature) Mesenchymal chondrosarcoma (formerly a subtype)

Adamantinomatous craniopharyngioma (formerly a subtype) Papillary craniopharyngioma (formerly a subtype)

Pituicytoma, granular cell tumor of the sellar region, and spindle cell oncocytoma (grouped rather than separate) Pituitary adenoma/PitNET (adds the term “PitNET”)

IDH-wildtype diffuse and astrocytic glioma in adults if there is microvascular proliferation or necrosis or TERT promoter mutation or EGFR gene amplification or +7/−10 chromosome copy number changes. In IDH-wildtype dif- fuse astrocytomas occurring in younger age groups, how- ever, consideration should be given to the different types of diffuse pediatric-type gliomas (see below).

Pediatric-type low-grade and high-grade diffuse gliomas.—Two new families of tumor types have been added to the classification to reflect the practical and con- ceptual importance of separating pediatric-type gliomas from other diffuse gliomas: one for Pediatric-type dif- fuse low-grade gliomas and one for Pediatric-type dif- fuse high-grade gliomas.  The low-grade group includes 4 entities that feature diffuse growth in the brain but with sometimes overlapping and less specific histological fea- tures; in all, molecular work-up helps to characterize the lesion as one type or the other. For CNS5, the 4 types are Diffuse astrocytoma, MYB- or MYBL1-altered; Angiocentric glioma; Polymorphous low-grade neuroepithelial tumor of the young (often abbreviated as PLNTY; Figure 1); and Diffuse low-grade glioma, MAPK pathway-altered. The last of these diagnoses encompass tumors with an astrocytic or oligodendroglial morphology. For these tumors (as for most other glioma types), precise classification requires molecular characterization and the integration of histo- pathological and molecular information in a tiered diag- nostic format.22 Clear delineation of the specific molecular features, in turn, sets the stage for targeted therapies of such tumors.

The high-grade family also comprises 4 types: Diffuse midline glioma, H3 K27-altered; Diffuse hemispheric glioma, H3 G34-mutant (Figure 2); Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype; and Infant-type hemispheric glioma. Diffuse midline glioma, H3 K27-altered had been in the 2016 classification, but as men- tioned above, its name has been changed to reflect the fact that other changes (eg, EZHIP protein overexpression) can

define this entity in addition to the previously recognized H3 K27 mutations. The other 3 are newly recognized types.

Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype is specified as being wildtype for both H3 and IDH gene families and, like many other CNS tumor types, requires molecular characterization and integration of histopathological and molecular data for diagnostic pur- poses. Infant-type hemispheric glioma is a novel type of high-grade glioma that occurs in newborns and infants and that has a distinct molecular profile, with fusion genes involving ALK, ROS1, NTRK1/2/3, or MET.37,38 Of note, the term “glioblastoma” is no longer used in the setting of a pediatric-type neoplasm.

Neuronal and glioneuronal  tumors.—All tumors with a neuronal component have remained grouped together in WHO CNS5. Three new types have been added, although the first is provisional (ie, will likely become a fully recog- nized type in a future classification but currently awaits further published characterizations): DGONC (provisional);

Myxoid glioneuronal tumor (Figure 3); and Multinodular and vacuolating neuronal tumor (Figure 4), which had been discussed in the 2016 classification in the chapter on Gangliocytoma.

Ependymomas.—Ependymomas should now be classi- fied according to a combination of histopathological and molecular features as well as anatomic site,16 thus dividing them into molecular groups across the supratentorial, posterior fossa (PF), and spinal compartments (Table 1).39 WHO CNS5 also now lists 2 molecularly defined types of supratentorial ependymoma: one with ZFTA (the new des- ignation for C11orf95, which is considered more repre- sentative of the tumor type than RELA because it may be fused with partners more than RELA) fusion and another with YAP1 fusion. It also now includes 2 molecularly de- fined types of PF ependymoma, group PFA and group PFB, as well as a spinal tumor defined by the presence

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of MYCN amplification. Also listed are ependymomas defined by anatomic location but not by a molecular al- teration; these can be used either when molecular anal- ysis finds a different molecular alteration to one used to define ependymomas at a particular site or when molec- ular analysis fails or is unavailable. As described above, the former situation utilizes the NEC suffix and the latter utilizes the NOS suffix. Myxopapillary ependymoma and Subependymoma remain tumor types; currently, although these can be identified with methylome studies, molecular classification does not provide added clinicopathological utility for these 2 tumors.16 In contrast to previous WHO classifications, the myxopapillary ependymoma is now considered CNS WHO grade 2 rather than 1, since its like- lihood of recurrence is now understood to be similar to conventional spinal ependymoma. Papillary, clear cell, and tanycytic morphological variants are no longer listed as subtypes of ependymoma, being included instead as pat- terns in the histopathological description of ependymoma.

