A brain tumour (intracranial tumour) is an abnormal growth in or on the brain. Although they are not always cancerous, all brain tumours are serious due to the buildup of pressure they cause within the brain and the compression of adjoining brain areas, both of which may occur as the tumour grows and expands. Expansion of a brain tumour within the rigid skull may also result in damage to the normal tissue that surrounds the tumour.
Brain tumours may be primary growths arising directly from tissues within the skull or metastases (secondary growths) that have spread via the bloodstream from cancerous tumours elsewhere in the body, particularly from those in the lung or breast.
The cause of primary brain tumours is not known. About 60 per cent are gliomas (which are frequently cancerous), and arise from the brain tissue. Other primary tumours include meningiomas, which arise from the meningeal membranes covering the brain; acoustic neuromas, which arise from the acoustic nerve; and pituitary tumours, which arise from the tissue of the pituitary gland. Most of these tumours are noncancerous, but their relatively large size can cause local tissue damage.
Some types of primary brain tumour affect mainly children. These include two types of glioma called medulloblastoma and cerebellar astrocytoma. Primary brain tumours virtually never spread (metastasize) outside the central nervous system. Secondary growths (metastases) are always cancerous and may be found in more than one organ.
Compression of brain tissue or nerve tracts near the tumour may cause muscle weakness, loss of vision, or other sensory disturbances, speech difficulties, and epileptic seizures.
The presence of a growing tumour can increase pressure within the skull, causing headache, visual disturbances, vomiting, and impaired mental functioning. Hydrocephalus (excess fluid in the brain) may occur if the circulation of cerebrospinal fluid is obstructed by the tumour.
Diagnosis and treatment
Many different brain imaging techniques may be used to locate the site of a brain tumour and to establish its size and the extent of its spread.
In some cases, complete removal of a brain tumour may be possible using guidance from MRI scanning during surgery. In such cases, the patient may be cured. However, many cancerous growths are inaccessible or too extensive for removal. In cases where a tumour cannot be completely removed, as much as possible of it will be cut away to relieve pressure. For primary and secondary tumours, radiotherapy or anticancer drugs may also be given. Corticosteroid drugs are often prescribed temporarily to reduce the size of a tumour and any associated swelling of brain tissues.
Intracranial tumours (brain tumours) in detail - technical
- Clinical features
- Further reading
Intracranial tumours represent about 2% of all cancers. There are no known risk factors apart from prior irradiation to the skull and brain and a few rare neurogenetic syndromes, e.g. neurofibromatosis, von Hippel–Lindau syndrome, Li–Fraumeni syndrome. They may be intrinsic or extrinsic, which determines potential resectability. Neuroepithelial tumours (predominantly gliomas) account for 50 to 60% of all primary tumours; 50% of secondary tumours are from the lung.
Typical manifestations include (1) progressive focal neurological deficit—typically subacute; present in over 50% of patients at time of diagnosis; (2) seizures—may be focal or secondarily generalized; the presenting symptom in 25 to 30% of patients with gliomas; (3) raised intracranial pressure—the classic picture of headache, vomiting, visual obscurations and papilloedema is easily recognized, but most patients present before this develops; and (4) altered mental state—cognitive and personality changes.
Diagnosis—this is made by a combination of CT/MRI scanning and pathological examination of either a biopsy or resection specimen.
Treatment—the conventional methods are (1) surgery—may be curative for extrinsic tumours, but rarely so for intrinsic tumours; (2) radiotherapy and chemotherapy—useful as adjuvant treatment; certain tumours may respond particularly well, e.g. oligodendrogliomas with chromosome 1p/19q deletion.
Prognosis—this is determined by age at presentation (young > old), performance status (high > low) and histological grade (low > high). As a general rule, survival with glioblastoma multiforme is 1 to 2 years, anaplastic gliomas 2 to 5 years, and low-grade gliomas 5 to 15 years. Tumours such as meningiomas and pituitary adenomas have over 90% 10-year survival if diagnosed before irreversible neurological damage has occurred.
Intracranial tumours comprise primary tumours that originate from the brain, cranial nerves, pituitary gland, or meninges, and secondary tumours (metastases) that arise from organs outside the nervous system. These tumours present to many different specialists and their management is difficult because of their location and their variable clinical manifestations.
There are no known risk factors apart from prior irradiation to the skull and brain and a few rare neurogenetic syndromes, such as neurofibromatosis (optic nerve glioma, meningioma, vestibular schwannoma), von Hippel–Lindau syndrome (haemangioblastoma), and Li–Fraumeni syndrome (glioma).
