GENERAL PRINCIPLES
Brain tumors are neoplasms that originate in different cells of the brain (primary brain tumors) or originate elsewhere in the body and metastasize to intracranial compartment (secondary brain tumor). Metastatic tumors are the most common type of brain tumors. 1
Classification
Primary brain tumors are classified according to cell type. The majority of primary brain tumors in adults are gliomas (oligodendrogliomas and astrocytomas), ependymomas, meningiomas, and primary CNS lymphomas. The most common parenchymal metastases are from lung cancer, renal cell cancer, melanoma, breast cancer, and lymphoma. Dural metastases are seen most commonly with breast or prostate cancer.
Epidemiology
Brain tumors are rare malignancies—the 16th most common in frequency among tumors in adult patients. Primary intracranial tumors have an incidence of 7.1 per 100,000, wit ~22,000 people diagnosed and 13,000 deaths in the United States each year.2 Metastases to the brain are more common, with one estimate that >100,000 patients per year die from a systemic cancer that has metastasized to the brain.
Risk Factors
Ionizing radiation and genetic predisposition in identified syndromes are currently the only known unequivocal risk factors for developing brain neoplasms. Irradiation of the cranium, even at low doses, can increase the incidence of meningiomas by a factor of 10 and the incidence of glial tumors by a factor of 3 to 7. Other potential risks, such as use of cellular phones, exposure to high-tension power wires, head trauma, and exposure to nitrosourea compounds have provided conflicting and unconvincing data and, currently, are not considered to be risk factors.
Management
Management of these tumors often involves a multidisciplinary approach involving the neurosurgeon, neuro-oncologist, radiation oncologist, and neurologist, among others. Rehabilitation efforts may be multidisciplinary and involve rehabilitation specialists, physical and occupational therapists, and nurses.
ASTROCYTOMA
GENERAL PRINCIPLES
The epidemiology of astrocytic tumors depends on their histological grade. Low-grade (grades I and II) astrocytomas are typically found in children and young adults. The peak incidence in adults occurs in the third to fourth decade of life. High-grade astrocytomas (grade III and IV) typically present in the fourth or fifth decade, and glioblastoma multiforme (GBM) usually presents in the sixth or seventh decade. High-grade glial tumors are most common, with an annual incidence of 3 or 4 per 100,000 populations. Of these, 80% are GBMs. GBMs may be either primary or secondary (meaning the GBM has arisen from a tumor that was initially a low-grade astrocytoma). These secondary GBMs tend to occur in younger adults, typically ≤45 years. The male-to-female ratio of malignant astrocytic tumors is 3:2.1
Classification/Grading
These tumors are graded by the World Health Organization’s four-tiered grading system.3 The criteria used to grade these tumors include the following features: nuclear atypia, mitotic activity, endothelial proliferation, and necrosis.
Grade I: absence of all features
Grade II: any one feature
Grade III: any two features (anaplastic astrocytoma)
Grade IV: any three features (GBM)
Pathophysiology
Astrocytomas are composed of cells with elongated or irregular, hyperchromatic nuclei and eosinophilic, expressing glial fibrillary acidic protein in the cytoplasma. GMBs may arise de novo from neural progenitor cells or transition from low-grade astrocytomas. Molecular genetic abnormalities include inactivation of tumor suppressor genes P53, PTEN, CDKNA, CDKN2B, and RB, overexpression of growth factors PDGF and EGFR, and isocitrate dehydrogenase mutation.4
DIAGNOSIS
Clinical Presentation
Presentation of these tumors depends on their grade. Low-grade astrocytomas present with seizure in ~90% of cases. Typically, the seizures are focal, but they may become generalized and cause loss of consciousness. Headache is found in 40% of patients. In general, the headache is worse in the morning and improves in a few hours, usually without treatment. On occasion, headache can be unilateral and throbbing, mimicking a migraine or even a cluster headache. Symptoms such as hemiparesis and mental status changes are found in 15% and 10% of patients, respectively. These symptoms reflect the location of the tumor. Malignant astrocytic tumors, on the other hand, present with seizure 15% to 25% of the time and present with headache 50% of the time. These tumors are much more likely to present with focal neurologic deficits such as hemiparesis, seen in 30% to 50% of patients, and mental status abnormalities, seen in 40% to 60% of patients.
