J Gastroenterol (2016) 51:144–152
DOI 10.1007/s00535-015-1094-8
ORIGINAL ARTICLE—LIVER, PANCREAS, AND BILIARY TRACT
Kupffer phase image of Sonazoid-enhanced US is useful
in predicting a hypervascularization of non-hypervascular
hypointense hepatic lesions detected on Gd-EOB-DTPA-enhanced
MRI: a multicenter retrospective study
Tatsuo Inoue1 • Tomoko Hyodo2 • Keiko Korenaga3,4 • Takamichi Murakami2
Yasuharu Imai5 • Atsushi Higaki3 • Takeshi Suda6 • Toru Takano7 •
Kennichi Miyoshi8 • Masahiko Koda8 • Hironori Tanaka9,10 • Hiroko Iijima9 •
Hironori Ochi11 • Masashi Hirooka11 • Kazushi Numata12 • Masatoshi Kudo1
•
Received: 26 August 2014 / Accepted: 6 June 2015 / Published online: 15 September 2015
Ó Springer Japan 2015
Abstract
Background It remains unknown whether Kupffer-phase
images in Sonazoid-enhanced ultrasonography (US) can be
used to predict hypervascularization of borderline lesions.
Therefore, we aimed to clarify whether Kupffer-phase
images in Sonazoid-enhanced ultrasonography can predict
subsequent hypervascularization in hypovascular borderline lesions detected on hepatobiliary-phase gadoliniumethoxybenzyl-diethylenetriamine pentaacetic acid (GdEOB-DTPA)-enhanced magnetic resonance imaging.
Methods From January 2008 to March 2012, 616 lowintensity hypovascular nodules were detected in hepatobiliary-phase images of Gd-EOB-DTPA-enhanced MRI at
nine institutions. Among these, 167 nodules, which were
& Tatsuo Inoue
[email protected]
Masatoshi Kudo
[email protected]
1
Department of Gastroenterology and Hepatology, Kinki
University School of Medicine, 377-2, Ohno-Higashi,
Osaka-Sayama 589-8511, Osaka, Japan
2
Department of Diagnostic Radiology, Kinki University
School of Medicine, 377-2, Ohno-Higashi,
Osaka-Sayama 589-8511, Osaka, Japan
3
Department of Hepatology and Pancreatology, Kawasaki
Medical School, Kurashiki, Japan
4
Department of Gastroenterology and Hepatology, Kohnodai
Hospital, National Center for Global Health and Medicine,
Chiba, Japan
5
Department of Gastroenterology, Ikeda Municipal Hospital,
Osaka, Japan
6
Division of Gastroenterology and Hepatology, Graduate
School of Medical and Dental Sciences, Niigata University,
Niigata, Japan
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confirmed as hypovascular by Gd-EOB-DTPA-enhanced
MRI and Sonazoid-enhanced US, were evaluated in this
study. Potential hypervascularization factors were selected
based on their clinical significance and the results of previous reports. The Kaplan–Meier model and log-rank test
were used for univariate analysis and the Cox regression
model was used for multivariate analysis.
Results The cumulative incidence of hypervascularization of borderline lesions was 18, 37, and 43 % at 1, 2, and
3 years, respectively. Univariate analyses showed that
tumor size (p = 0.0012) and hypoperfusion on Kupfferphase images in Sonazoid-enhanced US (p = 0.004) were
associated with hypervascularization of the tumor. Multivariate analysis showed that tumor size [HR: 1.086, 95 %
7
Division of Radiation Oncology, Graduate School of Medical
and Dental Sciences, Niigata University, Niigata, Japan
8
Division of Medicine and Clinical Science, Department of
Multidisciplinary Internal Medicine, Tottori University,
Tottori, Japan
9
Ultrasound Imaging Center, Hyogo College of Medicine,
Nishinomiya, Japan
10
Division of Hepatobiliary and Pancreatic Disease,
Department of Internal Medicine, Hyogo College of
Medicine, Nishinomiya, Japan
11
Department of Gastroenterology and Metabology, Ehime
University Graduate School of Medicine, Matsuyama, Japan
12
Gastroenterological Center, Yokohama City University
Medical Center, Yokohama, Japan
J Gastroenterol (2016) 51:144–152
confidence interval = 1.027-1.148, p = 0.004] and hypo
perfusion on Kupffer-phase images [HR: 3.684, 95 %
confidence interval = 1.798-7.546, p = 0.0004] were
significantly different.
