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. Author manuscript; available in PMC: 2023 Dec 1.
Published in final edited form as: Curr Opin Neurol. 2022 Oct 3;35(6):764–771. doi: 10.1097/WCO.0000000000001109

The 2021 WHO classification of central nervous system tumors: what neurologists need to know

Pouya Jamshidi 1, Daniel J Brat 1,*
PMCID: PMC9669114  NIHMSID: NIHMS1834862  PMID: 36226717

Abstract

Purpose of review:

The recently published 5th Edition of the World Health Organization classification of tumors of the central nervous system (WHO CNS-5) introduces substantial clinically relevant changes due to improved understanding of the molecular underpinnings of brain tumor types as biological entities. This review highlights pertinent changes for practicing neurologists.

Recent findings:

Diffuse gliomas are now divided into adult- and pediatric-types. Adult-types are greatly simplified, being classified into three groups based on IDH and 1p/19q status, with molecular grading criteria now included. Pediatric-types are divided into low- or high-grade and further classified based on molecular features corresponding to clinical behavior. While still recognizing previous morphological subtypes, meningioma is now a single tumor type, with greatly advanced correlations between molecular alterations, locations, morphologic subtypes and grades. For the first time, ependymomas are classified based on integration of anatomical location, histopathology and molecular alterations. Importantly, WHO CNS-5 includes a number of new tumor types that have similar clinicopathologic features and are grouped together by their distinctive molecular characteristics.

Summary:

The classification of CNS tumors according to objective, reproducible molecular genetic alterations provides greater opportunity for neurologists to offer individualized treatment options, enroll homogenous patient populations into clinical trials, and ultimately discover novel therapeutics.

Keywords: brain tumor, WHO classification, CNS neoplasm, molecular diagnostics, neurology

Introduction

Over the past two decades, advances in molecular diagnostics have transformed our concept of CNS tumors from morphologically-defined to biologically-defined entities. The 2021 WHO Classification of Tumours, Central Nervous System Tumours, 5th Edition (WHO CNS-5) (1) provides substantial evidence for the growing role of molecular diagnostics in establishing the diagnosis of a CNS neoplasm. A large majority of tumor types have molecular correlates and many incorporate molecular findings into an integrated diagnosis together with their histologic and immunohistochemical features. Neurologists that care for patients with brain tumors should have a firm understanding of the updated classification, since it informs the expected clinical behavior and optimal therapy for these tumors. Furthermore, given the increased recognition of molecular underpinning of many brain tumors, the updated classification enables enrollment of homogenous patient populations into clinical trials, improving chances to uncover novel and effective therapies. Herein, we briefly review the general changes codified in the WHO CNS-5 and highlight the clinically pertinent updates, accepted terminologies and diagnostic criteria for the most common primary brain tumors, including adult and pediatric diffuse gliomas, meningiomas and ependymomas. Lastly, we introduce newly recognized tumor types in the WHO CNS-5.

Overview of general changes

The Central Nervous System WHO Classification of Tumours series (also referred to as the WHO Blue Books) represents the primary source of internationally accepted diagnostic updates for neoplastic classes, grades, and criteria. The fifth edition (1) is the sixth and most recent of these guidelines. In this edition, some tumor types are characterized by defining molecular features that are integrated with morphology; for others, molecular parameters are not required but may support their classification; yet others are rarely or never diagnosed using molecular approaches.

Tumor taxonomy

Historically, the CNS tumor classification has been based on morphologic features and supported by ancillary tissue-based tests (e.g., immunohistochemistry). More recently, and certainly evident within the WHO CNS-5, molecular signatures play a greater role in establishing a diagnosis rather than informing it. Unless a certain method is unequivocally required for the diagnosis of a distinct tumor type or subtype (e.g., DNA methylation profiling), WHO CNS-5 does not provide recommendations on specific molecular techniques for assessing diagnostic genetic alterations. For instance, many diffuse gliomas are diagnosed based on the presence of molecular alterations (e.g. IDH mutation or H3 status), yet there is no recommendation for immunohistochemical versus gene sequencing techniques to test for these alterations. In other tumors, a more general oncogenic association (e.g. MAPK pathway alteration) is considered sufficient for diagnosis. In another break from the past for the WHO CNS-5, and in a manner to harmonize all WHO tumor classifications, the term “type” is used instead of the term “entity,” and “subtype” is used instead of “variant” (2).

