The most common glial tumor is the astrocytoma, which stains positive for glial fibrillary acidic protein (GFAP) and is classified or graded according to histologic characteristics reflecting aggressiveness and survival. The traditional classification system is the Kernohan grading system of astrocytoma, based on the pathologic characteristics of cellularity, pleomorphism, proliferation, and necrosis. Kernohan grades I and II represent “low-grade” or “welldifferentiated” astrocytoma, Kernohan grade III represents the intermediate or anaplastic astrocytoma, and grade IV astrocytoma is synonymous with a glioblastoma multiforme. In an attempt to improve the correlation between prognosis and grade of the tumor, the World Health Organization (WHO) in 1993 suggested a descriptive, three-tier system that includes the well-differentiated astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme. Because there is a slight difference between the pathologic characteristics described by the two systems, the clinician must know which system is being used.

Clinical Presentation The clinical presentation of astrocytoma is determined by tumor location, pathology, and age of the patient. The majority of astrocytomas in adults occur in the supratentorial compartment. Presenting symptoms may include headache, seizure, focal neurologic deficits, and personality change. The increasing availability of neuroimaging studies with improved resolution has resulted in earlier discovery of brain tumors.

▪SPECIAL CLINICAL POINT: Unexplained first seizures in adults, unusual neurologic symptoms, or an unexplained change in personality or mood should be investigated by either computed tomography (CT) or magnetic resonance imaging (MRI).

Contrast for the appropriate neuroimaging studies is important if a primary brain tumor is in the differential diagnosis (see Chapter 4, Fundamentals of Neuroradiology). Brainstem gliomas are less common and may present with sensorimotor abnormalities, coordination difficulties, or cranial nerve dysfunction. The tumor grade correlates somewhat with the abnormalities on the neuroimaging study. Low-grade tumors usually do not enhance, and they appear hypodense on a computed tomography (CT) scan and have abnormalities on magnetic resonance imaging (MRI) fluid-attenuated inversion recovery (FLAIR) and T2-weighted images. Increasing tumor grade results in increasing contrast enhancement. Central necrosis, with surrounding enhancement and peritumoral edema, is suggestive of a glioblastoma.

The most important factors that determine the prognosis of a patient with an astrocytoma include histology, age of the patient, and the level of disability or performance status. Patients with low-grade tumors have the best prognosis. Patients with an anaplastic astrocytoma have a significantly better prognosis than patients with a glioblastoma. Younger patients and patients with less disability do better than their older, more disabled counterparts. Less significant prognostic factors may include a long duration of symptoms prior to diagnosis, presence of
seizures, location of tumor, and degree of surgical resection. As our understanding of the genetic abnormalities of specific tumors increases, the presence or absence of chromosomal abnormalities may provide prognostic and therapeutic information.

Treatment Treatment options for astrocytoma are determined by pathology, location, clinical presentation, and age of the patient. Often, the patient is clinically symptomatic from cerebral edema; therefore, corticosteroids (usually dexamethasone) are started prior to surgery, and they often improve symptoms. Caution should be used if a primary CNS lymphoma (PCNSL) is in the differential diagnosis because the use of corticosteroid therapy prior to biopsy may decrease the chance of obtaining a positive biopsy. An anticonvulsant to prevent seizures for supratentorial lesions is also often started prior to surgery.

A definitive diagnosis is obtained by pathologic examination of brain tissue. Surgical debulking is preferred over a biopsy, when possible, to reduce the tumor burden, provide an adequate pathology specimen, and improve symptomatic relief from mass effect. Theoretically, tumor debulking also may improve the chance to respond to adjuvant therapy. Stereotactic biopsy is most often reserved for patients whose poor medical condition precludes a craniotomy and for those with deep-seated lesions or lesions in neurologically eloquent locations.

The use of neuronavigational systems and intraoperative neuroimaging studies have improved the ability of the neurosurgeon to attain maximal resection with minimal morbidity. Survival benefit has been correlated with good tumor resection, but the infiltrative nature of astrocytomas generally prohibits a complete resection.

