TUMORS OF THE BRAIN

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CHAPTER 98 TUMORS OF THE BRAIN

Tumors of the brain are regarded as one of the most devastating group of neurological diseases—they are associated with significant neurological morbidity, they lead to progressive physical, cognitive and emotional dysfunction and are frequently fatal. The term brain tumor is used to describe both primary tumors that originate from the brain, cranial nerves, pituitary gland. or meninges and secondary tumors (metastases) that arise from organs outside the nervous system. These tumors present in many different ways dependent on their location, their rate of growth, and their effect on healthy neural tissue. Diagnosis requires careful history and examination, imaging, and histological examination, and management is best determined in a multidisciplinary team environment comprising neurologists, neurosurgeons, oncologists, neuropathologists, neuroradiologists, and clinical nurse specialists.

Despite the dramatic advances in neurosurgical technology, imaging, neuroanesthesia, radiotherapy techniques, and new drug development, the prognosis for many brain tumors, particularly malignant gliomas, remains bleak. The lack of a “cure” for the majority of these patients requires increasing emphasis on quality of life issues, and assessment of these is a standard feature of modern brain tumor trials.

This chapter aims to cover the key points required to manage patients with brain tumors effectively and sensitively, with specific emphasis on diagnostic and treatment considerations.

EPIDEMIOLOGY

Intracranial tumors are the eighth most common neoplasm in adults (approximately 5% of all primary neoplasms) and the most common solid tumor in children. They are the second leading cause of death from neurological disease in the United Kingdom (second only to stroke) and account for 2% of all cancer deaths in adults.

The incidence of primary brain tumors is considerably higher than tumor registry figures suggest. Based on a study from the southwest of England ascertaining data mainly from radiology records, the crude annual incidence for primary tumors was found to be 21 in 100,000.¹ The annual incidence in the United States as ascertained from the Central Brain Tumor Registry is lower at 6.7 in 100,000 persons.² There is increasing evidence that the incidence of gliomas and lymphomas is increasing, particularly in elderly patients, although this is more likely to be due to increased case ascertainment, with the increasing availability of modern imaging techniques.³

Brain tumors can present at any age. In children, they are the most common solid tumor and mainly occur in the posterior fossa, such as medulloblastoma, ependymoma, and juvenile pilocytic astrocytoma. In contrast, adults more commonly present with supratentorial tumors, particularly gliomas and meningiomas, accounting for over 75% of brain tumors. The most frequent tumors of middle life (third and fourth decades) are astrocytomas, meningiomas, pituitary adenomas, and vestibular schwannomas, whereas glioblastoma multiforme and metastases are more frequent in the fifth and six decades of life. There is a strong female preponderance of meningiomas, particularly in the spinal canal, whereas gliomas occur slightly more frequently in men. Germ cell tumors, particularly of the pineal region, occur frequently in adolescent males.

ETIOLOGY

Numerous epidemiological studies have been carried out to investigate etiological factors, but no clear risk factors have emerged apart from therapeutic ionizing irradiation. Cranial radiotherapy, even at low doses, has been shown to increase the relative risk of meningiomas by a factor of 10 and gliomas by a factor of 3.⁴ Other radiotherapy-induced tumors include cranial osteosarcomas, soft tissue sarcomas, schwannomas, and peripheral nerve sheath tumors. They have been described following radiotherapy for tinea capitis, craniopharyngioma, and pituitary adenomas and prophylactic cranial irradiation for acute lymphoblastic leukemia. Second tumors tend to lie within the radiation field, usually in lower dose regions, and develop from a few years to many decades after irradiation. The reported median time to the development of gliomas is 7 years. Sarcomas develop with a longer lag time and meningiomas may be seen 30 or 40 years later. The histology is identical to spontaneous tumors, although meningiomas are more likely to contain atypical features and have a worse prognosis.

No other environmental exposure has been clearly identified as a risk factor. There is widespread concern about the possible risks of cellular telephones, but case-control studies have not shown any increased risk in respect of any subtype of brain tumor using measures of the type of telephone, duration and frequency of use, and cumulative hours of use.⁵ So far, the consensus of opinion based on four studies is that mobile telephone use does not increase the risk of developing a brain tumor. However, with the exponential increase in the ownership and duration of use of these hand-held devices, it is important to continue surveillance of brain tumor trends in order to detect a latent period of several decades for the development of a tumor.

