Advanced Imaging Techniques and Applications with DIPG
Magnetic Resonance Spectroscopy
Proton magnetic resonance spectroscopy (MRS) can currently be performed on most standard MRI machines. The interaction of protons with their environment helps to identify and measure various substances within the brain. The most commonly measured substances include:
- choline (Cho, 3.2ppm): related to the synthesis of cell membranes and increased in states of high membrane turnover (example tumor)
- creatine (Cr, 3.0ppm): a reflection of cellular metabolism and generally used as an internal reference
- N-acetyl aspartate (NAA, 2.0ppm): located primarily in neurons and considered a normal neuronal marker, decreased with neuronal destruction
- lactate (Lac, 1.3ppm): a product of anaerobic metabolism which is increased with abnormal blood flow, abnormal metabolism or necrosis
- lipids (Lip, 0.9ppm): a constituent of cell walls which is increased as a product of necrosis and cell membrane destruction
Theoretically, malignant lesions should demonstrate high Cho to Cr ratios and high Cho to NAA ratios due to the rapid turnover of cell membranes increasing Cho, and the destruction of normal neurons decreasing NAA. Accordingly, Smith and colleagues found that MRS may be helpful to distinguish neoplastic from non-neoplastic lesions in the brainstem, with neoplastic lesions having high Cho and low NAA levels and non-neoplastic lesions having normal to low Cho and low NAA levels. Furthermore, MRS may be helpful to differentiate between different tumor histopathologies when the conventional MRI appearance is uncertain. MRS may be helpful to suggest other histopathologies such as pilocytic astrocytoma or PNET, which can often have characteristic profiles on MRS.
Although no metabolic measures on MRS at tumor presentation have been found to be significantly associated with survival, several studies have reported the changes on MRS over time to help to understand tumor biology. Dr. Laprie and colleagues examined the changes in MRS with radiotherapy. They found that Cho to NAA ratios initially decreased within 2 months following radiotherapy corresponding clinical and conventional imaging responses. Subsequently, Cho to NAA and Cho to Cr ratios were observed to increase at the time of relapse. Furthermore, in some patients, changes in MRS preceded both clinical and MRI deterioration by 2 to 5 months. Similar results were obtained by Dr. Panigrahy and colleagues who also found that metabolic changes on MRS preceded clinical deterioration. Serial examination of tumors demonstrated increasing levels of Cho and Lipids and decreasing levels of NAA, Cr, and myo-inositol relative to Cho. These changes likely reflect malignant degeneration and possible transformation from low grade to high grade tumor.
Magnetic Resonance Perfusion
Magnetic resonance perfusion imaging (MRP) has recently been studied in supratentorial gliomas in adults and has been found to be a good predictor of World Health Organization (WHO) tumor grade, progression free survival, progression and death. MRP of tumors is typically performed using dynamic contrast enhanced perfusion imaging techniques.
MRP techniques rely on the magnetic susceptibility signal loss that intravenous gadolinium produces on T2* sequences during MRI. By measuring the degree of T2* signal loss caused by the gadolinium in blood vessels over time, one can determine the relative volume of blood, or relative cerebral blood volume (rCBV), within a tumor. Similarly, the relative cerebral blood flow (rCBF) and the mean transit time (MTT) can also be measured. These measurements are thought to be surrogate markers for blood vessel proliferation within malignant brain tumors—an important feature in the grading of gliomas on histopathology. Accordingly, several studies have shown that gliomas with low rCBV, and theoretically lower tumor blood vessel proliferation, have longer time to progression and gliomas with high rCBV, and theoretically higher tumor blood vessel proliferation, have shorter time to progression. This was found to be true regardless of WHO grade on biopsy. Some studies have even suggested that measurements of rCBV were more predictive of prognosis than histopathology and WHO grade on biopsy. It has been proposed that this finding is most likely the result of either sampling error on biopsy (as tumors are heterogeneous and the portion of the tumor with the highest WHO grade may be missed on biopsy) or variability in consistency of diagnosis among pathologists.
To date, little research has been performed utilizing MRP in the analysis of DIPG. This may be a promising avenue to help stratify patients based on the aggressiveness of their tumors and their prognosis.
Positron Emission Tomography
Positron Emission Tomography in combination with CT (PET/CT) is a tool that helps radiologists understand the metabolic activity of tumors. PET/CT measures the accumulation of tracers in cells that are incorporated into the cells during metabolism. The most commonly used tracer in PET/CT is 2[18F]fluoro-2-deoxy-D-glucose (FDG). FDG is a measure of glucose metabolism, and most tumors have increased glucose metabolism in comparison to normal tissues. A less frequently used and less widely available tracer in brain tumor imaging is 11C-L-methionine (MET), which is involved in amino acid transport, also increased in tumors. MET may be more sensitive for low grade tumors, in comparison to FDG, due to the lower background activity of MET in normal brain.
Several studies focusing on brain tumors have shown that PET/CT can help to separate less aggressive tumors from more aggressive tumors, tumor from radiation necrosis, and tumor from scar tissue. Fewer studies have focused exclusively on brainstem tumors in children. These studies have suggested that PET/CT may also be helpful in the evaluation of DIPG to differentiate low grade tumors from high grade tumors, with FDG uptake being increased in high grade tumors. Dr. Kwon and colleagues found that only WHO IV glioblastoma multiforme tumors were FDG hypermetabolic (“hot”).
Furthermore, Dr. Pirotte and colleagues noticed that patients with the highest FDG uptake had shorter survival times. PET/CT has also been found to be useful in planning biopsies. In comparison to utilizing contrast MRI for planning biopsies, PET/CT has a higher diagnostic yield, requiring a fewer number of biopsies. Furthermore, PET/CT guidance yielded an equivalent or higher tumor grade in comparison to MRI guidance. As mentioned previously in the section on perfusion imaging, DIPG are heterogeneous in their histopathology, and PET/CT can help to guide a biopsy to the areas of a tumor with the highest grade. This will help to prevent the under-grading of a tumor with a conventionally guided biopsy. There have only been a few small studies of PET/CT in brainstem tumors and further work is needed to develop this promising technology.
Advances in imaging techniques over the last several decades have improved our understanding of brainstem tumors. It is now generally accepted that there is a specific subtype of brainstem tumor that can be identified on imaging as a diffuse intrinsic pontine glioma (DIPG). This tumor invariably represents a fibrillary astrocytoma on histopathology and has an extremely poor prognosis— the worst of any type of brainstem tumor. On imaging this tumor is typically:
- T2 hyperintense (bright)
- arises from the pons
- is diffusely infiltrating with ill-defined margins
- involves more than one half of the pons
- expands the pons often engulfing the basilar artery
Despite advances in imaging technology, we have yet to find imaging features that can help to predict prognosis. New imaging techniques, including magnetic resonance spectroscopy (MRS), perfusion imaging and positron emission tomography (PET), may someday help us to better understand the biology of this tumor, and in turn improve the treatment of this tumor.