Elaboration
on CEUS based on our experience. If your CEUS exam is not conclusive, knowing
about these CEUS peculiarities and pitfalls and using optimal exam technique
may hopefully help leading to a more convincing conclusion.
Red links in
the guidelines open live video samples. These files are large, since they are tuned for
diagnostic quality. In some cases there is also a low resolution
alternative.
Over the years we have encountered many technical
issues, particularly during the first year of CEUS work. The past years we have
also had the honour of being consulted many times
about tricky CEUS exams that have been sent to us. In some cases
lesions certainly do not have circulatory patterns that are very typical, and a
biopsy may be the only answer. However, our own observations and some of the
consultations have made us aware of eight conditions that may be to blame in
inconclusive cases where the pathology is otherwise straightforward:
The typical haemangioma shows initial spots or "puddles" of intense
enhancement in some or all of the periphery while none more centrally, followed
by a continuous growth of these puddles of enhancement toward the centre, and there is no washout in the late phase. The
propagating enhancement pattern from the periphery to the centre
may take anywhere from a few seconds up to several minutes, but should
nonetheless be readily recognizable for the diagnosis. Within the first 30
seconds following TCA it is usually quite clear whether the
lesion is probably a haemangioma or something else.
The early presumption of a haemangioma may be a
reason to minimize MI and extend
scanning intervals.
Non-enhancing central areas are quite frequent, but the general character of the arterial
enhancement pattern should be recognizable for dependable verification of a haemangioma. Other lesions than haemangiomas
show immediate or almost immediate enhancement in all vascular areas, albeit
being very different from one another in vascular architecture and degree of
vascularity. Care must be taken not to mistake hypovascular
or necrotic areas of [metastases] for the initially non-enhancing parts of haemangiomas.
Typical haemangioma with a small
non-enhancing centre.
Fast-flow haemangiomas should have the same basic characteristics for diagnosis
as more common haemangiomas despite the fact that
they enhance from the periphery toward the centre in
a matter of seconds.
Fast flow haemangioma Enhances
completely within ten seconds. No washout.
Non-enhancing haemangiomas are encountered occationally.
Some small lesions looking like bright haemangiomas
on baseline have not enhanced whatsoever, and some have been biopsied
confirming haemangiomas. These are probably
completely thrombosed haemangiomas, and we tend to
report them as such in otherwise healthy individuals.
Non-enhancing haemangioma,
characterized as such by being completely avascular, probably thrombosed.
Haemangiomas with true washout are
encountered once in a while. Such washout is generally seen later than that of
a typical metastasis. However, clear visualization of convincing bright initial
peripheral enhancement with the mandatory central propagation is a very
reliable sign of a haemangioma. With experience a haemangioma showing washout is not necessarily a diagnostic
problem if the early phases of the exam are unequivocal. This is a good example
of when the excellent time resolution of ultrasound is an asset over that of
other modalities.
The typical FNH has a typical arterial enhancement from the centre and out, "spoke wheel" or tree shaped
arteries and a non-enhancing central scar. Typically
there is no washout of contrast in the late phase, thus indicating the benign
nature of the FNH.
Typical FNH Large FNH with all FNH characteristics
present.
Roughly 50% of FNH's lack one or more FNH
criterion except for the late phase
enhancement, or sometimes some of them can not be
seen unless settings are optimized. This means that many FNH's show two or less
arterial phase characteristics and some show none. Typically
there is a feeding artery which initially reaches directly into the centre of the FNH, and the arteries of the FNH enhance very
quickly (within a second) from this centre and out.
The central scar is obvious in all exam phases. If a lesion does not reveal any
typical FNH characteristics we rely on the absence of washout in the late phase
only in otherwise healthy individuals without a history of cirrhosis or
hepatitis.
Uncharacteristic FNH Diagnosed as highly probable FNH on
the basis of no washout in healthy individual. Small haemangioma
is also seen.
Arterial center-to-periphery flow may be visualized as a directional flow of microbubbles
before the entire FNH is uniformly enhancing, provided the framerate and region
of interest are optimized. An optimal exam should aim at distinguishing an FNH
from other lesions by displaying the special vessel characteristics.
Arterial center-to-periphery flow same as Typical FNH
above, with slow motion workup at workstation.