Diagnostic Testing
The diagnosis of the tumors is usually suggested by MRI. Low-grade astrocytoma is usually seen as a diffuse, nonenhancing mass that typically has a local mass effect and evidence of cortical infiltration with abnormal signal, reaching the surface of the brain. The radiologic borders of these tumors are usually distinct, with no surrounding edema. High-grade astrocytomas have an irregular contrast enhancement, which is often ringlike. These lesions are usually associated with edema, and the mass effect can be severe enough to cause herniation. Pathologic diagnosis of these tumors can be done by stereotactic biopsy or surgical excision of the lesion. A stereotactic biopsy can (and often does) provide adequate tissue for grading. However, in some instances it can underestimate the grade, especially in large tumors.
TREATMENT
Therapy of low-grade tumors involves surgical debulking of the tumor and perhaps excision of the entire tumor if the tumor does not involve critical structures such as the language areas. With low-grade lesions, the next step in treatment is typically radiation if the tumor is not completely resected, has high MIB-1 index, or the patient is over 40 years of age. In younger patients with low-grade tumors that are completely resected, observation is also appropriate. Radiation may be done immediately after surgery or may be deferred until there is radiographic evidence of tumor progression. Studies at this time have not shown a difference in survival benefit between immediate and delayed irradiation. Many physicians will wait to start radiation to provide another treatment option at the time of progression. Chemotherapy is also a treatment option in the recurrent setting. Surveillance for recurrence with an MRI is performed every 3 to 6 months for 5 years and then at least annually.
Therapy of anaplastic astrocytoma and GBM is identical. The initial step is to surgically excise the tumor. Every effort should be made to remove as much tumor as possible, as this is associated with longer survival and improved neurologic function. Subtotal resection is done if maximal safe resection is not feasible. During surgery, carmustine (BCNU) wafers may be placed for local chemotherapy. This is followed by 60 Gy in 30 fractions of high-dose irradiation of the involved field with concurrent daily oral temozolomide (75 mg/m 2).5Bactrim should be used for PCP prophylaxis during radiation. After completion of radiation, the temozolomide is continued with monthly treatments of 5-day duration for 6 cycles. MRI is performed 2 to 6 weeks after radiation therapy, and then 2 to 4 months for 2 to 3 years. At the time of recurrence, if the disease is localized, a second resection and BCNU wafer insertion should be done if possible. Bevacizumab, a vascular endothelial growth factor inhibitor, is FDA approved as a single agent for recurrent or relapsed anaplastic astrocytoma and GBM.6 Nitrosourea, cyclophosphamide, procarbazine, lomustine, and vincristine (PCV regimen) or platinum-based regimens are also treatment options for recurrence.7
Brainstem gliomas are inoperable. These tumors are treated with irradiation. If there is increased intracranial pressure, a shunt may be placed.
PROGNOSIS
Prognosis associated with astrocytomas is determined by their grade. The median survival for adult low-grade astrocytomas is 5 years. Most of these patients die from the progression of their disease to a higher grade. The median survival for malignant astrocytomas is typicall ~3 years. The median survival for GBM is typically 1 year.
OLIGODENDROGLIOMAS
GENERAL PRINCIPES
Epidemiology
Oligodendrogliomas are usually low-grade neoplasms and account for <5% of intracranial tumors and ~20% of glial neoplasms. Mean age at presentation is 38 to 45 years, with a slight male predominance.
Pathophysiology
Oligodendrogliomas arise from oligodendroglial cells, which are responsible for axonal myelination. More than one-third of these tumors have intermixed astrocytic or ependymal elements and are therefore considered “mixed gliomas.” They are classified as low-grade and anaplastic oligodendrogliomas (high-grade). Classical oligodendrogliomas are highly associated with the 1p/19q codeletion.
DIAGNOSIS
Clinical Presentation
Patients may present with seizure, progressive hemiparesis, or cognitive impairment, depending on tumor location. These tumors are known to have delicate vasculature and hemorrhage easily, and the patient may present with an acute onset of hemiparesis, headache, and/or lethargy.
Diagnostic Testing
Diagnostic evaluation usually begins with an MRI. The radiologic hallmarks differentiating this tumor from an astrocytoma are lack of contrast enhancement and calcification of the tumor. Biopsy, as in astrocytoma, is necessary for definitive diagnosis, and excisional biopsy is preferred to stereotactic biopsy. Exam by light microscopy shows oligodendroglioma cells that may have regular and rounded nuclei, with some nuclei having a halolike appearance (sometimes termed fried egg appearance). There are currently no immunohistochemical stains or markers that definitively establish the diagnosis.
