Epidemiology and Pathogenesis
Treatment: General Concepts
Pineal Region Tumors
Primary CNS Lymphomas
While the majority of primary central nervous system (CNS) tumors occur in patients over the age of 45 years, they are also the most prevalent solid neoplasms of childhood. About 16% of patients with brain tumors have a family history of cancer, and evidence points to chromosomal and genetic abnormalities. Magnetic resonance imaging (MRI) is superior to computed tomography (CT) in localizing tumors and in evaluating edema, hydrocephalus, and hemorrhage. Surgery is the most effective treatment, with radiotherapy playing a central role in the management of malignant tumors. Chemotherapy is important in increasing patient survival in some but not all types of tumors. Treatment approaches to specific types of tumors are discussed. These tumors include gliomas, astrocytomas, oligodendrogliomas, ependymomas, medulloblastomas, pineal region tumors, primary CNS lymphomas, meningiomas, neurilemomas, cerebral metastases, and meningeal carcinomatosis.
In 1995, it is estimated that 17,200 new cases of cancerous primary brain tumors will occur, with 13,300 deaths . Every year approximately 35,000 adult Americans develop primary or metastatic brain tumors [2,3]. Central nervous system tumors are the most prevalent solid neoplasms in children under 15 years old, the second (after leukemia) leading cancer-related cause of death in children, and the third leading cancer-related cause of death in adolescents and adults between the ages of 15 and 34 years [1,2,4]. The majority of intracranial tumors, however, occur in patients over the age of 45 years, and recent evidence suggests that the incidence of malignant gliomas among the elderly is increasing . In this review, we describe the principal concepts pertaining to malignant, benign, and metastatic brain tumors and briefly discuss epidemiology and pathogenesis, clinical presentation, diagnosis, and treatment approaches.
About 16% of patients with brain tumors have a family history of cancer . Various genetic disorders can predispose people to brain tumors. For instance, neurofibromatosis is associated with acoustic neuromas, meningiomas, and gliomas; tuberous sclerosis is associated with astrocytomas; von Hippel-Lindau disease is associated with hemangioblastomas; Turcot syndrome is associated with glioblastomas and medulloblastomas; and Li-Fraumeni syndrome, an autosomal dominant inherited disorder, is characterized by the occurrence of diverse tumors such as malignant glioma, breast cancer, soft-tissue sarcoma, osteosarcoma, leukemia, and adrenocortical carcinoma at a younger age. Patients with multifocal gliomas are more likely than other glioma patients to have germline cell p53 mutations, to have a second malignancy, or to have other family members with cancer [6,7].
Chromosomal abnormalities include an increased number of copies of chromosome 7 or 22, nonrandom losses associated with chromosomes 9p, 10p, 10q, and 17p [8-11], and sex chromosome aneuploidy with autosomal abnormalities . Loss of chromosome 17p with or without p53 gene alteration is seen in lower grades of astrocytoma [13,14], loss of 9p appears to represent an intermediate event that occurs in most higher-grade astrocytomas , and loss of a portion of chromosome 10 is a late event seen primarily in glioblastoma multiforme tumors [14-16]. Multiple deletions of chromosome 22 have been associated with meningiomas [12,17,18]. It has been postulated that such chromosomal losses may result in the deletion of tumor suppressor genes that normally inhibit tumorigenesis. Conversely, proto-oncogenes such as c-cis, c-erbB, gli, c-myc, and N-ras can be overexpressed in some brain tumors.
In addition to chromosomal abnormalities, cytokine and receptor aberrations are also seen in brain tumors. For instance, cells that produce tumor growth factor-alpha are seen in all grades of astrocytoma, although they are more often demonstrated in high-grade and more aggressive disease. Likewise, increased levels of epidermal growth factor receptors are seen in high-grade astrocytomas .
The following factors have been implicated as causes of some brain tumors: environmental exposure to vinyl chloride (glioma), Epstein-Barr virus (primary CNS lymphoma), head injury (meningioma), cranial irradiation (astrocytoma and meningioma), immunosuppression associated with organ transplantation (primary CNS lymphoma), and acquired immunodeficiency syndrome, or AIDS (primary CNS lymphoma). Chemotherapy has also been implicated but not substantiated as a cause of brain tumors [25,26].
