J Gastroenterol (2012) 47:1063–1072
DOI 10.1007/s00535-012-0662-4
REVIEW
Contrast-enhanced endoscopic ultrasonography in digestive
diseases
Yoshiki Hirooka • Akihiro Itoh • Hiroki Kawashima • Eizaburo Ohno • Yuya Itoh • Yosuke Nakamura •
Takeshi Hiramatsu • Hiroyuki Sugimoto • Hajime Sumi • Daijiro Hayashi • Naoki Ohmiya • Ryoji Miyahara
Masanao Nakamura • Kohei Funasaka • Masatoshi Ishigami • Yoshiaki Katano • Hidemi Goto
Received: 12 August 2012 / Accepted: 12 August 2012 / Published online: 25 September 2012
Ó Springer 2012
Abstract Contrast-enhanced endoscopic ultrasonography
(CE-EUS) was introduced in the early 1990s. The concept
of the injection of carbon dioxide microbubbles into the
hepatic artery as a contrast material (enhanced ultraso-
nography) led to ‘‘endoscopic ultrasonographic angiogra-
phy’’. After the arrival of the first-generation contrast
agent, high-frequency (12 MHz) EUS brought about the
enhancement of EUS images in the diagnosis of pancrea-
tico-biliary diseases, upper gastrointestinal (GI) cancer,
and submucosal tumors. The electronic scanning endoso-
noscope with both radial and linear probes enabled the use
of high-end ultrasound machines and depicted the
enhancement of both color/power Doppler flow-based
imaging and harmonic-based imaging using second-gen-
eration contrast agents. Many reports have described the
usefulness of the differential diagnosis of pancreatic dis-
eases and other abdominal lesions. Quantitative evaluation
of CE-EUS images was an objective method of diagnosis
using the time-intensity curve (TIC), but it was limited to
the region of interest. Recently developed Inflow Time
MappingTM can be generated from stored clips and used to
display the pattern of signal enhancement with time after
injection, offering temporal difference of contrast agents
and improved tumor characterization. On the other hand,
Y. Hirooka (&)
E. Ohno
Y. Nakamura
K. Funasaka

H. Goto
Department of Endoscopy, Nagoya University Hospital, 65
Tsuruma-Cho, Showa-ku, Nagoya City, Japan
e-mail: hirooka@med.nagoya-u.ac.jp
A. Itoh
H. Kawashima
Y. Itoh
T. Hiramatsu
H. Sugimoto

H. Sumi
D. Hayashi
N. Ohmiya
R. Miyahara
M. Nakamura

M. Ishigami
Y. Katano
H. Goto
Department of Gastroenterology and Hepatology, Nagoya
University Graduate School of Medicine, 65 Tsuruma-Cho,
Showa-ku, Nagoya City, Japan
•
three-dimensional CE-EUS images added new information
to the literature, but lacked positional information. Three-
dimensional CE-EUS with accurate positional information
is awaited. To date, most reports have been related to
pancreatic lesions or lymph nodes. Hemodynamic analysis
might be of use for diseases in other organs: upper GI
cancer diagnosis, submucosal tumors, and biliary disorders,
and it might also provide functional information. Studies of
CE-EUS in diseases in many other organs will increase in
the near future.
Keywords Contrast-enhanced EUS (CE-EUS)

Contrast-agents
Pancreatic diseases
Biliary diseases

Gastrointestinal tract
Time intensity curve
Introduction
The advent of color Doppler flow imaging in the clinical
setting in the early 1980s brought about a new era of
ultrasonography (US). Diagnosis with only B-mode imag-
ing changed to that utilizing the information of hemody-
namics. Hemodynamics may be interpreted in two ways;
one is for blood flow in the vessels (2 or 3 mm in minimum
diameter) and the other is for blood flow in the microvas-
culature, i.e., parenchymal perfusion. Color Doppler flow
imaging can estimate the blood flow in vessels but cannot
depict parenchymal perfusion.
In 1986, Matsuda and Yabuuchi [1] reported the feasi-
bility and usefulness of the enhancement of hepatic tumors
on transabdominal ultrasonograms by the injection of car-
bon dioxide microbubbles into the hepatic artery as a
contrast material (enhanced ultrasonography). This
enhancement enabled the evaluation of parenchymal per-
fusion by increased echo intensity as the inflow of carbon
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dioxide microbubbles. Enhanced US thus has two major
categories; one is the enhancement of color Doppler flow
imaging (power Doppler flow imaging started a few years
later), the other is the enhancement of B-mode-based
imaging.
However, endoscopic US (EUS) with a mechanical
radial scanning probe was not equipped with a color/power
Doppler imaging function and we had to wait for the arrival
of electronic radial or linear scanning probes to utilize
Doppler function. In regard to the contrast media for US,
sonicated serum albumin, the first contrast agent adapted to
peripheral vein injection for the purpose of enhancing US
images, appeared in the middle of the 1990s [2].
Contrast-enhanced EUS (CE-EUS) depends on both
contrast agents and an endosonoscope; here, we review the
developments in CE-EUS in chronological order, in terms
of both these factors, and refer to its present status and
future perspectives.
Endoscopic ultrasonographic angiography
The concept of enhanced US [1] inevitably led to the
development of CE-EUS. Originally, we named this pro-
cedure endoscopic ultrasonographic angiography (EUS-
angiography), but this might be regarded in the broad sense
as the original incarnation of CE-EUS.
