Cancer of the Central Nervous System

Cell Proliferation

Normal cells rely on growth factors secreted in their local environment to stimulate their growth. However, many CNS tumors have developed the ability to express their own growth factors along with the respective receptors, resulting in an autocrine loop that allows for self-stimulation. Platelet-derived growth factor receptor alpha (PDGFRα), for example, is overexpressed in all grades of astrocytomas, but only higher-grade tumors overexpress the ligands PDGFA and PDGFB. Insulin-like growth factors and their receptors both are expressed in brain tumors, including gliomas and meningiomas. The epidermal growth factor receptor (EGFR) is amplified or overexpressed in 50% of glioblastomas, and expression of transforming growth factor–α (TGF-α), a ligand that binds to this receptor, is increased in many gliomas. Both scatter factor (also known as hepatocyte growth factor ) and its receptor c-Met are expressed in gliomas, with the highest level of expression seen in the most malignant tumors.

As a result of increasing expression of receptors and ligands, increased signaling occurs in many brain tumors, resulting in activation of many different pathways that are important in proliferation (reviewed by Rao and James ). The best studied of these pathways is the mitogen-activated protein kinase (MAPK) pathway, which involves Ras and Raf. Another pathway that has attracted much attention is the phosphatidylinositol 3 (PI3) kinase pathway, which leads to activation of Akt. Mutation of PTEN , which occurs in 30% to 40% of glioblastomas, also can lead to increased Akt activation.

Ras activation commonly is seen in human astrocytomas and neurofibromas despite the fact that these tumors rarely contain Ras mutations. In astrocytomas, Ras activation probably occurs through activation of growth factor receptors such as EGFR and PDGFR. Other mechanisms of activation of aberrant G proteins have been identified in other CNS tumors (reviewed by Woods and coworkers ). In NF1, loss of expression of neurofibromin, an inactivator of Ras, is seen (see Table 63.3 ). This loss of neurofibromin leads to the increased Ras activation seen in NF1-associated astrocytomas. Pituitary adenomas often show activation of the alpha subunit of the large heterotrimeric Gs protein, resulting in mitogenic signaling.

The Wnt pathway has been shown to play a role in glioma tumorigenesis. Investigators have shown that the Wnt-specific secretory protein Evi is overexpressed in astrocytomas. Furthermore, the same researchers showed that the depletion of this protein in glioma cells leads to decreased cell proliferation and apoptosis. In addition, silencing of Evi in glioma cells leads to reduced cell migration and the ability to form tumors in vivo . Involvement of Wnt/β-catenin signaling in gliomas has been reviewed by Zhang and colleagues.

Cell proliferation is intimately tied to cell cycle regulation. Mutations in the p16/Cdk4 or Cdk6/cyclin D/Rb pathway or the p21/p53/Mdm2/p19 ^ARF pathway are common in many brain tumors, particularly gliomas.

Invasion

Many brain tumors, particularly gliomas, display an invasive phenotype with infiltration of tumor cells into surrounding tissues, making a cure very difficult to achieve. In fact, tumor recurrence was reported in one case even after resection of the entire hemisphere in which a glioma was located. The process of invasion involves several steps: detachment of the invading cell from the primary tumor mass, adhesion to extracellular matrix (ECM), degradation of ECM, and cell motility and contractility. The details of the mechanisms of glioma invasion are only beginning to be understood. Numerous molecules associated with invasion have been found to be upregulated in gliomas, including tenascin-C, secreted protein acidic and rich in cysteine (SPARC), various integrins, and matrix metalloproteinases (reviewed by Demuth and Berens ).

Some controversy exists regarding deregulated Rho guanosine triphosphatase (GTPase) signaling in brain tumors. For example, although RhoA and RhoB are reduced in some astrocytic tumors, some studies report Rho-dependent lysophosphatidic acid–induced migration in glioma cells. Expression of another member of the Rho subfamily, Rac1, has been found to be reduced in astrocytic tumors; in addition, this protein has been shown to be overexpressed and to have induced invasion in medulloblastoma tumors. The role of Rho GTPases has been reviewed by Khalil and El-Sibai.

Angiogenesis and Hypoxia

For a tumor to grow beyond a certain size, it must develop a blood supply. The vasculature of normal brain, which is composed of endothelial cells, pericytes, and astrocytes, is highly specialized. Together these cells form the blood-brain barrier, which selectively restricts exchange of molecules between the intracerebral and extracerebral circulatory systems. As primary brain tumors or brain metastases grow, the integrity of the blood-brain barrier is compromised.

