Primary brain tumors are tumors that arise from brain tissue itself as compared with metastatic tumors, whereby tumor cells travel to the brain from a distant site. This chapter deals specifically with primary brain tumors of adults, using the subcategories of benign tumors—meningiomas, realizing that a small subset can be malignant—and malignant gliomas (oligodendrogliomas and astrocytomas).

Definition

Benign Tumors

In 1922, Cushing coined the term meningioma to describe tumors originating from the meninges.¹ The World Health Organization (WHO) has now subdivided meningiomas into three separate categories defined as benign (I), atypical (II), and anaplastic or malignant (III) (Table 1).²

Malignant Tumors

Oligodendrogliomas are composed of diffusely infiltrating cells resembling oligodendrocytes with aggressive growth potential. WHO has stratified oligodendrogliomas as well-differentiated tumors (II) and anaplastic oligodendrogliomas (III).²

Astrocytic neoplasms are characterized by varying degrees of brain infiltration and aggressive growth potential. WHO has stratified astrocytomas as diffuse astrocytoma (II), anaplastic astrocytoma (III), and glioblastoma multiforme (IV).² For our purposes here, grade I tumors actually represent a separate tumor genotype and phenotype and are not discussed.

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Prevalence

The Cancer Brain Tumor Registry of the United States (CBTRUS) was formed in 1992 through the American Brain Tumor Association as a resource for epidemiologic data on primary brain tumors (http://www.cbtrus.org). There are currently eleven state registries involved in data collection. Primary brain tumors represent only 2% of all cancers, with 35,000 new cases diagnosed each year in the United States. Meningiomas occur at a rate of 7.8 per 100,000 per year, but only 25% are believed to be symptomatic, with the others being found incidentally.³ The male-to-female ratio is 1 : 1.8, and the incidence increases with age, peaking at age 85 years.

According to CBTRUS, the incidence of oligodendrogliomas, including anaplastic oligodendrogliomas, is approximately 0.3 per 100,000 persons. Depending on the study, these tumors account for 4% to 15% of intracranial gliomas.

The most commonly diagnosed primary brain tumor of adults is glioblastoma multiforme (grade IV). The incidence is two to three cases per 100,000 population per year. An estimated 13,000 deaths in 2000 were attributed to primary malignant brain tumors (PMBTs). Approximately 19,500 cases were expected to be diagnosed in 2000. Diffuse astrocytomas (WHO II) represent 10% to 15% of astrocytic brain tumors and have an incidence of 1.4 cases per 1 million population per year.

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Pathophysiology

Only about 5% of primary brain tumors have known hereditary factors. Specifically, the Li-Fraumeni syndrome, p53 defects, neurofibromatosis 1 (NF1) and 2 (NF2), tuberous sclerosis, von Hippel-Lindau disease, Turcot’s syndrome, and familial polyposis increase the risk of brain tumors. The polymerase chain reaction (PCR) assay and direct sequencing analysis can be used to diagnose von Hippel-Lindau disease.

For meningiomas, the strongest genetic link has been associated with NF2, with an almost 50% incidence. Sporadic meningiomas have been linked to chromosome 22 in the region of the NF2 gene.⁴ Meningiomas are known to express estrogen and progesterone receptors, with the former being more common. A high incidence of somatostatin receptors has also been found. The significance of these findings is uncertain but has led to diagnostic tests (e.g., octreotide single-photon emission computed tomography [SPECT], using the somatostatin receptors) and treatment strategies (antiprogesterone; mifepristone [RU-486]). Radiation is the only definite cause. Studies have shown that children receiving as little as 10 Gy for tinea capitis have increased risk for meningiomas, with tumor development taking at least 20 years from exposure.^5,6 Head injury is often cited as a causative factor, but a prospective study of 3000 patients with head injuries found no increased incidence.⁷

Viral infections, specifically the JC virus, has been implicated in oligodendrogliomas, but the data are inconclusive. The incidence of PMBTs (specifically astrocytomas) is increased in children with acute lymphocytic leukemia who have had prior brain radiotherapy. There have been reports⁸ of low-grade astrocytoma development in patients with inherited multiple enchondromatosis type I. Even though many of the molecular alterations involved in the progression of low-grade astrocytomas to higher grade tumors (glioblastoma multiforme) are known, the underlying causative factors are not well understood (Fig. 1).

