MRI contrast enhancement

Breast Cancer revealed on MRI through dynamic contrast ‘enhancement’ (DCE MRI)

For practical reasons, mammography is usually used in breast cancer detection, followed by ultrasound if there are suspected ‘cystic‘ features to a lesion. Magnetic resonance imaging (MRI) is used in breast cancer screening in certain instances, and can sometimes reveal lesions hidden to mammography.

With magnetic resonance imaging, breast lesions are usually identified because they ‘enhance‘ after the injection of contrast agents, due to the neovascularity induced by angiogenesis.

The image below shows invasive breast cancer scanned with MR imaging, which was not visible to either a mammogram and sonogram.

‘Enhancement‘ refers to a process by which lesions revealed on a breast MRI image increases in contrast at a specific rate over a given short-time interval, which indicates increased vascularity to the area.

A ‘neoplasm‘, such as a breast cancer neoplasm, will tend to have an increased vascularity when compared to normal breast tissue. However, contrast enhanchement is not specific to malignant breast tumor. Many benign breast tissues can exhibit variable degrees of contrast enhancement as well.

I just want to let you know that I have created a newer version of this page, with more up-to-date information on MRI contrast enhancement of the breast. However, this page is extremely long and has really fantastic information, I would still use it.

Breast cancer will ‘enhance’ quickly and strongly before washout

Contrast enhancement associated with breast cancer is differentiated from benign-type enhancement through the use of a fast dynamic scanning technique.

A fast dynamic technique takes rapid successive scans of the breast following contrast injection. The ‘signal intensity‘ vs ‘time‘ (the kinetics of enhancement) of the contrast change is plotted graphically in what might be called a ‘Kinetic Curve Assessment‘.

Generally speaking, invasive cancer in the breast will show a more than 70% increase in signal intensity over baseline within the first 60-90 seconds because of large vessels in the tumor. This marked increase in signal intensity is followed by a ‘wash out‘ phase, which is the result of increased vascular permeability and the presence of arterio-venous shunts.

The MR contrast enhanced image of invasive breast cancer shown below was not detectable on a breast cancer screening mammogram.

Neovascularity and angiogenesis

Neovascularization refers to the formation of new functional micro vascular networks with a perfusion of red blood cells. Neovascularization differs slightly from angiogenesis in that angiogenesis is primarily characterized by the protrusion and outgrowth of capillary ‘buds and sprouts‘ from pre-existing blood vessels.

Neovascular vessel density can help determine a breast cancer tumor stage

In order for a breast cancer tumor to grow and progress, there needs to be neovascularity. In fact, the pathologic stage of a breast cancer tumor can to a certain extent be estimated by the vessel density of neovascular blood vessels (measured in vessels per millimeter squared [vv/mm2]).

The microvascular density (the density of new, small blood vessels) plays a significant role in regulating the initial rate of uptake of the contrast agent, and also the heterogeneity of any breast tumor enhancements.

On a ‘time vs signal-intensity curve‘, the percentage of maximal signal increase will tend to correlate very well to the density of the micro-vessel count. In fact, microvessel density can in many cases be correlated, at least informally, to a pathologic stage for the tumor. It is more common to encounter a higher ration of micro-vessels in the tumor peripheray rather than in the tumor center when the tumor is malignant and not benign, and the pattern continues for higher vs lower grade breast cancer tumors.

Also, an early ‘rim enhancement‘ tends to correlate well with a high ratio of ‘peripheral-to-central micro vessel density‘, and, to increased peripheral vascular epithelial growth factor expression (VEGF).

Magnetic resonance angiography: contrast enhancement, time-of-flight, phase-contrast

Magnetic resonance angiography basically refers to the variety of techniques based on Magnetic Resonance Imaging (MRI) to specifically image blood vessels, based on flow effects or on contrast.

Contrast enhanced (CE-MRA): A contrast medium is injected into the vein and images are aquired while the medium passes through the arteries the first time. An alternative method of contrast enhancement is to use an agent that remains in the vascular system for up to an hour, rather than just a few minutes. This ‘blood-pool agent technique‘ will result in higher resolution images, but, since both arteries and veins are enhanced at the same time, it is more difficult to draw firm conclusions regarding neovascularity.

