Epidemiology

There were 9365 people diagnosed with a brain tumour in 2011 in the United Kingdom and 4975 deaths from brain tumours. Brain tumours are slightly more common in men than in women. Fifteen per cent of adults diagnosed with brain tumours survive for 5 years. A further 400 children are diagnosed with central nervous system (CNS) tumours in the United Kingdom each year. CNS tumours are the second most common cancer in childhood after leukaemia and account for 27% of all cancers in children. Metastases to the brain are about 10 times more common than primary brain tumours. The most common primary tumour sites amongst patients with brain metastases are lung, breast, melanoma and kidney. In addition, nasopharyngeal cancers may directly extend through the skull foramina. Meningeal metastases occur with leukaemia and lymphoma, breast and small-cell lung cancers, and from medulloblastoma and ependymal glioma as a route of spread. Primary tumours of the CNS account for 1.5% of all cancers and 3% of cancer deaths (Table 6.1). About 58% of CNS tumours arise in the brain, 23% in the meninges, 11% in the pituitary and 8% in the spinal cord. Similarly, astrocytomas account for 34% of CNS tumours, meningiomas for 21% and pituitary adenomas for 8%. The World Health Organization (WHO) International Classification of Diseases (ICD) attributes a code to all diseases and the current version is ICD-10, the first version of the ICD that has removed homosexuality from its ridiculous classification as a mental illness! CNS tumours are broadly grouped into malignant or benign tumours and the grade of the tumours in the WHO classification can be loosely translated into aggressive (generally grades II–IV) and indolent (generally grade I) tumours. Most (95%) astrocytomas are aggressive, but only 8% of meningiomas and 1–2% pituitary tumours are aggressive.

Aetiology

The first three of these are associated with brain tumours; von Recklinghausen’s neurofibromatosis with cranial and root schwannomas, meningiomas, ependymomas and optic gliomas (see Figure 2.15); tuberous sclerosis with gliomas and ependymomas; and von Hippel–Lindau disease with cerebellar and retinal haemangioblastoma (Table 6.2). In addition, an increased incidence of brain tumours is a feature of Gorlin’s basal nevus syndrome (medulloblastoma), Turcot syndrome (gliomas) and Li–Fraumeni syndrome (glioma) (see Table 2.3).

High-dose ionizing radiation to the head region administered in the past for benign conditions such as scalp tinea capitis fungal infection (ringworm) increases the risk of nerve sheath tumours, gliomas and meningiomas. There is much public concern that low-frequency non-ionizing electromagnetic fields such as those emitted by 60 Hz power cables may increase the risk of brain tumours, but there is no consistent evidence to support this hypothesis. Similarly, despite scares, there is no evidence to support an association with wireless radiofrequency devices such as mobile phones. This joins the long list of things that cause cancer according to the Daily Mail. It includes Facebook, deodorant, hair dye, talcum powder, mouthwash, tooth whitener, oral sex, chips and chocolate.

Pathology

Primary nervous system tumours may be glial tumours, non-glial tumours or primary cerebral non-Hodgkin’s lymphoma (Table 6.3). As you may recall from embryology lectures, the early embryo has three distinct germ layers of cells:

• Endoderm, the innermost layer that gives rise to the digestive organs, lungs and bladder
  
• Mesoderm, the middle layer that gives rise to the muscles, skeleton and blood system
  
• Ectoderm, the outer layer that gives rise to the skin and nervous system

Neuroectodermal tumours are classified on the basis of the predominant cell type and include tumours of both central and peripheral nervous system derived cells. After embryonic development ceases, neurons do not divide, but glial cells retain the ability to proliferate throughout life and thus most adult neurological tumours are derived from glial cells and are named gliomas. Glial cells (from the Greek term for glue) surround the neurons holding them in place, supplying them with nutrients and insulating them from one another; glia also remove pathogens and dead neurons.

Gliomas account for 50% of brain tumours and are divided into grade I (non-infiltrating pilocytic astrocytoma), grade II (well-to-moderately differentiated astrocytoma), grade III (anaplastic astrocytoma) and grade IV (glioblastoma multiforme). The prognosis deteriorates with rising tumour grade. In addition to these astrocytomas, there are other glial tumours including ependymomas that arise from ependymal cells (the epithelial like cells that line the ventricles of the brain and spinal cord), and oligodendrogliomas that arise from oligodendrocytes (the cells that make myelin sheaths). In the peripheral nervous system, neurofibromata (derived from non-myelin forming Schwann cells) and schwannomas (derived from Schwann cells that make myelin) are the most frequent glial tumours.

Medulloblastoma is a glial tumour of childhood usually arising in the cerebellum, which may be related to primitive neuroectodermal tumours elsewhere in the CNS. Non-glial brain tumours include pineal parenchymal tumours, extragonadal germ cell tumours, craniopharyngiomas, meningiomas and choroid plexus tumours. Meningioma is the commonest non-glial tumour and constitutes 21% of brain tumours. The majority of spinal axis tumours in adults are extradural, metastatic carcinoma, lymphoma or sarcoma. Primary spinal cord tumours include extradural meningiomas (26%), schwannomas (29%), intramedullary ependymomas (13%) and astrocytomas (13%).

Seventy per cent of primary brain tumours in adults are supratentorial, situated above the tentorium cerebelli, the tent of dura mater that lies between the cerebellum and the inferior portion of the occipital lobes. In contrast, primary brain tumours in children are usually located below the tentorium (Table 6.4).