We performed EUS angiography in lesions that could
not be clearly visualized by US [3]. EUS angiography was
performed by EUS with the injection of CO2 microbubbles
(prepared by vigorously mixing the same volumes
[5–10 ml] of CO2, heparinized saline, and the patient’s
blood) through a catheter into the gastroduodenal or celiac
artery following conventional US. The patients were
sedated with 10 mg diazepam, positioned on the left side
with a catheter in the gastroduodenal or celiac artery, and
Fig. 1 Gallbladder cancer. a Plain endoscopic ultrasonography (EUS) revealed a wide-based tumor in the gallbladder wall. b EUS angiography
demonstrated increased intensity of the tumor image on ultrasonogram, indicating it was hypervascular
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underwent EUS to detect pancreatico-biliary lesions. A
mechanical radial endosonoscope with 7.5-MHz transduc-
ers (GF-UM2; Olympus, Tokyo) was used.
EUS angiography was useful especially in those cases
that were difficult to observe with US. We also performed
intraductal ultrasonography (IDUS ) angiography in the
diagnosis of the depth of bile duct cancer [4]. IDUS
angiography was performed by the injection of CO2 mi-
crobubbles with an IDUS catheter advanced into the bile
duct through a percutaneous transhepatic biliary drainage
(PTBD) fistula.
Figures 1 and 2 show representative cases of EUS and
IDUS angiography.
Regardless of their diagnostic usefulness, because EUS
and IDUS angiography placed a considerable burden on
patients these modalities could not become widely used.
Contrast agents for ultrasonography
Contrast agents for US are agents that are injected into a
peripheral vein and are capable of enhancing ultrasono-
graphic images. Contrast agents generally consist of gas-
filled microbubbles encapsulated by a phospholipid or
albumin shell, and there are several ways of classifying
them. Three categories of classification are adopted in this
review: the contrast agents are categorized as first, second,
and third generation, based on their capability for trans-
pulmonary passage and their half-life in the human body
(Table 1). Commonly used first-generation agents were
AlbunexTM, LevovistTM, and EchovistTM. Second-genera-
tion agents include SonoVueTM, SonazoidTM, and Opti-
sonTM among others; these agents are long-lasting and
enable enhancement. The only third-generation agent cur-
rently available is EchogenTM, which is capable of a phase
shift from liquid to gas form once it reaches body
J Gastroenterol (2012) 47:1063–1072 1065

Fig. 2 Identification of epicholedochal arterial plexus. a Intraductal whose identification led, importantly, to the diagnosis of the depth of
ultrasonography (IDUS) showed anechoic parts along the bile duct bile duct cancer invasion. Small arrowheads indicated the outer
wall. b IDUS angiography revealed these anechoic parts to be the contour of bile duct wall (a) and large arrowhead indicated the
epicholedochal arterial plexus (EP) existing in the subserosa (ss ) area epicholedochal arterial plexus (EP): hyperechoic area (b)

Table 1 Contrast agents for ultrasonography

Contrast agents Composition Manufacturer

First generation
Albunex 5 % Sonicated serum albumin with stabilized microbubbles Mallinckrodt
Echovist (SHU 454) Standardized microbubbles with galactose shell Schering
Levovist (SHU 508) Stabilized, standardized microbubbles with galactose, 0.1 % palmitic acid Schering
shell
Myomap Albumin shell Quadrant
Qantison Albumin shell Quadrant
Sonavist Cyanoacrylate shell Schering
Second generation
Definity/Luminity C3F8 with lipid stabilizer shell Bristol-Myers Squibb Medical
Imaging
Sonazoid C4F10 with lipid stabilizer shell GE Healthcare
Imagent-Imavist C6F14 with lipid stabilizer shell Alliance
Optison C3F8 with denatured human albumin shell GE Healthcare
Bisphere/ Polylactide-coglycolide shell with albumin overcoat Commercially unavailable
Cardiosphere
SonoVue SF6 gas with lipid stabilizer shell Bracco
AI700/imagify C4F10 gas core stabilized with polymer shell Acusphere
Third generation
Echogen Dodecafluoropentane (DDFP) liquid in phase shift colloid emulsion Sonus Pharmaceuticals

temperature. The contrast agents in use today are relatively AlbunexTM

safe and have demonstrated no severe, long-lasting adverse
effects in humans [5].
In Japan, three contrast agents for US [AlbunexTM
(Shionogi, Osaka, Japan), LevovistTM (Bayer, Osaka,
Japan), and SonazoidTM (Daiichi-Sankyo, Tokyo, Japan)]
are actually used in clinical practice. This review centers
on these three agents while referring to other necessary
topics.
AlbunexTM was the first contrast agent to be injected
peripherally for US. The contrast material consisted of a
preparation of air-filled microspheres created by the soni-
cation of 5 % human serum albumin solution. Micro-
spheres in this preparation ranged in size from 1–10 lm
(mean particle size 4 lm; 95 % particles \10 lm), per-
mitting free passage through the pulmonary capillary

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circulation. There were 4 9 108 microspheres/ml of solu-
tion. No serious complications have been reported for this
agent. In the circulatory system, this agent enhanced the
contrast in the left ventricular system, suggesting its
applicability to the abdominal area [2, 6–8]. However,
there have been no reports of the enhancement of extra-
corporeal ultrasonographic images, including color Dopp-
ler images, by the peripheral injection of AlbunexTM. This
was probably due to the fragility of Albunex particles. In
addition, we speculate that Albunex particles or aggregated
Albunex particles do not reflect ultrasound at the low-fre-
quency range used for routine extracorporeal US. There-
fore, we used EUS, as this method allows observation at a
high frequency. As expected, enhancement effects of
Albunex were observed. With this method, observation at
7.5 MHz was also possible. However, observation at
7.5 MHz performed in some patients revealed no
enhancement, even in those showing an enhancement
effect at 12 MHz. These findings suggest that a frequency
of C12 MHz is necessary for contrast enhancement by
peripherally injected Albunex in the abdominal area [7].