Symptoms of intracranial tumors are produced primarily by the tumor mass itself, the surrounding edema, or the infiltration and destruction of normal tissue. The general signs and symptoms of a brain tumor are headache, nausea and vomiting, behavioral and personality changes, slowing of psychomotor function, visual changes, and speech disturbances. Seizures are the presenting symptoms in only about 20% of patients. These can be focal motor or sensory (complex partial) seizures or generalized seizures. Focal cerebral syndromes are summarized in Table 1 .
|Tumor locationª||Frontal lobe||Temporal lobe||Parietal lobe||Focal infratentorial|
|Dominant hemisphere||Nonfluent dysphasia, contralateral hemiparesis, apraxia, personality changes||Dysnomia, impaired perception of verbal commands, Wernicke-like aphasia, seizures||Alexia, apraxia, disgraphia, hemiparesis, seizures||—|
|Nondominant hemisphere||Contralateral primitive grasping and sucking reflexes, personality changes||Minor perception problems, spatial disorientation||Perception abnormalities and anosognosia, apraxia hemiparesis, homonymous hemianopia, visual inattention seizures||—|
|Both frontal lobes||Bilateral hemiplegia, spastic bulbar palsy, intellect impairment, mood liability, dementia, primitive reflexes||—||—||—|
|Either lobe (temporal or parietal)||—||Homonymous quadrantanopia, auditory hallucinations, aggressiveness||Mild-to-severe sensory extinction||—|
|Brain stem||—||—||—||Lower cranial nerve palsies (VI-VII), hemisensory deficit or hemiplegia due to involvement of long tracts, ataxia, paraplegia|
|Midbrain/fourth ventricle||—||—||—||Gait imbalance, ataxia of limbs or trunk, signs and symptoms of increased intracranial pressure|
|Cerebellum||—||—||—||Signs and symptoms of increased intracranial pressure, stumbling, gait imbalance, prominent morning headaches, nystagmus, dizziness, visual symptoms due to papilledema|
|Midline lesions (vermis)||—||—||—||Truncal and gait ataxia|
|Cerebellar hemispheres||—||—||—||Appendicular ataxia|
|Medullary||—||—||—||Cranial nerve deficits (VI, CII, IX, X), personality changes|
|ª Thalamic tumors can result in headache (due to hydrocephalus), sensory abnormalities, intention tremor, and hemiballistic-like movements|
In most primary spinal axis tumors, signs and symptoms arise not from parenchymal invasion but from spinal cord and nerve root compression. Primary spinal cord tumors account for 10% to 19% of primary CNS tumors. Although most spinal axis tumors are extradural metastases, the majority of primary spinal axis tumors are intradural gliomas. Ependymomas, followed by low-grade astrocytomas, are the most frequent gliomas of the spinal axis.
Clinically, patients with spinal axis tumors present to physicians with sensorimotor spinal tract syndrome, a painful radicular spinal cord syndrome, or central syringomyelia. Sensorimotor signs and symptoms caused by spinal cord compression can gradually develop over weeks or months, or they may suddenly occur in just hours or days. Initial presentation is asymmetric, and motor weakness is dominant with impairment of function at the affected levels. Because of external compression, dorsal column involvement occurs with paresthesias and the loss of pain and temperature sensations contralateral to the motor weakness. Radicular spinal syndrome presents as a sharp “knife-like” pain in the distribution of a sensory nerve root.
Radicular pain is of short duration but may be associated with a long-term, persistent ache. Pain can be exacerbated by coughing, sneezing, or anything that increases intracranial pressure. Local paresthesia, impairment of sensations of pain and touch, weakness, and muscle wasting are common. These findings sometimes antedate cord compression by months.
Spinal tumors, particularly intramedullary tumors, can also produce syringomyelic dysfunction by destruction and cavitation within the central gray matter of the cord. This destroys lower motor neurons, resulting in segmental muscle weakness, wasting, and loss of reflexes. Pain and temperature sensations are lost, but the sense of touch is preserved. With extension of the lesions, however, touch, vibration, and position senses are affected. Table 2 summarizes the clinical findings useful in localizing a spinal cord tumor.
|Foramen magnum||XIth and XIIth cranial nerve palsies; early development of ipsilateral arm weakness; cerebral ataxia; neck pain|
|Cervical||Ipsilateral arm weakness, eventually spreading to leg and opposite arm; wasting and fibrillation of neck, shoulder girdle, and arm muscles on ipsilateral side; early reduction in pain and temperature sensation in upper cervical regions; pain in cervical nerve distribution|
|Thoracic||Weakness of abdominal muscles; sparing of arms; unilateral root pains; sensory level changes, ipsilateral at first and becoming bilateral with time|
|Lumbosacral||Root pain in groin region and/or sciatic nerve distribution; weakened proximal pelvic muscles; impotence; bladder paralysis and decreased knee jerk and brisk ankle jerk reflexes|
|Cauda equina||Unilateral pain in back and leg, becoming bilateral when the tumor grows large; bladder and bowel paralysis|
Magnetic resonance imaging has been shown to be superior to CT in localizing tumors and in evaluating edema, hydrocephalus, and hemorrhage . Brain tumors occasionally bleed, and this bleeding can be insignificant or cause dramatic clinical consequences. Metastatic brain tumors that tend to bleed include melanoma, renal-cell carcinoma, choriocarcinoma, and thyroid carcinoma. Of the gliomas, glioblastoma and oligodendroglioma are more commonly associated with hemorrhage than ependymoma and the low-grade astrocytomas. Both CT and MRI can detect acute hemorrhage, but MRI is better for finding subacute hemorrhage.
