Current Techniques Used for the Radiologic Assessment of Intracranial Neoplasms

The purpose of this article is to provide the practicing pathologist with a basic understanding of the current and rapidly evolving technologies used in the evaluation of patients with cerebral neoplasms. In the radiologic assessment of brain tumors, multiple basic modalities may be used for lesion assessment and the formation of a differential diagnosis. These include computed tomography (CT), magnetic resonance imaging (MRI), and catheter angiography. Advanced imaging techniques, although continuing to rapidly evolve, are used in clinical practice today. These include CT and magnetic resonance (MR) angiography and venography, CT and MR perfusion, MR spectroscopy (MRS), functional MRI (fMRI), and positron emission tomography (PET). Plain film radiography has only a small role in the modern era.

In this article, we discuss the basic imaging techniques used to evaluate lesions in neuro-oncological patients. We also provide a basic discussion of the more advanced imaging techniques. This should give the reader an insight into what we feel will become the standard of practice in the not-too-distant future.

Computed tomography plays a vital role in imaging of the brain in oncology patients. It is most commonly used as a screening tool, often in patients referred from the emergency department, for a quick assessment of complications of primary and metastatic brain lesions. These complications include mass effect leading to uncal and cerebellar tonsillar herniation, intracranial hemorrhage, and acute stroke. It can also be used in the evaluation of patients who have conditions that are incompatible with MRI, such as those with pacemakers or other indwelling metallic devices. The standard CT examination of the brain takes only a few seconds to complete, with only a few minutes on the CT table. The only contraindication to CT would be the administration of iodinated contrast material in patients with renal failure. In this setting, MR examination with gadolinium could be obtained.

Newer techniques using CT include CT angiography (CTA), CT venography (CTV), and CT perfusion. Computed tomography angiography and CTV are quickly replacing catheter angiography and venography in the evaluation of the more proximal segments of arterial vessels1–3 (Figure 1) and of the larger venous structures. These studies involve the venous injection of radio-opaque contrast material and subsequent thin section imaging of the brain while the contrast material flows through the vascular tree. Common indications in neuro-oncological patients would be to assess the proximal arteries in conditions such as stroke4 or vasospasm5,6 (Figure 2). Computed tomography angiography can also be used to assess the arterial supply of tumors7 (Figure 3, A and B) and to better demonstrate the arterial anatomy in relation to tumors8 (Figure 4). In the venous system, CTV can be used to assess the anatomy of venous structures in relation to an adjacent tumor,2 such as a meningioma (Figure 5, A and B), and to exclude venous sinus thrombosis.9 The major advantage over catheter angiography is that CTA and CTV are not invasive procedures and do not carry complications such as vessel dissection, stroke, and groin hematoma. Computed tomography angiography and CTV are more limited in the evaluation of the distal arterial segments and the smaller, deep venous structures. In these cases, catheter angiography would be necessary for complete evaluation.

Computed tomography perfusion involves the rapid venous injection of contrast material with imaging through a focused region of brain parenchyma or a tumor. This is done primarily to evaluate angiogenesis, or new vessel formation, which is associated with brain tumors. The imaging starts before the arrival of contrast in the vessels and continues during the initial and subsequent passage of the contrast through the brain. This permits the calculation of physiologic parameters such as cerebral blood volume, tissue transit time, cerebral blood flow, and tissue permeability.10 Parameters reflecting leakage of contrast out of the vasculature into the tumor (K1), or leakage of contrast out of the tumoral tissue back into the vasculature (k2) can be characterized by this study. This technique may be used for the evaluation of benign and malignant intracranial and skull base tumors, as well as to investigate vascular pathology, which occurs in patients with a primary intracranial malignancy (Figure 6, A and B). However, MR perfusion imaging of brain tumors is currently a more commonly used technique and is described below.