Genetic causes of brain tumors are rare but important. Occasionally, brain tumors occur in successive generations without any other tumor predisposition. More commonly, they are associated with neurocutaneous syndromes such as neurofibromatosis (optic nerve glioma, meningioma, vestibular schwannoma) and tuberose sclerosis (subependymal giant cell astrocytoma), von Hippel-Lindau syndrome (hemangioblastoma), and familial tumor syndromes such as Li-Fraumeni syndrome (glioma) and Cowden disease (dysplastic cerebellar gangliocytoma or Lhermitte-Duclos disease).

PATHOGENESIS

Brain tumors arise from an accumulation of mutations in genes that normally regulate the pathways of cell proliferation and differentiation. As in all human cancers, oncogenes and tumor suppressor genes are involved in the pathogenesis of brain tumors. One of the more frequent aberrations in human cancers are deletions or mutations of the TP53 gene, located on chromosome 17p, which encodes a 53-kDa protein, p53. These are found in approximately 40% of astrocytic tumors. This protein influences multiple aspects of cell cycle control as well as DNA repair after radiation damage and the induction of apoptosis. Other important genetic aberrations seen in malignant gliomas include amplification and mutations of the epidermal growth factor receptor (EGFR) gene and deletions and mutations of PTEN (phosphatase and tensin homology). Studies of astrocytic tumors show that the accumulation of predictable genetic alterations is associated with increasing malignant progression.

The mammalian cell cycle is divided into four phases: G₁, S, G₂, and M. Unrestricted cell multiplication is one of the hallmarks of cancer and is controlled in the normal cell by a complex series of positive and negative regulators that constitute the cell cycle checkpoints. Important proteins involved in these checkpoints include p53, MDM2, p14^ARF, and p21, which regulate the progression of cells through the G₁ cell cycle phase. Disruption of these protein complexes by gene deletions or mutations is found in varying proportions of gliomas, such as MDM2 gene amplification (in 10% to 15% of anaplastic astrocytomas) and glioblastoma multiformes lacking TP53 mutations. MDM2 is a cellular protein, which binds to and inactivates p53 and thus acts as an oncogene promoting glioma growth.

Taken overall, the various gene mutations mentioned above can all lead to a slight growth advantage, which can be further amplified by a gradual accumulation of further mutations, particularly when associated with loss of heterozygosity of the other allele. Current theories of malignant transformation postulate that this process is a sequence of multiple genetic alterations, each of which contributes to some expression of the tumor’s malignant characteristics. The various cellular pathways involved in proliferation, growth control, apoptosis, DNA repair, and genomic stability may differ from one tumor to another, but the phenotypes of the resulting tumors are similar.

CLINICAL FEATURES

Brain tumors can present in many different ways, and with the increased accessibility to high quality neuroimaging, they are being detected at a much earlier stage of their natural history than was the case previously. In some respects, this has made management decisions more difficult, particularly when a tumor is found that is in an inoperable location and is causing very few symptoms. Asymptomatic tumors are sometimes detected when patients are scanned for unrelated conditions and in many cases may be left alone.

The symptoms of brain tumors can be either focal or generalized and are most conveniently classified into five clinical syndromes that may coexist in the same patient or be present at different stages of the disease course:

1. Raised intracranial pressure

2. Progressive focal or cranial nerve deficit

3. Seizure disorder

4. Cognitive/behavioral changes

5. Endocrine disorders (hypersecretion or hyposecretion of the hypothalamic-pituitary axis)

The precise combination of clinical features varies on the location, histology, and rate of growth of the tumor. For instance, a patient with a low-grade glioma typically presents with a seizure disorder that may remain static for many years, whereas a patient with a malignant glioma may present with a rapidly progressive neurological deficit and raised intracranial pressure and be dead within a few weeks.

Raised Intracranial Pressure

As a brain tumor grows, there is displacement of cerebrospinal fluid into the spinal compartment and a reduction of blood volume. Eventually, the intracranial pressure rises because the skull behaves as a rigid box. Headache is the most common symptom of brain tumors, occurring in 23% of patients at initial presentation and 46% by the time of hospital admission. Headache alone, however, is an extremely rare presenting symptom, occurring in only 1.9% of patients.⁶ Because headache is such a common symptom in the population as a whole, it accounts for a disproportionate number of referrals of patients to neurology clinics concerned about the possibility of a brain tumor. Most brain tumor headaches are intermittent and nonspecific and may be indistinguishable from tension headaches.⁷ They may occasionally indicate the side of the tumor. Certain features of a headache are suggestive but not pathognomic of raised intracranial pressure. These include headaches that wake the patient at night or are worse on waking and improve shortly after rising, as well as headache associated with visual obscurations (transient fogging associated with changes in posture). Supratentorial tumors typically produce frontal headaches, whereas posterior fossa tumors usually result in occipital headache or neck pain. Nausea and vomiting may be a feature of raised pressure but may also occur as an early symptom of fourth ventricular tumors.