The ability to produce high-quality coronal images without bone artifact makes MRI better than CT for evaluating the base of the skull and the posterior fossa. For intra- and extramedullary spinal cord lesions, high-quality MRI with gadolinium diethylenetetraminepentaacetic acid (Gd-DTPA) as the contrast agent is the diagnostic study of choice. Such imaging can delineate the spinal cord contour, visualize virtually all intrinsic tumors, and facilitate the diagnosis of leptomeningeal disease . Another important application of MRI is the use of the sagittal image in radiation treatment planning.
MRI angiography may be used to distinguish a vascular malformation or aneurysm from a neoplasm. MRI has gradually replaced myelography, which is now used only when MRI is contraindicated or unavailable. Stereotaxic biopsy is another possible diagnostic modality using CT or MRI. In the past, only peripheral cortical lesions allowed biopsy sampling. Now, lesions located almost anywhere in the brain can be safely biopsied using this technique .
When CT or MRI is used to follow the treatment response, it is often difficult to distinguish postoperative changes from residual tumor. The use of a contrast medium to enhance an image obtained within the first 5 days after surgery allows greater accuracy in identifying residual tumor. Corticosteroids profoundly affect CNS tissues for as long as 2 weeks after their administration. Therefore, at the time of postoperative imaging, patients should be receiving the same or a lower dose of steroid as when pretreatment scans were made. Positron emission tomography (PET) is the most reliable noninvasive scanning method for differentiating radiation-induced necrosis from tumor recurrence. Sometimes, a biopsy is needed to confirm the diagnosis .
Surgery is the fastest way to reduce tumor bulk. The goal is complete resection and cure. If complete resection is not possible, the second choice is to reduce tumor bulk and to decompress the brain. When the tumor is inaccessible, a stereotaxic needle biopsy should be performed to make the diagnosis.
In the case of a supratentorial tumor, an anticonvulsant agent and corticosteroids should be given to the patient before surgery; the former prevents seizures, and the latter may help to reduce cerebral edema and facilitate cerebral retraction, allowing better exposure of the tumor. In addition, diuretics and osmotic agents can be given to control intracranial pressure if the patient becomes lethargic or when deteriorating motor and language functions are noted by the physician.
Radiation therapy is central to the management of malignant tumors. Because most primary CNS neoplasms are focal, they are theoretically curable with effective local therapy. However, by the time of diagnosis, most gliomas and lymphomas have already infiltrated the surrounding normal CNS tissues, resulting in poorly demarcated borders. It is, therefore, often necessary to irradiate a substantial amount of normal tissue.
Using conventional radiation after surgical resection, the median surival time depends on tumor histology, with 3 to 4 years reported for anaplastic astrocytoma [31,32] and 10 to 13 months reported for glioblastoma multiforme . Radiation treatment of gliomas is complicated, because these tumors often display radioresistance as well as because radiation is so toxic to the surrounding normal brain tissues.
The total radiation dose commonly given is 60 Gy, in 180- to 200-cGy fractions over a limited tumor field. Unfortunately, this dose is inadequate to eradicate most primary tumors [34,35]. Strategies used to augment local radiation delivery include interstitial brachytherapy with iodine 125 or iridium 192 and radiosurgery with three-dimensional conformational photoradiation therapy (3D-CRT). To amplify the effects of radiotherapy or interstitial brachytherapy, a variety of dose-modifying agents and techniques are used, including interstitial hyperthermia, halogenated pyrimidine analogs, hypoxic cell radiosensitizers, and cisplatin (Platinol) chemotherapy. However, as local tumor control improves with brachytherapy, peripheral and distant CNS tumor recurrences become more common [36,37].
Adverse reactions associated with cranial irradiation can be classified according to their time of presentation. Acute reactions generally involve increased intracranial pressure caused by whole-brain irradiation or intensification of preexisting neurologic symptoms or signs when treatment is limited to the lesion. Symptoms are generally mild and self-limited. They can occur during or very shortly after radiation and are usually caused by demyelination and edema. These symptoms respond to corticosteroids.
Early delayed reactions are characterized by somnolence or exacerbation of preexisting signs and symptoms. These reactions are thought to stem from temporary demyelination caused by the effects of radiation on oligodendroglial cells  or on capillary permeability . These clinical findings are usually reversible. They occur 1 to 3 months after irradiation, are associated with demyelination and edema, and may also require corticosteroids to alleviate symptoms. In addition, early vascular abnormalities or tumor necrosis may induce clinical and radiographic changes that are indistinguishable from tumor progression .
