NEUROPATHOLOGY


one of the most important markers of glial differentiation. Expression of GFAP supports glial lineage and assists in distinguishing gliomas from metastatic tumours and other intracranial neoplasms. Ki-67 provides an estimate of cellular proliferative activity and contributes valuable prognostic information. High proliferative indices are generally associated with aggressive tumour behaviour and higher tumour grades. Additional markers including p53 and


ATRX support molecular classification. ATRX loss is commonly observed in IDH-mutant astrocytomas, while retained ATRX expression may suggest alternative molecular pathways. Similarly, p53 overexpression frequently reflects IDH mutations and can provide useful diagnostic information. Perhaps the most transformative immunohistochemical marker has been mutant IDH1 R132H. The introduction of this antibody enabled rapid identification of the most common IDH mutation directly within tissue sections and significantly streamlined diagnostic workflows. These biomarkers have become indispensable tools in contemporary neuropathology and illustrate the increasingly integrated nature of modern diagnostics.


Molecular diagnostics and genetic testing A significant development in modern neuropathology has been the integration of molecular genetics into routine diagnostic workflows. While morphology and IHC remain essential, genetic testing now plays a central role in the diagnosis, classification and management of gliomas. Genetic testing examines DNA and chromosomal alterations within tumour cells to identify molecular abnormalities that drive tumour development and progression. These molecular signatures often provide information that cannot be determined through histopathological assessment alone.


Importantly, gliomas that appear morphologically similar under the microscope may possess markedly different genetic profiles, resulting in substantial differences in prognosis and therapeutic response. The WHO 2021 Classification of Tumors of the Central Nervous System formally incorporated molecular findings into tumour classification, fundamentally changing the diagnostic approach to diffuse gliomas.3


now combines histopathological features with immunohistochemical and molecular findings to provide a biologically relevant classification.


A significant development in modern


neuropathology has been the integration of molecular genetics into routine


diagnostic workflows. While morphology and IHC remain essential, genetic testing now plays a central role in the diagnosis, classification and management of gliomas


IDH mutations


Mutations involving the isocitrate dehydrogenase genes (IDH1 and IDH2) represent one of the most important biomarkers in glioma diagnostics. IDH mutations result in altered cellular metabolism through the production of the oncometabolite D-2-hydroxyglutarate, which contributes to tumour development through epigenetic dysregulation.4 Clinically, the distinction between IDH- mutant and IDH-wildtype gliomas is highly significant. Patients with IDH- mutant gliomas generally experience longer survival and improved treatment responses compared to those with IDH-wildtype tumours. Consequently, determination of IDH status is now considered a fundamental component of glioma classification and prognostic assessment.


1p/19q codeletion


The combined deletion of chromosome arms 1p and 19q is another key molecular marker. This characteristic genetic alteration defines oligodendroglioma when present alongside an IDH mutation. The identification of 1p/19q codeletion is clinically important because these tumours often demonstrate greater sensitivity to chemotherapy and radiotherapy, and are associated with more favourable long-term outcomes. Detection of this molecular signature therefore assists both diagnostic classification and treatment planning.


MGMT promoter methylation As a result, integrated diagnosis


Methylation of the O6-methylguanine- DNA methyltransferase (MGMT) promoter is an established predictive biomarker in glioblastoma. MGMT encodes a DNA repair enzyme capable of reversing the effects of alkylating chemotherapeutic agents such as temozolomide. When the MGMT promoter is


methylated, expression of the repair


enzyme is reduced, rendering tumour cells more susceptible to chemotherapy- induced DNA damage. Patients with MGMT-methylated glioblastomas therefore generally demonstrate improved responses to temozolomide treatment and prolonged survival compared with patients lacking promoter methylation.


Additional molecular alterations


Several additional genetic alterations contribute to glioma classification and prognostication. These include: ATRX mutations and loss of expression, commonly observed in astrocytomas TP53 mutations, frequently associated with IDH-mutant astrocytomas TERT promoter mutations, often observed in glioblastoma and oligodendroglioma EGFR amplification, a hallmark of many glioblastomas. CDKN2A/B homozygous deletion, associated with more aggressive disease behaviour and incorporated into WHO grading criteria.


Together, these biomarkers illustrate how modern glioma diagnostics increasingly rely upon molecular information to complement traditional histopathology.


Next-generation sequencing and methylation profiling The growing adoption of next-generation sequencing (NGS) has expanded the capabilities of neuropathology laboratories. NGS enables simultaneous analysis of multiple genes within a single assay, providing comprehensive molecular characterisation of tumours. In glioma diagnostics, NGS panels may identify clinically relevant mutations involving IDH1, IDH2, TP53, ATRX, BRAF, TERT and other genes associated with tumour


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