We performed CE-EUS using AlbunexTM in the diag-
nosis of pancreatic diseases, gallbladder diseases, and
upper gastrointestinal tract diseases [7–9].
Pancreatic diseases
After the EUS procedure, AlbunexTM (0.22 ml/kg) was
injected intravenously at a rate of 1 ml/s into the right
median vein, and observation was continued for 10 min.
The presence or absence of enhancement of the lesion was
determined in each disease. Enhancement of the lesion was
observed in all patients with islet cell tumors and serous
cystadenoma, in eight with mucin-producing tumors, and
in three with chronic pancreatitis. However, no enhance-
ment effect was observed in the patients with ductal cell
Fig. 3 Pancreatic neuroendocrine tumor. a Non-enhanced EUS
showed a hypoechoic homogeneous mass with a clearly delineated
margin. b Contrast-enhanced EUS (CE-EUS) revealed increased echo
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carcinoma or in those with pseudo-cyst. We concluded that
the combined evaluation of plain and enhanced EUS ima-
ges was useful for the diagnosis of pancreatic diseases [7].
Figure 3 shows a pancreatic neuroendocrine tumor.
Gallbladder diseases
In the diagnosis of gallbladder cancer, CE-EUS mostly
contributed to the diagnosis of the depth of cancer inva-
sion. We compared the diagnostic accuracy (T factor in the
TNM classification) of standard EUS and CE-EUS. The
depth of tumor infiltration was determined according to the
pTNM classification as follows: T1, hypoechoic tumor
invades the first (T1a) or second layer (T1b); T2, hypo-
echoic tumor invades the third hyperechoic layer with no
extension beyond the third layer or into the liver; T3,
hypoechoic tumor invades beyond the third layer and/or
into an adjacent organ (extension 2 cm or less into the
liver); and T4, hypoechoic tumor extends more than 2 cm
into the liver and/or into two or more adjacent organs.
Enhancement of both the first and the third layers brought
about improved contrast resolution between the gallbladder
wall structure and the tumor, resulting in an increase of the
diagnostic accuracy [8].
Upper gastrointestinal tract diseases (esophageal cancer,
gastric cancer, and submucosal tumor of the stomach)
Enhancement of the third and fifth layers was observed in
all normal esophageal and gastric walls. No esophageal
cancer was enhanced. Enhancement was observed in 5
gastric carcinomas that had abundant, enlarged, and
winding vascular beds. In all esophageal and the other 25
gastric carcinomas, although the tumors per se were not
enhanced, enhancement of the third and fifth layers around
the lesions clearly demarcated the tumor boundaries. As a
intensity in the whole mass, indicating that it was hypervascular. The
combination of B-mode image and CE-EUS image led to the
diagnosis of pancreatic neuroendocrine tumor
J Gastroenterol (2012) 47:1063–1072
result, accuracy for detection of the depth of gastric car-
cinoma improved from 76.7 % for EUS to 90 % for con-
trast-enhanced EUS.
All gastric submucosal tumors were enhanced, and
irregularly shaped sonolucent areas within these tumors
became clear, but we could not distinguish between benign
and malignant lesions [9]. This diagnostic concept seems to
have opened the way to a recent study [10].
Recent progress in EUS (electronic scanning methods)
Recent progress in EUS is summarized in Fig. 4. Until the
early 2000s, the mainstream EUS method was a mechan-
ical radial scanning method (MR-EUS). In the early 2000s,
we first developed the endosonoscope with an electronic
radial scanning method [11–13]. From that time, both
electronic radial and linear (curved linear) type EUS was
employed, using the same methods as those used with a
high-end transabdominal ultrasound apparatus. Electronic
linear-type EUS (which arrived earlier than electronic
radial-type EUS) with color/power Doppler function
allowed the development of contrast-enhanced color/power
Doppler EUS [14].
Contrast-enhanced EUS (CE-EUS): color/power
Doppler and harmonic imaging
In general, there are two main categories of CE-EUS; the
first is contrast-enhanced color/power Doppler imaging
and the second is contrast-enhanced harmonic imaging.
Progress of EUS
Mechanical radial scanning method
Electronic scanning method
Radial scanning Linear (curved-linear) scanning
1. Improvement of B-mode 1. EUS-FNA
image quality including THI Histology / cytology
Gene expression analysis
2. Utilization of applications
Color / power Doppler and CE-EUS
2. Therapeutics
Harmonic imaging and CE-EUS
Drainage
3-D imaging
Anti-cancer therapy
Real time tissue elastography
Fig. 4 Progress of endoscopic ultrasonography. In the early 2000s,
the mainstream use of endoscopic ultrasonography (EUS) changed
from a mechanical radial scanning method to an electronic radial or
electronic linear scanning method, which enabled the endosonogra-
pher to make use of many applications. FNA Fine-needle aspiration,
THI tissue harmonic imaging, CE-EUS contrast-enhanced EUS,
3D three-dimensional
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CE-EUS using a Doppler method provides an image that
clearly divides the target into vascular-rich areas and
hypovascular areas [14–30]. CE-EUS using harmonic
imaging methods presents a more detailed view of the
vasculature of the target lesions [10, 23, 26, 28, 31–45]. In
addition, CE-EUS using harmonic imaging methods gives
quantitative information, such as a TIC showing the
changes of echo-intensity over time. These two methods
should be selected in accordance with the intended use.
