TUMOURS OF THE CENTRAL NERVOUS SYSTEM
General Approach to Brain Tumours
About 23,000 new primary brain tumours and nervous system cancers are diagnosed annually in the United States, making central nervous system (CNS) tumours more than twice as common as Hodgkin disease and approximately one third as common as melanoma. There is no definitive evidence that any of them are linked to cell phone use. In contrast, intracranial metastases are five times more common than primary brain tumours. More than 120 types of primary brain tumours arise from the different cells that make up the CNS. In addition to classifying tumours by their cell of origin, in clinical practice it is often useful to classify a tumour by its intracranial site as well, such as pineal region tumours or pituitary and suprasellar tumours.
World health organization classification of brain tumours
- Tumours of neuroepithelial tissue
- Astrocytic tumours
- Anaplastic (malignant) astrocytoma
- Pilocytic astrocytoma
- Pleomorphic xanthoastrocytoma
- Subependymal giant cell astrocytoma
- Oligodendroglial tumours
- Anaplastic (malignant) oligodendroglioma
- Ependymal tumours
- Anaplastic (malignant) ependymoma
- Myxopapillary ependymoma (spinal tumour)
- Mixed gliomas
- Anaplastic (malignant) oligoastrocytoma
- Choroid plexus
- Choroid plexus papilloma
- Choroid plexus carcinoma
- Neuronal and mixed neuronal—glial tumours
- Dysembryoplastic neuroepithelial tumour
- Anaplastic (malignant) ganglioglioma
- Central neurocytoma
- Pineal parenchymal tumours
- Embryonal tumours
- Primitive neuroectodermal tumour
- Tumours of cranial and spinal nerves
- Tumors of meninges
- Primary central nervous system lymphomas
- Germ cell tumours
- Embryonal carcinoma
- Yolk sac tumour (endodermal sinus tumour)
- Mixed germ cell tumours
- Cysts and tumour-like lesions
- Rathke cleft cyst
- Epidermoid cyst
- Dermoid cyst
- Colloid cyst of the third ventricle
- Tumors of the sellar region
- Pituitary adenoma
- Pituitary carcinoma
- Metastatic tumours
In contrast to tumours arising elsewhere in the body, there is little distinction between benign and malignant tumours when they occur in the brain. The growth of brain tumours is restricted to the CNS; they rarely if ever metastasize to other organs. In the CNS, a malignant tumour is characterized by aggressive pathologic features, including local tissue invasion, neovascularity, regional necrosis, and cytologic atypia. These features confer a growth advantage to malignant cells and lead to rapid expansion and, frequently, to early regrowth after treatment. Tumors lacking these aggressive histologic features are preferably classified as low grade rather than benign. Many low-grade tumours continue to grow within the CNS, causing progressive neurologic disability, and some may acquire a more malignant phenotype over time. The low-grade tumours that transform into high-grade neoplasms are primarily the intra-axial tumours that cannot be cured by resection because of their diffuse infiltration of brain. Almost all truly benign CNS tumours are extra-axial tumours, such as meningiomas and acoustic neuromas that can be cured with complete surgical resection.
A patient with a brain tumour can present with one or both of two types of symptoms and signs. Generalized symptoms, which typically reflect the increased intracranial pressure (ICP) that often accompanies cerebral tumours include headache, lethargy, personality change, nausea, and vomiting. Lateralizing symptoms, which reflect the specific location of the tumour include hemiparesis, hemisensory deficits, aphasia, visual field impairment, and seizures.
- Frontal lobe
- Generalized seizures
- Focal motor seizures (contralateral)
- Expressive aphasia (dominant side)
- Behavioural changes
- Gait disorders, incontinence
- Hemiparesis (contralateral)
- Basal ganglia
- Hemiparesis (contralateral)
- Movement disorders (rare)
- Parietal lobe
- Receptive aphasia (dominant side)
- Spatial disorientation (nondominant side)
- Cortical sensory dysfunction (contralateral)
- Hemianopia (contralateral)
- Occipital lobe
- Hemianopia (contralateral)
- Visual disturbances (unformed)
- Temporal lobe
- Complex partial (psychomotor) seizures
- Generalized seizures
- Behavioural changes
- Olfactory and complex visual auras
- Language disorder (dominant side)
- Visual field defect
- Corpus callosum
- Dementia (anterior)
- Memory loss (posterior)
- Behavioural changes
- Asymptomatic (middle)
- Sensory loss (contralateral)
- Behavioural changes
- Language disorder (dominant side)
- Paresis of vertical eye movement
- Pupillary abnormalities
- Precocious puberty (boys)
- Sella/optic nerve/pituitary
- Bitemporal hemianopia
- Monocular visual defects
- Ophthalmoplegia (cavernous sinus)
- Cranial nerve dysfunction
- Ataxia, nystagmus
- Weakness, sensory loss
- Cerebellopontine angle
- Deafness (ipsilateral)
- Loss of facial sensation (ipsilateral)
- Facial weakness (ipsilateral)
- Ataxia (ipsilateral)
Most patients have symptoms that progress during a week to a few months. A sudden intensification of symptoms may precipitate the patient’s initial visit to the physician; however, a careful history usually reveals symptoms that predated the acute deterioration and slowly worsened over time. Two exceptions are the new appearance of a seizure in a previously asymptomatic individual and sudden haemorrhage into a tumour.
Symptoms of brain tumours can be produced by tumour invading brain parenchyma, tumour and edema compressing brain tissue, cerebrospinal fluid (CSF) obstruction caused directly by the tumour or by a shift of brain tissue, and herniation. Invasion and compression typically produce focal symptoms, many of which can be relieved if the compression is reduced. Obstruction of CSF flow and herniation are frequently a consequence of elevated ICP and typically produce generalized symptoms of headache, nausea, and vomiting, but they can also cause false localizing signs, such as an abducens nerve palsy as a result of diffuse increased ICP.
Headache is a presenting symptom of approximately 35% of brain tumours. It is more common in younger than in older patients and more common in patients who have rapidly growing tumours than in those whose tumours have evolved slowly. Mental and cognitive abnormalities may be a reflection of local tumour (e.g., aphasia, alexia, agnosia) or of general impairment (e.g., lethargy, confusion, word finding difficulty, apathy). Seizures affect approximately one-third of patients with brain tumours, and they are especially common as the presenting and only symptom of a low-grade tumour. The seizures, which are focal because they originate at the site of the tumour, may remain restricted (e.g., focal motor seizures), or they may generalize secondarily, producing loss of consciousness, sometimes so quickly that the focal signature is missed by the patient or even an observant witness.