Magnetic resonance imaging is the most commonly used technique in the evaluation of the brain in oncology patients as it provides the most detailed imaging of the brain available. Magnetic resonance involves placing the patient in a magnetic field and then using a radiofrequency pulse to excite hydrogen protons in the brain, elevating them to a higher energy state. When the protons return to their resting, lower energy state, they release electromagnetic energy. This energy is received by a coil, or antenna, and converted by computer manipulation into an image. The time that it takes the hydrogen protons to return to their resting state is called the relaxation time. Different tissues have varying relaxation times depending on their chemical composition, which generates different signals to be used for image formation.

A standard MR study of the brain uses T1, fast spin echo (FSE) T2, fluid attenuated inversion recovery (FLAIR), and diffusion weighted imaging (DWI) sequences. The T1 sequence best demonstrates normal anatomy and can be performed with an intravenous contrast agent known as gadolinium. Where there is breakdown of the blood–brain barrier, which occurs in cerebral neoplasms, there is accumulation of gadolinium. Postcontrast sequences in 3 orthogonal directions (axial, coronal, and sagittal) are used to identify enhancing characteristics of normal and abnormal intracranial tissue, as tumors tend to enhance substantially more than normal brain parenchyma does. The FSE T2 sequence highlights tissues with a high concentration of water as bright signal or hyperintensity. On the FLAIR sequence, the cerebrospinal fluid signal is suppressed, improving lesion conspicuity, especially adjacent to the ventricular system. With DWI, where there is decreased movement of protons through tissues or spaces, such as in the extracellular space, there is signal hyperintensity. A common cause of signal hyperintensity on this sequence is acute cerebral infarction. In addition, certain tumors with dense cell packing, such as lymphoma (Figure 7, A and B), may also have decreased movement of protons, leading to DWI signal hyperintensity. Decreased diffusion is also seen in cerebral abscesses, assisting in the distinction between the abscess and centrally necrotic tumors, which do not have decreased diffusion. Another series that may be added is the gradient echo sequence, which demonstrates signal hypointensity in cases of hemorrhage, melanin, and calcification. This sequence is particularly useful when evaluating lesions such as melanoma or hemorrhagic metastasis.

The sensitivity of routine MRI for grading gliomas ranges from 55.1% to 83.3%, as illustrated in an article by Law et al.11 The standard MR examination of the brain takes approximately 45 to 60 minutes to complete.

When assessment of the cerebral vasculature is necessary, an MR angiogram (MRA) or MR venogram (MRV) may be performed. This technique makes vessels with flowing blood appear bright relative to the adjacent, stationary tissues. Magnetic resonance venography is performed using a 2-dimensional time-of-flight (TOF) sequence, which samples tissues in multiple thin imaging slices. Magnetic resonance angiography uses 3-dimensional TOF, where a volume of tissue is sampled to obtain the necessary data. The data from the MRA and MRV are then reconstructed into 3-dimensional images of the arterial (Figure 8) or venous (Figure 9) structures, similar to a conventional angiogram or venogram, using techniques called maximum intensity projection (MIP) and volume rendering. These images may be rotated to allow evaluation of the vessels from different angles. Similar to CTA and CTV, MRA and MRV can assess the arterial supply and venous drainage of tumors and further define the vascular anatomy in relation to a tumor.

The major advantages of the MR assessment of the cerebral arterial and venous systems, over CTA, are the lack of radiation and lack of need for iodinated contrast material, especially in patients in renal failure. However, we prefer CTA and CTV to MRA and MRV due to a superior resolution of the vasculature. There are also fewer artifacts with CTA resulting from situations such as slow or turbulent vascular flow and related to patient motion.

Magnetic resonance perfusion involves the rapid venous injection of gadolinium contrast material with imaging through a focused volume of tissue starting before arrival of contrast material and continuing during the passage of contrast through the region of interest. There are 2 main approaches to MR perfusion imaging. The first pass approach12–14 measures the contrast as it initially passes through the brain. The dynamic approach15 measures the passage of contrast through the brain for several minutes. Both approaches permit calculation of physiologic parameters such as cerebral blood volume (CBV), mean transit time (MTT), cerebral blood flow (CBF), and tissue permeability. These parameters can then be analyzed and are interpreted at the same time as conventional anatomical imaging and spectroscopic data. This technique is useful in the evaluation of benign and malignant intracranial and skull base tumors. Magnetic resonance perfusion parameters, particularly permeability, are sensitive to tumoral angiogenesis and may be useful in grading of primary brain neoplasia,11,12,16 as well as monitoring the effects of therapy on neovascular proliferation.14 Another use is to assist the surgeon in identifying the most aggressive portions of a tumor so that optimal biopsy locations can be chosen.12,17,18 Magnetic resonance perfusion is also useful in the follow-up of brain tumor patients by allowing differentiation between radiation effects and recurrent tumor.14,15 