There are many harmonic imaging modes, but, irrespec-
tive of the small differences between them, they share a
common basic principle. Harmonic imaging modes are
generally based on the cancellation and/or separation of
linear US signals from tissue and the utilization of the non-
linear response from microbubbles. The non-linear response
from microbubbles is based on two different mechanisms:
1. Non-linear response from microbubble oscillations at
low acoustic pressure, chosen to minimize disruption
of the microbubbles.
2. High-energy broadband non-linear response arising
from microbubble disruption. Non-linear harmonic US
signals may also arise in tissues themselves owing to a
distortion of the sound wave during its propagation
through the tissue. The extent of this harmonic
response from tissue at a given frequency increases
with the acoustic pressure, which is proportional to the
mechanical index (MI) [46].
Low-solubility gases (e.g., SonazoidTM) are character-
ized by a combination of improved stability with favorable
resonance behavior at low acoustic pressure. This allows
minimally disruptive contrast-specific imaging at a low MI
and enables effective investigations over several minutes
with the visualization of the dynamic enhancement pattern
in real time. Furthermore, low MI techniques lead to
effective tissue signal suppression, as the non-linear
response from the tissue is minimal when low acoustic
pressures are used. US imaging with air-filled microbub-
bles (e.g., LevovistTM) at high pressure is dependent on
microbubble disruption, which is a significant limitation for
real-time imaging.
Color/power Doppler-based CE-EUS
Using OptisonTM, Becker et al. [14] reported the usefulness
of CE-EUS with a power Doppler function in the differ-
entiation of pancreatic carcinoma from inflammatory
changes. Fifteen patients (100 %) with hypoperfused
(hypovascular) masses had pancreatic adenocarcinoma and
7 patients (88 %) with a hyperperfused (hypervascular)
lesion had focal inflammation. Similar results were repor-
ted from several centers [15, 17, 19, 20, 46]. We classified
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color -nhanced pancreatic images into 3 patterns of solid
masses and 5 patterns of cystic masses, using LevovistTM
[20]. The 3 patterns of solid masses were defined as fol-
lows: (1) filled with color signals throughout the tumor; (2)
color signals seen to the same degree as in the normal
parenchyma; and (3) scarcity of color signals or color
signals only associated with involved vessels. The 5 pat-
terns of cystic masses were defined as follows: 1, color
signals in both papillary growths and septa; 2, color signals
only in septa; 3, color signals filling microcystic regions; 4,
color signals seen mainly in the surrounding wall or in the
periphery of the mass; and 5, no color signals. All neuro-
endocrine tumors were classified as solid mass pattern 1,
and 81 % of invasive ductal carcinomas were classified as
solid mass pattern 3. Seven cases of invasive ductal car-
cinoma, 5 cases of acinar cell carcinoma, and 23 cases of
chronic pancreatitis were classified as solid mass pattern 2.
Figure 5 shows cystic pattern 3 (serous cystic neoplasm).
One of the most important factors for predicting the
malignant potential of intraductal papillary mucinous
neoplasm (IPMN) was thought to be the morphology of the
mural nodules (i.e., papillary growth) in the lesions. Ohno
et al. [21, 29] emphasized the importance of differentiating
the ‘‘true mural nodule’’ from mucin, using CE-EUS with
LevovistTM or SonazoidTM. According to the International
consensus guidelines 2012 for the management of IPMN
and mucinous cystic neoplasm of the pancreas [47],
Doppler signals in the mural nodule were highlighted as the
basis for diagnosing ‘‘true mural nodules’’. In our opinion,
because plain Doppler mode in EUS has not enough sen-
sitivity to detect blood flow, CE-EUS should be recom-
mended for this purpose.
Ishikawa et al. [24] proposed a predictor for the
malignancy grading of pancreatic neuroendocrine tumor
(PNET). Their study showed that heterogeneous ultraso-
nographic texture was the most significant factor for
Fig. 5 Serous cystic neoplasm. a Plain color Doppler flow imaging showed scattered color signals. b Contrast-enhanced color Doppler flow
imaging (LevovistTM) demonstrated enormous color signals in the microcystic-based background image
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malignancy (odds ratio [OR] = 53.33; 95 % confidence
interval [CI], 10.79–263.58). Most heterogeneous hypo-
echoic areas and anechoic areas corresponded to hemor-
rhage or necrosis on pathologic examination. These areas
were identified as filling defects on CE-EUS (color Doppler
mode with LevovistTM or SonazoidTM) and were more
clearly recognized than on conventional EUS.
