MALIGNANT CENTRAL NERVOUS SYSTEM TUMORS
Brain tumours are responsible for approximately 2% of all cancer deaths. Central nervous system tumours comprise the most common group of solid tumours in young patients, accounting for 20% of all paediatric neoplasms. The overall incidence of brain tumours is 8–10 per 100 000 population per year. The incidence increases after the 4th decade of life to reach a maximum of 16 per 100 000 per year in the 7th decade.
Classification
The general brain tumour classification is related to the cell of origin, and is shown in Table 6.1. Table 6.2 shows the approximate distribution of the more common brain tumours.
Aetiology
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Epidemiology studies have not indicated any particular factor (viral, chemical or traumatic) that causes brain tumours in humans, although a range of cerebral tumours can be induced in animals experimentally. There is no genetic predisposition but chromosome abnormalities have beeoted in many CNS tumours
There is no specific evidence linking CNS tumours to environmental carcinogens, although many chemicals, especially ethyl and methyl nitrosourea and anthracene derivatives, show carcinogenic activity in animals and produce CNS tumours. Viral induction of brain tumours has been used in animal models but there is no firm evidence for viral aetiology in humans. Ahuman polyoma JC virus injected into primates produces tumours similar to human astrocytomas after an 18-month incubation period. This type of ‘slow virus’ effect may account for some of the problems of isolating viruses from human tumours.
Although immunosuppression is known to increase markedly the risk of primary lymphoma of the brain, particularly in transplant recipients, there is not the corresponding increased incidence of gliomas.
At present there is considerable conjecture regarding the role of other possible aetiological agents, including trauma, electromagnetic radiation and organic solvents but, as yet, there is no convincing evidence to implicate these as being involved with the development of brain tumours in humans.
The four hallmarks of the development of a cancer cell are the ability to proliferate, with the intracellular growth pathways constituitively activated, the evasion of apoptosis, with the cancer cells having escaped from cell death pathways, the attraction and induction of new blood vessels(angiogenesis) to supply increased metabolic activity of tumour cells, and tissue invasion. Each of these are dependent on ligand–receptor interactions on the cell surface leading to a cascade of cytoplasmic events that eventually result in differential gene expression.
Molecular biology techniques have enabled the identification of a variety of alterations in the genome of the tumour cell, including those of brain tumours. The present concept of oncogenesis involves both the addition of oncogenes to the genome and the loss of the normally occurring tumour suppressor genes. Transformation (spontaneous or induced) is a multistep process requiring both initiation and promotion. Oncogenes encode proteins that participate in the signal transduction and second messenger systems that modulate cell metabolism and proliferation. These proteins include both growth factors and growth factor receptors such as epidermal growth factor receptor, platelet-derived growth factor, tryosine-specific protein kinases and guanine-binding proteins.
Tumour suppressor genes are normally present in the genome and act as a ‘brake’ on cell transformation. Mutations in the p53 tumour suppressor gene on chromosome 17 are the most common gene alteration found to date in tumours and have been shown to occur in both astrocytomas and meningiomas. The Li–Fraumeni syndrome is due to a germ line mutation in the
p53 gene with the development of numerous cancers including gliomas, ependymomas and medulloblastomas.
Glioma
Neuroectodermal tumours arise from cells derived from neuroectodermal origin. Gliomas comprise the majority of cerebral tumours and arise from the neuroglial cells. There are four distinct types of glial cells: astrocytes, oligodendroglia, ependymal cells and neuroglial precursors. Each of these gives rise to tumours with different biological and anatomical characteristics. The neuroepithelial origin of microglia is in question.
The most common gliomas arise from the astrocytecells which The tumours arising from astrocytes range from the relatively benign to the highly malignant. The term ‘malignant’ for brain tumours differs from its usage for systemic tumours. Intrinsic brain tumours very rarely metastasize (except for medulloblastoma and ependymoma), and ‘malignant’ refers to aggressive biological characteristics and a poor prognosis.
Classification
There are many classification systems of brain tumours in general and gliomas in particular. The period of systematic classification of tumours began in 1846, when Virchow described the neuroglia and related it to brain tumours. Although Virchow created the term ‘glioma’, these tumours had already been described under other names. In 1926, Bailey and Cushing described a histogenetic classification system which compared the predominant cell in the tumours with the embryonal development of the neuroglia. The comparison with stages of cytogenesis was probably more of a working hypothesis than an oncological theory for the origin of the tumours’ cells. The theory that gliomas originate from proliferation of cells of varying degrees of maturity lying dormant in the brain is not generally accepted except in the case of medulloblastoma, which may arise from a primitive layer in the cerebellar cortex.
A valuable prognostic system of subclassification of astrocytoma was described by Kernohan in 1949. Astrocytomas were graded from I to IV, with Grade IV being the most malignant and Grade I cytologically, but not necessarily biologically, benign. Ringertz simplified the four-grade classification of Kernohan into a three-tiered system; the comparison between the two is shown in Fig. 1. The glioblastoma multiforme, equivalent to the Kernohan Grade III and IV tumours, is the most common adult cerebral tumour, accounting for approximately half of all gliomas. The low-grade gliomas—the astrocytoma, or Grade I or II Kernohan astrocytoma—account for only 10–15% of astrocytomas.
The World Health Organization (WHO) classification recognizes four grades of astrocytoma. Grade I is assigned to the pilocytic astrocytoma which is biologically distinct from the diffuse astrocytomas, which are classified as astrocytoma (WHO Grade II), anaplastic astrocytoma (WHO Grade III) and glioblastoma multiforme (WHO Grade IV).
A grading system proposed by Daumas-Duport and also known as the St Anne–Mayo System assessed the tumours according to the presence or absence of four morphological features— nuclear atypia, mitosis, endothelial proliferation, and necrosis—and they are graded according to the cumulative features score. Grade I tumours have none of the features, Grade II tumours have one feature, Grade III tumours have two features and Grade IV tumours have three or four features.
Fig. 1 Relationship of the Kernohan system, the ‘three-tiered’ classification system, the WHO system and the StAnne/Mayo (Dumas-Deport) grading system for astrocytomas.
Pathology
Macroscopic changes
An astrocytoma may arise in any part of the brain, although it usually occurs in the cerebrum in adults and the cerebellum in children. A low-grade tumour in the cerebral hemispheres invades diffusely into the brain. The tumour does not have a capsule and there is no distinct tumour margin. The low-grade gliomas are usually relatively avascular with a firm fibrous or rubbery consistency. Fine deposits of calcium are present in 15% of astrocytomas. Occasionally, a low-grade astrocytoma may invade diffusely throughout the cerebral hemisphere. In contrast, the macroscopic appearance of a highgrade tumour, the glioblastoma multiforme, is characterized by a highly vascular tumour margin with necrosis in the centre of the tumour. Although in certain areas the margin of the tumour may seem to be macroscopically well defined from the surrounding brain, there are microscopic nests of tumour cells extending well out into the brain.
Microscopic changes
The histological appearance of the tumour varies with the tumour’s grade. The low-grade astrocytoma is characterized by an increased cellularity, composed entirely of astrocytes. Intermediate-grade tumours show nuclear pleomorphism, mitotic figures are frequent, and there is increased vascularity, as evidenced by endothelial and adventitial cell proliferation. In the high-grade astrocytoma very few astrocytes appear normal. There is marked cellular pleomorphism, extensive endothelial and adventitial cell proliferation and numerous mitotic figures with extensive necrosis. The major histological features of glioblastoma multiforme are endothelial proliferation and necrosis. The anaplastic astrocytoma is characterized by nuclear pleomorphism and mitoses, which are absent in the astrocytoma.
Clinical presentation
The presenting features can be classified under:
• raised intracranial pressure
• focal neurological signs
• epilepsy.
The duration of the symptoms and the progression and evolution of the clinical presentation will depend on the grade of the tumour—that is, its rate of growth. Apatient presenting with a low-grade astrocytoma (Grade I or II) may have a history of seizures extending over many years, antedating the development of progressive neurological signs and raised intracranial pressure. The tumours may evolve histologically into the more malignant anaplastic astrocytoma or glioblastoma multiforme. Patients with the higher-grade tumours present with a shorter history and glioblastoma multiforme is characterized by a short illness of weeks or a few months.
Raised intracranial pressure is due to the tumour mass, surrounding cerebral oedema and hydrocephalus due to blockage of the CSF pathways. The major symptoms are headache, nausea and vomiting, and drowsiness.
Headache is the most common symptom in patients with cerebral astrocytoma and occurs iearly three-quarters of patients; vomiting occurs in about one-third. The headaches are usually gradually progressive and although frequently worse on the side of the tumours, theymay be bitemporal and diffuse. Characteristically, the headache is worse on waking and improves during the day. Nausea and vomiting occur as the intracranial pressure increases, and the patient frequently indicates that vomiting may temporarily relieve the severe headache. Drowsiness, that is, a deterioration of conscious state, is the most important symptom and sign of raised intracranial pressure. The extent of impairment of conscious state will be related to the severity of raised intracranial pressure. An alert patient with severely raised intracranial pressure may rapidly deteriorate and become deeply unconscious when there is only a very small further rise in the pressure within the cranial cavity.
Focal neurological deficits are common in patients presenting with cerebral gliomas; the nature of the deficit will depend on the position of the tumour. Patients presenting with tumours involving the frontal lobes frequently have pseudopsychiatric problems, personality change and mood disturbance. These changes are particularly characteristic of the ‘butterfly glioma’, so called because it involves both frontal lobes by spreading across the corpus callosum, giving it a characteristic macroscopic (Fig. 4) and CT or MRI appearance. This type of tumour may also occur posteriorly, with spread across the splenium of the corpus callosum into both parieto-occipital lobes. Limb paresis results from interference with the pyramidal tracts, at either a cortical or a subcortical level, and occurs in just under 50% of patients. Field defects associated with tumours of the temporal, occipital and parietal lobes are common, but may be evident only on careful testing. Dysphasia, either expressive or receptive, is a particularly distressing symptom occurring in patients with tumours involving the relevant areas of the dominant hemisphere. The particular characteristics of posterior fossa and brainstem gliomas will be discussed in the following section on paediatric tumours.
Fig. 4 ‘Butterfly glioma’. Glioblastoma multiforme of corpus callosum spreading into both frontal lobes.
Epileptic seizures are the most frequent initial symptom in patients with cerebral astrocytoma and occur in 50–75% of all patients. Tumours adjacent to the cortex are more likely to be associated with epilepsy than those deep to the cortex and tumours involving the occipital lobe are less likely to cause epilepsy than those which are more anteriorly placed. Astrocytomas may produce either generalized or focal seizures; the focal characteristics will depend on the position within the brain and the cortical structures involved.
Investigations
Computerized tomography
CT scan or MRI of the brain are the essential radiological investigations (Figs 5 and 6); an accurate diagnosis can be made iearly all tumours. Low-grade gliomas show decreased density on the CT scan; this does not enhance with contrast and there is little or no surrounding oedema. Calcification may be present. High-grade gliomas are usually large and enhance vividly following intravenous injection of contrast material (Fig. 7). The enhancement is often patchy and nonuniform and frequently occurs in a broad, irregular rim around a central area of lower density. Although tumour cysts may occur in the highgrade tumours, the central area of low density surrounded by the contrast enhancement is usually due to tumour necrosis. High-grade tumours are surrounded by marked cerebral oedema and there is frequently considerable distortion of the lateral ventricles. Compression of the lateral ventricle in one hemisphere, with pressure extending across the midline, may result in an obstructive hydrocephalus involving the opposite lateral ventricle.
Magnetic resonance imaging
When used with gadolinium contrast enhancement, MRI improves the visualization and anatomical localization of the tumours (Figs 8 and 9). MRI has the advantage of being more sensitive than CT scan, enabling the detection of small tumours and particularly low-grade gliomas that might be missed by CT scan. MRI provides better anatomical detail and is more useful in visualizing skull base, posterior fossa and brainstem tumours.