Postoperative radiation therapy increases the median survival of patients with an anaplastic astrocytoma and glioblastoma. Limited-field brain irradiation with a “radiation boost” to the most active central portion of the tumor is performed over a course of 5 to 6 weeks. Additional techniques to deliver radiation therapy to astrocytomas include radiosurgery, three-dimensional conformal radiation therapy, boron neutron capture therapy, and the use of radiosensitizers. The role of these techniques for the treatment of high-grade astrocytomas has yet to be defined. Stereotactic radiosurgery, when added to fractionated radiotherapy, does not improve clinical outcome.

The role of radiation therapy for low-grade astrocytomas is even less clear. Statistically, patients with low-grade astrocytomas who have received radiation therapy have improved survival over those patients not so treated. However, the timing is controversial. It is not clear whether radiation therapy should be administered at the time of diagnosis (e.g., when the neoplasm has been identified after a single seizure or perhaps as an incidental finding by a neuroimaging study) or delayed until the tumor is more symptomatic from tumor transformation. Studies suggest that the timing is not a major prognostic determinant.

Historically, chemotherapy has not been a primary treatment for malignant astrocytomas, but the recognition that some subtypes of glial tumors (e.g., anaplastic astrocytomas in younger patients) are chemosensitive has increased enthusiasm for chemotherapy for primary brain tumors. The preferred combination of therapeutic agents for anaplastic astrocytomas has been procarbazine, CCNU, and vincristine (PCV regimen). Carmustine had previously been the most widely used single agent for glioblastoma, but temozolomide, a recently developed oral alkylating agent, has demonstrated significant activity against malignant gliomas. Temozolomide used concurrently with radiotherapy and then continued as adjuvant treatment has significantly
improved the survival outcome for patients with high-grade gliomas.

Glioblastoma multiforme is a highly vascular tumor and demonstrates elevated production of vascular endothelial growth factor (VEGF). Targeted therapy using angiogenesis inhibitors such as bevacizumab, a monoclonal antibody to VEGF, has shown efficacy in the treatment of recurrent malignant gliomas. Clinical studies are being conducted using bevacizumab with radiotherapy and temozolomide as initial therapy in newly diagnosed glioblastoma. Preliminary results are encouraging. Other angiogenic inhibitors are also under investigation.

▪SPECIAL CLINICAL POINT: Ethical decisions involving the appropriateness of participation in experimental treatment protocols for astrocytomas are challenging because patients and families are often desperate or frightened, potentially compromising informed consent. Furthermore, investigational treatments are potentially hazardous and full understanding of risk-benefit ratios is often unclear. Given the poor prognosis for patients with high-grade gliomas, however, it is important for the clinician caring for these patients to be aware of the clinical protocols available and to make an appropriate referral for patients interested in investigational treatment.

In a national survey, less than 8% of patients with astrocytoma were enrolled in treatment protocols. As participation in investigational protocols by patients with other malignancies has resulted in improved treatment modalities, it is important to encourage participation.

The oligodendroglioma is a type of glial tumor derived from the oligodendrocyte, the myelinproducing cell within the CNS. Histologically, this tumor is identified by its characteristic “fried-egg” appearance and a positive stain for myelin basic protein. The tumor tends to be slow growing; therefore, it is most often considered to be a low-grade tumor. However, varying degrees of anaplasia, and therefore aggressiveness, do occur. Most often, the tumor presents as a nonenhancing hypodense lesion on CT scan or a hypointense T1-lesion on MRI scan. Calcifications may be present. Enhancement may suggest a more aggressive tumor or the presence of a mixed oligoastrocytoma. Occasionally, symptom onset may be abrupt as the result of hemorrhage.

