R E V I E W

A R T I C L E

Contrast-enhanced Ultrasonography in
Small Liver Tumors (< 3 cm)
Jing-Houng Wang, Chi-Sin Changchien*

Ultrasonography is a safe, convenient, low cost and noninvasive diagnostic modality for
liver tumors. Power Doppler sonography may demonstrate fine tumor vessels in small
lesions and hypovascular lesions. However, it has limitations including motion artifacts,
less sensitivity to slow vascular flow, poor demonstration of deep-seated lesions (> 7 cm in
depth), and high sensitivity to tissue motion (heart beat or aortic pulsation). Owing to
improvements in contrast agents and new technologies such as harmonic and pulse
inversion imaging, contrast-enhanced ultrasound (CEUS) has improved the detection
rate compared with Doppler ultrasound in studies of liver lesions. The enhanced vascular
patterns have been proved to correlate well with the findings from dynamic computed
tomography or magnetic resonance imaging. CEUS provides the ability to detect small
focal liver lesions and even metastatic liver tumors of less than 1 cm in diameter. This
review attempts to determine ways to allow the diagnosis of small hepatocellular carcino-
mas (HCCs), especially in cirrhotic patients, using CEUS. Because HCCs are small, the
feeding arteries are fine and the arterial blood flow to the tumor is slow, CEUS used in
the diagnosis of nodules of 1–2 cm in cirrhotic patients is not satisfactory. The portal and
late phases in pulse inversion imaging may provide more information to detect small
lesions in the cirrhotic liver and improve the diagnostic sensitivity and specificity.
Contrast-enhanced flash echo with subtraction mode is another way of detecting this
type of small tumor. In the arterial phase, some tumors are hard to identify, owing to
the isoechoic status of the tumors with respect to the surrounding liver parenchyma.
However, these small lesions may be shown by flash echo subtraction imaging.
Concurrent delayed phase imaging is useful in the diagnosis of small hypovascular HCCs.
In conclusion, CEUS improves the diagnostic accuracy of focal liver lesions, even in
tumors as small as 1–2 cm. This safe, convenient, low cost and noninvasive diagnostic
modality should be promoted in routine clinical practice.

KEY WORDS — contrast-enhanced ultrasonography, focal liver lesion, hepatocellular

carcinoma, liver, ultrasound contrast agent

■ J Med Ultrasound 2008;16(1):26–40 ■

Received: September 17, 2007 Accepted: January 22, 2008

Division of Hepato-Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital–
Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
*Address correspondence to: Dr. Chi-Sin Changchien, Division of Hepato-Gastroenterology, Department of
Internal Medicine, Chang Gung Memorial Hospital–Kaohsiung Medical Center, 123, Ta-Pei Road, Niao
Sung Hsiang, Kaohsiung, Taiwan. E-mail: cschangchien@adm.cgmh.org.tw

26 J Med Ultrasound 2008 • Vol 16 • No 1 ©Elsevier & CTSUM. All rights reserved.

Introduction
Because real-time ultrasonography (US) demon-
strates small liver tumors (< 3 cm in diameter) [1],
conventional US is used for the detection of focal
liver lesions because of its efficiency, availability, non-
invasiveness, and relatively low cost. On conven-
tional US, it is sometimes difficult to differentiate
benign lesions from malignant lesions, especially
in smaller lesions. Anatomically, the blood supply
of a malignant tumor is mainly from the hepatic
artery, and Doppler ultrasound can demonstrate
the vessels in and around the tumor [2]. Color
Doppler US and power Doppler US have proved to
be useful in demonstrating tumor vascularity
[3–6]. However, color Doppler sonography failed
to show the blood flow in a hypovascular lesion
[2]. Although power Doppler sonography is supe-
rior to color Doppler sonography in demonstrat-
ing fine tumor vessels in small lesions (≤ 2 cm in
diameter) and hypovascular lesions, power Doppler
techniques have limitations such as motion arti-
facts, less sensitivity to slow vascular flow, poor
demonstration of deep-seated lesions (> 7 cm in
depth), and high sensitivity to tissue motion (heart
beat or aortic pulsation) [7]. The detection of
increased arterial flow in a tumor by Doppler US
is dependent on the size, depth, and blood flow
of the lesion. However, Doppler US studies in
patients at risk of developing hepatocellular carci-
nomas (HCCs) have not yet been proven to affect
the sensitivity of detection of small HCCs. Sen-
sitivity can be increased by improving contrast
resolution and by new technologies involving har-
monic frequencies (tissue harmonic imaging) [8].
Contrast-enhanced ultrasound (CEUS) improved
the detection rate up to 90–97% compared with
grayscale US in studies of liver metastatic lesions
[9,10]. In a study by Solbiati et al, CEUS detected
miliary metastases of 5–10 mm in diameter; the
detection rate was as high as 82%, even better
than that of helical computed tomography (CT) [8].
In an overview, Konopke et al stated that the use of
CEUS in 100 patients increased the correct diagnosis
of focal liver lesions from 64% to 87% compared
Contrast-enhanced US in Small Liver Tumors
with B-mode US, especially in the case of small
metastases and following chemotherapy [11].
The enhancement pattern of CEUS in the vas-
cular phase is based on the dynamic contrast
behavior of different focal lesions in the liver. The
enhanced vascular patterns were proved to corre-
late well with the findings from dynamic CT or
magnetic resonance imaging (MRI) [12]. The
enhancement patterns of liver HCC were also char-
acteristic [11,12]. Furthermore, for the detection
of focal liver lesions, CEUS was shown to improve
accuracy in liver metastasis detection and was
comparable to spiral CT [13]. Some studies have
suggested that CEUS can detect lesions not visible
on CT [5,13–18].
An initial report on the use of ultrasound con-
trast agents was published in 1969 [19]. The
development of effective US contrast agents and
of new sonographic techniques such as harmonic
and pulse inversion imaging has considerably
improved the possibilities of CEUS in the assess-
ment of liver tumors [20,21]. Small focal liver
lesions were correctly detected by CEUS [11,22–25],
and even metastatic liver tumors of less than 1 cm
in diameter as well as tumors located near the liver
surface or situated around the ligamentum teres
were also detected [25]. However, in small HCCs,
especially in cirrhotic patients, current imaging
techniques are still not accurate enough to estab-
lish a reliable diagnosis in nodular lesions of < 2 cm
[14,26] or in well-differentiated small HCCs [27].
The accurate and early diagnosis of HCC is essen-
tial for treatment planning in affected patients.
This review attempts to find ways of using CEUS in
the diagnosis of small HCCs.
Ultrasound Contrast Agents (UCAs)
Microbubbles with a diameter of < 8 µm have been
proved to pass through capillary vessels, and an
ultrasound pulse with a frequency of 2 MHz and
a negative pressure of about 700 kPa has the abil-
ity to disrupt the microbubbles and generate
echo signals [28]. Thus, contrast agents with
J Med Ultrasound 2008 • Vol 16 • No 1 27
 J.H. Wang, C.S. Changchien
transpulmonary stability, which are administered
intravenously into peripheral veins, have become
commercially available for use in sonographic
enhancement studies.
Among the UCAs, which include SonoVue,
Levovist, Sonazoid, Optison, Definity and Imagent,
three types of UCAs are commonly used in Europe
[29,30]. These are Levovist, SonoVue and Optison.
1. Levovist (SH U 508A): Levovist bubbles contain
air with galactose/palmitic acid surfactant
(introduced by Schering in 1996). The bubbles
in Levovist are coated with a thin layer of
palmitic acid. Flash echoes are not observed at
a depth of > 7 cm, because the acoustic pressure
fall below the threshold of bubble collapse is due
to tissue attenuation. Assuming the tissue atten-
uation is 0.6 dB/MHz/cm, transmission power
would attenuate at −10.5 dB or around 420 kPa
at a depth of 7 cm. These results suggest that
more power output is needed for Levovist to
obtain flash echoes deeper than 7 cm [31]. Main
indications for the use of Levovist include heart,
abdomen (including vesicoureteral reflux) and
transcranial studies.
2. SonoVue (second-generation agent): Bubbles
of SonoVue contain sulfur hexafluoride with
a phospholipid shell (introduced by Bracco,
Milan, Italy in 2001). SonoVue is a blood pool
perfluoro gas agent, which consists of micro-
bubbles of sulfur hexafluoride stabilized by a
phospholipid shell [32]. The microbubbles are
isotonic to human plasma and stable and resis-
tant to pressure. SonoVue improves the display
of focal tumor vascularity and normal parenchy-
mal liver vascularity [33]. Main indications for
the use of SonoVue are cardiac, macrovascular,
liver and breast lesions.
3. Optison: Optison contains octafluoropropane
(perflutren) with an albumin shell (introduced by
Amersham in 1998). Sole indication is cardiac.
UCAs consist of gas bubbles stabilized by a
shell; Levovist contains air, whereas SonoVue (sul-
fur hexafluoride) and Optison (perflutren) contain
low solubility gases which improve microbubble
stability [29].
28 J Med Ultrasound 2008 • Vol 16 • No 1
Techniques
Harmonic imaging
Because of the difference in acoustic impedance
between air and liquid, air microbubbles in the liq-
uid can reflect ultrasound signals which contain
significant energy, not only the fundamental fre-
quency from the original transducer, but also higher
order harmonics. Using these nonlinear properties
of microbubbles, a harmonic imaging study on
capillary blood flow was reported in 1992 [34]. In
this method, signals are transmitted at the funda-
mental frequency, but are received as higher order
harmonics. That is, an ultrasound scanner is trans-
mitting at one frequency and receiving double or
triple times the frequency transmitted. This tech-
nique improves the detection rate of the microbub-
ble contrast agents [35,36]. Harmonic imaging
makes it possible to visualize capillary blood flow
in tissues that cannot be detected by conventional
B-mode or color Doppler imaging [35,36].
Pulse inversion imaging
Because of the limitations of resolution due to
compromises forced by harmonic imaging that
restrict the bandwidth [37], pulse inversion imag-
ing mode was designed to allow low incidence
power and nondestructive, continuous imaging of
microbubbles in an organ (such as the liver) to
produce high-quality contrast-enhanced images.
The pulse inversion imaging mode is superior to
second harmonic imaging or conventional Doppler
imaging [37,38] and may present as harmonic
angio images [39]. In pulse inversion imaging, two
separate pulses (normal pulse and inverted pulse
at 180° out of phase) are transmitted in rapid suc-
cession into the tissue. The inverted pulse is a mir-
ror image of the normal pulse. The echoes from
these two successive pulses are received by the
scanner which forms their sum. The resulting
echoes from tissue behave in a linear manner can-
celing each other, and the sum of these two pulses
is zero. For an echo with nonlinear components,
such as that from a bubble, the echoes produced
from these two pulses will not be simple mirror