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Signs and symptoms

For meningiomas, the clinical symptoms are usually dependent on the anatomic site involved, but many are found incidentally. Most meningiomas are slow growing and cause signs and symptoms by compression of nearby structures. The three most common symptoms are headaches, mental status changes, and paresis, and the most common signs are paresis, normal examinations, and memory impairment.⁹ For PMBTs, the most common signs and symptoms are seizures and headache. The lower-grade glial tumors have a more indolent course that may persist over years, whereas the most aggressive tumors (e.g., anaplastic oligodendrogliomas, anaplastic astrocytomas, glioblastoma multiforme) may have a rapid onset of neurologic decline. Patients may, however, present with signs and symptoms of increased intracranial pressure, including nausea, vomiting, headache, and confusion.

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Diagnosis

As with most disease processes, the medical history is the most important initial step in the process of brain tumor diagnosis. Because many meningiomas are found incidentally, imaging studies are important. A physical examination usually follows the medical history. Computed tomography (CT) is probably used most often as the initial imaging study, but magnetic resonance imaging (MRI) is considered to be the gold standard when done with and without gadolinium contrast. On MRI, meningiomas are typically isodense, dura-based masses that often show homogeneous enhancement (Figure 2).

Meningiomas

Meningiomas typically appear as extra-axial lesions, and the presence of a dural tail aids in the diagnosis. CT can help evaluate bone involvement and the presence of calcifications, which can be seen in 30% of benign meningiomas but are rare in malignant meningiomas. Although benign tumors can have associated edema, it is much more common in malignant meningiomas. Other noninvasive imaging tests include octreotide SPECT scans, which measure somatostatin levels in meningiomas. Magnetic resonance venograms can help in determining venous sinus patency. Although noninvasive tests are helpful, the definitive diagnostic test is still histologic tissue evaluation after a surgical biopsy or larger resection. Most institutions now use the WHO histologic grading criteria. Grading of tumors is based on cell origin and biologic behavior (see Table 1). Figure 2 demonstrates a very large meningioma that crosses both sides of the tentorium on the left. This tumor was surgically resected in a staged procedure. A typical histologic appearance of a meningioma is shown in Figure 3.

Primary Malignant Brain Tumors

As with meningiomas, MRI with and without contrast is the test of choice for PMBTs. Oligodendrogliomas are more likely to demonstrate calcifications on CT than astrocytomas. With MRI scans, PMBTs are typically hypointense on T₁-weighted images and hyperintense on T₂-weighted and fluid-attenuated inversion recovery (FLAIR) images. The higher-grade lesions (WHO III and IV) are more likely to demonstrate enhancement (anaplastic oligodendrogliomas, anaplastic astrocytomas, glioblastoma multiforme), although ring enhancement is less common in anaplastic oligodendrogliomas and usually is associated with a worse prognosis.¹⁰ Glioblastoma multiforme often has ring enhancement around a central area of necrosis (Figure 4). Tumor-associated cysts are more common with the astrocytomas. The higher-grade lesions also tend to exhibit more peritumoral edema. Newer technologies such as magnetic resonance spectroscopy can help in the differential diagnosis of intracranial lesions. Gliomas tend to demonstrate decreased N-acetyl aspartate, increased choline, and decreased creatine levels. A lactate peak is common in higher grade tumors.¹¹ The diagnosis is ultimately made histologically after surgical biopsy or resection. Figure 5 shows a hematoxylin-eosin slide from an oligodendroglioma, and Figure 6 represents a glioblastoma multiforme at low power. As we increase our understanding of the molecular genetics of tumors, this technology will play an increasing role in tumor diagnosis (see later, “Advances”).

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Treatment

Pharmacologic Treatment

Initial therapy is symptom based and usually involves the use of steroids and anticonvulsant medication. I generally prefer dexamethasone (Decadron) as the steroid of choice. For all tumors other than lymphomas, steroids are used secondary to their antiedema function. Side effects can be significant, and all patients should be treated with a histamine 2 (H₂) receptor blocker. The dose of steroids should be tailored for each patient and assessed on a regular basis. I tend to avoid late-night dosing if possible, because it can lead to sleep disturbances and behavioral problems. The typical dexamethasone dosage used by most physicians preoperatively is 4 mg, PO or IV, every 6 hours, and the dose is tapered postoperatively. Patients need to be followed closely during the tapering period. Antiepileptic drug practice has historically depended on the neurosurgeon’s preference, and most patients are started on prophylactic anticonvulsants. The American Academy of Neurology issued a position statement in May 2000¹² that recommended not using prophylactic anticonvulsants in patients who have newly diagnosed brain tumors and who have never had a seizure. If patients need to be maintained on an antiepileptic drug, I attempt to convert them to a medication that will not affect the liver’s cytochrome P-450 system (Table 2), because this could affect chemotherapeutic drug levels if both drugs are metabolized in the liver.