TREATMENT
As is seen with low-grade astrocytomas, therapy may not be necessary at initial presentation if the patient is asymptomatic and seizures are adequately controlled. Therapy of low-grade tumors usually begins with the excisional biopsy performed to diagnose these tumors. After surgery, observation or focal irradiation and chemotherapy are performed. Adjuvant chemotherapy includes temozolomide, PCV regimen, nitrosourea, or platinum-based regimen. Studies have shown that 66% of these tumors respond to therapy. 7 Chemotherapy is not curative, but it can induce sustained remissions. Management should be individualized, and there is some evidence that 1p and 19q loss in the tumor is associated with increased survival.
PROGNOSIS
The median survival for patients with low-grade oligodendroglioma is currently 10 years and that for anaplastic oligodendroglioma is 3 to 5 years. This long survival is attributed to earlier diagnosis of these tumors with MRI and to their chemosensitivity. Most oligodendrogliomas progress by becoming malignant.
EPENDYMOMAS
GENERAL PRINCIPLES
Definition
Histologically, ependymomas arise from the ependymal cells, which are normally lining the ventricular chambers and the central canal of the spinal cord. Most are histologically benign. Usually they are classified as either high or low grade. These tumors may metastasize via cerebrospinal fluid (CSF) pathways. Spinal cord metastases that arise from a brain lesion are known as drop metastases. The overall risk of seeding is ~10%, and the greatest risk occurs with high-grade infratentorial lesions.
Epidemiology
Ependymomas have a bimodal incidence, with an early major peak at 5 years and a late minor peak at the median age of 34 years. They account for 5% of intracranial tumors in the adult population. There is a 3:2 male predominance.
Pathophysiology/Molecular Genetics
Ependymomas are generally slow-growing tumors. Genetic changes include losses of chromosome areas 6q and 22q and the X chromosome, or gains of either 1q or 9q, with monosomy 22 being the most frequent change in sporadic ependymomas.
DIAGNOSIS
Clinical Presentation
Clinical presentation depends on the location of the tumor. Most adult tumors occur in supra- and infratentorial regions. They are also frequently seen in the spinal canal, especially the lumbosacral region. The supra- and infratentorial lesions may lead to symptoms of increased intracranial pressure or focal neurologic deficits and seizures. Ataxia, vertigo, and neck stiffness are common presenting symptoms with infratentorial lesions.
Diagnostic Testing
Extent of disease is assessed with an MRI of the brain and spinal cord. More than 50% of these tumors will have calcification. Histological confirmation is required for diagnosis, and open surgery is favored to stereotactic biopsy. CSF cytology is important for staging.
TREATMENT
Therapy is surgical excision followed by observation if completely resected or irradiation if not completely resected. Gross total resection is the best determinant of outcome. Steroids may be given both before and after surgery to help decrease edema and other complications. Targeting only the local site with methods such as high-fractionation radiotherapy and stereotactic radiosurgery has shown promise in treating the tumor and limiting some of the complications seen. There is no definitive role for chemotherapy at this time.7
Evidence of dissemination, as determined by MRI, positive CSF cytology, or myelographic findings, warrants additional radiation of the spinal axis. The dose and the extent of irradiation are also determined by the histological grade, with anaplastic lesions generally receiving more intensive regimens.
PROGNOSIS
Prognosis for these patients is excellent after treatment if the tumor is completely resected. The 5-year disease-free survival is >80%. Ten-year survival rates range from 40% to 60%. Age is the most important prognostic factor, with younger patients having a worse outcome. Poor prognosis includes high histological grade, incomplete surgical resection, and a poor performance status. Patients should be followed by MRI, as the recurrence rate is significant.
MENINGIOMA
GENERAL PRNCIPLES
Meningiomas are extra-axial primary brain tumors. They are of leptomeningeal origin, arising from arachnoid cap cells. They account for 33.8% of all primary brain and CNS tumors.
Classification
Meningiomas typically are classified as one of four histological patterns: meningothelial, transitional, fibrous, and angioblastic. The first three subtypes account for the majority of the meningiomas and have benign behavior. The angioblastic subtype is the least common but most aggressive form. Malignancy is determined by the amount of brain invasion, increased and atypical mitotic figures, increased cellularity, a papillary histological pattern, and distant metastases. Malignant meningiomas account for between 1% and 10% of cases. Metastatic disease is seen in <0.1% of cases. Radiation-induced meningiomas are more commonly atypical or malignant.
Epidemiology
The annual incidence of meningiomas is ~7.8 per 100,000, although most are asymptomatic and discovered incidentally at autopsy. The incidence of symptomatic tumors is ~2 in 100,000, and they occur more frequently in women than men. They are primarily adult tumors, with a peak occurrence at age 45 years. There is an association with breast cancer, neurofibromatosis, and a history of cranial irradiation.