Conclusions Kupffer-phase images in Sonazoid-enhanced US and tumor diameter can predict hypervascularization of hypointense borderline lesions detected on
hepatobiliary-phase Gd-EOB-DTPA-enhanced MRI.
Keywords Kupffer phase Sonazoid-enhanced
ultrasonography Gadolinium ethoxybenzyldiethylenetriamine-pentaacetic acid-enhanced MRI Hepatocellular carcinoma Hypervascular transformation
Abbreviations
HCC
Hepatocellular carcinoma
US
Ultrasonography
CT
Dynamic computed tomography
MRI
Magnetic resonance imaging
DNs
Dysplastic nodules
Gd-EOBGadolinium
ethoxybenzyl
DTPA
diethylenetriamine pentaacetic acid
T2WI
T2-weigthed images
CTHA
CT during hepatic arteriography
HRs
Hazard ratios
CIs
Confidence intervals
CTAP
CT during arterial portography
Introduction
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is a major cause of death in
patients with cirrhosis.
Recent advances in imaging modalities and periodic follow-up of chronic liver disease, particularly cirrhosis, with
ultrasonography (US), dynamic computed tomography
(CT), magnetic resonance imaging (MRI), or measurement
of tumor markers, have aided in the detection of small, early
stage HCC including early HCC, low-grade dysplastic
nodules (DNs), and high-grade DNs. The majority of these
lesions are hypovascular because these nodules lacking
hypervascularity in the arterial phase on imaging modalities
and are called borderline lesions [1, 2]. A hepatocyte-specific
contrast agent, gadolinium ethoxybenzyl diethylenetriamine
pentaacetic acid (Gd-EOB-DTPA) (PrimovistÒ), has unique
pharmacodynamics: it is taken up by hepatocytes and subsequently excreted into the bile ducts [3]. Several previous
studies showed a significant correlation between the
expression level of organic anion transporting polypeptide
1B3 and enhancement ratio in HCCs in hepatobiliary-phase
images of Gd-EOB-DTPA-enhanced MR [4–7]. Kogita et al.
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reported that reduction in Gd-EOB-DTPA uptake might be
an early event of hepatocarcinogenesis that occurs before
portal blood flow reduction [8]. In fact, the detection of
premalignant/borderline lesions, which are difficult to detect
on the basis of intratumoral hemodynamic changes, has
improved dramatically with the use of Gd-EOB-DTPA-enhanced MRI [9–11]. It is important to identify the borderline
lesions that are at risk of hypervascularization. Previous
studies have revealed that tumor size, tumor growth rate,
presence of fat, and hyperintensity on T1- and T2-weighted
images indicate a high probability of hypervascularization of
borderline lesions [12–20].
Sonazoid is a second-generation sonographic contrast
agent that consists of perfluorobutane gas microbubbles
with phospholipid monolayer shells. In addition to a realtime fine vascular image in the vascular phase [21–24],
Sonazoid is phagocytosed by Kupffer cells in the liver after
administration, which enables persistent and stable
enhancement image, called Kupffer-phase imaging. Kupffer-phase imaging is typically performed 10 min after
Sonazoid injection, at which time the normal hepatic parenchyma is enhanced, and malignant lesions that contain
few or no Kupffer cells are clearly delineated as contrast
defects. A few studies have suggested a relationship
between enhancement patterns of the Kupffer phase in
Sonazoid-enhanced US and histological grading of HCC
[25, 26].