A
"fire ball" of tissue
enhancement from the center to the periphery of the lesion may occationally be captured by the Sonoscan
although the arteries are not clearly visualized. A sufficient frame rate along
with a proper region of interest is a prerequisite as well as slow motion
reading at a monitor. When present, the "fire ball" may be a useful
aid, but the pattern is a sibling of the "basket
sign" of some HCC's so it is wise to balance it against clinical and
other parameters. Nevertheless, in our experience a conspicuous "fire
ball" pattern may be diagnostic for an FNH.
FNH, "fire ball" Slow motion workup at
workstation
A central scar is usually straightforward.
FNH's with a clear washout have been encountered, although they are rare. Washout
probably depends on degeneration. If the arterial characteristics and the
central scar are clearly recognized, the lesion may still be diagnosed as a
highly probable FNH, but great care and convincing documentation is necessary
in order not to overlook a malignancy. Frequently FNH's with washout lead to
biopsy.
Further
tips on exam techniques for quickly enhancing FLL's
The typical metastsis is characterized by quite rapid washout in the portal or
late phase, usually visible within 30-60 seconds after TCA
and conspicuous after 90-120 seconds. All attempts to distinguish one type of
malignancy from another by the appearance of the metastasis circulation have
been disappointing in the light of a known primary tumour
or subsequent biopsies.
A characteristic "rim zone" appears as a
hypervascular rim around or in the circumference of
many metastases, but far from all. The rim zone varies from thin to thick, but
is usually quite uniform in the individual metastasis. It may represent microinfiltration or inflammation in the adjacent liver or
a hypervascular surface of the metastasis itself.
Thin rim zone in an intermediatly
vascularized metastasis.
The arterial phase appearance varies greatly, from very hypovascular
via "isovascular" to hypervascular.
The hypovascular metastases are hypoechoic to the
liver in all phases, but show washout and become even darker after the arterial
phase.
Hypervascular
metastasis with rapid washout.
"Isovascular"
metastasis practically
"isovascular" with liver in arterial phase,
quick washout.
A very hypovascular
lesion is obviously very different
clinically from one which is truly avascular, such as a simple cyst, thrombosed
haemangioma or RF-ablation. CEUS is extremely
sensitive even to minute enhancement, but detection of enhancement in very hypovascular lesions requires careful optimization of the
machine settings, especially regarding CEUS noise level. With optimal settings
CEUS can often rule out enhancement with quite great confidence.
Hypovascular
metastasis hypoechoic to liver in all phases. Note the thick rim
zone. Also metastasis with large necrosis and haemangioma.
Necrosis appears as non-enhancing areas, usually in the centre with an
irregular margin to viable tissue, but there is great variation in the shapes,
sizes and numbers of necrotic areas. Very few metastasis
are so necrotic that viable tissue is undetectable. Superficially hypervascular, very necrotic metastases may at first glance
mimic a haemangioma, but all parts of metastases that
do enhance typically show washout. Such a rim of superficial washout next to
necrosis is not as conspicuous as the preceding arterial phase enhancement, and
may be at risk of being overlooked. Also, the rapid flow of UCA is often seen
in the Sonoscan.
Metastasis, large necrosis Almost complete
washout in the viable superficial tissue.
Absent washout is extremely rare, but we have seen a few cases of metastases from renal and
uterus cancer which display very slight washout, and thereby being difficult to
detect with CEUS. However, these cases comprise a mere handful of all our cases
since 2002, and are very uncommon indeed. []
HCC, or
Hepatocellular Cancer, can be all from well circumscribed solitary lesions to
diffusely spread and practically infiltrating the liver. In larger lesions
there are frequently irregular areas of necrosis. HCC's
are common in liver cirrhosis, especially on the basis of hepatitis, but quite
rare in otherwise healthy individuals.
