G a s t r o i n t e s t i n a l I m a g i n g • R ev i ew

D’Onofrio et al.
CEUS of Focal Liver Lesions

Gastrointestinal Imaging
Review
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FOCUS ON:

Contrast-Enhanced Ultrasound of
Focal Liver Lesions
Mirko D’Onofrio1 OBJECTIVE. The purpose of this article is to discuss the use of contrast-enhanced ultra-
Stefano Crosara sound (CEUS) in focal liver lesions.
Riccardo De Robertis CONCLUSION. Focal liver lesions are usually detected incidentally during abdominal
Stefano Canestrini ultrasound. The injection of microbubble ultrasound contrast agents improves the character-
Roberto Pozzi Mucelli ization of focal liver lesions that are indeterminate on conventional ultrasound. The use of
CEUS is recommended in official guidelines and suggested as a second diagnostic step after
D’Onofrio M, Crosara S, De Robertis R, ultrasound detection of indeterminate focal liver lesions to immediately establish the diagno-
­Canestrini S, Pozzi Mucelli R sis, especially for benign liver lesions, such as hemangiomas, avoiding further and more ex-
pensive examinations.

Keywords: contrast-enhanced ultrasound (CEUS), focal
liver lesions, HCC, metastasis, microbubbles
DOI:10.2214/AJR.14.14203
Received November 29, 2014; accepted after revision
January 10, 2015.
1
All authors: Department of Radiology, G. B. Rossi
Hospital, University of Verona, Piazzale L.A. Scuro 10,
37134 Verona, Italy. Address correspondence to
M. D’Onofrio (mirko.donofrio@univr.it). 
WEB
This is a web exclusive article.
AJR 2015; 205:W56–W66
0361–803X/15/2051–W56
© American Roentgen Ray Society
C
ontrast-enhanced ultrasound
(CEUS) is an imaging method
that has been used in European
and Asian countries for more
than 10 years. The use of ultrasound con-
trast agents has been approved in several
countries, but the Food and Drug Adminis-
tration (FDA) in the United States has not
yet approved their application for a noncar-
diac use. The injection of microbubble con-
trast agents improves the accuracy of ultra-
sound study. The main liver application of
CEUS is for focal liver lesions.
Focal liver lesions are usually detected in-
cidentally during an abdominal ultrasound ex-
amination, during first evaluation or follow-up
for a primary neoplasm, or during surveillance
in chronic liver diseases and cirrhosis. In cases
of incidental findings, focal liver lesions can
be characterized by conventional B-mode and
color Doppler ultrasound when a typical pat-
tern is identified, as in the case of homoge-
neously hyperechoic hemangiomas [1] or fo-
cal nodular hyperplasia with a spoke-wheel
shaped central vascular pattern on color Dop-
pler ultrasound [2], but the accuracy of the fi-
nal definitive diagnosis can be limited. In fact,
even though color Doppler imaging during an
ultrasound study of the liver can improve di-
agnostic confidence in the characterization
of focal liver lesions, it has important limita-
tions because of limited sensitivity and spec-
ificity because benign and malignant lesions
may show similar appearance on B-mode and
Doppler ultrasound [3–9]. Moreover, it is im-
possible to characterize a focal liver lesion in
the presence of underlining oncologic history
of the patient or chronic liver disease and cir-
rhosis because the aspect of a malignant lesion
may be similar to a benign lesion. CEUS has
improved the detection and characterization of
focal liver lesions [10–16].
Technique and Protocol
Before CEUS, a thorough conventional ul-
trasound examination of the entire liver must
be performed. The baseline study includes
the assessment of the lesions on B-mode im-
aging and by means of color Doppler ultra-
sound together with the use of tissue har-
monic imaging [17].
The currently used contrast agents (sec-
ond-generation) are gas-filled (sulfur hexa-
fluoride) microbubbles stabilized by a shell
made by albumin, surfactants, or phospho-
lipids. They are designed to be smaller than
7 μm (mean diameter, 2.5 μm) to circulate
freely in the capillary beds, showing both
macrovasculature and microvasculature,
with no interstitial phase because they are
exclusively intravascular.
In CEUS, 2.4 mL (a much lower dose than
with CT and MRI) of microbubble contrast
agent is rapidly injected via an antecubital
vein followed by a 5-mL saline flush. A suf-
ficiently large needle (20-gauge minimum
diameter) should be used to avoid causing
bubble rupture.