images of each other. Because of the asymmetric
behavior of the bubble radius with time, the sum
of these two pulses is not zero. That means the
echo is present and contains nonlinear harmonic
components of the signal (including second har-
monics). So, the signal can be detected from
a bubble but not from tissues [37,40]. Pulse inver-
sion imaging mode has no restriction on band-
width; the full frequency range of sound emitted
from the transducer can be detected and this
mode provides an effective result [37,41].
Low mechanical index (MI) technique
Ultrasound pulse with an acoustic power has the
ability to disrupt the microbubbles of UCAs. Low
MI with very low acoustic power (such as < 0.2)
avoids disruption of the microbubble. This low MI
contrast technique allows dynamic imaging with
subsequent evaluation of the three different vascu-
lar phases using a low solubility gas UCA.
UCA is administered as a bolus injection, fol-
lowed by a 5–10 mL saline flush. The needle diam-
eter should not be smaller than 20 gauge to avoid
loss of bubbles due to mechanical impact during
injection. Continuous scanning for 60–90 seconds
is recommended to continuously assess the arterial
and portal venous phases. Under this assessment
until the disappearance of the UCA from the tis-
sues, the microvasculature has been observed
[29]. The setting of low MI is an insonating fre-
quency of 3 MHz, acoustic power of −75 to
−90 dB, and frame rate of 17–20. The scanning
time of a vascular study is up to 3.5 minutes,
including the arterial phase of 0–49 seconds, the
portal phase of 50–179 seconds and the late phase
of > 180 seconds.
High MI technique
High MI technique in which microbubbles are
deliberately destroyed is probably more useful for
focal liver lesion detection and can be used for
characterization of these lesions. High MI tech-
nique requires intermittent scanning of the lesion
during all three phases [29]. The destruction of
microbubbles by high MI ultrasound has been
Contrast-enhanced US in Small Liver Tumors
studied to allow a greater separation between the
tissue and the contrast agent. The high MI
destruction imaging technique has been referred
to as agent detection imaging (ADI). With Doppler
techniques, ADI displays microbubble signals as
a color overlay on the grayscale tissue image. In
studies with ADI, a bubble destruction image
showed the normal liver as bright and the metas-
tases as black without any signal. Thus, ADI makes
CEUS very sensitive [30].
Intermittent harmonic imaging with
subtraction mode
Using the second harmonic imaging technique
[31], intermittent harmonic (flash echo) imaging
with subtraction mode can be performed to evalu-
ate the dynamic perfusion of small lesions in which
power Doppler US failed to demonstrate the ves-
sels. Flash echo imaging in subtraction mode is
obtained in the following way. The scanner trans-
mits the ultrasound beam at, for example, 2.1 MHz
and receives echoes at 4.2 MHz and is set to
generate two bursts of high acoustic power (high
MI, 1.0–1.2) in rapid succession. The subtraction
image is automatically obtained by setting the
ultrasound machine to subtract the second frame
image from the first frame image. The flash echo
image with subtraction mode can be designed to
operate depending on the operator’s demand. The
real-time, low acoustic power imaging (low MI,
0.2) is used for monitoring during the intervals
between flash echo imaging.
Vascular Phase Study in Liver
Hepatic artery supply usually starts 10–20 seconds
post-injection into a peripheral vein and lasts for
approximately 10–15 seconds. This is followed by
the portal vein phase, which usually lasts 2 min-
utes after contrast agent injection. The late phase
lasts until clearance of the contrast agent from the
hepatic parenchyma, up to approximately 15–20
minutes post-injection for Levovist and 4–6 minutes
for SonoVue [29].
J Med Ultrasound 2008 • Vol 16 • No 1 29
 J.H. Wang, C.S. Changchien
1. Arterial phase: The contrast agent reaches the
liver first via the hepatic artery and provides
information on the degree and pattern of vascu-
larity. Tumors with abundant blood supply show
hypervascularity during this phase.
2. Portal vein phase: The contrast agent has passed
through the circulation and spreads through the
liver via the portal branches. This phase usually
lasts 2 minutes after contrast agent injection.
3. Late (parenchyma) phase: The late or parenchy-
mal phase follows the portal phase, in which
the agent is slowly distributed throughout the
entire liver parenchyma. The origin of the late
phase is the subject of ongoing scientific discus-
sion, and suggested mechanisms include sinusoid
pooling and reticuloendothelial system/Kupffer
cell uptake [42].
The portal and late phases provide information
regarding the wash-out of contrast agent from the
lesion compared with normal liver tissue. In the
case of hemangiomas, a progressive filling can be
observed during these phases. The portal and late
phase enhancement can provide important infor-
mation regarding the character of the lesions.
Most malignant lesions are hypo-enhancing, while
the majority of solid benign lesions are iso- or
hyper-enhancing [43–46].
The limitations of CEUS for characterization of
liver lesions are subject to the same limitations as
other types of ultrasound, and sensitivity is markedly
reduced in attenuating livers and deep lesions. As
a general rule, if baseline ultrasound is suboptimal,
results from CEUS may be disappointing.
Small Liver Lesions of < 3 cm
HCC
Pathologically, HCCs receive an arterial blood sup-
ply. In small HCCs of distinctly nodular type, most
of these tumors show hypervascularity despite the
small tumor size. While in small HCCs of indistinctly
nodular type, many of them show hypovascularity.
Meanwhile, the majority of well differentiated HCCs
of indistinctly nodular type (early HCC) receive
30 J Med Ultrasound 2008 • Vol 16 • No 1
portal blood supply in addition to the arterial blood
supply, because they contain portal tracts within the
tumor. The number of arterial vessels per square
millimeter in early-stage HCCs of < 1.5 cm in diam-
eter is about two-thirds of that in advanced tumors,
and it is only less than one-third in tumors smaller
than 1.0 cm. Early HCCs are not encapsulated, and
HCC cells proliferate as if they are replacing the
liver cell cords at the boundaries. The sinusoidal
blood spaces are incompletely vascularized, and
the sinusoidal spaces of the tumor are continuous
with the sinusoids of the surrounding liver tissue.
So, a certain proportion of blood flows into the
sinusoids of the surrounding liver tissue [47]. The
contrast agent will wash out from the tumor to
the liver parenchyma rapidly, and the tumor may
appear hypoechoic with respect to the surrounding
liver in the late phase.
With CEUS, HCCs are characterized by hyper-
vascularity in the arterial phase. Using real-time
evaluation with low MI, early intense enhance-
ment is usually identified and the feeding artery is
clearly visible in most cases. Tumor vessels usually
show a basket-like or an irregular branching pat-
tern extending from the periphery to the center of
the tumor [48]. Arterial enhancement of the tumor
may be inhomogeneous, because tumors may have
septa, different cell differentiation and arteriovenous
shunting among the neoformed vessels [15,26].
In small HCCs, the arterial phase shows hyper-
echoic enhancement, and in the portal and late
phase, enhancement also provides important infor-
mation regarding the character of the lesions. In the
late phase, the most malignant lesions are hypo-
enhancing, while the majority of solid benign lesions
are iso- or hyper-enhancing [43–46]. In a study by
Nicolau et al on the differentiation of benign from
malignant focal liver lesions using contrast-enhanced
imaging, the results showed that evaluation of all
three vascular phases was superior to the evaluation
of enhancement in the late phase alone. The sensi-
tivity increased from 78.4% to 98%, and the accu-
racy from 80.9% to 92.7% [49]. However, these
characteristic patterns are sometimes hard to de-
monstrate in small HCCs, owing to the small tumor
 Contrast-enhanced US in Small Liver Tumors

