Brain Tumors, Metastatic Cancer, and Paraneoplastic Syndromes

Primary Brain Tumors

Tumors may arise from the tissues of the brain or spinal cord ( parenchyma ) or from their covering membranes (meninges) ( Box 19.1 ). Pathologists have named the largest group of parenchymal tumors gliomas after their original cell line— glial cells —that normally provide the structural, biochemical, and immunologic support for the central nervous system (CNS). Growing in the substance of the brain, gliomas are classified as intraparenchymal or intra-axial tumors. In contrast, meningeal cells give rise to the most common primary brain tumors, meningiomas . Because these tumors arise from the coverings of the CNS rather than from the parenchyma, they grow outside of the brain as extraparenchymal or extra-axial tumors.

Of many potential etiologies of primary brain tumors, studies have established that only ionizing radiation, several neurocutaneous disorders (see Chapter 13 ), immune deficiency, and certain genetic mutations constitute risk factors. So far, studies have not proven either cellphone use or head trauma constitutes a risk factor.

Gliomas

Gliomas include tumors named for specific cell types: oligodendrogliomas , ependymomas , and astrocytomas . Oligo-dendrocytes , which normally produce the myelin sheath covering insulating CNS neurons, ^a

a Schwann cells produce the myelin insulation for the peripheral nervous system (PNS) (See Chapter 5 ).

may give rise to oligodendrogliomas. These tumors, which occur infrequently and grow slowly, produce manifestations like those of astrocytomas (see later).

Ependymomas arise from ependymal cells , which are the cells lining the ventricles of the brain and the spinal cord’s central canal. In general, ependymomas arise in the brain in adult patients, but in children they arise in the spinal cord. When ependymomas arise in the brain—due to their inopportune location—they often obstruct cerebrospinal fluid (CSF) flow and cause hydrocephalus (see below).

Astrocytomas, which arise from astrocytes , originate anywhere in the CNS. When they are low-grade, astrocytomas do not insinuate themselves into surrounding tissue. They occur in children as well as adults and are the most common brain tumor in children. In children, astrocytomas tend to be relatively benign, cystic, noninvasive masses in the cerebellum. If a cerebellar astrocytoma grows large enough, it will compress the fourth ventricle, occluding CSF flow, and cause obstructive hydrocephalus. Fortunately, because neurosurgeons can readily remove an entire cerebellar astrocytoma without causing an appreciable deficit, their surgical cure rate approaches 90%. However, sometimes an astrocytoma arises in a child’s brainstem where it invades cranial nerve nuclei and the corticospinal and other long tracts. Brainstem astrocytomas tend to be highly malignant and not amenable to surgery.

In adults, astrocytomas occur predominantly in the cerebrum and infiltrate extensively. Total surgical removal of astrocytomas is practical only when the surrounding brain can be sacrificed. Physicians may extend the life of patients with low-grade astrocytomas for 10 years with combinations of chemotherapy, surgery, and stereotactic radiosurgery (treatment with intense, focused radiation).

Glioblastomas , the most malignant variety of astrocytoma, are the most frequently occurring primary brain tumor of adults, especially of relatively young adults. The average age of patients at the time of a glioblastoma diagnosis is only 54 years. Although a seizure or the development of physical deficits may reveal a glioblastoma, this tumor notoriously presents more often with changes in personality, mood, or behavior. Psychiatrists are occasionally the first physicians to encounter an individual who is later diagnosed with a glioblastoma. Thus, these tumors are the bête noir of psychiatry.

Glioblastomas develop almost exclusively in the cerebrum. They not only grow rapidly and relentlessly, they infiltrate extensively. A common scenario is for a glioblastoma to develop in one frontal lobe and cross through the anterior portion of the corpus callosum, its genu , to proliferate in the other frontal lobe before physicians diagnose it. On magnetic resonance imaging (MRI) and computed tomography (CT), the tumor growing in both frontal lobes gives a “butterfly” appearance ( Fig. 19.1A , 20.8 , and 20.20 ).

Total surgical removal is impractical because of the tumor’s infiltration of surrounding healthy brain, but surgery can remove much of the mass (“debulk”) and provide tissue for histologic diagnosis. Maximal safe surgical resection followed by protocols of radiotherapy, chemotherapy, and immune checkpoint inhibitors (see later) may slow the growth of glioblastomas and provide the patient with a lucid and comfortable respite. Nevertheless, the prognosis is poor, and many patients—especially the elderly and those with pronounced neurologic deficits—gain little from treatment. Glioblastoma patients survive for only 15 to 20 months.