CE-EUS provided useful information to differentiate
malignant lymph nodes from benign lymph nodes [16, 18,
20, 23, 26]. According to the study by Kanamori et al. [16],
the enhancement pattern of lymph node blood flow signals
could be classified into three types; uniform enhancement
of the entire lymph node (Pattern A), no enhancement of
blood flow signals (Pattern B), and a defect of lymph node
enhancement (Pattern C). They found that 19 (86 %) and 1
(5 %) of the 22 patients with benign lymph nodes showed
Patterns A and B, respectively. Two patients (10 %)
showed Pattern C; one patient had tuberculosis-related
lymph node swelling and the other had sarcoidosis. On the
other hand, all patients with malignant lymph nodes
(100 %) showed Pattern C. Judging Pattern B or C as
malignant, the sensitivity, specificity, and accuracy rate of
CE-EUS were 100, 86.4, and 92.3 %, respectively.
As mentioned above, color/power Doppler-based CE-
EUS provides useful information especially in cases where
a rough classification (such as a ‘‘with or without’’ cate-
gory) holds great significance. Theoretically, in color/
power Doppler flow imaging, the smallest diameter
required to depict a lesion has a limitation (around
500 lm). Intermittent transmission of ultrasound destroys
the pooled contrast agent (i.e., LevovistTM) at one burst and
brings about the so-called ‘‘loss of correlation’’ phenome-
non, producing a quasi-perfusion image [48]. This quasi-
perfusion image disappears in a short time (low temporal
resolution), so harmonic imaging-based CE-EUS is nec-
essary for the evaluation of perfusion images.
J Gastroenterol (2012) 47:1063–1072
Harmonic imaging-based CE-EUS
Harmonic imaging-based CE-EUS differs from color/
power Doppler imaging-based CE-EUS in that the former
can provide parenchymal perfusion images and a long-
lasting (20–30 min) enhanced effect using second-genera-
tion contrast agents (Table 1).
Kitano et al. [32] reported that contrast-enhanced har-
monic EUS using SonoVueTM could depict a perfusion
image of the pancreas. Imazu et al. [33] revealed the
diagnostic role of contrast-enhanced harmonic imaging
endoscopic US with SonazoidTM in the diagnosis of the
T-stage of pancreaticobiliary malignancies. They reported
that the overall accuracy of conventional EUS and CE-EUS
for T-staging were 69.2 (18/26) and 92.4 % (24/26),
respectively (P \ 0.05). Napoleon et al. [34] studied
contrast-enhanced harmonic endoscopic ultrasound using
SonoVueTM to distinguish pancreatic adenocarcinoma from
other pancreatic masses; they reported the sensitivity,
specificity, negative predictive value (NPV), positive pre-
dictive value (PPV), and accuracy of hypointensity for
diagnosing pancreatic adenocarcinoma were 89, 88, 88, 89,
and 88.5 %, compared with corresponding values of 72,
100, 77, 100, and 86 % for EUS-fine-needle aspiration
(FNA). Of five adenocarcinomas with false-negative
results on EUS-FNA, four had a hypointense echo signal
on CE-EUS. Xia et al. [38] categorized abdominal lesions
as those having no, homogeneous, or heterogeneous
enhancement, and revealed that the malignant and benign
lesion groups differed significantly in terms of homoge-
neous and heterogeneous enhancement (P \ 0.001). They
concluded that CE-EUS using SonazoidTM depicted the
microvasculature of intra-abdominal lesions of undeter-
mined origin very clearly and may be useful for charac-
terizing such lesions. Kitano et al. [44] claimed that EUS
equipped with contrast harmonic imaging may play an
Fig. 6 Neuroendocrine tumor. a B-mode EUS image showed
a clearly delineated mass with calcification in its central area.
b CE-EUS image (color Doppler mode) revealed the tumor to be
1069
important role in the characterization of small tumors that
other imaging methods fail to depict and may improve the
diagnostic yield of EUS-FNA. The relationship between
CE-EUS and EUS-FNA remains unclear, and whether
CE-EUS is superior is controversial.
Matsubara et al. [41] proposed a different approach for
CE-EUS using SonazoidTM , i.e., quantitative evaluation
analyzing the TIC. They revealed that the echo intensity
reduction rate from the peak at 1 min was the greatest in
pancreatic cancer, followed by mass-forming pancreatitis,
autoimmune pancreatitis, and neuroendocrine tumor
(P \ 0.05). They concluded that CE-EUS with dynamic
quantitative analysis using a TIC increased the diagnostic
accuracy for pancreatic diseases. Imazu et al. [41] also
showed the usefulness of CE-EUS with SonazoidTM in the
discrimination of autoimmune pancreatitis from pancreatic
cancer on TIC analysis.
To date, most reports of hemodynamic analysis have
been related to pancreatic lesions or lymph nodes. How-
ever, hemodynamic analysis might be of use for diseases
of other organs: upper gastrointestinal cancer diagnosis
[9], submucosal tumors [9, 38], and biliary disorders, and
it might also provide functional information. Studies of
CE-EUS in the diseases of many other organs are
awaited.
Present statues and future perspectives
Three-dimensional EUS and CE-EUS is one of the new
topics in imaging studies [49–52]. These images are
obtained by the free-hand moving of an endosonoscope in
the course of CE-EUS. Figure 6c shows a three-dimen-
sional CE-EUS image (color Doppler mode). The degree of
fusion between color mapping and the B-mode image was
at the operator’s discretion. In the near future three-
hypervascular. c Three-dimensional CE-EUS image was created by
the free-hand movement of the endosonoscope and did not have
positional information
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Fig. 7 Inflow Time MappingTM (gallbladder cholesterol polyp).
Inflow Time MappingTM (Hitachi Aloka Medical, Tokyo, Japan)
can be generated from stored clips and used to display the pattern of
signal enhancement with time after injection, offering temporal
differences of contrast agents and improved tumor characterization.
dimensional EUS and CE-EUS may become useful with
accurate positional information.