A number of growth factors are known to be important in angiogenesis. The most prominent of these is vascular endothelial growth factor (VEGF), which is overexpressed in many brain tumors. In one study, increasing VEGF expression correlated with increasing malignant grade in astrocytomas, oligodendrogliomas, and ependymomas. In this study it also was found that increased expression of the VEGF receptors Flt-1 and KDR in tumor vasculature correlated with increasing VEGF expression and malignant grade. Hypoxia and acidosis have been shown to independently regulate VEGF transcription in brain tumors in vitro and in vivo. In addition, both tumor suppressors and oncogenes, hormones, cytokines, and other signaling molecules have been shown to regulate VEGF expression. Growth factors other than VEGF that may play a role in angiogenesis in gliomas include members of the TGF-β family, PDGF, placental growth factor, basic fibroblast growth factor, and scatter factor/hepatocyte scatter factor. Angiogenesis can also be negatively regulated by factors such as thrombospondins 1 and 2 (TSP1 and TSP2). TSP1 is positively regulated by p53, and thus loss of p53, which commonly occurs in gliomas, can lead to decreased TSP1 expression and increased angiogenesis.

Angiogenesis is particularly prominent within glioblastomas. Among the characteristic features of these tumors are endothelial proliferation and neovascularization. A variety of growth factors that can increase angiogenesis are expressed by glioblastomas, with the foremost being VEGF. VEGF, also known as vascular permeability factor, is a potent inducer of capillary permeability. The high levels of VEGF expression in glioblastomas may be responsible for the edema associated with these tumors. Some evidence indicates that genetic changes common to glioblastomas, such as EGFR activation and PTEN mutation, may contribute to high levels of VEGF expression, perhaps through activation of the PI3 kinase pathway.

Despite expressing high levels of VEGF, glioblastomas contain significant regions of hypoxia, which may be a cause of treatment resistance. Hypoxia has been shown to be present in malignant gliomas with both polarographic needle electrode measurement and binding of the 2-nitroimidazole EF5. Hypoxia, as measured by binding of EF5, has been shown to correlate with more rapid tumor recurrence. Evidence indicates that hypoxia is involved in many aspects of tumor growth, including induction of angiogenesis, increased invasion and metastases, resistance to chemotherapy, resistance to radiotherapy, increased brain tumor stem cell population, and stem cell genetic instability.

The histologic features of glioblastoma are consistent with this notion of hypoxia, including the presence of pseudopalisading necrosis and proliferative blood vessels. Pseudopalisades seen within glioblastomas represent a wave of tumor cells actively migrating away from central hypoxia and are thought to arise as a result of vasoocclusion and intravascular thrombosis. High VEGF levels and robust neovascularization may be explained by hypoxia-induced VEGF simulation of new vessels.

Stem Cells

The tumor stem cell hypothesis may help explain the resistance of glioblastoma to current therapies. The tumor stem cell hypothesis suggests that a subset of tumor cells, called tumor stem cells, stemlike cells, or tumor-initiating cells, are endowed with characteristics of normal stem cells, such that they can self-renew and are able to produce a variety of cell types. Because the stemlike cells have properties different from the cells constituting most of the tumor, a different approach to eradicating these stemlike cells may be necessary.

Identification of glioblastoma stemlike cells has proved to be challenging. Early studies showed differences between CD133+ and CD133− glioma cells, including differences in tumor-forming capacity in xenografts. However, other studies have shown that CD133− stemlike cells may also be capable of forming tumors, although these two cell populations exhibit distinct molecular profiles and growth characteristics.

Efforts are being made to elucidate transduction pathways that influence tumorigenicity and are unique to glioma stemlike cells to allow treatments to target these pathways. It has been demonstrated that glioma stemlike cells may be relatively radioresistant as a result of overexpression of DNA damage repair proteins, including the checkpoint kinases Chk1 and Chk2. The cells may be made more radiosensitive by using specific inhibitors of Chk1/Chk2. Piccirillo and colleagues showed that CD133+ glioblastoma stem cells have a functional bone morphogenetic protein receptor pathway. By exposing mice implanted with orthotopic glioblastomas to bone morphogenetic protein 4, these researchers were able to cause the CD133+ cells to differentiate toward glial cells and reduce tumor growth. These two strategies have the potential to be used to target stem cells in glioblastomas. Another potential strategy is to target the tumor stroma, which provides a specialized niche for tumor cells. Calabrese and associates showed that stem cells in brain tumors occupied a perivascular niche and could be targeted by antiangiogenic therapy.

Other potential targets include signal transducer and activator of transcription 3 (STAT3), a transcription factor activated by interleukin (IL)-6, a molecule that is overexpressed in glioblastoma. STAT3 is constitutively active in numerous cancers, including glioblastoma. Expression of a dominant negative mutant STAT3 or silencing STAT3 with a lentivirus have been shown to reduce proliferation of a glioblastoma cell line. Other groups are investigating nanotechnology to target glioma stemlike cells. Some investigators have used iron oxide nanoparticles conjugated to a glioblastoma-specific target of EGFRvIII in an animal model, whereas others have used curcumin nanoparticles to inhibit glioblastoma and medulloblastoma cell proliferation in culture. Glioblastoma stemlike cells have been reviewed in detail by Nduom and colleagues and by Tabatabai and Weller. The stemlike cell hypothesis also applies to other brain tumor histologic types. The roles of medulloblastoma and ependymoma tumor-initiating cells have been reviewed by Manoranjan and colleagues and Poppleton and Gilbertson, respectively.