Low-grade astrocytomas may show up on MRI as abnormal areas of increased T2 signal and decreased T1 signal, even if the CT scan was normal. High-grade astrocytomas characteristically have low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Gadolinium enhancement is more likely to occur in the higher-grade tumour.
Perfusion-weighted MRI is used to determine the regional cerebral blood volume, which is increased in high-grade glioma and may be of value in differentiating recurrent tumour from radiatioecrosis. Magnetic resonance spectroscopy (MRS) is a non-invasive technique that provides information on the composition and spatial distribution of cellular metabolites. On proton MRS, tumours have an increased lactate production, loss of N-acetyl aspartate (due to loss of neurones in the tumour area) and increased choline levels (due to active membrane biosynthesis).
Fig. 5 Low-grade astrocytoma. CT scan shows non-enhancing low-density lesion with little or no mass effect.
Fig. 6 MRI showing low-grade glioma in posterior frontal region. (a) T1 scan, (b) T2 scan.
Fig. 7 Glioblastoma multiforme. CT shows a large tumour with contrast enhancement particularly at the margins surrounding a necrotic centre. There is marked surrounding oedema with compression of the ventricles.
Cerebral angiography
This was the standard study in most patients with astrocytomas prior to the introduction of CT. It provides helpful information on the vascular supply of the tumours but is now only rarely indicated.
Plain X-rays
Plain X-rays of the skull do not need to be performed as a routine. The most common abnormality is erosion of the sella turcica due to long-standing raised intracranial pressure. Radiologically visible calcification is present in about 8% of patients with astrocyte-derived gliomas.
Management
Following the presumptive diagnosis of a glioma the management involves:
• surgery
• radiotherapy
• other adjuvant treatments.
Surgery
Surgery is performed with three principal aims.
• To make a definite diagnosis.
• Tumour reduction to alleviate the symptoms of raised intracranial pressure.
• Reduction of tumour mass as a precursor to adjuvant treatments.
The patient is started on glucocorticoid steroid therapy (e.g. dexamethasone) when presenting with clinical features of raised intracranial pressure with the aim of decreasing the cerebral oedema prior to surgery.
The type of operation performed will largely be determined by the position of the tumour and by the patient’s clinical presentation. In general, the tumour is excised as radically as possible, provided the surgery will not result in any disabling neurological deficit. Craniotomy is performed in the position that provides the best access to the tumour and usually with the aid of a frameless stereotactic system to aid accuracy of localization. If the tumour has not grown to involve the cortical surface, a small incision is made in a non-eloquent gyrus or sulcus and the subcortical brain is divided down to the tumour mass.The tumour is excised, often with the aid of an ultrasonic aspirator. Occasionally, the tumour may involve one of the ‘poles’ of the hemisphere and the excision may entail a partial lobectomy.
Although a craniotomy with radical tumour excision will alleviate the symptoms of raised intracranial pressure, there has been controversy as to whether a radical resection improves survival. Most high-grade gliomas weigh approximately 100 g at the time of diagnosis and consist of 1011 cells. A radical tumour excision is able to excise the macroscopic tumour but cannot remove the tumour cells that are infiltrating deep into the adjacent, often vital, areas of normal or oedematous brain. Consequently, a radical excision is unlikely to achieve more than a 90–95% reduction in tumour cell numbers, resulting in 1010 cells remaining. Whether the 1–2 logs of tumour cell reduction are a significant reduction in tumour burden prior to adjuvant therapy and whether it improves the effectiveness of subsequent treatment is still not completely resolved, although recent clinical studies do seem to show a survival benefit following tumour resection and this is favoured by most neurosurgeons provided the tumour excision can be performed without causing significant neurological mortality.
Alternatively, a biopsy, which can be performed most accurately using stereotactic methods, may be undertaken to obtain the definite histological diagnosis, without macroscopic tumour excision, if:
• the tumour is small and deep seated
• the tumour is diffuse, without major features of raised intracranial pressure, and macroscopic resection is not feasible
• the tumour involves highly eloquent areas (e.g. speech centre) without pronounced features of raised intracranial pressure.
Stereotactic biopsy involves localization of the tumour with a stereotactic frame applied to the head of the patient using the CT scan or MRI. The three-dimensional coordinates of the tumour are ascertained. The surgeon chooses the point of entry and the desired path through the brain and a computer program determines the necessary angles for the biopsy probe and the depth to the tumour (Fig. 6.10).
Fig. 10 Schematic diagram of stereotactic biopsy of cerebral tumour using the Cosman–Roberts–Wells (CRW) system.
Postoperative care
The postoperative management of astrocytoma involves the routine care of a patient following a craniotomy. Careful neurological observations are performed, as prompt intervention is essential if the patient’s neurological state deteriorates as a result of either increasing cerebral oedema or postoperative haemorrhage. A postoperative haematoma may occur in the region of the tumour excision or it may be extracerebral, either subdural or extradural. A CT scan should be performed urgently if there is neurological deterioration, to determine the exact pathology. Occasionally, postoperative deterioration may be so rapid as to require urgent re-exploration of the craniotomy without prior radiological assessment.
In the initial postoperative period it is essential to avoid overhydration of the patient so as not to precipitate cerebral oedema. The patient isnursed with the head of the bed elevated 20°, so as to promote venous return and reduce intracranial venous pressure. Steroid medication is usually required in the initial postoperative period and is gradually decreased over the following days. The steroids may need to be re-instituted during the course of radiotherapy. The patient is usually mobilized as soon as possible, if necessary with the help of a physiotherapist.
Radiation therapy
Postoperative radiation therapy is generally an effective adjunct to surgery in the treatment of higher-grade gliomas. It has been shown to double the median survival for high-grade gliomas to 37 weeks. Radiation treatment is planned to optimize the homogeneity of the radiation dose throughout the tumour volume selected and to minimize high dose regions iormal brain transited by the radiation beam. The size of the daily radiation fraction is related to the incidence of complications and a maximal daily dose is usually between 1.8 and 2.0 gray. The total radiation dose varies depending on the tumour type, location and size of field, but for gliomas it is usually between 45 and 60 gray. Opinion varies regarding the tissue volume that should be treated for malignant glioma but radiation to the tumour area and a ‘generous volume’ of surrounding brain is now advocated, rather than radiation to the whole brain. The selection of the proper radiation dose for gliomas is as controversial. Although increasing the radiation dosage from 50 to 65 gray does slightly improve survival, the higher dose of radiation therapy, especially over 65 gray, significantly increases the risk of braiecrosis.
Prognosis
At present there is no satisfactory treatment for the malignant cerebral glioma—the anaplastic astrocytoma and glioblastoma multiforme. The median survival following surgery is approximately 17 weeks and when radiation therapy is used as an adjuvant the median survival is approximately 37 weeks. Chemotherapy for highgrade gliomas has been disappointing and the best results with surgery, radiation therapy and chemotherapy consistently show a median survival time of less than 1 year. The mediaormal for the low-grade glioma (fibrillary astrocytoma; WHO Grade II, Daumus–Duport Grades I and II) is approximately 8 years, with most tumours progressing to a higher grade.
The role of surgery, radiation therapy and other adjuvant therapies in low-grade gliomas is even less certain than for the high-grade glioma. The low-grade tumour may remain relatively quiescent for some years before it either continues to grow slowly or changes to a more anaplastic tumour with resulting debilitating neurological deterioration. In general, the same principles for surgical excision apply for lowgrade gliomas as for high-grade gliomas. However, a number of clinical studies have shown that patients having a radical excision of a tumour have a longer 5-year survival than those with a subtotal excision. Radiation therapy has not been shown to improve the survival in patients with low-grade tumours. In general, other adjuvant therapies are not used for the treatment of low-grade astrocytoma, but may be of benefit for oligodendrogliomas.
Other adjuvant therapies
Many different adjuvant therapies have been investigated for the treatment of glioma. These include the use of new chemotherapeutic agents, new methods of administering cytotoxic chemicals, immunotherapy, hyperthermia, new techniques of radiotherapy, photodynamic therapy, and gene therapy.
The lack of effectiveness of the present treatment of gliomas is related to the biology of the tumour. The most common position for tumour recurrence following conventional treatment is locally, in the tumour bed, indicating that treatment has failed in local control. Although light microscopy shows high-grade gliomas to have a relatively well-defined border with the adjacent brain, special staining techniques, including monoclonal antibodies, show malignant cells extending well out into the surrounding brain. It is the failure to control the growth of these cells that is largely responsible for the local tumour recurrence. As indicated previously, a good surgical resection with 90% of the tumour excised would still result in 1010 cells being present. Effective radiotherapy will result in 1 log (90%) or at the most 2 logs (99%) of cell kill and it is unlikely that subsequent chemotherapy would reduce remaining tumour cells by more than 90%. Consequently, the effect of cytoreductive surgery, radiotherapy and chemotherapy would result in approximately 108 cells remaining; the immune system is unlikely to be able to cope with a tumour burden of more than 105 cells. It follows that, for any extra treatment to be effective, whether surgery or adjuvant therapy, it must provide at least 1 log of cell kill.
Chemotherapy
Conventional chemotherapy has been disappointing. Many of the chemotherapy agents that are active in vitro, or in other systemic tumours, have reduced activity in malignant brain tumours, either by exerting an inherently limited cytotoxic potential on brain tumour cells or by the inability of the chemotherapeutic agent to reach the cells that are responsible for the tumour recurrence. A study of brain tumour cell kinetics of high-grade gliomas shows only a small proportion of the cells (5–10%) in an active growth phase; this has serious consequences for any cell cycle-specific cytotoxic agent. Until recently the most commonly used single agent cytotoxic regime involves administration of nitrosourea compounds. The high lipid solubility and low ionization of these agents ensures a relatively effective penetration of the cytotoxic compound into the tumour. Combination therapy, utilizing many different cytotoxic compounds, has been used in various trials but none of the combinations has been shown to be more beneficial than the use of the single nitrosourea.
Temozolomide is an alkylating agent that can be taken orally, penetrates the CNS and is well tolerated with predictable myelotoxicity. Clinical studies have shown it to be effective in about 40% of patients. It is now the initial chemotherapy agent of choice, but it is usually used at the time of tumour recurrence, rather than as an adjuvant to surgery.
It has been postulated that a reason for the lack of effectiveness of chemotherapy is the inability of the cytotoxic compound to reach the tumour cells which are invading the normal adjacent brain. This has resulted iew techniques of delivering the cytotoxic agent. High-dose chemotherapy with bone marrow rescue has largely been abandoned because of its high morbidity and lack of effectiveness. Techniques of disrupting the blood–brain barrier have been used before chemotherapy infusion to improve the delivery of chemotherapeutic agents to tumour cells within the environment of a normal blood–brain barrier. This has resulted in substantially increased neurotoxicity to the normal brain without significantly improving survival. Intracarotid chemotherapy suffers from serious limitations— the perfusion of the tumour mass is less than expected because most tumours are not supplied entirely by one carotid artery and ‘streaming’ of the cytotoxic agent results in very high doses of chemotherapy to small areas, with relative hypoperfusion in other regions. Complications such as serious retinal damage and neurotoxicity have further reduced the attractiveness of this technique.
Radiotherapy
Attempts to enhance the effect of radiotherapy have included the use of radiosensitizers, such as metronidazole and misonidazole, which increase the radiosensitivity of hypoxic tumour cells without a corresponding increase in the sensitivity of euoxic cells. However, the clinical trials have shown only a marginal advantage. The use of interstitial brachytherapy, involving stereotactically implanted radioactive sources into the tumour, has the advantage of applying a high dose of radiotherapy to the tumour while sparing the surrounding brain. However, the clinical trials performed so far have resulted in a high incidence of radionecrosis to the surrounding brain and improvements in the technique will need to be devised before this method would become acceptable. Similarly, stereotactic radiosurgery, that involves radiation to a very highly focused area, is of limited use as it does not target the infiltrative tumour cells that are responsible for tumour recurrence.
Hyperthermia
This has inherent basic limitations as, although cell death occurs at approximately 42°C, damage to the surrounding brain occurs at 45°C, so there is a very narrow therapeutic index. In addition, there is a marked tolerance of tumour cells to hyperthermia and the treatment has not been effective.