size, fine feeding arteries, and slow arterial blood
flow to the tumor [50]. Contrast-enhanced flash
echo with subtraction mode is another way of
detecting liver tumors as small as 8 mm in diame-
ter. In the arterial phase, some tumors show faint
hyperperfusional status, which is isoechoic with
respect to the surrounding liver parenchyma dur-
ing arterial enhancement and is difficult to iden-
tify. Smaller lesion may be shown using flash echo
subtraction imaging (Fig. 1) [51]. In a study of 14
small liver tumors (diameter, 0.8–3.0 cm; mean,
1.8 ± 0.5 cm) by Wang et al, contrast-enhanced
flash echo with subtraction mode was sensitive and
effective in detecting these small liver tumors [51].
In cirrhotic liver, multistage processes can exist,
including regenerative nodules, dysplastic nodules
and HCC. Differentiation between these processes
is somewhat difficult. On a histopathologic basis,
evolving malignant change in a cirrhotic nodular
lesion shows that the arterial flow supply progres-
sively increases to the lesion [52,53]. This progres-
sive neoangiogenesis provides the clue for clinical
diagnosis with imaging techniques [54]. Therefore,
the European Association for the Study of the Liver
panel of experts determined that the diagnosis of
nodules of > 2 cm must be confirmed by two dif-
ferent imaging techniques. However, no reference
was made to the vascularity of nodules of 1–2 cm
in diameter. Many studies have used CEUS in the
characterization of liver lesions. In a study of 41
cirrhotic patients with small monofocal lesions
(< 3 cm in diameter) by Fracanzani et al [16], it was
reported that contrast-enhanced Doppler US using
Levovist was a noninvasive, sensitive technique in

A B C

D E F

Fig. 1. Intermittent harmonic (flash echo) imaging with subtraction mode in a patient with a small hepatocellular carcinoma of
1.0 cm in diameter. (A) Conventional ultrasound demonstrates a small hypoechoic lesion (arrow). (B) In the arterial phase of
contrast enhanced ultrasound, the hypervascular lesion cannot be differentiated from the enhanced surrounding normal liver
parenchyma. (C) Using subtraction mode, the lesion is clearly shown (arrow). (D, E) In the portal and late phases, the lesion shows
as hypoechoic (arrow). (F) By subtraction of the late phase image, the lesion is still hypoechoic (arrow).

