• Subacute to chronic onset of generalized and/or focal neurologic symptoms should alert the physician to order neuroimaging to investigate the possibility of a brain tumor.
• Magnetic resonance imaging (MRI) is preferable to computed tomography (CT) for imaging tumors.
• A biopsy or resection is necessary to diagnose a primary brain tumor or a metastatic tumor of unknown primary origin. The diagnostic yield is increased with a resection.
• Neuroimaging suggestive of meningioma does not require a tissue diagnosis and in many cases can be followed closely with serial neuroimaging.
• If a primary CNS lymphoma is suspected, corticosteroids should not be given unless absolutely necessary in order not to confound the biopsy diagnosis.
• Surgical resection is preferred for patients with most types of brain tumors as long as the resection does not leave the patient with permanent neurologic deficits.
• Whole-brain radiotherapy and stereotactic radiosurgery are the primary treatment modalities for patients with metastatic brain tumors.
• Surgical resection is preferred for patients with large or symptomatic meningiomas that are surgical accessible and in patients who can tolerate surgery.
• Patients with gliomas are treated with fractionated radiotherapy alone or in combination with chemotherapy.
• Patients with primary CNS lymphoma are treated with high-dose methotrexate alone or in combination with other chemotherapy drugs.
Brain tumors are categorized as metastatic or primary. The incidence and prevalence of metastatic tumors outweigh those of primary tumors up to 10:1. Lung and breast carcinoma make up the majority of metastatic tumors, largely because of their increased prevalence in the population compared to other tumors. Melanoma is a less prevalent malignancy but has a high propensity to metastasize to the brain.
Meningioma is usually a benign tumor that is found most often in the fourth through sixth decade, with a female-to-male ratio of 2:1.
Gliomas are primary brain tumors that are categorized as high-grade gliomas or low-grade gliomas. High-grade gliomas usually affect patients in the fifth and sixth decades and older, whereas low-grade gliomas usually affect patients in the third and fourth decades.
Primary central nervous system (CNS) lymphoma is a rare tumor that usually affects patients in the sixth decade and older.
There are very few identifiable risk factors for brain tumors. The histology of the primary neoplasm confers the risk of brain metastases because lung cancer, breast cancer, and melanoma are more likely to metastasize to the brain, whereas colorectal, ovarian, and prostate cancers are less likely to metastasize to the brain. Past exposure to ionizing radiation and a family history of a genetic cancer syndrome are the only known risk factors for primary tumors. Despite much press, cell phone use has not been irrefutably shown to be a risk factor for brain tumors. Immunocompromise such as HIV infection is a well- known risk factor for primary CNS lymphoma.
Brain tumors manifest with the subacute or chronic onset of generalized symptoms such as confusion, headaches, seizures, and nausea or focal symptoms and signs such as visual field deficit, loss of language, unilateral weakness, sensory neglect, or difficulty walking. There are no symptoms or signs specific to any brain tumor because the anatomic location of the tumor in the brain dictates the presentation. These symptoms and signs should prompt neuroimaging with MRI. MRI has largely replaced CT for evaluating brain tumors, although CT serves as a quick screening modality and must be used in patients who have contraindications to MRI. Radiographic features on MRI can predict the type of tumor but cannot accurately confirm the pathology. A tissue diagnosis through a biopsy or surgical resection is necessary to confirm the pathology, except in patients with metastatic tumors with a known primary tumor. The differential diagnosis of mass lesions in the brain includes abscess, demyelinating lesion, inflammatory disease, and other infections such as toxoplasmosis and cysticercosis.
A biopsy or surgical resection provides the definitive diagnosis of the tumor. For most tumors, a resection is preferred when safely possible, because the greater amount of tissue obtained avoids the sampling error that can occur with a biopsy. The goal of surgery for all brain tumors is to provide a maximal resection while leaving the patient free of permanent neurologic deficits. Metastatic brain tumors are classified according to the cell of origin. Primary brain tumors are classified according to the World Health Organization (WHO) classification system. Additional molecular classification that can provide prognostic and therapeutic information is often obtained on select primary brain tumors. Oligodendroglioma is a primary brain tumor that has well-characterized chromosomal deletions on the short arm of chromosome 1 and the long arm of chromosome 19 (1p/19q co- deletion) that have been shown to predict improved survival and increased sensitivity to treatment. Similarly, O-6-methylguanine- DNA-methyltransferase (MGMT) promoter methylation is a marker that predicts improved survival and may predict improved response to treatment in high-grade glioma.
A major challenge to treating brain tumor is to find drugs that cross the blood–brain barrier. Many chemotherapy drugs used to treat systemic tumors are too large or hydrophilic to cross the blood–brain barrier. Treatments designed to circumvent the blood–brain barrier have only been modestly successful to date.