Ohama et al. reported a correlation between the hepatobiliary-phase image of Gd-EOB-DTPA-enhanced MR
and the Kupffer-phase image in Sonazoid-enhanced US
[27]. They concluded that the uptake of Sonazoid begins to
decrease later than that of Gd-EOB-DTPA in stepwise
hepatocarcinogenesis of borderline lesions. Gd-EOBDTPA-enhanced MRI can be used to detect many borderline lesions; however, repeated MRI examinations are not
suitable because of their cost and severe side effects, such
as anaphylactic shock and nephrogenic systemic fibrosis
although the onset of severe side effects rarely occurs if
subjects are carefully selected [28]. In clinical practice, it is
important to evaluate the risk of hypervascularization of
borderline lesions by using cost-effective and safe methods. Therefore, we hypothesized that the Kupffer-phase
image in Sonazoid-enhanced US could be evaluated to
predict hypervascularization of borderline lesions. Thus
far, no study has reported the usefulness of Kupffer-phase
images in Sonazoid-enhanced US for prediction of hypervascularization of borderline lesions. Therefore, the aim of
our study was to evaluate whether the Kupffer-phase image
in Sonazoid-enhanced US can be used to predict subsequent hypervascularization in non-hyper borderline lesions
detected in the hepatobiliary-phase image of Gd-EOBDTPA-enhanced MR.
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J Gastroenterol (2016) 51:144–152
Methods
MR imaging
Patients
All the institutions that participated in the present study
were equipped with high-field-strength (at least 1.5 T) MRI
units. The pulse sequence parameters were set according to
the local experience of the readers. The MR machines were
3.0 T (Achieva, Philips Medical Systems, Best, Netherlands; and MAGNETOM Skyra, Siemens, Erlangen, Germany) or 1.5 T systems (Signa Excite HDxt, GE
Healthcare, Milwaukee, Wisconsin; Gyroscan Intera Nova
and Achieva, Philips Medical Systems; Excelart Vantage
Powered by Atlas, Toshiba Medical Systems, Tochigi,
Japan; and MAGNETOM Symphony and Avanto, Siemens, Erlangen, Germany). Unenhanced, arterial, portal
venous, late phase images were obtained according to the
local standard of care. Hepatobiliary phase images were
obtained more than 20 min after injection of Gd-EOBDTPA at each institution.
The selection of the study population is presented in a flow
chart (Fig. 1). In the present study, Gd-EOB-DTPA MR
was performed for routine examination or evaluation of a
nodule detected by B-mode US. Sonazoid-enhanced US
was performed to reevaluate tumor vascularity in the vascular phase and to evaluate uptake of Sonazoid in the
Kupffer-phase detected as low intense in the hepatobiliaryphase image of Gd-EOB-DTPA-enhanced MR. Between
February 2008 and March 2011, 616 hypovascular nodules
with low intensity in hepatobiliary-phase images of GdEOB-DTPA-enhanced MR were recruited from nine
institutions that participated in the present study. Of these,
we excluded patients with Child-Pugh class C because of
insufficient enhancement on MR imaging [29]; in addition,
214 patients who did not undergo Sonazoid-US were
excluded. Finally, 112 patients with 167 hepatic nodules
that were diagnosed as hypovascular hepatic nodules on
Gd-EOB-DTPA-enhanced MR and Sonazoid-enhanced US
were evaluated in the present study. The baseline characteristics of the patients are shown in Table 1. Our retrospective study design was approved by the institutional
review board of Kinki University Faculty of Medicine. The
requirement to obtain informed consent was waived.
Image analysis
All images were interpreted independently by an experienced board of certified radiologists, sonologists, and
gastroenterologists at each institution who were aware that
the patients were at risk for HCC but had no other clinical
information. Discrepancies between the readers were
resolved by discussion to reach consensus.
Ultrasonography
Different US systems were used at the different institutions
(Table 2). First, a grayscale US scan was obtained for each
lesion. Each focal liver lesion was measured. After baseline
US scan evaluation, the sonologist initiated the contrastspecific mode. Before intravenous injection of the
microbubble contrast agent Sonazoid (Daiichi Sankyo,
Tokyo, Japan), the persistence of the image display on the
US machine was set to zero, the signal gain was registered
below the noise threshold, and one focus was positioned
below the level of the lesion. The contrast-enhanced
examination consisted of the early vascular phase, late
vascular phase, and Kupffer phase (at least 10 min after the
injection of the contrast agent). The real-time images were
stored on a hard disk so that the images could be recalled as
necessary. We identified vascular patterns in the early
vascular phase as isovascular or hypovascular and classified tumor perfusion patterns on Kupffer-phase images as
hyper-perfusion, iso-perfusion, or hypo-perfusion.