Pathophysiology/Molecular Genetics
Deletion and inactivation of NF2 on chromosome 22 is a predominant feature in sporadic meningiomas. Additional genes on chromosome 22 are likely involved as well. 14q, 1p, 6q, and 18q are also lost in meningiomas. Meningiomas are reported in families of several cancer predisposition syndromes involving the genes NF1, PTCH, CREBBP, VHL, PTEN, and CDKNA.8
DIAGNOSIS
Clinical Presentation
Meningiomas can arise virtually anywhere along the leptomeninges. Ninety percent are intracranial, and 90% of these are supratentorial. The three most common sites are adjacent to the superior sagittal sinus, over the cerebral convexities, and along the sphenoid ridge. These three sites account for 60% of intracranial meningiomas. Clinical presentation of meningiomas varies greatly depending on where they arise. Focal neurologic deficits are common,as are symptoms of increased intracranial pressure. Seizures are particularly common, occurring in >50% of patients. Many are found incidentally on CT or MRI.
Diagnostic Testing
Diagnosis of these tumors is suggested by MRI. They have a characteristic appearance of marginal dural thickening that tapers peripherally (the “tail” sign), as well as circumscribed, extra-axial, homogeneously enhancing, dural-based masses. Peritumoral edema and mass effect are common. Twenty percent of the tumors have calcification.
TREATMENT
Observation is preferred for tumor <3 cm and asymptomatic patients. Surgical resection is recommended for tumor >3 cm or symptomatic patients.7 Total resection is curative for low-grade meningiomas. High-grade meningiomas require radiation therapy followed by surgical resection. Stereotactic radiosurgery is frequently used for tumors at the base of the skull, which are usually unresectable, because they are intertwined with vital structures. At the time of recurrence, a second resection should be performed, followed by external-beam irradiation.
PROGNOSIS
Meningiomas have an excellent prognosis. Disease-free survival at 10 years is 80% to 90% for all meningiomas. If the tumor is partially resected, the 10-year progression-free survival is 50% to 70%. Nearly 65% of malignant meningiomas will recur in 5 years, and nearly 80% will recur in 10 years. Patients who are younger, do not have CNS invasion, and are able to have more extensive resection do better overall. All patients should be followed closely for recurrence.
PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
GENERAL PRINCIPLES
Primary central nervous system lymphoma (PCL) is an uncommon variant of extrandal non-Hodgkin lymphoma that can affect the brain, leptomeninges, eyes, or spinal cord without evidence of systemic disease.
Classification
Ninety percent of non-HIV-associated PCLs are diffuse large B-cell type, with the remaining 10% being poorly characterized low-grade lymphomas, Burkitt lymphomas, or T-cell lymphomas.
Epidemiology
PCL accounts for approximately 3% of primary brain tumors. Patients with congenital or acquired immunosuppression have a markedly increased risk of PCL. The incidence of non-HIV-related PCL peaks in the sixth to seventh decades, with a male-to-female ratio of 2:1. There are no environmental or behavioral risk factors that are associated with the development of this disease. In immunocompromised patients, the risk increases 100- to 1000-fold. This increase is believed to most likely be secondary to infection with Epstein–Barr or other lymphatic viruses, which have been speculated to be possible transforming events.9
DIAGNOSIS
Clinical Presentation
PCLs are solitary in ~50% of patients on presentation, and patients most commonly present with behavioral or cognitive changes, seen in approximately two-thirds of patients. Hemiparesis, aphasia, and visual field deficits are seen in ~50% of patients and seizures in 15% to 20%. Approximately 15% will develop uveitis, sometimes preceding cerebral symptoms by months.
Diagnostic Testing
These tumors are typically diagnosed with the use of MRI. They usually are periventricular in location and have a homogeneous pattern of enhancement. Approximately 25% to 50% of patients will also have cells identified in the CSF. Stereotactic biopsy is necessary for tissue diagnosis. Further workup should also include a slit-lamp eye exam, CSF cytology with cell count and protein assessment, spinal MRI, chest x-ray, HIV test, blood cell count, and complete metabolic panel to assess for other sites of disease.
TREATMENT
Unlike other intracranial tumors, there is no role for surgery other than a stereotactic biopsy in primary CNS lymphoma treatment.
Corticosteroids can work rapidly to cause tumor regression and decrease peritumoral edema, but should be held prior to diagnostic biopsy in clinically stable patients. They have a direct lymphocytolytic effect that may disrupt cellular morphology and lead to diagnostic inaccuracy.
High-dose methotrexate as a single agent is now the standard care.
Whole-brain radiation therapy is used as salvage treatment of recurrence. The radiation ports should include the orbits if retinal or vitreous disease is present and also the spinal axis if CSF cytology findings suggest meningeal disease.