J Med Ultrasound 2008 • Vol 16 • No 1 31

 J.H. Wang, C.S. Changchien
differentiating malignant and premalignant focal
lesions. In this study, the intratumoral arterial blood
flow was detected in 19 of 20 HCCs (95%), and in
6/21 nonmalignant nodules (28%) by contrast-
enhanced Doppler US. Four of the six false-positive
findings were high-grade dysplastic nodules, and
the remaining two evolved to HCC during follow-
up [16]. The results showed that the likelihood of
detecting arterial flow in a nodular lesion in a cir-
rhotic patient with HCC was high. Bolondi et al [23]
reported 72 small nodules (1–2 cm, n = 41; 2.1–3 cm,
n = 31) in 59 cirrhotic patients, which depended on
the coincident arterial hypervascularity at contrast
perfusional sonography using SonoVue and helical
CT to detect small HCCs in cirrhotic nodules. The
detection rate was only 61% (44/72) in nodules of
< 3 cm in cirrhotic patients (44% in nodules 1–2 cm,
84% in nodules 2–3 cm). Relying on imaging tech-
niques in nodules of 1–2 cm, the missed diagnosis
of HCC was up to 38%, and any nodules of > 2 cm
should be regarded as highly suspicious for HCC
[23]. Thus, even with arterial hypervascularity shown
by CEUS, the diagnosis of nodules of 1–2 cm in
cirrhotic patients is not satisfactory.
The detection of small HCCs, especially in the
cirrhotic liver, is a problem. Small HCCs in cirrhotic
liver may be detected as areas of increased
enhancement in the arterial phase, and the short
duration of the arterial phase does not allow sur-
veillance of the whole liver. The portal and late
phases may provide more information in the de-
tection of small lesions in cirrhotic liver [43–46].
Forsberg et al reported that Levovist showed a tis-
sue-specific late phase with selective enhancement
of liver and spleen parenchyma [55]. The accumu-
lation of Levovist in parenchyma is known in retic-
ular endothelial (RE) cells [56], and Kono et al
suggested that this accumulation is the uptake of
Levovist by mechanisms including sinusoid pooling
and RE/Kupffer cells [42]. Therefore, pulse inversion
imaging allows visualization of liver parenchyma
on sonography [57]. Pathologically, HCC and me-
tastatic malignancies in liver lack RE cells, and no
HCC or metastasis have shown uptake of Levovist
in late-phase pulse-inversion sonography [17]. For
32 J Med Ultrasound 2008 • Vol 16 • No 1
the discrimination of malignant versus benign
liver lesions, late-phase pulse-inversion contrast-
enhanced sonography improved diagnostic sensi-
tivity from 85% to 100% and specificity from 30%
to 63% compared with baseline sonography, and
with lower interobserver variability [17]. In addi-
tion, Wang et al reported the highly specific visual-
ization of small HCCs (≤ 2 cm) in cirrhotic patients
using a combination of arterial enhancement (AE)
and absence of delayed phase enhancement (ADE)
using Levovist [58]. Scanning for the delayed
phase was carried out about 5–6 minutes later
after arterial phase evaluation. In the evaluation of
30 small hepatic nodules (diameter, 1–2 cm; mean,
1.5 ± 0.3 cm) using both AE and ADE for HCC
diagnosis, the sensitivity, specificity, accuracy, pos-
itive predictive value and negative predictive value
were 55.6%, 91.7%, 70%, 90.9% and 57.9%,
respectively. When using either AE or ADE for the
diagnosis of HCC, the same parameters were
94.4%, 66.7%, 83.3%, 81% and 88.9%, respec-
tively. The authors concluded that concurrent
delayed phase imaging is useful in the diagnosis
of small hypovascular HCCs [58].
For grading of small HCCs on the basis of the
presence of Kupffer cells in small tumors, Kitamura
et al reported that contrast-enhanced color Doppler
sonography appeared to reflect the histopatho-
logic features of HCCs in 20 tumors (mean diame-
ter, 2.8 ± 1.2 cm) and was useful for differentiating
liver tumors [59]. von Herbay et al [17] suggested
that CEUS could not grade HCCs. However, both
highly differentiated and less differentiated HCCs
were detected without contrast enhancement in
late-phase images [17], and Nicolau et al reported
that the echogenicity in the portal and late phases
correlated with cellular differentiation [27]. In 104
HCCs (36 cases; diameter, < 2 cm), 96.2% of HCCs
(including 27 well-differentiated HCCs) showed
enhancement in the arterial phase. Four (3.8%) of
the well-differentiated cases showed an isoechoic
pattern (p < 0.05). Therefore, in the arterial phase, no
enhancement may represent a well-differentiated
HCC. In the early portal phase, isoechoic echogeni-
city was found in well- and moderately differentiated

