Gliomas are tumors that arise from glial cells, the supportive cells of the brain and spinal cord, and represent the most common type of primary brain tumor in adults. The World Health Organization (WHO) Classification of Tumours of the Central Nervous System is the globally accepted standard for diagnosing these tumors. The 2021 fifth edition (CNS WHO 5) fundamentally reorganized how gliomas are defined and named. This update shifts the diagnostic process from relying primarily on microscopic appearance to an integrated approach incorporating specific molecular and genetic characteristics. This change reflects the understanding that a tumor’s molecular fingerprint is a stronger predictor of its behavior and patient outcome than its appearance alone.
The Foundational Change in Diagnosis
The 2021 classification moved away from the purely histology-based system used for decades. Previously, gliomas were classified mainly by cell type and grade of malignancy based on microscopic features. However, tumors with identical appearances often behaved differently, revealing the limitations of the traditional method. The 2021 edition mandates an “integrated diagnosis,” requiring both conventional tissue analysis and specific molecular testing results for final classification.
This integrated approach acknowledges that molecular alterations define a tumor entity more precisely than its cellular origin. For example, a tumor appearing low-grade may be reclassified as high-grade if its molecular profile indicates aggressive behavior. The classification elevates the importance of the tumor’s underlying biology over its morphology, providing a more accurate assessment of its potential progression.
The goal of the WHO Classification of Tumours of the Central Nervous System, 5th Edition, is to standardize diagnosis globally. This molecular stratification allows for a uniform grouping of patients with similar diseases, which is necessary for effective clinical research and treatment planning.
Key Molecular Markers Defining Subtypes
The new system relies on specific molecular markers that act as genetic signatures for different glioma subtypes. The primary marker is the status of the Isocitrate Dehydrogenase (IDH) gene (IDH1 or IDH2 mutations). Gliomas are first categorized as either IDH-mutant or IDH-wildtype, a distinction that significantly impacts prognosis.
A second defining alteration is the 1p/19q co-deletion, involving the simultaneous loss of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q). Its presence, alongside an IDH mutation, defines the Oligodendroglioma type. This combination creates a distinct tumor entity with a relatively favorable prognosis.
For gliomas in the central nervous system midline structures, especially in children, the H3 K27-altered status is a defining feature. This alteration, often involving the H3 K27M mutation, is associated with the aggressive Diffuse Midline Glioma (DMG). These molecular fingerprints dictate the diagnostic label and treatment approach, overriding traditional appearance.
The New Hierarchy of Glioma Types
The 2021 classification streamlines adult-type diffuse gliomas into three main diagnostic categories based on molecular data. These types are defined by IDH mutation status combined with other specific genetic changes.
Astrocytoma, IDH-mutant
This type includes all diffuse astrocytic tumors with an IDH mutation but lacking the 1p/19q co-deletion. This entity encompasses tumors previously classified as diffuse astrocytoma, anaplastic astrocytoma, and some IDH-mutant glioblastomas. Grading ranges from CNS WHO grade 2 to grade 4. Grade 4 is automatically assigned if the tumor shows homozygous loss of the CDKN2A/B gene, even without traditional signs of malignancy.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted
This distinct type is defined by the concurrent presence of both the IDH mutation and the 1p/19q co-deletion. These tumors are assigned a CNS WHO grade of 2 or 3, with grade 3 used for tumors showing increased cellularity and proliferative activity. The co-deletion is mandatory for this diagnosis due to its favorable prognosis.
Glioblastoma, IDH-wildtype
This remains the most common and aggressive adult glioma. The diagnosis is applied to IDH-wildtype astrocytic tumors that show either traditional microscopic features of malignancy (e.g., necrosis) or possess one of three specific molecular features: TERT promoter mutation, EGFR gene amplification, or combined whole chromosome 7 gain and chromosome 10 loss. Any one of these markers is sufficient to assign a CNS WHO grade 4, regardless of microscopic appearance.
Clinical Implications for Treatment and Prognosis
The precise molecular distinctions introduced by the 2021 WHO classification have direct consequences for patient management. Molecular status is the strongest predictor of a patient’s survival time. For example, a patient with an IDH-mutant glioma has a significantly longer life expectancy than one with an IDH-wildtype Glioblastoma, regardless of initial microscopic grade.
Knowing the specific molecular subtype allows doctors to select precise, targeted treatments. Oligodendrogliomas with the 1p/19q co-deletion are particularly responsive to combined radiation and chemotherapy (PCV), a regimen less effective for non-codeleted tumors. The new system also ensures that clinical trial participants share a genetically similar disease, leading to more meaningful research results.
Reclassification based on molecular markers, such as the automatic grade 4 designation for IDH-mutant astrocytomas with a CDKN2A/B deletion, ensures that patients with biologically aggressive tumors receive appropriate intensive treatment immediately. This molecular-driven classification provides an accurate roadmap for predicting tumor behavior and tailoring the intensity of surgery, radiation, and chemotherapy.