Pathophysiology of Signs and Symptoms

Parenchymal brain tumors produce clinical signs and symptoms by three main mechanisms, each of which has important implications for therapy. First, infiltration along nerve fiber tracts is typical of primary brain tumors such as low-grade astrocytomas and oligodendrogliomas. The first clinical manifestation may be seizures. Normal brain tissue may be present within areas appearing abnormal on magnetic resonance imaging (MRI), and functional mapping may be necessary for safe resection of these slowly growing tumors. Second, displacement of brain tissue with production of vasogenic edema is typical of cerebral metastases. Such tumors sometimes can be resected or irradiated focally with less risk to adjacent normal brain tissue than is the case with infiltrating tumors. Third, rapidly growing aggressive tumors such as high-grade astrocytomas may enlarge as a mass and also destroy surrounding neuropil to such an extent that surgical resection, although helpful for the reduction of mass effect and intracranial pressure (ICP), may not alleviate local symptoms and signs.

Intracranial neoplasms usually produce progressive symptoms. Location and rate of growth determine both general and specific localizing symptoms and signs. Thus a patient with a low-grade glial tumor may have seizures for many years or may exhibit behavioral alteration for many months before focal signs develop. With a more aggressive glial neoplasm, headache and focal signs may develop over a few weeks. Apoplectic onset is associated with hemorrhage or the development of hydrocephalus.

Brain tumor symptoms may be general, localizing, or falsely localizing. General symptoms include headache, lethargy, nausea, vomiting, and nonspecific cognitive or balance difficulties. These symptoms may be manifestations of increased ICP from a combination of expanding tumor volume and the production of associated vasogenic cerebral edema. Tumors also may cause raised ICP by obstruction of the ventricular system or blockage of the venous sinuses. Abrupt headache and exacerbation of neurologic signs may accompany the plateau waves of sudden increased ICP.

Sustained ICP in excess of 200 mm H ₂ O causes brain shifts that can displace brain tissue through fixed intracranial openings, producing life-threatening herniation syndromes ( Fig. 63.2 ). The uncal herniation syndrome is caused by tumors arising in the lateral aspect of the brain, most commonly the temporal lobe. An early, consistent sign of compressive uncal herniation is a unilaterally dilated pupil due to compression of the ipsilateral third cranial nerve, which is followed by extraocular movement abnormalities consistent with an oculomotor palsy. The posterior cerebral artery may be compressed against the tentorium, leading to homonymous hemianopia. Brainstem compression can cause compression of the contralateral cerebral peduncle against the edge of the tentorium, causing what is known as the Kernohan notch phenomenon. Patients with uncal herniation initially may be awake, but progression to obtundation, coma, and death may occur rapidly.

The central herniation syndrome results from tumors that arise along the midline axis of the brain, especially those deep in the basal ganglia and thalamus regions. The initial signs and symptoms are due to diencephalic compression. The syndrome often first manifests with an alteration in the level of alertness and behavior. Some patients become agitated, whereas others become very drowsy. Hemisensory or hemiparetic deficits and periodic Cheyne-Stokes respirations may develop in these patients. Initially with diencephalic compression, pupils are small (1–3 mm), but as the syndrome progresses to compress the midbrain and upper pons, the pupils dilate moderately and fix at midposition (3–5 mm). As the syndrome progresses, patients become progressively lethargic and apathetic and Cushing's signs of hypertension and bradycardia may develop as a result of direct compression of the hemodynamic control nuclei within the brainstem.

Tonsillar herniation may be caused by an expanding mass in the posterior fossa. Tonsillar herniation results in the cerebellar tonsils being pushed through the foramen magnum. The syndrome is characterized by posterior headache, vomiting, stiff neck, and sometimes opisthotonic posturing. Other features may include dysconjugate eye movements and syncope with cough or sudden postural change. As a result of direct compression of the medulla and its respiratory center, irregular breathing and acute apnea may develop.

These herniation syndromes can rapidly progress from the onset of symptoms to death. They can be precipitated by medical procedures. Lumbar puncture may lead to tonsillar herniation, and ventriculostomy may result in upward herniation in which the brainstem is forced up through the tentorial notch. A high index of suspicion is required to successfully diagnose and treat this condition with emergency intubation and administration of appropriate therapy (see the section on treatment of brain tumor symptoms ).

