Historical note and terminology

The Central Nervous System WHO Classification of Tumours series (also referred to as the WHO Blue Books) represent the primary source of diagnostic updates for classes, grades, and criteria. The fifth edition (WHO CNS-5) (25) is the sixth and most recent of these guidelines, following the prior publications from 1979, 1993, 2000, 2007, and 2016 (26; 11; 16; 17; 12). These publications have documented the advancements in the field. The most recent developments have been the incorporation of molecular diagnostics with established approaches in tumor characterization, including histology and immunohistochemistry. Prior to the WHO CNS-5, a group of neuropathology and neuro-oncology experts referred to as cIMPACT-NOW (Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO) provided update recommendations and proposed changes to the CNS tumor classifications and grading (13; 08). Since the 2016 WHO CNS-4, cIMPACT-NOW published seven updates with recommendations, which have largely been adopted in the 2021 WHO CNS-5 (15; 22; 21; 01; 02; 07; 06).

Biological basis

Advances in diagnostic molecular pathology have substantially enhanced our understanding of CNS tumors, providing new opportunities to refine their classification. Building on the recommendations of the cIMPACT-NOW, the WHO CNS-5 features substantial changes to advance the role of molecular diagnosis in CNS classification. Some tumor types are readily and consistently characterized by defining molecular features; for others, molecular parameters are not required but may support their classification; yet others are rarely or never diagnosed using molecular approaches. The most recent accepted terminology and diagnostic criteria of adult- and pediatric-type diffuse gliomas are discussed herein.

Overview of changes

Tumor taxonomy

Historically, the CNS tumor classification, and particularly regarding infiltrating glioma, has been based on morphologic features and supported by ancillary tissue-based tests (eg, immunohistochemistry), but more recently, molecular signatures have played a more central role in providing ancillary and defining diagnostic information. Thus, the most recent WHO CNS tumor classification integrates multiple molecular signatures that are important for the most accurate classification of diffuse gliomas.

Table 1. Major Diagnostic Genes and Molecular Alterations in Diffuse Gliomas

No recommendations on specific molecular techniques for assessing diagnostic genetic alterations are provided unless a certain method is unequivocally required for the diagnosis of a distinct tumor type or subtype (eg, DNA methylation profiling). For some infiltrating gliomas, WHO CNS-5 has combined tumors based on the molecular alteration that allows a diagnosis (eg, IDH and H3 status). In other cases, less definitive oncogenic associations, such as MAPK pathway alterations, are considered sufficient for diagnosis. In the WHO CNS-5, the term “type” is used instead of “entity,” and “subtype” is used instead of “variant.”

Tumor nomenclature

WHO CNS-5 follows the tumor nomenclature recommendations of the 2019 cIMPACT-NOW Utrecht meeting to make nomenclature more consistent and simple (21). The current recommendation states that only location, age, or genetic modifiers with clinical utility should be used. Although the WHO CNS-5 has suggested many other recommendations, the most pertinent for infiltrating gliomas refers to grading within tumor type. As such, modifiers such as “anaplastic” are no longer used, and names such as “anaplastic oligodendroglioma” and “anaplastic astrocytoma” are omitted in the new classification.

Tumor grading

Historically, brain and spinal cord tumors had grades applied across different entities (20). WHO CNS-5 has attempted to retain some main aspects of historical CNS tumor grading; however, for the most part, it has moved toward grading within tumor type. Two specific tumor-grading recommendations in WHO CNS-5 are (1) Arabic numerals are used instead of Roman numerals, and (2) tumors are graded within types instead of across different tumor types. The grading of tumors within types is aimed, first, to provide more flexibility in assigning grade relative to the tumor type and, second, to emphasize biological similarities within tumor types. Lastly, it may correspond with WHO grading in non-CNS tumor types. Given the unique grading of CNS tumors, WHO CNS-5 recommends using the term “CNS WHO grade” when assigning a grade.