Rapid, intense hypervascularity is typical for HCC's. Enhancement prior to surrounding
liver also in cirrhotic livers, which themselves enhance earlier than normal
because of arterialization of the parenchyma following reduced portal vein
flow. [multifocal]
No or little washout is unfortunately the case in many HCC's. Clear washout is a sign of malignancy, but
the absence of washout is of no real significance. This is the reason why HCC
always should be suspected in the advent of a hypervascular
lesion in a liver with cirrhosis or hepatitis, unless it is clearly a haemangioma or an FNH. []
The arterial phase enhancement pattern is often unspecific, but for some
lesions a detailed study of the arterial phase reveals patterns that support an
HCC:
Curly, irregular arteries can sometimes be identified in the HCC in the arterial
phase. []
The
"basket sign" is a term for
the visualization of rapid enhancement from the entry point of a feeding artery
on one side of the lesion to the other, combined with a characteristic
finger-like pattern of arteries that originate from the same spot and continue
inside and near the surface of the lesion. In essence, the distinction between
the typical basket sign and the typical FNH "fire
ball" enhancement is that the basket sign can be described as is
"fire storm" of enhancement in one direction along with arteries
bulging along the lesions periphery, while the FNH has
its main arteries more centrally, from which the enhancement expands to the
periphery. In the individual case a sound scepticism
is recommended before reading too much into this delicate distinction, but if
clear and conspicuous the basket sign can indeed be diagnostic for HCC. Again,
these arterial specifics are seen in the very first seconds following TCA,
and may require slow motion scrutiny.
HCC, basket sign with slow motion at
workstation. Diagnostic for HCC. Surgical resection performed on CEUS
characterization. Washout is not reliably strong.
Courtesy of Dr. Anna-Karin Siösteen-Tofte, Karolinska University Hospital, Sweden
In the arterial phase regenerative nodules may appear as virtually black lesions compared to the
enhanced liver until the portal enhancement of the lesions begins. They differ
from most other FLL:s (except haemangiomas)
in that they enhance later that the surrounding cirrhotic liver parenchyma. It
is speculated that the regenerative nodules have a more normal circulation than
the cirrhotic liver, which means that they depend more upon the portal than the
arterial flow for their own blood supply. The cirrhotic liver has much poorer
portal flow, which is compensated by increased arterial flow. Thus, the UCA
bolus enhances the cirrhotic liver prior to the regenerative nodules.
In the portal phase the enhancement of the lesions is quite rapid and uniform,
and there is no difficulty differentiating them from haemangiomas.
There is typically no washout in regenerative
nodules. Once they are isoechoic with the
rest of the liver, they can no longer be seen with CEUS.
In HCC detection
the characteristics of regenerative nodules make them quite conspicuously dark
in the arterial phase, which means that they turn up as black lesions while scanning
in the arterial phase to detect HCC:s, but they quickly "disappear"
following TCA
and may be isoenhancing by the end of the arterial Sonoscan.
Regenerative nodules in HCC detection
Appearance of regenerative nodules in cirrhotic liver. Note that nodules are
not seen at the end of the scan, since they have enhanced by then.
Courtesy of Dr. Anna-Karin Siösteen-Tofte, Karolinska University Hospital, Sweden
Dysplastic or malignant transformation make the regenerative nodules enhance quicker that the
surrounding liver cirrhosis. It has been encountered that a defined lesion has
turned from "early dark" in one exam to "early bright" half
a year later, as it has progressed from regenerative to dysplastic or
malignant. []
Fatty lesions enhance like the liver. This fact is actually the basis for their
characterization; there is no difference in comparison to the surrounding liver
parenchyma in any of the circulatory phases. The vessel architecture, speed of
enhancement and late phase enhancement are typically identical to that of the
surroundings. Sometimes a minute echo difference can be seen in the late phase,
but usually the lesion is discretely hyperechoic in these cases, which very
rarely causes diagnostic problems. We have not seen any exceptions to these
characteristics so far. [fatty]
Skip lesion Enhancement pattern like the
surrounding liver parenchyma, slightly brighter in late phase
The echo of abscesses may be very isoechoic. While most larger abscesses are
readily seen on conventional ultrasound, they may be notoriously evasive, often
discrete and may easily be overlooked. If one is discovered there may be many
more that are not seen because of different echo. On the other hand,
CEUS on liquefied abscesses makes them very conspicuous. Abscesses should liberally be
subject to CEUS detection according to the same principles as metastases
mentioned above.