W56 AJR:205, July 2015


Because microbubbles resist compression
better than expansion, when they are insonat-
ed at a low mechanical index (lower than 0.3)
the expansion and contraction phases are no
longer equal and the returning signal shows
nonlinear characteristics resulting in the
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generation of multiple harmonics from bub-
ble-filled vessels. At higher energy levels of
insonation, disruption of the bubbles occurs,
producing strong but transient harmonic sig-
nal. Contrast-specific software integrated in
ultrasound scanners cancels the linear ultra-
sound signal from tissues and uses the non-
linear responses from microbubbles [18].
The use of ultrasound contrast agents has
been approved in several countries, but the
FDA in the United States has not yet ap-
proved their application for a noncardiac use.
The CEUS contrast agent widely used in Eu-
rope is a sulfur hexafluoride contrast medi-
um (SonoVue, Bracco) with a main bubble
diameter of 2.5 μm. SonoVue has recently
been approved by the U.S. FDA for cardi-
ac use. Ultrasound contrast agents are safe,
with an extremely low incidence of side ef-
fects [19]. There are no cardio-, hepato-, or
nephrotoxic effects. Thus, it is not necessary
to perform liver or kidney function blood
tests before contrast medium administration.
The incidence of severe hypersensitivity
events is lower than with CT contrast agents.
Life-treating reactions have been seen, with
a rate of 0.001% and no deaths reported in
the literature [19].
Microbubbles are eliminated partly by
means of metabolization in the liver (sta-
bilizing shells) and partly by the patient
breathing out of the lungs (gas filling) in ap-
proximately 10–15 minutes [20], with no
risk of nephrotoxicity.
Different dynamic phases of contrast en-
hancement may be identified in the liv-
er study after the injection of a microbub-
ble-based contrast agent. The arterial phase
starts within 10–20 seconds and lasts for
35–40 seconds after the injection. The por-
tal phase is characterized by the arrival of
contrast agent through the portal system; it
lasts for 2 minutes after the injection, and the
overall liver echogenicity becomes more in-
tense. Because microbubbles are purely in-
travascular, unlike the CT and MR contrast
media that present an interstitial phase, there
is no interstitial or equilibrium phase, and for
the remaining observation time (late phase)
they are progressively cleared [18].
In noncirrhotic patients, the first aim of
liver CEUS is to distinguish between ma-
AJR:205, July 2015 W57
CEUS of Focal Liver Lesions
lignant and benign lesions. The late phase
of liver parenchyma contrast enhancement
has been shown to be the most useful for this
task. Benign lesions typically present persis-
tent microbubble uptake with a hyper- or iso-
vascular appearance relative to the adjacent
liver, whereas malignant lesions typically
display microbubble washout with a hypo-
vascular appearance because their vascular-
ization is almost exclusively arterial and mi-
crobubble contrast agents do not present an
interstitial phase [18, 21–24].
Video frames of the entire liver have to be
recorded in all three contrast phases because
it is not possible to simultaneously exam-
ine multiple lesions in the arterial and por-
tal phases [25]. If more than one lesion has
to be studied, a second bolus of contrast me-
dium should be administered after a washout
time of almost half an hour or a flash replen-
ishment technique can be applied, which is
an ultrasound technique that uses high-pow-
er flash pulses to destroy contrast microbub-
bles when scanning a liver lesion followed
by low-power pulses to show lesion replen-
ishment. However, this technique is not rec-
ommended because of the possibility of
introducing changes and therefore inhomo-
genicity of microbubble distribution in the
liver and impairing detection.
The late phase of CEUS is useful for de-
tection of malignant (metastases) focal liver
lesions. The late phase of CEUS enables bet-
ter ultrasound hepatic staging in oncologic
patients. However in the late phase, simple
cysts that are very small can be misinterpret-
ed as metastatic lesions because both appear
hypoechoic. This explains the importance of
a complete B-mode and color Doppler study
prior to the administration of the ultrasound
contrast agent.
In general, if an examination of the liver
by ultrasound is insufficient, examination by
CEUS will be insufficient. The limitations
that apply to CEUS are the same as those that
apply to ultrasound. Thus, the quality of the
examination still depends on the skill of the
operator. In addition, CEUS provides limited
ability to observe certain parts of the liver,
especially in obese patients. Further limita-
tions are related to the width of the acoustic
window and movement artifacts.
Benign Focal Liver Lesions
Benign focal liver lesions are a common
finding [26]. Noninvasive accurate charac-
terization using the most economic and con-
venient workup is preferred [27, 28].
Hemangiomas
Hemangiomas are the most common be-
nign tumor of the liver [29]. On B-mode ul-
trasound they typically present as homoge-
neously hyperechoic rounded lesions with
distinct margins, sometimes with slight poste-
rior acoustic enhancement [1]. When heman-
giomas are found in patients with no history
of malignancy, no further imaging is needed.
When B-mode ultrasound is not sufficient
to make a certain diagnosis, CEUS is indi-
cated. The typical CEUS pattern of hem-
angiomas is globular enhancement in the
peripheral area of the lesion in the arteri-
al phase with progressive centripetal fill-in
(Fig. 1). During the late phase the centrip-
etal fill-in appears complete in 40–50% of
cases, with a persistent hyper- or isoecho-
genicity. This pattern is considered diagnos-
tic of hemangioma whatever the B-mode ap-
pearance of the lesion [30–32]. Centripetal
filling is most often seen in large lesions but
can also be present in lesions smaller than
2 cm. In smaller lesions (16% of cases), the
fill-in is more rapid, probably due to the
abundant arterioportovenous shunts, and the
whole lesion may be enhanced in the arte-
rial phase [1, 24, 33], remaining hyperecho-
ic or isoechoic, but never hypoechoic, in the
portal and late phases. Occasionally, lesions
that are isoechoic in the arterial and portal
phases become progressively more echo-
ic than the surrounding parenchyma in the
late phase [11]. Persistent isoechogenicity,
instead, strongly suggests the diagnosis of a
benign lesion but is not specific for heman-
gioma. It also may, in fact, be present in fo-
cal fatty infiltration.
Unenhanced areas in the portal and late
phases of hemangiomas represent intrale-
sional thrombosis or fibrosis that may occur
in large hemangiomas. The finding of sus-
tained progressive enhancement of the non-
thrombosed and nonfibrotic portions in the
portal and late phases provides a reliable
diagnosis of a benign lesion. Atypical fea-
tures also include hemangiomas with calci-
fications and abundant thrombosis or fibrosis
and arteriovenous shunts.
Focal Nodular Hyperplasia
Focal nodular hyperplasia (FNH) is the
second most common benign lesion of the
liver [26]; it cannot be defined as a truly neo-
plastic lesion but rather a regenerative mass
of variable size resulting from a vascular ab-
normality [34, 35]. It may be detected more
frequently in women between 30 and 50

