Primary Brain Tumors

Primary brain tumors arise within the brain or spinal cord tissue (parenchyma) or their coverings (meninges) (Box 19-1). Pathologists have named them after their original cell line. The numerous, mostly small, glial cells, which normally provide the structural, biochemical, and immunologic support for the central nervous system (CNS), give rise to most tumors – gliomas. These tumors arise within the substance of the brain, i.e., in intraparenchymal or intra-axial locations. Meningeal cells give rise to the other large category of brain tumors, meningiomas. Because these tumors arise from the coverings of the CNS, rather than from actual brain or spinal cord tissue, they grow outside the brain, i.e., in extraparenchymal (extra-axial) locations. In contrast, CNS neurons rarely form tumors in adults.

Of the various potential etiologies of primary brain tumors, studies have established that only ionizing radiation, certain neurocutaneous disorders (see Chapter 13), and various genetic mutations constitute risk factors. So far, data have not proven that cellphone use constitutes a risk factor.

Gliomas

Parenchymal tumors, gliomas, include oligodendrogliomas and astrocytomas. Oligodendrocytes, which normally produce the myelin covering that insulates CNS neurons,* may give rise to oligodendrogliomas. These tumors, which occur infrequently and grow slowly, produce similar manifestations to the more commonly occurring astrocytomas (see later).

Astrocytomas, which arise from astrocytes, strike children as well as adults. They do not invade surrounding tissue when they are low-grade, but originate anywhere in the CNS. They are the most common tumor in children. In children, relatively benign astrocytomas grow into cystic, noninvasive tumors in the cerebellum. Because neurosurgeons can readily remove an entire cerebellar astrocytoma without causing appreciable sequelae, the cure rate approaches 90% of this variety of tumor in children. However, in children, astrocytomas may arise in the brainstem, where they invade cranial nerve nuclei and long tracks. Brainstem astrocytomas tend to be highly malignant and not amenable to surgery.

For adults, astrocytomas occur predominantly in the cerebrum, infiltrate extensively, and often degenerate into glioblastomas. Total surgical removal is practical only when the surrounding brain can be sacrificed. For low-grade astrocytomas, combined surgery and radiotherapy prolong life for approximately 10 years.

Glioblastomas, the most malignant variety of astrocytoma, are the most frequently occurring brain tumor. They develop almost exclusively in the cerebrum. The prognosis is grim. These tumors not only grow rapidly and relentlessly, they infiltrate widely. Frontal lobe gliomas frequently cross the corpus callosum to produce the infamous “butterfly glioma” (Figs 19-1, A, 20-8, and 20-20). Contrary to many physicians’ expectations that brain tumors, like most other cancers, arise in the elderly, the age of patients at the time of a glioblastoma diagnosis averages only 54 years.

FIGURE 19-1 A, A glioblastoma – the most malignant form of glioma – typically infiltrates along white-matter tracts. Sometimes it spreads through the heavily myelinated corpus callosum in a “butterfly” pattern (see Figs 20-8 and 20-20). B, Meningiomas arise from the meninges overlying the brain or spinal cord and grow slowly (see Fig. 20-10). They compress and irritate, but do not infiltrate, the central nervous system. C, Metastatic tumors, usually multiple and surrounded by edema, destroy large areas of brain and raise intracranial pressure (see Fig. 20-8). D, A subdural hematoma, typically located over one cerebral hemisphere (see Fig. 20-9), compresses the underlying brain and ventricles, and pushes away (shifts) midline structures. Large, acute, rapidly expanding subdural hematomas force the brainstem and ipsilateral oculomotor (third cranial) nerve through the tentorial notch. Such transtentorial herniation, which occurs with epidural as well as subdural hematomas (see Chapter 22), constitutes an immediately life-threatening condition. In contrast, small meningiomas and chronic subdural hematomas cause relatively few symptoms because they are extra-axial and exert little mass effect.

Radiotherapy, steroids, and chemotherapy may slow glioblastomas’ growth rate and provide a brief, physically comfortable period. Surgical excision rarely eliminates these tumors. In fact, many patients, especially the elderly and those with pronounced neurologic deficits, gain little from treatment. Glioblastoma patients survive for only about 15 months. Moreover, persistence of the tumor and side effects of treatment often produce progressive cognitive and emotional deterioration.

Metastatic Tumors

Systemic tumors metastasize to the brain and spinal cord by hematogenous routes. They cannot spread through a lymphatic system because the brain, unlike almost all other organs, does not have one. Metastatic tumors tend to be multiple, surrounded by edema, and rapidly growing. Although individual tumors may each be small, their combined mass constitutes an oppressive intracerebral burden (see Figs 19-1, C and 20-8).