Immunotherapy
The possibilities for immunotherapy as an adjuvant treatment have been investigated for many years. Investigations have included the use of active immunotherapy techniques and, more recently, the application of adoptive immunotherapy. This technique involves stimulating peripheral blood lymphocytes in vitro with human recombinant interleukin-2 to produce lymphokine activated killer cells (LAK cells) which can be administered in conjunction with interleukin-2. However, the LAK cells do not cross the blood–brain barrier and so need to be injected in close proximity to the tumour cells. Recent studies using this technique have been disappointing.
Photodynamic therapy
This is a technique that offers special advantages as an adjuvant therapy of malignant brain tumours since it has been shown to be an effective method of controlling local tumours. The technique involves the selective uptake of sensitizer into the brain tumour, followed by open or intraoperative irradiation of the sensitized tumour cells with light of an appropriate wavelength to activate the sensitizer and selectively destroy the tumour cells. Clinical studies using this method have shown a favourable trend, although formal phase III studies have not been undertaken.
Gene therapy
Experimental therapies of glioma at present being investigated involve the use of retrovirus, adenoviruses or adeno-associated viruses to carry a variety of gene therapies to the cancer cell. It is hoped that as these treatments are refined over the next decade they will be useful in the treatment of cerebral glioma.
Oligodendroglioma
Oligodendrogliomas are responsible for approximately 5% of all gliomas and occur throughout the adult age group with a maximal incidence in the 5th decade. The tumour is rare in children.
Pathology
Nearly all oligodendrogliomas occur above the tentorium; most are located in the cerebral hemispheres and about half of these are in the frontal lobes. Oligodendrogliomas may project into either the 3rd or lateral ventricles. Oligodendrogliomas have the same spectrum of histological appearance as astrocytomas, ranging from very slow growing, benign tumours to a more rapidly growing, malignant variety with abundant mitotic figures, endothelial proliferation and foci of necrosis. Calcium deposits are found by histological examination in up to 90% of oligodendrogliomas. Unlike the astrocyte group, most oligodendrogliomas are well differentiated. Not infrequently tumours have mixed histology, with both oligodendroglial and astroglial features.
Clinical presentation
The presenting features are essentially the same as for the astrocyte group but, as these tumours are more likely to be slow growing, epilepsy is common, occurring in 80% of patients and seen as an initial symptom in 50%. The features of raised intracranial pressure and focal neurological deficits are each present in approximately one-third of patients.
As for astrocyte tumours, MRI with contrast may be beneficial but other investigations are usually unnecessary.
Radiological investigation
CT scanning and MRI are the fundamental investigations. They will confirm the diagnosis of an intracranial tumour and in many cases the diagnosis of oligodendroglioma will be highly probable. Calcification will be present in 90% of cases and over half show contrast enhancement (Fig. 6.11).
Fig. 6.11 Oligodendroglioma Non-enhancing low-grade calcified tumour.
Treatment and results
Treatment involves:
• surgical resection
• radiotherapy
• other adjuvant treatments.
The standard treatment for oligodendroglioma has been an aggressive resection of the tumour followed by radiation therapy, although radiotherapy would now not be given to low-grade tumours, and utilized only for the intermediate- or high-grade oligodendroglial tumours. Oligodendrogliomas have been shown to be more sensitive to chemotherapy than the astrocytoma tumours, especially if the oligodendrogliomas belong to the group with loss of heterozygosity OF chromosome 1p or 19q.
The survival of patients depends on the degree of histological malignancy. Five-year survival rates are between 30 and 50% with a small number of patients living for many years (up to 5% for 20 years). However, many tumours with histological features of oligodendroglioma also have a component of astrocyte-derived cells, usually anaplastic astrocytoma, and the tumour behaves biologically and clinically as an anaplastic astrocytoma rather than an oligodendroglioma.
Recurrent cerebral glioma
As discussed earlier, most high-grade cerebral gliomas will recur within 1 year of the initial treatment with surgery and radiotherapy. Lowgrade tumours may either recur as a continuing progression of the slow growth or, alternatively, the histological characteristics may alter and the tumour may become more anaplastic and rapidly growing.
The clinical presentation of a recurrent tumour will be evidenced by either a progression of the focal neurological signs or the signs of an increase in the intracranial pressure. The diagnosis will be confirmed by CT scan or MRI in most cases. The major differential diagnosis is postradiotherapy radiatioecrosis, which may develop as early as 4 months or as late as 9 years after radiotherapy.
The radiological features of necrosis are an avascular mass, and the diagnosis may be suspected from the dose of radiotherapy that has been administered. However, there may be considerable difficulty in differentiating necrosis from recurrent glioma, and sometimes an operation is required both for definitive diagnosis and to remove the mass.
The initial deterioration following a diagnosis of recurrent glioma can usually be temporarily halted by the use of steroid medication. The major decision is whether further surgery and other adjuvant therapy should be undertaken. In general, a further operation involving debulking of the tumour would be considered if:
• the patient is less than 65 years old
• there has been a symptom-free interval of 1 year or more since the first operation
• debilitating irreversible neurological signs are absent
• the tumour is in an accessible position and repeat surgery would not result in additional morbidity.
Adjuvant therapies
Adjuvant therapies have limited benefit for patients with recurrent tumour and, considering the morbidity involved, may not be indicated. Chemotherapy, utilizing temozolomide administered orally, has shown to have a temporary benefit in up to 40% of patients. Other chemotherapy agents, especially the nitrosourea compounds, have much greater toxicity.
Ependymoma
Ependymomas are glial neoplasms arising from the ependyma and constitute approximately 5% of all gliomas. Approximately two-thirds of ependymomas occur in the infratentorial compartment and most of these present in children, adolescents and young adults. The supratentorial ependymomas occur mostly in adults.
Pathology
The tumour arises from the ependyma of the ventricle and, although predominantly intraventricular, the tumour often invades into the adjacent cerebellum, brainstem or cerebral hemisphere. Fourth ventricular tumours usually arise from the floor or lateral recess of the 4th ventricle and they may extend into the subarachnoid space to encase the medulla or upper cervical spinal cord. Alternatively, the tumour may grow laterally through the foramen of Luschka and into the cerebellopontine angle. The tumours are well demarcated, nodular, soft and pale. Calcification is common, especially in supratentorial ependymomas. There are numerous histological classification systems of ependymomas, and the World Health Organization classification divides these tumours into cellular, papillary and clear cell types of non-anaplastic ependymoma and anaplastic ependymoma.
The myxopapillary variety is a slow-growing distinct variant of ependymoma that occurs in the cauda equina. In an adult the subependymoma variant may be encountered as an incidental autopsy finding—a discrete nodular mass based in the brain’s ventricular surface, particularly the floor or lateral recess of the 4th ventricle or the septum pellucidum—or it may be large enough to present clinically. It is usually heavily calcified and is composed of cells with astrocytic as well as ependymal features.
The papillary and anaplastic varieties of ependymoma are responsible for the majority of clinically symptomatic ependymomas. The cellularity and architecture of the ependymomas vary but a diagnostic feature is the presence of rosettes, and most ependymomas contain areas in which perivascular pseudorosettes are conspicuously developed. In these formations the blood vessel is surrounded by an eosinophilic halo composed of the radiating tapering processes of the cells. Blepharoplasts frequently occur in ependymomas but may be difficult to visualize. These are tiny intracytoplasmic spherical or rod-shaped structures which represent the basal bodies of cilia, and are most frequently encountered in the apical portion of cells that form ependymal rosettes.
Clinical presentation
Posterior fossa ependymomas
Details will be discussed in the section on paediatric tumours (p. 91). Patients present with features of raised intracranial pressure due to hydrocephalus as a result of obstruction of the 4th ventricle, ataxia due to cerebellar involvement, and occasionally features of brainstem pressure or infiltration.
Supratentorial tumours
Virtually all patients with supratentorial ependymomas present with features of raised intracranial pressure, often due to hydrocephalus as a result of obstruction of the CSF pathways. Ataxia is common and focal neurological deficits may occur due to involvement of the underlying cerebral hemisphere.
Radiological investigation
The CT scan and MRI will show a tumour that arises in the ventricle and enhances after administration of intravenous contrast. Calcification is common in tumours arising from the lateral ventricles (Fig. 6.12). There is frequently associated hydrocephalus. In the posterior fossa differentiation from a medulloblastoma may be difficult.
Fig. 6.12 Calcified contrast-enhancing ependymoma involving lateral ventricles.
Treatment
The treatment of ependymomas is initially surgical, with an attempt to perform a radical macroscopic resection of the tumour. Supratentorial tumours are often very large and may extend throughout the lateral and 3rd ventricles, but the associated hydrocephalus makes the excision of the intraventricular portion feasible. However, the tumour may arise from the ventricular wall in
the region of the basal ganglia and blend imperceptibly with the underlying cerebral structures so that a complete excision is not possible. Fourth ventricular tumours can be excised from the ventricle but microscopic infiltration into the underlying brainstem cannot be removed surgically.
Postoperative radiation therapy is advisable and, as these tumours may spread through the CSF pathways, sometimes whole neuraxis radiation is recommended.
The prognosis is related to the degree of anaplasia of the tumour and for intratentorial tumours varies from 20% to 50% 5-year survival. The prognosis for the supratentorial tumours is better, particularly in adults.
Pineal tumours
Tumours arising in the region of the pineal gland are mostly not of pineal origin, but are generally called ‘pineal’, as they have a similar clinical presentation.
The tumours are relatively uncommon, accounting for 0.5% of all intracranial tumours.
However, they occur more frequently in Japan and China, where the incidence is up to 5%. Most tumours make their clinical appearance between 10 and 30 years of age.
Classification
Pineal region tumours are classified in decreasing frequency as:
• germinoma
• teratoma
• pineocytoma
• pineoblastoma
• miscellaneous
• glioma
• cyst.
Germinoma is the most common pineal region tumour and is similar in histological appearance to germinoma of the gonads and mediastinum; it occurs predominantly in males. These tumours may also arise in the suprasellar region, and synchronous tumours in both the pineal and suprasellar region occur occasionally. Teratoma is like germinoma; it also arises from displaced embryonic tissue. The other tumour types occur less commonly.
Clinical presentation
Patients with pineal tumours present with:
• raised intracranial pressure
• neurological signs due to focal compression
• endocrine disturbance.
Raised intracranial pressure. The features of raised intracranial pressure, such as headaches, drowsiness and papilloedema, are due to hydrocephalus, which is a result of the tumour occluding the aqueduct of Sylvius.
Focal compression. Compression of the efferent cerebellar pathways in the superior cerebellar peduncle results in limb ataxia and distortion of the quadrigeminal plate, produces limitation of upgaze, convergence paresis with impairment of reaction of pupils to light and accommodation (Parinaud’s syndrome), and may result in convergence-retraction nystagmus on upgaze (Koerber–Salius–Elschnig syndrome).
Endocrine disturbance. Endocrine disturbances are uncommon but include precocious puberty in 10% of patients, almost invariably male, and diabetes insipidus in 10%. The endocrine effects can either be due to direct tumour involvement of the hypothalamus or result from the secondary effects of hydrocephalus.
Radiological investigations
CT scan and MRI will show a pineal region tumour and will often suggest the correct pathological diagnosis (Fig. 13). On CT scan, before contrast, a germinoma will be a hyperdense lesion in the region of the pineal gland infiltrating into the surrounding tissue and there will be uniform vivid enhancement following intravenous contrast. Calcification is uncommon. On MRI germinomas are relatively isointense to normal white matter on T1-weighted images and slightlyhyperintense on T2-weighted scans. Gadolinium contrast defines the tumour well as germinomas enhance markedly and homogeneously.
Fig. 13 MRI showing pineal region germinoma causing obstructive hydrocephalus.
Management
This consists of surgery and radiotherapy. A ventriculoperitoneal shunt or drainage of CSF by a 3rd ventriculostomy may be required if the hydrocephalus is severe.