Management of the oligodendroglioma depends on location, clinical presentation, and neuroimaging appearance. Surgical resection generally is attempted if possible. The oligodendroglioma has been identified as a chemosensitive tumor; therefore, chemotherapy has played a major role in its treatment in recent years. The use of chemotherapy for lowgrade oligodendroglioma is being studied. Approximately 60% of oligodendrogliomas demonstrate genetic deletions or “loss of heterozygosity” (LOH) of 1p and 19q chromosomes. The presence of LOH of 1p and 19q is an indicator of chemosensitivity and favorable prognosis (greater than 90% response rate to chemotherapy and improved overall survival). Testing for these genetic abnormalities has become more readily available and an important part of the neuropathology report for oligodendroglioma. The chemotherapy most commonly used for this tumor has been the PCV regimen, but temozolomide is increasingly replacing PCV as first-line therapy. Although radiation therapy has been shown to improve survival of patients with oligodendroglioma, the role of radiation therapy remains controversial, especially if total resection has been accomplished. However, if subtotal resection or a limited biopsy has been performed, radiation therapy may offer some survival advantage.

The ependymoma is a glial tumor arising from the ependymal cells lining the ventricles and the cerebrospinal fluid (CSF)-filled spaces. This tumor usually occurs during childhood in the posterior fossa arising from the floor of the
fourth ventricle, but it may present in the spinal cord or in the cerebral hemispheres along the lining of the lateral ventricles. When an ependymoma occurs in the posterior fossa, it usually presents with symptoms of increased intracranial pressure, including headache, nausea, and vomiting, and it often causes obstructive hydrocephalus. The treatment of choice is surgical resection, and the prognosis depends on the degree of resection. A 45% overall 5-year survival is reported in the literature, with an increased chance of long-term survival after complete resection. This tumor lines the CSF pathways and may seed the neuraxis, although the majority of tumor recurrence is local within the posterior fossa. Local radiation therapy usually is recommended for supratentorial and spinal lesions. Local or craniospinal radiation therapy may be appropriate for ependymomas of the posterior fossa. Chemotherapy has been of limited benefit in the treatment of ependymoma.

Meningiomas are tumors derived from the arachnoid lining of the nervous system and, therefore, are extrinsic to the neuraxis. The tumors are most often histologically benign and are found more frequently with increasing age as the result of the slow growth rate.

▪SPECIAL CLINICAL POINT: Meningiomas may be found incidentally, and observation may be appropriate, especially when asymptomatic or when found in an elderly patient.

The incidence increases with age starting in the sixth decade. Women are affected two to three times more than men. Symptoms are dependent on location, size, and rate of growth. Symptoms may include seizures from cortical irritation over the convexity of the cerebral hemisphere, headache from pressure within the cranium, or symptoms of cranial nerve or brainstem dysfunction from direct compression of neural structures. Meningiomas typically demonstrate homogenous enhancement on CT or MRI studies following administration of contrast. Often a dural attachment or “dural tail” can be seen radiologically, which helps to identify the tumor as a meningioma. Significant edema surrounding the mass is not typically seen, and its presence should raise the suspicion for either an atypical, malignant meningioma or another type of tumor such as a metastatic tumor, especially from a breast or prostate primary. Meningiomas are also more common in women with breast cancer.

The treatment for meningioma is most often surgical resection with the goal of complete removal because the risk of recurrence is directly related to the completeness of the resection. This in turn mainly is determined by the location of the tumor; tumors that are not amenable to complete resection have a much greater risk for recurrence. For example, tumors over the cerebral convexities are more accessible surgically as compared to tumors at the base of the skull, and therefore cerebral convexity tumors are less likely to recur.

Radiotherapy by conventional fractionated radiation, stereotactic radiosurgery, or fractionated radiosurgery may play an important role for incompletely resected or recurrent tumors.

The role of traditional chemotherapy is limited, but agents such as hydroxyurea and interferon alpha-2b have been described as having some activity. Meningiomas may contain progesterone and, less frequently, estrogen receptors. Consequently, meningiomas may enlarge during periods of elevated hormonal levels such as pregnancy. Treatment with antiestrogen or antiprogesterone agents such as tamoxifen or mifepristone (RU-486), respectively, has been used.

