Theory in DCE-MRI

Dynamic contrast-enhanced MRI is a method of physiological imaging, based on fast or ultra-fast imaging, with the possibility of following the early enhancement kinetics of a water-soluble contrast agent after intravenous bolus injection. This technique provides clinically useful information, by depicting tissue perfusion, capillary permeability, and composition of the interstitial space. The most important advantages of this technique are its abilities to monitor response to preoperative chemotherapy, identify areas of viable tumor before biopsy, and provide physiological information for improved tissue characterization and detection recurrent tumor tissue after therapy [5].

The extracellular distribution of fluid MR contrast agents is among blood plasma and the interstitial spaces. When a contrast agent is administered intravenously by a rapid bolus injection, it is first diluted in the blood of the peripheral vein and the right heart, before it passes through the lungs and the left heart into the peripheral circulation (Fig. 1.2a).

During first pass of the contrast agent through the capillaries, a fast diffusion occurs into the tissue, due to the high concentration gradient between the intravascular and the interstitial space: in normal tissues, approximately 50% of the circulating contrast agent diffuses from the blood into the extravascular compartment during the first pass.

Fig 1.2 (a) Signal intensity curve before bolus injection. (b) Contrast agent is diffusion to the interstitial space. (c) After the first pass of the bolus, the SI increases further until the concentration of the contrast agent in the blood and the interstitial space of the tissue are equal. (d) After this equilibrium phase, the contrast medium is progressively washed out from the interstitial space as the arterial concentration decreases. [5]

This first-pass diffusion is essentially different from that during the second pass and later. At this initial moment, there is no contrast agent in the interstitial space, and the agent has its highest possible plasma concentration, because it is diluted in only a very small part of the total plasma volume, namely that volume that enters into the right side of the heart at the same time as the bolus (Fig. 1.2b).After the first pass, the diffusion rate immediately drops, because the concentration of the re-circulating contrast medium has decreased owing to further dilution in the blood and partial accumulation in the

interstitial space throughout the body. The length of the time interval between the end of the first pass and the equilibrium state, with equal concentrations of contrast medium in plasma and interstitial space, depends on the size of the interstitial space (Fig. 1.2c).

After this equilibrium phase, the contrast medium is progressively washed out from the interstitial space as the arterial concentration decreases (Fig. 1.2d).

Only in highly vascular lesions with a small interstitial space does early washout occur within the first minutes after bolus injection. The aim of dynamic contrast enhance MRI is detect and depict differences in early intravascular and interstitial distribution as this process is influenced by pathological changes in tissues [5].

Numerous studies using dynamic contrast enhanced MRI have demonstrated that malignant tumors generally show faster and higher levels of enhancement than is seen in normal tissue. This enhancement characteristic reflects the features of the tumor microvasculature which in general will tend to demonstrate increased proportional vascular and higher endothelial permeability to the contrast molecule than do normal or less aggressive malignant tissues.

Cancer can develop in any tissue of the body that contains cells capable of division.

The earliest detectable malignant lesions, referred to as cancer are often a few milli- meter or less in diameter and at an early stage. In vascular tumors cellular nutrition depends on diffusion of nutrients and waste materials and places a severe limitation on

the size that such a tumor can achieve.

Conversion of a dormant tumor to a more rapidly growing invasive neoplasm, may take several years and is associated with visualization of the tumor. The development of neovascularization within a tumor results from a process known as angiogenesis.

These angiogenically competent cells have the ability to induce neovascularization through the release of angiogenic factors. There are positive and negative regulators of angiogenesis. Release of a promoter substance stimulates the endothelial cells of the existing vasculature close to the neoplasia to initiate the formation of solid endothelial sprouts that grow toward the solid tumor [2].

The following figure (Fig 1.3) illustrate the concept from tumor cell angiogenesis to the MRI signal intensity curve during the process of inject contrast agent. (a) Growth of a malignant tumor depends on its ability to stimulate neighboring vasculature to initiate formation of new blood vessels that can grow into the tumor and supply it with oxygen and nutrients. Angiogenesis starts with cancerous tumor cells releasing molecules, angiogenic promoter substances that send signals to surrounding normal host tissue.

These signals activate certain genes in the host tissue that, in turn, make proteins to encourage growth of new vessels. A new blood capillary can form by sprouting of endothelial cells from the wall of an existing small vessel. The cells at first form a solid sprout, which then hollows out to form a tube. This process continues until the sprout

encounters another vessel, with which it connects, allowing blood to circulate.

(b) The resolution of an MR image is determined by the field of view (FOV) and the matrix size. The pixel size and the thickness of the image slice give the volume of the voxel shown in the figure. One voxel contains many different cells even when using the smallest FOV and the largest matrix size possible. This means that the MR signal obtained from one voxel is the average of the proportion of tissue covered by the voxel.

(c) The zoomed region shows a cross section through a blood vessel and the surrounding extravascular tissue consisting of tumor cells, extracellular components and normal cells. The vessel wall is mainly made up of endothelial cells. The small grey circles indicate contrast agent molecules. The contrast agent is administered as a single intravenous bolus injection at point 2. The contrast agent leaks into the extravascular- extracellular space (EES), also called the leakage space (line 2 to line 3). How fast the contrast agent extravasates is determined by the permeability of the microvessels, their surface area, and the blood flow.

At first the contrast agent accumulates in the extravascular tissue before it diffuses back into the vasculature from which it is excreted. It usually by the kidneys, although some contrast media have significant hepatic excretion (line 3 to line 4). In an MR image the accumulation and wash-out of contrast agent is observed as changes in the MR signal intensity which is proportional to the concentration of contrast media.

Fig 1.3 Angiogenesis starts with cancerous tumour cells releasing molecules, angiogenic promoter substances that send signals to surrounding normal host tissue. The small gray circles indicate contrast agent molecules. The contrast agent is administered as a single intravenous bolus injection at point 2. The contrast agent leaks into the extravascular-extracellular space (EES), also called the leakage space, through VVOs and widened interendothelial junctions (line 2 to line 3). At first the contrast agent accumulates in the extravascular tissue before it diffuses back into the vasculature from which it is excreted (line 3 to line 4). In an MR image the accumulation and wash-out of contrast agent is observed as changes in the MR signal intensity which is proportional to the concentration of contrast media. The time- intensity curve to the left in the fi gure shows the intensity of the MR signal from the zoomed region before (line 1 to line2) and after injection of contrast agent (line 2 to line 4). [2]

The time-intensity curve to the left in the figure shows the intensity of the MR signal from the zoomed region before (line 1 to 2) and after injection of contrast agent (line 2 to line 4)

The mechanisms underlying the signal enhancement patterns seen on dynamic MRI include variations in regional blood flow, proportional blood vessel density, vascularization of existing blood vessels and variations in the surface area permeability of the endothelial membranes as well as the concentration difference which exists between plasma and the EES [2].

In many tumor types including breast, lung, prostate, and head and neck cancer, measurements of microvascular density made on histopathological samples correlate closely with clinical stage and act as an independent prognostic factor of considerable sensitivity. The rationale for this relationship appears to be that rapid tumor growth can be supported only in the presence of highly active angiogenesis and more aggressive tumor are therefore associated with increased evidence of angiogenesis-related microvasculature abnormalities. On the basis of this histopathological evidence it has been suggested that dynamic contrast enhanced MRI may also be able to provide independent indices of angiogenic activity and therefore act as a prognostic indicator in a broad range of tumour types [2].