HCCs, and hypoechoic echogenicity in poorly dif-
ferentiated HCCs. In the late phase, isoechoic
echogenicity was found in well-differentiated HCCs
and hypoechoic in moderately and poorly differ-
entiated HCCs [27]. In a report by Wang et al on
18 small HCCs (diameter, ≤ 2 cm), no significant
correlations between cellular differentiation and
CEUS enhancement patterns were observed [58].
These results were limited by the small number of
cases. However, the correlation between cellular
differentiation and CEUS enhancement patterns
depends upon the vascularity of HCC in the arte-
rial phase, the speed of blood feeding in the portal
phase, and the number of Kupffer cells or sinusoid
spaces in the late phase. More research is needed
to confirm these findings.
Metastasis
Hepatic metastatic lesions are not uncommon and
are not always multiple. Histologically, most hepatic
metastatic lesions are hypovascular. Characteristics
of metastatic tumors include intratumoral hypovas-
cularity and hypervascularity in the tumor periph-
ery. Ten to fifteen percent of hepatic metastatic
tumors are hypervascular. Conventional grayscale
US can detect metastatic lesions as hypo-, hyper-
or mixed echogenicity, but conventional US can
miss isoechoic lesions and lesion size of < 1 cm in
diameter [10]. Many studies have confirmed the
improvement in accuracy of CEUS in diagnosing
liver metastatic lesions [13,17,18,60–62]. The detec-
tion rate of hepatic metastatic lesions was reported
by Bernatik et al in their study of 28 patients to be
97% [9]. Oldenburg et al reported the sensitivity
to be 90% in 128 metastases [10]. Solbiati et al
also reported that CEUS improved the detection of
miliary metastases (0.5–1 cm) [8]. Characteristic
features of hepatic metastatic lesions can be
demonstrated in three phases of continuous low-
MI imaging CEUS. In the arterial phase, hypovas-
cular metastases appear as hypo-effective lesions,
usually with a typical rim enhancement of varying
size, whereas hypervascular metastases appear as
bright enhancing hyper-effective and homogeneous
lesions. Rapid wash-out of arterial enhancement is
Contrast-enhanced US in Small Liver Tumors
found in the late arterial and portal phases [63].
Therefore, at the beginning of the portal phase,
the arterial enhancement fades and the entire hypo-
vascular lesion becomes hypoechoic. In the late
phase, both hypovascular and hypervascular metas-
tases invariably appear dark compared with the
enhanced background of normal liver parenchyma.
During this late phase, both portal venous and
late-phase imaging markedly increase the contrast
between the enhanced normal liver. Thus, non-
enhancing metastases improve detection, especially
of small lesions of < 1 cm in diameter and of lesions
which are isoechoic at baseline [11]. Benign focal
liver lesions (FLL) contain Kupffer cells and/or sinu-
soids (except hemangiomas), including dysplastic
nodules, which also consist of sinusoidal capillariza-
tion [47]. So, in the late parenchymal phase, FLL can
be enhanced in an isoechoic pattern with respect
to the surrounding liver. An isoechoic pattern in
relation to the adjacent liver in the last phase is
demonstrated in benign lesions, whereas metastases
appear more hypoechoic by the enhanced normal
liver background and are easily distinguished from
normal liver. A high diagnostic accuracy in the dif-
ferentiation between metastases and benign FLL in
the late phase has been reported [17,64,65].
Hemangiomas
Hemangiomas are the most frequent benign tumor
found in the liver. Pathologically, a hemangioma is
composed of cavernous vessels. In the tumor, the
blood flow in the vascular space is extremely slow
and blood pooling exists [66]. The velocity of flow
in the tumor is so slow that Doppler US can not
detect any signals [67]. Although most heman-
giomas show homogeneous hyperechoic patterns
on conventional US, the sonographic features of
hemangiomas are not specific. Furthermore, the
imaging diagnostic accuracy is low for small hem-
angiomas even by MRI [68]. CEUS has been shown
to increase the detection sensitivity of slow-velocity
blood flow in hepatic tumors [50] and provides
a progressive filling in hemangiomas in the portal
and late phases. Thus, in the arterial phase of
CEUS, characteristic images show the presence of
J Med Ultrasound 2008 • Vol 16 • No 1 33
 J.H. Wang, C.S. Changchien
peripheral globular or rim-like enhancement in
typical and atypical hemangiomas [48,69,70]. How-
ever, these characteristic patterns are also found in
malignant FLL, such as metastases [48,62]. In the
portal and late phases, the enhancement of heman-
giomas has a specific pattern [12,41,48,71]. In the
portal phase, progressive filling may gradually show
centripetal enhancement first and then complete
filling within several seconds in small hemangioma
and within 30–60 minutes in giant hemangioma.
Incomplete centripetal enhancement and/or incom-
plete tumor fill-in may occur in some tumors. In
the late phase, owing to the contrast agent, the
time elapsed, the filling velocity and intratumoral
thrombosis or fibrosis, the enhanced patterns show
complete enhancement or non-enhancing central
areas (partial thrombosis or fibrosis). As a result of
the persistence of contrast in the vascular bed of
hemangioma, the enhancement remains hyper-
echoic compared with the surrounding tissue [29].
In small hemangiomas (< 2 cm in diameter), the
arterial phase shows diffuse enhancement, which
may occur in hypervascular malignant tumors such
as HCC or metastases. However, in the portal and
late phases, small hemangiomas usually have hy-
perechoic or stronger enhancement with respect
to the surrounding liver tissue, while malignant
lesions become hypoechoic [11,12,29]. CEUS can
be used in the diagnosis of hemangioma, when
centripetal fill-in enhancement is a positive finding
in hemangioma. Ding et al reported that the sensi-
tivity of CEUS in the diagnosis of hemangioma was
96.23% and the specificity was 97.5% [72]. When
typical contrast-enhanced patterns in the vascular
and late phases were regarded as positive findings,
Nicolau et al showed that the correct identification
of 22 hemangiomas was 81.8% in the vascular
phase and 86.4% in the late phase [12].
Focal nodular hyperplasia (FNH)
FNH is the second most common benign liver neo-
plasm. FNH is a hyperplastic lesion composed his-
tologically of all the components of normal liver
tissue, and about 45% of cases have a central stel-
late fibrous scar [73]. In the arterial phase of CEUS,
34 J Med Ultrasound 2008 • Vol 16 • No 1
FNH rapidly enhances with atypical centrifugal
radiating enhancement (spoke-wheel pattern) [46,
12,74], then shows whole-lesion homogeneous
hyperechoic enhancement. The spoke-wheel pat-
tern represents a central feeding artery and cen-
trifugal blood supply from the center of the lesion
to the periphery.
In the portal phase, enhancement in FNH grad-
ually changes to isoechoic compared with the sur-
rounding liver parenchyma. In the late phase,
because the lesion contains all the components of
normal liver tissue, the lesion remains isoechoic;
some lesions even show as slightly hyperechoic
with respect to the surrounding normal liver
[17,41]. Due to the central stellate fibrosis scar,
CEUS does not show enhancement in the portal
and late phases and represents a key feature for
diagnosing FNH. The characteristic features of
FNH on CEUS include: (1) hypervascularity in the
arterial phase with a centrifugal blood supply; (2)
isoechogenicity in the late phase; and (3) a central
scar. Those features aid in the differential diagnosis
of FNH from other hypervascular tumors, includ-
ing hypervascular metastases, HCCs, small heman-
giomas and adenomas [12]. Di Stasi et al reported
on the characteristic features, and the sensitivity
and specificity of diagnosing FNH were 87.6% and
94.5%, respectively [74]. Yen et al [75] reported
that the sensitivity of the spoke-wheel sign or central
scar for FNH in 35 FNH lesions (1.3–7.0 cm; mean,
2.9 ± 1.4 cm) was 97.1%, 40%, 28.6%, and 50%
for CEUS, color/power Doppler US, CT scan, MRI
and hepatic angiography, respectively. Regardless
of the size of FNH, CEUS demonstrated the spoke-
wheel sign or central scar well (Fig. 2) [75].
Hepatocellular adenoma (HA)
Among the FLL, HA is relatively rare and mainly
found in young women with a history of oral con-
traceptive use, androgen steroid therapy and
glycogen storage disease [76]. Histologically, HA is
composed of cords of tumor cells, which closely
resemble hepatocytes and contain fat and glycogen.
On conventional US, HA showed variable US pat-
terns, such as hypo-, iso-, hyper- or mixed-echoic

A B
Fig. 2. Contrast-enhanced color Doppler ultrasound in 2-cm focal nodular hyperplasia. (A) Conventional US shows an isoechoic
mass of about 2 cm in diameter (arrows). (B) In the arterial phase, contrast-enhanced color Doppler ultrasound shows the
spoke-wheel pattern of the central artery (arrow) in the tumor.
images, depending on the presence of intratumoral
hemorrhage, necrosis or fatty change [77]. In the
arterial phase of CEUS, early and homogeneous
hyperechoic enhancement is found in most cases.
However, no enhancement will be seen if the
tumor contains hemorrhage or necrosis. Due to
the subcapsular feeding artery in HA, CEUS using a
continuous low-MI image may demonstrate an
early and hyper-enhanced tumor periphery. This
phenomenon is useful in distinguishing HA from
other hypervascular tumors [12]. In the portal and
late phases, the enhancement of HA is almost the
same as that of liver parenchyma and can remain
slightly hypoechoic in relation to the adjacent liver
tissue in later stages because of varying numbers
and activity of Kupffer cells [61,78]. However,
larger studies regarding the value of CEUS in HA
have not been carried out [11].
Focal fatty change and spared area in
diffuse steatosis of liver
On conventional US, focal fatty change and focal
spared areas are usually demonstrated adjacent
to the right main portal vein at area 4, the gall-
bladder bed or the falciform ligament. However,
a single well-demarcated nodule can be found
anywhere in the liver. Because this type of lesion
has normal liver components, CEUS shows the
same enhancement pattern with respect to the
Contrast-enhanced US in Small Liver Tumors
normal liver in all phases and remains isoechoic in
the post-vascular phase [62,79].
CEUS evaluation of small HCCs after
percutaneous ablation therapy
HCCs of < 2 cm are well differentiated and not
associated with abundant neoangiogenesis [80,81].
Although contrast-enhanced color Doppler sonog-
raphy was reported to be useful in the detection of
residual HCC after percutaneous local therapy
[82,83], the sensitivity of detection was low because
of slow blood flow [84] and reduced vascularity in
the residual mass. Flash echo contrast sonography
with subtraction (FECS) mode allows microbubble
contrast agents to flow into the capillaries before the
microbubbles are imaged and destroyed [31]. Using
this method, Wang et al reported the results of as-
sessing perfusion and the therapeutic effects after
percutaneous ablation in small HCCs (Fig. 3) [51,
85,86]. The agreement between FECS and CT, FECS
and hepatic angiography, and all three imaging mo-
dalities in a study of 35 small tumors (mean, 2.0 ±
0.5 cm) were 80%, 85.7% and 77.1%, respectively.
The sensitivity, specificity, accuracy, and positive and
negative predictive values of FECS in detecting viable
tumors were 53.8% (7/13), 90.9% (20/22), 77.1%
(27/35), 77.8% (7/9) and 76.9% (20/26), respec-
tively [86]. These results were lower than those
reported by Ding et al [87]. The explanation by
J Med Ultrasound 2008 • Vol 16 • No 1 35
 J.H. Wang, C.S. Changchien

A B

C D

Fig. 3. A patient with a small hepatocellular carcinoma. After ablation, the viable tissue is demonstrated by intermittent harmonic
(flash echo) imaging with subtraction mode. (A) A hypoechoic lesion of about 1.8 × 1.1 cm in diameter is found in the liver (arrow).
(B) After ablation, the hypoechoic area is larger than the original lesion (arrow). (C) Flash echo imaging with subtraction in the
arterial phase. A clear enhanced vessel is demonstrated at the edge of the hypoechoic lesion (arrow). (D) In the late phase, faint
enhancement at the edge of the lesion is still seen in the viable tissue (arrow).