Late delayed injuries are the most serious complications of therapeutic irradiation. Clinical features include seizure disorders and various degrees of neuropsychologic impairment. These injuries develop several months to years after treatment, are the result of direct damage to the brain and blood vessels, and may be fatal or cause permanent neurologic damage .
The brain's tolerance of radiation depends on the size of the dose per fraction and the total dose administered. Total doses in excess of 60 Gy delivered in 30 fractions over approximately 6 weeks will probably increase the risk of CNS tissue injury. Sheline et al  suggested that the threshold doses for brain injury are approximately 35 Gy for 10 fractions, 60 Gy for 35 fractions, and 76 Gy for 60 fractions. Factors that decrease the brain's radiation tolerance include incomplete development of the CNS in children , vasculopathy associated with endocrine disorders , CNS infection , and edema .
Corticosteroids may improve or stabilize the neurologic symptoms associated with radiation injury. Surgical resection may also benefit patients with focal radiation-induced lesions who deteriorate neurologically and become dependent on corticosteroids. The spinal cord is less tolerant of radiation than the cerebrum. Radiation myelopathy may present as a transient early delayed reaction or as a more ominous late delayed reaction. Transient radiation myelopathy can present clinically as Lhermitte's sign (electrical-shock–like paresthesias or numbness radiating from the neck to the extremities) when the neck is flexed. The syndrome develops after 3 to 4 months and gradually resolves over the ensuing 3 to 6 months without the need for specific therapy.
Persistent radiation myelopathy can be more serious; approximately 50% of patients die of secondary complications . In these more severe cases, onset is bimodal. The first peak occurs at 12 to 14 months and the second at 24 to 28 months after radiotherapy. This sequence of events may be explained by a dual mechanism of injury: The earlier peak may represent demyelination and white matter necrosis caused by the direct effects of radiation on oligodendroglia, whereas the later peak may reflect intramedullary microvascular injury. Damage that accompanies this form of radiation myelopathy may be irreversible. Sometimes it is partial, and sometimes there is progressive functional loss that becomes complete over a period of several months. Less commonly, radiation myelopathy is manifested by the acute onset of paraplegia or quadriplegia, resulting from infarction of the spinal cord, which evolves over several hours or a few days.
No laboratory tests or imaging studies can distinguish radiation myelopathy from other spinal cord lesions, and the diagnosis is frequently one of exclusion. The medical and legal consequences of radiation myelopathy are such that the radiation dose is often limited to a “safe” level. A dose of 50 Gy in 25 fractions over 5 weeks is generally considered to be safe, the risk of myelopathy being less than 0.5% .
Gliomas include astrocytomas, oligodendrogliomas, ependymomas, and mixed-type neoplasms. Astrocytomas are the most common type of malignant brain tumor in adults, accounting for 75% to 90% of such lesions. Histologically, astrocytomas are categorized as low-grade astrocytoma, mid-grade anaplastic astrocytoma, or high-grade glioblastoma multiforme. With the exception of juvenile pilocytic astrocytomas, subependymomas, and the limited number of astrocytomas that can be completely resected, even low-grade astrocytomas are highly lethal.
Traditionally, astrocytomas have been graded according to the four-tier system proposed by Kernohan and Sayre , but because this scheme did not correlate well with prognosis, other grading systems have been reported. Today, three-tiered grading systems are commonly used [48-51]. Cell density, pleomorphism, anaplasia, nuclear atypia, mitoses, endothelial proliferation, and necrosis are used to grade astrocytomas. The presence of necrosis separates anaplastic astrocytomas from glioblastoma multiforme . A broad range of anaplasia is seen in mid-grade anaplastic astrocytomas.
Cellular markers have been developed to assist the physician in assessing patient outcome. The Ki-67 antibody MIB-1 labels an antigen in all phases of the cell cycle except GO and is correlated with astrocytoma grade and patient survival rate. Cellular incorporation of bromodeoxyuridine (BrdU) is another marker that correlates with the DNA synthesis phase of the cell cycle and patient survival rate . BrdU is administered before surgery; MIB-1 can be applied to paraffin-fixed material.
When the three-tier grading system is used, initially each tumor grade is correlated with distinct and separate median survival curves [48,49]. However, a subsequent review of 251 cases at Massachusetts General Hospital found no statistical differences in rate of survival between grades II and III . Necrosis was found to be a significant predictor of short survival time, in agreement with previous studies .