Inflow Time MappingTM (Hitachi Aloka Medical,
Tokyo, Japan) is proposed as a new tool for quantitative
evaluation. Inflow Time MappingTM can be generated from
stored clips and used to display the pattern of signal
enhancement with time after injection, offering temporal
differences of contrast agents and improved tumor char-
acterization. A TIC indicates the change of echo intensity
only in the region of interest (ROI), but this new mode
provides the time-oriented movement of contrast agents in
the whole lesion. Figure 7b presents Inflow Time Map-
pingTM image of a cholesterol polyp.
The feasibility of new technologies using contrast-
enhanced (CE) ultrasound with microbubbles targeted to
molecules is currently being tested [5, 53, 54]. Several
applications of molecular imaging and targeted ultrasound
therapy can also be envisioned in the near future, including
determination of the detailed physical processes behind
sonoporation (increased uptake of drugs inside the cell
through transient porosities in the cell membrane in the
presence of contrast agents).
In my opinion, the most important factor of EUS is the
image quality. Indeed, EUS-FNA provides the easier or too
easy answer, causing my increased apprehension about
disinterestedness in the image quality itself. Of course, I
myself perform both EUS and EUS-FNA, and realize that
poor quality of image brings about the difficulty of EUS-
FNA procedure. CE-EUS is one of the potent procedures to
improve the image quality and is an authentic process.
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J Gastroenterol (2012) 47:1063–1072
a A pedunculated polyp around 10 mm in height was seen in the
gallbladder. b In this case, we could recognize time-oriented
movement of contrast agents: at first, a light green linear line (small
arrowheads) was seen in the center of the polyp, next, green to light
blue (large arrowheads) was shown up to the periphery
Conflict of interest The authors declare that they have no conflicts
of interest.
References
1. Matsuda Y, Yabuuchi I. Hepatic tumors: US contrast enhance-
ment with CO2 microbubbles. Radiology. 1986;161(3):701–5.
2. Hirooka Y, Naitoh Y, Goto H, Ito A, Taki T, Hayakawa T.
Usefulness of contrast-enhanced endoscopic ultrasonography
with intravenous injection of sonicated serum albumin. Gastro-
intest Endosc. 1997;46(2):166–9.
3. Kato T, Tsukamoto Y, Naitoh Y, Hirooka Y, Furukawa T, Ha-
yakawa T. Ultrasonographic and endoscopic ultrasonographic
angiography in pancreatic mass lesions. Acta Radiol.
1995;36(4):381–7.
4. Kuroiwa M, Tsukamoto Y, Naitoh Y, Hirooka Y, Furukawa T,
Katou T. New technique using intraductal ultrasonography for the
diagnosis of bile duct cancer. J Ultrasound Med.
1994;13(3):189–95.
5. Reddy NK, Ioncica AM, Saftoiu A, Vilmann P, Bhutani MS.
Contrast-enhanced endoscopic ultrasonography. World J Gas-
troenterol. 2011;17(1):42–8.
6. Bhutani MS, Hoffman BJ, van Velse A, Hawes RH. Contrast-
enhanced endoscopic ultrasonography with galactose micropar-
ticles: SHU508 A (Levovist). Endoscopy. 1997;29(7):635–9.
7. Hirooka Y, Goto H, Ito A, Hayakawa S, Watanabe Y, Ishiguro Y,
et al. Contrast-enhanced endoscopic ultrasonography in pancre-
atic diseases: a preliminary study. Am J Gastroenterol.
1998;93(4):632–5.
8. Hirooka Y, Naitoh Y, Goto H, Ito A, Hayakawa S, Watanabe Y,
et al. Contrast-enhanced endoscopic ultrasonography in gall-
bladder diseases. Gastrointest Endosc. 1998;48(4):406–10.
9. Nomura N, Goto H, Niwa Y, Arisawa T, Hirooka Y, Hayakawa
T. Usefulness of contrast-enhanced EUS in the diagnosis of upper
GI tract diseases. Gastrointest Endosc. 1999;50(4):555–60.
J Gastroenterol (2012) 47:1063–1072
10. Sakamoto H, Kitano M, Matsui S, Kamata K, Komaki T, Imai H,
et al. Estimation of malignant potential of GI stromal tumors by
contrast-enhanced harmonic EUS (with videos). Gastrointest
Endosc. 2011;73(2):227–37.
11. Niwa K, Hirooka Y, Itoh A, Hashimoto S, Hirai T, Takeda K,
et al. Preclinical study of endoscopic ultrasonography with
electronic radial scanning echoendoscope. J Gastroenterol Hep-
atol. 2003;18(7):828–35.
12. Niwa K, Hirooka Y, Niwa Y, Itoh A, Ohmiya N, Hashimoto S,
et al. Comparison of image quality between electronic and
mechanical radial scanning echoendoscopes in pancreatic dis-
eases. J Gastroenterol Hepatol. 2004;19(4):454–9.
13. Ishikawa H, Hirooka Y, Itoh A, Hashimoto S, Okada N, Itoh T,
et al. A comparison of image quality between tissue harmonic
imaging and fundamental imaging with an electronic radial
scanning echoendoscope in the diagnosis of pancreatic diseases.
Gastrointest Endosc. 2003;57(7):931–6.