Wang et al for the lower sensitivity in detecting viable
tumor tissue was the smaller tumor size when com-
pared with those of other studies [87–90] and the
longer follow-up interval [87,90]. Although CEUS
has its limitations in the depiction of tumor vascular-
ity for HCC located more than 7 cm from the ab-
dominal wall [31,51,85], CEUS has potential in the
evaluation of the therapeutic effects of percutaneous
ablation for HCC, even in small tumors [31,86].
demonstrate the vascular pattern and parenchy-
mal contrast in liver lesions. The effectiveness of
CEUS in diagnosing liver tumors (even small
tumors) is not less than that of CT scan, MRI or
angiography. CEUS also improves the diagnostic
accuracy of focal liver lesions, even for those as
small as 1–2 cm. This safe, convenient, low cost
and non-invasive diagnostic modality should be
promoted in routine clinical practice.

Conclusion References

Owing to the easy application of contrast agents 1. Sheu JC, Sung JL, Chen DS, et al. Ultrasonography of
into peripheral vessels and improvements in tech- small hepatic tumors using high-resolution linear-array
nologic devices and techniques, CEUS can clearly real-time instruments. Radiology 1984;150:797–802.

36 J Med Ultrasound 2008 • Vol 16 • No 1


2. Tanaka S, Kitamura T, Fujita M, et al. Color Doppler
flow imaging of liver tumors. AJR Am J Roentgenol
1990;154:509–14.
3. Liang JD, Yang PM, Liang PC, et al. Three-dimensional
power Doppler ultrasonography for demonstrating
associated arteries of hepatocellular carcinoma.
J Formos Med Assoc 2003;102:367–74.
4. Reinhold C, Hammers L, Taylor CR, et al. Characteri-
zation of focal hepatic lesions with duplex sonogra-
phy: findings in 198 patients. AJR Am J Roentgenol
1995;164:1131–5.
5. Choi BI, Kim TK, Han JK, et al. Power versus conven-
tional color Doppler sonography: comparison in the
depiction of vasculature in liver tumors. Radiology
1996;200:55–8.
6. Gaiani S, Volpe L, Piscaglia F, et al. Vascularity of liver
tumours and recent advances in Doppler ultrasound.
J Hepatol 2001;34:474–82.
7. Hosoki T, Mitomo M, Choi S, et al. Visualization of
tumor vessels in hepatocellular carcinoma. Power
Doppler compared with color Doppler and angiogra-
phy. Acta Radiologica 1997;38:422–7.
8. Solbiati L, Tonolini M, Cova L, et al. The role of
contrast-enhanced ultrasound in the detection of focal
liver lesions. Eur Radiol 2001;11(Suppl 3):E15–26.
9. Bernatik T, Strobel D, Hahn EG, et al. Detection of
liver metastases: comparison of contrast-enhanced
wide-band harmonic imaging with conventional
ultrasonography. J Ultrasound Med 2001;20:509–15.
10. Oldenburg A, Hohmann J, Foert E, et al. Detection
of hepatic metastases with low MI real time contrast
enhanced sonography and SonoVue. Ultraschall Med
2005;26:277–84.
11. Konopke R, Bunk A, Kersting S. The role of contrast-
enhanced ultrasound for focal liver lesion detection:
an overview. Ultrasound Med Biol 2007;33:1515–26.
12. Nicolau C, Bru C. Focal liver lesions: evaluation with
contrast-enhanced ultrasonography. Abdom Imaging
2004;29:348–59.
13. Albrecht T, Blomley MJ, Burns PN, et al. Improved
detection of hepatic metastases with pulse-inversion
US during the liver-specific phase of SH U 508A:
multicenter study. Radiology 2003;227:361–70.
14. Strobel D, Kleinecke C, Hansler J, et al. Contrast-
enhanced sonography for the characterisation of
hepatocellular carcinomas: correlation with histolog-
ical differentiation. Ultraschall Med 2005;26:270–6.
15. Kim TK, Kim AY, Choi BI. Hepatocellular carcinoma:
harmonic ultrasound and contrast agent. Abdom
Imaging 2002;27:129–38.
Contrast-enhanced US in Small Liver Tumors
16. Fracanzani AL, Burdick L, Borzio M, et al. Contrast-
enhanced Doppler ultrasonography in the diagnosis
of hepatocellular carcinoma and premalignant le-
sions in patients with cirrhosis. Hepatology 2001;34:
1109–12.
17. von Herbay A, Vogt C, Haussinger D. Late-phase
pulse-inversion sonography using the contrast agent
Levovist: differentiation between benign and malig-
nant focal lesions of the liver. AJR Am J Roentgenol
2002;179:1273–9.
18. Harvey CJ, Blomley MJ, Eckersley RJ, et al. Hepatic
malignancies: improved detection with pulse-inversion
US in late phase of enhancement with SH U 508A:
early experience. Radiology 2000;216:903–8.
19. Gramiak R, Shah PM, Kramer DH. Ultrasound car-
diography: contrast studies in anatomy and func-
tion. Radiology 1969;92:937–47.
20. Basilico R, Blomley MJ, Harvey CJ, et al. Which con-
tinuous US scanning mode is optimal for the detec-
tion of vascularity in liver lesions when enhanced
with a second generation contrast agent? Eur J Radiol
2002;41:184–91.
21. Sodhi KS, Sidhu R, Gulati M, et al. Role of tissue har-
monic imaging in focal hepatic lesions: comparison
with conventional sonography. J Gastroenterol Hepatol
2005;20:1488–93.
22. D’Onofrio M, Rozzanigo U, Masinielli BM, et al.
Hypoechoic focal liver lesions: characterization with
contrast enhanced ultrasonography. J Clin Ultrasound
2005;33:164–72.
23. Bolondi L, Gaiani S, Celli N, et al. Characterization
of small nodules in cirrhosis by assessment of vascu-
larity: the problem of hypovascular hepatocellular
carcinoma. Hepatology 2005;42:27–34.
24. Xu HX, Liu GJ, Lu MD, et al. Characterization of
small focal liver lesions using real-time contrast-