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A B
C D
Fig. 1—Cavernous hemangioma in 35-year-old man.
A, B-mode conventional ultrasound image shows small hypoechoic nodule (calipers) because of fatty
background liver visible in left lobe.
B–D, In ultrasound images obtained after contrast medium administration, nodule shows progressive globular
centripetal contrast enhancement (B and C) and appears homogeneously hyperechoic (calipers) in late phase (D).
years old, and patients are usually asymp-
tomatic. In 15–30% of cases, FNH is mul-
tiple [36]. The typical pathologic feature is
the presence of a large central (sometimes pe-
ripheral) fibrous scar in which an artery larg-
er than usual is located; the artery originates
from outside the nodule. This vascular dis-
order is responsible for the formation of the
nodule (composed of normal hepatic struc-
tures) and is characterized by the absence of
the central terminal hepatic vein and by cap-
illarization of the sinusoids derived from the
outside feeding artery [34]. This peculiar vas-
cularization is responsible for the typical dy-
namic appearance of FNH.
There is no specific B-mode imaging pat-
tern of FNH, it may be slightly hyperecho-
ic, slightly hypoechoic, isoechoic, or slightly
inhomogeneous. The central scar and radi-
ating fibrous septa can usually (70–80% of
cases) be identified as linear hyperechoic
structures. The central vessel radiating from
W58 AJR:205, July 2015
D’Onofrio et al.
the center to the periphery (a highly specif-
ic finding) can be identified at baseline color
Doppler ultrasound with a high flow and low
resistance index pattern [36, 37].
At CEUS, FNHs are typically hypervas-
cular, appearing homogeneously hyperecho-
ic in the arterial phase (Fig. 2). The fill-in is
characteristically centrifugal and very rap-
id; the feeding vessel may be clearly seen a
few moments before nodule enhancement.
The lesion can show hyperechogenicity in
the early portal and occasionally in the late
phase. Usually, however, FNHs are isoecho-
ic during the portal and late phases [38, 39].
The central scar appears as a hypoechoic
area in the late phase [36].
The spoke-wheel pattern is of key impor-
tance in distinguishing FNH from high-flow
hemangiomas, adenomas, and hypervascular
malignant focal liver lesions. The manage-
ment is conservative because FNHs do not
undergo malignant changes.
Adenoma
Adenoma is a rare benign hepatic neo-
plasm arising in normal liver, mainly in
young women and in people using steroid-
containing medications (e.g., oral contra-
ceptives or anabolizing hormones). The
clinical presentation is usually related to the
mass effect (40%) or pain due to intralesion-
al bleeding (40%) because of arterial pres-
sure blood perfusion and the lack of a portal
venous supply; the ease to bleeding is also
due to the architecture, which has large he-
patocytes and poor connective tissue sup-
port. Adenoma is asymptomatic in 20% of
cases [37]. Usually, adenomas are well en-
capsulated, 8–10 cm in size, and may be
multiple (more than 10).
At B-mode ultrasound, adenomas can be
hyperechoic, hypoechoic, isoechoic, or in-
homogeneous. Sometimes, intralesional cal-
cification can be present as the evolution of
bleeding episodes. Color Doppler ultrasound
shows arterial signals with high peak flow
and low impedance [40].
On CEUS, adenoma usually shows homo-
geneous contrast enhancement in the arterial
phase, typically with rapid complete centrip-
etal filling. In the early portal venous phase,
it usually becomes isoechoic or, more rare-
ly, remains slightly hyperechoic. Intratumor-
al nonenhancing areas are due to previous
bleeding episodes or to necrotic portions.
The correct differential diagnosis from
FNH is made because of the absence of the
central spoke-wheel pattern and because the
adenoma shows a centripetal enhancement
pattern [36, 41]. The management is very of-
ten surgical because of the risk of hemorrhag-
ic complications and possible degeneration.
Regenerative and Dysplastic Nodules
Regenerative nodules (macroregenera-
tive nodules if larger than 5 mm) represent
a region of liver parenchyma enlarged in re-
sponse to necrosis, abnormal circulation, or
other stimuli and can be seen in both noncir-
rhotic and cirrhotic liver diseases. Dysplastic
nodules contain cellular atypia without frank
malignant changes [37]. They usually show
a hypoechoic, often heterogeneous, appear-
ance on B-mode ultrasound with color Dop-
pler ultrasound displaying peripheral arterial
and venous vessels [42].
After microbubble injection, most mac-
roregenerative nodules show absent or per-
sistent dotted contrast enhancement, with a
hypo- or isovascular appearance during the
arterial phase followed by an isovascular ap-

