Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound in EU

Introduction

My name is Olivier Lucid Arm.

I am an academic radiologist in Petria Hospital in Paris, France.

And I'm going to talk about the guidelines and good clinical practice recommendations about contrast enhanced ultrasound in European Union.

We are going to speak about the guidelines and good clinical practice Recommendations for contrast enhanced ultrasound in the European Union.

Guidelines and Recommendations

The guidelines and good clinical practice recommendations were first published in 2005, updated in 2008 and updated again in 2011.

Concerning the non hepatic applications, they cover a lot of different clinical application, but we are going to focus and illustrate only the area where the contrast ultrasound is the most used in Europe and only the recommendation that were graded A and B.

According to the evidence-based medicine Oxford criteria.

History and Initial Use

At the beginning 15 years ago, contrast ultrasound was created to overcome the limitation of color or power doppler ultrasound.

But quickly this first use was replaced by the most interesting one, which was to enable the display of parenchymal microvasculature.

Major Indications for Microvascular System

Let's start quickly by the only three major remaining indications concerning the microvascular system.

Extracranial Carotids

First of all, the extracranial carotids contrast enhanced ultrasound is recommended to further improve the delineation of the endovascular borders in difficult cases in order to distinguish occlusion from type occlusive stenosis like on this example coming from the literature where you can clearly see the bubbles clearly delineating the lumen of the carotids and the stenosis.

Abdominal Aortic Aneurysm (AAA)

So then the second application concern the AAA where contrast enhanced ultrasound is recommended to identify and follow up on the leaks after abdominal AAA and therapy repair.

Like on this example where you can clearly see an endoleak of type two here after abdominal repair by endoprosthesis, some studies have shown that contrast enhanced ultrasound seems to identify and characterize endoleaks better than CT angiography.

Anyway, contrast enhanced ultrasound is very useful in case of renal impairment.

Transcranial Doppler

The third indication, which is definitively the major indication of contrast enhanced ultrasound concerning the large vessels is the transcranial doppler because microbubbles improves a lot the visibility of the polygon of Willis and its branches and it allows the detection of occlusion and even and of the polygon Willis.

But of course now most of the recommendation of use of the ultrasound contrast agents concern the study of the microvasculature and more than 90% of the exams perform in Europe concern liver and kidney.

Contrast-Enhanced Ultrasound for Liver

So let's start first by the liver.

Generally speaking, contrast enhanced ultrasound imaging provides new interesting features compared to MRI or CT.

First of all, for focal liver lesion, when usually CT and MRI offers only four images to get to have an idea of the enhancement pattern of a focal lesion like the arterial phase, the portal phase, the equilibrium and the late phase ultrasound imaging may provide real time imaging with 15 to 20 frames per second as long as you want.

Then you can see directly without extrapolation the contrast arriving into the lesion.

Hence for hemangioma for example, you will be able to see the apparition of the peripheral globular enhancement and their confluence in real time.

This is of course a very interesting in case of fast filling for FNH, you won't only see the strong arterial enhancement during the arterial phase, but you will be able to see what is happening right before, which is an enhancement starting from the central artery.

Then continuing by a spoke wheel pattern in a centrifugal direction from the center here toward the periphery in the centrifugal direction, which is completely different from the all over lesions that grow into the liver, pushing the parenchyma all around and recruiting their blood supply from the peripheral vessels coming from the host liver.

In this case, you will see the enhancements starting from the periphery toward the center.

It is a centripetal enhancement and it concerns metastasis HCC, adenoma, cholangiocarcinoma, et cetera.

In case of strong angiogenesis process, then you won't be able to see a peripheral enhancement, but you will rather see a diffuse enhancement all over the lesions, which is the equivalent.

The other very interesting feature concern the fact that microbubbles are true blood pool agents in contrary to iodine and gadolinium, they don't leak outside the vascular space.

Consequently, the enhancement during the equilibrium and the late phases are expected to be different from CT and MRI.

It is particularly true with malignant tumoral vessels because microbubbles do not flood the interstitial space.

They leave the tumor bed very quickly.

It is the washout and very interestingly for some reason not well elucidated, but probably because of the phagocytosis of the fer cells, the microbubbles stay for a while within the sinusoid system of normal liver.

It means that the normal liver remains homogeneously enhanced for several minutes after injection, but also the liver tumor that contains sinusoids and Q4 cells like FNH at the known mass and sometimes well differentiated HCCs for hemangioma.

The mechanism is different.

The bubbles stay for a long time in the blood lakes like iodine and gadolinium.

If we summarize, it appears that normal livers and benign liver lesions keep the bubbles at the late phase while malignant lesion exhibit a wash out.

So to characterize the focal liver lesion with contrast enhanced ultrasound, you need first to look at the late phase to see if it is a malignant or benign lesion and then to look at the enhancing pattern in real time during the arterial phase to put a name on the lesion and it works.

And let's see some example from the everyday practice.