Cancer of the lung, breast, kidney, and skin (malignant melanomas) most often give rise to cerebral metastases. In contrast, because the portal vein diverts metastases to the liver, gastrointestinal, pelvic, and prostatic cancers spread to the brain rarely or only late in their course.

Approximately 15% of all cancer patients initially have symptoms of cerebral metastases; however, as treatment drives systemic tumors into long remissions, cerebral metastases, which usually do not respond to therapy, cause symptoms in a greater proportion of patients. Metastases resist systemic chemotherapy because the blood–brain barrier ironically blocks most medications from attacking them. Moreover, chemotherapy and radiotherapy have relatively little effect against metastatic tumors because, compared to the primary tumor, they are poorly differentiated. On the other hand, the discovery of a metastatic brain tumor is occasionally the first indication that a person has cancer.

Whatever the origin of cerebral metastases, conventional treatments, such as steroids and radiotherapy, provide palliative care. Stereotactic radiosurgery, which consists of a cobalt device, linear accelerator, or a cyclotron delivering a highly focused beam of radiation to metastases, alone or in conjunction with whole-brain radiation, usually shrinks the tumors. In cases involving a single metastasis, surgeons can help the patient, at least temporarily, by removing it. Nevertheless, most patients with metastatic brain tumors survive less than 9 months.

Local Signs

By damaging surrounding tissue, brain tumors usually produce lateralized neurologic deficits, often called “local signs,” such as hemiparesis and dominant- or nondominant-hemisphere neuropsychologic disorders (see Chapter 8). Tumors arising in “eloquent” regions – cerebral cortex areas critical to motor or neuropsychologic function, such as Broca’s or Wernicke’s areas – produce obvious impairments. Tumors that are small, slowly growing, or located in “silent” regions of the brain, such as the right frontal lobe or either of the anterior temporal lobes, notoriously fail to produce symptoms. Tumors that arise from cranial nerves, although rare, almost immediately result in readily recognizable deficits. For example, optic nerve gliomas cause visual loss, and acoustic neuromas cause unilateral progressive hearing loss and tinnitus (see later).

Seizures in individuals older than 60 years are frequently the presenting feature of cerebral tumors. However, because strokes cause seizures nearly as often as tumors, a 60-year-old individual presenting with the first seizure is approximately equally likely to have sustained a stroke as have developed a brain tumor. When the etiology is either a brain tumor or stroke, seizures typically begin as a partial seizure that undergoes secondary generalization (see Chapter 10).

A brain tumor’s tendency to cause seizures also pertains to electroconvulsive therapy (ECT). For example, if a patient harboring a brain tumor were to undergo ECT, the procedure might give rise to multiple, uninterrupted, life-threatening seizures (status epilepticus). However, the benefits of ECT might outweigh the risks if the tumor were small enough not to cause neurologic deficits or surrounding cerebral edema. Large brain tumors, on the other hand, constitute an unequivocal problem regarding ECT. Not only might large brain tumors account for depressive symptoms, but also they might precipitate transtentorial herniation during ECT (Fig. 19-1, D). Thus, before their patients undergo ECT, neurologists order either an MRI or CT.

Signs of Increased Intracranial Pressure

In addition to damaging brain tissue, tumors may raise intracranial pressure through many mechanisms. They grow rapidly, constitute a large volume, accumulate surrounding edema, obstruct the flow of cerebrospinal fluid (CSF) through the ventricles, or impede CSF reabsorption through the arachnoid villi. Whatever the cause, increased pressure (pressures exceeding 200 mm H₂O) creates symptoms and signs that may add to or supersede local ones.

Headache, while the most common symptom of increased intracranial pressure, still occurs in only one-half of patients. Although brain-tumor-induced headache lacks distinctive features, it usually resembles tension-type headache because it consists of diffuse, dull, relatively mild pain that initially responds to mild analgesics, including aspirin. Sometimes, a predominantly localized or unilateral headache points to a tumor’s location and mimics migraine. In any case, as pressure rises, headaches worsen, especially in the early-morning hours, and begin to awaken patients from sleep. Increasing intracranial pressure eventually produces nausea and vomiting, as well as increasing intense headache.

Despite the statistic that fewer than 1 out of 1000 people with headache harbors a brain tumor, both patient and physician frequently have great concerns – spoken or unspoken – that any headache may indicate a brain tumor. These concerns sometimes thwart diagnosis of a less threatening disorder, such as migraine or depression. Neurologists, dispensing with lengthy explanations or reassurances, often simply order a CT or MRI to exclude a tumor and move on with their evaluation and treatment plan.