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A B
pearance in the late phase [24, 43]. Dysplas-
tic macroregenerative nodules may display
diffuse contrast enhancement [24] in the ar-
terial phase and are isovascular in the late
phase. When diffuse contrast enhancement
in the arterial phase is present, the differ-
ential diagnosis from well-differenced he-
patocellular carcinoma (HCC) can be diffi-
cult [44].
Focal Fatty Deposit or Sparing
Focal fatty deposits, or sparing, usually
are polygonal areas located along the por-
tal bifurcation or close to the gallbladder and
hepatic hilum. They do not produce mass ef-
fect and are typically hyper- and hypoecho-
ic, respectively, in comparison with the sur-
rounding liver parenchyma.
On CEUS, the dynamic behavior is the
same as that of the surrounding liver; the
arterial and portal vascularization are pre-
served so the areas (pseudolesions) appear
isovascularized in relation to the liver paren-
chyma in all dynamic phases [36].
Malignant Lesions
Malignant lesions may be primary or sec-
ondary, the latter much more common than
the former in patients not presenting with
AJR:205, July 2015 W59
CEUS of Focal Liver Lesions
C D
cirrhosis. The B-mode imaging appearance
may suggest a malignant nature of the lesions
(large number, known primary tumor, hy-
poechoic halo, and infiltration of intrahepatic
vessels). Malignancies are often hypoechoic,
but any pattern may be represented. Howev-
er, in a large number of cases, contrast-en-
hanced imaging is necessary [36].
Hepatocellular Carcinoma
HCC is the sixth most common neoplasm
and the most common primary liver malig-
nancy [45, 46]. In most cases, HCC develops
within an established background of chronic
liver disease (70–90% of cases), and most of
the patients have a background of liver cir-
rhosis [47].
Ultrasound is the most common imaging
modality for HCC surveillance in high-risk
patients because of its efficiency, availability,
noninvasiveness, and low cost [48]. However,
Doppler technique applied to B-mode ultra-
sound has low sensitivity in studying blood
flow features within a newly discovered le-
sion. CEUS can overcome this problem be-
cause it can clearly show blood flows and dis-
play tissue perfusion information [49].
HCC is characterized by arterial phase
hypervascularity and later and low wash-
Fig. 2—Focal nodular hyperplasia (FNH) in 41-year-
old woman.
A, B-mode conventional ultrasound image shows
small hypoechoic nodule (calipers) on right lobe.
B, Color Doppler ultrasound image with waveform
shows artery going into lesion with arterial-type
pattern with regular systolic peak and diastolic flow.
C and D, Ultrasound images obtained after
contrast medium administration show nodule to
be hypervascular in arterial phase (C) and slightly
hyperechoic in late phase (D).
out on CEUS (Fig. 3). The arterial phase en-
hancement is often diffuse or heterogeneous.
Peripheral rimlike enhancement is unusual
in HCC and is commonly seen in metastases
or intrahepatic cholangiocellular carcinoma
(ICC) [50]. Large HCCs often show nonen-
hancving areas due to necrosis or internal
hemorrhage. Washout in HCC tends to be
late and often begins later than 90 seconds
after injection of contrast medium, whereas
metastases or ICCs consistently show rap-
id washout (< 60 seconds) [51]. Most small
cholangiocarcinomas, which are infrequent-
ly detected during HCC surveillance, can
be differentiated from HCC because of the
presence of rimlike arterial enhancement
and rapid washout. Washout is slower or may
even not be seen in occasional cases of well-
differentiated HCC. Washout timing is relat-
ed to the pathologic differentiation of HCC:
Well-differentiated HCC tends to show later
washout or no washout, whereas poorly dif-
ferentiated HCC tends to show rapid wash-
out [52–54]. It is important to understand
that most newly discovered hypervascular
nodules on CEUS detected during HCC sur-
veillance are HCC regardless of washout if
the nodules do not show the typical appear-
ance of hemangioma [55]. However, a biopsy

