Primary brain tumors are diagnosed in approximately 52,000 people each year in the United States. At least one-half of these tumors are malignant and associated with a high mortality. Glial tumors account for about 30% of all primary brain tumors, and 80% of those are malignant. Meningiomas account for 35%, vestibular schwannomas 10%, and central nervous system (CNS) lymphomas about 2%. Brain metastases are three times more common than all primary brain tumors combined and are diagnosed in approximately 150,000 people each year. Metastases to the leptomeninges and epidural space of the spinal cord each occur in approximately 3–5% of patients with systemic cancer and are also a major cause of neurologic disability.
Approach to the Patient: Primary and Metastatic Tumors of the Nervous System CLINICAL FEATURES
Brain tumors of any type can present with a variety of symptoms and signs that fall into two categories: general and focal; patients often have a combination of the two (Table 49-1). General or nonspecific symptoms include headache, with or without nausea or vomiting, cognitive difficulties, personality change, and gait disorder. Generalized symptoms arise when the enlarging tumor and its surrounding edema cause an increase in intracranial pressure or direct compression of cerebrospinal fluid (CSF) circulation leading to hydrocephalus. The classic headache associated with a brain tumor is most evident in the morning and improves during the day, but this particular pattern is actually seen in a minority of patients. Headaches are often holocephalic but can be ipsilateral to the side of a tumor. Occasionally, headaches have features of a typical migraine with unilateral throbbing pain associated with visual scotoma. Personality changes may include apathy and withdrawal from social circumstances, mimicking depression. Focal or lateralizing findings include hemiparesis, aphasia, or visual field defect. Lateralizing symptoms are typically subacute and progressive. A visual field defect is often unnoticed by the patient; its presence may only be revealed after it leads to an injury such as an automobile accident occurring in the blind visual field. Language difficulties may be mistaken for confusion. Seizures are a common presentation of brain tumors, occurring in about 25% of patients with brain metastases or malignant gliomas but can be the presenting symptom in up to 90% of patients with a low-grade glioma. All seizures that arise from a brain tumor will have a focal onset whether or not it is apparent clinically.
NEUROIMAGINGCranial MRI is the preferred diagnostic test for any patient suspected of having a brain tumor and should be performed with gadolinium contrast administration. Computed tomography (CT) scan should be reserved for those patients unable to undergo magnetic resonance imaging (MRI; e.g., pacemaker). Malignant brain tumors—whether primary or metastatic—typically enhance with gadolinium and may have central areas of necrosis; they are characteristically surrounded by edema of the neighboring white matter. Low-grade gliomas usually do not enhance with gadolinium and are best appreciated on fluid-attenuated inversion recovery (FLAIR) MRIs. Meningiomas have a characteristic appearance on MRI because they are dural-based with a dural tail and compress but do not invade the brain. Dural metastases or a dural lymphoma can have a similar appearance. Imaging is characteristic for many primary and metastatic tumors and sometimes will suffice to establish a diagnosis when the location precludes surgical intervention (e.g., brainstem glioma). Functional MRI is useful in presurgical planning to define eloquent sensory, motor, or language cortex. Positron emission tomography (PET) is useful in determining the metabolic activity of the lesions seen on MRI; MR perfusion and spectroscopy can provide information on blood flow or tissue composition. These techniques may help distinguish tumor progression from necrotic tissue as a consequence of treatment with radiation and chemotherapy or identify foci of high-grade tumor in an otherwise low-grade-appearing glioma.
Neuroimaging is the only test necessary to diagnose a brain tumor. Laboratory tests are rarely useful, although patients with metastatic disease may have elevation of a tumor marker in their serum that reflects the presence of brain metastases (e.g., β human chorionic gonadotropin [β-hCG] from testicular cancer). Additional testing such as cerebral angiogram, electroencephalogram (EEG), or lumbar puncture is rarely indicated or helpful.