Magnetic resonance imaging (MRI) is far superior to computed tomography (CT) and should be used in all cases of suspected intracranial tumour. MRI should be performed both without and with intravenous administration of gadolinium. A well performed MRI scan identifies any intracranial tumour, and a normal finding on MRI effectively excludes a neoplasm. The MRI of some extra-axial tumours (e.g., acoustic neuromas, meningiomas) is so characteristic that histologic confirmation is not required. A non–contrast-enhancing infiltrative lesion that is visible primarily on T2-weighted or fluid-attenuated inversion recovery images is most consistent with a low-grade glioma, whereas a contrast-enhancing lesion with an area of central necrosis and surrounding edema is most likely to be a glioblastoma or possibly a brain metastasis. Although these diagnoses must be confirmed histologically, the preoperative diagnostic possibilities affect the surgical approach to the lesion.
Perfusion MRI after rapid infusion of gadolinium can measure the relative cerebral blood volume and neovascularity associated with a tumour; high perfusion is associated with higher grade of malignancy. This technique can help estimate the tumour grade preoperatively and guide the planning of treatment.
Magnetic resonance spectroscopy noninvasively assesses tissue composition. High-grade primary brain tumours are associated with a decrease in N -acetylaspartate and an increase in choline. More malignant tumours are associated with a greater choline/ N-acetylaspartate ratio and frequently contain areas with elevation of lactate and lipid.
Surgical resection is a major objective in the treatment of almost every kind of brain tumour, but resection must be balanced against possible damage to adjacent normal brain. The development of functional MRI (fMRI), which measures cerebral blood flow when areas of cortex are activated, has greatly enhanced the ability to localize critical neurologic functions and their relationship to the tumour preoperatively. When the fMRI is fused with the anatomic MRI, essential functions can be identified in relationship to the patient’s tumour, and a safer and more complete resection may be planned.
On positron emission tomography (PET), high-grade tumours are usually hypermetabolic, whereas low-grade tumours are hypometabolic. New technologies using 11 C-methionine PET may differentiate low- from high-grade gliomas much more efficiently than deoxyglucose PET.
CT, without and with intravenous administration of contrast material, should be used only for patients who cannot undergo MRI. A CT scan, even with the administration of contrast material, may miss low-grade tumours and tumours in the posterior fossa.
Angiography no longer has a role in the diagnosis of intracranial tumours. However, angiographic embolization is occasionally useful preoperatively to reduce the vascularity of some meningiomas, thereby making a complete resection safer and more feasible.
Electroencephalography is rarely needed in the diagnosis or management of brain tumours. An electroencephalogram can occasionally be useful in a patient who has prolonged or unexplained stupor and in whom nonconvulsive status epilepticus is a consideration. Intraoperative monitoring is also used frequently to help guide resection of epileptogenic cortex adjacent to or within brain tumour tissue.
CSF analysis has little role in the diagnosis of most intracranial neoplasms. In primary CNS lymphoma the diagnosis may be established on CSF cytologic examination in about 15% of patients. The sensitivity of CSF cytology in the diagnosis of CNS lymphoma increases when it is combined with flow cytometry and is further enhanced by immunophenotypic and molecular genetic analyses of the CSF. Rarely, a lumbar puncture is required to exclude inflammatory conditions or other processes that may be confused with a primary brain tumour. Lumbar puncture must be avoided in patients with cerebellar tumours because the release of pressure through the spinal needle may result in herniation of the cerebellar tonsils through the foramen magnum.
Patients who present with symptoms of raised ICP or the new onset of central neurologic symptoms, such as hemiparesis or seizure, should be evaluated rapidly. Prompt neuroimaging discloses a mass, and the radiographic features narrow the differential diagnosis. Extra-axial tumours, such as a meningioma or acoustic neuroma, can be confused with a dural metastasis. Low-grade intra-axial tumours, which are nonenhancing on MRI, have been confused with infections such as herpes encephalitis when they involve the temporal lobe. Contrast-enhancing intra-axial tumours can be confused with a stroke, brain abscess, or focal plaque of demyelination. Subacute infarction can show brisk contrast enhancement, usually in a gyral pattern, unlike brain tumours in which enhancement is primarily in the white matter; however, the two are occasionally indistinguishable radiographically. Brain abscesses typically have a thinner enhancing wall than a malignant tumour and have restricted diffusion. Despite careful evaluation, patients thought to have a malignant glioma occasionally are found at surgery to have a brain abscess. A single large plaque of demyelination can also be confused radiographically with a brain tumour, and sometimes the diagnosis can be established only by biopsy.
Differential diagnosis of intracranial tumours
- Brain abscess
- Parasitic (e.g., cysticercosis)
- Herpes encephalitis
- Vascular disease
- Intracranial haemorrhage
- Inflammatory conditions
- Granuloma (sarcoid)
- Multiple sclerosis: tumefactive single large lesion
- Vascular malformations
- Cavernous angiomas
- Venous angiomas
- Congenital abnormalities
- Cortical dysplasia
When MRI suggests a primary brain tumour, there is no need for an extensive systemic search for a possible source of metastasis. Brain metastases are more common than primary brain tumours, but most occur in patients with known cancer, typically with active systemic disease. If an obvious systemic cancer is not revealed by a thorough physical examination, chest radiograph, routine blood tests, and urinalysis, the patient should proceed to craniotomy. Even if a brain metastasis is found at surgery, resection of a single brain metastasis is the appropriate treatment, and the pathologic examination of the lesion guides the subsequent search for the primary tumour.
The treatment for all brain tumours can be divided into two main categories: symptomatic and definitive. Symptomatic treatment addresses the associated problems, such as cerebral edema, seizures, and thromboembolic disease, which can contribute substantially to clinical symptoms. Definitive treatment addresses the tumour itself.
