Primary brain tumors are tumors that arise from brain tissue itself as compared with metastatic tumors, where tumor cells travel to the brain from a distant site. This chapter will deal 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). More detailed information on these and other brain tumor histologies can be found using the link www.clevelandclinic.org/neurosurgery/braintumor/

DEFINITION

Benign Tumors:

Meningiomas
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
Tumors composed of diffusely infiltrating cells resembling oligodendrocytes with aggressive growth potential. WHO stratifies oligodendrogliomas as well-differentiated tumors (II) and anaplastic oligodendrogliomas (III).²

Astrocytomas
Astrocytic neoplasms are characterized by varying degrees of brain infiltration and aggressive growth potential. WHO stratifies astrocytomas as diffuse astrocytoma (II), anaplastic astrocytoma (III), and glioblastoma multiforme (IV).² For the purposes of this paper, grade I tumors really represent a separate tumor genotype and phenotype and will not be discussed.

The Cancer Brain Tumor Registry of the US (CBTRUS) was formed in 1992 through the American Brain Tumor Association as a resource for epidemiologic data on primary brain tumors (www.cbtrus.org). There are currently 11 state registries involved in data collection. Primary brain tumors represent only 2% of all cancers, with 35,000 new cases diagnosed per year in the United States. Meningiomas occur at a rate of 7.8 per 100,000 per year, but only 25% are thought to be symptomatic, with the others being found incidentally.³ The male-to-female ratio is 1 to 1.8, and the incidence increases with age, peaking at age 85 years.

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

The most commonly diagnosed primary brain tumor of adults is the glioblastoma multiforme (Grade IV). The incidence rate is 2 to 3 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.

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 Hipple-Lindau disease (PCR and Direct Sequencing analysis for this disease process is available), Turcot's syndrome, and familial polyposis increase the risk of brain tumors.

For meningiomas, the strongest genetic link has been associated with NF2, with an almost 50% incidence rate. 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 (octreotide single-photon emission computed tomography [SPECT], utilizing the somatostatin receptors) and treatment strategies (antiprogesterone; 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 3,000 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 are reports⁸ of low-grade astrocytoma development in patients with inherited multiple enchondromatosis type I. Even though we know many of the molecular alterations involved in the progression of low-grade astrocytomas to higher-grade tumors (glioblastoma multiforme), the underlying causative factors are not well understood (Figure 1).

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 (anaplastic oligodendrogliomas, anaplastic astrocytomas, and glioblastoma multiforme) may have a very rapid onset of neurologic decline. Patients may, however, present with signs and symptoms of increased intracranial pressure, including nausea, vomiting, headache, and confusion.

As with most disease processes, the medical history is the most important initial step in the process of brain tumor diagnosis. Since many meningiomas are found incidentally, imaging studies are very important. A physical examination usually follows the medical history. Computerized 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 completed with and without gadolinium contrast. On MRI, meningiomas are typically isodense, dural-based masses that often show homogeneous enhancement (Figure 2).

Meningiomas typically appear as extra-axial lesions, and the presence of a dural tail aids in the diagnosis. CT can help to evaluate bony 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 either a surgical biopsy or larger resection. Most institutions now utilize the WHO histologic grading criteria. Grading of tumors is based on the cell origin and biologic behavior (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 seen in Figure 3.

Primary Malignant Brain Tumors
As with meningiomas, MRI with and without contrast is the test of choice. Oligodendrogliomas are more likely to demonstrate calcifications on CT than do astrocytomas. With MRI scans, the 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 multiformes often have 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. A lactate peak is common in higher-grade tumors.¹¹ Diagnosis is ultimately made histologically after surgical biopsy or resection. Figure 5 shows a hemotoxylin-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 section on Advances).