| HIGH-GRADE GLIOMA (%) | LOW-GRADE GLIOMA (%) | MENINGIOMA (%) | METASTASES (%) | |
|---|---|---|---|---|
| Generalized | ||||
| Impaired cognitive function | 50 | 10 | 30 | 60 |
| Hemiparesis | 40 | 10 | 36 | 60 |
| Headache | 50 | 40 | 37 | 50 |
| Lateralizing | ||||
| Seizures | 20 | 70+ | 17 | 18 |
| Aphasia | 20 | <5 | — | 18 |
| Visual field deficit | — | — | — | 7 |
TREATMENT: Brain Tumors
Therapy of any intracranial malignancy requires both symptomatic and definitive treatments. Definitive treatment is based on the specific tumor type and includes surgery, radiotherapy, and chemotherapy. However, symptomatic treatments apply to brain tumors of any type. Most high-grade malignancies are accompanied by substantial surrounding edema, which contributes to neurologic disability and raised intracranial pressure. Glucocorticoids are highly effective at reducing perilesional edema and improving neurologic function, often within hours of administration. Dexamethasone has been the glucocorticoid of choice because of its relatively low mineralocorticoid activity. Initial doses are typically 12–16 mg/d in divided doses given orally or IV (both are equivalent). Although glucocorticoids rapidly ameliorate symptoms and signs, their long-term use causes substantial toxicity including insomnia, weight gain, diabetes mellitus, steroid myopathy, and personality changes. Consequently, a taper is indicated as definitive treatment is administered and the patient improves.
Patients with brain tumors who present with seizures require antiepileptic drug therapy. There is no role for prophylactic antiepileptic drugs in patients who have not had a seizure. The agents of choice are those drugs that do not induce the hepatic microsomal enzyme system. These include levetiracetam, topiramate, lamotrigine, valproic acid, and lacosamide (Chap. 31). Other drugs, such as phenytoin and carbamazepine, are used less frequently because they are potent enzyme inducers that can interfere with both glucocorticoid metabolism and the metabolism of chemotherapeutic agents needed to treat the underlying systemic malignancy or the primary brain tumor. Venous thromboembolic disease occurs in 20–30% of patients with high-grade gliomas and brain metastases. Therefore, prophylactic anticoagulants should be used during hospitalization and in nonambulatory patients. Those who have had either a deep vein thrombosis or pulmonary embolus can receive therapeutic doses of anticoagulation safely and without increasing the risk for hemorrhage into the tumor. Inferior vena cava filters are reserved for patients with absolute contraindications to anticoagulation such as recent craniotomy.
No underlying cause has been identified for the majority of primary brain tumors. The only established risk factors are exposure to ionizing radiation (meningiomas, gliomas, and schwannomas) and immunosuppression (primary CNS lymphoma). Evidence for an association with exposure to electromagnetic fields including cellular telephones, head injury, foods containing N-nitroso compounds, or occupational risk factors are unproven. A small minority of patients have a family history of brain tumors. Some of these familial cases are associated with genetic syndromes (Table 49-2).
| SYNDROME | INHERITANCE | GENE/PROTEIN | ASSOCIATED TUMORS |
|---|---|---|---|
| Cowden’s syndrome | AD | Mutations of PTEN (ch10p23) | Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease), meningioma, astrocytoma |
| Breast, endometrial, thyroid cancer, trichilemmomas | |||
| Familial schwannomatosis | Sporadic | Mutations in INI1/SNF5 (ch22q11) | Schwannomas, gliomas |
| Hereditary | |||
| Gardner’s syndrome | AD | Mutations in APC (ch5q21) | Medulloblastoma, glioblastoma, craniopharyngioma |
| Familial polyposis, multiple osteomas, skin and soft tissue tumors | |||
| Gorlin syndrome (basal cell nevus syndrome) | AD | Mutations in Patched 1 gene (ch9q22.3) | Medulloblastomas Basal cell carcinoma |
| Li-Fraumeni syndrome | AD | Mutations in p53 (ch17p13.1) | Gliomas, medulloblastomas |
| Sarcomas, breast cancer, leukemias, others | |||
| Multiple endocrine neoplasia 1 (Werner’s syndrome) | AD | Mutations in Menin (ch11q13) | Pituitary adenoma, malignant schwannomas Parathyroid and pancreatic islet cell tumors |
| Neurofibromatosis type 1 (NF1) | AD | Mutations in NF1/neurofibromin (ch17q12-22) | Schwannomas, astrocytomas, optic nerve gliomas, meningiomas |
| Neurofibromas, neurofibrosarcomas, others | |||
| Neurofibromatosis type 2 (NF2) | AD | Mutations in NF2/merlin (ch22q12) | Bilateral vestibular schwannomas, astrocytomas, multiple meningiomas, ependymomas |
| Tuberous sclerosis (TSC) (Bourneville disease) | AD | Mutations in TSC1/TSC2 (ch9q34/16) | Subependymal giant-cell astrocytoma, ependymomas, glioma, ganglioneuroma, hamartoma |
| Turcot syndrome | AD | Mutations in APCa (ch5) | Gliomas, medulloblastomas |
| AR | hMLH1 (ch3p21) | Adenomatous colon polyps, adenocarcinoma | |
| von Hippel–Lindau (VHL) | AD | Mutations in VHL gene (ch3p25) | Hemangioblastomas |
| Retinal angiomas, renal cell carcinoma, pheochromocytoma, pancreatic tumors and cysts, endolymphatic sac tumors of the middle ear |
As with other neoplasms, brain tumors arise as a result of a multistep process driven by the sequential acquisition of genetic alterations. These include loss of tumor-suppressor genes (e.g., p53 and phosphatase and tensin homolog on chromosome 10 [PTEN]) and amplification and overexpression of protooncogenes such as the epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptors (PDGFR). The accumulation of these genetic abnormalities results in uncontrolled cell growth and tumor formation.