Treatment of brain tumours
- Venous thromboembolism prophylaxis and treatment
- Goal is gross total excision
- Radiation therapy
- Standard external beam
- Usually focal
- Stereotactic radiosurgery
- Limited by intrinsic drug resistance and blood-brain barrier
Symptomatic management includes the use of corticosteroids, anticonvulsants, and prophylaxis for deep venous thrombosis. Corticosteroids decrease the vasogenic edema that surrounds primary and metastatic brain tumours. Blood vessels associated with tumour formation are leaky and do not share the normal morphologic and physiologic features that form the blood-brain barrier; corticosteroids effectively reconstitute the blood-brain barrier by decreasing the abnormal permeability of these neovessels. Clinical improvement may begin within minutes, and frequently patients are dramatically improved within 24 to 48 hours.
Dexamethasone is the most commonly used glucocorticoid because it has the least mineralocorticoid activity. The usual starting dose is 12 to 16 mg/day, but this can be adjusted to find the lowest possible dose that alleviates neurologic symptoms. After definitive treatment is instituted, many patients can be tapered off their corticosteroid completely. Chronic high-dose corticosteroid therapy is associated with substantial side effects and should be avoided if possible. Patients who will be taking glucocorticoids for 6 weeks or longer should receive prophylaxis against Pneumocystis jiroveci (formerly Pneumocystis carinii).
Anticonvulsants are administered to any patient who has had a seizure, but prophylactic anticonvulsants should not be prescribed for patients who have never had a seizure, except in the immediate perioperative period. A taper should begin 2 to 3 weeks after craniotomy.
Venous thromboembolism, which occurs in about 25% of patients with brain tumours, can occur early in the illness or at any time during treatment. All patients undergoing neurosurgery should have pneumatic compression boots in the postoperative period to reduce the incidence of venous thromboembolism. Prophylactic anticoagulants have also been used successfully in the immediate postoperative period without increasing postoperative haemorrhage. Appropriately regulated anticoagulation is the optimal therapy for deep venous thrombosis and is not associated with an increased risk of intracerebral haemorrhage in patients with intracranial tumours. Inferior vena cava filters can be used for patients who have deep vein thrombi or pulmonary emboli and who cannot be fully anticoagulated.
Complete excision is the goal for a primary brain tumour. Surgical excision can often be accomplished for primary extra-axial tumours, such as meningiomas and acoustic neuromas, unless their intracranial location makes resection impossible. Tumors of the skull base are particularly difficult to remove, and partial resection for decompression is often performed to preserve neurologic function. The safe boundaries for resecting cortical lesions while preserving function can often be elucidated by preoperative fMRI and intraoperative cortical mapping. However, lesions involving critical structures, such as the brainstem or thalamus, cannot be excised safely.
Lesions that cannot be resected are still amenable to biopsy for diagnostic purposes. Stereotactic biopsy can reach lesions in almost any area of the brain with minimal morbidity. The risks of stereotactic biopsy include inadequate tissue sample to make a diagnosis; a tissue sample that does not accurately reflect the most malignant grade of the tumour; and a procedure-related complication, such as haemorrhage. Haemorrhage that causes neurologic impairment occurs in only 2% of stereotactic biopsies, typically in patients with glioblastoma.
Complete excision can cure an extra-axial primary brain tumour and is associated with prolonged survival and better neurologic outcome even in patients with primary intra-axial tumours. Gross total excision, as measured by postoperative neuroimaging, is associated with prolonged survival in patients with malignant gliomas and probably in those with low-grade gliomas as well. However, most low-grade gliomas are not amenable to gross total excision, and usually only partial excision is feasible. Macroscopic tumour can frequently be removed completely in patients with high-grade gliomas, but there is always remaining microscopic disease that infiltrates surrounding brain.
Some tumours, such as brainstem gliomas, are in such critical locations that biopsy is not attempted. Their characteristic radiographic appearance permits diagnosis and initiation of medical treatment.
A course of external beam radiation therapy is delivered in small daily fractions to a total cumulative dose usually between 45 and 60 Gy. Dividing the treatment into small daily fractions permits sublethal repair in normal tissues and markedly reduces neurologic toxicity associated with cerebral irradiation. External beam irradiation, which is the most effective nonsurgical treatment of brain tumours, doubles median survival time of patients with malignant primary brain tumours or metastatic lesions. It can also be useful for recurrent meningiomas and acoustic neuromas. However, it only rarely cures any of these lesions, and most patients develop recurrent disease despite maximal radiation therapy.
Stereotactic radiosurgery has been developed to deliver high fractions of focused radiation therapy that spare normal surrounding tissue. The technique is limited to tumours that are 3 cm in diameter or smaller and is less useful for malignant gliomas because of their infiltrative nature.
The neurologic complications of radiation therapy, which are usually observed in patient’s months to years after completion of treatment, include radionecrosis, dementia, and leukoencephalopathy. The incidence is reported as less than 5%, and most patients die of their brain tumour before the delayed consequences of treatment can be observed. However, in long-term survivors (e.g., patients with low-grade glioma or children with medulloblastoma), the late consequences of radiation therapy are important. Dementia accompanying radiation-induced leukoencephalopathy can progress and result in severe neurologic impairment. Radionecrosis can mimic recurrent tumour with a large contrast-enhancing lesion on MRI. Corticosteroids can reduce the edema and sometimes are sufficient to treat small areas of radionecrosis. However, if the lesion is sufficiently large, resection may be required to decompress the mass and reduce the steroid requirements.
Chemotherapy for brain tumours has usually been disappointing because of the intrinsic resistance of these tumours to most conventional agents. Carboplatin and cisplatin are active agents against medulloblastoma, even when the tumour is disseminated in the CSF. Temozolomide (150 to 200 mg/m 2 for 5 days every 4 weeks) is active in all gliomas, and high-dose methotrexate (3 to 8 g/m 2 for 3 to 12 months) is effective for primary CNS lymphoma. For patients with glioblastoma, polymers impregnated with carmustine (BCNU) and placed in a resection cavity offer modest benefit compared with no chemotherapy, but they are associated with local tissue injury and edema.
The most common primary extra-axial tumours are meningiomas, pituitary adenomas, and acoustic neuromas. These tumours arise within the intracranial cavity but are not tumours of brain tissue. Almost all are benign; because the brain is rarely invaded, complete excision often enables cure with full recovery of neurologic function. These tumours produce neurologic symptoms and signs by compressing the underlying brain; however, edema of the underlying brain is infrequent, so glucocorticoids have a limited role.
Meningiomas are usually benign. Between 5 and 10% of meningiomas are atypical or malignant variants with a more aggressive course. Meningiomas are more common in women, may be multiple in about 10% of patients with sporadic meningioma, and are occasionally part of a familial syndrome. They occur with increased frequency in patients with neurofibromatosis type 2. NF2 inactivation is seen in approximately 50% of sporadic tumours, and mutations in AKT1 , SMO , and TRAF7 have also been identified.
