NEUROPATHOLOGY
Understanding glioma biology Gliomas arise from glial cells or their precursor populations within the central nervous system and encompass a spectrum of tumours ranging from relatively slow-growing, low-grade lesions to highly aggressive glioblastomas. According to WHO CNS5, diffuse gliomas, are broadly categorised into adult-type diffuse gliomas and paediatric-type diffuse gliomas, reflecting distinct biological and molecular characteristics.3 Among adult diffuse gliomas, molecular alterations have become the defining features of classification. IDH-mutant astrocytomas generally demonstrate slower growth, greater sensitivity to treatment and improved survival compared with IDH-wildtype tumours. In contrast, glioblastoma, IDH-wildtype, remains associated with rapid progression and poor prognosis despite aggressive treatment.4
One of the most challenging aspects of glioma biology is its heterogeneity. Tumour cells within the same lesion can display substantial genetic, epigenetic and phenotypic diversity. This heterogeneity contributes significantly to treatment resistance and disease recurrence. It also explains why gliomas remain difficult to eradicate despite multimodal therapeutic approaches. Increasingly, researchers recognise that tumour behaviour cannot be explained solely by intrinsic genetic alterations. Instead, gliomas function as complex biological ecosystems in which malignant cells interact continually with surrounding cellular and molecular components. This collective environment is known as the tumour microenvironment.
Glioma tumour microenvironment The tumour microenvironment (TME) is now recognised as a major determinant of tumour growth, invasion and therapeutic response.5
Rather than
existing in isolation, glioma cells interact with a diverse network of immune cells, endothelial cells, extracellular matrix proteins, astrocytes, neurons and molecular signalling pathways. These interactions influence virtually every aspect of tumour progression. Through the secretion of cytokines,
growth factors and extracellular vesicles, glioma cells actively modify their surroundings to create conditions favourable for survival and expansion. Simultaneously, surrounding cells influence tumour behaviour through reciprocal signalling mechanisms. The brain presents a unique microenvironment due to the presence of the blood-brain barrier and highly
IHC Necrosis H&E stain Tumour GFAP
Ki67
IDH1 Vessels
Typical histopathological assessment (H&E stain) and IHC ‘Glioma Panel’ interpretation, which includes GFAP, Ki-67, p53, ATRX and IDH1.
specialised resident immune populations. This distinctive environment creates both challenges and opportunities for tumour development. In routine histopathology, evidence
of these biological interactions is visible on haematoxylin and eosin (H&E)- stained sections. Features such as pseudopalisading necrosis, microvascular proliferation, diffuse infiltration and inflammatory cell recruitment provide morphological evidence of the underlying molecular processes driving tumour progression. Each area of necrosis, each proliferating blood vessel and each infiltrating immune cell reflects an active process occurring within the tumour ecosystem.
Immune cells: friend or foe? One of the most intriguing aspects of glioma biology is the relationship between tumour and the immune system. Intuitively, immune infiltration might be expected to reflect an effective host response against malignancy. However, gliomas have evolved sophisticated mechanisms to manipulate immune populations and evade destruction. Tumour-associated macrophages and microglia may constitute 30–50% of glioblastoma tumour mass,6 but, although these cells normally contribute to immune surveillance and tissue homeostasis, gliomas frequently reprogramme them into immunosuppressive phenotypes that promote tumour progression. These altered macrophages produce
growth factors, cytokines and angiogenic mediators that support tumour invasion and vascular development. Rather
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than attacking malignant cells, they become active participants in tumour growth. Similarly, T lymphocytes within glioblastoma often display features of functional exhaustion.7
Exhausted T
cells demonstrate reduced proliferative capacity and diminished cytotoxic activity, limiting their ability to eliminate tumour cells effectively. This phenomenon contributes significantly to the poor efficacy of many immunotherapeutic approaches in glioblastoma. Markers such as CD68, CD163, CD3 and CD8 are not simply stains performed within the laboratory; they provide insight into the biological relationships occurring between tumour and host. Each positive cell identified under the microscope represents part of a larger story regarding tumour progression, immune regulation and potential therapeutic vulnerability.
Histopathology and IHC in modern neuropathology Although molecular pathology has transformed neuro-oncology diagnostics, histopathology remains the foundation upon which diagnosis is built. Careful microscopic assessment continues to provide essential information regarding tumour architecture, cellular morphology and pathological grade. The introduction of IHC has greatly enhanced diagnostic accuracy by enabling visualisation of specific protein expression paterns within tissue sections. Modern glioma diagnosis frequently
incorporates panels of IHC markers alongside routine morphology. Glial fibrillary acidic protein (GFAP) remains
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