EFSUMB Guidelines and Recommendations on CEUS - HD

Introduction

Thank you very much, Paul.
And thank you for inviting me to join this meeting.
It looks it's going to be great fun for the next two days.
So I'll be talking just about the work
of the guidelines committees in the liver,
because today's primarily a liver day,
and I know other speakers will be talking about
non-liver applications.
And also the LRADs work on the HCCs.

This is a World Federation
and WFUMB, of course, embraced in the World Federation.
And really before I go on, just to say that,
if you would like to have a look at the document,
it's freely available on the WFUMB website
so you can get hold of it.
It's quite long, but it's freely available there.

And I'd also like to acknowledge all of the vendors who've been instrumental in making this happen by facilitating face-to-face meetings and things like that.
I should also say that nothing in the guidelines is written by these folks.
They just facilitated and allowed the meeting to happen.

Focus on Focal Liver Lesions

So we're gonna talk primarily about focal liver lesions
because in diffuse liver disease at the moment,
contrast doesn't have a recommended role.
And we'll be talking about characterization
and detection and it's also used for monitoring ablation therapy and for tumor responses.
And these are in the guidelines,
but I'm not going to spend time on them
because they're relatively minor indications,
although we will have some opportunity to discuss them.
And if there are questions, I'll be happy to take them.

So let's focus on characterization and detection.
And I've put them in that order.
And you may think that's rather an odd order,
but it is the order in which they appear in the guidelines.
And the reason is that we tend to use,
for characterization, we tend to use the arterial phase to tell us what kinds
of lesions we're looking at, and
keep the detection for use in the late phase.
And not to say that any of these phases aren't used in all aspects, they are,
but there's a bias that way,
and you'll see how that works out as we carry on.

Contrast Phases in the Liver

Just before I go too far, let me just mention
that in the liver, and it's almost uniquely the liver,
but also actually applies in the spleen,
although that's a relatively minor application.
We have not just the wash in
and wash out that you would get, for example,
in a kidney or a thyroid.
We saw some examples from Martin Creek earlier today.
But you also have an additional late phase.

So there's an arterial phase,
which starts maybe about 20 seconds
after injection, something like that.
And then goes on for something like maybe a minute.
And then the portal phase begins
because of the dual supply of the liver.
And that kicks in at about 45 seconds.
There's overlap between these phases, of course,
and lasts for up to about two minutes.

And then the SonoVue
that we're talking about, and it's only SonoVue
that I'm going to be discussing
because that's the only agent that's in
these guidelines.
The SonoVue then somehow
sticks in the sinusoidal apparatus of the liver.
It's not entirely clear what, where it is there.
Some agents are phagocytosed by Kupffer cells.
But it's not certain that
that's the mechanism for SonoVue.
But this late phase is extremely important.
It lasts for five six, if you're lucky, maybe seven minutes.

And it's really important
because it depends entirely on the intact functioning
of the sinusoidal apparatus.
So any focal lesion,
which does not contain a functioning sinusoidal structure
will appear as a late phase defect.
And that's really a crucial component
in the characterization of lesions.

And so you can imagine that,
structures which have normal liver, for example, fatty,
focal fatty deposition
or fatty sparing, they will just disappear in that late phase.
'Cause they behave exactly the same way
as the normal liver.
However, metastasis which doesn't,
or an HCC, which doesn't have a proper
functioning sinusoidal structure will appear
as a defect in the late phase.
That's a really crucial part
of this whole process.

And I think when we first started in this field,
we didn't actually anticipate that this would happen.
It was a serendipity.
And it's really a very important part
of the use of SonoVue
and other contrast agents as well.

Characterization of Lesions

So let's first start off with a characterization.
And here we're kind of mentioned this,
malignant lesions give a late phase defect, whereas benign,
solid lesions, for the most part, be warned,
it is solid lesions
that we're talking about in this context.
They retain contrast. So they disappear.
They appear at the same intensity,
signal intensity as the rest of the liver.

Obviously, any structure which doesn't have any
vascularization, for example, cysts
or abscesses de vitalized tissue,
like in trauma, for example.
All of these are a defect,
not only in the late phase, but in every phase.
They don't, they've got no supply.
So they're, they don't appear in any phase.