Surgery, Radiation, and Chemotherapy

Most patients will undergo a surgical procedure for diagnostic and treatment purposes. For patients with meningioma or PMBT, location usually defines the surgical risk. For meningiomas, if the tumor is located in proximity to a venous sinus, a magnetic resonance venogram is generally used and, if the sinus is patent, it usually represents a higher surgical risk. Surgeons may elect to complete cerebral angiography and have the patient undergo tumor embolization before surgical resection to decrease bleeding complications. Postsurgical treatments include observation, usually for WHO I and II meningiomas that undergo a gross total resection; focused external beam radiation for symptomatic tumors that cannot be resected, recurrent tumors, or highly aggressive tumors; chemotherapy (the Southwest Oncology Group currently has an ongoing hydroxyurea study for benign meningiomas); or hormone modulation, because many meningiomas express estrogen or progesterone receptors, or both. However, antihormonal therapy (anti-estrogen tamoxifen or the antiprogestin agent mifepristone) has not been shown to be effective in clinical trials.¹³Interferon alfa-2b has been used with some success for higher-grade meningiomas.¹⁴

For all grades of glial tumors, surgical resection is often recommended; however, by the very nature of their invasiveness, they cannot be cured surgically. A glioblastoma multiforme before and after surgical resection (see Fig. 4) demonstrates what is referred to as a “gross total resection.” Depending on the tumor histology, grade, and patient’s functional level (Karnofsky performance status [KPS], Table 3¹⁵), patients are usually treated after surgery (biopsy or resection) with external beam radiotherapy or chemotherapy. Radiation therapy typically is administered over a 6-week period with limited-field exposure (i.e., not the whole brain). Patients receive approximately 6000 cGy in 30 fractions (200 cGy per fraction). Oligodendrogliomas are usually more chemosensitive than astrocytomas, and hence radiotherapy is often delayed for these tumors.¹⁰ Historically, oligodendrogliomas and anaplastic astrocytomas have been treated with procarbazine-lomustine-vincristine (PCV) chemotherapy, and glioblastoma multiforme has been treated with carmustine (BCNU). The U.S. Food and Drug Administration (FDA) has approved the use of temozolomide (Temodar) for recurrent anaplastic astrocytomas; however, it is clinically being used for tumors of all grades, including meningiomas. The last several years have seen an increase in phases I and II clinical trials. Through our involvement in New Approaches to Brain Tumor Therapy (NABTT), a National Cancer Institute–sponsored consortium of 11 institutions, new and innovative treatments are being developed.

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Outcomes

Meningiomas

The overall prognosis for meningiomas is good and, as expected, somewhat depends on tumor histopathology. Because many meningiomas are found incidentally, observation may be reasonable for many patients. Radhakrishnan and colleagues³ followed 57 asymptomatic meningiomas for 32 months. None of the patients became symptomatic. A subset of 10 patients showed growth rates of 0.24 cm/year; however, 35 patients showed no growth during an average 29-month follow-up. In a single series of 1799 meningiomas from 1582 patients followed for an average of 13 years after resection, the nonrecurrence rate was 93% of WHO I tumors, 65% of WHO II, and 27.3% of WHO III.¹⁶ Other studies have shown higher recurrence rates after surgery alone.¹⁷ For patients undergoing subtotal resection and radiation therapy, the 5-year progression-free survival for WHO grades I and II was 98% and, for WHO III, slightly less than 50%.¹⁸

Stereotactic radiosurgery is now being used more commonly, but long-term follow-up data are limited. Lunsford¹⁹ has shown 4-year control rates of 92% for benign meningiomas treated with stereotactic radiosurgery. The roles of hydroxyurea, temozolomide, tamoxifen, mifepristone, and interferon alfa-2b remain to be determined. Several of these are being used in clinical trials but as of now play no real role in initial management and are used when no other treatment options exist.