General Signs and Symptoms

Headache results from traction on pain-sensitive structures of the intracranial contents, including the large cerebral vessels, the dura and meninges, the venous sinuses, cranial nerves V and IX, and the second and third cervical nerve roots. Headache is the most common symptom of a brain tumor and occurs in approximately 50% of patients at some time during the course of the illness. Headache more frequently accompanies rapidly growing than slowly growing tumors. Tumors located in neurologically noneloquent brain areas such as the nondominant frontal and temporal lobes may manifest with headache as the sole clinical manifestation. The “classic” brain tumor–associated headache often is worse in the morning and lateralized to the affected side of the brain. Brain tumor–associated headache may be worsened by coughing or straining. A majority of patients with brain tumors, however, do not have these classic symptoms but instead have headaches that are deep, aching, and difficult to distinguish from tension-type headache. Headaches from posterior fossa tumors are localized to the back of the head or neck, whereas headaches from tumors of the anterior and middle cranial fossae may be referred to the forehead or eye, at times being misconstrued as a sinus headache.

Brain tumor–associated cognitive changes initially may be subtle and frequently are misdiagnosed as depression or, in the older patient, age-associated forgetfulness or early Alzheimer disease. Frontal lobe tumor location is the most common site for tumors producing these symptoms as the initial manifestation of a neoplasm.

Several other symptoms may emerge that roughly parallel cognitive decline and are of poor localizing value by themselves. Dysphagia is a common complaint, and caregivers may note that the patient with cognitive impairment seems to take a long time to chew and swallow. Oral candidiasis is a potential complicating issue in patients undergoing long-term corticosteroid therapy, and appropriate treatment should be instituted. Similarly, incontinence tends to parallel the degree of cognitive impairment. Urinary retention may occur in patients with bifrontal brain disease or with spinal cord problems. Opiate medications may exacerbate the urologic problems.

Seizures occurring for the first time in adults are more likely to be due to focal brain pathology, particularly neoplasms, than are seizures occurring in childhood. Intracranial tumors produce generalized tonic-clonic seizures, secondarily generalized tonic-clonic seizures, and partial, localization-related seizures. Seizures are more common in persons with cortical tumors than in persons with infratentorial or deep thalamic lesions, and they occur more often in low-grade astrocytomas, oligodendrogliomas, or oligoastrocytomas (60%–80%) than in high-grade gliomas (20%–40%) or cerebral metastases (15%–20%) Seizures occur at some time in 25% to 50% of patients with brain tumors. Seizure frequency may increase during radiation treatment and continue at an increased frequency for several months thereafter because of localized swelling.

Papilledema—that is, swelling of the optic nerve head with engorgement of retinal veins—usually indicates raised ICP. Currently, papilledema is seen in fewer than 20% of patients at presentation, down from 59% in the 1971 report by Huber. The development of papilledema is dependent on the location of the tumor and the rate of growth.

Vomiting with or without nausea may occur as a result of direct simulation of emetic centers in the floor of the fourth ventricle. This mechanism explains the nausea and vomiting seen with raised ICP, particularly when the rise in pressure has been rapid and is associated with hemorrhage or herniation. Patients with posterior fossa tumors frequently experience nausea and vomiting. More commonly, however, nausea is a nonlocalizing symptom, and thus the differential diagnosis must include adverse drug reactions from antiepileptic drugs (AEDs), analgesics, or other concurrent medications and gastritis from high-dose corticosteroid treatment.

Localizing Signs of Intracranial Tumors

Focal clinical signs of an intracranial tumor reflect the location of the mass and its associated vasogenic edema, which often is of much greater volume. This chapter does not provide a detailed discussion of every possible localizing sign but rather focuses on the general principle of neurologic localization and the specific emergent syndromes that should be recognized because of their localizing and management importance.

Disorders associated with frontal lobe lesions include early impairment of intellectual function and language function if the dominant frontal lobe is involved. Patients with bilateral frontal tumors appear to lack initiative and spontaneity—a state called abulia. Such patients may have an impaired gait with difficulty initiating walking. Personality changes include inattentiveness, apathy, depression, and the less common disinhibition and inappropriate affect leading to socially inappropriate behaviors. As tumors enlarge to involve the motor cortex, contralateral motor problems, such as hemiparesis or monoparesis, may develop.

Receptive language, auditory discrimination, and memory all are important functions of the dominant temporal lobe. Patients with nondominant temporal lobe tumors may have seizures involving visual, olfactory, or gustatory hallucinations. Deep temporal tumors may cause a contralateral visual field cut (superior quadrantanopia).

The parietal lobe is demarcated from the frontal lobe by the central sulcus. Parietal lobe functions include tactile perceptions; integration of sensory, visual, and auditory information; and visual discrimination in the inferior contralateral quadrant. When tumor involves the nondominant parietal lobe, inattention to the deficit (anosognosia) may be a prominent feature of the presentation.

