Neurologic Tumors

Lisa M. DeAngelis

I. EPIDEMIOLOGY AND ETIOLOGY

A. Incidence. Malignant primary brain tumors represent 2% (17,000 cases) of all cancers and 2.5% (10,000 cases) of cancer deaths annually in the United States (Table 14.1). The male-to-female ratio is 3:2. The incidence peaks at 5 to 10 years of age and again at 50 to 55 years of age. Brain cancers are the most common solid tumors in children, and childhood brain cancers are discussed further in Chapter 18, “Brain Tumors.”

B. Etiology

1. Environmental factors, such as tobacco, alcohol, and diet, have not been associated with primary central nervous system (CNS) tumors. Exposure to ionizing radiation, however, can induce the formation of meningiomas, nerve sheath tumors, sarcomas, and astrocytomas. Exposure to electromagnetic radiation, including cell phones and computer terminals, does not cause brain tumors. Occupational exposure to vinyl chlorides may be a risk factor for astrocytomas; animal studies have shown that exposure to N-nitroso compounds, aromatic hydrocarbons, triazenes, and hydrazines increases the risk for astrocytoma formation, but it is not clear whether these compounds play a role in human tumor formation. Recent data suggest that individuals with atopy or chronic asthma may be at lower risk of glioma.

2. Hereditary neurocutaneous syndromes

a. Neurofibromatosis I is a dominantly inherited condition of multiple neurofibromas, café-au-lait spots, axillary freckling, and Lisch nodules of the iris that confers an increased risk for optic glioma, intracranial astrocytoma, neurofibrosarcoma, neural crest-derived tumors (glomus tumor, pheochromocytoma), embryonal tumors, leukemia, and Wilms tumor. The gene for this disorder is on chromosome 17q11, and its product, neurofibromin, is a tumor suppressor that regulates the Ras pathway, which transmits mitogenic signals to the nucleus.

b. Neurofibromatosis II is a condition of multiple schwannomas, especially vestibular schwannomas, that is also associated with an increased risk for ependymoma and meningioma. The gene for this disorder is located on chromosome 22q12, and its product, merlin, encodes a member of the ezrin-radixin-moesin (ERM) family of membrane and cytoskeletal linker proteins thought to be important for cell motility and adhesion.

c. Tuberous sclerosis (Bourneville disease) is a dominantly transmitted disorder characterized by the development of hamartomas, including subependymal nodules and cerebral cortical tubers that have abnormal cortical architecture and can be associated with mental retardation, epilepsy, and behavioral disturbances such as autism. Hamartomatous lesions of other organ systems include facial angiofibromas, forehead plaques, shagreen patches, cardiac rhabdomyomas, and renal angiomyolipomas and cysts. This disorder is associated with the formation of subependymal giant-cell astrocytomas. Two responsible tumor-suppressor genes,
TSC-1 (chromosome 9q34) and TSC-2 (chromosome 16p13), have been identified.

Table 14.1 Features of Common Central Nervous System Tumors

Tumor Type	Age	Common Location	Clinical Features	Survival	RT	Chemotherapy
Astrocytoma	Adult > child	Supratentorial	Slow growing, may be present for years	5 yr MS	Yes	At recurrence
Anaplastic astrocytoma	Adult	Supratentorial	Rapidly growing	2.5 yr MS	Yes	Yes
Glioblastoma	Adult, elderly	Supratentorial	Rapidly growing, highly malignant	1 yr MS	Yes	Yes
Oligodendroglioma	Any	Supratentorial, often frontal	Seizures more common	5 yr MS	Yes	Yes
Brainstem glioma	Child > adult	Brainstem, especially pons	Marked morbidity from cranial nerve deficits	1 yr MS	Yes	Seldom
Pilocytic astrocytoma	Child > adult	Cerebellum and hypothalamus	Cure with total resection	80% 10 yr	Yes	Yes
Ependymoma	Child, adult	Fourth ventricle, cauda equina	Cure with total resection; can disseminate in CSF	70% 5 yr	Yes	Yes
Medulloblastoma	Child > adult	Cerebellum	Likely to disseminate in CSF	70%-80% 5 yr	Yes	Yes
Meningioma	Adult	Convexity, clival, thoracic	More common in women; cure with total resection	Long term	Yes	Rare
Primary CNS lymphoma	Adult	Multifocal, periventricular	CSF/ocular dissemination common	3-5 yr MS	Yes	Yes
Germinoma	Second and third decades	Pineal and suprasellar	Highly sensitive to chemotherapy and RT	80% 5 yr	Yes	Yes
Nongerminoma germ cell tumor	Second and third decades	Pineal and suprasellar	Mixed histologies, often marker positive	25% 5 yr	Yes	Yes
MS, median survival; CSF, cerebrospinal fluid; CNS, central nervous system; RT, radiation therapy.

d. Nevoid basal cell carcinoma syndrome (Gorlin syndrome) is a dominantly inherited syndrome of multiple basal cell carcinomas that may be associated with medulloblastoma, meningioma, craniopharyngioma, and some systemic tumors (ovarian tumors, cardiac fibroma, maxillary fibrosarcoma, adrenal cortical adenoma, rhabdomyosarcoma, seminoma). Other features include jaw cysts, palmar and plantar pits, and spine and rib anomalies. The loss of a tumor-suppressor gene on chromosome 9q22 is responsible for this disorder. Its gene product, PTCH, is the human homologue of the Drosophila patched gene, part of the hedgehog signaling pathway, which is important in embryonic patterning and cell fate.

e. Neurocutaneous melanosis is a developmental rather than inherited condition of large, hairy, pigmented benign nevi of the skin associated with infiltration of the meninges by melanin-containing cells. Although the pigmented lesions of the skin remain benign, the pigmented cells in the meninges often undergo malignant transformation with neural invasion, resulting in primary CNS melanoma.