There is controversy over whether the definitive treatment should be an attempt at surgical excision or radiotherapy. As most of the tumours are germinomas, and these tumours are very radiosensitive, a course of radiotherapy can be given as the initial treatment if the radiological appearance is typical for germinoma. If serial CT scans show the tumour has failed to respond to radiotherapy then surgery may be necessary. Alternatively, if the features on the initial CT and MRI scans are atypical, and the lesion does not resemble a germinoma, exploration of the tumour and surgical excision may be appropriate as the initial procedure.
The preferred surgical approach is usually by a posterior fossa craniotomy, above the cerebellum and below the tentorium cerebelli. Alternative supratentorial surgical exposures include approaching the tumour through the corpus callosum or by retracting the occipital lobe.
Metastatic tumours
Metastatic tumours are responsible for approximately 15% of brain tumours in clinical series but up to 30% of brain tumours reported by pathologists. Approximately 30% of deaths are due to cancer and 1 in 5 of these have intracranial metastatic deposits at autopsy. The metastatic tumours most commonly originate from:
• carcinoma of the lung
• carcinoma of the breast
• metastatic melanoma
• carcinoma of the kidney
• gastrointestinal carcinoma.
In 15% a primary origin is never found. Most metastatic tumours are multiple and onethird are solitary. In about half of these systemic spread is not apparent. The incidence of tumours in the cerebrum relative to the cerebellum is 8 : 1, and most occur in the distribution of the middle cerebral artery. The size of the tumours may vary considerably if the deposits are multiple. Metastatic tumours are often surrounded by intense cerebral oedema.
Clinical presentation
The interval between diagnosis of the primary cancer and cerebral metastases varies considerably. In general, secondary tumours from carcinoma of the lung present relatively soon after the initial diagnosis, with a median interval of 5 months. Although cerebral metastases may present within a few months of the initial diagnosis of malignant melanoma or carcinoma of the breast, some patients may live many years (up to 15 years) before an intracranial tumour appears. The presenting features are similar to those described for other intracranial tumours:
• raised intracranial pressure
• focal neurological signs
• epileptic seizures.
Headache and vomiting, indicative of raised intracranial pressure, occur in most patients and the presenting history is usually short, often only a few weeks or months. The increased intracranial pressure will be caused by either the tumour mass and surrounding oedema or, in posterior fossa tumours, obstructive hydrocephalus. The pattern of focal neurological signs will depend on the position of the tumour deposits and the patient may present with a progressive hemiparesis or speech disturbance with supratentorial tumours or gait ataxia with cerebellar tumours. Epileptic seizures occur in approximately 25% of patients and may be either focal or generalized.
Occasionally, metastases, especially melanoma or choriocarcinoma, present following an intracerebral haemorrhage.
Radiological investigations
CT scan or MRI will diagnose the metastatic tumour and will show whether the deposits are solitary or multiple. Most metastatic tumours are relatively isodense on the unenhanced CT scan and they enhance vividly after intravenous contrast injection. Tumours that may be hyperdense prior to contrast are melanoma, choriocarcinoma, mucoid adenocarcinoma (e.g. from the gastrointestinal tract) and 50% of lymphomas. There is usually considerable surrounding cerebral oedema with distortion of the ventricular system. MRI following gadolinium contrast will demonstrate small metastatic tumours ofteot visible on the CT scan (Fig. 15).
Fig. 15 MRI following gadolinium shows multiple small metastatic tumours.
Treatment
Steroid medication (e.g. dexamethasone) will control cerebral oedema and should be commenced immediately if there is raised intracranial pressure.
Surgery to remove the metastasis is indicated if:
• there is a solitary metastasis in a surgically accessible position
• there is no systemic spread.
Removal of a solitary secondary is preferable only if the primary site of origin has been, or will be, controlled. However, excision of a single metastasis will provide excellent symptomatic relief and consequently may be indicated even if the primary site cannot be treated satisfactorily. Surgery is, of course, mandatory if the diagnosis is uncertain.
Radiotherapy, together with steroid medication to control cerebral oedema, is used to treat patients with multiple cerebral metastases and may be advisable following the excision of a single metastasis. The treatment, up to 45 gray, is usually given in a 2-week course.
Over the past decade stereotactic radiosurgery utilizing a highly focused beam of radiation has been used to treat single and multiple cerebral metastases. The therapy does seem to be effective in some cases and its role relative to surgery is being evaluated.
Anticonvulsant medication is given both to patients who have suffered epileptic seizures and as a prophylactic measure.
Prognosis
About 30% of patients with solitary metastatic deposits from carcinoma of the lung or melanoma and 50% of patients with carcinoma of the breast survive 1 year following surgical excision. In those patients where the source of the metastatic tumours is undetermined, about 50% survive 1 year.
Leptomeningeal metastases
Meningeal carcinomatosis is widespread, multifocal seeding of the leptomeninges by systemic cancer. The clinical presentation includes:
• hydrocephalus, causing headaches and vomiting
• cranial nerve abnormalities due to direct invasion by the tumours
• spinal root involvement due to local infiltration.
The CT scan or MRI findings may be subtle but frequently show excessive enhancement of the meninges. Lumbar puncture can be performed if there is no evidence of raised intracranial pressure. Malignant cells may be seen in the CSF, the protein concentration is increased and the glucose reduced.
Paediatric tumours
Intracranial tumours are the most common form of solid tumours in childhood, with 40% of the tumours occurring above the tentorium cerebelli. The most common supratentorial tumours are astrocytomas, followed by anaplastic astrocytomas and glioblastoma multiforme. Craniopharyngioma occurs more commonly in children than in adults and is situated in the suprasellar region. Other, less common, supratentorial tumours include primitive neuroectodermal tumours (PNETs), ependymomas, ganglioglioma and pineal region tumours.
Posterior fossa tumours
Sixty per cent of paediatric brain tumours occur in the posterior fossa. The relative incidence of the tumours is:
1 cerebellar astrocytoma 30%
2 medulloblastoma (infratentorial primitive neuroectodermal tumour) 30%
3 ependymoma 20%
4 brainstem glioma 10%
5 miscellaneous 10%:
(a) choroid plexus papilloma
(b) haemangioblastoma
(c) epidermoid, dermoid
(d) chordoma.
Clinical presentation
The presenting clinical features of posterior fossa neoplasms in children are related to:
• raised intracranial pressure
• focal neurological signs.
Raised intracranial pressure
This is the most common presenting feature. It is due to hydrocephalus caused by obstruction of the 4th ventricle and is manifest by headaches, vomiting, diplopia and papilloedema. The headaches begin insidiously, gradually becoming more severe and frequent; they are worst in the early morning. There is usually no specific headache localization. Vomiting is frequently associated with the headaches and may temporarily relieve the headache. Raised intracranial pressure may result in a strabismus causing diplopia due to stretching of one or both of the 6th (abducens) cranial nerves. This is a so-called ‘false localizing sign’. Papilloedema is usually present at the time of diagnosis. In infants, an expanding head size is an additional sign of raised intracranial pressure.
Focal neurological signs
These are due to the tumour invading or compressing the cerebellum (nuclei and tracts), the brainstem and cranial nerves. Truncal and gait ataxia result particularly from midline cerebellar involvement. Horizontal gaze paretic nystagmus often occurs with tumours around the 4th ventricle. Upbeat vertical nystagmus is indicative of brainstem involvement.
Disturbances of bulbar function, such as difficulty in swallowing with nasal regurgitation of fluid, dysarthria and impaired palatal and pharyngeal reflexes, result from brainstem involvement. In addition, compression or tumour invasion of the pyramidal tracts may result in hemiparesis and, if the ascending sensory pathways are involved, sensory disturbance will occur in the trunk and limbs.
The tumour may directly envelop the lower cranial nerves—glossopharyngeal, vagal, spinal accessory and hypoglossal—as well as the 7th cranial nerve.
Neck stiffness and head tilt may occur in children with posterior fossa neoplasms, and may be due to herniation of a cerebellar tonsil or tumour tissue resulting in dural irritation.
Investigations
CT scan and MRI have replaced the need for the previous radiological investigations that included radio-isotope brain scanning, air ventriculography and posterior fossa angiography. The CT scan and/or MRI will show the presence of a posterior fossa tumour, its position and whether it arises primarily in the brainstem, 4th ventricle or the cerebellum (Figs 20–24).
Management
The treatment of posterior fossa tumours involves:
• surgery
• radiotherapy
• chemotherapy.
Apreliminary CSF shunt may need to be performed in a child with severely raised intracranial pressure due to hydrocephalus. The CSF diversion can be achieved by either an external drain or a ventriculoperitoneal shunt. An external drain is a temporary measure only, because of the risk of infection. A ventriculoperitoneal shunt provides immediate and controlled relief of intracranial hypertension and the subsequent posterior fossa operation can be performed as a planned elective procedure, rather than an urgent operation in suboptimal conditions. A criticism of a preoperative ventriculoperitoneal shunt is that it might promote the metastatic
spread of tumour. A filtering chamber in the shunt system may lessen this risk but this predisposes to shunt malfunction.
Steroid medication to control local oedema is commenced preoperatively. The operation is performed in either the sitting or prone position through a vertical midline incision. A posterior fossa craniotomy is performed, usually with excision of the bone down to and around the foramen magnum.
Postoperative care involves careful monitoring of the neurological signs. Postoperative haemorrhage or oedema may result in rapid deterioration of the neurological state, and in respiratory arrest. An urgent CT scan may indicate the cause and site of the problem but the deterioration may be so rapid that the wound may need to be reopened without the benefit of prior scanning. If a ventriculoperitoneal shunt has not been inserted prior to tumour removal an exacerbation of the obstructive hydrocephalus may occur if the tumour excision has failed to relieve the CSF obstruction. Disturbances of bulbar and lower cranial nerve function may cause difficulty in swallowing. Nasogastric feeding may be necessary until the protective mechanisms return, and great care should be taken to avoid aspiration.
Medulloblastoma
Medulloblastoma, also referred to as an infratentorial PNET, is a malignant tumour usually arising in the midline from the cerebellar vermis, although it may occur more laterally in a cerebellar hemisphere in older patients. The tumour expands to invade the adjacent cerebellum and large tumours completely fill the 4th ventricle. Fig.20
Fig.20 (a) CT scan. Contrast-enhancing medulloblastoma arising from the vermis causing obstructive hydrocephalus. (b) MRI scan Medulloblastoma.
Presenting features. The presenting features are related to hydrocephalus and cerebellar dysfunction. Truncal ataxia is typically present in children with medulloblastoma but cranial nerve deficits, except for a 6th nerve palsy, are uncommon in the early stages.
Surgery. At surgery the cerebellar vermis is split in the midline and it is usually possible to obtain a gross macroscopic excision of the tumour with complete removal from the 4th ventricle.
Radiation therapy. Medulloblastoma is relatively radiosensitive and radiation therapy is recommended to the entire neuraxis because of the tendency of the tumours to seed along the CSF pathways.
Chemotherapy. Adjuvant chemotherapy is usually recommended Young children are exquisitely sensitive to the neurotoxicity due to radiation therapy, such that the possibility of utilizing chemotherapy alone and postponing the use of radiotherapy has been trialled.
Prognosis. Although the combination of radical surgery and irradiation has improved the prognosis, the 5-year survival rate is approximately 40%.
Cerebellar astrocytoma
The cerebellar astrocytoma is frequently a benign, slowly growing cystic tumour which is the most favourable of all the intracranial paediatric neoplasms. The tumours may arise in either the hemisphere or vermis and frequently consist of a large tumour cyst with a relatively small solid component in the wall of the cyst (see Fig. 21). Less frequently the tumour may be entirely solid with little or no cystic component. Histologically, the solid portion of the tumour is usually a Grade 1 or 2 astrocytoma.
Fig. 21 Cystic cerebellar astrocytoma causing obstructive hydrocephalus. There is a contrastenhancing nodule in a large cyst.