Presentation

Glial tumours

Glial tumours may produce both generalized and focal effects, and these will reflect the site of the tumour and the speed of its growth. General symptoms from the mass effect, increased intracranial pressure, oedema, midline shift and herniation syndromes are all seen, including progressive altered mental state and personality, headaches, seizures and papilloedema. Focal symptoms depend upon the location of the tumour (Figure 6.2). Although seizures are a feature of up to half of all glial tumours, fewer than 10% of first fits are due to tumours and only 20% of supratentorial tumours present with fits.

Adult	Child
Supratentorial	Supratentorial
Metastases	Craniopharyngioma
Glioma	Pinealoma
Meningioma	Optic glioma
Pituitary tumour
Infratentorial	Infratentorial
Metastases	Medulloblastoma
Acoustic neuroma	Cerebellar astrocytoma
Cerebellar haemangioblastoma	Ependymoma of fourth ventricle

Investigation and staging

Neuroradiology has developed into the most important investigation in patients with suspected brain tumours, following the introduction of computed tomography (CT) in the mid-1970s by Geoffrey Hounsfield and magnetic resonance imaging (MRI) in the 1980s. Newer techniques, such as positron emission tomography (PET), single photon emission computerized tomography (SPECT) and functional MRI have also found roles in the diagnosis and management of patients with brain tumours. MRI with gadolinium enhancement is the imaging technique of choice with advantages over CT particularly for posterior fossa tumours and non-enhancing low-grade gliomas (see figures in Chapter 1). PET with fluorodeoxyglucose-18, which accumulates in metabolically active tissues, may help to differentiate tumour recurrence from radiation necrosis (Figure 6.4). Stereotactic biopsy is required to confirm the diagnosis, although occasionally tumours are diagnosed on clinical evidence, because biopsy might be hazardous, for example, in brain stem gliomas.

Tumour site	Clinical features
Parasagittal falx	Progressive spastic weakness
	Numbness of legs
Olfactory groove	Anosmia
	Visual loss
	Papilloedema (Foster–Kennedy syndrome)
	Frontal lobe syndrome
Sella turcica	Visual field loss
Sphenoid ridge	Cavernous sinus syndrome (medial)
	Exophthalmos and visual loss (middle)
	Temporal bone swelling and skull deformity (lateral)
Posterior fossa (foramen magnum, tentorium)	Hydrocephalus (tentorium)
	Gait ataxia and cranial neuropathies
	V, VII, VIII, IX and X (cerebellopontine angle)
	Suboccipital pain, ipsilateral arm and leg weakness (foramen magnum)

Treatment

Some gliomas are curable by surgery alone and some by surgery and radiotherapy; the remainder require surgery, radiotherapy and chemotherapy, and these tumours are rarely curable. Surgical removal should be as complete as possible within the constraints of preserving neurological function. Radiation can increase the cure rate or prolonged disease-free survival in high-grade gliomas and may also be useful symptomatic therapy in patients with low-grade glioma, who relapse after initial therapy with surgery alone (Figure 6.5). Newer radiotherapy delivery techniques that have been pioneered in the treatment of brain tumours include both Gamma Knife and CyberKnife treatments, which have caught the attention and interest of the gently dozing neurosurgeon in the multidisciplinary team. Gamma Knife radiotherapy is delivered by 201 cobalt-60 sources arranged in a ring in a helmet that is bolted to the patient’s skull. CyberKnife radiotherapy uses a linear accelerator to deliver radiotherapy via a robotic arm that is linked to an image guidance system. CyberKnife radiotherapy does not need a skull frame because the real-time image linking means that if the patient moves, the robotic arm also moves so that the radiotherapy dose is delivered to the correct site.

Chemotherapy with lipid-soluble nitrosoureas or temozolomide may prolong disease-free survival in patients with oligodendrogliomas and high-grade gliomas, although its high toxicity may not always merit this approach. One recent advance is the use of biodegradable wafers implanted with BCNU chemotherapy that may be inserted at the time of surgery. Gene therapy has been adopted for trials in gliomas with viral vectors being administered either into the blood or directly into the tumour by surgeons. The genetically modified viral vectors may be non-replicating viruses that deliver a transgene that causes an anticancer effect, or replicating oncolytic viruses that directly lyse cancer cells by replicating. Gliomas are a good model to try these methods because they are pretty much the only cells dividing in the brain (apart from microglia and endothelial cells). Similarly, anti-angiogenic therapies chiefly targeting vascular endothelial growth factor (VEGF) are used in clinical trials in high-grade glioma. Another line of research in gliomas has focussed on the development of immunotherapy targeting HER2 expression and autologous dendritic cell therapies. Similarly, some gliomas have activation of the AKT intracellular signalling pathway and this can be targeted by a number of drugs in development. The name AKT originates from the inbred strain of mouse that developed spontaneous lymphomas from which the AKT protein kinase was identified.

Therapy of meningiomas is surgical resection, which may be repeated at relapse. Radiotherapy reduces relapse rates and should be considered for high-grade meningiomas or incompletely resected tumours. Relapse rates are 7% at 5 years if completely resected and 35–60% if incompletely resected.

Unlike with other brain tumours, surgical resection does not have a useful role in primary cerebral lymphomas. In immunocompetent patients, the combination of chemotherapy and radiotherapy produces median survivals of 40 months. In contrast, in the immunocompromised patients, especially those with HIV infection, the prognosis is far worse, with a median survival of under 3 months. Palliative radiotherapy or best supportive care is the appropriate treatment options here.

Prognosis

The prognosis of glial tumours depends upon the histology, the grade and size of the tumour, on the age and performance status of the patient and on the duration of the symptoms (Table 6.6). The median survival for anaplastic astrocytoma is 2–5 years, and for glioblastoma multiforme is 10–14 months. Meningiomas, if completely resected, are usually cured and the median survival is over 10 years.

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