3. Hereditary cancer syndromes

a. von Hippel-Lindau disease is a dominantly transmitted disorder characterized by hemangioblastomas of the retina, cerebellum, and, less commonly, spinal cord. Other associated tumors include renal carcinoma, pheochromocytoma, islet cell tumors, endolymphatic sac tumors, and benign renal, pancreatic, and epididymal cysts. The disorder is due to the loss of a tumor-suppressor gene on chromosome 3p25-26. This loss results in the overexpression of vascular endothelial growth factor (VEGF) and erythropoietin, which are normally induced by hypoxia.

b. Turcot syndrome is a rare autosomal dominant or recessive familial syndrome associated with colon cancer, glioblastoma, and medulloblastoma. It is due to a germline mutation of the APC gene on chromosome 5q21, or germline mutations of genes governing the DNA replication mechanism including the hMLH-1 or hPMS-2 genes, both of which encode proteins responsible for DNA mismatch repair.

c. Li-Fraumeni syndrome is a clinical syndrome of familial breast cancer, sarcomas, leukemia, and primary brain tumors that is associated with germ line p53 (chromosome 17) mutations.

4. Immune suppression. Transplant recipients and patients with acquired immunodeficiency syndrome (AIDS) have a markedly increased risk for primary CNS lymphoma.

II. DIAGNOSIS

A. Clinical presentation depends on the location of the tumor and its rate of growth. In general, slow-growing tumors cause little in the way of focal deficits because the brain tissue is slowly compressed and compensatory mechanisms appear to occur. After they reach a certain size, the compensatory mechanisms fail or cerebrospinal fluid (CSF) pathways may be obstructed, causing increased intracranial pressure (ICP). Fast-growing tumors tend to be associated with considerable surrounding cerebral edema; the edema, in addition to the tumor mass, is more likely to cause focal deficits. Usually, the deficits caused by edema are reversible, whereas those caused by the tumor may not
be reversible. Specific signs and symptoms associated with tumors of the CNS include the following:

1. Headache occurs in about 50% of brain tumor patients. They are most likely to occur in younger patients with fast-growing tumors and are typically deep, dull, and not intense or throbbing. They are characteristically worse on arising in the morning and are exacerbated by straining or lifting. Lateralization of headache occasionally facilitates tumor localization.

2. Seizures. In 20% of patients >20 years of age, the onset of seizures is caused by a neoplasm. The seizures may be generalized or partial (focal). Simple partial seizures commonly consist of transient sensory or motor phenomena of a single limb or side. Complex partial seizures, often of frontal or temporal lobe origin, consist of changes in the level of consciousness or awareness of surroundings, frequently in conjunction with abnormal olfactory or gustatory phenomena. Speech arrest may also occur. Generalized seizures result in loss of consciousness, bowel and bladder incontinence, and bilateral tonicclonic movements. In patients with brain tumors, generalized seizures always have a focal origin even if the focal signature is not evident at seizure onset; evidence of focality is often found on postictal examination of the patient.

3. Increased ICP may result from a large mass or from obstructive hydrocephalus. Large supratentorial masses cause progressive obtundation and can lead to transtentorial herniation, which classically presents with an ipsilateral third cranial nerve palsy and contralateral hemiparesis. Hydrocephalus causes gait ataxia, nausea, vomiting, headache, and decreased alertness. If untreated, hydrocephalus can lead to central herniation, which is not heralded by a third nerve palsy. Papilledema is a sign of increased ICP, but it is rarely seen in current brain tumor patients because of the availability of modern neuroimaging, which facilitates early diagnosis. Unusual signs and symptoms of increased ICP include visual obscurations, dizziness, and false localizing signs, the most common of which is sixth cranial nerve dysfunction owing to stretching of the nerve from downward pressure caused by a large supratentorial mass.

4. Supratentorial tumors usually present with focal signs and symptoms, including hemiparesis (frontal lobe), aphasia (left frontal and posterior temporal lobes), hemineglect (parietal lobe), and hemianopsia (temporal, parietal or occipital lobes).

5. Hypothalamic tumors may be associated with disturbance of body temperature regulation, diabetes insipidus, hyperphagia, and, if the optic chiasm is involved, visual-field deficit, typically a bitemporal hemianopia.

6. Brainstem tumors, such as brainstem gliomas, present with multiple cranial nerve deficits, hemiparesis, and ataxia.

7. Nerve-sheath tumors, such as acoustic neuromas, result in deficits of the involved cranial or spinal nerve. As the tumor enlarges, surrounding neural structures may also be compressed, leading to further symptoms.

8. Cerebellar tumors are associated with dysmetria, ataxia, vertigo, nystagmus, headache, and vomiting.

9. Spinal cord tumors present with spastic paraparesis and sensory loss below the level of the tumor as well as disturbances of bowel and bladder function.

10. Meningeal involvement by primary CNS tumors is less common than with metastatic tumors (see Chapter 32) and is seen primarily with medulloblastoma, pineoblastoma, germ cell tumor, primary CNS lymphoma, and, to a lesser degree, ependymoma. The hallmark of meningeal disease is neurologic dysfunction at multiple levels of the neuraxis. Nonspecific features include seizures and changes in mentation.

B. Evaluation. Imaging studies must be performed to evaluate patients suspected of having CNS mass lesions.

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