Tumors in the occipital lobes cause a contralateral quadrantic or hemianopic defect, sometimes with sparing of central macular vision.

Tumors of the brainstem cause a great many focal deficits early in their course. Typically, a combination of cranial nerve palsies and long tract signs such as hemianesthesia or hemiparesis coupled with ataxia reflecting cerebellar involvement give a clue to the localization. Patients with brainstem tumors experience difficulty with swallowing and speech articulation and are at risk for aspiration.

Cerebellopontine (CP) angle tumors such as acoustic neuromas impair function of the eighth cranial nerve and produce unilateral hearing loss, tinnitus, and, later, vertigo. Involvement of adjacent cranial nerves VII and V leads to facial palsy and facial anesthesia. Later cerebellar dysfunction reflects tumor growth in this area.

Tumors of the pituitary and suprasellar region produce endocrinologic abnormalities either by hormonal production by secretory adenomas or by impingement on hypothalamic-pituitary connections. Visual defects reflect chiasmatic involvement. The most common pituitary region field defect is a bitemporal hemianopia.

Pineal region tumors (e.g., germ cell tumors, pineocytomas, pineoblastomas, gliomas of this region) may compress the aqueduct of Sylvius, causing hydrocephalus. Compression of the pretectal area produces a characteristic syndrome (Parinaud syndrome) with paralysis of upgaze, ptosis, and loss of pupillary light reflexes, along with retraction-convergence nystagmus.

Many primary tumors are capable of diffuse infiltration of the meninges . Gliomas, lymphomas, and oligodendrogliomas all may invade the subarachnoid space. They produce variable cranial nerve and spinal root dysfunction and diffuse headache, and sometimes lead to communicating hydrocephalus. Elevated levels of cerebrospinal fluid (CSF) protein, low levels of CSF glucose, and positive results on cytologic studies are the diagnostic hallmarks.

On occasion, the clinician will be faced with symptoms that appear to give a clue to the patient's tumor site but in fact are false localizing symptoms . Palsies of the abducens nerve (cranial nerve VI) may reflect brainstem involvement but commonly are a nonlocalizing sign of raised (or, much less commonly, low) ICP. Ocular pain is of little localizing value because it may reflect any of the structures innervated by the first division of the fifth cranial nerve. Thus eye pain may reflect any process in the anterior or middle cranial fossa. Diplopia may result from cranial nerve invasion by brainstem or leptomeningeal tumor but also can be caused by excess levels of AEDs.

Posterior head pain may reflect posterior fossa disease but also may come from the upper cervical segments, and spinal cord tumor or caudal extension of a primary brainstem tumor should be considered if the patient reports pain in the occiput. Another sign of cervical cord disease is bilateral upper limb weakness or numbness.

Gait disorders pose another potential hazard for falsely localizing signs and symptoms. A frontal lobe gait ataxia may mimic basal ganglia or even cerebellar disease. The affected patient walks slowly, with a wide-based gait, and seems to have difficulty initiating movements. Proximal leg weakness may reflect spinal metastases from intracranial or systemic tumor, but probably the most common cause of proximal leg weakness is corticosteroid-induced myopathy.

Treatment of Brain Tumor Symptoms

Magnetic Resonance Imaging

MRI is the study of choice for evaluating brain tumors. The increased tissue contrast resolution provides exquisite anatomic definition, which is accentuated after administration of gadolinium contrast material. Therefore when possible, MRI sequences should be performed before and after administration of contrast material. Much like with the use of iodinated contrast material in computed tomography (CT) imaging, tumor-related disruption of the blood-brain barrier allows interstitial leakage of contrast material, and depending on scanning parameters, it may appear as increased (spin echo T1) or decreased (gradient echo imaging) signal. Gadolinium enhancement can be crucial in identifying leptomeningeal disease, which appears as thickened, enhancing areas of the dura and leptomeninges. The absence of bony artifacts common with CT has enabled MRI to provide exceptional information regarding brain tumors, particularly in the posterior fossa. In addition, localization of the lesion is precise because MRI is usually reconstructed in three orthogonal planes.

Multiple sequences may be obtained from the MRI scans, highlighting different properties of both brain and tumor. Of particular interest are the T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. These sequences highlight tumor-related vasogenic edema and nonenhancing portions of the tumor, which appear as areas of increased T2 signal compared with normal brain. Evaluating this signal pattern is very important in assessing the degree of mass effect, because the increased signal may represent the true limits of a glial tumor, as tumor cells are invariably present in the nonenhancing tissue surrounding the enhancing component. This phenomenon provides the rationale for extending the irradiated zone in standard external beam radiation therapy to include the edematous volume of brain plus a margin. The presence of an edema pattern extending into the corpus callosum implies direct tumor invasion into the corpus callosum. The extremely compact fiber tracts passing through the corpus callosum impede passage of edematous fluid, and thus any increased T2 signal that is present is likely created by tumor infiltration. This point is very important to keep in mind in assessing the extent of tumor.