Gliomas

Outcome for gliomas is based on tumor pathology or grade. For oligodendrogliomas, I retrospectively reviewed the last 96 oligodendrogliomas histologically analyzed at our institution. Prognosis was correlated best with chromosome 1p deletion, not age or tumor pathology grade (also see later, “Advances”).²⁰ Cairncross and associates¹⁰ have shown a median survival time of at least 10 years in anaplastic oligodendrogliomas with a combined 1p-19q deletion. The Radiation Therapy Oncology Group (RTOG) has completed a phase III study evaluating the long-term outcomes of low-grade gliomas (astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas). The study (RTOG 98-02) stratified patients into an observation arm (age <40 years and gross total resection of tumor) and treatment arm (age >40 years plus biopsy or subtotal tumor resection, or both) that randomized patients to external beam radiation alone or external beam radiation followed by PCV chemotherapy. The study closed June 2002, with the results pending at this time.

For higher-grade astrocytic tumors, the RTOG has reviewed 1578 anaplastic astrocytoma-glioblastoma multiforme patients entered in three trials from 1974 to 1989 and performed recursive partition analysis (RPA).²¹ Twenty-six pretreatment characteristics and six treatment-related variables were analyzed. Based on this analysis, six classes were developed (Table 4). It will be important in future studies that patient outcomes for new treatments are stratified based on RPA.

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Advances

The major advances in brain tumor understanding and treatment over the past 5 years have come from our understanding of oligodendrogliomas, which have specific molecular genetic alterations that distinguish them from astrocytomas. Allelic loss of chromosomes 1p and 19q is a molecular signature of oligodendrogliomas and occurs in 50% to 70% of WHO II and III oligodendrogliomas.²² Molecular testing of brain tumors helps determine their treatment. The loss of heterozygosity (LOH) of chromosome 1p and 19q are predictive of chemosensitivity for oligodendrogliomas, regardless of tumor histology, KPS score, or age.²⁰ Figure 7 shows how chromosomal LOH is determined in the molecular laboratory. The integrity of chromosome 1p and 19q can be evaluated by fluorescence in situ hybridization (FISH) and the polymerase chain reaction assay.

Cairncross and colleagues¹⁰ were the first to show this relation. They initially looked at 39 patients with anaplastic oligodendrogliomas and correlated chromosome 1p status with treatment effect. They found that allelic loss of chromosome 1p is a significant predictor of chemosensitivity and that combined loss of 1p and 19q shows a significant association with chemosensitivity and recurrence-free survival. These conditions were strongly associated with longer overall survival, and tests for these disorders are now done routinely on all my glioma patients.

The molecular story for malignant gliomas is much more complicated (see Fig. 1). The presence of an epidermal growth factor receptor (EGFR) likely indicates a primary (de novo) glioblastoma multiforme, whereas its absence suggests a secondary glioblastoma multiforme. Mutations of p53, on the other hand, are seen most commonly in secondary glioblastoma multiforme and EGFR and p53 mutations are not found together. Treatments are currently being developed to target these receptors. At my institution, an EGFR antagonist erlotinib (Tarceva, OSI-774) trial has been initiated.

Thus, although mortality statistics for most primary brain tumors have not changed significantly over the past 10 years, morbidity and our understanding of the molecular basis for tumor development have changed. New strategies aimed at targeted sites on tumors are now being developed. We look forward to the challenge.

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Summary

• Primary brain tumors represent only 2% of all cancers, with 35,000 new cases diagnosed each year in the United States. Meningiomas occur at a rate of 7.8 per 100,000 per year, but only 25% are believed to be symptomatic, with the others being found incidentally. The most commonly diagnosed primary brain tumor in adults is the glioblastoma multiforme.
• Only about 5% of primary brain tumors have known hereditary factors.
• For meningiomas, the three most common symptoms are headaches, mental status changes, and paresis, and the most common signs are paresis, normal examinations, and memory impairment. For primary malignant brain tumors, the most common signs and symptoms are seizures and headache.
• Computed tomography is probably used most often as the initial imaging study, but magnetic resonance imaging is considered to be the gold standard when done with and without gadolinium contrast.
• Initial therapy is symptom based and usually involves the use of steroids and anticonvulsant medication.

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