Voxel-by-voxel analysis of perfusion studies gives maps of the distribution of CBV, CBF, MTT, and permeability (Figure 10). These maps are interpreted at the same time as conventional anatomical imaging and spectroscopic data. Magnetic resonance perfusion has a reported sensitivity of 50% with a specificity of 90%.14 Magnetic resonance perfusion imaging adds less than 10 minutes to the length of a standard MR examination.

Proton MRS imaging has, during the past 10 years, become available for the clinical evaluation of various brain lesions and adds an important functional aspect to conventional anatomical brain imaging. Magnetic resonance spectroscopy can distinguish normal brain tissue from abnormal tissue by analyzing certain metabolites in the brain and calculating their ratios. These compounds are most notably N-acetylaspartate (NAA), choline (Cho), creatine and phosphocreatine (Cr), and myo-inositol (m-I), as well as lipid and lactate. The prescribed region in which tissues are measured is called a voxel. These metabolites can be displayed as individual metabolite peaks or metabolite ratios. The metabolites are expressed as parts per million. Metabolite maps can be fused with routine anatomical MRI images facilitating correlation of functional and structural information. Since the MRS metabolite pattern of the normal brain at a given age is known and predictable, deviation from the expected normal metabolite pattern can give additional information about tumor composition, the grade of a malignancy, and any change over time. Successful application of MRS in the young pediatric age group also requires knowledge and understanding of the differences between a developing child's brain and adult levels of metabolic activity.

Magnetic resonance spectroscopy can facilitate the differential diagnosis of various brain lesions and provide information about a tumor's biological characteristics19 and response to treatment. Tumor recurrence and change in biological degree of malignancy may also be seen with MRS. Magnetic resonance spectroscopy may also answer the important question: tumor recurrence or treatment-induced tissue injury?20 Magnetic resonance spectroscopy analyzes certain metabolites using either a multivoxel (Figure 11) or single voxel technique (Figure 12). Magnetic resonance spectra can be acquired with short and long echo times, with more metabolites visible at short echo MRS.21 Using a multivoxel approach, spectra are simultaneously generated from a large number of volume elements within a slab of tissue, allowing large parts of the brain to be evaluated at one time.

In MRS studies, the most notable peak is that of NAA, which is a marker of mature neuronal density and viability and is therefore decreased in tumor tissue because malignant cells in a tumor replace healthy neurons. N-acetylaspartate is also reduced or absent in ischemia, degenerative diseases, inborn errors of metabolism, and trauma. Choline is one of the most important peaks for analyzing brain tumors, reflecting metabolism of cellular membrane turnover. The choline peak is increased in all malignant primary and secondary brain tumors. Low-grade gliomas show slightly decreased NAA and slightly increased choline peaks. The level of choline activity is usually compared to levels of creatine activity; an elevated ratio of choline to creatine suggests the presence of a tumor. Elevated choline is also seen in young, developing brain and with remyelination in demyelinating disorders, such as multiple sclerosis and acute disseminated encephalomyelitis. Another metabolite that is useful in evaluating intracranial malignancy is lactate. The presence of lactate indicates that the normal metabolic respiration of tissue has been altered. This situation occurs in highly activeand cellular lesions that outgrow their blood supply, entering an anaerobic metabolic state. Pilocytic astrocytomas display unique features: despite their benign nature and histology, MRS presents lactate peaks without necrosis. Tumors that are necrotic or areas of treatment-induced necrosis exhibit lipid metabolites, which can also be identified with MRS. In an untreated tumor, lipid usually is an indicator of high-grade malignancy. The typical pattern of a high-grade malignancy demonstrates a spectrum with an elevated choline-to-creatine ratio and a depressed NAA peak (Figure 13).