Another sign of increased intracranial pressure, papilledema, occurs as pressure is transmitted along the optic nerve to the optic disks (Fig. 19-2). Although papilledema has a notorious association with brain tumors, it occurs late, if at all, in their course. In fact, among young adults, especially overweight females with menstrual irregularity, idiopathic intracranial hypertension (pseudotumor cerebri) is much more likely than a brain tumor to explain papilledema (see Chapter 9). In general, because only a small proportion of brain tumor patients have papilledema during an initial examination, its absence should not be taken as evidence against the presence of a brain tumor.

FIGURE 19-2 Papilledema’s main features consist of reddening of the optic disk, which loses its distinct margin, and distension of the retinal veins. In addition, the disk is elevated and hemorrhages appear at its edge. (Compare this disk to the normal optic disk in Figure 4-4.)

In considering manifestations of brain tumors, meningiomas constitute a special category. Unlike gliomas, as discussed previously, small meningiomas are common and usually small. Even large ones may remain asymptomatic. Also, they arise and usually remain entirely in extra-axial locations and produce characteristic syndromes. For example, a meningioma arising from the falx, a parasagittal meningioma, can compress the medial motor cortex and cause spastic paresis of one or both legs. A meningioma arising from the sphenoid wing can damage the adjacent temporal lobe and, because of its proximity to the orbit, cause proptosis and paresis of eye movement. Likewise, an olfactory groove meningioma can compress the adjacent olfactory and optic nerves and the overlying frontal lobe (see Foster–Kennedy syndrome, Chapter 4), causing anosmia, unilateral blindness, and, when large, frontal lobe dysfunction (see Chapter 7).

Direct Effects of Tumors

As a preliminary practical point, most rapidly evolving tumor-related cognitive impairments or personality changes result from a glioblastoma. Another point is that tumors in the frontal lobe produce “frontal lobe personality changes,” consisting of psychomotor retardation, emotional dulling, loss of initiative, poor insight, and reduced capacity to execute complex mental tasks. This clinical picture, like the clinical picture of frontotemporal dementia (see Chapter 7), consists of disturbances in behavior and affect that overshadow cognitive impairments, and those disturbances in turn overshadow physical impairments.

In a somewhat opposite effect, frontal lobe tumors sometimes impair normal inhibitory systems. Patients with lack of inhibition (disinhibition) may overreact to an irritation, liberally use profanities, cry with little provocation, jump excitedly from topic to topic, and speak without tolerating interruptions. By way of contrast, parietal or occipital lobe, as well as right-sided far anterior frontal, tumors, unless they cause increased intracranial pressure, have relatively little effect on mood or cognitive function.

Overall, with numerous potential causes, depression is a frequent comorbidity of brain tumor. Depressive symptoms not only arise soon after diagnosis, but they increase in prevalence and severity during the ensuing illness, and predict a poor quality of life.

In brain tumor cases, a psychiatrist might attempt to determine the patient’s mood, cognitive capacity, neurologic deficits, and iatrogenic factors. With no standard guidelines for prescribing antidepressants or other psychotropics, psychiatrists must approach each situation entirely on an individual basis. In addition to prescribing a psychotropic and precluding ECT, psychiatrists might offer advice on alterations in mental status, guide pain management, assist in appointing a health care proxy, and help with decisions about end-of-life care.

Cerebellar Degeneration

The most well-established paraneoplastic syndrome consists of a subacute, generalized cerebellar degeneration associated with an underlying neoplasm. A gynecologic cancer, lymphoma, or, most often, small cell tumor of the lung usually incites the syndrome. In fact, cerebellar degeneration and other paraneoplastic syndromes complicate 1–3% of cases of small cell lung cancer. In this syndrome, blood tests reveal antineuronal antibodies, such as anti-Hu and anti-Cv2 antibodies, directed against the relevant CNS neurons.

Paraneoplastic Limbic Encephalitis

Limbic encephalitis, as a paraneoplastic phenomenon, results from an antibody-mediated limbic system inflammation. As its clinical hallmark, over several days to several weeks, individuals develop pronounced memory impairment (amnesia), often accompanied by irritability and behavioral disturbances. In addition, the temporal lobe inflammation causes partial complex seizures. Limbic encephalitis often heralds small cell carcinoma of the lung or testicular cancer, but it may also be a manifestation of occult, nonmalignant disorders.

Whatever the underlying disorder, neurologic tests usually reflect temporal lobe abnormalities. MRIs may show atrophy of the mesial temporal lobes and electroencephalograms (EEGs) show spikes or slow waves emanating from the temporal lobes. Serum often contains anti-VGKC, anti-Hu, anti-Ma2, or other antibodies that react with limbic system neurons.