Longstanding controversy surrounds the reproduci- bility and clinicopathological utility of grading ependymal tumors,40 although use of WHO grade in the thera- peutic stratification of adult patients with supratentorial ependymoma remains established practice41 while the full clinical associations of molecular alterations in this patient population are being evaluated. WHO CNS5 allows only a histologically defined diagnosis of Ependymoma to be made at any of the 3 anatomic sites; the term “anaplastic ependymoma” is no longer listed.16 Nonetheless, as for other tumors in WHO CNS5, a pathologist can still choose to assign either CNS WHO grade 2 or grade 3 to an ependymoma, according to its histopathological features.

In an integrated diagnosis, CNS WHO grade can be pre- sented in a specific tier (eg, Tables 4–6).22

Choroid Plexus Tumors

The classification of choroid plexus tumors remains largely unchanged, although this family of tumors has been separ- ated from the category of primary neuroepithelial tumors that feature more glial and/or neuronal differentiation and less epithelial differentiation.

Medulloblastomas

WHO CNS5 has altered the classification of medulloblastomas to mirror new knowledge of their clin- ical and biological heterogeneity. Initially, consensus es- tablished 4 principal molecular groups: WNT-activated, sonic hedgehog (SHH)-activated, group 3, and group 4.42 WNT and SHH medulloblastomas were included in the 2016 classification, and SHH tumors divided on the basis of TP53 status (with TP53-mutant and TP53-wildtype tumors having markedly different clinicopathological characteris- tics). Non-WNT/non-SHH medulloblastomas comprised group 3 and group 4 tumors. These groups are represented in WHO CNS5 (Table 1); however, through large-scale meth- ylation and transcriptome profiling, new subgroups have emerged at a more granular level below the 4 principal molecular groups: 4 subgroups of SHH and 8 subgroups of

non-WNT/non-SHH medulloblastomas.43–47 Like the 4 prin- cipal molecular groups of medulloblastoma, some of these subgroups are associated with clinicopathological and ge- netic features that provide clinical utility, having either di- agnostic, prognostic, or predictive value. One example is the delineation of 2 (out of 4) SHH subgroups, SHH-1 and SHH-2, both dominated by medulloblastomas from young children.47,48 These subgroups show significantly different outcomes, and recent clinical trial data suggest that spe- cific chemotherapeutic regimens can help those patients with tumors in the poor prognosis subgroup49,50 indicating that these distinctions may be predictive rather than solely prognostic.

The histopathological classification of medulloblastoma listed in the 2016 WHO classification comprised 4 morphologic types: classic, desmoplastic/nodular, medulloblastoma with extensive nodularity (MBEN), and large cell/anaplastic. These have now been combined into 1 section that describes them as morphologic patterns of an inclusive tumor type, Medulloblastoma, histologically defined (Table 1). The morphologic differences have their own specific clinical associations,51–54 and molecularly defined medulloblastomas demonstrate distinct associ- ations with the morphologic patterns. For example, all true desmoplastic/nodular medulloblastomas and MBENs align with the SHH molecular group,55 and most are in the SHH-1 and SHH-2 subgroups.47 Nearly all WNT tumors have classic morphology, and most large cell/anaplastic tumors belong either to the SHH-3 subgroup or to the Grp3/4 sub- group 2.46

Given their heterogeneity and the need to classify medulloblastomas according to a combination of histo- pathological and molecular features, these tumors should be reported in a layered and integrated format. NOS and NEC options also exist for these lesions in the appropriate settings.

Other Embryonal Tumors

The other embryonal tumors (ie, aside from Medulloblastoma) are AT/RT; Embryonal tumor with multi- layered rosettes (ETMR); CNS neuroblastoma, FOXR2- activated; and CNS tumor with BCOR internal tandem duplication (ITD; Figure 5). Whereas AT/RT and ETMR were included in previous WHO classifications, CNS neuro- blastoma, FOXR2-activated and CNS tumor with BCOR ITD are new to CNS5. In addition, CNS5 recognizes 3 molec- ular subtypes of AT/RT and an ETMR with DICER1 altera- tion (in addition to the more common C19MC type). CNS tumors with BCOR ITD are now included in WHO CNS5 as embryonal tumors, but these neoplasms are not defini- tively neuroectodermal. Exon 15 BCOR ITDs have been reported in several morphologically similar sarcomas, and there is currently no consensus as to whether these tumors should be considered neuroepithelial or mesen- chymal neoplasms; the nosology of such tumor types may need to change in light of future findings. CRINET has been introduced as a provisional entity within this category, and the broad designation CNS embryonal tumor is included for embryonal tumors that defy a more specific diagnosis, ie, that are NEC or NOS.12,13 Given the histological and

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Hague) 21, no.1 (Jan 1979) 1-19,以及”Two Problems in the History of Indian Buddhism: The Layman/Monk Distinction and the Doctrines of the Transference of Merit,” in

To investigate the characteristics of Tsongkhapa’s meditation thought, the study is divided into five parts: (1) introduction, (2) Tsongkhapa’s exposition of meditation practice,