is needed to confirm HCC for hypervascular
nodules without washout. CEUS is superior
to CT or MRI for detecting hypervascular-
ity of HCC because of real-time evaluation
of arterial phase enhancement that can be
missed by CT and MRI because of the prede-
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termined scanning delay [56–58]. There is a
small subset of hypovascular HCCs, particu-
larly those that are well-differentiated. These
lesions usually show transient hypovascular-
ity followed by gradual enhancement, and
the lesions become isoechoic relative to nor-
mal in the portal venous and late phases [59].
CEUS is also a useful tool in the guidance
of radiofrequency ablation procedures as
well as in the monitoring of procedure effi-
cacy. It can help to localize the lesion before
the procedure in cases of nodules not easily
detectable on B-mode ultrasound. Moreover,
marginal disease recurrence adjacent to the
ablation zone may not be easily located on
gray-scale ultrasound because of the preex-
isting abnormality. CEUS can therefore eas-
ily identify the exact location of recurrent
HCC [60].
The role of CEUS in the differential di-
agnosis between HCC and ICC is contro-
A B
Fig. 3—Hepatocellular carcinoma in 77-year-old man.
A, B-mode conventional ultrasound image shows hypoechoic mass (calipers) in right lobe.
B and C, Ultrasound images obtained after contrast medium administration show nodule to be hypervascular in arterial
phase (B) and slightly hypoechoic in comparison with surrounding liver parenchyma in portal and late phases (C).
W60 AJR:205, July 2015
D’Onofrio et al.
versial. ICC always enhances later and more
slightly and washes out more quickly than
HCC on CEUS [61]. The other major con-
cern in cirrhotic livers is to make a distinc-
tion between HCC and other nodules, such
as large regenerative nodules and low- and
high-grade dysplastic nodules. Pathological-
ly, large regenerative nodules and low-grade
dysplastic nodules generally show arterial
and capillary supply similar to that detect-
ed in the adjacent cirrhotic nodules, whereas
high-grade dysplastic nodules and HCC may
show abnormally increased arterial supply
with a decreased portal supply [62]. About
33.3–60.0% of high-grade dysplastic nod-
ule cases show arterial hyperenhancement,
whereas 40.0–66.7% show hypoenhance-
ment [63, 64]. Washout is seldom found in
the late phase for high-grade dysplastic nod-
ules in contrast to typical HCC, which is
supplied by abnormal arteries alone, best
displayed with the use of a flash replenish-
ment technique with maximum intensity
processing. Occasionally, cancerous foci of
well-differentiated HCC are encountered
within dysplastic nodules, which are called
nodule-in-nodule lesions, or dysplastic nod-
C frequency: peripheral irregular rimlike en-
ules with a focus of HCC. Differentiation
between HCC and these nodules is always a
major concern in cirrhotic livers because the
appearance on conventional ultrasound may
be similar but their prognosis is substantially
different from each other. CEUS facilitates
the detection of the HCC portion in dysplas-
tic nodules because the HCC portion gener-
ally shows arterial hyperenhancement [61].
Little information is available concern-
ing the role of CEUS in the diagnosis of HCC
in noncirrhotic livers. On CEUS, the en-
hancement pattern has no difference in com-
parison with that in cirrhotic livers, but the
differential diagnosis is different, comprising
FNH, adenomas, and small hemangiomas [61].
Intrahepatic Cholangiocarcinoma
ICC is a highly malignant epithelial tumor
that originates in the second branch of the in-
trahepatic bile duct. It is the second most
common primary liver tumor. Although it is
a relatively rare neoplasm, its incidence and
mortality are increasing because of its late clin-
ical presentation with nonspecific symptoms
and lack of an effective nonsurgical therapy
[65–68]. A combined HCC-cholangiocarcino-
ma also exists. ICCs usually arise on a healthy
liver background. Although rare, ICCs can
grow in a cirrhotic liver (1–2% of newly dis-
covered nodules in a cirrhotic liver are ICCs).
In these cases, the main issue is the differential
diagnosis with HCC nodules [69–71].
In previous studies, CEUS had similar
diagnostic accuracy to CT for ICC and was
suggested as an alternative diagnostic option
when CT was not available (patients with io-
dine allergy or impaired renal function) [72].
ICC is subcategorized into three different
types: mass-forming, periductal infiltrating,
and intraductal growing.
Mass-Forming ICC
Mass-forming ICC is the most common
form [73, 74]; it spreads between hepatocyte
plates and expands via the hepatic sinusoidal
spaces. It often invades the adjacent periph-
eral branches of the portal vein.
On conventional B-mode ultrasound, it
usually appears as an ill-defined irregular-
ly hypoechoic mass [75, 76]. On the arte-
rial phase of CEUS, four enhancement pat-
terns can be recognized, with descending
hancement, heterogeneous hyperenhance-
ment, homogeneous hyperenhancement, and
heterogeneous hypoenhancement [72, 77–
79]. In the portal phase, mass-forming ICC
 CEUS of Focal Liver Lesions