And then we use the arterial phase to differentiate the different kinds of focal liver lesions.
And here there's a long list,
and we'll go a little bit more into detail on these
as we go through.
And I've got some examples as well to show you.
And some of them are very similar, very familiar
to people who use contrast in CT or MR.
They're very much the same sorts of patterns.

For example, the peripheral nodular enhancement,
that's characteristic of hemangiomas
and where you get these blobby dots
and then gradual filling in.
And then the very characteristic pattern.
And often this lesion, FNH, is the one of the nicest
to look at with contrast
because the pattern is so specific and clear cut the central filling from a central artery
that then spreads out in a radial spoke
wheel type of fashion.

And so we can characterize the
different lesions in this way.

Patient Examples

So let's look at a couple of examples.
Here's a patient with an mammary carcinoma,
and you'll see that this is, this has come in,
after one minute, one
and a half minutes approximately.
And you'll see that the contrast image on the left side
of this screen has got numerous defects in it.
I'll play it again because that went a bit quickly.
And as you scan through,
you see these tiny little holes everywhere.
Well, not everywhere, but a great number of them.
And these were not visible on the B mode scan at all.

And so here we've detected,
so it's a staging process we've detected these lesions.

Here's a recent patient from King's, a young lady
with a carcinoma of the breast.
I don't think I can point, I'm afraid on the screen there,
so I have to revert.
It's not working, it's not working.
I can see it here, but I, it didn't work up there before.
So I know. Anyway, this is the lesion here.
And so we needed to characterize it.
This was a young woman with a,
with a known breast cancer.

So now we're coming in in the arterial phase.
And you can see we split the screen.
And so we're looking in this region here,
nothing much is happening early on, patient's breathing.
So the area of interest is moving in and out.
And now at 20 seconds
or so, we're starting to see it appear as a defect.
So this lesion's taken up, it's become,
it was iso enhancing in the arterial phase,
and now in the late portal
and into the late phase, it's starting to appear
as a defect.
So this was a metastasis, a very small one.
You can see it's well under a centimeter in size,
but confidently characterized using this technique.
So straightforward solution.

Here's another patient also with a breast cancer
and a young woman.
And a lesion is visible on the B mode here,
and it's behaving like a metastasis.
You see, it was iso enhancing the arterial phase,
and now it's starting to wash out.
And then we do a sweep through the rest
of the liver in the late phase.
And you'll see we're picking up several additional lesions.
I'll go back again because there's also a group down here
that you may not have spotted.

So we're sweeping through the liver
after analyzing this lesion.
And now you see there are defects here as well.
So this woman didn't just have that one lesion,
but had several, a bad result.
Okay. That's same patient. So let's move on.

And I'd like to contrast that with this lesion.
Here you see a very brightly reflective lesion on the B mode.
This patient's got reflux into the hepatic vein, so you have
to learn to ignore that sometimes very striking.
And here's the arterial phase beginning
and the liver's filling up.
And you'll notice that the entire region
that we're looking at, again, ignoring the hepatic veins,
is filling up equally
and uniformly so that lesion's disappearing
as we move into the late phase.

So that even though this patient had a malignant
background, that lesion is not behaving like a metastasis.
And the way it's disappeared like
that is strongly suggestive that it's focal fatty change.
So a region of focal fatty change.

Now, HCC is a very important tumor to analyze.
This is a large one that makes it easy
to see what's going on.
And you can see this is extremely hypervascular,
lighting up very brightly indeed.
So hyper enhancing in the arterial phase.

And HCC, the patterns that follow are quite complex
because they depend on
how well differentiated the lesion is.
If it's towards the well differentiated end of the spectrum,
it behaves much more like a regenerating nodule
or a dysplastic nodule.
So it will be often they are iso in all phases with the rest of the liver.
We're always comparing the
lesion with the rest of the liver.

But if they're poorly differentiated,
then they've lost their sinusoidal structure,
and so they wash out later.
So the late phase is really important here.