Endothelial proliferation with neovascularity is a hallmark of malignancy in brain neoplasms. Both MRI and CT perfusion imaging can be performed in combination with conventional MRI examinations to determine the extent of neovascularity. The correlation between relative cerebral blood volume (rCBV) and grade of malignant glioma appears to be very good. Perfusion imaging with dynamic susceptibility contrast-enhanced MRI is especially helpful in distinguishing grade III from grade IV malignant gliomas, but it can also be used to distinguish gliomas from other neoplasms such as intracranial metastases ( Fig. 63.3 ). It has been shown that anaplastic astrocytomas that enhance have a higher vascularity index than do nonenhancing anaplastic astrocytomas. Perfusion imaging may enable monitoring of the antiangiogenic effects of treatment in brain tumors. Furthermore, perfusion imaging is also useful in determining vascularity in benign tumors such as meningiomas, a phenomenon that may be associated with disease progression.

Functional MRI techniques have been used to identify areas of brain activity in real time, which is quite useful in identifying regions of eloquent brain adjacent to tumors. By identifying language and motor areas adjacent to tumors, one can determine the extent of surgical resection that can be carried out while attempting to preserve functional activity. It is now possible to import functional MRI images into frameless stereotactic units that are used for intraoperative surgical planning. Through use of discrete motor, sensory, language, or visual paradigms, the functional activity of relevant cortical brain can be imaged. One limitation to functional MRI scanning is its inability to identify subcortical white matter tracts adjacent to the gray matter activated by the investigated activity. For this reason, diffusion tensor imaging (DTI) is increasingly being used to map subcortical white matter tracts. It has been shown that combining DTI with conventional anatomic images of the lesion of interest facilitates extended resection of tumor while preserving function.

A great deal of interest has centered on the capability of clinical MRI scanners to perform magnetic resonance spectroscopy (MRS) to evaluate molecular components of a defined voxel within the brain tissue. Today's smaller voxel sizes allow a much greater degree of selectivity in evaluating components of a tumor. MRS of malignant gliomas has been evaluated extensively, and the presence or absence of five metabolites provides the most useful information. N -acetylaspartate (NAA) is a marker of healthy neurons, whereas increases in choline are associated with high cellular turnover. Creatine serves as an internal marker and is related to the energy state of the tumor. A lipid peak indicates the presence of necrosis and suggests higher-grade malignancy, whereas lactate indicates the presence of hypoxia. Malignant gliomas exhibit a higher choline peak relative to creatine and a lower NAA peak relative to choline, with increasing grade of malignancy ( Fig. 63.4 ). Lipid and lactate peaks, which also constitute markers of malignancy, can be seen both in primary gliomas and in metastatic tumors. MRS can help determine whether an enhancing region in a previously treated tumor bed represents active tumor or radiation necrosis. MRS is also used to monitor treatment effects over an extended period.

MRI has the capability to specifically identify vascular structures. As noninvasive techniques, magnetic resonance angiography (MRA) and magnetic resonance venography can be useful in evaluating major vessels at the base of the skull in preparation for surgical treatment of skull base tumors.

Computed Tomography

A CT scan usually is the first study obtained in a patient with a neurologic complaint. In part because of its extensive availability and rapid acquisition times, CT provides a robust screening tool. Hemorrhagic lesions can be seen as a result of the increased density of extravasated blood products in comparison with surrounding tissues. Infarcts manifest acutely as edematous hypodense tissue and can be confused with tumors, especially low-grade gliomas, which may not enhance with contrast agents. However, cytotoxic edema associated with infarcts often involves both gray and white matter, whereas vasogenic edema as a result of the presence of tumor predominately involves the white matter. Iodinated contrast agents may be useful to differentiate tumor from the surrounding edematous brain tissue because disruption of the blood-brain barrier permits leakage of the contrast agent into the interstitial space. The pattern of ring enhancement of tumors may be difficult to distinguish from the ring enhancement of a cerebral abscess, although brain tumors are far more common than brain abscesses in the United States. Infarcted brain tissue may also enhance after administration of contrast material. This finding is most common 2 to 3 weeks after a stroke, and thus clinical history should complement image interpretation.

CT has limitations in evaluating structures near the irregular bony surfaces of the skull base because of volume averaging and streak artifact. This limitation makes interpretation in and around the skull base and in the posterior fossa (the region between the tentorium and the foramen magnum) difficult. Nevertheless, CT is the study of choice in patients who cannot undergo MRI, such as patients with claustrophobia, implanted pacemakers, defibrillators, or other metal devices that preclude imaging with MRI.

