Neoplastic Disorders Part 1

Neoplasms can damage the nervous system in three ways: cells within the central nervous system or peripheral nervous system can become neoplastic1; tumors located outside the nervous system (i.e., systemic cancers) can metastasize to neural structures2,3; and systemic cancers can cause neural dysfunction indirectly [see Table 1].2,4 This topic focuses on primary and metastatic tumors of the CNS. Strictly speaking, meningiomas, pituitary tumors, and pineal region tumors are not brain tumors; however, because they arise within the intracranial cavity, they are considered here. Some nonmetastatic effects of cancer on the nervous system are also discussed.

Primary Nervous System Tumors—General Principles

Epidemiology

Neoplasms can develop in the brain and spinal cord, especially from glial cells or their precursors; neoplasms can also develop from intracranial structures outside of the brain and spinal cord, such as the meninges and the pituitary and pineal glands. Brain tumors of neuronal origin are uncommon.5 The American Cancer Society (http://www.cancer.org) estimates that in 2004, 18,400 new cases of brain cancer and other CNS cancers developed (10,540 in males and 7,860 in females) and 12,690 patients died of CNS cancer.

Although the incidence of brain tumor increases with age and thus most brain tumors are encountered in the elderly, brain tumors are the most common solid tumor of childhood and are the second most common cause of cancer death, after leukemia, in males under the age of 40 and in females under the age of 20.6 Brain tumors affect both sexes and all races. Meningiomas and pituitary adenomas are more common in women and African Americans, whereas gliomas are more common in men and whites. Meningiomas and pituitary tumors7 are quite common. Low-grade gliomas, such as astrocytomas, are more common in the young; high-grade gliomas, such as anaplastic astrocytomas and glioblastomas multiforme, are more common in the elderly. The incidence of glioma may actually decrease in the very old (i.e., persons 75 to 80 years of age or older).8 The apparent incidence of CNS cancers increased during the late 1970s and 1980s as a result of better diagnosis, but the overall rate now is stable.8 However, the incidence of primary CNS lymphoma (PCNSL) in immunocompetent persons (e.g., those who are not infected with HIV) continues to increase.9 Although once rare, PCNSL is now an important consideration in the diagnosis and treatment of brain tumors, particularly because the tumor is sometimes curable.

Classification

The World Health Organization (http://www.who.int) classifies CNS and peripheral nervous system tumors by their presumed cell of origin [see Table 2].5 Most parenchymal brain and spinal cord tumors are of neuroepithelial origin—glial cells (as-trocytes or oligodendroglia) or their precursors. Oligoden-droglial tumors constitute 5% to 10% of glial tumors. Glial tumors are classified as either high grade or low grade; nuclearatypia, mitotic figures, microvascular proliferation, and necrosis indicate high-grade tumors. If three or all four of these features are present, the prognosis is poor.

Although often used, the terms benign and malignant have less meaning in tumors of brain and spinal cord parenchyma than in other cancers. Brain and spinal cord tumors are seldom truly benign because surgery rarely cures; they are not truly malignant in the usual sense because they seldom metastasize to other organs. Surgery fails because even histologically benign intrinsic brain tumors (e.g., gliomas) infiltrate normal tissue, thereby preventing total resection and allowing tumor recurrence. Certain tumors, such as medulloblastoma, ependymoma, glioblastoma, and PCNSL, may seed the leptomeninges or spread to distant sites within the neuraxis, but they rarely spread outside the CNS.

Etiology

Environmental Risk Factors

Immunosuppression—either congenital or acquired—and exposure to ionizing radiation are the only well-established environmental risk factors for brain tumors.11 Low-dose irradiation of the scalp, once a treatment of tinea capitis, has been shown to cause a 10-fold increase in the incidence of meningiomas, many of which are anaplastic or malignant, and a threefold increase in the incidence of glial tumors. High-dose irradiation for intracra-nial or extracranial cancers, including prophylactic irradiation for leukemia,12 increases the incidence of glioma, meningioma, and sarcoma. Dental radiography is probably not a risk factor.

