Complementary but Distinct Roles for MRI and 18F-Fluoromisonidazole PET in the Assessment of Human Glioblastomas

Glioblastoma multiforme (World Health Organization grade IV) is a highly anaplastic, rapidly proliferating, primary brain neoplasm characterized by diffuse invasion of the normal-appearing tissue peripheral to the contrast-enhanced abnormality seen on clinical imaging (1). These tumors respond poorly to the most aggressive treatments. The current standard of care includes surgical resection, followed by radiation therapy and chemotherapy, with a prognosis of survival generally falling in the range of 6–14 mo (2). MRI and PET play important roles in the assessment of patients with gliomas. 18F-fluoromisonidazole PET (18F-FMISO) allows for imaging of hypoxia in vivo (3,4). On the basis of the biologic links between hypoxia and the aggressiveness of disease, including tumor-induced neoangiogenesis, it is instructive to compare 18F-FMISO images of hypoxia with MRI scans to reveal aspects of new vasculature and invasion. Gadolinium-enhanced T1-weighted MRI (T1Gd) provides morphologic imaging of the blood–brain barrier breakdown in regions of angiogenesis usually surrounding central necrosis (5). Central necrosis appears hypointense when imaged by T1Gd because of the lack of viable vessels. In addition, edema associated with infiltrated glioma cells is hyperintense on T2-weighted MRI (T2). Exposure to ionizing radiation increases the permeability of the vasculature and may affect both T1Gd and T2 (6). PET with the radiotracer 18F-FMISO detects regions of hypoxia independent of the tumor anatomy and perfusion (7). 18F-FMISO is a 2-nitroimidazole derivative that undergoes intracellular reduction in cells that are alive, generating a radical anion. Oxygen acts as an electron acceptor for the 18F-FMISO radical anion. In the absence of oxygen, the unstable 18F-FMISO radical anion is further reduced and covalently bound to intracellular macromolecules and cannot exit the hypoxic cells (8). Binding of 18F-FMISO is proportional to the concentration of oxygen, with significant retention occurring at oxygen levels below 3 mm Hg (9). Thus, 18F-FMISO binds to hypoxic tumor tissue but not to the oxygenated brain or oxygenated tumor (10). The Angiogenic Cascade As tumor cells proliferate, the local tissue becomes relatively oxygen-depleted (hypoxic). Tumor cell growth outstrips vascular development so that oxygen delivery is decreased beyond its diffusion distance. Hypoxia promotes neovascularization through a variety of molecular signals that drive tumor survival (11,12). On the molecular level, hypoxia-inducible factor-1—a transcription factor that is constantly produced but survives only in hypoxic cells—binds to a hypoxic response element that activates the transcription of more than 100 genes, promoting cell survival, invasiveness, and aggressiveness, including vascular endothelial growth factor (VEGF) (13,14). VEGF is a dominant cytokine regulating the expression of growth factor receptor genes at the onset of the angiogenic cascade (15). In its role as an angiogenic factor, VEGF serves to recruit and induce proliferation of vascular endothelial cells. In addition to the role of hypoxia in neoangiogenesis, tumor cells show adaptation to hypoxia by decreasing the proliferation rate, remaining longer in the resting phase G0, and escaping to some degree the impact of conventional treatments that principally target cells in the S phase of their cycle. A greater dose of photon irradiation (2–3 times) is required to kill hypoxic tissue relative to normoxic tissue (16), a factor that further implicates hypoxia in primary tumor recurrence (2). This study considers the assessment of disease burden by 18F-FMISO relative to T1Gd and T2. Motivated by the biologic link between hypoxia and tumor-induced neovasculature and tumor aggressiveness, we analyzed detailed spatial and volumetric data of 18F-FMISO uptake relative to MRI-defined regions. This initial analysis provides the basis for exploring the benefit of combining MRI and PET data into a more complete picture of the disease burden for better disease assessment and prognosis.