Meningiomas grow slowly and produce symptoms that are insidious in onset and typically slowly progressive. Tumors can reach a considerable size, but they grow so slowly that the brain accommodates to the progressive compression. Meningiomas typically occur in specific locations: over the convexity, along the falx and parasagittal area, in the olfactory groove, at the base of the skull near the sphenoid bone, in the cavernous sinus, in the cerebellopontine angle, and in the foramen magnum. Cortical and parasagittal tumours typically are manifested with seizures or progressive hemiparesis. Tumors in the anterior cranial fossa can cause slowly progressive changes in personality and cognition. Meningiomas at the base of the skull are manifested with cranial neuropathies and gait difficulties when there is brainstem compression. Frequently, tumours are completely asymptomatic and are identified on neuroimaging done for another purpose, such as head trauma.
On MRI, meningiomas have a characteristic appearance consisting of a diffusely enhancing, dural-based lesion that is associated with a thin enhancing dural tail extending from the tumour. The radiographic features are often so characteristic that surgery is performed for therapeutic purposes only. The radiographic differential diagnosis includes the less common hemangiopericytoma and dural metastasis. Most meningiomas are not accompanied by significant edema, but marked edema is seen with high-grade malignant lesions or the secretory variant.
If small meningiomas are discovered in the absence of clinical symptoms or the symptoms are minor, lesions may be monitored with serial images because growth can be so slow.
If treatment is indicated, complete resection is often curative, but even completely resected benign tumours may recur (as many as 20% in some series), so radiologic follow-up is essential. Tumors at the base of the skull often cannot be resected completely and tend to recur despite successive attempts at surgical resection. Stereotactic radiosurgery may be an alternative to surgery if the lesion is small or there is progressive or residual tumour. External beam radiation therapy may slow progression of recurrent lesions and is essential for the treatment of malignant meningiomas. No effective chemotherapy has yet been identified.
Acoustic neuromas, better called vestibular schwannomas, are benign tumours that arise from the eighth cranial nerve. Acoustic neuromas are twice as common in women as in men; the peak age is between 40 and 60 years. Sporadic vestibular schwannomas are unilateral; bilateral acoustic neuromas are pathognomonic of neurofibromatosis type 2.
Acoustic neuromas usually arise from the vestibular portion of the nerve and typically are manifested with unilateral hearing loss, sometimes preceded or accompanied by tinnitus and a sensation of dizziness or unsteadiness but not true vertigo. The slow, progressive enlargement of the tumour produces ipsilateral facial numbness or weakness by compressing the fifth or seventh cranial nerve, respectively. Tumors originate within the internal auditory meatus but grow out of the acoustic canal and into the cerebellopontine angle, where they can compress the brainstem and cause ataxia and ipsilateral cerebellar signs. Cranial MRI with gadolinium delineates even small acoustic neuromas with ease.
Treatment is often surgical; stereotactic radiosurgery may be an alternative for lesions smaller than 3 cm. It is preferable to treat the tumours when they are small to preserve facial nerve function and hearing.
Pituitary adenomas can be classified according to their size as microadenomas (<1 cm in diameter) or macroadenomas; by the presence or absence of endocrine function; and by the endocrinologic or neurologic syndromes caused by tumour compression. Microadenomas typically manifest with endocrine symptoms. As pituitary tumours enlarge and become macroadenomas, they compress the surrounding neural structures, including the optic chiasm and optic nerves, typically causing bitemporal hemianopia and occasionally causing unilateral visual loss. Macroadenomas are frequently nonsecreting but destroy pituitary tissue, causing panhypopituitarism. Rarely, pituitary tumours manifest with the abrupt onset of headache, ophthalmoplegia, unilateral blindness, and even a depressed level of alertness or coma—a syndrome of pituitary apoplexy caused by haemorrhage or infarction.
Cranial MRI, particularly with coronal images and gadolinium administration, can completely outline the pituitary tumour and surrounding neural structures. All microadenomas and some macroadenomas can be treated with transsphenoidal pituitary surgery, which is associated with minimal morbidity. On occasion, residual or recurrent tumour necessitates radiation therapy. Some hormone-secreting tumours, particularly prolactinomas or growth hormone–secreting tumours, can be treated medically with cabergoline or somatostatin analogues such as octreotide, respectively. These medications not only correct the hormonal excess but also shrink the tumour; they must be taken for life.
Other tumours in the pituitary and suprasellar region include craniopharyngiomas, suprasellar epidermoid cysts, Rathke cleft cysts, germinomas (discussed later), and lymphocytic hypophysitis, which is a benign inflammatory condition that usually is manifested with diabetes insipidus. MRI frequently differentiates these conditions, which are usually suprasellar and erode into the pituitary fossa only secondarily. Some of these lesions also have characteristic radiographic features. These lesions are benign. Except for hypophysitis, which resolves completely with corticosteroid treatment (e.g., methylprednisolone 120 mg daily for 2 weeks and then tapered for 1 additional week), complete surgical excision is the curative therapy.
Pineal region tumours all have a characteristic clinical presentation that includes Parinaud syndrome, which consists of paresis of upward gaze, poor pupillary reaction to light with brisk reaction on accommodation, impairment of convergence, and convergence-retraction nystagmus. Some of these lesions may also cause hydrocephalus and symptoms of increased ICP. Pineal region tumours include pineal parenchymal tumours, such as pineocytomas and the more aggressive pineoblastomas, and germ cell tumours, including germinomas and nongerminomatous germ cell tumours. Germinomas can be completely cured with focal radiation therapy, whereas nongerminomatous germ cell tumours are more aggressive and frequently relapse despite chemotherapy plus cranial irradiation.
Chordomas are rare tumours of residual notochordal tissue. They usually occur at the base of the skull, are locally invasive, and are characterized by multiple recurrences despite surgery and radiation therapy. Chordomas are characterized by overexpression of the transcription factor brachyury. They also have activation of several receptor tyrosine kinases with overactivation of the downstream pathways, specifically the PI3K/AKT mTOR pathway. Inhibitors of the epidermal growth factor receptor and platelet-derived growth factor β have each been reported to produce responses and clinical benefit in patients with recurrent disease. PI3K/AKT/mTOR inhibitors are under investigation.