And here's an image at four and a half minutes,
and you can see that this lesion compared with the rest
of the liver around it.
And we try to compare it the same depth so that we equalize the effects of a, for example, tissue,
a bubble destruction or attenuation phenomena.
So it's starting to wash out at four
and a half minutes, and then it's washed out much more completely by five and a half minutes.
And you can see clear wash out there,
but the wash out isn't to blackness in metastases.
There're often pitch black at this stage in HCC,
there's often a little bit of retention.
So we call it mild washout in that situation.

Patterns in the Late Phase

So now let's just summarize that looking at the patterns in the late phase.
So here we're looking first at non-cirrhotic livers,
and the guidelines make a clear distinction
between cirrhotic and non-cirrhotic
because of the complexity of the patterns in HCC.
And we're gonna hear a lot more about
that from Fabio Piscaglia a bit later on.

So here, if the lesion shows a sustained enhancement
or no washout, if it's, if that's true,
then those lesions are likely to be benign.
And so then we have a number
of options based on the arterial phase,
and I'll go through them in a moment.
But if there's no retention,
then the lesion is likely to be malignant.
And again, we look at the arterial phase
to help us distinguish the different patterns.

So here are the different arterial phases.
So for example, if you have a hyper enhancing lesion
with centrifugal filling,
that's the spoke wheel pattern I mentioned, then we think
of it as a FNH,
and it really is extremely reliable
for diagnosing lesions like that.

If it has peripheral nodules
with gradual centripetal fill, then you will call it a hemangioma.
Adenomas are one of the most difficult.
Luckily they're not that common,
but they're one of the most difficult
because they can be hyper
or various patterns of enhancement in the arterial phase,
and we often can't be absolutely sure about that particular one.

And I already showed you an example
of focal fatty change.
And focal fatty sparing does exactly the same thing.
They look, they just behave the same way as the rest of the liver and so on.
So you can go through all these and try to analyze the detail structure of the lesion.

Patterns in Cirrhotic Livers

Now, if we look at the cirrhotic liver,
then it's a slightly different game.
We are looking now at the arterial phase
to see if they're hyper enhancing,
as in the example that I showed you.
If they are, then it's the late phase we're going to be looking at to tell a little bit more about the lesion.
If they don't show enhancement, then it similarly we're going
to be looking at the late phase.

And so here's what the late phase does.
If it's hypo enhancing as we already saw, it's likely to be an HCC.
Cholangiocarcinoma does the same thing,
but they wash out very early.
Rather like a metastasis,
although mets in this situation of the cirrhotic liver are
of course rather rare.

If there's a slight hypo enhancement,
then it's very suspicious for an HCC.
And as I said, Fabio will go into this a lot more when he talks about the
RADS discussion.

Detection and Staging

So that's really for characterization, for detection,
which essentially is staging.
Of course, we're looking at the late phase, like in
that example I showed you of the breast cancer patient.
And we are looking for a defect at one to five minutes.

And just remember
that cholangiocarcinoma behaves
in the same way as metastases.
And I repeat it because it's so important.
In the liver focal lesion analysis
that benign solid lesions
and only solid lesions retain contrast.

There are a few exceptions
and these are important to understand.
I mentioned already
that avascular lesions like trauma ablation, cavities
and so on, as you'd expect,
if you think about the hemodynamics
and what's going on, they don't show
enhancement in any phase.
So they're dark throughout,
very important and very helpful for sorting these out.
Some of them have particular patterns in
trauma, for example.

They're often relate to the nature of the trauma.
So you could see a knife shape if it's a stab wound.
And also very often it's extremely helpful in trauma
'cause it shows a peri hepatic collections extremely well.
'Cause you see the surface of the liver much more clearly
than on the unenhanced scan.

Abscesses are also interesting
because they tend to have a pattern
where you see septa dividing up the different
LOEs of the abscess.
And often very characteristic.

I mentioned the problem with adenomas
remains a really difficult one.
We're just not very good at sorting them out.
I don't think any imaging modality's very good at sorting
out adenomas.
And we get stuck there too.

Granulomas and inflammatory masses, they're rare, of course.
But they tend not
to show very much enhancement in the arterial phase,
and they often wash out.
So they can be a trap
and they can look like a malignancy.
And you need to of course weigh all
of these findings in the clinical background,
the clinical context that you're working in.