Presenting features. The clinical presenting features are similar to those of a medulloblastoma, but as the tumour may be located more laterally the presenting features are accompanied by ipsilateral cerebellar disturbance. The duration of symptoms is variable but tends to be longer than with medulloblastoma, averaging 6–12 months.
Surgery. Acomplete surgical excision is usually possible and it is only necessary to excise the solid component from the cystic tumour.
Radiation therapy. Postoperative radiation therapy is not usually indicated if an excision has been possible. The prognosis is the most favourable of all intracranial childhood tumours with a cure rate in excess of 75%.
Ependymoma
The ependymoma of the 4th ventricle arises from the floor of the 4th ventricle and is attached to, and may infiltrate, the underlying brainstem (see Fig. 6.21).
Fig. 6.22 Contrast-enhancing ependymoma in the 4th ventricle causing obstructive hydrocephalus.
Pathological features and histology are described earlier.
Presenting features. The presenting features are similar to those described for a medulloblastoma,although the initial symptoms and signs are usually due to hydrocephalus. Involvement of the dorsal brainstem results in unilateral or bilateral facial weakness.
Surgery. The surgical excision of the ependymoma involves splitting the inferior vermis to obtain access to the 4th ventricle. It is usually possible to perform a gross macroscopic excision of the tumour from the ventricle and adjacent cerebellum but, as the tumour often originates from the floor of the 4th ventricle, total excision is rarely possible.
Radiation therapy. Postoperative radiation therapy is usually administered to the posterior fossa and, as the tumour seeds along the CSF pathways, entire neural axis irradiation is often recommended, particularly in the higher-grade ependymoma.
There is no definite advantage from adjuvant chemotherapy, although it may be used at the time of tumour recurrence.
Brainstem glioma
The brainstem glioma arises predominantly in the pons, less frequently in the medulla but may infiltrate extensively throughout the brainstem.
Clinical presentation. The clinical presentation characteristically includes progressive multiple bilateral cranial nerve palsies with involvement of pyramidal tracts and ataxia. Facial weakness and 6th cranial nerve palsy are common and an internuclear ophthalmoplegia is indicative of an intrinsic brainstem lesion. The child’s personality often changes—they become apathetic. Raised
intracranial pressure is less common than with other paediatric posterior fossa neoplasms, as obstruction of the 4th ventricle or aqueduct of Sylvius occurs late in the illness.
The CT and MRI appearance is of an expanded brainstem. MRI has considerably improved the accuracy of the diagnosis (Fig. 6.23).
Fig. 6.23 MRI scan showing (a) pontine glioma, (b) cystic brainstem glioma.
Surgery. Surgical treatment is not usually indicated, although either an open or a stereotactic biopsy may be performed to confirm the diagnosis.
Radiation therapy. Palliative radiation therapy is the only treatment. The tumour usually causes death within 24 months of diagnosis, although some patients with low-grade tumours will live longer.
Chemotherapy has limited benefit.
BENIGN BRAIN TUMOURS
The benign brain tumours may be intimately associated with, and surrounded by, the adjacent brain, but the tumour cells do not invade the underlying brain. This is in contradistinction to the gliomas, which are intrinsic brain tumours actively invading the adjacent brain.
Meningioma
Meningiomas are the most common of the benign brain tumours and constitute about 15% of all intracranial tumours, being about one-third of the number of gliomas. Although they may occur at any age, they reach their peak incidence in middle age, are very uncommon in children and occur more frequently in women than men. The term meningioma was introduced by Harvey Cushing in 1922, although the tumour had been described in the late eighteenth century. The tumour arises from the arachnoid layer of the meninges, principally the arachnoid villi and granulations.
Aetiology
As for other brain tumours, no definite aetiological factor has been identified. However, the possibility that head trauma predisposes to the development of meningioma has been the subject of controversy for many years. Although epidemiological studies do not support trauma as an aetiological factor, there have been cases reporting the development of meningiomas at the site of substantial meningeal trauma. Meningiomas are known to occur following low levels of irradiation as was given in the past for tinea capitis, and an analysis of the Nagasaki atomic bomb survivors found a high correlation between the incidence of meningiomas and the distance from the epicentre of the explosion. Meningiomas occur with a high frequency in patients with neurofibromatosis type 2 (NF2) (often multiple). This association has prompted cytogenetic studies, which have shown that monosomy of chromosome 22 is the most common chromosomal abnormality noted in meningiomas, occurring in 50–80% of sporadic tumours. In addition, alterations of many other chromosomes (including chromosomes 1, 6, 9, 10, 11, 13, 14, 18 and 19) have beeoted to be involved in the formation and progression of meningioma.
The importance of sex hormones and their receptors in meningioma is suggested by the 2–4 times incidence in females. Oestrogen binds in less than 30% of meningiomas, with the majority of those receptors being type II subtype, that have a lower affinity and specificity for oestrogen than the classic type I receptor usually found in breast cancer. Progesterone receptors are much more commonly associated with meningiomas, occurring in 50–100% of tumours tested.
Position of meningiomas (Fig. 7.1)
Meningiomas arise from the arachnoid layer of the meninges, especially the arachnoid cap cells. The most common location is in the parasagittal region arising either from the wall of the superior sagittal sinus (parasagittal) or from the falx (falcine). Less frequently the tumours may arise from the convexity of the cranial vault, where they are particularly concentrated in the region of the coronal suture. Sphenoidal ridge meningiomasare divided into those that arise from the inner part of the lesser wing of the sphenoid and the adjacent anterior clinoid process, and those arising from the outer sphenoidal ridge, comprising the greater wing of the sphenoid and theadjacent pterion (the junction of the temporal, parietal and frontal bones). Less frequently, the tumours may arise from the olfactory groove, tuberculum sella (suprasellar), floor of the middle cranial fossa, cavernous sinus or posterior fossa (Table 7.1). Meningiomas usually occur as a single intracranial tumour but multiple intracranial meningiomas may present in NF2.
Fig. 7.1 Typical positions of intracranial meningiomas.
Pathology
Unlike gliomas, where the classification system is based on the histological appearance of the tumour, meningiomas are usually classified according to their position of origin rather than their histology. The reason for this is that the biological activity of the tumour, the presenting features, the treatment and prognosis are all related more to the site of the tumour than to the histology.
The major histological types are listed below.
• Syncytial or meningotheliomatous—sheets of cells with varying amounts of stroma.
• The transitional type is characterized by whorls of cells which may undergo hyalin degeneration with subsequent deposition of calcium salts. These calcified concentric psammoma bodies form the characteristic feature of many transitional meningiomas but they may also be present in the syncytial or fibroblastic types.
• The fibroblastic type contains abundant reticulin and collagen fibres.
• Angiomatous meningiomas are much less common and their characteristic feature is the predominance of vascular channels separated by sheets of cells. Histologically, these tumours resemble cerebellar haemangioblastomas.
• Malignant meningiomas occur infrequently. The indications of malignancy include cellular pleomorphism, necrosis, increased numbers of mitotic figures and local invasion of brain. Atypical meningiomas are tumours that lack the histological features of malignancy, but have a biological behaviour intermediate between the typical and malignant meningioma. These tumours are most likely to recur.
Clinical presentation
Meningiomas present with features of:
• raised intracranial pressure
• focal neurological signs
• epilepsy.
The position of the tumour will determine the features of the clinical presentation. The tumours grow slowly and there is frequently a long history, often of many years, of symptoms prior to the diagnosis.
Parasagittal tumours (Fig. 7.2)
These tumours most often arise in the middle third of the vault and the patient may present with focal epilepsy and paresis, usually affecting the opposite leg and foot as the motor cortex on the medial aspect of the posterior frontal lobe is affected. Tumours arising anteriorly are often bilateral and patients present with features of raised intracranial pressure. As these tumours involve the frontal lobes, pseudopsychiatric symptoms, as well as impairment of memory, intelligence and personality, may occur. Urinary incontinence is occasionally a symptom of a large frontal tumour, especially if it is bilateral. Tumours arising from the posterior falx may affect the parieto-occipital region and produce a homonymous hemianopia. If the tumour lies above the calcarine fissure the inferior quadrant is more affected; when the tumour is below the fissure the upper quadrant is predominantly affected.
Fig. 7.2 Parasagittal meningioma. (a) CT scan. (b) MRI.
Convexity tumours (Fig. 7.3)
Convexity tumours may grow to a large size if situated in front of the coronal suture. They present with raised intracranial pressure. More posterior tumours will cause focal neurological symptoms and focal epilepsy.
Fig. 7.3 Convexity meningioma. (a) CT scan. (b) MRI.
Sphenoidal ridge tumours (Fig. 7.4)
Tumours arising from the inner sphenoidal ridge cause compression of the adjacent optic nerve and patients may present with a history of uniocular visual failure. If the tumour is large enough to cause raised intracranial pressure papilloedema will develop in the contralateral eye. syndrome is known as the Foster Kennedy. Inner sphenoidal ridge tumours may also cause compression of the
olfactory tract, resulting in anosmia. Patients with tumours involving the outer sphenoidal ridge present with features of raised intracranial pressure, often severe papilloedema with relatively inconspicuous localizing symptoms or signs. Tumours in this region occur as a thin sheet, and are known as ‘en plaque’. They may cause an excessive bony reaction (hyperostosis) resulting in proptosis.
Fig. 7.4 (a) CT scan. Hyperostosis of the left sphenoidal ring causing unilateral proptosis due to a sphenoidal ring meningioma. (b) MRI. Inner sphenoidal wing meningioma.
Olfactory groove tumours (Fig. 7.5)
Olfactory groove meningiomas cause anosmia, initially unilateral and later bilateral. The presenting features may include symptoms of raised intracranial pressure, and failing vision either from chronic papilloedema or from direct compression of the optic nerve or chiasm causing visual field defects. These tumours may also present with the Foster Kennedy syndrome and the intellectual and psychiatric problems caused by frontal lobe compression described for inner spheroidal ridge meningiomas.
Fig. 7.5 (a) CT scan. Olfactory groove meningioma. (b) MRI. Olfactory groove meningioma extending on to tuberculum sella and over pituitary fossa.
Suprasellar tumours (Fig. 7.6)
Suprasellar meningiomas arising from the tuberculum sellae will cause visual failure and a bitemporal hemianopia, but the lack of endocrine disturbance will distinguish the clinical presentation of this tumour from that of a pituitary tumour.
Ventricular tumours (Fig. 7.7)
Tumours arising in the lateral ventricle present with symptoms of raised intracranial pressure extending over several years and associated with a mild global disturbance of function of one hemisphere and frequently a homonymous hemianopia.
Fig. 7.7 Intraventricular meningioma.
Posterior fossa tumours (Fig. 7.8)
Posterior fossa tumours may arise from the cerebellar convexity or from the cerebellopontine angle or clivus. The cerebellopontine angle tumours simulate an acoustic neuroma with symptoms involving the acoustic nerve, trigeminal nerve and facial nerve, ataxia due to cerebellar involvement and raised intracranial pressure, often due to hydrocephalus caused by obstruction of the 4th ventricle. Meningiomas arising from the clivus or the foramen magnum region may compress the brainstem directly.
Fig. 7.8 (a) CT scan. Meningioma arising in the cerebellopontine angle and from the tentorial edge. (b) MRI. Clivus meningioma. (c) MRI. Foramen magnum meningioma.
Radiological investigations
The CT scan appearance shows a tumour of slightly increased density prior to contrast; it enhances vividly and uniformly following intravenous contrast. Hyperostosis of the cranial vault may be a focal process at the site of the tumour attachment or, as seen with en plaque meningioma, a more diffuse sclerosis. These bone changes may also be seen on plain skull X-ray.
Magnetic resonance imaging will demonstrate meningiomas following the intravenous injection of gadolinium contrast Meningiomas are usually isointense on T1- weighted images, but enhance intensely and usually homogeneously following administration of gadolinium.
Cerebral angiography is no longer necessary as a diagnostic investigation but may be useful preoperatively to ascertain the position of the cerebral vessels. It will demonstrate external carotid artery supply to the tumour with a characteristic tumour blush, differentiating it from a glioma or metastatic tumour (Fig. 7.12). Angiography also allows preoperative embolization of the tumour, if necessary.