The inflammatory capsule is typically hypervascular, and
thicker capsule areas typically wash out. However, not all abscesses show a
clear capsule, probably depending on their age and the aggressiveness of the pathogenes involved. There are also abscesses that appear
as simple cysts on US, but these may be characterized by the very thin hyperenhancing periphery in the arterial phase. This
appearance may be brief, why CEUS parameters must be optimal. The inflammation
of their periphery may be far to thin to be seen as
washout in the late phase.
Liver abscess slightly hyperemic capsule,
and with some incomplete septations.
Septations within the abscess are often surprisingly enhancing due to CEUS's extreme
sensitivity to small amounts of UCA. Thin septations may be exaggerated on
CEUS, and not necessarily a sign that the abscess is not "ripe" for
drainage. []
Non-liquefied abscesses resemble metastases (such as many fungal abscesses or early bacterial
abscesses). They are typically hypervascular and show
a washout in the late phase; in fact, such abscesses fulfil the criteria of
metastases, and the same detection technique is used.
Fungal abscesses in patient with leucemia.
Adenomas are quite rare, and there are not many CEUS cases of verified adenomas
reported. We have seen two verified adenomas over the years, and they followed
the reported pattern of a quick, homogenous enhancement with no washout.
Adenoma Biopsy verified adenoma. MI goes
from low to high and back in this exam. A bright ring of vessels can be seen in
the periphery, and finally there is a late phase with no washout.
Courtesy of Dr. Knut Brabrand, Rikshospitalet
University Hospital, Oslo, Norway
Washout is the significant trait of metastases. The onset of visible washout may vary, but
predominantly takes place at some time in the portal phase.
Washout is the basis for detection. The greater the washout, the greater the detectability.
It is not unusual for conspicuous washout to take place quite late,
near the late phase. Regarding very small metastases of about five mm, or
even less, there must be enough time between injection and scanning to let the
washout make the metastases hypoechoic enough to be detected.
90-120 seconds after injection is an appropriate starting point for the beginning of the detection Sonoexam. If scanning begins within the first minute
there is a substantial risk that some metastases are not yet dark enough to be
clearly seen. By waiting at least 90 seconds before scanning begins, the risk
for encountering metastases that are not yet dark enough is greatly diminished.
Prescan interval monitoring
of some metastases while waiting for the 90 seconds after injection may give a
hint as to how fast the washout is in the actual case, and how dark metastases
to anticipate in the Sonoexam.
Very slowly darkening metasteses may be a reason to return to the beginning of the Sonoexam for a second exam of the first points of the
protocol.
Lack of reliable washout is very rare indeed, but has been encountered as stated under "Characterization/Metastasis" above.
Haemangiomas are excellent for demonstration of technical pitfalls thanks to their predictable enhancement pattern, which
initially includes a completely non-enhancing centre.
There are several pitfalls examplified by haemangioma videos in this section. However, these examples
serve as a reminder to consider the possibility of technical pitfalls in all
CEUS procedures.
MI (the Mechanical Index) should be regarded as
a dynamic parameter just like image gain,
and needs attention throughout any exam. MI is a parameter that is new to US
examiners beginning using CEUS in clinical practice. There are legal
restrictions as to how high the MI may go in conventional US, but in practice
the examiner never really thinks about it (except regarding the eyes which have
much lower legal limits of their own). However, CEUS is a different story, and
introduces MI as a very important player.
Proper MI is the responsibility of the examiner in each individual case. MI settings in CEUS using second
generation microbubbles can very easily be set way too high and ruin the exam. Unfortunately this fact has to date not been emphasized
enough by US machine vendors nor their application specialists. In most cases
MI is set to a default value in the machines contrast programs at installation,
and the users unfortunately get the impression that this value is the one to be
used in future.
For lesions that are not very superficial or
deep, most default MI settings will work
well most of the time, but such a fixed MI may have unexpected and bad effects
on the interpretations of CEUS exams if one is not aware of the problem. The
effects of MI to lesions depend on many things in our experience, such as the
distance from the transducer, degree of steatosis, examination time, lesion circulation
speed etc.
Depth setting affects MI; increasing the image depth decreases MI.
Slightly too high an
MI is the most difficult to recognize,
since the negative effects may gradually but substantially affect CEUS results
as microbubbles are slowly destroyed. Excessive MI has the greatest impact on
superficial slowly filling haemangiomas
and on the detection of superficial metastases. []
Too low an MI is usually more straightforward to recognize and is negative for CEUS of any deep lesions.