Time-of-flight (TOF) or ‘Inflow angiography‘, uses a short echo time and flow compensation. This makes ‘flowing blood‘ much brighter than blood in stationary tissues. Flowing blood entering an area being scanned will have a much higher signant than saturated stationary tissues, as it has only seen a limited number of excitation pulses. However, this method is really only effective in areas of high blood flow, such as the head and neck.

Using the Phase-contrast (PC-MRA) technique, the phase of the MRI signal is manipulated by special bipolar gradients (varying magnetic fields) already set to an expected maximum flow velocity. So, a second scan is obtained to acquire and image that is the ‘reverse‘ of the bipolar gradient, and then the difference between the two is calculated. Static tissues such as muscle or bone will subtract out, but moving tissues such as blood will acquire a different phase. But phase-contrast can only acquire flow in one direction at a time. Therefore 3 separate image acquisitions in all three directions must be computed to give the complete image of blood flow. This is a slow method, but the advantage is that in addition to imaging the flowing blood, quantitative measurements of blood flow occur at the same time.

“Hypervascularity” can precede the appearance of breast tumors, sometimes by years

It is speculated that angiogenesis in breast tissue may actually precede the development of a breast tumor by years, even decades. This is not an unreasonable idea, but neovasculariy would preceed the build up of enough neoplastic cells to all it a ‘lump‘. In order to survive as a lump, the cells will need a good blood supply. Sometimes these neovascular formation may appear on a mammogram, but be dismissed as normal asymmetry because no lesion is visible. Calcified arteries, enlarged or engoged arteries, and hypervascularity might be an indication that neoplastic breast cancer cells are beginning to accumulate in a given area of the breast. It is not clear how this would benefit screening and treatment of breast cancer, but it is an intersting observation and could prompt a shorter term follow up screening and observation.

Angiogenesis

Angiogenesis is literally defined as the growth of new blood vessels from pre-existing vessels. Sometimes the terms neovascularity and angiogenesis are used interchangeably in an informal way, but both point to unexpected increased blood supply to a given area of tissue, more than likely to supply newly developed cells. Angiogenesis is normal and vital in ‘wound healing‘ and the normal growth and development of the body. However, it is also a fundamental step in the transition of potential breast cancer tumors from a dormant state into a malignant one. Angiogenesis also plays a central role in the distant metastasis of breast cancer.

Spatial resolution of MRI breast images can help distinguish between benign and malignant breast tumors

The high spatial resolution of MRI images allows a more detailed analysis of the morphology of a breast lesion, resulting in an increase in specificity. Spatial resolution refers to the smallest distance between two points in the object that can be distinguished as separate details in the image. Generally, spatial resolution in indicated as a length or a number of black and white line pairs per mm (lp/mm).

Using MRI, a benign breast lesion will tend to have well-circumscribed margins and often exhibit internal septations. A malignant breast lesion, however, will tend to have a spiculated appearance which suggests invasion into the surrounding breast tissue.

Temporal Resolution

‘Temporal resolution‘ refers to the MRI contrast enhancement properties of a breast lesion as they intensify and fade over time. Sometimes this is referred to as the ‘kinetic’ curve assessment of the process, and various names are given to the different phases of the observed process. Malignant breast cancer lesions will typically show an intense enhancement very early after the injection of intravenous gadolinium, but will show a ‘washout‘ (a gradual fade) in it’s central areas in scans taken after a few minutes. This ‘contrast enhancement characterization‘ can be done right on the monitor by comparing early and late phase images after the contrast injection.

The entire breast is imaged using 3D T1W FSPGR sequence. Then a bolus of gadolinium is injected. The same scanning sequence is then repeated 4 times at exactly the same location, one immediately following another. This is sometimes called a ‘rapid dynamic scan‘.

The image of a breast cancer lesion above shows an early phase (<2min) contrast enhancement, while the image below shows the same lesion in the late phase (approximately 8 min). The early phase image above is intensely bright, but after 8 minutes one can clearly see the ‘wash out‘ effect in the center of the lesion.

Contrast injection images of suspected breast cancer lesions are ‘subtracted’ from a ‘pre-injection’ image

Occasionally a breast cancer patient might be shown an MRI image of her breast, which might have the lettering “Subtract TIW C+” at the top. This is a technical description of what has taken place. ‘C+‘ means that an intravenous contrast agent was given. ‘Subtract‘ means that the case was scanned before and after the injection of the contrast agent. Then the two sets of images were ‘subtracted‘, so that the only thing showing, is whatever changed from the contrast injection. (All of the common features to both scans are removed, leaving only what was different). Since the contrast agent travels in the blood supply, one will typically see blood vessels, and also tumors, on subtraction images. ‘T1W‘ means T1 weighted, and with MRI imaging T1 is just one kind of “look“. Sometimes MRI will employ T2 weighted imaging, which shows different kinds of tissue.