Astroglial tumors may also be classified by anatomic location (ie, optic-nerve glioma, hypothalamic glioma, brainstem glioma, cerebellar astrocytoma, and corpus callosum glioma). The location of such a tumor may have important implications for treatment and prognosis, even if the tissue is histologically benign.
Treatment and Prognosis
Low-grade gliomas constitute about 10% to 20% of all adult primary brain tumors. The majority are astrocytomas; approximately 5% are oligodendrogliomas or mixed oligoastrocytomas. Pathologically, low-grade gliomas are well differentiated and lack all the cellular features (high cellularity, pleomorphism, mitoses, vascular endothelial proliferation, and necrosis) that characterize anaplastic glioma. In patients whose low-grade astrocytoma has been completely resected, radiation does not appear to increase survival rates. Incompletely resected tumors may benefit from radiotherapy [55-58], although the timing of treatment delivery remains controversial.
It is generally agreed that patients with neurologic impairment, tumor progression, or malignant transformation after surgery should undergo radiotherapy. Some practitioners commonly defer treatment, although close clinical and radiologic observation is maintained in asymptomatic patients or in those whose seizures are medically controlled . Proponents of this approach argue that CT and MRI allow diagnosis of the disease early in its natural history. It is uncertain whether early irradiation is better than delayed irradiation or whether radiotherapy alters the prognosis . With standard radiation therapy, the survival rate is 50% to 60% at 5 years and 30% to 40% at 10 years.
At recurrence, all patients should be evaluated for another biopsy and possible resection. A repeated course of standard radiation is seldom feasible, but some patients can be considered for radiosurgery or brachytherapy. Currently, chemotherapy has little role in the management of these tumors .
Maximal surgical resection improves the results of subsequent radiation therapy and chemotherapy. Clinically, the extent of resection was a significant independent variable for survival in patients treated for malignant glioma [61,62]. Other variables such as preoperative Karnofsky performance status, use of adjuvant chemotherapy, and volume of residual disease had a significant impact on the time to tumor progression [61,63]. Studies have also demonstrated that repeat surgery is effective against recurrent cerebral astrocytoma [64,65] but only if an additional treatment modality is implemented after the surgery. Response to such a regimen can be improved if the patient is young and has a good performance status.
In cases of high-grade astrocytoma, the prognosis for patients with anaplastic astrocytomas is superior to that for patients with glioblastoma multiforme, and the addition of radiotherapy confers a significant improvement in survival rates over those of surgery alone [66-68]. Irradiation of the tumor and the close adjacent margins appears as effective as whole-brain irradiation and results in less morbidity.
Chemotherapy: Astrocytomas have been the most extensively treated of the primary intracranial tumors. Carmustine (BiCNU), lomustine (CeeNU), procarbazine (Matulane), and eflornithine (DFMO [Ornidyl]) have shown good, long-lasting antitumor activity. Tumor histology, patient age and performance status, and extent of surgical resection at onset of therapy influence the likelihood and duration of response. Generally, younger patients are more likely to respond and to have longer remissions, patients with better performance status do best, and patients who have a more extensive original resection do better than those who do not have surgery or have a biopsy only [64,69,70].
Adjuvant chemotherapy following surgery and radiotherapy increases both time to disease progression and length of survival for patients with anaplastic gliomas . Reoperation may be needed following apparent tumor progression to differentiate between active tumor growth and radiation necrosis or to debulk a large tumor mass [72-74].
Specific recommendations for chemotherapy can only be made tentatively. In a meta-analysis of 16 trials, published in 1993, Fine and colleagues reported a small (10%) but statistically significant increase in the 1-year survival of patients who received chemotherapy . Some individual studies show far better results. However, nitrosourea-based drug combinations, including the PCV combination (procarbazine, lomustine [CCNU], and vincristine), appear to be superior to single-agent therapy, according to one controlled study by the Northern California Oncology Group. In that study, postirradiation carmustine was compared with the PCV combination . The greatest benefit from chemotherapy, based on time to progression and length of survival, was seen in PCV-treated anaplastic astrocytoma (82 vs 157 weeks) but not in glioblastoma multiforme.
New agents such as topotecan and temozolomide, with CNS penetration properties, are undergoing clinical trials. High-dose chemotherapy with autologous bone marrow rescue and intraarterial chemotherapy have not been beneficial . Osmotic blood-brain barrier disruption followed by intraarterial or systemic therapy showed activity in preliminary phase II trials but was associated with significant morbidity.
Interstitial therapy can provide local delivery of high concentrations of drugs, which minimizes systemic side effects, but its real benefit is yet to be proven in randomized phase III trials. For recurrent astrocytomas, single-agent nitrosoureas and the PCV regimen are most commonly used, but they generate only limited responses. Other drugs and drug combinations continue to be studied . Nevertheless, current advances in surgery make it unlikely that radiation or chemotherapy alone will provide a cure for gliomas and astrocytomas.