Tumor nomenclature

WHO CNS-5 adopted the tumor nomenclature recommendations by the 2019 cIMPACT-NOW Utrecht meeting, primarily for consistency (3). This more contemporary recommendation suggests that the location, age or genetic association of a tumor type should be used in its name only if it has clinical value. Furthermore, within a given tumor type (e.g. Astrocytoma, IDH-mutant), modifiers that have indicated grade in the past, such as “anaplastic”, are no longer used. Rather, only the numerical grade is used within a tumor type in most instances. Therefore, names such as “anaplastic oligodendroglioma, IDH-mutant, 1p/19q codeleted, WHO grade 3” and “anaplastic astrocytoma, IDH-mutant, WHO grade 3” have been replaced by oligodendroglioma, IDH-mutant, 1p/19q codeleted, grade 3 and astrocytoma, IDH-mutant, WHO grade 3, respectively.

Tumor grading

Historically, brain and spinal cord tumors have had grades applied to specific entities (e.g. anaplastic astrocytomas were always grade 3) (4). While WHO CNS-5 has attempted to maintain some aspects of historical CNS tumor grading, in most cases grading is now established within tumor type, as noted above. The two main tumor-grading changes found within WHO CNS-5 include: 1) Arabic numerals are now used instead of Roman numerals for grade designation; and 2) tumors are graded within types rather designated to an individual type. The latter guideline provides flexibility in assigning grade relative to the tumor type, but also to emphasizes biological similarities within tumor types. This grading system is consistent with WHO grading in non-CNS tumors and provides a stable platform for the future. WHO CNS-5 recommends using the term “CNS WHO grade” when assigning a grade to a CNS tumor.

NOS (not otherwise specified) and NEC (not elsewhere classified) diagnoses

The addition of the NOS suffix after a diagnosis implies that the necessary test results for classification or grading a specific WHO tumor type were not available. This is intended to alert the treating neurologist that an essential molecular workup either has not yet been fully performed or has failed due to technical problems. For example, if a low grade, diffusely infiltrative astrocytoma without mitotic activity was recognized following the review of H&E-stained slides, yet additional molecular and immunohistochemical testing was not available, a diagnosis of Astrocytoma, NOS, WHO grade 2, could be established. On the other hand, the NEC suffix indicates that the necessary diagnostic molecular tests were performed successfully, yet the results do not allow for WHO classification as a recognized tumor type. The NEC designation notifies the treating neurologists that the tumor does not fit nicely into to the current classification and that a “descriptive diagnosis” has been provided. For example, if a low-grade infiltrating glioma was found to be IDH-mutant by IHC staining, yet testing for 1p/19q, ATRX loss and TP53 mutation were all negative, a diagnosis of Diffuse Glioma, IDH-mutant, NEC, WHO grade 2, could be reported. For both NOS and NEC diagnoses, a note or comment would typically explain the findings and interpretation (5, 6).

Methylome profiling

Whole genome CpG DNA methylome profiling is a recently developed methodology that is proving to be a powerful tool for CNS tumors classification (7-9). The majority of recognized CNS tumor types and subtypes can be reliably classified and graded by traditional diagnostic techniques, such as histology, immunohistochemistry, and genetic testing. If traditional testing does not yield a definitive diagnosis, DNA methylation profiling can provide additional information to support a diagnosis in some cases. For occasional brain tumor types and subtypes in the WHO CNS-5 (eg. high-grade astrocytoma with piloid features and pediatric-type high grade gliomas) DNA methylation profiling is essential for establishing a definitive diagnosis. Although only a few centers have currently implemented DNA methylation for tumor profiling, it is expected that this capability will be more readily available in the future.

