Overview of Gliomas and Its Histopathology

Tumors of the central nervous system (CNS) constitute 1–2% of all malignancies. However, CNS malignancies arguably have the most varied manifestations among all cancer sites. There are several anatomical subregions in the craniospinal axis, and each of these has a predilection for a particular tumor subtype. Further, each tumor can be subdivided into prognostic groups based on surgical resection extent, performance status, imaging findings, grade, age, and molecular characteristics. Among CNS neoplasms, gliomas are the most common tumors. The incidence of CNS tumors in India ranges from 5 to 10 per 100, 000 population with an increasing trend and accounts for 2% of malignancies. Astrocytomas (38. 7%) were the most common primary tumors with the majority being high-grade gliomas (59. 5%). More interestingly during the presentation, the median age of glial tumors was seen to be at least a decade earlier than reported in the Western population, which could be partially explained by the lower life expectancy and a higher proportion of the younger population in India2. Diffusely infiltrating gliomas (IGs) are a diverse set of primary neoplasms of the CNS characterized by tumor cells that perniciously invade the surrounding CNS parenchyma from which they arise. Relative to cancers arising in other organs, one of the unique features of IGs is that neoplastic precursor lesions have not been described. That is, by the time they declare themselves either to the patient, to the treating physician, or at the pathologist's microscope, IGs are already universally expected to progress. Precursor dysplastic lesions or in situ neoplastic entities that have not yet become invasive, that may be cured by surgical excision, and that do not inherently represent a fatal threat to the patient, are foreign to the spectrum of IGs.

Infiltrating gliomas, when discussed from a histologic and historical frame of reference, consist of 2 broad classes of tumors, originally designated based on their morphologic characteristics alone that recall 2 nonneoplastic glial cell types: oligodendrogliomas and infiltrating astrocytomas. The latter group excludes noninfiltrating astrocytomas, such as pilocytic astrocytoma, subependymal giant cell astrocytoma, and pleomorphic xanthoastrocytoma3. The clinical and histopathological profile of these tumours range from being indolent to highly anaplastic and rapidly growing neoplasms. Rapid growth of these lesions require neoangiogenesis, which in turn is dependent on vascular endothelial growth factor (VEGF), that has been shown to be an important inducer of brain tumor angiogenesis. Further, cyclooxygenase 2 (COX-2) might be involved in regulating angiogenesis by modulating VEGF

With multidimensional molecular data sets spanning increasingly larger numbers of patients with infiltrating gliomas, our understanding of the disease at the point of surgical resection has improved dramatically and this understanding is reflected in the updated WHO classification. However, despite all this progress, the prognosis of gliomas remains bleak. Therefore, it is timely and necessary to analyse the value of a new immunohistochemical markers for the grading and possible prognostication of diffusely infiltrating gliomas.

Introduction to gliomas

Gliomas are a large group of genetically and pathologically diverse neoplasms that tend to grow into the surrounding brain parenchyma in a diffuse infiltrative manner. The tumor cells tend to invade along the white matter tracts, perivascular spaces, subpial regions and surrounding neurons (which is known as perineuronal satellitosis).

The term glioma embraces astrocytoma, glioblastoma, ependymoma and oligodendroglioma as well as their various subtypes and combinations. As a general rule, gliomas tend to contain glial fibrillary astrocytic protein (GFAP) and lack reticulin, collagen and fibronectin which distinguish them from the non-glial neoplasms. Neoplastic glial cells in the CNS parenchyma can also be difficult to distinguish from gliosis. Glioma cells tend to be pleomorphic with nuclear atypia, mitoses and calcifications. Gliomas expand whereas gliosis contracts. Granular calcifications scattered among hypercellular glia favour a glioma over gliosis. Cellular density in gliosis tends to be relatively even, whereas certain gliomas tend to display uneven distribution of neoplastic cells. Another feature is nuclear spacing: glioma nuclei frequently touch each other and may even indent each other while normal glial nuclei or those in gliotic parenchyma do not.

The histopathology of gliomas

Microscopic recognition of diffusely infiltrative gliomas

The histopathological diagnosis is the gold standard for the classification of gliomas. An adequate microscopic diagnosis carries important prognostic information and forms the basis for further patient management. Most gliomas are characterized by diffuse infiltrative growth of tumour cells in the preexistent parenchyma of the CNS and can be typed based on their histopathological features as astrocytic, oligodendroglial, or oligoastrocytic tumours. Additionally, a malignancy grade is attributed to these gliomas based on the presence of esp. the following features: nuclear atypia, mitotic activity, florid microvascular proliferation, and necrosis.