Much less common than the astrocytic tumors, oligodendrogliomas have a somewhat even peak incidence in people between the ages of 25 and 49 years, accounting for approximately 6% of all intracranial neoplasms in this age group. These tumors are derived from oligodendrocytes or their precursors in the O2A cell lineage [77,78]. In general, they tend to infiltrate the cerebral cortex more than do astrocytomas.
Histologic features have been used for grading, but they correlate less well with prognosis and with survival. Clinically, these tumors present in the typical fashion of hemispherical astrocytomas in the frontal or temporal lobe. The slow-growing low-grade oligodendroglioma appears on CT or MRI scans as a hypodense, non–contrast-enhancing mass that is calcified in approximately 50% of cases.
Surgical resection remains the primary mode of treatment in symptomatic patients and those with progressive disease. Total removal of gross tumor, when consistent with good neurologic outcome, is the surgical goal. Patients with unresectable or incompletely resected large tumors should be treated with radiotherapy. However, no randomized prospective trials have evaluated surgery alone vs surgery plus radiation in the treatment of oligodendroglioma. As yet, chemotherapy has no established role in the treatment of low-grade oligodendrogliomas, but some investigators are interested in evaluating regimens such as PCV for controlling these tumors.
Both anaplastic oligodendroglioma and mixed oligoastrocytoma are chemosensitive tumors, but the benefit of adjuvant chemotherapy has not been proven in prospective trials. Ongoing cooperative trials are comparing focal irradiation alone with neoadjuvant PCV chemotherapy followed by radiation.
Ependymomas are tumors arising from cells of ependymal lineage. Sixty percent of intracranial ependymomas are infratentorial and 40% are supratentorial . The fourth ventricle is the most common infratentorial site. Extension into the subarachnoid space occurs in 50% of these cases, and encasement of the medulla and upper cervical cord can occur. Of supratentorial ependymomas, 50% are primarily intraventricular; the remainder are parenchymal, arising from ependymal nests. Frequent findings of chromosomal aberrations in patients with these tumors suggest that the deletion of tumor suppressor genes is involved in the development of ependymomas [12,79,80].
Clinical presentation depends on tumor location. Intraventricular tumors frequently cause increased intracranial pressure and hydrocephalus. As a result, most patients present with headache, nausea, vomiting, papilledema, and ataxia.
Either MRI or CT is sufficient for preoperative anatomic diagnosis. Ependymomas are best treated by extirpation followed by radiation. Tumor grade has been considered the most important determinant of tumor behavior and prognosis. The 5-year survival rate for patients with low-grade tumors ranged from 60% to 80%, whereas for those with anaplastic ependymomas, it was 10% to 47% . When spinal irradiation was delivered in addition to the cranial treatment, no improvement of outcome was observed [82,83].
This approach is used by most radiation therapists when treating malignant ependymomas of the posterior fossa. In patients with spinal cord ependymomas who were treated with radiation or surgery plus radiation, overall 5- and 10-year survival rates of 83% and 75% were seen, respectively .
Medulloblastomas most likely originate from germinative neuroepithelial cells in the roof of the fourth ventricle . Most medulloblastomas (50% to 60%) occur in children 1 to 10 years old, with a peak between ages 5 and 9 years. A second, lesser peak occurs in adults between 20 and 30 years old.
Childhood medulloblastoma typically arises in the cerebellum, mostly in the midline and posterior vermes. In adults, it typically arises in a cerebellar hemisphere. Regardless of location, the risk of metastasis within the craniospinal intradural axis is relatively high. At presentation, up to 30% of cases will have positive cytology or myelographic evidence of spinal metastasis [86,87]. Extra-CNS metastases occur in less than 5% of cases; most metastases are to long bones .
The overall disease-free 5-year survival rate for medulloblastoma is approximately 50% [86,88-91]. However, the extent of disease at initial diagnosis defines risk. Poor risk is defined as a less than 75% tumor resection; invasion of the brainstem; metastasis to the spinal cord, cerebrum, leptomeninges, or cerebellum; positive cytology 2 weeks or longer after surgery; and patient age under 4 years [88,90,92]. The 5-year disease-free survival rate of poor-risk patients who receive craniospinal irradiation with or without chemotherapy is approximately 25% to 30% . Good-risk patients, on the other hand, have a 5-year disease-free survival rate of 66% to 70% .
Treatment consists of complete surgical resection, if possible, followed by craniospinal irradiation . Chemotherapy with combined regimens is an important adjunct [95,96]. In children under 2 years old, such chemotherapy is increasingly used to postpone radiotherapy.