Lipomas are benign tumours that can occur in midline structures, particularly near the corpus callosum. They can be cured by complete removal.
Arachnoid cysts are not tumours but can manifest with headache, seizures, or focal neurologic symptoms if they become large enough to compress underlying brain tissue. Many are completely asymptomatic and are found incidentally on neuroimaging. Only symptomatic cysts require removal.
Most primary intra-axial brain tumours are gliomas, including the astrocytomas, oligodendrogliomas, and ependymomas. Less common are medulloblastomas, other rare neuroectodermal tumours, and primary CNS lymphomas. All of these tumours have a tendency to invade brain tissue, and none can be completely excised surgically.
Astrocytomas, which are the most common glioma, are classified into one of four World Health Organization categories: grade I, the pilocytic astrocytoma; grade II, the fibrillary astrocytoma; grade III, the anaplastic astrocytoma; and grade IV, the glioblastoma. Pilocytic astrocytomas (grade I) are extremely low-grade focal tumours that are more common in children and may be associated with neurofibromatosis type 1; they are often cured by complete surgical excision. Fibrillary astrocytomas, anaplastic astrocytomas, and glioblastomas are diffuse tumours that infiltrate widely into brain; even grade II tumours progress over time, and most acquire the histologic features and growth patterns of grade III and IV tumours.
Gliomas occur at any age, but the peak age is 20 to 30 years for an astrocytoma, 40 years for anaplastic astrocytoma, and 55 to 60 years for glioblastoma. Age is the single most important prognostic factor; younger patients live substantially longer than older patients. Histology is also critical; patients with glioblastoma do significantly worse than patients with lower-grade lesions. Performance status, duration of symptoms, and whether a complete resection has been achieved are also strong predictors of improved outcome and prolonged survival. For all grades of glioma, men are more frequently affected than women, and whites are significantly more frequently affected than blacks. Gliomas are typically single lesions, but multifocal disease is seen in approximately 5% of patients with high-grade tumours. A variant of gliomas, called gliomatosis cerebri, causes widespread infiltration of the entire brain; most patients have relatively low-grade pathologic findings on biopsy, but focal regions of high-grade transformation can exist.
At least 95% of gliomas are sporadic, and only 5% occur in patients with a family history of brain tumour. Furthermore, patients with a familial history of glioma usually do not fall into a well-recognized hereditary syndrome. However, neurofibromatosis 1 (von Recklinghausen disease) is associated with an increased incidence of gliomas, particularly in the optic pathway, hypothalamus, and brainstem. Gliomas also occur with increased frequency in Turcot and Lynch syndrome, in which colorectal neoplasms are seen in association with a variety of CNS tumours. Somatic mutations of the isocitrate dehydrogenase 1 and 2 genes ( IDH1 and IDH2 ) have been identified in most low-grade gliomas and secondary glioblastomas; these patients have a better outcome than do those with wild-type IDH genes. Molecular profiling has identified four subclasses of glioblastoma: (1) classical, defined by overactivation of the epidermal growth factor receptor pathway; (2) proneural, defined by IDH mutation and alterations of PDGFRA and expression of neural markers; (3) mesenchymal, defined by NF1 loss and expression of mesenchymal markers; and (4) neural, characterized by expression of neuronal markers. These categories define distinctly different pathways to histologically identical glioblastomas. The prognostic and therapeutic implications of these distinctions are under investigation.
Clinical Manifestations and Diagnosis
Patients with gliomas often present with seizures, headache, and lateralizing signs such as hemiparesis, aphasia, or a visual field deficit. On MRI, low-grade gliomas typically appear as diffuse, nonenhancing lesions with a propensity to occur in the frontal lobe and insular cortex. High-grade gliomas, which typically enhance with contrast material, occur in the cortical white matter and are accompanied by significant surrounding edema. Glioblastomas frequently have regions of central necrosis, and haemorrhage can occur in 5 to 8% of patients.
For all gliomas, treatment frequently involves surgery, radiation therapy, and chemotherapy. The surgical goal of complete removal of all visible disease is often impossible. A prospective, randomized trial provided evidence for the use of intraoperative MRI guidance in optimizing the extent of resection of gliomas. The adequacy of resection is best assessed on a postoperative MRI study, without and with gadolinium, performed within 72 to 96 hours after surgery. Glioma resections with intraoperative stimulation mapping are associated with fewer severe neurologic deficits and more extensive resection. Surgical removal usually improves neurologic function and reduces dependency on corticosteroids.
All anaplastic astrocytomas and glioblastomas should be treated with postoperative radiation therapy to a dose of approximately 60 Gy. In a randomized trial of patients with glioblastoma, the alkylating agent temozolomide (75 mg/m 2 daily), administered concurrently with radiation therapy and followed by adjuvant temozolomide (150 to 200 mg/m 2 for 5 consecutive days every 4 weeks for six cycles), significantly improved survival (median, 14.6 months) compared with radiation therapy alone (median, 12.1 months; P < .001), and the 2-year survival rate more than doubled to 26.5%. Patients whose tumours contained a methylated promoter of the O 6 -methylguanine-DNA methyltransferase ( MGMT ) DNA repair gene benefited most from the addition of temozolomide. On the basis of these data, combined treatment is the current standard of care for patients with glioblastoma. Chemotherapy is generally well tolerated and associated with minimal toxicity. Elderly patients often do poorly, but a randomized trial showed that radiation therapy (compared with supportive care only) results in a modest improvement in survival, without reducing quality of life or cognition, in elderly patients with glioblastoma. In the Nordic randomized phase III trial, standard radiation therapy was associated with poor outcomes in elderly patients with glioblastoma, especially those older than 70 years. Both temozolomide and hypofractionated radiation therapy should be considered as standard treatment options in elderly individuals with glioblastoma. The addition of bevacizumab (an anti-vascular endothelial growth factor molecule, initially at 10 mg/kg intravenously every 2 weeks) may further improve progression-free survival. Recurrences can be treated with re-resection, additional chemotherapy or, occasionally, stereotactic radiosurgery or a combination of these. Despite aggressive treatment, disease recurs in almost all patients, and the median survival time is 15 months for glioblastoma. Patients with anaplastic gliomas (including anaplastic oligodendrogliomas) had an identical median survival of about 7 years whether the initial treatment was radiation therapy alone or chemotherapy alone. However, some young patients with anaplastic astrocytoma can survive much longer before the tumour recurs.