Table 1 How Neoplasms Damage the Nervous System

Means of Damage	Examples
Primary tumors	Brain, spinal cord, and meninges
	Gliomas
	Meningiomas
	Cranial and peripheral nerves
	Schwannomas (neurilemomas)
	Neurofibromas
	Other intracranial structures
	Pituitary
	Pineal region
Metastatic tumors	Intracranial structures (usually brain)
	Spinal cord (usually epidural)
	Leptomeninges
	Peripheral nerves
	Vascular disorders
	Infections
Nonmetastatic effects	Metabolic and nutritional disorders Side effects of therapy Paraneoplastic syndromes

Table 2 Classification of Primary Brain Tumors

Tumor Type	Examples	% Brain Tumors	% Gliomas
Neuroepithelial tumors	Gliomas (Total)	29	100
	High-grade Gliomas (Subtotal)	17	62
	Anaplastic astrocytoma, oligodendroglioma
	Glioblastoma Low-grade Gliomas (Subtotal)	12	38
	Astrocytoma	7	20
	Pilocytic astrocytoma*	1	6
	Oligodendroglioma	3+	10+
	Ependymoma	1	1
Neuronal tumors	Neurocytoma
	Medulloblastoma*	2
	Neuroblastoma*
	Dysembryonic neuroepithelial tumor
Mixed neuronal and glial tumors	Ganglioglioma Plesiomorphic xanthoastrocytoma
Meningeal tumors	Meningioma	40
	Pineocytoma	< 1
Pineal region tumors	Pineoblastoma
	General tumors*
Pituitary tumors	Adenoma	10
Primary CNS lymphomas	Non-Hodgkin lymphoma	1+
	Hemangioblastoma	1
Tumors of blood vessel origin	Capillary hemangioblastoma Vascular malformations
Nerve sheath tumors Malformative tumors	Neurofibroma (schwannoma)	4
	Craniopharyngioma	2
	Colloid cyst of third ventricle

*Usually children.

+Probably underestimated.

Genetic Risk Factors

Most CNS tumors are sporadic, but some run in families [see Table 4].20,21 Gliomas develop in as many as 14% of patients with neurofibromatosis type 1 (NF-1, or von Recklinghausen disease). Schwannomas, meningiomas, and, less commonly, ependymomas are found in patients with neurofibromatosis type 2 (NF-2). Both NF-1 and NF-2 tumor suppressor genes have been cloned, as have the genes responsible for other familial CNS tumors.22 However, the low concordance of brain tumors in monozygotic twins indicates that inherited factors are a minor cause of brain tumor.

Acquired (i.e., nonfamilial) genetic abnormalities are associated with CNS tumors [see Table 5]. These abnormalities include the loss or mutation of a tumor suppressor gene, such as p53 or the retinoblastoma gene, and the amplification and rearrangement of oncogenes.22 Many oncogenes code for growth factors or growth factor receptors that can self-stimulate tumor cells (i.e.,autocrine stimulation) or stimulate cells nearby (i.e., paracrine stimulation). The two most common abnormalities identified in patients with glial tumors are mutations in p53, which occur in 40% of patients with astrocytoma and with approximately equal frequency in patients with anaplastic astrocytoma or glioblas-toma multiforme, and overexpression of the epidermal growth factor receptor, in either normal or mutated form, which occurs in approximately 40% of patients with glioblastoma multiforme. Platelet-derived growth factor and its receptor have also been implicated. A sequence of genetic abnormalities can be identified in the progression of some tumors from low grade (astrocytoma or oligodendroglioma) to high grade (anaplastic glioma or glioblastoma multiforme).5 However, glioblastoma multiforme can also arise de novo. Mutations in p53 are rare in patients with glioblastomas who are younger than 18 years; they are common in patients between the ages of 18 and 45 years and are less common in patients older than 45 years. This suggests that glioblas-tomas in the young and elderly may arise via a different pathway or pathways than those that arise in midlife.

Pathophysiology

The pathophysiology of CNS tumors explains why even relatively small growths often cause symptoms, whereas small systemic tumors usually do not.1,2 First, small, strategically located tumors (e.g., tumors of the brain stem) damage vital pathways of the brain and spinal cord, thereby causing severe dysfunction.