Fig. 7.12 Cerebral angiogram of olfactory groove meningioma showing displacement of anterior cerebral arteries (a,b) and the characteristic tumour blush, usually due to the external carotid artery supply (c).
Preoperative management
Meningiomas are frequently surrounded by severe cerebral oedema and patients should be treated with high-dose steroids (dexamethasone) prior to surgery if possible. Preoperative embolization of the tumour vasculature may be considered advisable in some anterior basal and sphenoidal wing tumours where the major Vascular supply is not readily accessible in the early stages of the operation.
Treatment
The treatment of meningiomas is total surgical excision, including obliteration of the dural attachment. Although this objective is usually possible there are some situations where complete excision is not possible because of the position of the tumour. Tumours arising from the clivus, in front of the brainstem or those situated within the cavernous sinus, are notoriously difficult to excise without causing serious morbidity. Radiation therapy may be used to treat residual tumours following subtotal resection, in order to reduce the risk of recurrent growth. Stereotactic radiotherapy has been used to treat small meningiomas (less than 3 cm in diameter), particularly if the tumours are located in portions not easily amenable to surgery, or in the elderly or medically infirm patient. Clinical studies have shown short-term control rates of over 90%, but long-term studies will be necessary to prove the efficacy and safety of focused radiation treatment.
Postoperative management
The postoperative care of patients following excision of a meningioma involves the routine management of patients following a craniotomy but with particular attention to the minimization of cerebral oedema. Steroid therapy is continued initially and gradually tapered. Care is taken to avoid excessive hydration and the patient is nursed with the head of the bed elevated to promote venous return. Neurological deterioration requires urgent assessment and a CT scan will determine the pathological cause, either postoperative haemorrhage or cerebral oedema.
Tumour recurrence
The risk of tumour recurrence depends on the extent of tumour excision. When the tumour and its dural origins are completely excised, the risk of recurrence is remote. The most common source of recurrence is from a tumour that has invaded a venous sinus and which was not resected (e.g. superior sagittal sinus or cavernous sinus). Recurrence is more common if the tumour has histological features of malignancy.
Meningeal haemangiopericytoma
Meningeal haemangiopericytoma is a malignant neoplasm with sarcoma-like behaviour. It was originally classified by Cushing and Eisenhardt in 1938 as an angioblastic variant of meningioma.The tumour’s radiological and macroscopic appearance resembles a vascular meningioma, but it arises from the meningeal capillary pericyte and typically contains a subpopulation of cells that express actor VIIIa. The tumour incidence is 2–4% of meningioma and it is slightly more common in males than in females.
The presenting features are dependent on the tumour location, with symptoms usually being present for less than 1 year.
Acoustic neuroma
Acoustic schwannomas arise from the 8th cranial nerve and account for 8% of intracranial tumours. Schwannomas occur less frequently on the 5th cranial nerve and rarely involve other cranial nerves. The acoustic schwannoma takes origin from the vestibular component of the 8th cranial nerve near the internal auditory meatus, at the transition zone where the Schwann cells replace the oligodendroglia. As such it should more correctly be called a vestibular schwannoma, although the term acoustic neuroma or schwannoma is more commonly used.
Macroscopically, the acoustic schwannoma is lobulated with a capsule that separates it from the surrounding neural structures. Small tumours usually arise from within the internal auditory canal and occupy the porus of the internal auditory canal and, as the tumour grows, the 8th nerve is destroyed and the adjacent cranial nerves become stretched around the tumour. The 7th nerve is typically displaced on the ventral and anterior surface of the tumour and the trigeminal nerve is carried upwards and forwards by the upper pole. The 6th nerve lies ventral and usually medial to the major mass and the lower cranial nerves are displaced around the inferior pole of the tumour. As the tumour grows medially it compresses and displaces the cerebellum and distorts the brainstem. Large tumours will result in obstruction of the 4th ventricle and hydrocephalus.
Bilateral acoustic neuromas are the hallmark of neurofibromatosis type 2 (NF2), inherited as an autosomal dominant condition Clinical presentation
The presenting features will depend on the size of the tumour at the time of diagnosis. The earlier symptoms are associated with 8th nerve involvement. Tinnitus and unilateral partial or complete sensorineural hearing loss are the earliest features. Episodes of vertigo may occur but these may be difficult to distinguish from Menière’s disease. Although the tumour causes compressionof the facial nerve, the growth of the tumour is so slow that facial paresis is not evident until the tumour is large. At that stage 5th nerve compression may be evident, with diminished facial sensation and a depressed corneal reflex. Cerebellar involvement will result in ataxia, and compression of the pyramidal tracts from a very large tumour causing brainstem compression will cause a contralateral hemiparesis. If a large tumour has caused obstructive hydrocephalus the patient will also present with features of raised intracranial pressure.
Radiological investigations
The CT scan or MRI will show an enhancing tumour extending from the internal auditory canal into the cerebellopontine angle (Fig. 7.13). The internal auditory meatus will be widened indicating that the tumour has arisen from the 8th cranial nerve (Fig. 7.14). While there is no difficulty in diagnosing a tumour large enough to be evident on the CT scan, very small acoustic neuromas, which are predominantly within the internal auditory canal, may be more difficult to diagnose. These tumours may be seen on highquality CT scan but are particularly evident using MRI, especially following gadolinium contrast (Fig. 7.15), which is now the investigation of choice.
Fig. 7.13 Acoustic neuroma. Acontrast-enhancing tumour in the cerebellopontine angle arising from the 8th cranial nerve in the internal auditory canal.
Other investigations
Pure tone audiometry, by both air and bone conduction, is an essential part of the investigation of a patient with an acoustic neuroma, the most common finding being high-frequency hearing loss. Other special auditory tests include the use of brainstem auditory evoked responses which are particularly sensitive for changes in the retrocochlear auditory system; these are helpful in diagnosing a small intracanalicular tumour. Vestibular function is impaired early in patients with acoustic neuroma. The Hallpike caloric test is carried out with the patient supine on a couch and the head raised to 30°C above horizontal, bringing the horizontal canals into the vertical plane with the position of maximum sensitivity to thermal stimuli. Warm and cool water is irrigated and the nystagmus reaction observed. The caloric response on the side of the acoustic nerve tumour is depressed or absent.
Differential diagnosis
The major differential diagnoses for a cerebello-pontine angle tumour, in decreasing frequency, are: meningioma, metastatic tumour, exophytic brainstem glioma, epidermoid tumour.
Treatment
The total excision of a large acoustic neuroma remains one of the major operative challenges in what Cushing has described as ‘the gloomy corner of neurologic surgery’.
The aim of the operation is complete resection of the tumour while sparing the adjacent neural structures. If the patient presents with a large tumour causing severe hydrocephalus and raised intracranial pressure, a preliminary ventriculoperitoneal shunt or ventricular drain may be considered. Steroid administration prior to surgery may be advisable if the tumour is large.
There are three basic approaches to the cerebellopontine angle: by excision of the labyrinth (translabyrinthine); through a posterior fossa craniectomy (suboccipital/retrosigmoid); or via the middle cranial fossa. The route chosen is governed by tumour size, the degree of hearing loss, the hearing level in the contralateral ear, and the surgical preference and expertise of the operator.
The major advantage of the translabyrinthine operation is that the facial nerve can be identified lateral to the tumour at an early stage in the dissection, and access to the fundus of the internal auditory meatus is excellent. Furthermore, retraction of the cerebellum is minimal and the risk of postoperative oedema is consequently less. The major disadvantage of this route is that residual hearing is irrevocably destroyed. translabyrinthine operation is favoured for large tumours, regardless of hearing level, and for medium-sized lesions with poor hearing. It provides a more direct approach to the cerebellopontine angle, and retraction of the cerebellum is negligible.
As a consequence of progressive improvements in operative results, particularly in mortality and facial nerve outcome, attention has
turned more recently to the ability to preserve useful hearing. The suboccipital operation provides good access to the cerebellopontine angle but, if hearing is to be conserved, tumour at the fundus of the internal auditory meatus may be difficult to expose under direct vision. For hearing preservation the retrosigmoid approach for tumours with up to 2 cm cerebellopontine angle extension is preferred.
Recently there has been renewed interest in the middle fossa approach for removal of intracanalicular tumours or those with a small cerebellopontine angle component, particularly where the tumour in the internal auditory canal extends to the fundus. Higher rates of hearing preservation have been reported without any compromise of facial nerve function, but this route provides more limited access to the cerebellopontine angle, and is therefore restricted to the treatment of small lesions. The middle fossa approach is preferred for intracanalicular tumours and for those with up to 1 cm cerebellopontine angle extension where tumour completely fills the internal auditory canal.
Stereotactic radiosurgery using either a 60CO Gamma Knife or a highly focused linear accelerator has been advocated for the treatment of smaller tumours, less than 3 cm in diameter. The control rates are greater than 90% over a 5-year period, but post-radiatioeurological complications have been reported including delayed facial numbness and dysaesthesia, facial weakness and hearing loss. To minimize the complications of single-dose stereotactic radiosurgery many centres advocate fractionated stereotactic radiotherapy.
There is continuing debate as to the relative advantages of surgery and stereotactic radiation treatment. Whilst some clinicians advocate radiation treatment for smaller tumours, others would only recommend it for elderly or medically infirm patients or if there is residual tumour or regrowth after subtotal resection.
The management plan for patients with bilateral acoustic neuromas (NF2) is complex, and must be tailored for each patient, with the aim of preserving useful hearing for as long as possible, whilst minimizing the possible serious neurological complications from enlarging tumours causing cranial nerve, cerebellar and brainstem compression. Therapeutic options include surgery, radiosurgery and hearing preservations/restoration utilizing brainstem electrode implants at the time of tumour resection.
Haemangioblastoma
Haemangioblastomas are uncommon intracranial tumours accounting for 1–2% of all brain tumours and approximately 10% of posterior fossa tumours.
The haemangioblastoma arises from proliferation of endothelial cells. The tumour usually occurs in young adults, although it may occur at any age. It usually occurs in the posterior fossa and often produces a large cyst. Although haemangioblastoma may occur as a component of von Hippel–Lindau’s disease, which includes multiple haemangioblastomas, haemangioblastomas of the retina (von Hippel tumour), renal tumour, renal cyst, pancreatic cyst and tubular adenomata of the epididymis, the majority of patients with the cerebellar tumour do not have von Hippel–Lindau’s disease. Incomplete forms of the syndrome may occur and cerebellar haemangioblastomas occur in about 20% of patients with retinal haemangioblastoma.
The tumour presents as a slowly growing posterior fossa mass with features of raised intracranial pressure and cerebellar involvement. Occasionally the patient may be polycythaemic due to increased circulating erythropoietin.
Fig. 7.17 MRI. Cystic haemangioblastoma.
CT scan or MRI show a cerebellar tumour which may involve the vermis and hemispheres and which shows vivid enhancement following intravenous contrast. There is usually a low-density cyst surrounding the tumour nodule (Fig. 7.17), although haemangioblastomas may sometimes be solid. If considered necessary, vertebral angiography will confirm the highly vascular mass.
Total surgical excision through a posterior fossa craniotomy is nearly always possible. Great care must be taken not to enter the highly vascular tumour during the dissection and excision.
Colloid cyst of the 3rd ventricle
The colloid cyst of the 3rd ventricle is situated in the anterior part of the ventricle and is attached to the roof just behind the foramen of Monro. Several possibilities as to the origin of the tumour have been proposed, including the paraphysis, choroid plexus epithelium, ependyma or a diverticulum of the diencephalon.
The cyst consists of a thin, outer fibrous capsule lined by a layer of epithelium; the contents consist of mucoid material, epithelial debris and mucin. The cyst may be very small and asymptomatic. As the tumour grows it will cause bilateral obstruction to the foramina of Monro, leading to raised intracranial pressure from hydrocephalus. The headaches may fluctuate, being aggravated by stooping and relieved by standing upright. Episodes of abrupt, sudden leg weakness causing the patient to fall may occur without a change in conscious state. Alternatively, an abrupt loss of consciousness may occur and this, although usually transient, might be fatal.