Optic gliomas, which can involve the optic nerve or optic chiasm, are usually associated with neurofibromatosis type 1. These gliomas are typically pilocytic tumours that can have an indolent course including rare spontaneous regression. They are often not amenable to surgical resection, and they can have a stuttering clinical course, with periods of visual loss punctuated by prolonged periods of visual stability. When necessary, radiation therapy or even chemotherapy may be useful, but often no treatment is required. Brainstem gliomas usually involve the pons, less often the medulla or midbrain. Brainstem gliomas are most commonly seen in children in the first decade of life but can be found even in elderly people; they can have a low-grade or high-grade histology, but outcome is primarily determined by the location of the tumour. In general, most brainstem gliomas have a dismal outcome with survival of 1 year or less, but relatively benign variants occasionally occur.
Low-grade astrocytomas have a variable course. In patients who present with isolated seizures that can be controlled easily with antiepileptics, treatment with radiation therapy or chemotherapy immediately after surgery may prolong progression-free but not overall survival, and such patients can be monitored until there is clinical or radiographic evidence of tumour progression. However, resection should be performed at diagnosis, if feasible. Patients with progressive neurologic symptoms or cognitive impairment require immediate treatment after diagnosis, and focal radiation therapy to a total of about 54 Gy is the optimal choice. For low-grade gliomas, progression-free and overall survival appear to be better when chemotherapy is added to radiation therapy. An astrocytoma can progress as a low-grade tumour or transform to a higher-grade malignant neoplasm, a change that typically is associated with the appearance of contrast enhancement on MRI. Resection or a biopsy may be necessary in these patients, followed by radiation therapy if they have not received it previously; chemotherapy with temozolomide (150 to 200 mg/m 2 for 5 days every 4 weeks for anywhere from 6 to 24 cycles) is also used. Patients with an astrocytoma have a median survival of about 5 years, but the range is wide.
Oligodendrogliomas occur as low-grade tumours and, less commonly, as anaplastic lesions. Treatment of these tumours differs from that of their astrocytic counterparts because oligodendrogliomas are uniquely chemosensitive due to their characteristic loss of chromosomes 1p and 19q. As with the low-grade astrocytomas, treatment should be withheld in patients with low-grade oligodendrogliomas who have no symptoms other than well-controlled seizures. Patients with progressive neurologic symptoms or radiographic progression require treatment, and initial therapy is often chemotherapy, usually with single-agent temozolomide (150 to 200 mg/m 2 for 5 days every 4 weeks for 6 to 24 cycles) or the combination of procarbazine, lomustine, and vincristine (PCV). Radiation therapy is withheld until chemotherapy fails.
By comparison, all anaplastic oligodendrogliomas require immediate treatment. The standard approach includes focal radiation therapy. Adjuvant chemotherapy significantly prolongs disease-free and overall survival in patients with codeleted tumours but not in those with intact 1p and 19q chromosomes. However, there is a growing movement toward treatment of high-grade tumours with chemotherapy alone initially; this can be considered only in neurologically healthy patients. Tumour progression should be treated with re-resection, radiation therapy if it has not been previously administered, and additional chemotherapy. Patients with low-grade oligodendrogliomas have a median survival time in excess of 15 years. Median survival is about 14 years for patients with a 1p/19q codeleted anaplastic oligodendroglioma compared with the median survival of about 3 years for patients with an intact 1p/19q.
Medulloblastomas usually occur in the vermis of the cerebellum and principally affect children and young adults. Boys outnumber girls by about 2:1, and peak onset is 7 years of age; medulloblastoma in adulthood is rare and usually affects the cerebellar hemisphere.
Transcription profiles have identified four distinct subclasses that include: (1) the Wnt subtype driven by a stabilizing mutation in CTNNB1 (β-catenin), which has an excellent prognosis; (2) the SHH subtype with mutations in PTCH1 , SMO , GLI2 , or SUFU , which has an intermediate prognosis; (3) group 3, which has an increased expression of MYC and has the worst prognosis; and (4) group 4, which is characterized by isochromosome 17q and marked male predominance. Medulloblastomas have a characteristic clinical presentation, with ataxia (due to cerebellar and brainstem involvement) and headache, nausea, and vomiting (due to increased ICP from obstructive hydrocephalus). Aggressive surgery with complete excision is strongly associated with improved outcome. Surgery is always followed by neuraxis radiation therapy. Chemotherapy with vincristine, etoposide, carboplatin, and cyclophosphamide significantly improves 5-year event-free survival from 60 to 74% but has not significantly prolonged overall survival, which is about 70 to 80% at 5 years when all patients are considered together. However, clinical high-risk patients do worse and standard-risk patients do better. It is unknown if molecular subclasses should supersede clinical stratification or dictate treatment selection. This vigorous therapy often results in delayed complications in survivors, including intellectual deficits, growth impairment, and endocrinologic dysfunction. Late relapses as well as secondary neoplasms compromise long-term outcome.
Gangliogliomas, as the name implies, possess both a glial component and a neoplastic neural component (ganglion cell). Some low-grade gangliogliomas are indolent and do not require additional treatment after surgical extirpation. Patients with anaplastic tumours may fare better than patients with malignant gliomas, but recurrence is the rule despite surgery and radiation therapy.
Primary CNS lymphomas are associated with immunodeficiency states, particularly acquired immunodeficiency syndrome and organ transplantation, and are seen with increased frequency among the apparently immunocompetent population, in whom the median age at diagnosis is about 60 years. These tumours are usually diffuse large B-cell non-Hodgkin’s lymphomas identical to systemic diffuse large B-cell lymphoma. The tumour can involve the CSF, eye, and brain, where it is multifocal in about 40% of patients at presentation. In contrast to all other brain tumours, surgical resection may not be associated with improved survival and can cause significant neurologic morbidity; therefore, biopsy is usually the preferred surgical approach. Chemotherapy is the primary treatment, and high-dose methotrexate (3 to 8 g/m 2 on alternate weeks for 3 to 12 months) is the most important chemotherapeutic agent. In most patients, radiation therapy is avoided because the necessary whole brain irradiation causes significant cognitive impairment when it is combined with chemotherapy and does not prolong survival. Corticosteroids (e.g., dexamethasone 8 to 16 mg/day), which are frequently used as part of the chemotherapeutic regimen, not only help manage the associated cerebral edema but also can cause tumour regression. With the use of multiagent chemotherapy, with or without cranial irradiation, median survival times is 3 to 5 years.