Evaluation of tumor vascularity
Fig. 1 Flow chart depicting selection of the study population
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Tumor vascularity was evaluated by Sonazoid-enhanced
US and Gd-EOB-DTPA-enhanced MRI at each institution.
A non-hypervascular nodule was defined as a nodule that
showed non-hypervascularity relative to the surrounding
liver parenchyma during the arterial phase of dynamic
imaging for both the modalities. Arterial enhancement was
assessed by visual inspection. The exclusion criteria for
hypointense lesions observed in hepatobiliary-phase images of Gd-EOB-DTPA-enhanced MR were as follows:
(a) hypervascularity on initial dynamic MRI and/or early
vascular phase of Sonazoid-enhanced US (i.e., exclusion of
J Gastroenterol (2016) 51:144–152
147
Table 1 Baseline characteristics of the patients and imaging findings of the nodules
Parameters
Hypervascularization at follow-up
examinations
Yes (n = 43)
No (n = 124)
p value*
Tumor diameter
12 ± 4.6
10.4 ± 4.06
0.04
Coexistence of hypervascular HCC (yes/no)
25/18
51/73
0.075
Liver disease (chronic hepatitis/liver cirrhosis/unknown)
8/28/7
44/80
0.13
Etiology (HCV/HBV/other/unknown)
19/12/6/6
69/29/16/10
0.52
Child–Pugh score (A/B/C/unknown)
34/3/0/6
97/14/0/13
0.63
Previous history of HCC treatment (yes/no)
Unenhanced T1-weighted images on MRI (low intensity/iso-hyper intensity)b
25/18
29/14
51/73
84/40
0.075
0.56
Fat-containing lesions on in- and opposed-phase images on MRI (yes/no)b
10/33
26/98
0.83
Unenhanced T2-weighted images on MRI (hyper intensity/iso-low intensity)b
9/34
16/108
0.22
Kupffer-phase image of Sonazoid-enhanced US (hypo-perfusion/iso-hyper perfusion)b
15/28
17/107
0.005
0.29
a
Arterial-phase image of dynamic study (hypovascular/isovascular)
b
23/20
53/71
Portal-phase image of dynamic studya (hypovascular/isovascular)b
15/28
52/72
0.47
Serum a-fetoprotein level (AFP) (\12 ng/ml/[12 ng/ml/NA)
17/26/0
65/57/2
0.11
Serum des-c-carboxy prothrombin (DCP) (\21mAU/ml/
16/24/3
60/57/7
0.88
483
434
0.74
[21 mAU/ml/NA)
Observation period
Data are mean ± SD
When CTHA and CTAP were performed, we assessed the respective imaging findings
HCC hepatocellular carcinoma, HCV hepatitis C virus, HBV hepatitis B virus, NA not assessed
* p \ 0.05 indicates statistical significance
a
Dynamic study refers to any of the available modalities (Gd-EOB-DTPA–enhanced MRI, dynamic CT, contrast-enhanced US, CTHA, and
CTAP)
b
Qualitative assessment
Table 2 US equipment and contrast-enhanced modes
No. of lesions
scanned
Amount of
Sonazoida
Scan time of Kupffer
phase (min)
Mechanical
index (MI)
High MI
burstb
0.2 ml/bodyc
10
0.25
0.8
Equipment,
manufacturer
Scanning mode
GE lOGIQ 7
Coded harmonic angio
GE lOGIQ E9
Phase inversion amplitude
modulation
71
0.01 ml/kg
Toshiba Aplio
XG
Pulse subtraction
94
0.01 ml/kg
1
Toshiba Aplio
XV
HITACHI Aloka
Prosound alpha10
0.26
10–30
0.2–0.3
0.7–1.0,
1.52
10
0.24
–
0.5 ml/body
Pure harmonic detection
mode
1
0.01 ml/kg
0.5 ml/body
a
The amount of Sonazoid was set at each institution
b
To eliminate background B-mode findings, the high MI contrast mode was used when the tumor showed hyper echogenicity on B-mode US
c
A total of 0.2 ml Sonazoid was injected
classical HCC and other hypervascular tumors); (b) delayed enhancement on initial dynamic MRI and/or late
vascular phase of Sonazoid-enhanced US (i.e., exclusion of
slow-filling hemangiomas); (c) strong high intensity on T2-
weigthed images (T2WI) (i.e., excluding cysts); and
(d) lesion size of less than 3 mm (because the slice thickness for the hepatobiliary phase of Gd-EOB-DTPA-enhanced MR was 3 mm).