14. Becker D, Strobel D, Bernatik T, Hahn EG. Echo-enhanced
color- and power-Doppler EUS for the discrimination between
focal pancreatitis and pancreatic carcinoma. Gastrointest Endosc.
2001;53(7):784–9.
15. Hocke M, Schulze E, Gottschalk P, Topalidis T, Dietrich CF.
Contrast-enhanced endoscopic ultrasound in discrimination
between focal pancreatitis and pancreatic cancer. World J Gas-
troenterol. 2006;12(2):246–50.
16. Kanamori A, Hirooka Y, Itoh A, Hashimoto S, Kawashima H,
Hara K, et al. Usefulness of contrast-enhanced endoscopic
ultrasonography in the differentiation between malignant and
benign lymphadenopathy. Am J Gastroenterol. 2006;101(1):
45–51.
17. Dietrich CF, Ignee A, Braden B, Barreiros AP, Ott M, Hocke M.
Improved differentiation of pancreatic tumors using contrast-
enhanced endoscopic ultrasound. Clin Gastroenterol Hepatol.
2008;6(5):590–7.
18. Hocke M, Menges M, Topalidis T, Dietrich CF, Stallmach A.
Contrast-enhanced endoscopic ultrasound in discrimination
between benign and malignant mediastinal and abdominal lymph
nodes. J Cancer Res Clin Oncol. 2008;134(4):473–80.
19. Hocke M, Schmidt C, Zimmer B, Topalidis T, Dietrich CF,
Stallmach A. Contrast enhanced endosonography for improving
differential diagnosis between chronic pancreatitis and pancreatic
cancer. Dtsch Med Wochenschr. 2008;133(38):1888–92.
20. Hirooka Y, Itoh A, Kawashima H, Ohno E, Ishikawa T, Matsu-
bara H, et al. Diagnosis of pancreatic disorders using contrast-
enhanced endoscopic ultrasonography and endoscopic elastog-
raphy. Clin Gastroenterol Hepatol. 2009;7:S63–7.
21. Ohno E, Hirooka Y, Itoh A, Ishigami M, Katano Y, Ohmiya N,
et al. Intraductal papillary mucinous neoplasms of the pancreas:
differentiation of malignant and benign tumors by endoscopic
ultrasound findings of mural nodules. Ann Surg. 2009;249(4):
628–34.
22. Saftoiu A, Vilmann P. Role of endoscopic ultrasound in the
diagnosis and staging of pancreatic cancer. J Clin Ultrasound.
2009;37(1):1–17.
23. Giovannini M. The place of endoscopic ultrasound in bilio-pan-
creatic pathology. Gastroenterol Clin Biol. 2010;34(8–9):436–45.
24. Ishikawa T, Itoh A, Kawashima H, Ohno E, Matsubara H, Itoh Y,
et al. Usefulness of EUS combined with contrast-enhancement in
the differential diagnosis of malignant versus benign and preop-
erative localization of pancreatic endocrine tumors. Gastrointest
Endosc. 2010;71(6):951–9.
25. Saftoiu A, Iordache SA, Gheonea DI, Popescu C, Malos A,
Gorunescu F, et al. Combined contrast-enhanced power Doppler
and real-time sonoelastography performed during EUS, used
in the differential diagnosis of focal pancreatic masses (with
videos). Gastrointest Endosc. 2010;72(4):739–47.
1071
26. Hirooka Y, Itoh A, Kawashima H, Ohno E, Ishikawa T, Itoh Y,
et al. Clinical oncology for pancreatic and biliary cancers:
advances and current limitations. World J Clin Oncol.
2011;2(5):217–24.
27. Hocke M, Ignee A, Dietrich CF. Contrast-enhanced endoscopic
ultrasound in the diagnosis of autoimmune pancreatitis. Endos-
copy. 2011;43(2):163–5.
28. Kitano M, Kudo M, Sakamoto H, Komaki T. Endoscopic ultra-
sonography and contrast-enhanced endoscopic ultrasonography.
Pancreatology. 2011;11(Suppl 2):28–33.
29. Ohno E, Itoh A, Kawashima H, Ishikawa T, Matsubara H, Itoh Y,
et al. Malignant transformation of branch duct-type intraductal
papillary mucinous neoplasms of the pancreas based on contrast-
enhanced endoscopic ultrasonography morphological changes:
focus on malignant transformation of intraductal papillary
mucinous neoplasm itself. Pancreas. 2012;41(6):855–62.
30. Sakamoto H, Kitano M, Suetomi Y, Maekawa K, Takeyama Y,
Kudo M. Utility of contrast-enhanced endoscopic ultrasonogra-
phy for diagnosis of small pancreatic carcinomas. Ultrasound
Med Biol. 2008;34(4):525–32.
31. Dietrich CF, Ignee A, Frey H. Contrast-enhanced endoscopic
ultrasound with low mechanical index: a new technique. Z Gas-
troenterol. 2005;43(11):1219–23.
32. Kitano M, Sakamoto H, Matsui U, Ito Y, Maekawa K, von
Schrenck T, et al. A novel perfusion imaging technique of the
pancreas: contrast-enhanced harmonic EUS (with video). Gas-
trointest Endosc. 2008;67(1):141–50.
33. Imazu H, Uchiyama Y, Matsunaga K, Ikeda K, Kakutani H,
Sasaki Y, et al. Contrast-enhanced harmonic EUS with novel
ultrasonographic contrast (Sonazoid) in the preoperative T-stag-
ing for pancreaticobiliary malignancies. Scand J Gastroenterol.