enhanced sonography: diagnostic performance analy-
sis in 200 patients. J Ultrasound Med 2006;25:349–61.
25. Konopke R, Kersting S, Bergert H, et al. Contrast-
enhanced ultrasonography to detect liver metas-
tases: a prospective trial to compare transcutaneous
unenhanced and contrast-enhanced ultrasonography
in patients undergoing laparotomy. Int J Colorectal Dis
2007;22:201–7.
26. Nicolau C, Vilana R, Bru C. The use of contrast-
enhanced ultrasound in the management of the cir-
rhotic patient and for detection of HCC. Eur Radiol
2004;14(Suppl 8):63–71.
27. Nicolau C, Catala V, Vilana R, et al. Evaluation of
hepatocellular carcinoma using SonoVue, a second
J Med Ultrasound 2008 • Vol 16 • No 1 37
 J.H. Wang, C.S. Changchien
generation ultrasound contrast agent: correlation with
cellular differentiation. Eur Radiol 2004;14:1092–9.
28. Holland AK, Apfel RE. An improved theory for the
prediction of microcavitation thresholds. IEEE Trans
Ultrason Ferroelectr Freq Control 1989;36:204–8.
29. Albrecht T, Blomley M, Bolondi L, et al; for the
EFSUMB Study Group. Guidelines for the use of con-
trast agents in ultrasound. Ultraschall Med 2004;25:
249–56.
30. Averkiou M, Powers J, Skyba D, et al. Ultrasound
contrast imaging research. Ultrasound Q 2003;19:27–37.
31. Kamiyama N, Moriyasu F, Mine Y, et al. Analysis of
flash echo from contrast agent for designing optimal
ultrasound diagnostic systems. Ultrasound Med Biol
1999;25:411–20.
32. Schneider M, Arditi M, Barrau MB, et al. BR1: a new
ultrasonographic contrast agent based on sulfur
hexafluoride-filled microbubbles. Invest Radiol 1995;
30:451–7.
33. Leen E, Angerson WJ, Yarmenitis S, et al. Multi-centre
clinical study evaluating the efficacy of SonoVue,
a new ultrasound contrast agent in Doppler investi-
gation of focal hepatic lesions. Eur J Radiol 2002;42:
200–6.
34. Schrope B, Newhouse VL, Uhlendorf V. Simulated
capillary blood flow measurement using a nonlinear
ultrasonic contrast agent. Ultrason Imaging 1992;14:
134–58.
35. Burns PN. Harmonic imaging with ultrasound con-
trast agents. Clin Radiol 1996;51(Suppl 1):50–5.
36. Kono Y, Moriyasu F, Mine Y, et al. Gray-scale second
harmonic imaging of the liver with galactose-based
microbubbles. Invest Radiol 1997;32:120–5.
37. Burns PN, Wilson SR, Simpson DH. Pulse inversion
imaging of liver blood flow: improved method for
characterizing focal masses with microbubble con-
trast. Invest Radiol 2000;35:58–71.
38. Jang HJ, Lim HK, Lee WJ, et al. Ultrasonographic
evaluation of focal hepatic lesions: comparison of
pulse inversion harmonic, tissue harmonic, and con-
ventional imaging techniques. J Ultrasound Med 2000;
19:293–9.
39. Wen YL, Kudo M, Zheng RQ, et al. Characterization
of hepatic tumors: value of contrast-enhanced coded
phase-inversion harmonic angio. AJR Am J Roentgenol
2004;182:1019–26.
40. Albrecht T, Hoffman CW, Schettler S, et al. B-mode
enhancement at phase-inversion US with air-based
microbubble contrast agent: initial experience in
humans. Radiology 2000;216:273–8.
38 J Med Ultrasound 2008 • Vol 16 • No 1
41. Dill-Macky MJ, Burns PN, Khalili K, et al. Focal
hepatic masses: enhancement patterns with SH U
508A and pulse-inversion US. Radiology 2002;222:
95–102.
42. Kono Y, Steinbach GE, Peterson T, et al. Mechanism
of parenchymal enhancement of the liver with a
microbubble-based US contrast medium: an intra-
vital microscopy study in rats. Radiology 2002;224:
253–7.
43. Dietrich C, Ignee A, Trojan J, et al. Improved charac-
terisation of histologically proven liver tumours by
contrast enhanced ultrasonography during the por-
tal venous and specific late phase of SH U 508A.
Gut 2004;53:401–5.
44. Bryant T, Blomley M, Albrecht T. Improved charac-
terization of liver lesions with liver-phase uptake of
liver-specific microbubbles: prospective multicenter
study. Radiology 2004;232:799–809.
45. Quaia E, Degobbis F, Tona G, et al. Differential pat-
terns of contrast enhancement in different focal liver
lesions after injection of the microbubble US con-
trast agent SonoVue. Radiol Med (Torino) 2002;107:
155–65.
46. Leen E. The role of contrast-enhanced ultrasound in
the characterisation of focal liver lesions. Eur Radiol
2001;11(Suppl 3):E27–34.
47. Kojiro M, Roskams T. Early hepatocellular carci-
noma and dysplastic nodules. Semin Liver Dis
2005;25:133–42.
48. Furuse J, Nagase M, Ishii H, et al. Contrast enhance-
ment patterns of hepatic tumours during the vas-
cular phase using coded harmonic imaging and
Levovist to differentiate hepatocellular carcinoma
from other focal lesions. Br J Radiol 2003;76:385–92.
49. Nicolau C, Vilana R, Catala V, et al. Importance of
evaluating all vascular phases on contrast-enhanced
sonography in the differentiation of benign from
malignant focal liver lesions. AJR Am J Roentgenol
2006;186:158–67.
50. Hosten N, Puls R, Lemke AJ, et al. Contrast-enhanced
power Doppler sonography: improved detection of
characteristic flow patterns in focal liver lesions.
J Clin Ultrasound 1999;27:107–15.
51. Wang JH, Lu SN, Changchien CS, et al. Flash-echo
gray-scale imaging in the subtraction mode for
assessing perfusion of small hepatocellular carci-
noma. J Clin Ultrasound 2003;31:451–6.
52. Park Y, Yang C, Fernandez G, et al. Neoangiogenesis
and sinusoidal “capillarization” in dysplastic nodules
of the liver. Am J Surg Pathol 1998;22:656–62.