Intracranial tumours represent the eighth most common neoplasm in adults (c.2% of all cancers) and the second most common neoplasm in children. After stroke, intracranial tumours are the leading cause of death from neurological disease in the United Kingdom and are responsible for 7% of years of life lost from cancer before the age of 70.
The crude annual incidence for primary intracranial tumours is 7.4 per 100 000 (males 9.1/100 000, females 6.1/100 000) and for secondary tumours 14.3 per 100 000 population. There is evidence that the incidence is increasing, particularly in older patients. Different tumour types present at different ages. Supratentorial gliomas are uncommon below the age of 30 years but become increasingly prevalent thereafter. The most frequent tumours of middle life (third and fourth decades) are astrocytomas, meningiomas, pituitary adenomas, and vestibular schwannomas, whereas glioblastoma multiforme and metastases are more frequent in the fifth and six decades of life. In contrast, children tend to have infratentorial tumours: 70% of childhood primary intracranial tumours originate below the tentorium cerebelli, whereas in adults the figure is only 25%. There is a strong female preponderance of meningiomas and schwannomas, whereas gliomas are more common in men.
Gliomas are thought to arise from neoplastic transformation of glial cells. Recently, there has been increasing incidence in the role of stem cells in the origins of brain tumours—stem cells are defined as having the ability to renew themselves in perpetuity and to differentiate into mature cells. The existence of a cancer stem cell has now been proven for glioblastoma and medulloblastoma, and may explain why these tumours recur after treatment. Certain genetic lesions are associated with brain tumours. Chromosomal deletions—particularly chromosome 10, which contains multiple tumour-suppressor genes—are found in astrocytic tumours, occurring in up to 70% of glioblastomas. Mutations of a tumour-suppressor gene, TP53, located on chromosome 17p, have also been reported in approximately 40% of astrocytic tumours. In general the accumulation of predictable genetic alterations is associated with increasing malignant progression. Primary glioblastomas arise in older patients and are associated with amplification and overexpression of the epidermal growth factor receptor (EGFR) gene, whereas secondary glioblastomas occur in younger people and are associated with early loss of TP53.
With increasing sophistication of neuroimaging, tumours are being detected at an earlier stage than before. Patients typically present with one or more of four clinical syndromes:
- ◆ progressive neurological deficit
- ◆ seizures
- ◆ raised intracranial pressure
- ◆ altered mental states
The particular combination of clinical features varies depending on the location, histology, and rate of growth of the tumour, e.g. patients with low-grade gliomas present typically with a seizure disorder that may remain static for many years, whereas patients with malignant gliomas typically develop a rapidly progressive neurological deficit and raised intracranial pressure
Progressive neurological deficit
Focal neurological symptoms due to brain tumour are typically subacute and progressive, with over 50% of patients having focal signs by the time of diagnosis. Cortical tumours produce contralateral weakness, sensory loss, dysphasia, dyspraxia, and visual field loss depending on their location. Posterior fossa tumours cause ataxia and cranial nerve palsies. Vestibular schwannomas cause progressive unilateral deafness followed by ipsilateral facial sensory loss. Pituitary tumours may cause a bitemporal hemianopia if there is chiasmal compression or endocrine disturbances due to either hypopituitarism or hypersecretion of specific hormones.
Brain tumours account for about 5% of epilepsy cases although they are over-represented in cases of intractable epilepsy. Seizures are the presenting symptom in 25 to 30% of patients with gliomas and are present at some stage of the illness in 40 to 60% overall. Approximately one-half of the patients have focal seizures and the other half have secondarily generalized seizures. Low-grade gliomas are associated with seizures in over 90% of cases and these frequently remain the only complaint for many years. Conversely, malignant gliomas have a lower frequency of seizures, presumably because of their more rapid growth and destructive characteristics. In these patients, seizures are associated with a better prognosis. Seizures are also common initial manifestations of meningiomas (40–60%) and metastases (15–20%). Supratentorial tumours and those superficially located are particularly likely to cause seizures, particularly in the frontal and temporal lobes. Todd’s paresis, which may persist, is an uncommon but characteristic feature of tumour-associated epilepsy. About 10% of patients presenting anew in status epilepticus have an underlying tumour.
Raised intracranial pressure
Intracranial tumours increase intracranial pressure by a direct mass effect, provoking cerebral oedema, or producing obstructive hydrocephalus. The most common symptom of raised intracranial pressure is headache, which is the presenting symptom in 25 to 35% of patients; papilloedema is found in up to 50% of patients with headache due to tumours. The classic picture of headache, vomiting, and visual obscurations (transient fogging of vision usually on rapid changes in posture) due to raised intracranial pressure is well known and easily recognized, but most patients present before this develops. Less than 1% of patients presenting with isolated headache have a brain tumour.