2010;45(6):732–8.
34. Napoleon B, Alvarez-Sanchez MV, Gincoul R, Pujol B, Lefort C,
Lepilliez V, et al. Contrast-enhanced harmonic endoscopic
ultrasound in solid lesions of the pancreas: results of a pilot study.
Endoscopy. 2010;42(7):564–70.
35. Sakamoto H, Kitano M, Kamata K, El-Masry M, Kudo M.
Diagnosis of pancreatic tumors by endoscopic ultrasonography.
World J Radiol. 2010;2(4):122–34.
36. Seicean A, Badea R, Stan-Iuga R, Gulei I, Pop T, Pascu O. The
added value of real-time harmonics contrast-enhanced endo-
scopic ultrasonography for the characterisation of pancreatic
diseases in routine practice. J Gastrointestin Liver Dis.
2010;19(1):99–104.
37. Seicean A, Badea R, Stan-Iuga R, Mocan T, Gulei I, Pascu O.
Quantitative contrast-enhanced harmonic endoscopic ultraso-
nography for the discrimination of solid pancreatic masses.
Ultraschall Med. 2010;31(6):571–6.
38. Xia Y, Kitano M, Kudo M, Imai H, Kamata K, Sakamoto H, et al.
Characterization of intra-abdominal lesions of undetermined
origin by contrast-enhanced harmonic EUS (with videos). Gas-
trointest Endosc. 2010;72(3):637–42.
39. Hijioka S, Sawaki A, Mizuno N, Hara K, Mekky MA, El-Amin
H, et al. Contrast-enhanced endoscopic ultrasonography (CE-
EUS) findings in adrenal metastasis from renal cell carcinoma.
J Med Ultrason. 2011;38(2):89–92.
40. Kitano M, Sakamoto H, Komaki T, Kudo M. New techniques and
future perspective of EUS for the differential diagnosis of pan-
creatic malignancies: contrast harmonic imaging. Dig Endosc.
2011;23(Suppl 1):46–50.
41. Matsubara H, Itoh A, Kawashima H, Kasugai T, Ohno E, Ishik-
awa T, et al. Dynamic quantitative evaluation of contrast-
enhanced endoscopic ultrasonography in the diagnosis of pan-
creatic diseases. Pancreas. 2011;40(7):1073–9.
42. Romagnuolo J, Hoffman B, Vela S, Hawes R, Vignesh S.
Accuracy of contrast-enhanced harmonic EUS with a second-
123
1072
generation perflutren lipid microsphere contrast agent (with
video). Gastrointest Endosc. 2011;73(1):52–63.
43. Imazu H, Kanazawa K, Mori N, Ikeda K, Kakutani H, Sumiyama
K, et al. Novel quantitative perfusion analysis with contrast-
enhanced harmonic EUS for differentiation of autoimmune pan-
creatitis from pancreatic carcinoma. Scand J Gastroenterol.
2012;47(7):853–60.
44. Kitano M, Kudo M, Yamao K, Takagi T, Sakamoto H, Komaki T,
et al. Characterization of small solid tumors in the pancreas: the
value of contrast-enhanced harmonic endoscopic ultrasonogra-
phy. Am J Gastroenterol. 2012;107(2):303–10.
45. Kitano M, Sakamoto H, Kudo M. Endoscopic ultrasound: con-
trast enhancement. Gastrointest Endosc Clin N Am. 2012;22(2):
349–58.
46. Giovannini M. Contrast-enhanced endoscopic ultrasound and
elastosonoendoscopy. Best Pract Res Clin Gastroenterol. 2009;
23(5):767–79.
47. Tanaka M, Jang JY, et al. International consensus guidelines
2012 for the management of IPMN and MCN of the pancreas.
Pancreatology. 2012;12(3):183–97.
48. Calliada F, Campani R, Bottinelli O, Bozzini A, Sommaruga MG.
Ultrasound contrast agents: basic principles. Eur J Radiol.
1998;27(Suppl 2):S157–60.
123
J Gastroenterol (2012) 47:1063–1072
49. Saftoiu A, Gheonea DI. Tridimensional (3D) endoscopic ultra-
sound—a pictorial review. J Gastrointestin Liver Dis. 2009;
18(4):501–5.
50. Giovannini M. Contrast-enhanced and 3-dimensional endoscopic
ultrasonography. Gastroenterol Clin North Am. 2010;39(4):
845–58.
51. Hocke M, Dietrich CF. New technology–combined use of 3D
contrast enhanced endoscopic ultrasound techniques. Ultraschall
Med. 2011;32(3):317–8.
52. Hocke M, Ignee A, Dietrich CF. Three-dimensional contrast-
enhanced endoscopic ultrasound for the diagnosis of autoimmune
pancreatitis. Endoscopy. 2011;43:Suppl 2 UCTN:E381-2.
53. Pochon S, Tardy I, Bussat P, Bettinger T, Brochot J, von Wronski
M, et al. BR55: a lipopeptide-based VEGFR2-targeted ultrasound
contrast agent for molecular imaging of angiogenesis. Invest
Radiol. 2010;45(2):89–95.
54. Anderson CR, Hu X, Zhang H, Tlaxca J, Decleves AE, Hough-
taling R, et al. Ultrasound molecular imaging of tumor angio-
genesis with an integrin targeted microbubble contrast agent.
Invest Radiol. 2011;46(4):215–24.