The usual CT scan picture is a high-density, rounded tumour in the anterior 3rd ventricle which enhances following intravenous contrast (Fig. 7.18), although isodense, hypodense and non-enhancing tumours have been reported. MRI helps to define the position of these tumours (Fig. 7.18) and will be able to differentiate between a colloid cyst and an aneurysm of the basilar tip, which may occasionally be indistinguishable on CT scan.
Fig. 7.18 Colloid cyst of the 3rd ventricle. (a) CT scan shows hyperdense tumour before contrast. (b) MRI. Colloid cyst. (c) MRI. Colloid cyst sagittal view.
Surgical excision is performed through a craniotomy with a small incision in the anterior corpus callosum giving access to the lateral ventricle. The tumour is seen expanding the foramen of Monro and, using the operating microscope, a complete excision is usually possible. Great care must be taken during the operation to preserve the venous structures, including the septal veins, thalamostriate vein and internal cerebral veins. Damage to the columns of the fornix will result in severe postoperativememory disturbance.
Epidermoid and dermoid cysts
Epidermoid and dermoid cysts arise from epithelial cells embryologically misplaced intracranially, particularly into the meninges and ventricles and, less frequently, into the parenchyma of the brain. Rarely, the cells can be implanted as a result of trauma such as a lumbar puncture, which can implant skin into the spinal canal causing an epidermoid cyst.
Epidermoid tumours are found principally in the arachnoid spaces, the cisterns or the diploe of the bone. The most frequent localizations are the cerebellopontine angle, the suprasellar and parasellar regions, the lateral or 4th ventricles, and the quadrigeminal cistern. Dermoid tumours occur mostly in the posterior fossa as a midline lesion and a fistula may connect the dermoid with the skin.
The epidermoid cyst contains desquamated epithelium surrounded by keratin-producing squamous epithelium. The dermoid cyst includes dermal elements such as hair follicles, sebaceous glands and sometimes sweat glands.
The cysts usually present following a long history of symptoms related to their position. Cranial nerve abnormalities such as trigeminal neuralgia and hemifacial spasm may occur with cerebellopontine angle epidermoid tumours and the suprasellar cyst will produce visual impairment with optic atrophy and often a bitemporal hemianopia. Leakage of epidermoid cyst contents may result in a chemical meningitis, and in patients with posterior fossa dermoid cysts, bacterial meningitis may occur through the dermal sinus connecting the cyst with the skin.
The CT scan of an epidermoid cyst is characterized by a low-density lesion that does not enhance. The dermoid cyst will also have areas which are even less dense than CSF, indicating the presence of fat (Fig. 7.19). MRI has superceded CT for accurate preoperative evaluation and planning. Epidermoid lesions are usually manifest as low signal on T1 and high signal on T2 images, although depending on lipid content, variable signal intensities may be seen within thesame lesion.
Fig. 7.19 MRI. Epidermoid cyst adjacent to brainstem.
The treatment is operative, with resection of the cyst. Complete excision may be prevented if the cyst wall is densely adherent to major vessels and important neural structures.
PITUITARY ADENOMAS
Pituitary adenomas account for 8–10% of all intracranial tumours.
In 1886 Pierre Marie first made the connection between acromegaly and pituitary adenomas. Patients may present either with signs of endocrine disturbance or with compression of the adjacent neural structures, especially the optic pathways.
Classification
Historically, three main types of pituitary adenomas were defined by their cytoplasmic staining characteristics: chromophobic, acidophilic and basophilic—the implication being that these tumours were either hormonally inactive, secreted growth hormone, or produced adrenocorticotrophic hormone (ACTH), respectively.
The development of immunoperoxidase techniques and electron microscopy has provided a more refined classification of pituitary adenomas based on the specific hormone that is produced. This classification is shown in Table 8.1.
Pathology
Pituitary adenomas arise from the anterior lobe (adenohypophysis) of the pituitary gland which develops from Rathke’s pouch, an ectodermal diverticulum arising from the roof of the stomodeum, immediately in front of the buccopharyngeal membrane. The posterior lobe (neurohypophysis/pars nervosa) arises from the infundibulum developing from the floor of the diencephalon (Fig. 8.1).
The tumour arises within the pituitary fossa. If it is less than 10 mm in diameter it is known as a ‘microadenoma’. The tumour may grow locally within the sella and cause erosion and remodelling of the floor of the sella and posterior clinoid processes (macroadenoma). The tumour usually spreads superiorly into the suprasellar cisterns, where it may cause compression of the optic
pathways, particularly the optic chiasm. Further growth superiorly causes compression of the hypothalamus and, if large enough, obstruction of the 3rd ventricle, resulting in hydrocephalus (Figs 8.2).
Fig. 8.2 Anatomical relations of the pituitary gland.
The tumour may also grow laterally out of the sella into the cavernous sinus. Occasionally the lateral extension may be sufficient to cause disturbance of the cranial nerves in the cavernous sinus. Uncommonly the tumour penetrates further laterally, into the temporal lobe.
The tumour may infrequently extend inferiorly through the floor of the pituitary fossa into the sphenoid sinus, resulting in CSF rhinorrhoea.
The localization of microadenomas within the pituitary fossa corresponds somewhat with the regional distribution of the normal adenohypophyseal cells. Prolactin- and growth hormonesecreting microadenomas tend to occur laterally, whereas most adenomas secreting ACTH occur in the central zone.
Multiple endocrine neoplasia type 1 (Werner’s syndrome) is an autosomal dominant disorder representing the inherited occurrence of both benign and malignant neoplasms involving the pituitary gland, parathyroid gland and pancreas.
About 10% of pituitary adenomas are invasive, with extensive penetration of the pituitary capsule, dural sinuses and surrounding bone. Most invasive pituitary adenomas are sparsely granulated or chromophobic and are either hormonally inactive or prolactin producing. Metastasizing pituitary carcinoma, either extracranially or throughout the CSF pathway, is extremely rare.
Clinical presentation are due to:
• the size of the tumour
• endocrine disturbance.
Headache occurs principally in patients with macromegaly and is uncommon in other types of pituitary tumour.
Visual failure
Careful assessment of the visual fields, the visual acuity and the optic fundi is essential. Suprasellar extension of the pituitary tumour causes compression of the optic chiasm resulting in a bitemporal hemianopia. The bitemporal hemianopia initially involves the upper quadrants,before extending to the lower quadrants of the visual field. If the chiasm is prefixed, that is, placed more anteriorly than usual, a homonymous hemianopia may occur due to compression of the optic tract. Bilateral central scotomas result from the tumour pressing on the posterior part of the chiasm where the macular fibres decussate. Primary optic atrophy will be evident in patients with long-standing compression of the chiasm. Ocular palsies occur in about 10% of patients and are due to invasion of the cavernous sinus. The 3rd nerve is the most frequently affected, followed by the 6th and 4th cranial nerves. Facial pain results from compression of the trigeminal nerve, usually the ophthalmic division, as a result of cavernous sinus invasion.
Endocrine abnormalities
Endocrine disturbance is due to either hypopituitarism or excess secretion of a particular pituitary hormone.
Hypopituitarism
Hypopituitarism results from failure of the hormones secreted by the adenohypophysis and it gives rise to the clinical features first described by Simmonds in 1914. Pituitary gland failure does not occur if the tumour is a microadenoma, but may be clinically evident in the larger tumours. The endocrine secretions are not equally depressed but there is a selective failure and the order of susceptibility is as follows: growth hormone, gonadotrophin, corticotrophin, thyroidstimulating hormone.
Gonadotrophic deficiency prior to puberty retards the development of secondary sex characteristics; adult men have poor beard growth, women suffer from amenorrhoea and both sexes have loss of libido and deficient pubic and axillary hair. The biochemical abnormality is manifest by a low oestrogen and androgen production with reduced urinary 17-ketosteroids. Hypopituitarism initially results in vague symptoms, including lack of energy, undue fatiguability, muscle weakness and anorexia and, when prolonged and severe, it will cause low blood pressure. Clinical hypothyroidism is manifest by physical and mental sluggishness and a preference for warmth. When the hypopituitarism is severe, episodic confusion occurs and the patient will become drowsy. It is essential to recognize the features of severe pituitary insufficiency as an endocrine crisis can be precipitated by minor stressful events occurring during hospital investigation or as a result of an intercurrent infection.
Pituitary apoplexy results from spontaneous haemorrhage into a pituitary tumour. It is characterized by sudden, severe headache followed by transient or more prolonged loss of consciousness with features of neck stiffness, vomiting and photophobia. The condition is similar to subarachnoid haemorrhage resulting from a ruptured aneurysm, but is often associated with paralysis of one or more of the ocular muscles (usually bilateral) and acute visual deterioration. An acute endocrine crisis may be precipitated by
the apoplexy.
Prolactinoma
The prolactin-secreting tumour may be a microadenoma or macroadenoma within the pituitary fossa. The patients are usually women who present with infertility associated with amenorrhoea and galactorrhoea, although the tumour may occasionally cause infertility in men. Large prolactinomas occur in the elderly and in males, and these can cause endocrine disturbance associated with hypopituitarism and visual failure.
Acromegaly
Acromegaly results from a growth hormonesecreting pituitary adenoma which, as described previously, consists of cells that stain either as acidophils, chromophobes or both. The onset of acromegaly is slow and insidious, usually during the 3rd and 4th decades of life, with both sexes being affected equally. The clinical features (Table 8.3) include bone and soft tissue changes that are evident as an enlarged supraciliary ridge, enlarged frontal sinuses and increased mandibular size, which will cause the chin to project (prognathism) (Fig. 8.6). The hands and feet enlarge, and the skin becomes coarse and greasy and sweats profusely. The voice becomes hoarse and gruff and thoracic kyphosis occurs as a result of osteoporosis. Other problems associated with acromegaly include hypertension, cardiac hypertrophy and diabetes. Headache is often severe in patients with pituitary tumours causing acromegaly and patients complain of lack of energy, physical weakness and lassitude. Suprasellar extension of the tumour occurs in about 15% of cases and may result in compression of the optic pathways.
A pituitary adenoma with excessive growth hormone secretion occasionally presents in childhood and results in gigantism.
Cushing’s disease
Cushing’s disease is due to ACTH-producing pituitary adenomas. Over 80% of the tumours are microadenomas and the remainder are macroadenomas involving the whole of the sella or with extrasellar extension. The onset is insidious and the disease may affect children or adults. Severe obesity occurs, the skin is tense and painful, and purple striae appear around the trunk. Fat is deposited, particularly on the face (moon face), neck, cervicodorsal junction (buffalo hump) and trunk. The skin becomes a purple colour due to vasodilatation and stasis. Spontaneous bruising is common. The skin is greasy, acne is common and facial hair excessive. Patients complain of excessive fatigue and weakness. There is wasting and flaccidity of the muscles. Osteoporosis predisposes to spontaneous fractures.
Glucose tolerance is impaired, the serum potassium is low and vascular hypertension occurs. If untreated, 50% of cases are fatal in 5 years.
Laboratory investigations
Radioimmunoassay will help to identify the hormone being secreted.
Serum prolactin level in patients with prolactinomas will vary from just above the upper limit of normal to values greater than 20 000 mIU/l (normal 70–550 mIU/l). The levels may show considerable variation in a particular patient and prolactin levels greater than 2000 mIU/l are almost always indicative of a pituitary tumour. As mentioned previously, hyperprolactinaemia may be associated with other pituitary tumours and has beeoted in some patients with acromegaly. Null cell tumours may be associated with mild hyperprolactinaemia due to distortion of the pituitary stalk or impingement on the hypothalamus.
Serum growth hormone is measured by radioimmunoassay, the normal values being less than 5 mIU/l in males and less than 10 mIU/l in females. Growth hormone exerts its effects on peripheraltissues indirectly via somatomedins—polypeptides produced primarily by the liver and fibroblasts. Serum somatomedin C (insulinlike growth factor I, IGF-I) is a more accurate indicator of growth hormone bioactivity than the serum growth hormone levels. Provocative tests of growth hormone secretion are useful in confirming acromegaly. Most patients with acromegaly do not show the normal suppression of growth hormone following glucose load.