53. Roncalli M, Roz E, Coggi G, et al. The vascular pro-
file of regenerative and dysplastic nodules of the
cirrhotic liver: implications for diagnosis and classifi-
cation. Hepatology 1999;30:1174–8.
54. Gaiani S, Celli N, Piscaglia F, et al. Usefulness of
contrast-enhanced perfusional sonography in the
assessment of hepatocellular carcinoma hypervascu-
lar at spiral computed tomography. J Hepatol 2004;
41:421–6.
55. Forsberg F, Goldberg BB, Liu JB, et al. Tissue-
specific US contrast agent for evaluation of he-
patic and splenic parenchyma. Radiology 1999;210:
125–32.
56. Schlief R. Galactose-based echo-enhancing agents.
In: Goldberg BB, ed. Ultrasound Contrast Agents.
London: Dunitz, 1997:75–82.
57. Harvey CJ, Blomley MJ, Eckersley RJ, et al. Pulse-
inversion mode imaging of liver specific microbub-
bles: improved detection of subcentimetre metastases.
Lancet 2000;355:807–8.
58. Wang JH, Lu SN, Hung CH, et al. Small hepatic
nodules (≤ 2 cm) in cirrhosis patients: characteriza-
tion with contrast-enhanced ultrasonography. Liver
Int 2006;26:928–34.
59. Kitamura H, Kawasaki S, Nakajima K, et al.
Correlation between microbubble contrast-enhanced
color Doppler sonography and immunostaining for
Kupffer cells in assessing the histopathologic grade
of hepatocellular carcinoma: preliminary results.
J Clin Ultrasound 2002;30:465–71.
60. Albrecht T, Hoffmann CW, Schmitz SA, et al. Phase-
inversion sonography during the liver-specific late
phase of contrast enhancement: improved detection
of liver metastases. AJR Am J Roentgenol 2001;176:
1191–8.
61. Blomley MJK, Sidhu PS, Cosgrove DO, et al. Do dif-
ferent types of liver lesions differ in their uptake of
the microbubble contrast agent SH U 508A in the
late liver phase? Early experience. Radiology 2001;220:
661–7.
62. Tanaka S, Ioka T, Oshikawa O, et al. Dynamic sonog-
raphy of hepatic tumors. AJR Am J Roentgenol 2001;
177:799–805.
63. Hohmann J, Albrecht T, Hoffmann CW, et al. Ultra-
sonographic detection of focal liver lesions: increased
sensitivity and specificity with microbubble contrast
agents. Eur J Radiol 2003;46:147–59.
64. Quaia E, Bertolotto M, Forgacs B, et al. Detection
of liver metastases by pulse inversion harmonic
imaging during Levovist late phase: comparison with
Contrast-enhanced US in Small Liver Tumors
conventional ultrasound and helical CT in 160
patients. Eur Radiol 2003;13:475–83.
65. Yucel C, Ozdemir H, Gurel S, et al. Detection and dif-
ferential diagnosis of hepatic masses using pulse
inversion harmonic imaging during the liver-specific
late phase of contrast enhancement with Levovist.
J Clin Ultrasound 2002;30:203–12.
66. Wright TL, Venook AP, Millward-Sadler GH. Hepatic
tumors. In: Millward-Sadler GH, Wright R, Arthur
MJP, eds. Wright’s Liver and Biliary Disease, Volume 2,
3rd edition. Philadelphia: WB Saunders, 1992:
1079–121.
67. Bleuzen A, Tranquart F. Incidental liver lesions: diag-
nostic value of cadence contrast pulse sequencing
(CPS) and SonoVue. Eur Radiol 2004;14(Suppl 8):
53–62.
68. Sasaki K, Ito K, Koike S, et al. Differentiation
between hepatic cyst and hemangioma: additive
value of breath-hold, multisection fluid-attenuated
inversion-recovery magnetic resonance imaging using
half-Fourier acquisition single-shot turbo-spin-echo
sequence. J Magn Reson Imaging 2005;21:29–36.
69. Kim TK, Choi BI, Han JK, et al. Hepatic tumors: con-
trast agent-enhancement patterns with pulse-inversion
harmonic US. Radiology 2000;216:411–7.
70. Lee JY, Choi BI, Han JK, et al. Improved sonographic
imaging of hepatic hemangioma with contrast-
enhanced coded harmonic angiography: comparison
with MR imaging. Ultrasound Med Biol 2002;28:
287–95.
71. Quaia E, Bertolotto M, Dalla Palma L. Characteriza-
tion of liver hemangiomas with pulse inversion
harmonic imaging. Eur Radiol 2002;12:537–44.
72. Ding H, Wang WP, Huang BJ, et al. Imaging of focal
liver lesions: low-mechanical-index real-time ultra-
sonography with SonoVue. J Ultrasound Med 2005;24:
285–97.
73. Wanless IR, Mawdsley C, Adams R. On the patho-
genesis of focal nodular hyperplasia of the liver.
Hepatology 1985;5:1194–200.
74. Di Stasi M, Caturelli E, De Sio I, et al. Natural
history of focal nodular hyperplasia of the liver:
an ultrasound study. J Clin Ultrasound 1996;24:
345–50.
75. Yen YH, Wang JH, Lu SN, et al. Contrast-enhanced
ultrasonographic spoke-wheel sign in hepatic focal
nodular hyperplasia. Eur J Radiol 2006;60:439–44.
76. Ros PR, Menu Y, Vilgrain V, et al. Liver neoplasms and
tumor-like conditions. Eur Radiol 2001;11(Suppl 2):
S145–65.
J Med Ultrasound 2008 • Vol 16 • No 1 39
 J.H. Wang, C.S. Changchien
77. Hung CH, Changchien CS, Lu SN, et al. Sonographic
features of hepatic adenomas with pathologic corre-
lation. Abdom Imaging 2001;26:500–6.
78. Lim AK, Patel N, Gedroyc WM, et al. Hepatocellular
adenoma: diagnostic difficulties and novel imaging
techniques. Br J Radiol 2002;75:695–9.
79. Solbiati L, Kirn V, Cova L, et al. Other benign lesions
and pseudolesions. In: Solbiati L, ed. Contrast-enhanced
Ultrasound of Liver Diseases. Rome: Springer-Verlag,
2003:60–1.
80. Kojiro M, Yano H, Nakashima O. Pathology of early
hepatocellular carcinoma: progression from early to
advanced. Semin Surg Oncol 1996;12:197–203.
81. Nakashima Y, Nakashima O, Hsia CC, et al.
Vascularization of small hepatocellular carcinomas:
correlation with differentiation. Liver 1999;19:12–8.
82. Bartolozzi C, Lencioni R, Ricci P, et al. Hepatocellular
carcinoma treatment with percutaneous ethanol
injection: evaluation with contrast-enhanced color
Doppler US. Radiology 1998;209:387–93.
83. Choi D, Lim HK, Kim SH, et al. Hepatocellular carci-
noma treated with percutaneous radio-frequency
ablation: usefulness of power Doppler US with a
microbubble contrast agent in evaluating therapeu-
tic response—preliminary results. Radiology 2000;217:
558–63.
84. Kim AY, Choi BI, Kim TK, et al. Hepatocellular car-
cinoma: power Doppler US with a contrast agent—
preliminary results. Radiology 1998;209:135–40.
40 J Med Ultrasound 2008 • Vol 16 • No 1
85. Wang JH, Lu SN, Changchien CS, et al. Flash echo
gray scale imaging with subtraction in assessment of
small hepatocellular carcinoma treated with percu-
taneous ethanol injection. J Ultrasound Med 2001;20:
539–44.
86. Wang JH, Lu SN, Tung HD, et al. Flash-echo contrast
sonography in the evaluation of response of small
hepatocellular carcinoma to percutaneous ablation.
J Clin Ultrasound 2006;34:161–8.
87. Ding H, Kudo M, Onda H, et al. Contrast-enhanced
subtraction harmonic sonography for evaluating
treatment response in patients with hepatocellular
carcinoma. AJR Am J Roentgenol 2001;176:661–6.
88. Meloni MF, Goldberg SN, Livraghi T, et al.
Hepatocellular carcinoma treated with radiofrequency
ablation: comparison of pulse inversion contrast-
enhanced harmonic sonography, contrast-enhanced
power Doppler sonography, and helical CT. AJR Am J
Roentgenol 2001;177:375–80.
89. Wen YL, Kudo M, Zheng RQ, et al. Radiofrequency
ablation of hepatocellular carcinoma: therapeutic
response using contrast-enhanced coded phase-
inversion harmonic sonography. AJR Am J Roentgenol
2003;181:57–63.
90. Youk JH, Lee JM, Kim CS. Therapeutic response
evaluation of malignant hepatic masses treated by
interventional procedures with contrast-enhanced
agent detection imaging. J Ultrasound Med 2003;22:
911–20.