It is important to exclude other diagnoses before reaching a diagnoses of diffuse glioma. Non-neoplastic changes such as reactive astrocytosis, inflammatory lesions and infarcts should be excluded. Occasionally, high grade diffuse gliomas may show extensive epithelial or sarcomatoid change and in these cases it is essential to exclude a metastatic malignancy.

The diffusely infiltrating gliomas should be distinguished from other neoplasms like the so-called ‘circumscribed’ gliomas (pilocytic astrocytoma), ependymal tumors and neoplasms that show a combination of glial and neuronal differentiation. Histopathologically, the glioma tumor cells tend to invade individually or in small groups in the neuropil and glial cell processes in grey and white matter. This arrangement of diffuse infiltrative glioma cells along pre-existing tissue elements is very helpful in recognising a tumor as a diffuse glioma. These arrangements are called ‘secondary structures of Scherer’ after the German pathologist Hans-Joachim Scherer who was a pioneer in the study of glioma growth patterns.

Morphological typing of diffusely infiltrative gliomas

Most diffusely infiltrating gliomas can be morphologically typed as astrocytic, oligodendroglial or mixed oligo-astrocytic tumors. Astrocytes are stellate cells with oval to elongated nucleus, little eosinophilic cytoplasm and delicate eosinophilic cell processes. Astrocytic tumor cells show a mixture of phenotypes with varying degrees of nuclear atypia and mitotic activity. Several phenotypic variants of low grade diffusely infiltrating gliomas have been described: fibrillary astrovytoma, the most common variant composed of tumor cells with fibrillary cell processes; protoplasmic astrocytoma; which consists of cell bodies with a few flaccid processes and the gemistocytic astrocytoma which consist of at least 20% of tumor cells which have neoplastic astrocytes with distended, plump, hyaline cytoplasm packed with GFAP fibrils.

Oligodendrocytes are cells with a round, dense nucleus and a perinuclear halo. These cells lack GFAP expression. Oligodendroglial tumors are cellular and have compact fields of small round cells along with less cellular areas where the diffusely infiltrating nature can be more easily be appreciated. Additionally, a branching network of delicate capillaries (‘chicken wire pattern’) and calcification can also be found in these tumors. Mixed oligoastrocytomas show the presence of neoplastic glial cells with morphological characteristics of both astrocytes and oligodendrocytes. However, the extent to which oligodendroglial part or the astrocytic part should exist has not been defined and can lead to considerable inter-observer variability. Glioblastomas are considered the most malignant of all gliomas. Low grade gliomas progress to glioblastomas over time and many of these progression are associated with specific genetic defects. However, de novo glioblastomas also appear to exist. A diffusely infiltrating glioma with features of necrosis and florid microvascualar proliferation are characteristic of glioblastomas. Microvascular proliferation which is an increase in the density of cells in the vascular walls is an important characteristic feature of grade IV diffuse gliomas. Other malignant features like hypercellularity, bizzare nuclei, multinucleated cells, mitoses and abnormal mitotic spindles are also present.

Grading of diffusely infiltrating gliomas

Histological grading of gliomas is a means of predicting the biological behaviour and prognosis. Although grading is not an absolute requirement for the application of the WHO 2016 classification of gliomas, numerical grades are a useful addition to the diagnoses.

Grade I lesions are generally tumors with a low proliferative potential and possibility of cure after surgical resection alone. This entity is reserved for only specific ‘circumscribed gliomas’ like the pilocytic astrocytoma. For diffusely infiltrating gliomas, the Grades II, III and IV are used. The grading of gliomas is done on the basis of nuclear atypia, mitotic activity, microvascular proliferation (MVP) and the presence or absence of necrosis. A diffuse astrocytic neoplasm without marked mitotic activity, necrosis or florid MVP is diagnosed as low-grade diffuse astrocytoma, irrespective of the degree of nuclear atypia. When the tumour shows marked mitotic activity the diagnosis of anaplastic astrocytoma is rendered. The presence of necrosis and/or florid MVP leads to a diagnosis of glioblastoma. In oligodendroglial and mixed oligoastrocytic tumours the malignancy grade is assessed using the same set of histological criteria but in a somewhat different way. In (pure) oligodendroglial tumours necrosis and florid MVP do not have the same unfavourable connotation as in diffuse astrocytic neoplasms. Oligodendrogliomas with MVP or necrosis are still considered as WHO grade III lesions. In mixed oligoastrocytic tumours the presence of MVP is compatible with WHO grade III, but the presence of necrosis in this category leads to a diagnosis of glioblastoma with oligodendroglial component (GBM-O).