Intrathecal chemotherapy is needed if CSF cytology or spinal MRI is positive.
PROGNOSIS
Prognosis is dependent on treatment regimen. Radiation alone usually results in a median survival of 12 to 18 months, but is not recommended for patients older than 60 years. When chemotherapy is used before radiation, the median survival improves to 42 months, with 25% of patients alive at 5 years. Important indicators of poor prognosis include age >60 years, ECOG performance status >1, elevated serum LDH, elevated CSF protein, and involvement of deep regions of the brain.10
METASTATIC TUMORS OF THE
CENTRAL NERVOUS SYSTEM
GENERAL PRINCIPLES
Metastatic lesions to the brain typically occur via hematogenous spread and are 10 times as common as primary CNS tumors. There typically is a predilection for the gray matter–white matter junction in which cerebral blood flow is greatest. Spinal involvement may be secondary to spread from the primary site to the vertebral body, with subsequent compression of the spinal cord, retrograde spread via the vertebral venous plexus, or direct invasion of the epidural space via the intervertebral foramen. Alternatively, multifocal spread to the meninges may occur. Twenty percent of cancer patients will develop brain metastases, and 10% will develop spinal metastases. Refer to Chapter 35 for more information regarding spinal cord compression.
The lung is the most common origin of brain metastases. Other sources include breast (especially ductal carcinoma), melanoma, renal cell cancer, lymphoma, GI malignancies, germ cell tumors, and thyroid cancer.
DIAGNOSIS
Clinical Presentation
Metastatic tumors present with the same clinical features common to any intracranial mass but occur with a much more rapid rate of progression. Focal deficits, seizures, and symptoms of increased intracranial pressure are the usual presenting symptoms. The rapid progression is believed to be secondary to the development of cerebral edema, which is usually associated with metastatic lesions.
Diagnostic Testing
Diagnosis of these lesions is suggested by their appearance on MRI or CT using contrast. Ring-enhancing or diffusely enhancing lesions, typically surrounded by a zone of edema disproportionate to the size of the lesion, are most commonly seen. MRI is also useful and is more sensitive in identifying multiple lesions. Meningeal involvement requires both brain and spinal imaging, where hydrocephalus or more diffuse enhancement may be seen. CSF with positive cytology is diagnostic, and an elevated CSF protein level is suggestive of meningeal disease. These cancers are typically considered incurable with few exceptions.
TREATMENT
Therapy is palliative in nature. High-dose glucocorticosteroids will frequently provide a rapid improvement in symptoms as the surrounding edema decreases. Improvement occurs within 6 to 24 hours and is sustained with continuous therapy. There is no role for prophylactic anticonvulsants in patients with brain metastases. Whole-brain radiation therapy is the primary treatment mode for focal brain metastases. For those patients who have a single lesion in the brain, surgical excision or gamma-knife radiation may be used as a palliative measure. Surgical excision is typically followed by whole-brain irradiation. For leptomeningeal disease, radiation is limited to symptomatic sites and intrathecal chemotherapy is initially administered weekly, and then monthly after four treatments. Methotrexate is the most often used regimen, but cytarabine and thiotepa are other options. In primary cancers that are chemotherapy responsive, systemic chemotherapy may provide some improvement, although there is typically less of a response than seen in the primary tumor.
PROGNOSIS
Survival in untreated brain metastases is typically 1 month. Survival improves to a median of 3 to 6 months with the use of steroids and radiation. If the tumor is amenable to surgical excision, the survival may improve to a median of 40 weeks.
REFERENCES
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2. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.
3. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.
4. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–1812.
5. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–996.
6. Vredenburgh JJ, Desjardins A, Herndon JE, 2nd, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25:4722–4729.
7. National Comprehensive Cancer Network. Central Nervous System Cancers. Version I, 2011. Adult cancer pain. In:National Comprehensive Cancer Network Practice Guidelines in Oncology, 2011:1. Last accessed:4/5/2011 <http://www.nccn.org/professionals/physician_gls/pdf/cns.pdf>.
8. Wiemels J, Wrensch M, Claus EB. Epidemiology and etiology of meningioma. J Neurooncol. 2010;99:307–314.
9. Gerstner ER, Batchelor TT. Primary central nervous system lymphoma. Arch Neurol. 2010;67:291–297.
10. Ferreri AJ, Blay JY, Reni M, et al. Prognostic scoring system for primary CNS lymphomas:the International Extranodal Lymphoma Study Group experience. J Clin Oncol. 2003;21:266–272.