Imaging of Supratentorial Gliomas

WHO grade I (pilocytic) astrocytomas show enhancement on CT and MRI scans. By contrast, WHO grade II astrocytomas typically are poorly defined, hypodense, or isodense lesions on CT scans and do not enhance. Either localized or homogeneous enhancement, however, can be seen in up to 30% to 40% of cases, with calcification in 5% to 10% of cases. MRI shows low signal intensity on T1-weighted images and high signal intensity on T2-weighted images ( Fig. 63.5A–B ). Grade III anaplastic astrocytomas and grade IV glioblastomas typically enhance with contrast, although in one study, enhancement was not seen in 40% of the former and in 4% of the latter (see Fig. 63.5C–D ) The region of enhancement typically has a ringlike appearance surrounding an area of necrosis. The perimeter of the enhancing region does not define the border of the tumor, and malignant cells may be present beyond this perimeter. T2-weighted MRI images show abnormalities that are more extensive than those seen on a contrast-enhanced CT scan or a T1-weighted MRI scan. In one study in which stereotactic biopsy findings were correlated with radiologic findings in patients with gliomas, isolated tumor cells often were found as far away as the region showing increased signal intensity on T2-weighted images. Perfusion MRI can measure rCBV and cerebral blood flow, which can be used to determine tumor grade and to assess progression after treatment.

At least 50% of oligodendrogliomas show calcifications, which can be appreciated on plain films of the skull and on CT scans. Enhancement of oligodendrogliomas can be seen on CT and MRI scans but is often mild and poorly defined.

Positron Emission Tomography

Positron emission tomography (PET) imaging uses a radioactive isotope analogue of glucose, fluorine-18 fluorodeoxyglucose (FDG), to image glucose metabolism. Because glucose is the sole fuel for brain tissue, this metabolic imaging allows visualization of brain physiology. Because glioblastomas, untreated PCNSL, oligodendrogliomas, and malignant meningiomas have increased glucose metabolism compared with normal brain tissue, these tumors have greater FDG avidity and will be PET positive. Anaplastic astrocytomas, oligodendrogliomas, meningiomas, and metastatic tumors show variable FDG uptake ( Fig. 63.6 ), whereas low-grade gliomas and radiation necrosis show little to no FDG uptake. PET imaging using targeted tracers, such as the somatostatin-receptor ligand gallium-68 DOTATOC in meningiomas, might be more useful for tumors in which FDG is too variable for accurate delineation.

Challenges to Imaging Modalities

Complicating assessment of chemotherapy in patients with a brain tumor is the observation that corticosteroids also often reduce MRI contrast enhancement and relieve symptoms, making it difficult to distinguish chemotherapy effects from corticosteroid effects. For almost 20 years, standard response criteria have been the Macdonald criteria, which use two-dimensional measurements of enhancing tumor and account for corticosteroid use and clinical status. However, it has been recognized that reliance on contrast enhancement is a limitation in many anaplastic gliomas. Two situations in particular have led to the development of a new set of response criteria (Response Assessment in Neuro-Oncology, or RANO). First, pseudoprogression is defined as an increase in contrast enhancement or edema on MRI without true tumor progression, a phenomenon made more common by the addition of temozolomide to radiotherapy. The first postradiation MRI image shows increased contrast enhancement in up to 50% of patients ( Fig. 63.7 ), in half of whom the enhancement eventually subsides. The phenomenon may be asymptomatic but can also cause neurologic decline. Failure to recognize pseudoprogression may cause the physician to prematurely terminate effective therapy. Second, pseudoregression refers to a decrease in contrast enhancement on MRI without true response, a phenomenon increasingly seen in patients treated with VEGF pathway antiangiogenic agents. Infiltrative tumor may be distinguished from radiation-related FLAIR and T2 signal MRI changes by diffusion-weighted MRI sequences that show diffusion restriction in areas infiltrated by neoplastic cells.

Some of the important features of the updated RANO criteria that are just now being implemented in clinical trials include precise definitions of measurable disease, exclusion of patients within the first 3 months after radiotherapy from clinical trials to avoid confounding chemotherapy failure with pseudoprogression, and inclusion of stable or decreased nonenhancing disease as a criterion for tumor response in patients who have received antiangiogenic therapy.

Similarly, confusion may arise when neuroimaging documents enlargement of a mass after stereotactic radiosurgery (SRS) that may progress over many months. Because PET scanning may not reliably distinguish radiation necrosis from tumor progression, the results of concurrent chemotherapy may be ambiguous. Multicentric recurrence outside original radiation fields and after temozolomide appears to be more common when patients have positive O -methylguanine DNA-methyltransferase (MGMT) promoter methylation status.