The reliability of MRS findings is dependent on voxel position (Figure 14). The ideal location of the sample volume is at the enhancing edge of the tumor. This position yields a spectrum that more accurately reflects the lesion pathology than a spectrum obtained from the lesion center would. The multivoxel MRS study covers a large volume, and even heterogenous lesions are likely to be properly sampled. Multiple technical factors in MRS make it less useful in inexperienced hands than in experienced hands.

Magnetic resonance spectroscopy is not limited to the tumor diagnosis. It can easily be performed at the same time as the conventional MR imaging study and is helpful in separating an abscess from other ring-enhancing lesions such as necrotic tumors. A recent retrospective review indicated that MRS correctly identified lesions as neoplastic in 82% of cases.22 Magnetic resonance spectroscopy could take up to an hour to complete depending on the complexity of the exam.

Functional MRI involves detection of eloquent cerebral cortex, which should be avoided during tumor resection, and is a useful adjuvant to neurosurgical cortical mapping.23 Functional MRI operates on the premise that areas of the brain that are activated during certain activities will have a higher oxygen demand and therefore an increase in blood flow. This increase in blood flow brings more oxygen into the local environment. The higher oxygen concentration changes the signal that is produced during an MR examination. The change in signal is measured by the BOLD (blood oxygen level–dependent) functional MRI technique during a study where both language and motor activity are assessed. During this study, the patient is placed in an MRI unit and a technician asks the patient to perform multiple tasks designed to cause increased, measurable blood flow to eloquent language and motor cortex (Figure 15). This examination requires a trained technician to administer the motor and/or language tasks and could take up to an hour to complete.

The most common use of PET involves the administration of [18F]fluorodeoxyglucose (FDG), a cyclotron-produced radionuclide, which competes with serum glucose for cellular uptake within the body. Tumors within the brain have a higher metabolic demand and therefore increased glucose utilization. When FDG is taken up by the cells of a tumor, it becomes phosphorylated by the enzyme hexokinase, which slows the degradation of FDG by the glycolytic cycle and reduces FDG's diffusibility out of the cell. In addition to the increased utilization of glucose by tumors, they also have increased amounts of transport proteins and the hexokinase enzyme, which lead to a greater accumulation of FDG.

The FDG will decay and emit 2 photons, which are detectable by a coincidence scanner. The images that are then produced reflect the concentration of FDG within the tumor. The main use of FDG PET imaging in the brain is an attempt to define an area of enhancement around a tumor resection cavity as tumor, with higher metabolic activity and greater glucose uptake (Figure 16, A and B), versus radiation necrosis, with a lower metabolic activity and less glucose uptake. The reported sensitivity for FDG PET in the detection of tumor versus radiation necrosis is between 80% and 90% with a specificity of 50% to 90%.24 Once the FDG is administered, patients must lie still in a quiet room for 30 to 60 minutes and then undergo 15 to 30 minutes of scanning time. Experimental PET imaging using labeled amino acids such as tyrosine, methionine, and choline may have promise in the future for greater accuracy, although it is not yet conclusively proven and is currently quite expensive.

The radiologic assessment of intracranial neoplasms depends primarily upon the features seen with MRI. Other modalities such as CT also aid in the diagnostic workup, although to a lesser degree. New and developing technologies such as CT and MR angiography and venography, MRS, and CT/MR perfusion imaging, as well as PET, add significant information to the evaluation of patients with cerebral neoplasms. Functional MRI is complementary to intraoperative cortical mapping in localization of eloquent cortex prior to surgical resection of an intracranial neoplasm.

Currently, CT and MRI are available at most community hospitals. The advanced imaging techniques described above, including MRS, fMRI, and PET, are currently available at larger hospitals and tertiary referral centers. These techniques are best utilized in experienced hands.