Most brain tumour headaches are intermittent and nonspecific and may be indistinguishable from tension headaches. Supratentorial tumours typically produce frontal headaches, whereas posterior fossa tumours usually result in occipital headache or neck pain. Certain features of a headache are suggestive but not pathognomonic of raised intracranial pressure. These include headaches that wake the patient at night or are worse on waking and improve over the course of the day.
Mental state changes
These are an uncommon presentation of brain tumours occurring in about 20% of patients at diagnosis. Personality changes may initially be quite subtle and may show themselves as an inability to cope at work. In these cases it is essential to obtain a collateral history from relatives or colleagues at work.
Neuroepithelial tumours (predominantly gliomas) account for approximately 50 to 60% of all primary brain tumours. The other common types are meningiomas (20%), pituitary adenomas (15%), vestibular schwannomas (5%), and primary central nervous system (CNS) lymphomas (5%). The most common sites of origin of secondary tumours are lung (50%), breast (15%), melanoma (10%), and unknown (15%).
The gliomas are a family of neoplasms that are thought to arise from astrocytes, oligodendrocytes, and ependymal cells. Astrocytomas are the most common type of glioma and are infiltrating neoplasms composed of fibrillary astrocytes. Almost all these tumours have the propensity to undergo anaplastic change to a more malignant lesion. Thus a fibrillary astrocytoma progresses to an anaplastic astrocytoma and then to the most malignant form, glioblastoma multiforme (GBM). The oligodendroglioma is characterized by the presence of uniform round nuclei with small nucleoli. This also has the propensity to undergo anaplastic change but, unlike anaplastic astrocytomas, oligodendrogliomas are frequently chemosensitive (see below).
The grading systems that have been used have attempted to describe degrees of anaplastic change and thereby correlate the histological appearances with prognosis. The most widely accepted classifications of gliomas are the World Health Organization’s (WHO) three-tiered system (Table 1). These systems have been retrospectively applied to large series of patients and have been shown to provide reproducible and prognostically useful information. They have recently been updated to include some new diagnostic entities.
The diagnosis of a brain tumour is made by a combination of CT/MR scanning and pathological examination of either a biopsy or a resection specimen. Newer techniques include MR spectroscopy and metabolic imaging (single photon emission CT (SPECT) and positron emission tomography (PET)). These may permit a noninvasive method of differentiating between low-grade and high-grade gliomas and between tumour recurrence and radiation necrosis.
The three conventional methods of treatment for brain tumours are surgery, radiotherapy, and chemotherapy. Targeted biological agents, gene therapy, and immunotherapy have still not been widely taken up because of the lack of proven benefit over and above standard therapies. In line with other areas of oncology, there is increasing use of combination therapies, particularly concomitant chemoradiation to improve survival.
|Table 1 Pathological classification of astrocytomas|
|WHO classification||St Anne–Mayo classificationa|
|Pilocytic astrocytoma||I||1 (0 variables)|
|Diffuse/fibrillary astrocytoma||II||2 (1 variablea)|
|Anaplastic astrocytoma||III||3 (2 variablesa)|
|Glioblastoma multiforme||IV||4 (3 or 4 variablesa)|
a Based on presence or absence of four variables: nuclear atypia, mitoses, vascular proliferation, and necrosis. In practice, grade 2 lesions contain nuclear atypia, grade 3 mitoses, and grade 4 either or both vascular proliferation and necrosis.
Recent advances in tumour neurosurgery include the use of computerized neuronavigation techniques, and intraoperative cortical mapping during awake craniotomy. Preoperatively, important anatomicofunctional information can be derived from functional MRI (fMRI) which allows functional localization of eloquent motor, speech, and memory cortex as well as diffusion tractography, which can delineate the anatomical relationship between tumour and important white matter tracts. These have all contributed to improving the extent of tumour resection with an attendant decrease in morbidity and mortality of neurosurgery, but an effect on overall survival has not been clearly demonstrated.
Surgery is indicated as a first-line treatment for meningiomas, nonsecreting pituitary adenomas, and vestibular schwannomas. The role of surgery in the management of primary intracranial tumours, particularly gliomas, is more controversial. Some types of glioma, e.g. pilocytic astrocytomas, can be cured by surgical resection. For most types, however, removal is not curative. Although surgery is of undoubted benefit in relieving the symptoms and signs of raised intracranial pressure or an evolving focal deficit, there are no prospective randomized data to support its use for prognostic purposes alone, particularly in patients with malignant gliomas. However, the conventional surgical wisdom in patients with low-grade gliomas is tumours that are completely or subtotally resected (leaving a residual tumour volume of <10 ml) have a better prognosis than tumours that are biopsied and treated with radiotherapy alone. Overall, about 50% of patients with medically refractory seizures derive considerable seizure reduction from surgery.