Rare, intra-axial cerebral tumours include the ependymoma , which is optimally treated with surgical excision followed by radiation therapy. Choroid plexus papillomas and carcinomas may be manifested with hydrocephalus or lateralizing signs. Resection may be sufficient for the benign papilloma, but carcinomas rapidly recur even when postoperative radiation therapy is also used. Colloid cysts of the third ventricle are benign tumours that can cause obstructive hydrocephalus; they may be treated with a third ventriculostomy or with resection by use of an intraventricular endoscope. Haemangioblastomas occur primarily in the cerebellum but can also occur in the spinal cord and the hemispheres. About 15% of patients with a hemangioblastoma have the autosomal dominant disorder von Hippel–Lindau disease, which is characterized by hemangioblastomas in the CNS and retina, renal cell carcinoma, pheochromocytoma, endolymphatic sac tumours, and cysts in a variety of visceral organs. Hemangioblastomas are treated by surgical excision and require radiation therapy only for recurrence. Complete removal usually results in cure.
Definition and Epidemiology
Every systemic cancer is capable of metastasizing to the brain. Melanoma has the greatest propensity to spread to the CNS, but the most common causes of CNS metastases are cancers of the breast and lung, followed by cancers of the colon and kidney. CNS metastases are being seen with greater frequency as patients with systemic cancers have prolonged survival with better treatments. In most patients with brain metastases, CNS disease develops late in the course of their illness, but a brain metastasis may be the initial presentation of a systemic cancer. In most of these patients, lung cancer is the primary site; in some, however, a primary site is never identified.
Clinical Manifestations and Diagnosis
Patients with brain metastases present with progressive neurologic symptoms and signs that typically include headache, seizures, and lateralizing signs. Metastases are best diagnosed by cranial MRI with gadolinium. All lesions can be clearly seen by MRI, which is better than CT for visualizing the posterior fossa. Metastases, which are usually well-circumscribed lesions at the grey matter–white matter junction, are often associated with extensive edema. Haemorrhage into a metastasis occurs most frequently with metastases from melanoma, renal cancer, or thyroid cancer; however, because brain metastases from lung cancer are so common, they are the type most commonly associated with haemorrhage. Sometimes, haemorrhage into a brain metastasis is best visualized by noncontrast head CT.
Because brain metastases do not widely infiltrate into brain tissue and tend to have a pseudocapsule around them, they can be completely excised surgically. In randomized controlled studies, complete removal of a single brain metastasis substantially prolonged life and maintained neurologic function for a longer period. Postoperative whole brain radiation therapy significantly improves control of CNS disease after resection of a single brain metastasis, but it does not prolong survival because patients die of progressive systemic tumour. Consequently, the use of postoperative whole brain radiation therapy is frequently decided on an individual basis. If multiple lesions can be completely resected, these patients do as well as those with a single lesion that has been removed.
Most patients with multiple brain metastases are best treated with a course of whole brain radiation therapy, most commonly 3 Gy in 10 fractions for a total of 30 Gy. Some patients with single brain metastasis are also treated with whole brain irradiation if they are in poor general condition, have uncontrolled systemic disease, or are not good candidates for surgical treatment.
Stereotactic radiosurgery, with either a gamma knife that delivers gamma radiation from multiple cobalt sources or a linear accelerator that delivers x-rays to a highly focused area involving the tumour, has been effective for the treatment of one or a few brain metastases. Most patients tolerate radiosurgery without difficulty, but the procedure is occasionally complicated by seizures or acute swelling that causes more neurologic dysfunction. Approximately 20 to 30% of patients develop radionecrosis, which may be indistinguishable clinically and on MRI from recurrent tumour. One advantage of stereotactic radiosurgery is that most of the normal brain is not exposed to the radiation.
Chemotherapy is used to treat brain metastases from only a few chemosensitive primary cancers, such as choriocarcinoma, small cell lung cancer, and, to a lesser extent, breast cancer. Because few patients have a significant response to chemotherapy, it is usually used as a last resort, although it has increasingly been employed in asymptomatic patients in whom brain metastases are identified at diagnosis on a screening MRI examination and who require chemotherapy for their systemic disease. The planned chemotherapy is often administered and the brain metastases will frequently respond in a fashion comparable to other systemic sites of disease. The choice of agents is based on the primary cancer type and the patient’s prior drug exposures. Some targeted therapies have also been effective against brain metastases, such as in BRAF mutant melanoma, in which responses are seen after vemfurafenib.
The brain is the most common intracranial site of metastases, but systemic cancer can spread to the dura and the leptomeninges as well. Dural metastases most commonly arise from breast or prostate cancer, frequently from a metastasis in the overlying calvaria. Metastasis to the leptomeninges often is manifested as multifocal neurologic symptoms and signs. These metastases involve the cranial nerves to cause diplopia or bulbar palsy; the cervical and lumbar roots to cause limb pain or weakness; and the intracranial space to cause headache, nausea, vomiting, and elevated ICP. The diagnosis is established by the presence of tumour cells in the CSF, by cytologic examination or novel techniques to identify isolated cancer cells, or by neuroimaging that definitively outlines tumour in the subarachnoid space. Treatment frequently involves radiation therapy to symptomatic sites; intrathecal chemotherapy, usually through an intraventricular cannula (Ommaya reservoir); or systemic chemotherapy with agents or doses that penetrate into the CSF.
Tumors involving the spine can be classified according to the anatomic area they involve: extradural, intradural extramedullary, and intramedullary tumours. Extradural tumours typically arise from the bone elements of the spine and cause neurologic symptoms and signs by spinal cord compression. Intradural but extramedullary tumours arise from the pachymeninges or nerve roots (meningiomas or schwannomas) and can cause either radicular symptoms or spinal cord compression. Intramedullary spinal cord tumours are rare; they arise from the spinal cord parenchyma and have a biology similar to that of brain tumours.