Diffuse gliomas, with division into adult- and pediatric-type

One of the most clinically important changes implemented within WHO CNS-5 is the separation of the diffuse gliomas types into the “adult-type and pediatric-type” categories. Prior editions had attempted to provide uniform diagnoses across all ages. As the names imply, diffuse gliomas that primarily occur in adults are considered “adult-type,” and those that primarily occur in children are designated as “pediatric-type.” This distinction is based on the unique clinicopathologic, biological and molecular characteristics associated with each group (table 1) (10). Not surprisingly, some pediatric-type gliomas may occur in adults, while occasional adult-type gliomas may rarely occur in children. Separation of adult-type and pediatric-type diffuse gliomas will provide opportunities for clinicians and investigators to further explore the distinct biological, molecular and prognostic elements of each tumor group.

Table 1.

Adult-type and pediatric-type diffuse gliomas with corresponding genes and cytogenetic changes that are associated with each diagnosis.

Ault-type diffuse gliomas Typical genes altered and cytogenetic findings
  Astrocytoma, IDH-mutant IDH1, IDH2, ATRX, TP53, CDKN2A/B
 Oligodendroglioma. IDH-mutant, 1p/19q codeletion IDH1, IDH2, 1p/19q, TERT promoter, CIC, FUBP1, NOTCH1
 Glioblastoma, IDH-wildtype IDH-wildtype, TERT promoter, EGFR, chromosomes +7/−10
Pediatric-type diffuse low-grade gliomas
 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
Pediatric-type diffuse high-grade gliomas
 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, IDH-wildtype IDH-wildtype, H3-wildtype, PDGFRA, MYCN, EGFR
 Infant-type hemispheric glioma NTRK family, ALK, ROS, MET
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Classification of common adult-type, diffuse gliomas: a simplified approach

Adult-type diffuse gliomas are divided into three dominant types: oligodendroglioma, IDH-mutant and 1p/19q codeleted; astrocytoma, IDH-mutant; and glioblastoma, IDH-wildtype (figure 1). The new classification has been greatly simplified compared to previous editions, which stems directly from the power of molecular diagnostics to identify biologically distinct and objectively defined entities. Moreover, in the current classification, grades are assigned within types without designating a different name to each grade (3, 11). Previously recognized morphologic types of glioblastoma (e.g. giant cell glioblastoma and gliosarcoma) are no longer recognized as such in the current classification. Rather, there are now 3 recognized GBM subtypes (giant cell, gliosarcoma and epithelioid) as well as numerous tissue patterns (e.g. gemistocytic, small cell, granular cell, primitive cell, and others).

Figure 1.

Figure 1.

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Diagnostic algorithm for classification of adult-type diffuse gliomas.

Common adult-type, diffuse astrocytic gliomas, nomenclature and grading

All infiltrating astrocytomas with IDH1/IDH2 mutations are now considered a single type: Astrocytoma, IDH-mutant. They are defined by the IDH mutations and a loss of ATRX. Depending on histologic and molecular features, they are graded as CNS WHO Grade 2,3 or 4. New to the current classification is the addition of homozygous deletion of CDKN2A/B as an independent grading criterion for grade 4 in IDH-mutant astrocytoma, even in the absence of microvascular proliferation or necrosis (figure 1). The criteria for distinguishing grades 2 and 3 remain largely the same. For oligodendroglioma, IDH-mutant and 1p/19q codeleted, the finding of CDKN2A/B homozygous deletion was recognized as being associated with a grade 3 diagnosis, yet it has not yet been added as an independent grading criterion.