It makes the image gradually dark with increasing depth in the affected areas,
with no dependable CEUS echoes and disturbing noise levels by gain
compensation. Of course this is negative for the
detection of metastases, which depends on the contrast resolution, as well as
to characterization.
"One finger always on the MI knob" is the way one ought to think about it. In 2002 when we
started practicing CEUS, the MI levels were set by default to a level that
permitted good penetration and gave a bright and clear signal in most cases,
but we soon found that this MI level was far too high for superficial lesions
and for repeated scanning in detection of metastases, with excessive
microbubble destruction. Nowadays it seems that the default settings are more
careful after lots of feedback to the industry.
It is impossible to compare MI settings between
different machines. Some vendors display
the mean MI value, while others use the peak value in their settings. An MI of
0.18 in one machine type may correspond to 0.06 in another (by experience).
Another problem is that some machines change the MI level by too large
increments when one turns the knob; another is that the lowest possible MI may
not be low enough for very superficial lesions in thin patients.
For haemangiomas
MI settings and scanning time
within "normal CEUS limits" may occasionally be too much. In most haemangiomas the circulation is extremely slow, a reason
why the virtually stationary microbubbles seem more susceptible to mechanical
destruction by sound waves than in other lesions. Under unfortunate
circumstances this means that a "false washout" may be inflicted in
superficially located haemangiomas by the examiner by
exposing the haemangioma to an otherwise "normal
CEUS level" MI, while the enhancement of the surrounding liver is actually
preserved. The haemangioma may even falsely seem not
to enhance at all. While a re-injection and a new exam with a very low MI
setting may lead to a conclusion, it is advisable to scan superficial lesions
cautiously according to the Sonoexam characterization protocol
in the first place, in order to avoid misunderstandings.
Iatrogenic bubble destruction in haemangioma
resembling washout Examiner inflicted darkening of shallow haemangioma in late phase, by going from MI 0,07 to 0,18
(which normally is within normal CEUS limits) and prolonged examination time.
Enhancement of haemangioma not seen
Microbubbles in slowly enhancing haemangioma are
destroyed as they enter the lesion. Remedy is re-injection at a very low MI and
finally long intervals between Sonoscans.
Image noise is a result of setting gain too
high. As a general rule, the pre-contrast
gain level should be set immediately below the level where noise is just barely
seen. [noise]
Gain compensation for low MI is a mistake that is fairly common when trying to brighten an image
caused by too low MI. In effect it is the image noise that increases, which
should of course be avoided.
Not enough MI compensated by too much
gain causes too much noise. In this case increased MI
might have destroyed the microbubbles. It’s better to find a spot closer to the
lesion for characterization.
Scanning a lesion for a long time to see how characterization evolves after the injection of
UCA may be tempting, but prolonged ultrasound exposure to the UCA has an effect
on its longevity, and thereby on the clarity of the results. This is especially
true after the first minute following TCA, since the inflow concentration of UCA
rapidly decreases.
"Fanning" and increasing intervals is the proper Sonoexam technique
to preserve the UCA optimally. “Fanning” is done over the lesion during the
arterial phase, later followed by single scans through the lesion at increasing
intervals, each one being recorded for later scrutiny. It is not necessary to
“keep looking” bedside after the arterial phase, since the rest of the exam
almost always involves the documentation of whether there is washout or not.
This is more confidently done by repeated short scans through the lesion at 30
seconds intervals than by continuous scanning, since the latter does affect the
microbubble concentration in the surrounding liver in a negative way and
thereby rendering the washout less conspicuous. See the characterization Sonoexam protocol for suggestions.
Workstation review of the exam very often has the clue to the diagnosis if the scanning
follows basic Sonodynamics principles. Remember that
there should always be the possibility to look at the Sonoscans
after the exam for final diagnosis.
The amount of data to be stored in PACS is greatly reduced by interval short one-direction
Sonoscans of the lesion in the portal and late
phases.
FLL characterization deeper than 12 cm is
rarely a great success. The smaller the
lesion, the worse the depth problem. There is a limit for how deep into the
tissues CEUS is possible to reach, since deep lesions involve high MI settings
and low spatial resolution. A particularly difficult situation is trying to
characterize a small lesion close to the lung at the top of the right liver
lobe, maybe because of the added effect of reflection of sound against the
surface of the base of the lung.