- Primary bone tumours arising in the spine
- Osteogenic sarcoma
- Intradural extramedullary
- Arachnoid cysts
- Epidermoid cysts
Epidemiology and Clinical Manifestations
Most extradural tumours originate from a metastasis to the bone elements of the spine, typically the vertebral body and occasionally the vertebral lamina or spinous process. Less common are primary tumours of the spine, including chordoma, osteogenic sarcoma, plasmacytoma, and chondrosarcoma. Expansile growth of the bone tumour impinges on the spinal canal and, if untreated, compresses the spinal cord or the nerve roots as they exit the intervertebral foramina. Whereas most of these lesions arise from bone metastases, extradural tumours can also arise from paravertebral metastases that can grow through the intervertebral foramina and into the epidural space without affecting surrounding bone structures; very rarely, a direct metastasis to the epidural space is also seen. The most common primary cancers that cause extradural metastases are prostate cancer, breast cancer, and lung cancer as well as the lymphomas. Hematologic malignant neoplasms may also be associated with paravertebral disease that grows through the intervertebral foramina.
Whether the mass is a primary bone tumour or a metastasis from a distant source, 98% of patients present with pain that is usually localized to the site of the tumour. Because there are more thoracic than cervical or lumbar vertebrae, the tumour and pain are likely to be in the middle or high back, a less common site for benign pain. Motor impairment and sensory symptoms are present in about 50% of patients, whereas sphincter disturbances are found in only about 25% of patients. Back pain often precedes the development of any other neurologic symptom or sign, frequently by weeks and occasionally by months.
Severe back pain in a patient with cancer should be evaluated by MRI which does not require intravenous administration of contrast material. Plain films of the spine, bone scans, or even CT scans may show bone disease, but epidural tumour can be seen only on MRI. Furthermore, MRI is the only technique that can reveal paravertebral or direct epidural metastasis. Patients who cannot have an MRI study should be imaged by CT with sagittal reconstruction images.
The differential diagnosis of extradural tumours includes epidural abscess, acute or subacute epidural hematomas, herniated intervertebral discs, spondylosis, epidural lipomatosis, and, rarely, extramedullary haematopoiesis. On occasion, a percutaneous needle biopsy or decompressive laminectomy is required to make a definitive diagnosis.
Epidural metastases require immediate treatment because patients can develop acute and unpredictable neurologic deterioration resulting in paraplegia. Patients should be started on high-dose corticosteroids (usually >20 mg IV dexamethasone), which rapidly relieve pain and may contribute to neurologic recovery. Surgery followed by postoperative radiation therapy is superior to radiation therapy alone in preserving the ability to walk and may prolong survival in a wide population of patients with metastatic spinal cord compression, but its advantage may be lost in patients 65 years of age and older. It is much easier to preserve neurologic function than to reverse impairment, so clinically silent areas of extradural tumour that are detected on MRI should be treated before neurologic compromise develops. Patients with epidural metastasis can have a good neurologic outcome if they are treated before the onset of severe neurologic compromise, but their overall survival is usually short because of the presence of widespread metastatic disease. Patients whose primary tumour arises in the spine, such as an osteogenic sarcoma, should undergo definitive surgery; the need for postoperative radiation therapy is based on the tumour’s histology.
Most intradural extramedullary tumours are benign. Meningiomas are benign, slow-growing tumours that occur primarily in middle-aged women and are predominantly located in the thoracic region. Back pain is a common symptom, but about 25% of patients have no pain and present with slowly progressive neurologic dysfunction, typically a gait disorder that has been progressing, frequently for years. Spinal MRI with gadolinium clearly delineates the lesion. Surgical resection is curative, and a complete resection can usually be accomplished easily.
Nerve Sheath Tumors
Nerve sheath tumours include schwannomas and neurofibromas. Both typically arise from the dorsal root, and the first symptom is often radicular pain that precedes symptoms of spinal cord compression by months or even years. Some patients with spinal neurofibroma or schwannoma have neurofibromatosis type 1, but most do not. The diagnosis is clearly established by gadolinium-enhanced MRI of the spine. The treatment is surgical, and complete removal results in cure.
Metastasis to the spinal leptomeninges can be manifested as an intradural extramedullary lesion. A single large tumour nodule can cause focal symptoms and signs referable to that spinal level, but in most patients, multiple levels of the neuraxis are involved, causing multifocal neurologic symptoms and signs. Cervical and lumbosacral radicular pain as well as sensory and motor loss is seen in more than half of patients. The diagnosis is established by gadolinium-enhanced MRI showing multifocal nodules or sometimes a layer of cells coating the spinal cord or nerve roots. If imaging is negative, the diagnosis can be established by demonstrating tumour cells in the CSF. Treatment is complicated and frequently requires radiation therapy to symptomatic sites of disease, intrathecal chemotherapy best administered through an intraventricular cannula (Ommaya device), and occasionally systemic chemotherapy. Radiation therapy can ameliorate neurologic symptoms, particularly pain, but the disease often has a relentless progressive course, resulting in death in 3 to 6 months despite aggressive therapy. Because of the diffuse nature of the disease, surgery is not an option.
Intramedullary spinal cord tumours are similar to neoplasms that arise in brain parenchyma. The most common spinal cord tumours are ependymomas and astrocytomas; hemangioblastomas (particularly in association with von Hippel–Lindau disease), lipomas, and, rarely, intramedullary metastases are also seen.
Clinical Manifestations and Diagnosis
All intramedullary tumours have a similar clinical presentation, and pain is a common initial symptom. Signs of spinal cord dysfunction subsequently ensue and reflect the location of the lesion. In addition, some intramedullary tumours are accompanied by a syrinx, which can contribute to symptoms. The classic signs of intramedullary spinal cord lesions, such as dissociated sensory loss, sacral sparing, and early sphincter problems, are not sufficiently reliable to distinguish intramedullary from extramedullary lesions on the basis of clinical findings. The diagnosis is established by gadolinium-enhanced and T2-weighted MRI.
Surgery is the first therapeutic intervention, both to obtain a definitive diagnosis and to resect the lesion. Complete resection of spinal cord tumours is possible, particularly in the case of ependymomas and hemangioblastomas. However, spinal cord tumours are rare, and only neurosurgeons experienced in removal of this type of lesion should perform the procedure. High-grade gliomas and residual ependymomas should be treated with postoperative radiation therapy. Low-grade astrocytomas of the spinal cord can be treated with radiation therapy when the patient develops symptomatic neurologic impairment, but presymptomatic treatment does not prevent the development of impairment nor necessarily delay it. Intramedullary metastases do not require surgery because the diagnosis is usually straightforward; radiation therapy provides limited benefit because these patients typically have other CNS metastases.