Molecular criteria have also been added for the grading of IDH-wildtype infiltrating gliomas. Based on an abundance of evidence related to biomarkers and clinical outcomes of histologic grade 2 and 3 IDH-wildtype diffuse gliomas, the presence of one or any combination of the following genetic alterations is now considered sufficient for the diagnosis of Glioblastoma, IDH-wildtype, WHO grade 4: 1) TERT promoter mutation; 2) EGFR amplification; or 3) combined gain of chromosome 7 and loss of chromosome 10 (+7/−10) (12, 13). Thus, the presence of necrosis or microvascular proliferation or one of these defining genetic alterations is sufficient to establish the diagnosis of Glioblastoma, IDH-wildtype, WHO grade 4. It’s worth noting that IDH-wildtype diffuse gliomas of low histologic grade with the finding of a solitary TERT promoter mutation (no other genetic alterations identified) may have a favorable prognosis compared to other IDH-wildtype glioblastomas (14). It’s also important to point out that when evaluating an IDH-wildtype diffuse glioma in younger patients, other types of diffuse pediatric-type gliomas should remain in the differential diagnosis.

Pediatric-type diffuse gliomas: low- and high-grade

Two new families of tumor types have been included in the WHO CNS-5 to highlight the distinct diagnostic features and clinical behavior of pediatric-type gliomas from other diffuse gliomas. 1) pediatric-type diffuse low-grade gliomas and 2) pediatric-type diffuse high-grade gliomas.

The low-grade gliomas have a diffuse growth pattern with non-specific and often overlapping histological features. The identification of divergent genetic alterations is critical for their proper diagnosis. In WHO CNS-5 low-grade gliomas include four tumor types: 1) diffuse astrocytoma, MYB- or MYBL1-altered; 2) angiocentric glioma; 3) polymorphous low-grade neuroepithelial tumor of the young; and 4) diffuse low-grade glioma, MAPK pathway-altered (table 1). Given the substantial impact on prognosis and treatment for patients with these low-grade gliomas, molecular features should be assessed in addition to morphological characteristics in order to properly categorize them (15).

Similarly, the family of high-grade pediatric-type diffuse gliomas encompasses four tumor types that depend on the combination of histological and molecular features for their diagnosis: 1) diffuse midline glioma H3 K27-altered; 2) diffuse hemispheric glioma, H3 G34-mutant; 3) diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype; and 4) infant-type hemispheric glioma (table 1). The change of name from H3 K27-mutated (as originally described in 2016 WHO classification) to H3 K27-altered for midline diffuse gliomas reflects the new understanding that other genetic alterations (i.e. EGFR mutation and EZHIP protein overexpression) are also now considered to be a part of this tumor spectrum in addition to H3 K27 mutation; all of these alterations lead to the same loss of H3 K27 trimethylation that defines the tumor type. The other three types are newly-introduced tumors in the WHO CNS-5. As the name implies, diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype do not harbor mutations in H3 or IDH gene families and require molecular profiling to both rule out other diseases and support the specific diagnosis. While they are most accurately defined by DNA methylation class, there are three dominant subgroups that are characterized by EGFR, PDGFRA and MYCN amplification, respectively. Infant-type hemispheric glioma is a novel high-grade glioma that occurs in newborns and infants with a distinct molecular profile characterized by gene fusion involving ALK, ROS1, NTRK1/2/3, or MET (table 1) (16, 17).