Metastatic Tumors

Tumors of other organs metastasize to the brain and spinal cord by hematogenous routes. In the brain, metastatic tumors tend to be multiple, surrounded by edema, and rapidly growing. Although individual metastases may be small in size and number, their total mass including their surrounding edema forms an oppressive intracerebral burden ( Fig. 19.1C 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 brings gastrointestinal and pelvic cancers to the liver, these tumors metastasize to the brain rarely or only late in their course. Overall, metastatic brain tumors, which occur more commonly than primary brain tumors, occur in 20% to 40% of patients with cancer. For some individuals, the discovery of a metastatic brain tumor (or a paraneoplastic syndrome, see later) is the first indication that they have a cancer.

In many cases involving a single metastasis in a resectable location, neurosurgeons can help the patient, at least temporarily, by removing the brain tumor. Metastases resist systemic standard chemotherapy because the blood-brain barrier blocks most agents. Whole brain radiation and stereotactic radiosurgery provide relatively little benefit. Novel therapies hold the promise of being effective for metastatic brain disease, but currently most patients survive less than 1 year.

Local Signs

Brain tumors usually produce neurologic deficits, including ataxia, hemiparesis, aphasia, or anosognosia (see Chapter 8 ) by invading and destroying brain tissue. Tumors arising in “eloquent” regions—cerebral cortex areas critical to motor or neuropsychologic function, such as the motor cortex or Broca’s or Wernicke’s areas—produce obvious impairments early in the course. Tumors that are small, slowly growing, or located in “silent” regions of the brain—such as the right frontal lobe or the tip of either temporal lobe—notoriously fail to produce symptoms. Tumors that arise from cranial nerves almost immediately result in readily recognizable deficits. For example, optic nerve gliomas cause visual loss, and acoustic neuromas cause unilateral hearing loss and tinnitus (see later).

A first-time seizure in an individual older than 60 years frequently heralds a cerebral tumor. 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 to have developed a brain tumor.

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) or precipitate transtentorial herniation during ECT ( Fig. 19.1D ). More important, the tumor may have been the cause of the depressive symptoms in the first place. Nevertheless, the benefits of ECT may outweigh the risks if a cerebral tumor were small and without surrounding edema. In any case, before their patients undergo ECT, neurologists order either an MRI or CT.

Except in cases where a patient has had a brain lesion or epilepsy, transcranial magnetic stimulation (TMS) rarely causes seizures and appears not to be complicated by status epilepticus or transtentorial herniation. Nevertheless, the caveat still applies about looking for a tumor as the cause of severe depression.

Signs of Increased Intracranial Pressure

In addition to causing symptoms by destruction of brain tissue, tumors may cause symptoms by raising intracranial pressure (ICP) to abnormal levels (pressures exceeding 200 mm H ₂ O). Tumors increase ICP if they grow to occupy a large volume, block the flow of CSF through the ventricles, or impede CSF reabsorption through the arachnoid villi. Whatever the cause, increased pressure creates symptoms and signs that may add to or supersede ones caused by direct tissue damage.

Headache, while the most common symptom of increased ICP, actually occurs in only one-half of patients. Usually resembling tension-type headaches, tumor-related headaches most often consist of diffuse, dull, relatively mild pain that initially responds to mild analgesics, including aspirin. Sometimes, localized or unilateral headache points to a tumor’s location and mimics a migraine. As ICP rises, headaches worsen, especially in the early morning hours, and the pain begins to awaken patients from sleep. Increasing ICP eventually also causes nausea and vomiting as well as an unremitting headache.

Despite the statistic that less than 1 out of 1000 people with headache harbors a brain tumor, both patient and physician frequently have concerns—spoken or unspoken—that any headache may indicate a brain tumor. These concerns sometimes thwart the diagnosis of a less threatening neurologic or psychiatric disorder, like migraine or Somatic Symptom Disorder. 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.

One sign of increased ICP, papilledema , occurs because ICP is transmitted along the optic nerve to the optic disks ( Fig. 19.2 ). Although papilledema has a notorious association with brain tumors, it develops late, if at all. Thus, 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. In fact, idiopathic intracranial hypertension (pseudotumor cerebri) is a much more common explanation of papilledema than a brain tumor (see later and Chapter 9 ).

In considering manifestations of brain tumors, meningiomas constitute a special category. Unlike gliomas, as discussed previously, meningiomas are common and usually small, and even large ones may remain asymptomatic. Also, they arise and usually remain entirely in extra-axial locations, but when symptomatic, they often 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, due to 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 with optic atrophy, and, when large, frontal lobe dysfunction (see Chapter 7 ).