Initial therapy is symptom-based and usually involves the use of steroids and anticonvulsant medication. We most commonly employ decadron (dexamethasone) as our steroid of choice. For all tumors other than lymphomas, the steroids are used secondary to their anti-edema function. Side effects can be significant, and all patients should be treated with an H₂-receptor blocker. The dose of steroids should be tailored for each patient and assessed on a regular basis. We tend to avoid late-night dosing if possible, as it can lead to sleep disturbances and behavioral problems. The typical dexamethasone (Decadron) dose employed by most physicians preoperatively is 4 mg (po/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 been dependent on the neurosurgeon's preference, and most patients are started on prophylactic anticonvulsants. The American Academy of Neurology issued a position statement¹² in May 2000 that recommends not using prophylactic anticonvulsants in newly diagnosed brain tumor patients who have never had a seizure. If our patients need to be maintained on an antiepileptic drug, we attempt to convert them to a medication that will not induce the livers cytochrome P-450 system (Table 2), as this could affect chemotherapeutic drug levels if both drugs are metabolized in the liver.

Surgery/radiation/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, then a magnetic resonance venogram is usually employed, and if the sinus is patent it usually represents a higher surgical risk. Surgeons may elect to complete a cerebral angiogram 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 a hydroxyurea study for benign meningiomas); or hormone modulation, since many meningiomas express estrogen and/or progesterone receptors. However, antihormonal therapy (anti-estrogen tamoxifen or the antiprogestinal agent RU-486) overall has not been shown to be very effective in clinical trials.¹³ Interferon-α-2b has been used with some success in 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. Figure 4 shows a glioblastoma multiforme before and after surgical resection, demonstrating what is referred to as a "gross total resection." Depending on the tumor histology, grade, and the patient's functional level (Karnofsky Performance Status¹⁵ [KPS], Table 3), patients are treated most commonly post surgery (biopsy or resection) with external beam radiotherapy or with chemotherapy. Radiation therapy typically is administered over a 6-week period with limited-field exposure (ie, not whole brain). Patients receive around 6,000 cGy in 30 fractions (200 cGy per fraction). Oligodendrogliomas are usually more chemosensitive than are astrocytomas, and hence radiotherapy is often delayed in these tumors.¹⁰ Historically, oligodendrogliomas and anaplastic astrocytomas have been treated with procarbazine, lomustine, and vincristine (PCV) chemotherapy, and glioblastoma multiformes have been treated with carmustine (BCNU). The US Food and Drug Administration has approved the use of temozolamide (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 phase I and phase 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.

Meningiomas:

The overall prognosis for meningiomas is good and, as expected, somewhat dependent on tumor histopathology. Since many meningiomas are found incidentally, observation may be reasonable for many patients. Radhakrishnan et. al³ 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 per year; however, 35 patients showed no growth during an average 29-month follow-up. In a single series of 1,799 meningiomas from 1,582 patients followed for an average of 13 years postresection, 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 being employed more commonly these days 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, temozolamide, tamoxifen, RU-486, and interferon-α-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 is based on tumor pathology or grade. For oligodendrogliomas, we recently 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 Advances section).²⁰ Cairncross et al¹⁰ have previously 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 recently completed a phase III study evaluating the long-term outcome of low-grade gliomas (astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas). The study (RTOG 98-02) stratified patients into an observation arm (age < 40 and gross total resection of tumor) and treatment arm (age > 40 and/or biopsy or subtotal tumor resection) that randomized patient to either 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 previously reviewed 1,578 anaplastic astrocytomas/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 the RPA.

The major advances in brain tumor understanding and treatment over the past 5 years have come from our understanding of oligodendrogliomas. Oligodendrogliomas 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 both WHO II and III oligodendrogliomas.²² Molecular testing of brain tumors will guide in 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 both fluorescence in-situ hybridization (FISH) and polymerase chain reaction.

Cairncross et al¹⁰ were the first to show this relationship. 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 was a significant predictor of chemosensitivity and that combined loss of 1p and 19q showed a significant association with both chemosensitivity and recurrence-free survival. These conditions were strongly associated with longer overall survival. These tests are now done routinely on all our glioma patients.

The molecular story for malignant gliomas is much more complicated (Figure 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 multiformes, and EGFR and p53 mutations are not found together. Treatments are currently being developed to target these receptors. At our institution, an EGFR antagonist Tarceva (erlotinib hydrochloride, OSI-774) trial has recently been opened with more detailed information at the following web site www.clevelandclinic.org/neurosurgery/braintumor/

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