Metastatic brain tumors are the most common brain tumors, with as many as 170, 000 new cases diagnosed in the United States each year. Metastatic tumors can occur with or without evidence of a primary neoplasm. Findings on brain MRI suspicious for a metastatic tumor should prompt an investigation for a primary malignancy with body imaging (Figure 1). The discovery of a systemic mass that can be biopsied might avoid a brain biopsy or resection in select patients.
Occasionally, after an extensive evaluation, no evidence of a primary tumor is found. About 50% of patients have a single metastasis, and the rest have multiple tumors. In general, prognosis is poor, but some patients with less-aggressive primary tumors (breast, non–small cell lung carcinoma) can achieve long-term survival.
FIGURE 1 Contrast-enhanced magnetic resonance image shows a homogeneously enhancing mass with surrounding edema at the gray– white junction, suggesting a metastatic tumor.
Tumors can metastasize to the nervous system through infiltration of the cerebrospinal fluid (CSF), a process termed leptomeningeal carcinomatosis or carcinomatous meningitis. Symptoms suggesting leptomeningeal carcinomatosis include altered mental status, headaches, loss of vision, double vision, slurred speech, difficulty swallowing, and lower extremity pain and weakness. Brain MRI can show enhancement of the meninges, and CSF from lumbar puncture shows low glucose and elevated protein with malignant cells. A lumbar puncture is not necessary to confirm the diagnosis in a patient with a known primary malignancy and characteristic clinical presentation and MRI findings. The prognosis is poor, on the order of several months. Patients with lymphoma and breast cancer might realize longer survival.
Several factors determine the approach to treatment of metastatic tumors. The age, comorbidities, functional status, degree of neurologic impairment, and extent of the systemic disease determine whether surgery is indicated. Solitary metastases and large symptomatic tumors in patients with multiple tumors are generally resected in patients who are good surgical candidates. Whether a patient undergoes surgical resection or not, radiotherapy is the mainstay of treatment for metastatic tumors.
The two approaches to radiotherapy are whole-brain radiotherapy and stereotactic radiosurgery. In whole-brain radiotherapy, a dose of radiation is fractionated into several treatment sessions and given to the entire brain. In stereotactic radiosurgery, a high dose of radiation is given only to areas of brain involved with tumor and often in one treatment session. The effectiveness of whole-brain radiotherapy versus stereotactic radiosurgery has not been established in large randomized trials. Whole-brain radiotherapy is more suited for patients with multiple metastases or large tumors (more than 3 cm diameter). Stereotactic radiosurgery is indicated for patients with fewer than four metastases, for smaller-volume tumors (less than 3 cm diameter), and for radioresistant tumors such as melanoma. Whole- brain radiotherapy has the advantage of treating the visible and undetectable tumors, but it carries a risk of delayed neurotoxicity that often manifests as cognitive impairment. Stereotactic radiosurgery has the advantage of local control by treating the visible tumors and carries less risk of delayed neurotoxicity. Stereotactic radiosurgery can be repeated if new tumors develop in areas of brain not previously radiated. The disadvantage of stereotactic radiosurgery is the potential for new tumors to develop in areas of brain not treated.
There is no specific role for chemotherapy for metastatic solid tumors, although some chemotherapy drugs used to treat systemic disease can cross the blood–brain barrier. This is especially true for newer targeted agents in NSCLC and melanoma.
Treatment of leptomeningeal carcinomatosis involves chemotherapy or radiotherapy. Chemotherapy is often administered directly into the spinal fluid (intrathecal), usually through a ventricular (Omaya) reservoir. Alternatively, chemotherapy can be given systemically. Common chemotherapeutic agents include methotrexate (Methotrexate PF), cytarabine (Cytarabine PF), and thiotepa.1 Radiotherapy is usually only used as a salvage treatment after chemotherapy failure.
Meningiomas are the most common primary brain tumor, accounting for more than 32% of all tumors. Meningiomas arise from the arachnoid cap cells. They are often discovered incidentally when a patient undergoes neuroimaging for symptoms that are unrelated to the meningioma. The radiographic appearance of meningiomas is one of the most specific of all brain tumors and allows a confident diagnosis without the need for a confirmatory biopsy (Figure 2). The most common radiographic mimicker is a metastatic tumor to the meninges, but usually a patient in this circumstance has a known history of malignancy. Small meningiomas may be followed with serial imaging. Meningiomas that correlate with neurologic deficits or tumors that have grown significantly over time should be treated.
FIGURE 2 Contrast-enhanced magnetic resonance image shows a homogeneously enhancing mass arising from the dura, with the typical appearance of a meningioma.
