Radiographic Detection and Advanced Imaging of Glioblastoma

Computed Tomography

CT is the most common neuroimaging modality in the acute setting and usually the first study performed on patients with symptoms of acute intracranial disorder. Depending on tumor location and presence or acuity of hemorrhage or mass effect, the clinical presentation of GBM can range from signs of increased intracranial pressure or herniation to focal neurologic deficits, seizures, functional decline, personality changes, or headaches. Note that the clinical history may be incomplete and should not dissuade the clinician from considering a primary brain tumor, particularly in the primary and secondary care settings, in which stroke, metastases, or hypertensive hemorrhage are typically higher on the differential diagnosis and may bias the provided history. In tertiary and quaternary care settings, patients may present with a known diagnosis of brain tumor on outside institution CT and MRI studies. In these cases, the CT should not be ignored because it provides complementary information that may help refine the differential diagnosis.

Although CT lacks the exquisite soft tissue resolution of MRI, significant diagnostic information can be obtained in most cases. A complete discussion of head CT physics and interpretation is beyond the scope of this chapter. Briefly, the CT scanner consists of 1 or more x-ray sources positioned across a ring from an array of detectors. As in conventional radiographs, high-energy photons are variably blocked (attenuated) as they travel through tissue. Passing the patient through the spinning ring enables attenuation to be calculated (reconstructed) at each point within the volume and a set of cross-sectional, quantitative, gray-scale images to be produced with brightness proportional to density. Reconstructions can emphasize different tissue types, such as soft tissue or bone, and the range and center (window level) of the gray-scale display values can be adjusted to bring out different features. Iodinated contrast increases density wherever it accumulates. Images can be reformatted in multiple planes and rendered to visualize bones, vessels, or other structures in 3 dimensions. CT excels relative to MRI in its spatial resolution, assessment of osseous structures, speed, and availability.

Consistent with its pathology, GBM typically appears as a peripherally isodense to slightly hyperdense, centrally hypodense intra-axial mass compared with normal gray matter ( Fig. 7.1 ). These imaging findings correlate with the pathologic findings of areas of dense cellularity and central regions of necrosis. Findings may be subtle and are usually better seen following careful windowing of CT images to maximize gray-white differentiation. Although regions of central necrosis generally appear hypoattenuating, superimposed hemorrhage can result in varied levels of attenuation.

Hypercellular and centrally necrotic areas are surrounded by a variable degree of hypoattenuation reflecting a combination of infiltrative tumor and superimposed edema. Expansion of adjacent cortex may be present, indicating infiltrative tumor and increasing the likelihood of a primary neoplasm (see Fig. 7.1 ; Fig. 7.2 ). The presence or absence of calcium should be noted on CT, because parenchymal calcification in GBM is uncommon but is commonly seen with more slowly growing glial neoplasms, particularly oligodendroglioma and ganglioglioma. Associated mass effect can manifest as asymmetric parenchymal expansion; variable effacement of ventricles, sulci, and cisterns; midline shift or herniation; and obstructive hydrocephalus or ventricular trapping. Intratumoral hemorrhage may also be present and is common in patients presenting with acute symptoms. Most important is to recognize when 1 or more signs of mass effect, edema, cellularity, or infiltration indicate that a scan is not showing a typical case of chronic small vessel ischemic disease and merits further evaluation with enhanced MRI.

Conventional MRI

Contrast-enhanced MRI remains the gold standard for imaging of brain tumors and is critical in assessing the full extent of neoplastic involvement, minimizing the risk of incorrect diagnosis, and identifying potential complications of tumor or therapy. Technical principles of MRI are also beyond the scope of this chapter, although the general terminology of different pulse sequences is likely familiar to clinicians. Magnetic resonance (MR) images are created by measuring the current generated when spinning protons (typically hydrogen nuclei in water molecules) are induced by resonant radiofrequency pulses to flip out of and then return to alignment with a strong magnetic field. T1 and T2 are time constants describing different components of this relaxation and are influenced by the type of tissue in which the water molecules are located. Varying the strength of the magnetic field across the imaged area and the timing of pulses enables localization of signals in 3 dimensions and variable signal intensity according to tissue type. In T1-weighted images, white matter is bright and gray matter dark and the opposite is true for T2-weighted images. Cerebrospinal fluid (CSF), essentially water, is bright on T2-weighted images and dark on T1-weighted images. Typical gadolinium-based MRI contrast agents cause increased signal on T1-weighted images.

Routine brain imaging protocols include T2-weighted, fluid-attenuated inversion recovery (FLAIR; which is like T2 but suppresses signal from simple fluid), diffusion-weighted imaging (DWI), and multiplanar T1-weighted pregadolinium and postgadolinium contrast-enhanced sequences. Susceptibility-weighted or gradient echo sequences may be used to increase sensitivity for blood products and mineralization. Each sequence provides complementary information about the fundamental tissue properties of brain lesions and surrounding brain parenchyma (see Figs. 7.1 and 7.2 ). For glial tumors, both the enhancing potentially necrotic tumor components and surrounding nonenhancing components must be assessed. So-called advanced imaging techniques, which require additional postacquisition processing, can further characterize tumor tissue. These techniques include perfusion and permeability imaging as well as MR spectroscopy (MRS) and are discussed later. DWI could be considered advanced imaging but has become part of routine scans. High-resolution three-dimensional T1-weighted images are often added when the need for operative guidance is anticipated. Similarly, diffusion tensor imaging or functional MRI may be performed to aid surgery depending on tumor location. These topics are discussed in more detail in Chapter 14. Intraoperative MRI is only available at select centers and also discussed separately in Chapter 14.