Important progress has been made in understanding the molecular pathogenesis of several types of brain tumors, including glioblastoma and medulloblastoma. Morphologically indistinguishable glioblastomas can be separated into four subtypes defined by molecular profiling: (1) classical, characterized by overactivation of the EGFR pathway; (2) proneural, characterized by overexpression of PDGFRA, mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes, and expression of neural markers; (3) mesenchymal, defined by expression of mesenchymal markers and loss of NF1; and (4) neural, characterized by overactivity of EGFR and expression of neural markers. The clinical implications of these subtypes are under study. Medulloblastoma is the other primary brain tumor that has been highly analyzed, and four molecular subtypes have also been identified: (1) the Wnt subtype is defined by a mutation in β-catenin and has an excellent prognosis; (2) the SHH subtype has mutations in PTCH1, SMO, GLI2, or SUFU and has an intermediate prognosis; (3) group 3 has elevated MYC expression and has the worst prognosis; and (4) group 4 is characterized by isochromosome 17q. Targeted therapeutics are under development for some of the medulloblastoma subtypes, especially the SHH group.
These are infiltrative tumors with a presumptive glial cell of origin. The World Health Organization (WHO) classifies astrocytomas into four prognostic grades based on histologic features: grade I (pilocytic astrocytoma, subependymal giant cell astrocytoma); grade II (diffuse astrocytoma); grade III (anaplastic astrocytoma); and grade IV (glioblastoma). Grades I and II are considered low-grade astrocytomas, and grades III and IV are considered high-grade astrocytomas.
These tumors occur predominantly in children and young adults.
Pilocytic astrocytomas (WHO grade I) are the most common tumor of childhood. They occur typically in the cerebellum but may also be found elsewhere in the neuraxis, including the optic nerves and brainstem. Frequently they appear as cystic lesions with an enhancing mural nodule. These are well-demarcated lesions that are potentially curable if they can be resected completely. Giant-cell subependymal astrocytomas are usually found in the ventricular wall of patients with tuberous sclerosis. They often do not require intervention but can be treated surgically or with inhibitors of the mammalian target of rapamycin (mTOR).
These are infiltrative tumors that usually present with seizures in young adults. They appear as nonenhancing tumors with increased T2/FLAIR signal (Fig. 49-1). If feasible, patients should undergo maximal surgical resection, although complete resection is rarely possible because of the invasive nature of the tumor. Radiation therapy (RT) is helpful, but there is no difference in overall survival between RT administered postoperatively or delayed until the time of tumor progression. A recent large trial demonstrated the benefit of chemotherapy plus RT compared to RT alone following surgical resection. The tumor transforms to a malignant astrocytoma in the majority of patients, leading to variable survival with a median of about 5 years.
These account for approximately 15–20% of high-grade astrocytomas. They generally present in the fourth and fifth decades of life as variably enhancing tumors. Treatment is the same as for glioblastoma, consisting of maximal safe surgical resection followed by RT with concurrent and adjuvant temozolomide or by RT and adjuvant temozolomide alone.