Similar lesions in more homogeneous organs, such as the lung or liver, must destroy large areas of these organs before symptoms appear. Second, because the brain and spinal cord are encased in unyielding dura and bone, there is little room for a neoplasm to grow without compressing normal tissue [see Figure 1]. Third, tumor vessels do not possess a normal blood-brain barrier. Because these neovessels leak, proteins and other potentially noxious substances can enter the tumor and diffuse into the surrounding normal tissue, causing edema and further compressing normal structures [see Figure 1]. Edema removal is slow because the brain itself lacks lymphatics, although lymphatics around cranial nerves empty into cervical lymph nodes.24 Tumors create their own vascular supply by secreting angiogenesis factors such as vascular endothelial growth factor. Angiogenesis factors are now targets for brain tumor therapy.25

Although small tumors often cause symptoms, exceptions do occur. Slowly growing tumors, especially those in the so-called silent brain areas (e.g., the frontal pole), may not cause symptoms until they become very large. Even glioblastoma multiforme sometimes causes fewer symptoms than might be expected from the size of the lesion and the degree of shift seen on imaging studies. CNS symptoms are caused by three mechanisms:

1. The tumor invades, irritates, and replaces normal tissue. This mechanism is characteristic of infiltrating low-grade gliomas but rarely occurs in metastatic tumors or meningiomas.

Table 3 Possible Risk Factors for Primary Brain Tumors of Neuroepithelial, Meningeal, or Lymphocytic Origin11

Hereditary syndromes [see Table 4]

Ionizing radiation: therapeutic, diagnostic, and other sources

Family history of brain tumors

Immunosuppression

Constitutive polymorphisms

Lymphocyte mutagen sensitivity to gamma radiation

Prior cancers

Infectious agents or immunologic response: viruses, Toxoplasma gondii

Allergies

Head trauma

Epilepsy, seizures, or convulsions

Drugs and medications

Diet and vitamins: nitrosamine/nitrosamide/nitrate/nitrite consumption

Tobacco smoke exposure (women)

Alcohol use

Coffee use

Hair dyes and sprays

Traffic-related air pollution

Occupations and industries: synthetic rubber manufacturing, vinyl chloride, petroleum refining/production work, licensed pesticide applicators, agricultural work, and others

Cellular telephone use

Exposure to radio waves

Exposure to electromagnetic fields associated with power lines

Left-handedness (fewer gliomas in left-handed persons)

Sociodemographic status (more low-grade tumors in affluent; more high-grade tumors in Medicaid patients)

2. Both the tumor and the edema compress normal tissue and its blood vessels, causing ischemia.

3. Tumors that compress or grow in the third or fourth ventricle (e.g., ependymomas) or the leptomeninges obstruct cere-brospinal fluid pathways, causing hydrocephalus.

The effects of tumor invasion, peritumoral edema, and hy-drocephalus combine to cause herniation in normal cerebral structures under the falx cerebri, through the tentorium cerebel-li, or through the foramen magnum [see Figure 1], thus causing symptoms at a distance from the tumor site.

Symptoms and signs

Patients with brain tumors may have generalized symptoms caused by diffuse intracranial pressure, focal symptoms caused by ischemia and compression at the site of the brain tumor, or false localizing symptoms caused by shifts of cerebral or spinal structures.1 Generalized or false localizing symptoms are probably caused by slowly growing tumors in silent areas, whereas focal symptoms occur with even small tumors in more functionally important areas of the brain, such as the motor cortex and brain stem, or in the spinal cord.

Generalized Symptoms and Signs

Headache, the most common symptom of increased intracra-nial pressure, is the first symptom in about 40% of patients with a brain tumor.26 It is more frequently the first symptom of brain tumor in those who have a history of headache than in those who have no such history. Most of the headaches associated with brain tumors are nonspecific. A brain tumor should be suspected when headache is present on awakening from sleep but disappears within 1 hour, when headaches begin in a middle-aged or an older person who has not previously experienced them, or when the character or severity of headache suddenly changes in a chronic headache sufferer. Localized headache is a reliable indicator of the side of the head that contains the tumor but does not mark the precise location of the tumor. For example, a right frontal headache indicates that the tumor is on the right side but does not indicate that the tumor is frontal; it could be occipital or even cerebellar.

Vomiting that is or is not preceded by nausea—particularly vomiting that occurs on awakening—is a common symptom of brain tumor in children but is less common in adults. Acute headache that is immediately followed by vomiting is characteristic of a brain tumor and indicates increased intracranial pressure. In contrast, a headache that is followed by vomiting several hours later is characteristic of migraine. Papilledema is a sign of increased intracranial pressure; it commonly occurs in children but is less common in the elderly. Papilledema is usually asymptomatic but may cause transient episodes of blindness.

