Introduction

After the release of the 5th edition of the WHO Classification of the Central Nervous System (WHO CNS5) in 2021 [1], various challenges have arisen in applying its diagnostic criteria in daily practice. This editorial highlights the issues that need to be addressed in the subsequent edition of the WHO classification (Table 1).

Table 1 Issues that need to be clarified in the subsequent edition of the WHO classification
Full size table

The definitions of tumor groups, types, and subtypes

The most significant revision in WHO CNS5 was the separation of pediatric-type diffuse gliomas from the adult types [5], creating three distinct tumor types in the adult group: ‘astrocytoma, IDH-mutant,’ ‘oligodendroglioma, IDH-mutant and 1p/19q deleted,’ and ‘glioblastoma (GBM), IDH-wildtype.’ In contrast, the definition of pediatric-type diffuse gliomas remained unclear, with their molecular alterations being quite heterogeneous. In the 4th edition of the WHO Classification of the Central Nervous System, published in 2007, clear criteria were set for defining tumor types (referred to as entities at that time), requiring distinctive morphology, location, age distribution, and biological behavior, rather than solely relying on unusual histopathological patterns [9]. Additionally, at least two independent groups were required to describe the lesion to be accepted as an entity. WHO CNS5 allows the definition of a tumor type solely based on the DNA-methylation profile determined by a single classifier [2], making the definition of tumor types less stringent.

Hereditary tumor predisposition syndrome (HTPS)

Another issue that was insufficiently addressed in WHO CNS5 is hereditary tumor predisposition syndrome (HTPS). This condition has seen rapid advancements through genetic screening assays, such as next-generation somatic and germline DNA sequencing. Genetic screening was traditionally recommended in cases with significant family history, known specific combinations of malignancies (such as plexiform neurofibromas with neurofibromatosis type 1), and physical features typical of HTPS. Recent data suggest that between 5 and 10% of cancers may be related to HTPS [10]. Consequently, all individuals with brain tumors are primary candidates for affordable, high-throughput sequencing methods [11]. However, the WHO CNS5 has yet to provide standardized guidelines for screening HTPS.

The tumor types that need further clarification

This significant revision also resulted in the omission of minor, unclassified tumor subtypes from the classification due to a lack of sufficient evidence. One such subtype is the IDH-wildtype diffuse gliomas, which do not show molecular alterations characteristic of molecular GBM or other tumor types defined within WHO CNS5.

TERT promoter mutation-only diffuse gliomas, one of the IDH-wildtype diffuse gliomas, is a critical issue that needs urgent clarification, as this mutation is one of the criteria for classifying a tumor as molecular GBM. WHO CNS5 recognizes that a TERT promoter mutation alone can qualify a tumor as molecular GBM. However, recent studies have shown that some gliomas with only the TERT promoter mutation exhibit more favorable outcomes [4], suggesting that the standard GBM treatment protocol might be excessive for such patients. In our experience, most cases of molecular GBM also present additional alterations, such as EGFR amplification or PTEN loss, in addition to the TERT promoter mutation. Therefore, the current criteria for molecular GBM should be re-evaluated to prevent potential overtreatment.

Another issue with GBM, IDH-wildtype involves the criteria for ‘diffuse pediatric-type high-grade gliomas, H3-wildtype, and IDH-wildtype.’ These criteria significantly overlap with those for molecular GBM [8]. DNA methylation profiling is the sole method for distinguishing these pediatric-type gliomas from their adult counterpart, but this technique is only available in a limited number of institutes, even in developed countries. In clinical practice, it is not uncommon for younger adult patients to present with pediatric-type gliomas, making accurate diagnosis essential.

Regarding pediatric-type diffuse low-grade glioma, the definition of polymorphous low-grade neuroepithelial tumor of the young (PLNTY) partially overlaps with that of diffuse low-grade glioma, MAPK pathway-altered. The only distinguishing feature between these two is the presence or absence of CD34 immunoreactivity, which is nonspecific and can be found in various tumors, including ganglioglioma and other glioneuronal tumors [6].

As previously mentioned, a fundamental issue is the lack of clear and uniform criteria for defining tumor types. Therefore, the forthcoming WHO classification must establish consistent standards for identifying each tumor type before introducing new types.

Malignancy scale (CNS WHO grade)

The standard method for assessing the malignancy level and biological behavior (CNS WHO grade) of tumors relies on historical data regarding the prognosis of each tumor type following surgical resection without adjuvant therapy [7]. However, creating criteria for newly recognized malignant tumor types is difficult due to the lack of historical data. Ethical concerns prevent withholding adjuvant therapy from patients with malignant tumors.

An example is the molecular redefinition of ependymomas, such as posterior fossa group A (PFA) and group B (PFB) [3]. For these tumors, new prognostic factors are required to assess their risk levels accurately. While some data indicate that the histological assessment of anaplasia of posterior fossa ependymoma remains predictive when there is a consensus among pathologists, other findings are inconclusive.

Another area that needs clarification in the upcoming WHO classification is the criteria for anaplastic meningioma. WHO CNS5, for the first time, incorporated molecular information into the criteria for anaplastic meningioma, requiring either a TERT promoter mutation or a CDKN2A homozygous deletion [1]. However, verifying the presence of such alterations in all meningiomas is impractical due to the costs and technical difficulties associated with these common tumors. Criteria for molecular testing I anaplastic for anaplastic meningioma in routine practice should be established.

In conclusion, while WHO CNS5 has made significant strides by incorporating recent advancements in molecular pathology into its classification system, it is an ongoing process that requires continuous revisions to ensure consistency across all tumor types.