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

The addition of the NOS suffix indicates that the necessary diagnostic information, either histological or molecular, required to assign a specific WHO diagnosis was not available at the time of diagnosis. This is meant to alert the clinical team that a necessary molecular work-up either has not yet been performed or has failed due to technical issues. In contrast, the NEC suffix indicates that although the required diagnostic testing has been successfully performed, the results do not allow for a standard WHO diagnosis. The designation of NEC alerts the treating physician that despite an adequate pathological workup, the tumor does not conform to a currently recognized WHO diagnosis (22; 14).

Methylome profiling

DNA methylome profiling is proving to be a powerful tool for the classification and diagnosis of CNS tumors (03; 04; 10). Most tumor types and subtypes can be reliably diagnosed by other established techniques, including histology, immunohistochemistry, and defining genetic alteration. However, WHO CNS-5 introduces rare but new tumor types or subtypes (eg, high-grade astrocytoma with piloid features) that are only identified by DNA methylation profiling.

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

In the most recent edition of the World Health Organization Classification of Tumours of the Central Nervous System, 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 stems from the clinicopathologic and molecular features associated with each group (see Table 1). However, it is imperative to note that pediatric-type gliomas occasionally may occur in adults, particularly young adults, and on rare occasions, adult-type gliomas may occur in children. Division of adult-type and pediatric-type diffuse gliomas will likely help further investigate the contributing biological and subsequently prognostic elements of each tumor group.

Classification of common adult-type, diffuse gliomas: a simplified approach

In the fifth edition of the CNS classification (WHO CNS-5), adult-type diffuse gliomas are assigned into three entities: (1) astrocytoma, IDH-mutant; (2) oligodendroglioma, IDH-mutant and 1p/19q co-deleted; and (3) glioblastoma, IDH-wildtype. The current classification is the result of (A) recognition of the value of molecular diagnostics in assigning more objectively defined entities, (B) assigning grades within types without giving each grade a different name (02; 21), and (C) more synchronized use of NOS and NEC terminology as suggested in cIMPACT-NOW Update 1 (22). Furthermore, in the most recent edition of WHO Blue Books, subtypes (eg, gliosarcoma and giant cell glioblastoma) are not listed in the classification; however, these classic variants are discussed in their respective chapters.

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

In WHO CNS-5, all IDH-mutant infiltrating astrocytomas are considered a single entity (ie, astrocytoma, IDH-mutant) and are graded as CNS WHO Grade 2, 3, or 4 depending on both histologic and molecular features. For example, even in the absence of tumor necrosis or microvascular proliferation, homozygous deletion of CDKN2A/B warrants designation of CNS WHO Grade 4.

For IDH-wildtype infiltrating gliomas in adults, a number of reports have shown that the presence of one or more of these genetic alterations (TERT promoter mutation, EGFR amplification, and combined gain of chromosome 7 and loss of chromosome 10 (+7/-10) is sufficient for designation of WHO Grade 4 (01; 23). As such, these three genetic alterations are considered by WHO CNS-5 as criteria for a diagnosis of glioblastoma, IDH-wildtype. It is imperative to note that when assessing an IDH-wildtype in younger age groups, other types of diffuse pediatric-type gliomas should be considered.

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

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

The low-grade group encompasses four subtypes, all of which have a diffuse growth pattern within the brain but somewhat overlapping and nonspecific histological characteristics. However, distinct genetic alterations help distinguish between these groups. In WHO CNS-5, the four types are (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 (see Table 1). For precise classification of these tumors, in addition to histological features (most commonly with astrocytic or oligodendroglial morphology), molecular characterization should be determined (18).

The high-grade family also includes four types: (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 (see Table 1). Although diffuse midline glioma, H3 K27-altered was mentioned in the 2016 classification, the change of name in this tumor type (H3 K27-altered instead of H3 K27-mutated) in the WHO CNS-5 reflects the fact that, in addition to H3 K27 mutations, other genetic alterations (eg, EZHIP protein overexpression) can also define this entity. The other three types are newly- introduced tumors in the WHO CNS-5. Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype is specified as being wildtype for both H3 and IDH gene families, requiring both histologic evaluation and identification of molecular features. Infant-type hemispheric glioma is a novel type of high-grade glioma that occurs in newborns and infants and has a distinct molecular profile with fusion genes involving ALK, ROS1, NTRK1/2/3, or MET (see Table 1) (09; 05).