Find a position nearer the FLL. Very often it is possible to see at least part of the
lesion intercostally from a much closer position.
Characterization failure by depth Light
steatosis. At long distance there is no enhancement. Moving to a closer
position in late phase shows no enhancement; the slow microbubbles in the haemangioma were probably destroyed by high MI used at long
distance, with added effect of reflection from lung surface. New low MI
CEUS from the closer position characterizes the haemangioma.
For detection of metastases the problem is not quite as bad, since it is usually
possible to detect a dark lesion against the surrounding bright parenchyma, but
beyond 14-15 cm the results are less encouraging for smaller metastases.
CEUS is more influenced by incorrect focus positioning than conventional US, and again MI plays a
role. The sound beam is most concentrated at the levels of the focal points,
which of course has an effect on the longevity of the microbubbles at that
level. The deeper the focal points, the smaller the problem.
Image quality beyond the deepest focal point is more adversely affected in CEUS than in conventional US
in our experience. Again, it is important to keep the deepest of the focal
points as deep as possible at all times during CEUS.
TCA and the following seconds are
sometimes crucial to characterization. Sometimes the very first seconds of the
arterial phase may reveal characteristics of an FNH or an HCC, a very clear rim
enhancement of a metastasis or a very quickly enhancing haemangioma.
It is not good enough to start recording the first Sonoscan
just after TCA.
Sometimes a replenishment study following a high MI burst may save the
situation, but one can not count on it since the
replenishment tends to enhance the lesion and its surroundings and “soak” the
area with microbubbles extremely quickly. If the arterial phase has been missed
and the diagnosis is not obvious without it, it is safest to make a second exam
when the UCA concentration has fallen.
False appearance of enhancement in a lesion is a problem whenever the absence of enhancement
in a lesion is required for a conclusion. Such lesions are haemangiomas,
abscesses, RF-ablations, infarctions, portal venous thrombosis and others,
where a false impression of enhancement may lead to the false conclusion that
there is viable tumour tissue, when in fact the
absence of enhancement proves the opposite.
This problem most probably occurs due to reflection of the intense scattered contrast echo from the
surrounding liver parenchyma in the lesions tissues,
with added effect if the lesion is close to the reflecting lung surface or the
intensely enhancing kidney.
In most cases of CEUS the problem is of minor
importance, but it is important to keep
the possibility of reflection artefacts in mind in order not to judge affected
lesions as enhancing by mistake.
The appearance of the artefact differs from
true enhancement by the fact that no
"live motion" of microbubbles is seen. When the lesion is close
enough for this discrepancy to be obvious, the distinction is quite clear for
the experienced examiner.
Reflection artefacts increase with depth in our experience. Lesions close to the lung surface and
more than 10 cm from the transducer are notoriously difficult to prove
non-enhancing. Characterizations under those conditions may be impossible.
A significantly smaller dose of contrast may be an efficient remedy to the problem.
Strong glare artefact in arterial phase of haemangioma.
Ghost artefacts appear without the presence of
microbubbles. They can be seen in echoic
tissues, echoic cysts and as reverberations from more superficial ghost areas. Ghost
artefacts can also be seen in the usual enhancement behind cysts and deep into
liquids.
Ghost artefacts in a complex non-enhancing liver cyst. Contrary to glare artefacts, ghost artefacts don’t
disappear with high MI microbubble destruction.
15 frames per second is the lowest limit to aim at for the arterial phase of characterization
and for detection. It is important to keep the frame rate up in order to get a
feeling for the “fluent” conditions of the arterial enhancement, and in order
not to overlook small lesions when detecting metastases. The latter applies to
both baseline and to CEUS. We have seen examples of detection exams where the
frame rate has been as low as 6 fps, which is far too low and obviously causes
big spatial gaps between the frames of a normal Sonoscan,
where small metastases may hide.
Sacrifice a little spatial resolution to enable a higher frame rate. The great contrast
resolution of CEUS compensates for this in most cases.
In extreme cases up to 50 fps have been captured to catch the very first seconds of a
focal lesion. In the Sequoia this can be accomplished by selecting a ROI
(Region of Interest) for the Sonoloop.