Brain tumors cause increased intracranial pressure by a variety of different mechanisms. They may have grown so large in a relatively short space of time that they cause stretching of pain-sensitive intracranial structures by a direct mass effect or by an effect on the microvasculature leading to cerebral edema. Smaller tumors, particularly those located in the posterior fossa, may cause headaches by obstructing cerebrospinal fluid circulation and producing obstructive hydrocephalus. Tumors may also cause raised intracranial pressure by producing large cysts. Occasionally, meningeal-based tumors cause localized headache through stretching of overlying dura. As a general rule, headaches with migrainous features are rarely due to an underlying tumor, although occasionally occipital tumors produce occipital seizures that are similar in many respects to migraine.

Untreated intracranial pressure leads to gradual deterioration in cognition, intermittent drowsiness, and eventually coma. Brainstem compression is the usual mode of death in patients with progressive brain herniation. The exact structures that are involved depend on the type of herniation—the most common types are uncal herniation, where the medial temporal lobe herniates across the tentorium, giving rise to an ipsilateral third nerve palsy, and tonsillar herniation, where the cerebellar tonsils are pushed down into the foramen magnum, leading to coma and death.

Progressive Neurological and Cranial Nerve Deficits

Focal neurological symptoms due to brain tumor are typically subacute and progressive with over 50% of patients having focal signs by the time of diagnosis. However, they may present acutely with strokelike symptoms, particularly if there is intratumoral hemorrhage, or even as a reversible event similar to a transient ischemic attack. Cortical tumors produce contralateral weakness, sensory loss, dysphasia, dyspraxia, and visual field loss depending on their location. A progressive hemianopia is often not detected by the patient, who may simply complain of bumping into objects or having a number of unexplained scrapes with parked vehicles or other stationary objects. Nondominant parietal tumors may present with topographical disorientation. Posterior fossa tumors cause gait ataxia, usually associated with headache and vomiting, whereas tumors in the cerebellopontine angle present with progressive unilateral deafness followed by ipsilateral facial sensory loss. Tumors in the fourth ventricle may present with effortless vomiting without nausea, a symptom that may predate more classic “posterior fossa” symptoms by many months or even years. Pituitary tumors compressing the optic chiasm cause a bitemporal quadrantanopia progressing onto hemianopia or pituitary apoplexy if there is hemorrhage or infarction. Subfrontal meningiomas may present with anosmia due to compression of the olfactory nerves in the anterior cranial fossa but may grow to a large size before clinical symptoms become apparent.

Seizure Disorder

Brain tumors account for about 5% of epilepsy cases, although they are overrepresented in cases of intractable epilepsy. Seizures are the presenting symptom in 25% to 30% of patients with gliomas and are present at some stage of the illness in 40% to 60% of patients. Approximately one half the patients have focal seizures, and the other one half have secondarily generalized seizures. Seizures occur in over 90% of cases of low-grade gliomas and frequently remain the only complaint for many years. Conversely, malignant gliomas have a lower frequency of seizures presumably because of their more rapid growth and destructive characteristics. Seizures are also common presenting symptoms for meningiomas (40% to 60%) and metastases (15% to 20%).

Temporal and frontal tumors are more likely to cause seizures than are occipital or parietal tumors, particularly when cortically based. The characteristics of the seizure depend on the location of the tumor. Frontal lobe tumors cause typically brief, frequent, and nocturnal seizures, which tend to spread rapidly and may become generalized. Common manifestations of a frontal lobe seizure include bicycling movements of the legs at night, turning of the head and eyes to the side away from the tumor (frontal adversive seizure), speech arrest, and hemiclonic spasms with a jacksonian march (posterior frontal tumors) in clear consciousness. In contrast, mesial temporal tumors can begin with olfactory or gustatory hallucinations, an epigastric rising sensation, or psychic experiences such as déjà vu or depersonalization. Once the seizures progress to a loss of awareness, the patients may stare blankly, speak unintelligibly, or exhibit lip smacking, picking at clothing, or other automatisms. Secondary generalized tonic-clonic seizures may follow on from partial seizures, more frequently in untreated patients. The presence of seizures is a favorable prognostic factor for survival, possibly due to lead-time bias in diagnosis and possibly due to the slow growth of epileptogenic tumors compared with more high-grade destructive tumors. In a study of patients with low-grade astrocytomas, the 5-year survival for patients with epilepsy as the only sign of tumor was 63% compared with 27% among the whole group.⁸