Although the majority of meningiomas are histologically benign, infrequently atypical or malignant variants with more aggressive behavior may occur. A subtype of meningeal tumor, the hemangiopericytoma, may present similarly, but it has a high rate of recurrence and a propensity to seed the leptomeninges and metastasize outside of the CNS.

PCNSL is a non-Hodgkin lymphoma, usually of B-cell origin, that arises within the brain, spinal cord, or leptomeninges. This tumor may occur in otherwise healthy patients with normal immune systems, usually in older men, but it more often occurs in patients with a compromised immune system. It has been seen with increasing frequency as a result of the growing population with human immunodeficiency virus (HIV). This tumor does not tend to metastasize systemically and is a separate entity from systemic lymphoma with CNS metastasis. Patients with inherited, acquired, or iatrogenically induced immunodeficient states, particularly transplant patients, are at an increased risk for developing this tumor, and it may occur in up to 10% of patients with acquired immunodeficiency syndrome (AIDS). The clinical presentation may include headache, personality changes, seizures, and focal neurologic symptoms. Often the lesions are multifocal, frequently involving deep midline structures with contrast enhancement and minimal surrounding edema on neuroimaging studies. The diagnosis usually is established by biopsy, but surgical resection is usually not an option. The use of corticosteroid therapy prior to biopsy may decrease the opportunity to obtain an accurate pathologic diagnosis.

The presentation of PCNSL in an immunecompromised patient may resemble CNS toxoplasmosis clinically. It is therefore common to treat a patient with a known immunodeficiency empirically for toxoplasmosis for a limited period with clinical and radiologic follow-up. If the lesions improve, the assumption is that the patient has toxoplasmosis, whereas if the lesions progress or do not improve, then the possibility of CNS lymphoma increases and a biopsy may be performed. Occasionally, an immune-compromised patient may have simultaneous toxoplasmosis and CNS lymphoma, complicating the interpretation of the empiric trial. A lumbar puncture with cytologic examination may be helpful if the tumor is in the midline or if the leptomeninges are involved. CSF cytology may help to distinguish between a neoplastic monoclonal lymphocytosis and an inflammatory process. Intraocular involvement can occur, and a slit lamp examination or vitreous biopsy may be helpful in establishing the diagnosis. A systemic evaluation including a bone marrow biopsy may help to exclude the possibility of systemic lymphoma or other small-cell malignancies. Most often, a brain biopsy is indicated, however.

Once the diagnosis of PCNSL has been established, corticosteroid therapy may offer improvement of neurologic symptoms. For many years, radiation therapy has been the mainstay of treatment, but the prognosis was limited. The median survival of immunocompetent patients with PCNSL is approximately 14 months, and it is much less in patients with immunodeficiency. Combined treatment with chemotherapy and radiation therapy has resulted in improved survival. Unfortunately, relapse remains common, and late neurologic toxicity from combined therapy is a significant complication resulting in a progressive dementing leukoencephalopathy.

Chemotherapy has generally not been used in patients with CNS lymphoma associated with immunodeficiency because of the overall poor prognosis and response rate. PCNSL has been associated with the presence of Epstein-Barr virus in patients with AIDS. As a result of this observation, antiviral therapy has been suggested for treatment of PCNSL. Recently, rituximab, a monoclonal antibody that targets CD20, has shown some promise as well.

Systemic cancer may spread to the CNS to involve the skull, dura, parenchyma, or leptomeninges. Specific tumors may metastasize in predictable patterns, and understanding
these trends is important to correctly diagnose metastases in order to offer palliative therapy.

Neurologic symptoms are most common if the tumor involves the base of the skull, resulting in localized pain, headache, or cranial nerve dysfunction (Fig. 25.1). Special views on a CT or an MRI scan may be necessary to identify skull base metastases. Standard screening studies may not image this region well, giving the false impression of a negative study; thus, the opportunity to offer effective palliative therapy may be missed. The nuclear bone scan is not a very sensitive study (despite the fact that the symptoms are the result of bony metastases) because of the overlapping nuclear isotope uptake by the venous sinuses in this region. Localized radiation often offers effective palliation of symptoms, especially pain.