Meningiomas

In WHO CNS-5, meningioma is considered a single tumor type, yet previously described morphologic subtypes continue to be recognized. Although no new morphologic subtypes have been added to the updated edition, there has been significant advances on correlations between genetic alterations, location, morphologic subtype, grade and behavior (table 2). Grading criteria remains largely the same, with a few notable exceptions. WHO grade 2 continues to be defined by the presence of brain invasion; increased mitotic figures (≥4 and <20 per 10HPF); or a combination at least 3 of 5 morphologic features (small cell change, sheeting, macronucleoli, hypercellularity, necrosis). Clear cell and chordoid meningiomas are considered grade 2, also reflecting their increased risk of local recurrence when compared with WHO grade 1 meningiomas. A recent study of chordoid meningiomas has suggested that its designation as WHO grade 2 alone may not accurately reflect clinical behavior in some cases and that other atypical histological features and genetic alterations should be considered for more complete clinical risk stratification and patient management (18). A WHO grade 3 (anaplastic) designation is appropriate when mitotic activity is ≥20 per/10HPF or when highly anaplastic features are present, such that tumors resemble carcinoma or sarcoma. Papillary and rhabdoid meningiomas are regarded as grade 3. Despite their recognized aggressive clinical behavior in most instances, some studies have suggested that rhabdoid cytology and papillary architecture should not be the sole criteria for grading these tumors (19). Specific molecular alterations have been described in some subtypes of meningiomas that have implications for grading as well as classification. For example, SMARCE1 is strongly associated with the clear cell subtype (grade 2) and BAP1 with the rhabdoid and papillary subtypes (grade 3). Notably, TERT promoter mutation and homozygous deletion of CDKN2A/B are now considered as independent criteria for a WHO grade 3 designation regardless of morphological subtype (20, 21). Meningiomas with loss of H3 K27me3 nuclear expression have also been shown to have a worse prognosis (22). DNA methylome profiling has demonstrated its value as an objective method for prognostic subtyping of meningiomas that could be used in the near future (23). Since the publication of WHO CNS-5, a number of multi-institutional studies have suggested that a molecularly integrated grading scheme should be adopted to better help clinicians predict clinical behavior of meningiomas (24, 25).

Table 2.

Meningioma: molecular alterations associated with specific morphologies, anatomic locations and grades

Meningioma molecular alteration associated with specific morphology or location
 SMARCE1 mutation Clear cell meningioma
 BAP1 mutation or deletion Rhabdoid meningioma
 22q deletion and/or NF2 mutation Convexity and (majority) of spinal meningiomas
 AKT1, TRAF7, SMO and/or PIK3CA mutations Skull base meningioma
Molecular alterations warranting WHO grade 3 designation (regardless of morphologic features)
 TERT promoter mutation
 Homozygous deletion of CDKN2A and/or CDKN2B
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Ependymomas

In WHO CNS-5, ependymomas are classified based for the first time based on their anatomical location as well as their histopathological and genetic alterations, representing a major step forward in the clinical understanding and management of these tumor types (26). Thus, within the supratentorial, posterior fossa (PF), and spinal compartments, ependymomas are now divided into molecular groups that have substantial implications for clinical behavior (27). WHO CNS5 identifies two supratentorial ependymoma types that are defined primarily by their molecular alterations: 1) ZFTA fusion (the new designation for C11orf95 is ZFTA, which is the fusion partner of RELA, as well as other genes): and 2) YAP1 fusion. Among posterior fossa (PF) tumors, ependymomas are subclassified as PFA and PFB subtypes. PFA tumors are more clinically aggressive and are distinguished from PFB by methylation profiling or by demonstrating the global loss of H3 K27me3 by immunohistochemistry. In the spinal compartment, the majority of ependymomas are recognized by their morphology and do not have a specific gene signature. However, it is now recognized that a small subset of spinal ependymomas harbor MYCN amplification and represent a distinct type with more aggressive clinical behavior, often displaying leptomeningeal dissemination. The ependymomas are rounded out by the myxopapillary ependymoma, which occurs exclusively in the spinal compartment and subependymoma, which can arise in all compartments. These two tumor types are recognized by their morphologic features and molecular classification does not provide added clinicopathological utility (26). However, the myxopapillary ependymoma is now designated as CNS WHO grade 2, instead of grade 1 in previous editions, reflecting recent evidence that the frequency of recurrence corresponds to a grade 2 designation, similar to conventional spinal ependymoma. Previously recognized morphological variants of ependymoma, including tanycytic, clear cell and papillary are no longer considered ependymoma subtypes.