Fewer than 1% of intracranial tumors occur in the pineal region, although in children they constitute 3% to 8% . About half are germ-cell tumors that most often occur in the second decade of a person's life; a few present after the third decade . Increasingly, chemotherapy plus irradiation is used to manage these tumors. Gliomas account for about 25% of pineal tumors. The remaining are tumors of pineal parenchymal cells or benign cysts. Neurologic signs and symptoms result from obstructive hydrocephalus and involvement of ocular pathways. The major ocular manifestation is Parinaud's syndrome.
Histology, tumor size, and extent of disease at presentation determine prognosis. Typically, patients with mature teratoma fare well with surgery. Germinomas respond best to radiation, although preradiation chemotherapy may increase the cure rate and allow reduction of the total radiation dose. Gliomas respond to therapy in the manner discussed in earlier sections. The remaining tumors respond variably to chemotherapy and radiotherapy, with survival ranging from months to years before recurrence.
Only about 1% of all non-Hodgkin's lymphomas are primary CNS lymphomas. The incidence of this disease has increased threefold over the last two decades, and this is not fully explained by the AIDS epidemic or the greater number of immunodeficient patients . Increased incidence of CNS lymphoma is correlated with the disappearance of intermediate-grade histology, suggesting a shift in the biology of the neoplasms .
Primary CNS lymphomas have been associated with inherited immunosuppression (ataxia telangiectasia, Wiskott-Aldrich syndrome, and severe combined immunodeficiency syndrome), acquired immunosuppression (systemic lupus erythematosus, tuberculosis, vasculitis, and AIDS), immunosuppressive therapy given to transplant patients , and Epstein-Barr virus infection .
Both AIDS-related and non–AIDS-related primary CNS lymphomas are frequently B-cell lymphomas of the histiocytic type (large-cell immunoblastic or small noncleaved-cell lymphoma). If a corticosteroid is given to a patient before brain biopsy, severe regression may alter the morphologic appearance of the tumor . Because of the AIDS-associated CNS lymphomas, the age for overall peak incidence is decreasing, with these tumors becoming more common in a person's third and fourth decades. CNS lymphomas most often occur in men. The literature review by Murray et al  found that 52% of cases were supratentorial, 34% were multiple, 12% were cerebellar, 2% were in the brainstem, and less than 0.5% were spinal.
The average time from onset of symptoms to diagnosis is approximately 1 to 2 months. The pattern of presentation varies, with four broad categories: (1) Some lymphomas cause increased intracranial pressure; (2) some are associated with deficits in higher cortical function, including personality change and dementia; (3) others are associated with focal neurologic deficits; and (4) still others cause seizures.
The contrast-enhanced CT and MRI appearance of these lesions is sometimes distinctive. Multiple lesions and homogeneous enhancement or signal is suggestive of CNS lymphoma. Sometimes the extent of disease appears disproportionate to the neurologic deficit.
Because of the diffuse nature of primary CNS lymphoma, the role of surgery is limited to biopsy. Whole-brain radiotherapy is considered standard treatment, producing a median survival time of 12 to 16 months in patients who do not have AIDS but only 2 to 5 months in patients with AIDS. Several studies suggest a dose-response survival relationship in patients receiving more than 5,000 cGy [103-105]. Some investigators have advocated prophylactic spinal-axis radiation , but this is not the treatment norm.
It is clear that systemic chemotherapy can induce significant responses in patients with either newly diagnosed or recurrent primary CNS lymphoma who do not have AIDS. Methotrexate and other agents have been used . When combination chemotherapy was given prior to radiation treatment, an overall response rate up to 80% was seen in those who completed the treatments. The median survival time ranges from 7 months to 16.5 months. However, relapse is rapid and few patients experience prolonged survival [107-110].
Meningiomas arise from arachnoidal cells in the meninges. Overall, they are the most common type of benign brain tumor. They occur twice as often in women as in men  and are more common in patients with breast carcinoma. Therefore, it is important to make a tissue diagnosis of an apparent single intracranial metastasis in patients with breast cancer .
Histologically, the majority of meningiomas are differentiated, with low proliferative capacity and limited invasiveness. Less commonly, meningiomas are more anaplastic, have a higher proliferative capacity, and are invasive. On CT and MRI scans, meningiomas are well-defined lesions that are easily enhanced with an intravenous contrast agent [113,114].
Surgery remains the primary mode of treatment. In a large series of surgically resected meningiomas, Simpson  reported that even when there was a perceived total resection, the disease recurrence rate was 9%. A review from Massachusetts General Hospital showed that a “total resection” is followed by 7%, 20%, and 32% recurrence rates at 5, 10, and 15 years, respectively . Two variables used to predict recurrence are mitotic rate and Simpson grade of tumor resection .