Example: Hemangioma

This is a 50-year-old men underwent ultrasound for abdominal pain.

We discovered this lesion developed at the inferior border of the left lobe.

This is an heterogeneous lesion hard to characterize without contrast after injection.

If you jump at the late phase more than three minutes after injection, which is displayed here, you see the persistence of the enhancement without wash out.

So what does do you think it is?

We are in this configuration.

So it was obviously an hemangioma and as I said, this technique is very convenient for the fast filling hemangioma.

And here is an example of fast filling hemangioma.

It was an hypoechoic lesion within a hyperechoic liver and look in real time what happened after injection just to show you how fast the filling occurs in real time and only the contrast ultrasound is able to see that look again in 23 Second, the lesion was completely filled with bubbles as shown here.

Example: Focal Nodular Hyperplasia (FNH)

Another example, this is the first ultrasound examination of a woman, 47-year-old who was diagnosed for breast cancer a few weeks earlier.

We saw a large slightly hyperechoic lesion in the right liver.

Of course, statistically it is more likely to be a benign lesion than a metastasis and also because we could see a large artery penetrating the lesion in color doppler.

But you need to be sure so you could perform an MRI, but you could also inject microbubbles to get the answer immediately and to be able to reassure the patient.

So after injection on this slow motion replay of the contrast specific mode, you can see the enhancement starting from the central artery followed by Arif Ugal enhancement.

Here is the summary of the enhancement.

So we got a strong arterial enhancement, 14 seconds after injection and after two minutes you don't see any wash out.

So the late phase tell us that it was probably an hepatic lesion, probably benign, that contains sinusoids.

And the early phase tells us that it is an FNH, it is definitively not a metastasis.

Here is the corresponding MRI and it was clearly a FNH with a strong arterial enhancement and even a central scar.

But please note that the central scar, even if it was well visible on MRI here and here, was not visible on contrast enhanced ultrasound.

Usually we don't see the central scar with contrast enhanced ultrasound, but it is not mandatory to make the diagnosis of FNH.

Here is another focal liver lesion discovered in the left lobe of a 35-year-old woman.

The Doppler shows a large artery in the center of the lesion here.

So you would like to say that it was also an FNH, but to date Doppler alone is not sufficient to make the diagnosis and you need additional clues.

Here is the injection.

It goes very fast.

It's a real time imaging look.

That's why we need to record the injection.

And here is the slow replay of the injection and you can clearly see the centrifugal enhancement and the spoke wheel pattern of the enhancement.

So here is the summary of this lesion, the arterial enhancement with a spoke wheel pattern and a delayed phase, no washout at all and you can even see which is rare, a central scar.

So it was obviously an FNH.

Now you have enough to say with confidence that it was an FNH.

Example: Metastasis

This man underwent an ultrasound examination for colorectal cancer and we found in the right liver this slightly hyperechoic lesion.

Is it a met or an FNH?

Here is the early phase where you can clearly see a strong arterial enhancement without spoke wheel patterns.

So it was clearly a rim of angiogenesis.

But if you continue to look at the lesion, you will see after 30 seconds in real time the arrival of the wash out.

Look, the wash out occurs in real time in this lesion.

And if we jump at the late phase, you see that this lesion is clearly hypoechoic, meaning that it was a metastasis, not only one, but you can see also two other metastasis on the images.

So it's clearly a metastasis with a large rim of peripheral angiogenesis.

Example: Adenoma

One more example, another large lesion depicted in the right liver of a 40-year-old woman with a stein disease.

This time you see clearly that the enhancement start from peripheral vessels in a centripetal direction.

Look, and looking at the late phase here, you don't see any wash out.

The lesion remains strictly isoechoic compared to the surrounding parenchyma.

Consequently, it is suggestive of a benign liver lesion recruiting its blood supply from the periphery vessels, probably not an FNH but more an adenoma.

But each time you say adenoma, you need to think about the possibility of an well differentiated HCC, which has the same pattern.

So unfortunately like CT and MRI contrast enhanced ultrasound does not allow us to differentiate an adenoma from a well differentiated HCC.

Here it was an adenoma.

Accuracy and Recommendations for Liver Lesions

Using this different pattern, it has been shown in the literature that the use of microbubbles increases the accuracy of ultrasound to characterize focal liver lesion from 65% without contrast, mainly cyst or typical hemangioma or multiple metastasis in an oncologic context to 92%.

The added value was particularly high for FNH at typical hemangioma but not adenomas and metastasis.

And more generally because of the washout at the late phase, it is very useful to differentiate benign and malignant lesions.

The semiology is trustable and contrast ultrasound may replace MRI to characterize a typical hemangioma FNH and metastasis.

It is so efficient that more and more contrast ultrasound is performed after an inconclusive CT or MRI.

Washout and Metastasis in Liver Lesions

Now let's go a little bit deeper about the washout and the metastasis.