There is evidence that a combination of surgery and radiotherapy offers a survival advantage over radiotherapy alone for the treatment of solitary metastases in patients whose systemic cancer is well controlled.
Radiotherapy is the only treatment that has been proved to extend survival in patients with primary malignant brain tumours. Radiotherapy provides useful palliation in patients with low-grade gliomas. When given early, radiotherapy prolongs progression-free survival but not overall survival, compared with radiotherapy given at the time of tumour progression. Meningiomas are also partially radioresponsive and should be treated with radiotherapy where there is atypical or malignant histology or where there is recurrent tumour that is not surgically accessible.
Advances in technology have allowed greater accuracy of radiotherapy delivery and, in particular, the use of stereotactic frames that permit the focusing of radiation to a small tumour with minimal dosage to the surrounding normal tissue. This can be done either in a single high dose (stereotactic radiosurgery) or in smaller fractions (stereotactic radiotherapy) and is predominantly indicated for lesions less than 3 cm in diameter which are well circumscribed, extra-axial, and more than 5 mm away from vital structures. Intensity-modulated radiotherapy (IMRT) allows more precise ‘dose painting’ whereby different regions of the tumour are treated with varying doses of radiotherapy, and may be useful for the treatment of benign tumours close to vital regions, e.g. the optic nerve apparatus.
There has been increased awareness of the chemosensitivity of certain tumours, particularly anaplastic oligodendrogliomas and primary lymphomas of the nervous system in adults, and diencephalic gliomas in children. Approximately two-thirds of anaplastic oligodendrogliomas respond dramatically to a combination of treatment with procarbazine, lomustine (CCNU), and vincristine (PCV); however, recent phase III data have failed to demonstrate a survival benefit for either neoadjuvant or adjuvant PCV over and above radiotherapy in anaplastic oligodendrogliomas. The presence of combined deletions of chromosomes 1p and 19q in these tumours is a favourable prognostic factor independent of treatment modality.
Adjuvant nitrosurea chemotherapy is used in patients with malignant gliomas although it offers only a marginal survival advantage. An oral alkylating agent, temozolomide, has recently been shown to improve survival in patients with newly diagnosed glioblastoma multiforme when given together with radiotherapy and then adjuvantly. Although the improvement in median survival was modest (12.1 vs 14.6 months), the proportion of patients surviving 2 years increased from 10% to 26%. This is the first significant advance in the treatment of malignant glioma for over 30 years and has rekindled enthusiasm for chemotherapy trials in tumours previously regarded as chemoresistant. Whether this treatment can improve the survival of patients with anaplastic astrocytomas is unknown and currently being tested in clinical trials. Carmustine wafers are another recent advance that allows local delivery of carmustine (a nitrosurea) into the resection cavity of a malignant glioma, hence avoiding the systemic toxicity of these compounds. Chemotherapy does not improve survival in patients with low-grade gliomas over radiotherapy alone. There is no chemotherapy that is effective for the treatment of meningiomas. The addition of methotrexate-based chemotherapy to cranial irradiation markedly improves disease control and survival of patients with primary CNS lymphomas.
The three most important prognostic factors for patients with gliomas are age, performance status, and histological grade. The survival advantage for different treatments is modest in comparison. Any trial claiming a significant survival advantage for a new treatment therefore needs to show that this effect is independent of other prognostic factors. The median survival for patients with malignant gliomas varies from 6 months to 5 years dependent on the above. As a general rule, patients with GBM survive for 1 to 2 years, whereas patients with anaplastic gliomas survive for 2 to 5 years.
The outlook for patients with low-grade gliomas is considerably better, with a median survival of 5 to 15 years depending on age, preoperative performance status, histology, and tumour growth rate. Oligodendrogliomas are more chemosensitive than astrocytomas and have a more indolent course, so their prognosis is correspondingly better, with patients surviving 10 to 15 years after diagnosis.
At least 40% of primary intracranial tumours are extra-axial (not arising from within the brain substance itself) and are thus readily treatable, if not curable. Some tumours such as meningiomas and pituitary adenomas are associated with 10-year survival rate of over 90% if diagnosed before irreversible neurological damage has occurred.