Glioblastoma accounts for the majority of high-grade astrocytomas. They are the most common malignant primary brain tumor, with over 10,000 cases diagnosed each year in the United States. Patients usually present in the sixth and seventh decades of life with headache, seizures, or focal neurologic deficits. The tumors appear as ring-enhancing masses with central necrosis and surrounding edema (Fig. 49-2). These are highly infiltrative tumors, and the areas of increased T2/FLAIR signal surrounding the main tumor mass contain invading tumor cells. Treatment involves maximal surgical resection followed by partial-field external-beam RT (6000 cGy in thirty 200-cGy fractions) with concomitant temozolomide, followed by 6–12 months of adjuvant temozolomide. With this regimen, median survival is increased to 14.6 months compared to only 12 months with RT alone, and 2-year survival is increased to 27%, compared to 10% with RT alone. Patients whose tumor contains the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) are relatively resistant to temozolomide and have a worse prognosis compared to those whose tumors contain low levels of MGMT as a result of silencing of the MGMT gene by promoter hypermethylation. Implantation of biodegradable polymers containing the chemotherapeutic agent carmustine into the tumor bed after resection of the tumor also produces a modest improvement in survival.
Despite optimal therapy, glioblastomas invariably recur. Treatment options for recurrent disease may include reoperation, carmustine wafers, and alternate chemotherapeutic regimens. Reirradiation is rarely helpful. Bevacizumab, a humanized vascular endothelial growth factor (VEGF) monoclonal antibody, has activity in recurrent glioblastoma, increasing progression-free survival and reducing peritumoral edema and glucocorticoid use (Fig. 49-3). Treatment decisions for patients with recurrent glioblastoma must be made on an individual basis, taking into consideration such factors as previous therapy, time to relapse, performance status, and quality of life. Whenever feasible, patients with recurrent disease should be enrolled in clinical trials. Novel therapies undergoing evaluation in patients with glioblastoma include targeted molecular agents directed at receptor tyrosine kinases and signal transduction pathways; antiangiogenic agents, especially those directed at the VEGF receptors; chemotherapeutic agents that cross the blood-brain barrier more effectively than currently available drugs; gene therapy; immunotherapy; tumor-treating fields delivered by electrodes on the scalp; and infusion of radiolabeled drugs and targeted toxins into the tumor and surrounding brain by means of convection-enhanced delivery.
The most important adverse prognostic factors in patients with high-grade astrocytomas are older age, histologic features of glioblastoma, poor Karnofsky performance status, and unresectable tumor. Patients whose tumor contains an unmethylated MGMT promoter resulting in the presence of the repair enzyme in tumor cells and resistance to temozolomide also have a worse prognosis.
Rarely, patients may present with a highly infiltrating, nonenhancing tumor of variable histologic grade involving more than two lobes of the brain. These tumors may be indolent initially, but will eventually behave aggressively and have a poor outcome. Treatment involves RT and temozolomide chemotherapy.
Oligodendrogliomas account for approximately 15–20% of gliomas. They are classified by the WHO into well-differentiated oligodendrogliomas (grade II) or anaplastic oligodendrogliomas (AOs) (grade III). Tumors with oligodendroglial components have distinctive pathologic features such as perinuclear clearing—giving rise to a “fried-egg” appearance—and a reticular pattern of blood vessel growth. Some tumors have both an oligodendroglial as well as an astrocytic component. These mixed tumors, or oligoastrocytomas (OAs), are also classified into well-differentiated OA (grade II) or anaplastic oligoastrocytomas (AOAs) (grade III).
Grade II oligodendrogliomas and OAs are generally more responsive to therapy and have a better prognosis than pure astrocytic tumors. These tumors present similarly to grade II astrocytomas in young adults. The tumors are nonenhancing and often partially calcified. They should be treated with surgery and, if necessary, RT and chemotherapy. Patients with oligodendrogliomas have a median survival in excess of 10 years.
AOs and AOAs present in the fourth and fifth decades as variably enhancing tumors. They are more responsive to therapy than grade III astrocytomas. Co-deletion of chromosomes 1p and 19q, mediated by an unbalanced translocation of 19p to 1q, occurs in 61–89% of patients with AO and 14–20% of patients with AOA. Tumors with the 1p and 19q co-deletion are particularly sensitive to chemotherapy with procarbazine, lomustine (cyclohexylchloroethylnitrosourea [CCNU]), and vincristine (PCV) or temozolomide, as well as to RT. Median survival of patients with AO or AOA is approximately 3–6 years, but those with co-deleted tumors can have a median survival of 10–14 years if treated with RT and chemotherapy.
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