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148
Table 3 Stepwise multiple Cox
regression analysis
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Results of univariate analysis
Parameters
p value*
Age (\70/C70 years)
0.76
Sex (male/female)
0.29
Tumor size (continuous value)
0.0012
Coexistence of hypervascular HCC (yes/no)
0.17
Liver disease (chronic hepatitis/liver cirrhosis/unknown)
0.87
Etiology of liver disease (HCV/HBV/other/unknown)
0.89
Child-Pugh score (A/B/C/unknown)
0.13
Unenhanced T1-weighted images on MRI (low intensity/iso-hyper intensity)
0.57
Previous history of HCC treatment (yes/no)
0.17
Fat-containing lesions on in- and opposed-phase images on MRI (yes/no)
0.93
Unenhanced T2-weighted images on MRI (hyper intensity/iso-low intensity)
Kupffer-phase image of Sonazoid-enhanced US (hypo-perfusion/iso-hyper perfusion)
0.43
0.004
Arterial-phase image in dynamic study (hypovascular/isovascular)
0.91
Portal-phase image in dynamic study (hypovascular/isovascular)
0.07
Serum a-fetoprotein level (AFP) (\12 ng/ml/C20 ng/ml/NA)
0.22
Serum des-c-carboxy prothrombin (DCP) (\ 21 mAU/ml/C 21 mAU/ml/NA)
0.14
Results of multivariate analysis
Parameters
Ex (B)
95 % CI
p value*
Tumor diameter (mm)
1.086
1.027-1.148
0.004
Kupffer phase (hypo-perfusion)
3.684
1.798-7.546
0.0004
Coexistence of hypervascular HCC
1.465
0.7634-2.811
0.25
History of local therapy for HCC
Image of fat-suppressed MR T2-weighted images
1.501
1.501
0.7993-2.820
0.6332-2.361
0.21
0.55
Fat-containing lesions on in- and opposed-phase images
1.508
0.6895-3.298
0.30
* p \ 0.05 indicates statistical significance
Definition of hypervascular transformation
During the follow-up period, when a CT hepatic arteriography (CTHA) image, Sonazoid-enhanced US, dynamic
CT, and MR in the early phase indicated a region of hyperattenuation relative to the area surrounding the nodule, it
was described as hypervascularization. Hypervascularization was confirmed by more than one modality, and the
earliest date of the imaging examinations was used as the
reference point.
Statistical analysis
All analyses were conducted at the nodule level. R software (Version 2.12.0; R Foundation for Statistical Computing, Vienna, Austria) was used for statistical analysis.
To evaluate the independent prognostic significance of
baseline covariates for subsequent hypervascularization, a
multivariate Cox proportional hazard model was used.
Because 26 patients had multiple nodules detected at two
or more follow-up examinations, we used the coxph
123
function from the survival package in the R software, with
the cluster option. This method accounted for correlation
induced by having multiple nodules per patient and used
robust variance estimates [30]. Before model selection,
bivariate analysis was performed by using Spearman rank
correlations to test for collinearity among independent
variables. As a result, Spearman correlation coefficients for
variables were generally below 0.5, which suggests that
multicollinearity was not a concern. Hazard ratios (HRs)
and 95 % confidence intervals (CIs) were calculated.
Continuous variables were presented as the median and
range. Continuous variables such as tumor size and
observation period were compared with Mann–Whitney
U test, and other categorical variables were compared by
Fisher’s exact test or the Chi-squared test. Based on the
analysis of lesions, the cumulative risk of a non-hypervascular tumor transforming into classical HCC was calculated according to the Kaplan–Meier method. We
calculated the relative risk using Cox proportional hazard
regression analysis. Actuarial analysis of the cumulative
incidence of vascularization was performed with the
Kaplan–Meier method, and the differences were tested by
J Gastroenterol (2016) 51:144–152
Fig. 2 Cumulative rates for hypervascularization of hypointense
lesions. The overall cumulative incidence of hypervascular transformation was 18 % at 12 months, 37 % at 24 months, and 43 % at
18 months. Forty-three (25.7 %) out of the 167 cases showed
hypervascular transformation in the arterial phase of dynamic
imaging during the follow-up period
the log-rank test. A p value \0.05 was considered to
denote a statistically significant difference.