Surgical resection is the preferred treatment if it can be safely accomplished, but it should be avoided in the elderly. Meningiomas are graded WHO I to III; 90% are grade I (benign), and grade III (anaplastic) are the most aggressive and likely to recur. Complete resection is curative in most cases, but some meningiomas recur. If recurrent tumors are large or symptomatic, surgery is the preferred treatment if possible. Radiotherapy, either fractionated or stereotactic radiosurgery, can be used postoperatively to treat residual tumor or to treat tumors that cannot be resected. Meningiomas have an intermediate response to radiotherapy, and grade III tumors often show minimal response.
There is no defined chemotherapy for meningiomas, although several drugs are being actively investigated.
Gliomas consist of astrocytomas, oligodendrogliomas, and ependymomas, in decreasing order of prevalence. It was once thought that these tumors derived from mutations of normal glial cells,but it is increasingly recognized that gliomas derive from brain tumor progenitor cells. Glioblastoma is the most malignant glioma and accounts for 60% to 70% of all gliomas. Gliomas are classified by the glial cells from which they originate and the histologic features that give them a grade according to the WHO classification (Table 1).
Grade III and IV tumors are high-grade gliomas, and grade II tumors are low-grade gliomas. Grade I glioma (pilocytic astroctyoma) is rarely seen in adults. A maximal surgical resection that leaves the patient with minimal neurologic deficits is the preferred initial treatment for all grades of gliomas.
World Health Organization Classification of Common Gliomas in Adults
Most high-grade gliomas are glioblastoma or anaplastic astrocytoma (WHO grade III); anaplastic oligodendroglioma and anaplastic ependymoma are less common. The brain MRI often shows a ring- enhancing mass centered in the white matter surrounded by edema and causing mass effect (Figure 3). A maximal surgical resection that leaves the patient without permanent neurologic deficits is the goal in high-grade glioma. A maximal resection, younger age, and good performance status are favorable prognostic factors. Methylation of the MGMT promoter correlates with improved survival. High-grade gliomas are aggressive, incurable tumors; the median survival for glioblastoma is 14 to 18 months and for anaplastic astrocytoma is 2 to 2.5 years.
FIGURE 3 Contrast-enhanced magnetic resonance image shows a ring-enhancing mass with surrounding edema with the typical appearance of glioblastoma.
Treatment of high-grade glioma is based on the histology of the tumor. Glioblastoma is the only high-grade glioma with a standard treatment, but anaplastic astrocytoma are often treated like glioblastoma. The standard treatment consists of fractionated radiotherapy given over 6 weeks with temozolomide (Temodar), an oral chemotherapeutic drug. Temozolomide is given 1 month after the completion of radiotherapy until tumor progression, which occurs on average around 7 months after the original diagnosis for glioblastoma (Table 2). Patients with glioblastoma and anaplastic astrocytoma are usually treated with 6 to 12 months of temozolomide or until tumor recurrence. Careful consideration should be given to neuroimaging findings suggesting tumor progression within the first 6 months after radiotherapy because these changes can reflect radiation necrosis (pseudoprogression) rather than true tumor progression.
Common Chemotherapy for Gliomas
|Generic Name Trade Name Dose|
|Temozolomide||Temodar||75 mg/m2 daily during radiotherapy, 150–200 mg/m2 after radiotherapy on 5 d per 28 d schedule 50 mg/m2 daily or 75 mg/m2 3 wk on, 1 wk off, for recurrent high-grade glioma|
|Bevacizumab||Avastin||10 mg/kg every 2 wk|
In the setting of tumor progression, salvage chemotherapy is the mainstay of treatment. Bevacizumab (Avastin), a drug that inhibits blood vessel formation around tumors, is the most common drug that is given at tumor recurrence. Bevacizumab is sometimes combined with other drugs such as irinotecan (CPT-11 [Camptosar]).1 Temozolomide given in low dose daily is another standard approach for recurrent high-grade glioma. Experimental chemotherapy through a clinical trial is a common option used in recurrent high-grade glioma. Occasionally, surgical resection is indicated to improve symptoms, but it has not been shown to improve survival. Likewise, focused radiation such as stereotactic radiosurgery has not been shown to affect survival.
Anaplastic oligodendroglioma treated with radiation followed by chemotherapy, either PCV (procarbazine [Matulane1], CCNU [Lomustine], vincristine1) or temozolomide while anaplastic ependymoma is usually treated with radiotherapy alone.