Mental State Changes

These are an uncommon presentation of brain tumors occurring in about 20% of patients at diagnosis. Personality changes may be quite subtle initially and may present as an inability to cope at work. In these cases, it is essential to obtain a collateral history from relatives or colleagues at work. Subfrontal meningiomas may present as loss of interest and motivation by virtue of their slow growth in a noneloquent region and may be mistaken for depression or early dementia. Often, personality changes are evident in retrospect and are more commonly noted by the patient’s family than by the patient.

Endocrine Syndromes

A detailed review of endocrine syndromes associated with pituitary tumors is beyond the scope of this chapter. Tumors may present with hormonal disturbances due either to hypersecretion of pituitary hormones (e.g., amenorrhea, acromegaly, galactorrhea) or hyposecretion (e.g., hypopituitarism).

DIAGNOSIS

The diagnosis of a brain tumor is made by a combination of contrast-enhanced computed tomography scanning/magnetic resonance imaging and pathological classification of either a biopsy or resection specimen. Over the past decade or so, there have been a number of newer techniques introduced to complement conventional structural imaging, including proton magnetic resonance spectroscopy, functional metabolic imaging (single photon and positron emission tomography), and advanced magnetic resonance techniques, such as perfusion imaging (measuring blood flow and blood volume), diffusion weighted imaging (measuring cellularity), and diffusion tensor imaging (assessing integrity of white matter pathways). These are being gradually integrated into the routine preoperative evaluation of a brain tumor but add little to the conventional sequences in terms of refining diagnostic certainty.⁹

Just as there is clinicopathological correlation between World Health Organization (WHO) grade and prognosis, there is also a radiological/pathological correlation, specifically with respect to the degree of contrast enhancement seen within the tumor. Most grade II gliomas do not enhance, unlike grades III and IV, where there is usually irregular ring enhancement and, in the case of grade IV tumors, central necrosis. However, as mentioned, certain grade I gliomas, particularly juvenile pilocytic astrocytomas, also enhance, and this can occasionally give rise to diagnostic confusion, particularly in adults, in whom juvenile pilocytic astrocytomas are much less common than malignant gliomas. The key imaging characteristics of common types of tumors are summarized in Table 98-1; see also Figure 98-3 for radiological/pathological correlations.

TABLE 98-1 Imaging Characteristics of Common Brain Tumors

Figure 98-3 Radiological and pathological correlations of common central nervous system tumors. Each row of figures shows imaging appearances (magnetic resonance imaging or computed tomography) (left), macroscopic aspect on formalin fixed postmortem brains with a tumor at similar locations (center), and representative histological sections (right), stained with hematoxylin and eosin, which stains nuclei dark blue and cytoplasm and extracellular matrix pink.

Low-grade astrocytoma: Magnetic resonance imaging (T1-weighted with contrast) shows involvement of the temporal and frontal lobes and considerable mass effect with midline shift. Gross section of a brain with a similar tumor shows effacement of cortical structures, basal ganglia, and midline shift. Histology shows a tumor with low density of tumor cells, ample fibrillary background, and thin vessels.

Glioblastoma multiforme: magnetic resonance imaging (T1-weighted with contrast) shows ring enhancement indicating neovascularization and vascular permeability as well as central necrosis. The brain section shows a hemorrhagic tumor in the left temporal and frontal lobes. There is considerable midline shift and hemorrhage in the corpus callosum and fornix, indicating tumor extension over the midline. Histologically, the tumor is characterized by a very high density of cells (dark nuclei with sparse cytoplasm), and a typical feature is necrosis with pseudopallsading arrangement of tumor cells.