usually shows hypoechogenicity (Fig. 4).
All mass-forming ICCs are invariably hy-
poechoic on the CEUS late phase [75, 76].
Peripheral enhancement during the arteri-
al phase corresponds with the pathologic fea-
tures of the lesion: marked fibrous stroma in
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rial phase, with hypoenhancement in both
the portal and late phases [75].
Intraductal Growing ICC
Intraductal growing ICCs are usually
small or polypoid and do not invade deep-
are exclusively blood pool tracers and are
confined to the intravascular space.
Metastases
Metastases are the most common malig-
nant liver lesions. They mainly arise from

the center and abundant carcinoma cells at
the edge [75, 76]. On the other hand, in ho-
mogeneously or heterogeneously hyperen-
hancing mass-forming ICCs, carcinoma cells
were prominent in the center as well as in the
periphery. This dynamic behavior can be re-
lated to the tumor size: Usually small ICCs
show homogeneous enhancement in the ar-
terial phase because they are abundant in tu-
mor cells with little fibrous tissue; on the other
hand, in large ICCs, more fibrous tissue and
central necrosis appear, giving rise to the char-
acteristic enhancing peripheral rim [80, 81].
Periductal Infiltrating ICC
Periductal infiltrating ICCs tend to spread
along the bile duct wall via the nerves and
perineural tissue of Glisson capsule to-
ward the porta hepatis. On conventional B-
mode ultrasound, they usually appear as hy-
poechoic ill-circumscribed irregular lesions
with ambiguous boundaries and adjacent
bile duct dilation [75]. On CEUS, they ap-
pear heterogeneously enhancing in the arte-
ly into the submucosal layer, often spread-
ing superficially along the mucosa surface.
Because of this nonaggressive behavior, the
prognosis is much better than that of the pre-
viously mentioned subtypes [73, 82].
On conventional B-mode ultrasound, in-
traductal ICCs usually appear as hyperecho-
ic lesions with well-circumscribed bound-
aries and local bile duct dilation [75]. On
CEUS, in most cases, homogeneous hyper-
enhancement in the arterial phase is visible,
with hypoenhancement in both the portal
and late phases [75].
The areas of typical delayed enhancement
in ICC at CT have been reported to corre-
spond to fibrotic stroma at histopatholog-
ic examination [73, 82–84]. However, ICCs
do not show delayed enhancement on CEUS.
The delayed enhancement of ICC is due to
the CT contrast material characteristics; it is
rapidly cleared from the blood pool and re-
tained within the interstitial space in the fi-
brous stroma of the tumor during the late
phase [83, 84]. Ultrasound contrast agents
cancers in the gastrointestinal tract, pancre-
as, breast, and lung. CEUS has markedly im-
proved the detection rate of liver metasta-
ses, with reported sensitivity and specificity
ranging from 80% to 95% [85–87].
Hypovascular Metastases
Most liver metastases (e.g., from gastro-
intestinal adenocarcinomas or squamous
cell carcinomas) usually are hypovascular or
weakly enhanced during the arterial phase
(15–30 seconds after contrast injection),
with enhancement, when present, more pro-
nounced at the periphery of the lesion [18,
24, 50]. This phase of hypervascularity is of-
ten undetected on CT and MRI because of its
brevity (its washout usually takes place after
20 seconds from the injection of the contrast
medium, whereas the arterial phase of MRI
and CT starts after about 40 seconds from
the injection). On the other hand, CEUS en-
ables a real-time dynamic lesion study, with
continuous target lesion monitoring. After
the washout, all metastases are invariably

A B

Fig. 4—Intrahepatic mass-forming cholangiocarcinoma (ICC) in 70-year-old woman.