Approximately 75% of all meningiomas display some cytogenetic abnormalities. Frequent allele loss from chromosome 22 is found in 60% of cases. This loss of anti-oncogene may be the starting point for future studies of oncogene mechanisms and a tumor's potential for recurrence .
In patients with partially resected tumors, fractionated radiation or radiosurgery can improve the overall outcome if the lesion is less than 35 mm or located 3 to 5 mm from the optic nerve or chiasm [119,120]. For meningiomas that are surgically unresectable, radiation may provide important adjuvant therapy [121-124].
Currently, chemotherapy is not used for newly diagnosed and unirradiated meningiomas. In patients with histologically malignant meningiomas or recurrent surgically inaccessible tumors, little objective antitumor activity has been seen with cytotoxic chemotherapy. Clinical trials are needed to develop effective chemotherapies. Progesterone receptors and androgen receptors may be potentially useful in devising therapeutic regimens .
The major tumors occurring in the cerebellopontile angle are the acoustic nerve tumors and meningiomas. Acoustic neuromas or neurilemomas can originate on the VIIIth cranial nerve, involving the vestibular division at the point where the nerve acquires its reticulin and Schwann-cell component. Because these tumors grow slowly, they can reach substantial size before being detected. Neurilemomas can compress the Vth, VIIth, IXth, and Xth cranial nerves alone or in various combinations. These tumors can also compress the medulla and obstruct the flow of cerebrospinal fluid (CSF), leading to hydrocephalus.
Acoustic schwannomas are more common among people in the fifth decade of life. However, when they are associated with familial neurofibromatosis, they occur earlier, in late childhood and adolescence, and they may be bilateral. In a series from the Massachusetts General Hospital , auditory and vestibular branch involvement occurred in 98% of the cases, facial weakness with disturbances of taste in 56%, sensory loss over the face in 56%, gait abnormality in 41%, and appendicular ataxia in 20%.
The aim of surgery is complete resection. The surgical approach is chosen after consideration of the patient's age and residual hearing and the size and location of the tumor . Mortality ranges from 2% to 4%, depending on the size of the tumor . Radiation, especially stereotaxic radiotherapy, has been used as an alternative to surgery in selected patients. Use of conventional external-beam radiotherapy for partially resected tumors is not common practice.
Brain metastases occur in 25% to 35% of all cancer patients, of which approximately 15% will be symptomatic. The peak incidence of brain metastasis is bimodal, occurring first in children under 10 years old and then in adults between 55 and 59 years old. Eighty percent of brain metastases are supratentorial [127-129]. Most cerebral metastases originate from lung, melanoma, kidney, colon, soft-tissue sarcoma, breast, and non-Hodgkin's lymphoma . The signs and symptoms at presentation include progressive neurologic deficit, seizure, headaches, and hemorrhage. Intracerebral hemorrhage is more likely to be present with melanoma, renal-cell carcinoma, or choriocarcinoma.
Surgery is the best treatment for a single metastatic lesion [129-131] and may be indicated under the following circumstances: (1) The primary site is unknown; (2) the primary site is known, but the nature of the intracranial mass is in doubt (eg, meningiomas in patients with breast carcinoma); (3) the primary tumor is a well-controlled tumor, and a single intracranial lesion is present; or (4) serious symptoms from an accessible site of metastasis are present, even with known tumors elsewhere .
Radiation therapy also plays an important role when primary tumors are responsive to radiation, eg, small-cell carcinoma of the lung or lymphoma.
In patients with multiple metastases, the goal is to palliate neurologic symptoms and signs. Radiation therapy is the most common modality used, while surgery has a very limited role. Chemotherapy may be useful in some patients with persistent or recurrent cerebral metastases, eg, small-cell carcinoma, breast carcinoma, germ-cell tumor, and non-Hodgkin's lymphoma. Use of steroids can increase and/or improve survival . If the tumor is left untreated, survival time is between 1 and 2 months.
Meningeal carcinomatosis is found in 5% to 8% of patients with solid tumors [134,135]. The most common tumors to metastasize to the leptomeninges are lung tumors, breast tumors, non-Hodgkin's lymphoma, melanoma, and genitourinary carcinomas. Mode of spread is via hematogenous seeding of the arachnoid.
The most common signs and symptoms include headache, lower motor weakness, paresthesias, back and neck pain, diplopia, mental status change, reflex asymmetry, sensory loss, and cranial nerve paresis .
Direct examination of the CSF for tumor cells is a reliable and common way to make the diagnosis. Often, repeat lumbar punctures are required to identify malignant cells. Myelography and MRI with gadolinium-DTPA may be helpful in the diagnosis . Treatment is palliative and includes craniospinal axis radiation and intrathecal chemotherapy . Currently used agents are methotrexate, cytarabine, and thiotepa (Thioplex).
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