Oligodendroglioma: magnetic resonance imaging (coronal FLAIR sequence) shows involvement of parietal cortex and subcortical white matter with expansion of the tumor outside of the brain and erosion of the inner skull table. A brain section of a similar tumor shows a relatively well-demarcated cystic, partially hemorrhagic space occupying lesion. Classic histological features of oligodendroglioma are cells with clear appearance (“fried-egg” cells), central nuclei, and a network of thin, branching vessels (not shown).

Medulloblastoma: computed tomography scan with contrast shows an enhancing midline mass lesion arising from the cerebellar hemisphere. Note the hydrocephalus as a result from compression of the fourth ventricle. A sagittal section shows a large tumor in the posterior fossa that displaces the cerebellar vermis and compresses the brainstem. Typical histological features are wedge-shaped nuclei that are arranged to rosettes with neuropil-like matrix in their center.

Meningioma: computed tomography scan with contrast shows a typical strongly enhancing tumor that is dural based. Meningiomas are often associated with considerable edema, and in this case, there is very significant displacement of brain tissue, which becomes symptomatic relatively late, due to the slow growth of these tumors. Postmortem finding of an asymptomatic meningioma impressing the temporal lobe in situ (upper section) and after (lower section) removal, leaving a cavity. Histologically, meningiomas show variable features. A typical feature shown here is the concentric arrangement of tumor cells, which can become calcified.

(Courtesy of Professor Sebastian Brandner.)

PATHOLOGY

There are over 160 types of primary brain tumors arising from neuroepithelial tissue within the brain, the meninges covering the brain, the sellar region, and the cranial nerves.

The WHO published a landmark classification in 1993 and, in 2000, further refined their classification system (Table 98-2).¹⁰ The key to the WHO classification is the stratification of tumors according to their biological activity so that the lower the WHO grade, the better the overall prognosis. As a general rule, the category of grade I tumors is reserved for neoplasms that have a stable histology and that are potentially curable by surgical removal alone. In contrast, tumors that appear histologically “benign,” yet are known to progressively transform over time into higher grade lesions, are categorized as grade II neoplasms. Those tumors with anaplastic histology are regarded as grade III high-grade neoplasms, and the most malignant phenotype is classified as grade IV. The peak of age of incidence is proportional to the most common histological grade; that is, grade I tumors usually present in childhood, grade II in young adulthood, grade III in middle age, and grade IV in older age. The exception to this rule is the grade IV primitive neuroectodermal tumors, which occur most frequently in childhood.

TABLE 98-2 World Health Organization Classification and Grading of Tumors of the Nervous System

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Tumors of Neuroepithelial Tissue	WHO Grade
Astrocytic tumors
Pilocytic astrocytoma	I
Pleomorphic xanthoastrocytoma	I, II
Subependymal giant cell astrocytoma	I
Desmoplastic infantile astrocytoma	I
Diffuse astrocytoma	II
Anaplastic astrocytoma	III
Glioblastoma multiforme	IV
Gliosarcoma	IV
Oligodendroglial tumors
Oligodendroglioma	II
Anaplastic oligodendroglioma	III
Mixed astrocytic and oligodendroglial tumors
Oligoastrocytoma	II
Anaplastic oligoastrocytomas	III
Ependymal tumors
Subependymoma	I
Myxopapillary ependymoma	I
Ependymoma	II
Anaplastic ependymoma	III
Choroid plexus tumors
Choroid plexus papilloma	I
Choroid plexus carcinoma	IV
Neuronal and mixed neuronal-glial tumors
Gangliocytoma	I
Ganglioglioma	I, II
Desmoplastic infantile ganglioglioma	I
Dysembryoplastic neuroepithelial tumor	I
Central neurocytoma	I
Pineal parenchymal tumors
Pineocytoma	I
Pineoblastoma	IV
Embryonal tumors
Primitive neuroectodermal tumors	IV
Medulloblastoma	IV
Meningeal tumors
Meningioma	I
Atypical meningioma	II
Anaplastic meningioma	III
Hemangiopericytoma
Melanocytic tumor of the meninges
Tumors of vascular origin
Cavernous angioma
Hemangioblastoma
Germ cell tumors
Germinoma
Embryonal carcinoma
Yolk sac tumor (endodermal sinus tumor)
Choriocarcinoma
Teratoma
Tumors of the sellar region
Pituitary adenoma
Pituitary carcinoma
Craniopharyngioma
Primary central nervous system lymphomas
Peripheral nerve sheath tumors
Vestibular schwannoma
Trigeminal schwannoma
Facial nerve schwannoma