Results
Nodule characteristics
Table 1 shows the characteristics of the nodules that were
vascularized and of those that were not. Of the 167 nodules, 43 (25.7 %) showed hypervascular transformation in
the arterial phase of dynamic imaging during the follow-up
period. Fisher’s exact test showed that at the start of follow-up, nodules with and without vascularization showed
significant differences with respect to the average tumor
diameter (p = 0.04) and Kupffer-phase images in Sonazoid-enhanced US (p = 0.005).
Cumulative incidence of hypervascular
transformation
The overall cumulative incidence of hypervascular transformation was 18 % at 12 months, 37 % at 24 months, and
43 % at 18 months (Fig. 2).
Univariate analysis using the log-rank test revealed that
hypoperfusion on Kupffer-phase images of contrast-enhanced US using Sonazoid and tumor diameter were correlated with hypervascular transformation (Table 3). Next,
the two significant factors identified by univariate analysis
and another four variables, including coexistence of
hypervascular HCC, history of local therapy for HCC, fat-
149
suppressed T2-weighted images, and fat-containing lesions
on in- and opposed-phase images, were further analyzed by
multivariate analysis using the Cox regression model
because these 4 variables have been described as important
predictors
[14].
Consequently,
tumor
diameter
(HR = 1.086; p = 0.004, 95 % CI: 1.027, 1.148) and
hypo-perfusion on Kupffer-phase images in Sonazoid-enhanced US (HR = 3.684; p = 0.0004, 95 % CI: 1.798,
7.546) were identified as independent factors for hypervascular transformation (Table 3). Subsequently, we compared the incidence of hypervascular transformation of
tumors with these risk factors based on the Kaplan–Meier
curve. The incidence of hypervascularization was significantly higher in the groups with these prognostic factors
(Figs. 3, 4). The optimum cut-off point for tumor size was
estimated to be 8.6 mm by receiver operating characteristic
(ROC) curves (figure not shown).
Discussion
To the best of our knowledge, this study is the first to show
the usefulness of Kupffer-phase images in Sonazoid-enhanced US for predicting hypervascularization of non-hypervascular borderline lesions detected in hepatobiliaryphase images of Gd-EOB-DTPA-enhanced MR.
Previously, Kupffer cells were thought to be absent in
overt HCC tissues, but recently investigators have shown
that Kupffer cells exist in early stage HCCs [31]. Furthermore, the histologic grade of HCC has been shown to
correlate with the number of Kupffer cells present. Kupffer
cells, the resident liver macrophages, constitute 31 % of
the sinusoidal cells [32]. They are more numerous (43 %)
in the periportal zone of the lobule. In addition to being
more numerous, periportal Kupffer cells are larger, have
more lysosomes, and take up more particles than do middle- or central-zone Kupffer cells [33]. Sugihara et al. [34]
reported that cancerous tissue of well-differentiated HCCs
possesses blood spaces that are similar to the normal
sinusoids. Therefore, blood spaces are expected to possess
morphologic and functional characteristics similar to those
of normal sinusoids but that as tumors grew in size and
came to have a lower histologic grade, the blood spaces
increased in apparent capillarization and became morphologically different from normal sinusoids. When neovascularization suggested by unpaired artery [35] occurred,
normal sinusoids were gradually destroyed and the portal
supply declined. Therefore, we speculate that Kupffer cells
lose their functional ability to take up microbubbles.