And well differentiated HCCs, I also mentioned
that problem, that they may escape detection on contrast ultrasound
because they look like normal liver.

Comparison with Other Modalities

So analyzing
how this all fits in the greater scheme of things, it seems,
and lots of papers have now studied this.
And many august bodies like NICE
and the FDA have accepted that this is the case.
That's contrast CT is the equivalent of contrast ultrasound
for detection and characterization of focal liver lesions.
They both have their strengths and weaknesses.

CUS has can see smaller lesions
and you can easily see on contrast CT.
On the other hand, some of the problems that Martin mentioned about depth
and is a problem for CUS.
And we basically don't do very well deeper than
about 10 centimeters.
That's being worked on by the manufacturers, of course.
So there's improvement in the offering there, probably CT
CE-MR is slightly better.
But there is overlap.

And as a matter of fact, in our practices,
we often are asked to evaluate focal liver lesions
that are perhaps too small or are equivocal on MR, as well as on CT.
And that's quite a flow of patients into a contrast ultrasound laboratory.

Adverse Events

One part of the guidelines mentions adverse events.
And I'll just put up Fabio's meta-analysis here,
just to say that they're rare,
they are less common than for other contrast agents, both for x-ray and MR.

And in this meta-analysis of Italian patients who are receiving contrast ultrasound for radiological abdominal type studies.
So leaving aside cardiac, which is a separate question
and we'll refer to it, they did a
survey of 23,000 patients treated,
and they only had less than 30 adverse events.
And so the rate there was
what 0.01 perhaps we could say,
which is much less than for CT
and MR, and importantly, most of these reactions were minor.
They're mostly things like itching, funny taste,
a little bit of backache, that sort of thing.
And they're transient. They disappear.

So the one that's really a concern is hypotension.
And that happens occasionally.
And I think in this group of patients, there were only three that had this effect.

And this is why it's really important to be able
to manage them because they're managed
by standard resuscitation, epinephrine, IV fluids.
And so anyone doing contrast studies with some
of you must be trained in resuscitation,
and they must have the right apparatus to hand.
Otherwise there can be problems.

And in fact, you maybe know
that in historically there were some deaths associated
with the use of various contrast agents.
And the FDA got very excited and worried about it
and started to put warning labels.
And they were exclusively in cardiac patients.
And I think the problem there is
that they've got limited cardiac reserve.
And so the resuscitation is more difficult.
And I don't think there've been any deaths in
for radiological patients.

LI-RADS

Now, just a very short mention of something new
that's coming along, which is RADS that's the liver imaging equivalent of BI-RADS.
And I know Fabio is going to talk a little bit more about that,
but to me it's a very exciting development
because the Americans are being very behind in
actually ultrasound in general, but especially in contrast.

And so it was very,
I was very pleased when they decided that it was time
to think about adding contrast ultrasound
to the existing LI-RADS recommendations, which relate only
to CT and to MR.
So it's very good that they've done that.

And there's a working group based in the states,
of course, but because the Americans didn't have much
experience, they drafted in
some Europeans.
And Fabio is on the telcos.
And as I am.

This looks like a very complicated slide.
And this is the heart of the LI-RADS lexicon.
But some of it's really easy.
If the study's inadequate, if the lesions already been treated,
then they don't get scored in this.
And there's also a group for malignancy.
So these are metastases, non HCC lesions, so metastases
and the drift of the LI-RADS approach is to try
and identify the lesions that you can confidently call HCCs.
So that's the whole thread of this of the RADS recommendations.

And they're due to be published this year, so hopefully will be out quite soon.

Conclusion

So just to wrap up contrast,
the guidelines are widely used.
I think they're very helpful for training purposes, also
for sorting out standards of practice.
And along with the NICE recommendations
that we'll also be hearing about, they're very helpful
if you are trying to get your administrators to agree
that it's a good idea and it saves money and so forth.
And so very useful.

There's a new edition
of the non-liver guidelines in progress,
and that should be published next year,
but we're not sure whether they'll also be a liver
a new edition of the liver guidelines.

So thank you very much for your attention.