Other provocative tests utilize thyrotrophinreleasing hormone and growth hormonereleasing hormone.
In contrast to other pituitary tumours that rely on imaging studies as the foremost diagnostic investigation, a careful endocrinological assessment is critical in the diagnosis of Cushing’s disease, especially as iearly 50% a tumour is not evident on MRI.
There are three essential steps in the diagnosis of Cushing’s disease due to pituitary pathology.
1 Confirm excess secretion of cortisol (normal 120–650 nmol/l).
2 Distinguish ACTH-dependent from ACTH-independent causes of hypercortisolaemia.
3 Distinguish pituitary-based Cushing’s disease from ectopic states of ACTH production.
A24-hour urine specimen is the simplest initial means of establishing hypercortisolaemia.
The investigation of Cushing’s disease involves the measurement of ACTH by radioimmunoassay of samples of both peripheral blood and blood from the petrosal sinus. A differential level of ACTH in petrosal vein blood and peripheral blood will help confirm the presence of a pituitary basis for the ACTH production, especially after administration of corticotrophin-releasing hormone (CRH). A dexamethasone suppression test will help diagnose Cushing’s syndrome and its cause. The urine- and plasma-free cortisol is measured and is normally suppressed following administration of low-dose dexamethasone (0.5 mg 6-hourly). The levels will be suppressed following high-dose dexamethasone (2mg 6-hourly) in pituitary-dependent Cushing’s disease. There will be a failure of suppression of the levels with high-dose dexamethasone if the Cushing’s syndrome is due to other than pituitary causes.
Radiological investigations
High-resolution CT scanning and magnetic resonance imaging using thin slices and intravenous contrast are the appropriate investigation. Pituitary microadenomas are usually hypodense and may cause upward bulging and convexity of the upper border of the gland in adults, deviation of the pituitary stalk and thinning of the sellar floor on the side of the tumour. High-quality CT scanning is able to demonstrate tumours as small as 4 mm in diameter. Macroadenomas enhance after intravenous contrast and the exact nature of the extrasellar extension can be best appreciated with direct coronal scans (Fig. 8.8).
Fig. 8.8 Axial and coronal CT scans showing large pituitary tumours.
MRI has improved the identification of microadenomas, which appear as low-density focal lesions on T1-weighted scans and high intensity on T2-weighted scans (Fig. 8.9). Macroadenomas usually appear as isointense on the T1-weighted images and moderately hyperintense on the T2- images. Haemorrhage into a tumour, such as occurs following pituitary apoplexy, shows as high-intensity areas because of methaemoglobin on the T1- and T2-weighted scans intermingled with low-density regions due to haemosiderin (see Figs 8.5 and 8.9). Dynamic scans taken at 30-second intervals following intravenous gadolinium may help demonstrate small microadenomas.
Fig. 8.9 MRI scan (T1) showing large pituitary tumour with area of recent haemorrhage.
Plain skull X-rays may show enlargement of the sella with thinning erosion or bulging of its contours (Fig. 8.11).
In the past angiography has been performed to exclude incidental aneurysms and to determine the position of the internal carotid arteries in the cavernous sinuses, but this information caow be obtained satisfactorily from good-quality MRI and, if necessary, magnetic resonance angiography.
Fig. 8.11 Plain lateral skull X-ray showing thinning of the dorsum sellae and destruction of the pituitary fossa in a patient with a large pituitary tumour.
Differential diagnosis
The major differential diagnoses are:
• craniopharyngioma
• suprasellar meningioma (arising from the tuberculum sellae).
Uncommon masses around the suprasellar region also include optic nerve and hypothalamic glioma, giant aneurysm arising from the carotid artery, Rathke’s cleft cysts, suprasellar germinomas and chordomas.
Treatment
The objectives of treatment of patients with pituitary tumours depend on whether the patient has presented with features of endocrine disturbance or problems related to compression of adjacent neural structures. The methods of treatment used are:
1 Operative procedures:
(a) transsphenoidal excision
(b) transcranial excision.
2 Radiotherapy.
3 Medical treatment with antisecretory drugs.
Surgical excision
This will be used as the primary method of treatment for:
• large tumours causing compression of adjacent adjacent neural structures, particularly the visual pathways
• GH-secreting tumours causing acromegaly
• ACTH-secreting tumours causing Cushing’s disease
• the occasional treatment of a prolactin-secreting adenoma, either microadenoma or macroadenoma confined within the sella, when medical treatment using bromocriptine is not tolerated.
Fig. 8.13 (a) Diagram of operative exposure in transsphenoidal resection of pituitary tumour. Aselfretaining retractor is inserted and the anterior wall of the sphenoid sinus is removed. (b) Intraoperative Xray showing the retractor in position and the forceps in the pituitary fossa.
Most tumours can be excised via the transsphenoidal approach to the pituitary fossa (Fig. 8.13).
The development of the surgical microscope and fluoroscopic radiography has made this a safe procedure. The sphenoid sinus is usually entered using a unilateral trans-septal approach, with the incision either in the nasal mucosa or sublabially. The mucosa is reflected from the nasal septum and floor and the sphenoid is opened. The anterior wall of the sella is removed and the pituitary fossa entered. Microadenomas (tumours less than 10mm in diameter) may be evident on the surface of the gland or may become evident only once the gland is incised. These tumours can be completely excised, preserving pituitary function. The suprasellar extension of the tumour can be gently coaxed down into the pituitary fossa by slightly raising the intracranial pressure using a Valsalva manoeuvre or by the anaesthetist injecting small increments of nitrous oxide and oxygen mixture into the lumbar theca until the intracranial pressure forces the suprasellar tumour into the operative field. This will also have the additional benefit that the intracranial gas will provide a pneumoencephalogram, outlining the remaining suprasellar extension of tumour.
A transcranial operation is occasionally necessary, particularly where there is a subfrontal or retroclival extension of the tumour.
Postoperative management requires careful attention to the fluid balance and hormonal status. Endocrine deficiency in the immediate postoperative period will require replacement with parenteral hydrocortisone and possibly the use of vasopressin for the treatment of diabetes insipidus, which often occurs at least transiently after the excision of a large pituitary tumour. In the early postoperative period aqueous vaso-pressin (Pitressin ®) should be given by intramuscular or subcutaneous injection and, if the diabetes insipidus persists, by the intranasal route. Other long-term hormonal replacements may include cortisone acetate (12.5–25 mg twice daily), thyroxine and testosterone.
Radiotherapy
Postoperative radiotherapy may be used if there has been a subtotal excision of the tumour or if the postoperative endocrine studies demonstrate residual excessive hormone secretion.
Medical treatment
Treatment of pituitary adenomas is undertaken to restore the endocrine status of the patient by replacement of either the pituitary hormone itself or the hormone of the pituitary-dependent glands. This will be a necessary preoperative procedure in patients with evidence of hypopituitarism and will frequently be necessary after the surgical excision of a macroadenoma. Prolactin-secreting pituitary tumours are treated with bromocriptine, a dopamine agonist. This is the preferred treatment for a symptomatic prolactin- secreting microadenoma and may be used either as the definitive treatment of larger prolactin- secreting tumours or in conjunction with surgery. Some patients show poor tolerance to bromocriptine, as it may cause intractable nausea, vomiting and postural hypotension, and these patients will require surgical treatment of the tumour.
Craniopharyngioma
This tumour may occur at any age, although nearly half occur in the first 20 years of life. They are thought to arise from the epithelial remnants of Rathke’s pouch. The tumours occur in the region of the pituitary fossa and extend through the suprasellar cisterns to the hypothalamus. There are two histological types of tumours. The adamantinous type resembles adamantinoma of the jaw and is encountered in virtually all children. The papillary type, so-called adult craniopharyngioma, occurs in about one-third of adults and is rare in children.
Clinical presentation
Clinical features include:
• raised intracranial pressure
• visual impairment
• endocrine dysfunction.
Raised intracranial pressure
This is common, particularly in children, who present with headache, vomiting and papilloedema.
Visual impairment
This is due to papilloedema, chiasmal compression or a combination of both. Papilloedema is due to hydrocephalus as a result of 3rd ventricular obstruction by the tumour. The visual field defect is frequently similar to that produced by a pituitary tumour, a bitemporal hemianopia, but homonymous defects are more common than in pituitary adenoma.
Endocrine abnormalities
These are frequent in children and consist of:
• hypogonadism
• stunting of growth
• diabetes insipidus.
Endocrine failure due to craniopharyngioma arising in adults is essentially similar to that caused by a pituitary tumour, except that diabetes insipidus occurs more commonly in patients presenting with craniopharyngioma.
Investigations
The CT scan usually shows a cystic tumour in the suprasellar region with calcification (Fig. 8.14). Tumours in adults may be solid and are less calcified than those seen in younger patients. MRI is useful in showing the full extent of the tumour (Fig. 8.15). Changes in the sella turcica are seen in approximately 50% of patients. Suprasellar tumours and the associated hydrocephalus press downwards on the dorsum sellae and anterior clinoids and may enlarge the sella. Nearly 90% of tumours in children have radiographically identifiable calcification in the tumour, whereas only 40% of adults have radiologically demonstrable calcification. The calcification consists of aggregates of small flecks of calcium and may be curvilinear, outlining a portion of the cyst wall.
CT and MRI. Craniopharyngioma.
Treatment
Preoperative visual and endocrine assessment is essential. The standard treatment for craniopharyngioma is operative, with an attempt at maximal resection of the tumour. However, complete resection may not be possible due to the extent of the tumour and the intimate attachment to hypothalamic vital structures. The usual surgical approach is through a pterional craniotomy or a bifrontal craniotomy with separation of the frontal lobes and division of the lamina terminalis. Tumours extending into the 3rd ventricle may also need to be approached through the corpus callosum. An extended transsphenoidal approach is sometimes advised for those tumours extending down to the floor of the pituitary fossa.
Postoperative management will include careful attention to fluid and electrolyte balance as many patients have at least a transient diabetes insipidus following surgery. Other hormones may need replacement depending on endocrinological assessment.
The role of postoperative radiotherapy in patients with a subtotal resection is controversial but radiotherapy may be beneficial in decreasing the production of cyst fluid and delaying recurrence of the tumour.
Empty sella syndrome
The empty sella refers to a communicating extension of the subarachnoid space into the pituitary fossa (Fig. 8.17). This may occur as a result of an incomplete anatomical formation of the diaphragma sellae which allows the arachnoid to herniate directly into the pituitary fossa or as a secondary phenomenon following either pituitary There is good reason to regard the empty sella as an anatomical variant rather than a syndrome. However, defects in the diaphragma are not the only requirement for formation of an empty sella. Increased intracranial pressure associated with benign intracranial hypertension or long-standing hydrocephalus will cause herniation of the subarachnoid space into the sella and will result in the remodelling of the pituitary fossa to produce the classic globular appearance on plain X-ray and CT scan (Fig. 8.18). It is possible that the normal variations in CSF pressure may be transmitted into the fossa through an incompetent diaphragma and so result in the bony changes.
Clinical presentation
Most patients with the radiological features of an empty sella are asymptomatic. The majority of patients presenting with symptoms are obese, middle-aged, hypertensive women. Headache is the most common symptom associated with the empty sella but the features are so varied that their relevance to the intrasellar subarachnoid space is dubious without an underlying cause for possible raised intracranial pressure. Visual field defects and endocrine abnormalities are subtle and uncommon in patients with primary empty sella syndrome. In patients with a secondary empty sella, e.g. following surgery or radiotherapy, field defects may be more pronounced but are rarely severe.
The most serious consequence of an empty sella is spontaneous CSF rhinorrhoea. This usually occurs only if there has been an underlying cause of raised intracranial pressure, such as benign intracranial hypertension. It is managed by repairing the leak in the floor of the sella with crushed muscle and fascia lata and performing a CSF shunt.