The mental changes associated with a brain tumor begin with irritability and progress to apathy. All activities are performed more slowly. Patients sleep longer, seem preoccupied when awake, and often fail to initiate activity, including conversation. However, if spoken to, they usually respond appropriately. Psychiatric consultation for the treatment of what is thought to be depression is often obtained before a brain tumor is suspected.

Brain tumors may be associated with episodic symptoms such as headache, visual loss, altered consciousness, and sometimes transient weakness of the extremities. These episodes are often precipitated by rising from a recumbent position, coughing, or sneezing and are associated with plateau waves—abrupt increases in an already elevated intracranial pressure that last for 5 to 20 minutes.1 These symptoms are not seizures; they respond to a decrease in the intracranial pressure but do not respond to anticonvulsant therapy.

Table 4 Familial CNS Tumor Syndromes

Disorders	CNS Tumors	Tumors of Other Organs and Tissues	Skin Lesions	Genes	Chromosomes
Neurofibromatosis-1	Gliomas, neurofibromas	Iris hamartomas, osseous lesions, pheochromocytoma, leukemia	Cafe au lait spots, cutaneous axillary freckling, neurofibromas	NF1	17q11.2
Neurofibromatosis-2	Schwannomas, meningiomas	Posterior lens opacities, retinal hamartoma	None	NF2	22q12.2
von Hippel-Lindau disease	Hemangioblastoma, endolymphatic sac	Retinal hemangioblastomas, renal cell carcinoma, pheochromocytoma, visceral cysts, endolymphatic sac tumor	None	VHL	3p25-p26
Tuberous sclerosis	Astrocytomas	Cardiac rhabdomyomas, adenomatous polyps of the duodenum and small intestine, cysts of the lung and kidney, lymphangioleiomyomatosis, renal angiomyolipoma	Cutaneous angiofibroma ("adenoma sebaceum"), peau de chagrin, sub-ungual fibromas	TSC1, TSC2	9q34 16p13.3
Li-Fraumeni syndrome	Gliomas (10%)	Breast carcinoma; bone and soft tissue sarcomas; adrenocortical, lung, and GI carcinomas; leukemia	None	TP53	17p13.1
Cowden disease	Cerebellar mass (Lhermitte-Duclos disease)	Hamartomatous polyps of the eye, colon, and thyroid; breast carcinoma, thyroid cancer	Multiple trichilemmo-mas, fibromas	PTEN	10q22.3 10q23.31
Turcot A syndrome Turcot B syndrome	Medulloblastoma Glioma	Colorectal polyps, colon carcinoma Colon cancer, no polyps	Cafe au lait spots	APC MLH1 PMS2	5q21-22 3p21.3 7p22
Nevoid basal cell carcinoma syndrome (Gorlin syndrome)	Medulloblastoma (anaplastic)	Jaw cysts, ovarian fibromas, skeletal abnormalities	Multiple basal cell carcinomas, palmar and plantar pits	PTCH	9q22.3-31
Retinoblastoma	Pineal tumors	Retinal tumors, osteosarcomas and other tumors	None	RB1	13q14
Bloom syndrome	Medulloblastoma, meningioma	Characteristic face and voice, gonadal failure, diabetes, immunodeficiency	Sun sensitivity, patches of hyperpigmentation and hypopigmentation	BLM	15q26.1
Fanconi anemia	Astrocytoma, medulloblastoma	Anemia, skeletal malformations, enlarged cerebral ventricles, gastrointestinal malformations	Cafe au lait spots, hyper-pigmentation and hypopigmentation	FANCA	16q24.3
Familial melanoma	Astrocytoma	None	Patches of hyperpigmen-tation	MLM CDKN2 A/p14 ARF	1p36 9p21
Rhabdoid predisposition syndrome	PNET, choroid plexus carcinoma	Renal tumors, extrarenal malignant rhabdoid tumors	None	HSNFA/ 1NH1	22q11
Multiple endocrine neoplasia (MEN-1 Carney complex)	Pituitary adenomas	Hyperparathyroidism, gastrinoma, insulinoma, thyroid/bronchial carcinoid	Facial angiofibroma, lipo-mas, collagenomas	MEN1	11q13
Ataxia-telangiectasia	Astrocytoma, medulloblastoma, cerebellar ataxia	Lymphomas, hypogonadism, radiation sensitivity, insulin resistance, premature aging, small stature	Telangiectasias	ATM	11q22-q23

PNET—primitive neuroectodermal tumor