Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. Classified by the World Health Organization (WHO) as a Grade IV astrocytic tumor, GBM is highly malignant. The tumor is characterized by rapid, invasive growth, making complete surgical removal impossible in most cases. Despite standard treatment involving surgery, radiation, and chemotherapy, GBM has a poor prognosis and an almost inevitable rate of recurrence.
Cellular and Genetic Factors Driving Aggression
The aggressive nature of glioblastoma is rooted in specific molecular and cellular abnormalities that promote uncontrolled growth and resistance to therapy. A primary molecular determinant of aggression is the tumor’s isocitrate dehydrogenase (IDH) status. The majority of glioblastomas are IDH-wildtype, meaning they lack the IDH gene mutation seen in less aggressive gliomas. This IDH-wildtype classification identifies a more rapidly growing tumor that typically affects older adults and is associated with a significantly shorter survival time.
The status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter influences tumor behavior and treatment response. The MGMT enzyme functions as a DNA repair mechanism, removing damage caused by alkylating chemotherapy agents like temozolomide (TMZ). If the MGMT promoter is unmethylated, high enzyme production quickly repairs TMZ damage, conferring resistance to the drug. Conversely, methylation of the MGMT promoter silences the gene, leading to low MGMT production, which sensitizes the tumor cells to TMZ.
Glioblastoma exhibits profound intratumoral heterogeneity, meaning the tumor mass is composed of multiple distinct subpopulations of cancer cells. This cellular diversity includes glioblastoma stem cells (GSCs), which possess the ability to self-renew and differentiate into other tumor cell types. GSCs are resistant to conventional radiation and chemotherapy, acting as the reservoir of cells that survive initial treatment and drive recurrence. This variability allows the tumor to quickly adapt to therapeutic pressure, contributing to its progression.
The rapid growth of glioblastoma relies on its capacity to generate a new blood supply, a process called angiogenesis. Glioblastomas are highly vascularized tumors, often observed as microvascular proliferation in pathological samples. Tumor cells in regions of low oxygen (hypoxia) release Vascular Endothelial Growth Factor (VEGF), a signal that triggers the formation of new, often leaky blood vessels. This abnormal vasculature provides the oxygen and nutrients needed to sustain the tumor’s expansion into the surrounding brain tissue.
Clinical Monitoring and Detection of Progression
The primary method for monitoring glioblastoma progression is routine follow-up using Magnetic Resonance Imaging (MRI). Scans are typically performed at regular intervals following initial treatment to establish a baseline and watch for changes indicating recurrence. The imaging protocol includes T1-weighted imaging performed after the injection of a gadolinium-based contrast agent. Tumor disruption of the blood-brain barrier allows the contrast agent to leak into the tumor tissue, appearing as areas of bright enhancement on the T1 scan.
T2-weighted and T2 FLAIR (Fluid Attenuated Inversion Recovery) sequences assess non-enhancing tumor components, such as edema or diffuse infiltration. New or growing areas of enhancement or increased signal abnormality on the FLAIR sequence suggest tumor progression. These imaging findings are correlated with the patient’s clinical status. Clinicians monitor for symptoms like new or more frequent seizures, increased severity of headaches, or a decline in cognitive function or motor skills.
Clinicians use the Response Assessment in Neuro-Oncology (RANO) criteria to standardize the definition of progression. The RANO system provides specific, measurable rules based on changes observed on MRI scans. Progression is defined, in part, by a 25% or greater increase in the size of the contrast-enhancing lesion compared to the smallest size measured since treatment began. The RANO criteria also incorporate the appearance of new lesions outside the original radiation field and definitive clinical deterioration not attributed to other causes.
Distinguishing True Progression from Treatment Effects
A major challenge in monitoring glioblastoma is differentiating genuine tumor growth (true progression or recurrence) from changes caused by the body’s reaction to therapy. The most common treatment-related effect is pseudoprogression (PsP), which frequently occurs in patients who have received radiation combined with temozolomide chemotherapy. PsP appears on MRI scans as an increase in contrast enhancement and swelling, mimicking the radiographic signs of tumor recurrence.
This phenomenon is an exaggerated inflammatory response caused by radiation damage to the tumor and surrounding blood vessels. PsP typically manifests early, often within the first 12 weeks after completing chemoradiation, and is seen in about 30% of patients. Pseudoprogression is a temporary condition that often stabilizes or resolves without requiring a change in treatment. Due to this confusion, the RANO criteria recommend a confirmation scan to define progression if changes are seen within this initial 12-week window.
A later-occurring treatment effect is radiation necrosis (RN), which represents the irreversible death of brain tissue caused by the radiation dose. RN also presents as an enhancing lesion on MRI, making it visually indistinguishable from true tumor recurrence, but it tends to occur later, often six to 18 months after radiation therapy. Distinguishing between these entities is important because true progression demands an immediate change in therapy, while PsP and RN do not.
Advanced imaging techniques are often employed to help make this distinction. Dynamic Susceptibility Contrast (DSC) perfusion MRI measures blood flow within the lesion. True tumor progression typically shows a higher relative cerebral blood volume (rCBV) than the blood flow seen in radiation necrosis. Positron Emission Tomography (PET) scans using amino acid tracers, such as FET-PET, can also be used, as metabolically active tumor tissue shows higher tracer uptake than the low metabolic activity found in necrosis or inflammation. If advanced imaging remains inconclusive, a period of “watchful waiting” with a repeat MRI in a few weeks may be the strategy to observe whether the enhancement pattern resolves.