The questions are, are all the metastasis hypoechoic at the late phase?

In other words, are there metastasis non hypoechoic at the late phase?

And the second question is, are all the hypoechoic lesions metastasis?

The answer of the first question is yes.

Almost all common metastasis are hypoechoic at the late phase.

However, in some very special histology it may happen that the lesion does not exhibit washout.

Like on this example, There was a strongly hypoechoic lesion in this liver here, but after injection, we could see in this lesion a rapid peripheral enhancement and this lesion appeared as strongly hypervascularized here.

But if you look at the late phase, after two minutes and even after five minutes here, you couldn't see any wash out.

So this lesion did not have any wash out, but it was a metastasis, but it was a metastasis of malignant angio paroma.

Thus sometimes in case of special histology, particularly highly vascularized lesion, the rule of the washout may be wrong, but it is extremely rare.

And here even the CT made a wrong diagnosis as fast filling hemangioma because of the enhancement at the late phase.

The answer of the second question are all the hypoechoic lesions metastasis?

The answer is obviously no.

10% of the benign lesion like FNH and even Hemangioma may exhibit a wash out at the late phase.

Just one example of an hemangioma with a wash out.

Look at this hemangioma with a typical peripheral globular enhancement during the early phase here.

But if you look at the late phase, after two minutes, you clearly see a wash out, but it was an hemangioma.

So in summary, if a lesion is not hypoechoic at the late phase, it is not a metastasis with a high level of confidence.

If a lesion exhibits a washout, it may be a metastasis in an oncology context, but it may be also something else.

And here are the European recommendations in case of focal liver lesion.

If the quality of the images is good, injection of microbubbles may be done at the same time to get an immediate answer in case of hemangioma or typical FNH.

If you don't see any wash out at the late phase, it's probably not a metastasis, at least a metastasis from common histology.

If you see a wash out at the late phase in an oncology context, it's probably a metastasis.

But keep in mind that 10% of the benign lesions exhibit a washout at the late phase.

Contrast-Enhanced Ultrasound for Kidney

Another large field of contrast ultrasound is the kidney, and here the application are more based on the third interesting feature provided by contrast ultrasound.

This technique is very sensitive to a low amount of circulating microbubbles, much more sensitive than CT to iodine or MRI to gadolinium it means that no enhancement means no or almost no circulating vessels.

This property is very useful for kidney indeed about kidney and unlike liver, microbubbles are not very helpful to differentiate the solid tumors because they behave the same after injection except in case of complex cystic mass.

Because of this extreme sensitivity to the presence of the micro bubbles, contrast ultrasound will be helpful to identify vascularized wall or an ignoble within this mass in order to characterize this lesion as benign indeterminate or malignant.

For the same reason, contrast enhanced ultrasound is recommended to make the distinction between hypovascular solid lesions on CT and atypical cyst, like on this example of a non-classified lesion on B mode here and after color doppler where you couldn't see any vessels within the lesion.

But after injection, this lesion appeared vascularized with a lot of bubbles in it, showing vessels in it.

So this lesion was considered as a solid lesion with cystic component.

The overall indication is the suspicion of infarction of the kidney in fact appears as a wedge shape, non enhancing area of the cortex of the kidney.

And because of the high special resolution of the ultrasound, it is also possible to see the cortical necrosis, which will appear as a lack of enhancement at the periphery of the cortex.

Example: Renal Infarction

Here is an example of a renal infarction.

The B mode and the color doppler was were normal after injection.

You could see a diffuse enhancement of the cortex and the medulla of the kidney, except in this area that remained dark.

So it was an infarction of the purple pole of the kidney here.

Example: Cortical Necrosis

And here is an example of a cortical necrosis where you could see the lack of enhancement of the cortex of the kidney.

Here the cortical necrosis was here and confirmed by the corresponding MRI.

Another example of a cortical necrosis on 3D where you can clearly see the absence of enhancement of the cortex of the kidney after injection on this 3D acquisition here.

Other Applications

So you understood that contrast ultrasound is a very powerful technique to quickly assess the micro circulation of an organ or a tumor.

And this can be used in many other indication than only liver and kidney contrast.

Ultrasound is also recommended to study cystic masses on the pancreas and even using endoscopic ultrasound like on this example coming from the literature where you can see the enhancement of the wall of this lesion after contrast, but also to assess the level of inflammation of bowel wall in Crohn disease.

Here you can clearly see the strong enhancement of the wall of this small bowel loop or, and it is very important to better identify fractures of the spleen or of the liver after a trauma.

We all know that it's very difficult to identify fresh fracture in the spleen in the emergency room, but after contrast, it becomes obvious and it is very useful in the emergency room.

Conclusion

In conclusion, this is a very convenient technique to assess liver tumors and renal vascular disorder, but also in many other organs and vessels.

And in addition, microbubbles are very well tolerated, making this technique an interesting solution in case of renal impairment where we need to inject contrast anyway.