It is essential to obtain a very fast sequence (under two minutes) with contrast enhanced MRI rapid scans. The initial rise in signal intensity of any latent breast cancer can be missed. After a few minutes, the breast cancer is really not distinguishable from the normal enhancing breast parenchyma which enhances diffusely over time.

Fat Suppression and MRI breast cancer scans

Unfortunately, on T1 weighted sequences used in dynamic breast scans, fat will appear hyperintense just like the Gadolinium injection. Therefore it becomes very important to suppress the fat signal in order to discriminate between a contrast enhance breast cancer lesions and the breast background, which contains variable amounts of fat.

Fat suppression is an important aspect of breast MRI, even though younger woman screening for breast cancer will tend to have a decreased proportion of fat tissue. (Breast stromal tissue tends to be replaced by fat tissue as women age). High fat density can obscure areas of contrast enhancement, and therefore certain methods are typically used to suppress the fat tissue signal. Subtraction, (subtracting the precontrast image from the postcontrast image) can be helpful in subtracting the fat signal, but requires absolutely no patient movement between precontrast and postcontrast scans. The selection of a more specific fat suppression technique will generally depend on the purpose of the fat suppression (whether it is contrast enhancement vs tissue characterization) and the relative amount of fat in the tissue being analyzed.

In the two breast MR images above and below, one notes how the fat suppression technique has revealed two distinctive areas of increased contrast intensity, suggestive of a suspicious lesion.

Breast tissue MRI with fat saturation, inversion-recovery imaging, and opposed-phase imaging

The three main MRI techniques for fat suppression of contrast enhanced breast tissue scans are fat saturation, inversion-recovery imaging, and opposed-phase imaging. The ‘fat saturation‘ technique is generally recommended for suppression of signal from large amounts of fat. But a drawback of this technique is the sensitivity to magnetic field nonuniformity, unrealiability when used with low-field-strength magnets, and misregistration artifacts.

The ‘inversion-recovery‘ technique allows global and homogeneous fat supression and can be used with low-field-strength magnets. However, this technique is not specific for fat, and the intensity of the signal in breast tissue with a long T1 or a short T1 can be ambiguous.

‘Opposed phase‘ is a fast and readily available technique for fat suppression in breast tissue scans, and is recommended for viewing lesions that are suspected of containing small amounts of fat. The main drawback of the opposed-phase technique is that the detection of small tumors embedded in fatty tissue is somewhat unreliable.

Characteristics of normal breast tissue enhancement: inflow phenomenon

In a contrast-enhanced MRI scan of normal (non-cancerous) breast tissue, the radiologist will be looking for certain consistent features. Normal fibroglandular breast tissue will demonstrate enhancement, but this enhancement is rather easily recognized as it is visible in the lateral part of both breasts. Normal fibroglandular breast tissue enhancement will also be simultaneous in both breasts, symmetrical, and with show a slow and continuous signal increase. This characteristic ‘normal tissue‘ enhancement, which is called the inflow phenomenon, results from blood flow of the lateral thoracic artery.

The images above and below show a ‘fat saturation‘ T1W contrast enhanced MRI, showing enhancement of the breast parenchyma in the early phase, while the delayed enhancement showed a coninous signal incrase of the parenchyma. (This patient also has breast implants, but otherwise contrast enhancement MRI shows breast tissues to be normal). Some of the ‘specs‘ in the early image or due to phase encoding artefact.

So, it is important to remember that enhancement (contrast enhancement) indicates increased vascularity. Since increased vascularity is not specifice to malignant tumors, as many benign tissues will also exhibit enhancement to varying degrees, the radiologist has to carefully analyze the type of enhancement in order to differentiate benign from malignant lesions. However, this kind of expertise is standard ‘bread and butter‘ task for a radiologist with experience in breast cancer diagnosis.

The nipple-areola complex will also enhance

When a contrast enhancement MRI technique is administered for breast cancer screening and diagnosis, there will usually be slow and gradual enhancement of the nipple-areola complex as well.