Anti-NMDA Receptor Encephalitis

Anti-NMDA receptor encephalitis, which results from antibodies directed against NMDA receptors, is a variety of paraneoplastic limbic encephalitis. It typically presents, like other forms of limbic encephalitis, with several days of progressively severe amnesia and behavioral disturbances. Then psychosis, seizures, involuntary movements, and autonomic instability often occur and eclipse the prodrome. This disorder typically occurs in young adults, especially young women. Neurologists might initially suspect – in decreasing order of probability – herpes simplex encephalitis, bacterial meningitis, phencyclidine (PCP) or other illicit drug intoxication, an anti-VGKC antibody paraneoplastic syndrome, and variant Creutzfeldt–Jakob – or an acute psychosis.

In most cases the MRI initially shows no abnormalities; however, the CSF shows a lymphocytic pleocytosis. The CSF and serum contain antibodies to NMDA receptors. The antibody concentration, greater in the serum than CSF, roughly correlates with the severity of the illness. The CSF also contains oligoclonal bands, as it does in the CSF of cases of multiple sclerosis and other CNS inflammatory illnesses.

The classic example of anti-NMDA receptor encephalitis consists of amnesia with mood change and depersonalization, involuntary movements, and eventually seizures in a young woman found to be harboring an ovarian teratoma. Overall, almost 50% of young adult women with this disorder harbor an ovarian teratoma, which presumably has triggered an antibody response to its neural tissue.

Lambert–Eaton Myasthenic Syndrome

In LEMS, small cell lung cancer provokes antibodies directed against the presynaptic side of the neuromuscular junction where they impair release of acetylcholine (ACh) (see Chapter 6). The antibody-induced neuromuscular junction dysfunction in LEMS causes proximal limb muscle weakness, which patients partly overcome with repetitive actions. Their weakness has different qualities and different distribution than myasthenia gravis – the well-known disorder of the ACh receptors on the postsynaptic side of the neuromuscular junction. Patients with myasthenia primarily have facial and extraocular muscle weakness that worsens on exertion. Antibody tests and electromyograms readily distinguish these two neuromuscular junction disorders.

Pituitary Adenomas

Although clinicians often view pituitary adenomas as brain tumors, their symptoms, histology, and treatment differ considerably from those of glioblastomas, astrocytomas, and meningiomas. In classic studies, the usual manifestations of pituitary adenomas included profound mental, physical, and visual loss; however, those studies reported on patients whose symptoms resulted from large pituitary tumors that produced extraordinary levels of hormones, expanded out of the sella to encroach on the adjacent temporal lobes and optic chiasm, and obstructed the flow of CSF through the third ventricle. Physicians now routinely diagnose pituitary adenomas early in their course, while they remain microscopic in size, by using MRI and blood tests for hormone levels.

In both men and women, prolactinomas produce infertility, decreased libido, headache, and eventually characteristic visual field deficits. Additionally, in women, they produce amenorrhea and galactorrhea, and in men, erectile dysfunction and gynecomastia. Because their loss of libido encompasses the nonsexual as well as sexual aspects of their lives, patients with pituitary adenomas may appear depressed or cognitively impaired.

Most pituitary adenomas are either prolactinomas, which secrete prolactin, or chromophobe adenomas, which do not. Although prolactinomas usually remain microscopic, they sometimes grow larger than 10 mm, in which case neurologists consider them macroadenomas. Pituitary adenomas of that size may exert pressure on surrounding structures (Fig. 19-4). Their upward pressure on the diaphragm sellae usually causes bitemporal and generalized headache. Compressing the optic chiasm, which is above the diaphragm, causes the visual field deficits. Initially they cause bitemporal superior quadrantanopia and, with further enlargement, bitemporal hemianopsia (see Fig. 12-9).

FIGURE 19-4 Pituitary adenomas grow laterally and inferiorly against the walls of the sella turcica and upward against the diaphragm sellae. Large adenomas compress the optic chiasm, which causes a distinctive bitemporal hemianopsia or bitemporal superior quadrantanopia (see Fig. 12-9).

MRI reveals almost all pituitary adenomas. Serum prolactin level determination usually shows elevations with prolactinomas and some chromophobe adenomas. Visual field testing helps detect those that have expanded out of the sella. Treatment varies with tumor type and size, presence of visual deficit, and institutional expertise, but the usual options include radiation, transsphenoidal microsurgery, and, with prolactin-secreting tumors, a dopamine agonist, such as bromocriptine or cabergoline. As in a previous caveat, treating large tumors with radiation or craniotomy risks causing panhypopituitarism and, from temporal lobe damage, memory impairment and seizures.

Less commonly occurring pituitary growths secrete growth hormone, which can cause acromegaly, or adrenocorticotropin hormone, which can lead to Cushing syndrome

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