Despite being lower-grade tumors, low-grade gliomas are not benign. The natural history is that patients with low-grade gliomas ultimately progress to high-grade glioma. Low-grade gliomas account for about 15% of all primary brain tumors. Low-grade gliomas are more likely to manifest with seizures than high-grade gliomas. The brain MRI often shows a nonenhancing mass with involvement of white matter and sometimes abutting the cerebral cortex (Figure 4). Prognosis varies considerably by tumor histology: Patients with astrocytoma live 5 to 10 years after diagnosis, whereas patients with oligodendroglioma live 10 to 15 years after diagnosis. The isocitrate dehydrogenase I (IDH 1) mutation correlates with improved survival. This mutation is seen in the majority of patients with low-grade glioma.
FIGURE 4 Fluid-attenuated inversion recovery (FLAIR) magnetic resonance image shows a nonenhancing tumor abutting the cerebral cortex with the typical appearance of a low-grade glioma. The tumor proved to be a grade II oligodendroglioma.
There is no accepted standard treatment for low-grade gliomas.
Tumor histology and individual patient characteristics guide treatment decisions. Tumors with oligodendroglial features are more sensitive to chemotherapy than their astrocytic counterparts, especially those with chromosomal 1p/19q co-deletions. The results of a recent randomized clinical trial revealed superior progression free survival and overall survival in patients with low grade gliomas treated with radiation followed by adjuvant PCV.
In the absence of a head to head clinical trial of PCV with temozolomide, many clinicians would use temozolomide in place of PCV since temozolomide is better tolerated. It still common practice to take a watch and wait approach in select patients with newly diagnosed low grade glioma who have had a gross total resection.
When patients with low-grade gliomas have findings on neuroimaging that suggest progressive tumor, a surgical resection or biopsy is often conducted to alleviate symptoms and to establish the grade of the tumor. Patients with low-grade gliomas that progress to high-grade glioma are treated similarly to patients with de novo high- grade glioma but with consideration to previous treatments.
Primary Central Nervous System Lymphoma
Primary CNS lymphoma is a rare non-Hodgkin lymphoma that affects the brain, eyes, meninges, and spinal cord and accounts for about 5% of all brain tumors. This tumor is associated with the immunocompromised state, but it has a significant incidence in the immunocompetent. The characteristic radiographic appearance suggests but does not confirm the diagnosis (Figure 5). If primary CNS lymphoma is suspected, corticosteroids should not be given unless they are necessary to reduce increased intracranial pressure. This is because corticosteroids are directly cytotoxic to lymphoma cells, which can confound the tissue diagnosis. Occasionally, the diagnosis can be obtained through CSF testing, but a brain biopsy is often necessary.
FIGURE 5 Contrast-enhanced magnetic resonance image shows a homogenously enhancing mass near the surface of the ventricle, suggesting primary central nervous system lymphoma.
Surgical resection has no role in treating this tumor because lymphoma is sensitive to chemotherapy and radiotherapy. Staging tests are necessary to rule out a systemic lymphoma that has metastasized to the CNS. Despite being incurable, primary CNS lymphoma is a more treatable tumor, and many patients live 5 years or longer after diagnosis.
Primary CNS lymphoma is treated with intravenous or intrathecal chemotherapy with or without radiotherapy. Methotrexate is the principal drug used either alone or in combination with other chemotherapy drugs. High doses of methotrexate (3.5–8 g/m2)3 must be used to overcome the blood–brain barrier. Owing to the potential for renal toxicity, high-dose methotrexate must be given in a setting where kidney function can be carefully monitored (usually the inpatient setting).
Radiotherapy was previously used as an initial treatment, but it is associated with profound cognitive impairment, especially in patients older than 60 years. However, more recent approaches have used lower doses of radiotherapy combined with chemotherapy with less neurotoxicity reported. Opinion is divided about the use of radiotherapy. Chemotherapy can also be used as a salvage treatment. Besides methotrexate, other commonly used chemotherapy drugs include cytarabine,1 etoposide (Toposar),1 rituximab (Rituxan),1 and procarbazine (Matulane).1 In younger patients, an increasingly used treatment at the time of relapse is high-dose chemotherapy with autologous stem cell transplantation. This approach is increasingly being investigated in the newly diagnosed setting.
1. Ellis T.L., Neal M.T., Chan M.D. The role of surgery, radiosurgery, and whole brain radiation therapy in the management of patients with metastatic brain tumors. Int J Surg Oncol. 2012;2012:952345.
2. Gerstner E.R., Batchelor T.T. Primary central nervous system lymphoma. Arch Neurol. 2010;67:291–297.
3. Norden A.D., Drappatz J., Wen P.Y. Advances in meningioma therapy. Curr Neurol Neurosci Rep. 2009;9:231–240.
4. Sanai N., Chang S., Berger M.S. Low-grade gliomas in adults. J Neurosurg. 2011;115:948–965.
5. Wen P.Y., Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492–507.
1 Not FDA approved for this indication.
3 Exceeds dosage recommended by the manufacturer.