Contrast enhanced breast MRI may be effected by menstruation

Many premenopausal women will demonstrate patchy or irregular enhancement to various degrees, dependent upon the timing of the menstrual cycle and the MRI scan. This can complicate the use of MRI breast cancer screening for premenopausal high-risk women. Hormonal fluctuations during the menstrual cycle have been known to cause an uptake of gadolinium in normal breast tissue that can make dynamic breast MRI scans challenging to interpret. Ideally, MRI scans should be taken during the second week of a woman’s cycle.

In contrast enhanced breast MRI, some women with dense breast tissue and lots of fibrocystic changes will tend to have many ‘enhancing targets‘, and ring-enhancement around cysts. These can be confusing signals to a radiologist looking for breast cancer. So, it is suggested that the best time to perform a contrast-enhanced MRI breast scan is just after menses is finished, when the hormonal effects should be lowest.

Some radiologists working in the area of breast cancer have now started testing for serum progesterone concentrations. There are premenopausal women who lack cyclic menses due to a variety of reasons, and testing for serum progesterone can help determine the follicular phase of a normal menstrual cycle, and aid in scheduling the optimum time for a contrast-enhanced breast MRI. But on the whole, scheduling breast MRI scans around menstrual cycle days usually turns out to be impractical and of little or no benefit, because when the breasts are dense and fibrocystic and have lots of enhancing areas, those cause uncertainties for the radiologist, no matter what part of the cycle the scan is done.

In the contrast enhanced ‘subtraction‘ breast MRI below, we can see how the breast fibroglandular tissue has increased in intensity during the delayed phase of the scan, which would be typical of benign breast changes.

Dense Breasts can present problems with contrast enhanced MRI

Dense breast tissue doesn’t cause increased hormones levels, but dense breasts do present more problems for the radiologist interpreting contrast enhanced MRI scans because they contain more incidental ‘enhancement‘ than normal. In the contrast enhanced breast MRI below, one can see that basically all of the fibroglandular breast tissue is enhancing. Unfortunately, this means that any breast cancer lesions, if present, would be hidden from view. It is quite likely that this particular breast MRI scan was performed with too-long a delay after the injection of the contrast agent. The longer the delay time before the scan, the more likely it becomes that normal fibroglandular breast tissue will also enhance. However, an experienced breast cancer radiologist, aware of the timing sensitivities involved in contrast enhanced MRI, particularly for women with dense breasts, will not mistake enhanced fibroglandular tissue for breast cancer. They may, however, request additional, confirmation scans or other procedures.

If increased ‘background enhancement‘ on MRI contrast enhanced scans is due to higher levels of proliferative fibroglandular breast tissue (dense breasts), then there may be a remote possibility of increased breast cancer risk in women for whom this occurs. Increased breast density is thought to be a risk factor for breast cancer, but there remains no statistically significant studies which actually connect increased background enhancement to breast density, or to any increased breast cancer risk.

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This is quite a fairly long page. However, everything you need to know about MRI contrast enhancement is listed above. I will try and think of a few Q&A we could go over…

• What are some reasons for the use of contrast agents in MRI scans? Relaxation characteristics of normal and pathologic tissues are not always different enough to produce obvious differences in signal density, pathology that is sometimes occult on enhanced images becomes obvious in the presence of contrast, enhancement significantly increases MRI sensitivity, in addition to improving delineation between normal and abnormal tissues, the pattern of contrast enhancement can improve diagnostic specificity by facilitating characterization of the lesion in question, contrast can yeild physiologic and functional information in addition to lesion delineation, and imaging of arteries and veins with contrast enhanced angiography.
• What are the different ways MRI contrast agents can be classified? Chemical composition, administration route, magnetic properties, effect on the image, presence and nature of metal atoms, and bio distributions and applications (extracellular fluid agents, blood pool agents, organ specific agents, active targeting/cell labeling agents, responsive agents, and pH-sensitive agents.
• What is the most commonly used compound for contrast enhancement? The most commonly used compound for contrast enhancement are gadolinium-based.
• How do MRI scanners work with the body? In MRI scanners sections of the body are exposed to a very strong magnetic field, then a radio frequency pulse is applied causing a tip of the net magnetization generated from hydrogen nuclei (mostly water protons). Signal can then be detected.
• What are water protons and how does it do? Water protons in different tissues have different T1 values, which is one of the main sources of contrast in images. A contrast agent shortens the value of T1 of nearby water protons, such that the contrast in the image is modified.

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