While the use of WHO grading schemes for supratentorial ependymomas is common practice in order to provide clinicians an assessment of clinical behavior and risk of recurrence in adult patients (28), the reproducibility and clinicopathological utility of grading remains in question, leaving the door open for more investigation (29) (26). In WHO CNS5, the designation of WHO grade 2 or 3 ependymoma based on histopathological features is accepted, yet in keeping with other changes in nomenclature of the diffuse gliomas, the term “anaplastic ependymoma” is no longer used (15).

Newly Recognized Entities and Revised Nomenclature

Advances in diagnostic molecular pathology, especially Next Generation Sequencing (NGS) and DNA methylation profiling, have been instrumental in recognizing new and distinct tumor types within the WHO CNS5. These new additions typically have similar clinical settings, morphologic features and behavior, but are held together most tightly by their distinctive molecular characteristics (table 3). In addition to newly added types, additional changes in nomenclature were made to previously recognized tumor types to reflect their defining genetic alterations (3). Given that additional empirical data is needed for some newly discovered tumor types, three have been provisionally accepted as types: 1) Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC); 2) Cribriform neuroepithelial tumor (CRINET); and 3) Intracranial mesenchymal tumor, FETCREB fusion-positive. In addition, a few tumor types were deemed by the WHO editorial board to be insufficiently described, but worthy of further study for potential inclusion in the future. For example, only few case reports have been published on Neuroepithelial tumor, PATZ1 fusion-positive (30-32). While a common molecular alteration has been linked to this tumor type, the histopathological features and clinical behavior are diverse and in need of additional investigation before official recognition in the WHO classification.

Table 3.

Newly recognized tumor types, 2021 WHO CNS-5

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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Conclusion

The WHO CNS-5 represents a major advance, given that it incorporates and codifies a tremendous body of discovery and investigation derived from the global neuro-oncology community over the course of the past 6 years. Our current understanding of the molecular genetic signatures and biological behavior of specific tumor types has led to integrated diagnoses, molecular criteria for grading and a number of new diagnostic entities, all of which improve diagnostic reproducibility and clinical relevance. The CNS tumors that are commonly encountered by neurologists, including the diffuse gliomas, meningiomas and ependymomas have all seen substantial changes to criteria and classification that will affect clinical decisions and patient care. The advances noted in the WHO CNS-5 provide the practicing neurologist with confidence that they are treating well-defined clinicopathologic tumor types defined by molecular criteria, which should enable improved prognostication, refine treatment decisions and allow for the development of more meaningful and successful clinical trials.

Key points.

  • Adult-type diffuse gliomas are now simplified into three types; 1) glioblastoma, IDH-wildtype, 2) astrocytoma, IDH-mutant and 3) oligodendroglioma, IDH-mutant and 1p/19q co-deleted.

  • Pediatric-type diffuse gliomas have been divided into low-grade and high-grade based on their morphologic features, molecular characteristics and clinical behavior

  • Meningioma is now considered a single tumor type, with grading based on specific morphological features, mitotic activity, molecular and cytogenetic alterations.

  • Ependymomas are now classified based on their anatomical location as well as their histopathological and genetic alterations.

  • Newly recognized entities in the WHO CNS-5 typically have distinctive molecular characteristics, morphologic features and clinical behavior.

Financial support and sponsorship:

This work was supported by the National Institutes of Health (R01 CA214928, R01 CA247905, P50 CA221747, U01 CA217613 and U01 CA199288).

