Astrocytes are more numerous than neurons and are the source of numerous brain pathologies, including the major contributor to malignancy in the central nervous system. There are three commonly seen astrocytic gliomas:
- Diffuse astrocytoma
- Anaplastic astrocytoma
In addition, there are several subtypes that are significantly rarer:
- Pilocytic astrocytoma
- Subependymal giant cell astrocytoma
- Pleomorphic xanthoastrocytoma
- Gliomatosis cereberi
In adults, infiltrative astrocytomas account for between 60 and 80% of central nervous system malignancies. 50% of these tumours are glioblastoma with a very poor prognosis. The incidence is between 5 - 7 cases per 100,000 people per year worldwide; there is minimal geographical variation. The age of presentation is dependent on histology:
- Pilocytic astrocytoma occurs in childhood and adolescence
- Diffuse astrocytoma presents between the ages of 30-40
- Anaplastic astrocytoma presents between 40-50 (ten years later)
- Glioblastoma incidence peaks from 50-60
Aetiology and Pathogenesis
The aetiology of all brain malignancies is poorly understood. Two causative factors are known:
- Ionising radiation was shown to increase the risk of intracerebral malignancy, including astrocytic tumours, in children who received treatment for tinea capitis or childhood leukaemia.
- There are several genetic syndromes associated with gliomas. These include:
- Li Fraumeni (heterozygous loss of TP53)
- Neurofibromatosis 1 & 2 (NF1/NF2 genes)
- Turcott syndrome (mismatch repair genes)
- Tuberous sclerosis (TC2), which is linked with subependymal giant cell astrocytoma
Pathogenesis is thought to be through the standard multistep carcinogenesis, with additional mutations acquired over time that eventually lead to an invasive tumour.
The pathogenesis of glioblastoma multiforme, the most well understood of the astrocytomas, appears to have two pathways:
- De novo glioblastoma multiforme (80% of cases) occurs in an older age group (median age 55) with symptoms present for weeks or months.
- Common genetic mutations in de novo glioblastoma include deletion/mutation of PTEN, ERBB1 overexpression, MDM2 overexpression, CDKN2A deletion and loss of RB1.
- Secondary glioblastoma (20% of cases) occurs in patients who have previously been diagnosed with a lower grade astrocytoma (diffuse or anaplastic astrocytoma)
- Lower grade gliomas typically have TP53 deactivation and PDGFR-α overexpression
- Glioblastoma that arises from a low grade glioma will typically show loss of RB1, but not overexpression of ERBB1 or MDM2.
- These glioblastomas will usually have heterozygous loss of PTEN but no mutation of the remaining gene.
Glioblastoma typically causes symptoms over a number of weeks. Progress depends on tumour location, but survival is usually short (under 6 weeks) if no action is taken, usually due to cerebral oedema and coning.
Lower grade gliomas may have a more protracted course. Grade 2 and 3 astrocytomas will usually progress to glioblastoma over a number of years.
Symptoms and Signs
Headache is a common presentation of cerebral tumours. This can arise from increased intracranial pressure or from involvement of pain sensing structures (such as venous sinuses or dura mater). Seizure is another common presentation. An important set of symptoms is due to cognitive decline, which is diagnostic as well as prognostic. Other neurological signs, such as weakness, sensory changes, visual disturbance or ataxia may all occur depending on the site of the tumour.
Raised intracranial pressure may be evidenced by papilloedema on examination. Other neurological findings may be uncovered on a full neurological examination. A full body examination is warranted to exclude the possibility of metastatic disease from a non-CNS primary.
Diffuse astrocytomas are best appreciated on MRI. They appear as non-enhancing and ill-defined lesions. They are usually seen in the cerebral hemispheres.
Anaplastic astrocytoma has a similar appearance to diffuse astrocytoma, but occasionally shows enhancement.
Glioblastoma is often rim enhancing, reflecting the increased vascularity of the outer parts. Central areas may be necrotic. The surrounding normal brain tissue is usually oedematous, and midline shift may be seen.
Tumour/Normal Tissue Features
Diffuse Astrocytoma (Grade II)
The name of this tumour arises from the pattern of invasion. Diffuse astrocytomas rarely form a distinct mass, and may be difficult to visualise on imaging or with the naked eye. Disease often extends beyond the area that may look macroscopically normal. The anatomy of the brain may be distorted but is not destroyed.
On H&E staining there is an increased number of cells. Cytological atypia is present, with growth occuring in gemistocytic, fibrillary or protoplasmic patterns. Necrosis, microvascular proliferation and mitotic activity are all absent.
The most useful stain is for GFAP, which indicates a glial cell lineage. S-100 is used when GFAP is negative.