Although all most all premalignant/borderline lesions
possess portal areas and blood spaces similar to those of
normal sinusoids may take up microbubbles in a manner
similar to non-nodular adjacent tissue, some of the
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J Gastroenterol (2016) 51:144–152
Fig. 3 Cumulative rates for hypervascularization of hypointense
lesions. Lesions are stratified according to the tumor size and Kupfferphase image in Sonazoid-enhanced US. The incidence of
hypervascularization was significantly higher when the tumor diameter was greater than 8.6 mm
Fig. 4 Case presentation of borderline lesions (arrowheads indicate
the tumor). a, b Tumors showing isovascularity on CTHA (a) and
CTAP(b). Initial Gd-EOB-DTPA–enhanced MRI (c–f). Tumors
showing: Isointensity on in-phase (c) and opposed-phase images (d).
e Isointensity on T2-weighted image. f Low intensity in hepatobiliaryphase image of Gd-EOB-DTPA-enhanced. MRI Initial Sonazoid-
enhanced US (g–i). g, k Monitor mode, h, i, l contrast mode. Tumors
showing: g, h Hypovascularity in early vascular phase. i Hypoperfusion in Kupffer-phase. j Hypervascular spot in nodule in arterial-phase
of Gd-EOB-DTPA-enhanced MRI at 30 months after start of followup. k, l hypervascular spot in nodule in early vascular phase in
Sonazoid-enhanced US
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J Gastroenterol (2016) 51:144–152
premalignant/borderline lesions might have lost their
ability to possess microbubbles resulting in the tumorous
perfusion defects observed in Kupffer phase imaging
before hypervascularization detected by other imaging
modalities. In the present study, 135 out of 167 nodules
showed iso-perfusion on the Kupffer-phase image.
Although the improved detection ability of Gd-EOBDTPA-enhanced MRI enabled us to detect many premalignant/borderline lesions, which are difficult to detect on
the basis of intratumoral hemodynamic changes, the new
challengeisindecidingwhichlesionsshouldbemonitoredmore
carefully.However,byusingSonazoid-enhancedUS,Kupffer
cellfunctioncanbeevaluatedfortumorsthatcannotbeevaluated
by other imaging modalities. Therefore, we evaluated the
Kupffercellfunctionofthesepremalignant/borderlinelesions
using Sonazoid, and we found that it can be a useful tool for
predicting hypervascularization. Sonazoid-enhanced US is
easytoperform,anditismorecost-effectivethanMRIanddoes
not involve exposure to ionizing radiation, unlike contrast-enhancedCT,CTHA,andCTduringarterialportography(CTAP).
In general, when non-hypervascular hypointense lesions are
detected byGd-EOB-DTPA-enhancedMRI, we strongly suggest that Sonazoid-enhanced US should be performed to evaluateKupffercellfunctionandpredicthypervascularization.
Although we conducted a cooperative study, collecting
several non-hypervascular tumors and investigating the
natural outcome of hypointense lesions in a nationwide
manner, this study did have some limitations. The principal
limitation of this study was the variation in the equipment
used at different institutions. Although this limitation may
have been inevitable because of the multicenter nature of
the study, the different sensitivities of the different equipment used should be considered in future investigations.
Second, this was a retrospective study, which may have
introduced bias in data homogeneity. Moreover, the interval between the follow-up examinations varied for each
individual and among the patients. Prospective studies with
consistent follow-up intervals must be performed to overcome this limitation. In this study, most of the follow-up
studies were performed at intervals of 3 and 6 months,
which is consistent with the usual practice for follow-up of
patients at high risk of HCC [36, 37]. Third, on imaging
analysis, our study was potentially limited by consensus
review. To minimize operator bias, well-trained radiologists and physicians reviewed the images. However, in the
future, assessment of interobserver variability is warranted.
Fourth, the ability of Sonazoid-enhanced US to detect
hypervascularization in a nodule varies considerably
according to depth from the surface of the liver, coarseness
of liver parenchyma, and patient’s obesity. It would be
appropriate to use Gd-EOB-DTPA-enhanced MR only for
the evaluation. Finally, no pathologic proof existed for the
nodules evaluated in the present study. However, the major
151
purpose of the present study was to evaluate whether the
Kupffer-phase image in Sonazoid-enhanced US can predict
hypervascular transformation in borderline lesions; we did
not aim to distinguish among dysplastic nodules, early
HCCs, and well-differentiated HCCs. In conclusion, this
study shows that the Kupffer-phase image in Sonazoidenhanced US is useful for the prediction of hypervascularization of non-hypervascular hypointense hepatic lesions
detected on Gd-EOB-DTPA-enhanced MRI.
Conflict of interest
of interest.
The authors declare that they have no conflict
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