Lumbar Puncture

Lumbar punctures are not commonly used for the diagnosis of brain tumors owing to the low yield of the procedure in primary gliomas. Leptomeningeal seeding from supratentorial malignant gliomas is usually an end-stage finding. Once life-threatening conditions such as mass effect have been excluded, lumbar puncture may be performed for confirmation of leptomeningeal disease. Lumbar puncture remains part of the staging workup for some primary brain tumors, such as medulloblastoma and CNS lymphoma.

Radiation Therapy: Technical Details

Treatment planning starts with a review of the MRI scan to identify the target volumes. The appropriate volume to be irradiated varies according to the tumor type. Most brain tumors including gliomas and meningiomas are treated with focal radiation to the lesion plus a margin. The actual abnormality seen on imaging studies is termed the gross tumor volume (GTV). Additional tissue surrounding the GTV that is thought to potentially contain tumor cells is included in the clinical target volume (CTV). For some tumors such as glioblastoma, which can be highly infiltrative, the CTV includes the area of edema as demonstrated on the FLAIR or T2 sequences plus up to a 2.5-cm margin. For other tumors that do not infiltrate, such as meningiomas, pituitary adenomas, acoustic neuromas, and craniopharyngiomas, the CTV typically would be much tighter than that used for glioblastomas. An additional volume is included around the CTV to take into account day-to-day setup error and to allow for buildup of dose, resulting in the planning target volume (PTV).

Treatment planning begins with CT simulation of the patient with appropriate immobilization devices. Fig. 63.8 shows thermoplastic mask and bite-block immobilization devices. A previously obtained MRI image or an MRI image obtained at the time of simulation may be fused with the CT images in the treatment planning system to facilitate better target volume delineation. Computerized treatment planning is then used to generate radiation beam angles, blocks, and dose distributions.

Most brain tumors are treated with focal radiation therapy, and often brain metastases and some leukemias and lymphomas require whole-brain radiotherapy; however, for some tumors, such as primitive neuroectodermal tumors (PNETs) and metastatic germ cell tumors of the CNS, it may be necessary to include the entire craniospinal axis in the irradiated zone. Proton therapy for craniospinal irradiation has the advantage of reducing dose to the vertebral bodies and essentially eliminating the exit dose through the thorax, abdomen, and pelvis. E-Fig. 63.1 shows sample treatment plans for craniospinal irradiation using three-dimensional conformal radiotherapy, tomotherapy, and proton beam techniques.

Stereotactic Radiotherapy

Stereotactic radiotherapy is a technique for delivering high-dose radiation to a target volume with very tight margins, thereby sparing surrounding normal tissues. This technique can be implemented with various devices, including (1) a Gamma Knife machine, which, depending on the model, typically contains 192 or 201 fixed cobalt-60 sources that converge to a single point; (2) a conventional linear accelerator (“linac”) outfitted with additional hardware so it can deliver focused radiation, generally with three to five arcs; (3) CyberKnife, which is a radiosurgery system composed of a linac mounted on a robot and directed under image guidance; and (4) delivery of charged particles such as protons, which, because of their physical properties, deposit energy in a narrower region than is possible with x-rays.

Stereotactic radiation can be delivered in a single large fraction; this technique is termed stereotactic radiosurgery , although no surgery is performed. A stereotactic head frame often is screwed to the skull. The head frame permits three-dimensional localization and immobilization of the head during treatment, thereby allowing delivery of radiation with precision to a very tightly defined volume defined with MRI imaging. The usual dose of single-fraction radiation used in SRS ranges from 12 to 24 Gy and is based on the histologic tumor type and the volume of tissue irradiated. The doses used are based on the likelihood of tumor control and the risk of development of radiation necrosis.

Stereotactic radiotherapy also can be delivered in a fractionated regimen over several days or weeks. CyberKnife does not require the use of a head frame but instead uses real-time image tracking while patients are immobilized with a face mask.

Intensity-Modulated Radiation Therapy

Intensity-modulated radiation therapy uses multiple segmented fields with inverse treatment planning algorithms. In addition to defining the doses to be delivered to the GTV and CTV, dose constraints are placed on normal structures to limit their radiation exposure. Constraints include the maximum or mean dose to the entire structure, limits to a portion of the structure, and the maximum point dose within the structure. The most common mechanism of delivering this dose is use of multiple fields, typically five to nine, with use of a specialized blocking apparatus called a multileaf collimator to divide each field into multiple beamlets. From 50 to more than 100 beamlets may be used.

Heavy Charged Particle Radiation Therapy

The delivery of charged particles, primarily protons, has been used to treat brain tumors. The potential benefit of protons is the result of their physical properties, which are different from those of photons. The advantage of proton radiation therapy compared with photon radiation therapy is the reduction of the total dose to the patient as a result of the absence of an exit dose. This attribute results in a decreased dose to the normal part of the brain, which may decrease acute and long-term toxicities, which is particularly important in pediatric patients.

Adverse Effects After Irradiation of the Brain or Spine