As described above, diffuse astrocytoma is frequently associated with loss of chromosome 17p and mutation of TP53. Further mutations lead to development of anaplastic astrocytoma or glioblastoma.
This is a rare condition where a large portion of the brain is infiltrated by an astrocytoma. Regardless of the grade, these tumours have a poor prognosis.
Anaplastic Astrocytoma (Grade III)
Similar to diffuse astrocytoma; there may be contrast enhancement in some cases.
Anaplastic astrocytoma has similar features to diffuse astrocytoma, but with more cells present and, importantly, the presence of mitotic figures.
GFAP and S-100 are usually positive. Detection of Ki-67 may be used to differentiate from diffuse astrocytoma.
Anaplastic astrocytoma shares the TP53 mutation and chromosome 17p loss with diffuse astrocytoma. In addition, there is mutation or loss of the CDKN2A (p16) gene, an important regulator of RB1, which accounts for the increased proliferation.
Glioblastoma (Grade IV)
Glioblastoma has a vastly different appearances to the grade II and III malignancies. On macroscopic examination there is usually a well defined, heterogenous mass which may have visible areas of haemorrhage or necrosis. The outer tumour is usually hyperemic. The normal architecture of the brain is destroyed by the process; adjacent areas of normal brain show oedema on examination as well as with imaging. The lesion may track along white matter pathways, including the corpos callosum; this type of lesion is known as a butterfly glioblastoma.
Rarely, glioblastoma may arise as a multifocal lesion. Other unusual growth patterns include seeding through CSF spaces to distant sites in the central nervous system. Metastasis outside the CNS is very rare.
Glioblastoma has all of the hallmarks for high grade disease, including:
- Cytological atypia
- Mitotic figures
- Microvascular proliferation
Viable tumour cells often lie around the areas of necrosis, a phenomenon known as pseudopalisading.
There are several variants of glioblastoma, including small cell glioblastoma, giant cell glioblastoma, and gliosarcoma. These all have a similarly poor prognosis.
Glioblastoma will usually stain for GFAP and S-100. Ki-67 expression is usually detected, reflecting the high mitotic rate. In addition, about 40% of primary glioblastomas will show amplification of EGFR, which is not seen in lower grade tumours.
Primary glioblastomas often have EGFR amplification, but often lack the TP53 mutations seen in lower grade glioma. An important epigenetic change is methylation of MGMT, a gene which codes for a DNA repair protein. The low levels of MGMT lead to increased activity of temozolomaide, increasing the benefits seen from this drug.
Pilocytic Astrocytoma (Grade I)
Pilocytic astrocytoma is an uncommon tumour of childhood. Macroscopically, the lesions may be cystic (particularly in the cerebellum) or solid (if arising in the optic nerves). The are well circumscribed macroscopically and on imaging. Microscopically these tumours have a biphasic growth pattern, with dense 'pilocytic' regions mixed with loose 'microcystic' regions. Most cases also have Rosenthal fibres and eosinophilic granular bodies. 5 year survival is about 80%.
Rosenthal fibres are thick, pink bundles seen when there is a proliferation of glial cells. They are not seen in higher grade tumours but can be seen in other conditions (such as scarring).
Subependymal Giant Cell Astrocytoma (Grade I)
This is a very uncommon tumour that is seen in association with tubular sclerosis. The tumour typically causes a 'candle guttering' appearance of the ventricular wall, and is red when cut due to the high number of blood vessels. Calcification is common and the tumours are often rock-like in consistency. Most cells show positive staining for GFAP. These tumours are relatively benign.
Pleomorphic Xanthoastrocytoma (Grade II-III)
This is a lower grade tumour that is rarely seen; it must be distinguished from glioblastoma as it carries a much better prognosis. There are very few mitotic figures (if any) and eosinophilic granular bodies. Prognosis is similar to pilocytic astrocytoma, although a small subgroup have aggressive variants which progress more rapidly.
Staging is not performed for astrocytomas. Instead, the WHO has determined four grades of disease that reflect patient progress:
- Grade I tumours are typically benign or have an excellent prognosis
- These mostly benign tumours are uncommon; they include pilocytic astrocytoma and subependymal giant cell astrocytoma
- Grade II tumours are low grade malignant, but have a relatively slow rate of progression
- Grade II tumours include diffuse astrocytoma and most pleomorphic xanthoastrocytomas
- Grade III tumours are medium grade malignant, with survival not extending beyond several years
- This grade includes anaplastic astrocytoma and aggressive pleomorphic xanthoastrocytomas
- Grade IV tumours are high grade malignant, with survival usually measured in months
- This grade includes glioblastoma and gliosarcoma