A, B-mode conventional ultrasound image shows small hypoechoic nodule
(calipers) in left liver lobe.
B and C, Ultrasound images obtained after contrast medium administration
show nodule to be hypervascular in arterial phase (B) and markedly hypoechoic
in comparison with surrounding liver parenchyma in portal and late phases
(C). ICC contrast washout in portal and late phases is more intense than that of
hepatocellular carcinoma.
C

AJR:205, July 2015 W61

 D’Onofrio et al.

hypoechoic on CEUS (Fig. 5) in the portal
and late phases.
Hypervascular Metastases
Hypervascular metastases frequently
arise from neuroendocrine tumors (NETs);
Downloaded from www.ajronline.org by 115.124.42.24 on 05/27/23 from IP address 115.124.42.24. Copyright ARRS. For personal use only; all rights reserved
after injection) phases, both hyper- and hy-
povascular metastases usually appear as
dark defects on the liver background because
they lack portal supply [85–90].
Several authors have stated that CEUS has
significantly higher sensitivity in detecting
or when CT and MRI are contraindicated or
inconclusive.
However, it is important to emphasize that
CEUS is complementary to CT or MRI in
preoperative staging before liver resection. It
cannot replace the other imaging modalities

melanomas; sarcomas; and renal, breast, and
thyroid neoplasms. Most NET liver metas-
tases show increased arterial enhancement
on CEUS. CEUS behavior of gastroentero-
pancreatic NET liver metastases shows hy-
pervascularization (Fig. 6) during the arte-
rial phase with portal venous and late phase
washout; however, contrast washout is slight-
ly delayed in HCC in comparison with hy-
pervascular metastases [88, 89].
In the portal (30–120 seconds after con-
trast injection) and delayed (up to 5 minutes
liver metastases than B-mode ultrasound and
a similar detection rate to CT and MRI, with
some studies showing higher, although not
statistically significant, CEUS sensitivity in
comparison with CT and MRI [13, 85, 90, 91].
According to the European Federation of
Societies for Ultrasound in Medicine and Bi-
ology (EFSUMB) guidelines [92], CEUS is
indicated for lesion characterization when a
lesion or suspected lesion is detected with ul-
trasound in patients with a known history of
malignancy, as an alternative to CT or MRI,
in the preoperative workup or follow-up of
patients with liver metastases during chemo-
therapy because CT and MRI provide more
comprehensive information.
Accuracy of CEUS and Review of
the Literature
CEUS has improved the characterization
of focal liver lesions, offering comparable re-
sults to those with CT and MRI when ultra-
sound exploration is technically satisfactory
[10, 11]. CEUS, when performed by experi-

A B C

Fig. 5—Hypovascular liver metastasis in 42-year-old woman.

A, B-mode conventional ultrasound image shows hypoechoic mass in left lobe.
B and C, Ultrasound images obtained after contrast medium administration show nodule to be hypovascular with small peripheral rim of enhancement in arterial phase
(B) and intensely hypoechoic in comparison with surrounding liver parenchyma in portal and late phases (C).

A B C

Fig. 6—Hypervascular liver metastasis in 65-year-old man.

A, B-mode conventional ultrasound image shows small hypoechoic nodule (calipers) in right liver lobe.
B and C, Ultrasound images obtained after contrast medium administration show nodule to be hypervascular in arterial phase (B) and clearly hypoechoic in comparison
with surrounding liver parenchyma in portal and late phases (C). Larger metastatic lesion is visible on late phase (C).