Nonenhancing Components

Most primary glial tumors have a typical appearance on T2 and FLAIR imaging, with areas of hyperintense infiltrative signal abnormality following white matter tracts and variably associated with focal cortical or gyral expansion. White matter abnormalities are occasionally subtle but are usually readily identifiable when comparing affected regions with more typical-appearing white matter farther from the epicenter of the dominant lesion. FLAIR images generally increase the conspicuity of abnormal signal but the precise extent, especially of cortical involvement, may be better depicted on T2. Therefore, both sequences should be carefully scrutinized to identify the visible margins of the tumor, keeping in mind that tumor cells infiltrate much more widely. In our experience, cortical involvement, when present, is highly specific for glial neoplasm. This finding is in contrast with the increased signal caused by reactive vasogenic edema, which may compress the cortex because of mass effect but remains confined to the white matter. In glial tumors there is usually a combination of infiltrative signal and vasogenic edema causing signal abnormality. Surrounding edema is generally less extensive relative to neoplastic burden than that seen with secondary neoplasms, but can be striking in some cases (as in Fig. 7.2 ).

DWI assesses the flow of water molecules within tissues, producing images that are brighter where diffusion is limited by the microenvironment. Because T2 weighting is inherent in this technique, vasogenic edema and overall increased water content also cause increased signal (T2 shine-through). To account for this, quantitative apparent diffusion coefficient (ADC) maps are calculated from DWI images, showing restricted diffusion as areas of decreased signal intensity. DWI images and ADC maps are interpreted in tandem, looking for areas of increased signal on DWI and corresponding low signal on ADC. For simplicity, some figures in this chapter may show DWI alone but restricted diffusion was confirmed on ADC maps.

Clinicians are most familiar with DWI from its striking sensitivity for acute cerebral infarcts, caused by increased intracellular water in areas where ischemia disrupts cell homeostasis. However, DWI has been used extensively to characterize GBM and other tumors, because the ratio of intracellular to extracellular water is also proportional to cell density and tumor grade. Areas of diffusion restriction usually correspond with enhancing regions, although the presence of restricted diffusion in regions of nonenhancing signal abnormality can help differentiate areas of glial neoplasm from vasogenic edema. Diffusion restriction is also a well-known property of infected (and thus proteinaceous and viscous) fluid collections, including pyogenic cerebral abscess and empyema. The necrotic components of GBM can show restricted diffusion and are sometimes difficult to distinguish from abscess, but associated peripheral enhancement is usually thicker with GBM. In general, the degree of restricted diffusion is less in tumor tissue (less intense on DWI and less dark on ADC) compared with that seen in infarct or abscess.

DWI is affected by magnetic susceptibility, so apparent alterations in peritumoral signal may be caused by paramagnetic substances such as blood products, as seen in hemorrhagic tumors and postoperative studies. In the immediate postoperative period, small areas of restricted diffusion reflecting cytotoxic edema (infarct) can be expected at resection cavity margins, but should be distinguished from neoplasm and artifact from blood products. The purpose of identifying small areas of infarct induced by surgery is to recognize that these areas may enhance in the subacute phase when they might be confused for progressive neoplasm.

Blood products cause characteristic signal changes on T1-weighted and T2-weighted images depending on their age. More sensitive sequences tailored to assess for blood products are helpful and complementary in preoperative and postoperative assessment of GBM. Gradient echo and susceptibility-weighted imaging sequences exploit local magnetic field inhomogeneity produced by blood, mineralization, metal, and gas to better identify these materials. These substances show blooming; that is, conspicuous dark areas on the image extending beyond their physical boundaries, caused by perturbation of the local magnetic field. Note that gradient echo along with spin echo is a fundamental technique for acquiring MR images used in many different sequences, but in this case refers to a particular sequence attuned to hemorrhage.

Contrast Enhancement

Normal cerebral vessels possess specialized tight junctions between endothelial cells that form the BBB, excluding contrast and other molecules from the interstitium. Thus, contrast is particularly useful for brain MRI in general, because parenchymal accumulation highlights areas of BBB breakdown due to pathology, with low background signal. In GBM, contrast enhancement reflects a combination of inflammation causing disruption of the BBB and abnormal, leaky, tumoral vasculature. Contrast-enhancing areas may be solid, cystic with thin walls, or obviously necrotic. The presence of thick, irregular, nodular peripheral enhancement with central nonenhancement indicates necrosis (see Fig. 7.1 ) and is a defining pathologic and radiologic feature of GBM compared with lower grade glial tumors. Regions of enhancement typically correspond with areas of hypercellularity (again seen as mildly restricted diffusion) and perfusional abnormalities on advanced imaging caused by the abnormal vasculature. Increasing patient age, tumor size, cellularity, necrosis, and perfusion are all predictive of higher grade.

Enhancing lesions in GBM can vary from 1 or more small foci, to a dominant lesion with satellite nodules, to a large lobar or transcallosal (butterfly) mass ( Fig. 7.3 ). Although larger masses in general indicate more aggressive tumors, there is interplay between size and location causing symptomatic lesions that prompt imaging. Larger lesions with little nonenhancing signal abnormality are more typical of the mesenchymal GBM subtype. Small enhancing lesions in a background of more extensive nonenhancing tumor may suggest secondary GBMs (proneural subtype) in younger patients. However, most lesions are primary GBMs in older patients and have variable-sized enhancing and nonenhancing components.

GBM may extend to the ventricular margin and show associated ependymal or subependymal enhancement. Sometimes tumoral enhancement is inseparable from choroid plexus, which precludes complete resection. More rarely, GBM shows extra-axial spread, leptomeningeal enhancement, involvement of adjacent vessels or dura, or dissemination in the CSF. Proximity to major vessels or evidence of vascular encasement or invasion should be noted preoperatively. Evidence of leptomeningeal spread or CSF dissemination usually mandates imaging of the spinal cord to assess for drop metastases.