Footnotes

Conflicts of interest: None

References:

  • 1.WHO Classification of Tumours Editorial Board. World Health Organization Classification of Tumours of the Central Nervous System. 5th ed. Lyon: International Agency for Research on Cancer; 2021. [Google Scholar]
  • 2.**. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231–51. This is a comprehensive summary, written by many of the WHO editors, highliting the major general changes in the 2021 WHO CNS tumors classification and the specific changes in each taxonomic category.
  • 3.Louis DN, Wesseling P, Aldape K, Brat DJ, Capper D, Cree IA, et al. cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading. Brain Pathol. 2020;30(4):844–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Louis DN, von Deimling A. Grading of diffuse astrocytic gliomas: Broders, Kernohan, Zulch, the WHO… and Shakespeare. Acta Neuropathol. 2017;134(4):517–20. [DOI] [PubMed] [Google Scholar]
  • 5.Louis DN, Wesseling P, Paulus W, Giannini C, Batchelor TT, Cairncross JG, et al. cIMPACT-NOW update 1: Not Otherwise Specified (NOS) and Not Elsewhere Classified (NEC). Acta Neuropathol. 2018;135(3):481–4. [DOI] [PubMed] [Google Scholar]
  • 6.Louis DN, Ellison DW, Brat DJ, Aldape K, Capper D, Hawkins C, et al. cIMPACT-NOW: a practical summary of diagnostic points from Round 1 updates. Brain Pathol. 2019;29(4):469–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, et al. DNA methylation-based classification of central nervous system tumours. Nature. 2018;555(7697):469–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Capper D, Stichel D, Sahm F, Jones DTW, Schrimpf D, Sill M, et al. Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience. Acta Neuropathol. 2018;136(2):181–210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Jaunmuktane Z, Capper D, Jones DTW, Schrimpf D, Sill M, Dutt M, et al. Methylation array profiling of adult brain tumours: diagnostic outcomes in a large, single centre. Acta Neuropathol Commun. 2019;7(1):24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.*. Brat DJ, Aldape K, Bridge JA, Canoll P, Colman H, Hameed MR, et al. Molecular Biomarker Testing for the Diagnosis of Diffuse Gliomas. Arch Pathol Lab Med. 2022;146(5):547–74. This is a guildeline and systematic review of the literature by an expert panel from College of American Pathologists (CAP) in collaboration with American Association of Neuropathologists (AANP), Association of Molecular Patholopgy (AMP) and Soceity for Neuro-Oncology (SNO) to provide an evidence-based recommendation for incorporation of molecular biomarkers for diagnosis of diffuse gliomas.
  • 11.Brat DJ, Aldape K, Colman H, Figrarella-Branger D, Fuller GN, Giannini C, et al. cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol. 2020;139(3):603–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Brat DJ, Aldape K, Colman H, Holland EC, Louis DN, Jenkins RB, et al. cIMPACT-NOW update 3: recommended diagnostic criteria for "Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV". Acta Neuropathol. 2018;136(5):805–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Tesileanu CMS, Dirven L, Wijnenga MMJ, Koekkoek JAF, Vincent A, Dubbink HJ, et al. Survival of diffuse astrocytic glioma, IDH1/2 wildtype, with molecular features of glioblastoma, WHO grade IV: a confirmation of the cIMPACT-NOW criteria. Neuro Oncol. 2020;22(4):515–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Berzero G, Di Stefano AL, Ronchi S, Bielle F, Villa C, Guillerm E, et al. IDH-wildtype lower-grade diffuse gliomas: the importance of histological grade and molecular assessment for prognostic stratification. Neuro Oncol. 2021;23(6):955–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Louis DN, Perry A, Burger P, Ellison DW, Reifenberger G, von Deimling A, et al. International Society Of Neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol. 2014;24(5):429–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Clarke M, Mackay A, Ismer B, Pickles JC, Tatevossian RG, Newman S, et al. Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes. Cancer Discov. 2020;10(7):942–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Guerreiro Stucklin AS, Ryall S, Fukuoka K, Zapotocky M, Lassaletta A, Li C, et al. Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas. Nat Commun. 2019;10(1):4343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Daoud EV, Zhu K, Mickey B, Mohamed H, Wen M, Delorenzo M, et al. Epigenetic and genomic profiling of chordoid meningioma: implications for clinical management. Acta Neuropathol Commun. 2022;10(1):56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Vaubel RA, Chen SG, Raleigh DR, Link MJ, Chicoine MR, Barani I, et al. Meningiomas With Rhabdoid Features Lacking Other Histologic Features of Malignancy: A Study of 44 Cases and Review of the Literature. J Neuropathol Exp Neurol. 2016;75(1):44–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Sahm F, Schrimpf D, Olar A, Koelsche C, Reuss D, Bissel J, et al. TERT Promoter Mutations and Risk of Recurrence in Meningioma. J Natl Cancer Inst. 2016;108(5). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Sievers P, Hielscher T, Schrimpf D, Stichel D, Reuss DE, Berghoff AS, et al. CDKN2A/B homozygous deletion is associated with early recurrence in meningiomas. Acta Neuropathol. 2020;140(3):409–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Gauchotte G, Peyre M, Pouget C, Cazals-Hatem D, Polivka M, Rech F, et al. Prognostic Value of Histopathological Features and Loss of H3K27me3 Immunolabeling in Anaplastic Meningioma: A Multicenter Retrospective Study. J Neuropathol Exp Neurol. 2020;79(7):754–62. [DOI] [PubMed] [Google Scholar]
  • 23.Nassiri F, Mamatjan Y, Suppiah S, Badhiwala JH, Mansouri S, Karimi S, et al. DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management. Neuro Oncol. 2019;21(7):901–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.*. Driver J, Hoffman SE, Tavakol S, Woodward E, Maury EA, Bhave V, et al. A molecularly integrated grade for meningioma. Neuro Oncol. 2022;24(5):796–808. This is a multi-institutional study to improve prediction of progression-free survival in meningiomas based on a molecularly integrated grading scheme by incorporating chromosomal copy-number alterations and mitotic count.
  • 25.**. Nassiri F, Liu J, Patil V, Mamatjan Y, Wang JZ, Hugh-White R, et al. A clinically applicable integrative molecular classification of meningiomas. Nature. 2021;597(7874):119–25. This is a multi-institutional study to help classify and risk stratify clinical behavior of meningiomas based on combination of DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation and messenger RNA abundance.
  • 26.Ellison DW, Aldape KD, Capper D, Fouladi M, Gilbert MR, Gilbertson RJ, et al. cIMPACT-NOW update 7: advancing the molecular classification of ependymal tumors. Brain Pathol. 2020;30(5):863–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F, et al. Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell. 2015;27(5):728–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Vera-Bolanos E, Aldape K, Yuan Y, Wu J, Wani K, Necesito-Reyes MJ, et al. Clinical course and progression-free survival of adult intracranial and spinal ependymoma patients. Neuro Oncol. 2015;17(3):440–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Ellison DW, Kocak M, Figarella-Branger D, Felice G, Catherine G, Pietsch T, et al. Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. J Negat Results Biomed. 2011;10:7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Siegfried A, Rousseau A, Maurage CA, Pericart S, Nicaise Y, Escudie F, et al. EWSR1-PATZ1 gene fusion may define a new glioneuronal tumor entity. Brain Pathol. 2019;29(1):53–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Stichel D, Schrimpf D, Casalini B, Meyer J, Wefers AK, Sievers P, et al. Routine RNA sequencing of formalin-fixed paraffin-embedded specimens in neuropathology diagnostics identifies diagnostically and therapeutically relevant gene fusions. Acta Neuropathol. 2019;138(5):827–35. [DOI] [PubMed] [Google Scholar]
  • 32.Burel-Vandenbos F, Pierron G, Thomas C, Reynaud S, Gregoire V, Duhil de Benaze G, et al. A polyphenotypic malignant paediatric brain tumour presenting a MN1-PATZ1 fusion, no epigenetic similarities with CNS High-Grade Neuroepithelial Tumour with MN1 Alteration (CNS HGNET-MN1) and related to PATZ1-fused sarcomas. Neuropathol Appl Neurobiol. 2020;46(5):506–9. [DOI] [PubMed] [Google Scholar]

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