W62 AJR:205, July 2015


enced operators, significantly improves over-
all diagnostic accuracy by more than 30%
compared with unenhanced ultrasound [24].
The two most important multicenter stud-
ies regarding CEUS application for the char-
acterization of focal liver lesions were the
Downloaded from www.ajronline.org by 115.124.42.24 on 05/27/23 from IP address 115.124.42.24. Copyright ARRS. For personal use only; all rights reserved
German Society of Sonography (DEGUM)
multicenter study [93] and a French study
[94], both of which showed good value for
CEUS for focal liver lesion characteriza-
tion. The accuracy was slightly different in
the German versus the French study and also
different when accuracy in focal liver lesions
on noncirrhotic liver was compared with le-
sions occurring in cirrhotic liver. The accu-
racy of focal liver lesion characterization has
been proven to be higher for hemangiomas or
metastasis and lower for HCCs or adenomas.
The DEGUM study [93] included 1349 pa-
tients with focal liver lesions on ultrasound.
A total of 1328 focal liver lesions (755 ma-
lignant and 573 benign) were assessed. The
reference standard diagnosis was made by
means of liver biopsy in 75% of cases and by
contrast-enhanced CT or contrast-enhanced
MRI in the other cases. The accuracy of
CEUS for the diagnosis of focal liver lesions
was 90.3%. CEUS showed 95.8% sensitivi-
ty and 83.1% specificity, with 95.4% positive
predictive value and 95.9% negative predic-
tive value for differentiating benign versus
malignant lesions. Moreover, CEUS correct-
ly diagnosed 82.2% of the hemangiomas,
87.1% of the FNHs, 57.9% of the adenomas,
84.9% of the HCCs, and 91.4% of the me-
tastases. Thus, CEUS has been shown to be
an accurate method for the diagnosis of liv-
er metastases and HCCs but less accurate for
the diagnosis of adenoma.
The aim of another study based on the
­DEGUM multicenter study was to assess the
value of tumor-specific vascularization pat-
terns [28], such as spoke-wheel pattern and
arterial hyperenhancement followed by isoen-
hancement in the late phase in FNH, globular
peripheral enhancement and partial or com-
plete fill-in pattern in hemangiomas, or late
phase hypoenhancement in metastases. The
tumor-specific vascularization pattern could
be assessed in the majority of cases, and the
diagnostic accuracy of CEUS was 83.1% for
all benign lesions, 95.8% for all malignant le-
sions, 91.4% for liver metastases, and 84.9%
for hepatocellular carcinomas.
The French study [94] assessed the clin-
ical value of CEUS using SonoVue for the
characterization of focal liver lesions discov-
ered in patients with a cancer history or in
AJR:205, July 2015 W63
CEUS of Focal Liver Lesions
those with chronic liver disease. The study
included 1034 focal liver lesions undiag-
nosed on ultrasound alone. The reference
standard methods were contrast-enhanced
CT, contrast-enhanced MRI, or liver biop-
sy. In this study, CEUS had 79.4% sensitivity
and 88.1% specificity in differentiating be-
nign versus malignant focal liver lesions.
In another German study [95], CEUS was
the more cost-effective method in all sce-
narios in which CEUS examinations were
performed at specialized centers compared
to CT. With about 40,000 relevant liver le-
sions per year, systematic implementation of
CEUS would result in a cost savings of 4m€
per year [95].
Guidelines for Use of CEUS in
Liver Studies
In the 2005 edition [96] of the American
Association for the Study of Liver Diseases
(AASLD) guidelines for HCC, CEUS, CT,
and MRI were included as indicated imag-
ing modalities for HCC diagnosis. In 2010,
Vilana et al. [77] from the Barcelona Clinic
Liver Cancer Group found that the ICC con-
trast-enhancement pattern corresponds with
findings that were diagnostic of HCC on ap-
proximately half of the patients of their co-
hort. On the basis of this study, CEUS was ex-
cluded from the 2011 edition of the ­AASLD
guidelines [48] and subsequently from the
2012 European Association for the Study of
the Liver (EASL) guidelines [97] because
of the risk of misdiagnosing HCC and ICC.
Both of these guidelines accept only contrast-
enhanced multiphase CT and dynamic MRI.
Another reason for the removal of CEUS
from the AASLD guidelines is that SonoVue
is not yet approved by the FDA and thus is not
available in the United States.
The EFSUMB released the first guidelines
on the use of CEUS for liver applications in
2004 [98], followed by updates in 2008 [18]
and 2012 [92]. The EFSUMB 2012 guide-
lines recommended the use of CEUS for fo-
cal liver lesion characterization in the fol-
lowing most common clinical situations:
incidental findings on routine ultrasound,
lesion or suspected lesion detected with ul-
trasound in patients with a known history of
malignancy, need for a contrast-enhanced
study when CT and MRI contrast media are
contraindicated, and inconclusive MRI or
CT. In addition, the EFSUMB 2012 guide-
lines recommended the use of CEUS for the
characterization of all nodules found on sur-
veillance and routine ultrasound.
The Asian Pacific Association for the
Study of the Liver (APASL) and Japanese
Society of Hepatology (JSH) guidelines [99,
100], on the other hand, accept CEUS as an
imaging modality for HCC diagnosis. How-
ever, the APASL guidelines recommend the
use of CT and MRI for first-line diagnosis
and CEUS as a second or third line in case of
inconclusive CT and MRI findings, whereas
JSH guidelines accept CEUS even as a first-
line modality.
Conclusion
CEUS is an imaging method used in Eu-
ropean and Asian countries for more than 10
years. The injection of microbubble contrast
agents improves the accuracy of the ultra-
sound study.
Whether a patient is symptomatic or not,
in Europe, usually at the beginning of a
study for abdominal evaluation, ultrasound
is performed because it is inexpensive and
available in all hospitals. Focal liver lesions
are usually detected incidentally during an
abdominal ultrasound study, during the first
evaluation or follow-up for a primary neo-
plasm, or during surveillance in chronic liver
diseases and cirrhosis. CEUS improved the
detection and characterization of focal liver
lesions. Thus, the diagnosis of an indetermi-
nate focal liver lesion, such as in the case of
the common hypoechoic aspect, can be im-
mediately made. CEUS is the most economi-
cally appropriate second-line imaging meth-
od after inconclusive baseline ultrasound for
the diagnosis of benign focal liver lesions.
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