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J.-Y. Cao et al.
essential to keep the same dose of contrast agent injected each
time, and the same preset conditions of the ultrasound machine.
Ultrasound contrast media, was injected intravenously as a
2.0–2.4 ml bolus followed by 5 ml of normal sterile saline
ush. A low mechanical index (MI), ranging from 0.10 to
0.14, was used for real-time imaging. After carefully determining the position and direction of the probe contacted after
2D-CEUS, 3D-CEUS should be performed in the same session with an interval time of at least 10min.
14.4 3D-CEUS Procedures
The patients can be examined lying on the left ank or in the
supine position, and the liver should be rstly scanned completely by conventional B mode ultrasound. Conventional
2D-CEUS is also essential before 3D-CEUS examinations. In
dynamic 3D-CEUS examination, patients should be guided to
keep regular shallow breathing as far as possible to reduce
interference of great breathing movement. The probe remains
stable on the surface of the scanning area to store ongoing clip
in DICOM format after injection of contrast agent. During
3D-CEUS acquisition, three orthogonal planes of 2D-CEUS
and one 3D-CEUS volume image can be observed simultaneously in four quadrants of the same view window and 3D
stereo images are displayed in the last quadrant at the same
time, as shown in Fig.14.1. The “multi- slice” mode can also
help us to observe the internal enhancement of the FLL from
various directions on several equidistant slices to acquire
more details, as shown in Fig.14.2.
The recent research hot spot of 3D-CEUS has gradually
been shifted from the spatial stereo-anatomy of tumor to the
combined application of quantication technology, which is
expected to evaluate the local treatment response of malig-
nant tumors. The previously used 3D-CEUS storage capacity
can only capture dynamic raw data of about only 20–30s at
a time, so it may miss other enhanced information beyond
the capture period. At present, the limitation of storage time
has been overcome of some ultrasound unit by upgrading
3D-CEUS system, and the ability of continuous unlimited
storage that allows the quantitative analysis possible has further potentiated dynamic 3D-CEUS.
The post-processing includes rotation of any frame and
adjustment of contrast degree to highlight 3D reconstruction
effect of the FLL slice by slice, when the dynamic 3D-CEUS
raw data is activated. During the quantication, region of interest (ROI) should be selected to envelop the whole FLL at the
clearest displaying frame, which was suggested in the arterial
Fig. 14.2 An example of three-dimensional contrast enhanced ultrasound (3D-CEUS) “multislice” mode image. A hepatocellular carcinoma (HCC) lesion after several transarterial chemoembolization
(TACE) procedures was shown on eight equidistant two-dimensional
(2D) slices extracted from 3D-CEUS data. Several hyperechoic artifacts and an enhanced residual nodule within the tumor
Fig. 14.1 An example of three-dimensional contrast enhanced ultrasound (3D-CEUS) examination image of hepatocellular carcinoma
(HCC) patient treated by radiofrequency ablation (RFA). Three orthogonal planes of two-dimensional contrast enhanced ultrasound
(2D-CEUS) and a 3D-CEUS volume image can be observed simultaneously in four quadrants of the same view window during 3D-CEUS
acquisition (a). The residual tumor was visible clearly. Gross specimen
after surgical section conrmed the residual tumor (b)
14 Dynamic Three-Dimensional Contrast Enhanced Ultrasound withQuantication ofFocal Liver Lesions
263
phase of the contrast process. In order to improve the tting
degree of TIC and reect the contrast process as accurately as
possible, ROI can be selected in arterial phase, and the position
of ROI can be adjusted appropriately in late phase other than in
portal phase. Dynamic 3D-CEUS showed FLLs most obviously in arterial phase, followed by late phase, and the worst in
portal phase [2]. The average value of TIC parameters, which is
obtained from current-used CEUS quantitative analysis technology, whether 2D or 3D, may mask the heterogeneity of the
tumor. In the process of TIC generation, the size and shape of
ROI could be adjusted to make the tting curve as close as possible to the original curve. Seven TIC parameters can be
extracted from the smooth tting curve: (1) peak intensity (PI)
represents the highest intensity value obtained by TIC with
dened ROI; (2) slope (S) is literally dened as the slope of the
tangent of the wash-in at half maximum; (3) area under the
curve (AUC) corresponding to area under the TIC; (4)AUC of
wash-in (AWI) represents the wash-in part of the AUC; (5)
AUC of wash-out (AWO) represents the wash-out part of the
AUC; (6) time to peak intensity (TP), which is the time required
for the contrast media from arriving in ROI to reaching PI; and
(7) mean transit time (MTT) is the time interval during which
the intensity value was higher than PI/2. Quality of tting
(QOF) is required to evaluate the tting degree of the original
curve and the tting curve. The TIC parameters would be
invalid if the value of QOF was no more than 0.75.
The relative displacements caused by breathing can be corrected and compensated by the built-in motion tracking system
and manually adjusting the axial and sagittal planes of FLLs.
14.5 Clinical Application
Dynamic 3D-CEUS is an effective method to visualize the
characteristic vascular structure of FLLs. On 3D-CEUS, different kinds of FLLs show different enhancement. Early
homogeneous or heterogeneous tumor enhancement patterns
had an acceptable sensitivity and specicity for diagnosing
FLLs. Compared with 3D CECT, 3D-CEUS was shown to
have similar sensitivity and specicity in characterizing various FLLs. Similar to 2D-CEUS, most HCC lesions are
enhanced in an early diffuse enhancement pattern, while
most metastatic lesions are enhanced in various patterns,
including heterogeneous hypo-enhancement, ring-like
enhancement, and non-enhancement [4]. The most common
focal benign lesions, including hemangiomas and focal nodular hyperplasia (FNH), are enhanced in peripheral nodular
enhancement and spoke-wheel hyperenhancement, respectively (Fig.14.3). Dynamic 3D-CEUS exhibits a higher spatial resolution of the continuous perfusion of the feeding
vessels and their origin, continuity, and distribution
(Fig.14.4).
Dynamic 3D-CEUS could reect the spatial relationship
of liver tumor and its vessels. It could also highlight the spatial stereo structure of the tumor. It is worth mentioning that
dynamic 3D-CEUS has been explored more in treatment
response monitoring than in the differential diagnosis of
FLL.It can be used to evaluate whether the nutrient artery
has been blocked after minimally invasive treatment. Several
studies have applied 3D-CEUS to evaluate TACE and RFA
response of HCC. 3D-CEUS was reported to show a highly
consistent assessment of ablation efcacy for HCC compared with contrast CT.PI of TIC from 3D-CEUS has shown
potential to evaluate HCC TACE response as early as 1–2
weeks post treatment [6]. Recently, preclinical studies have
already demonstrated that dynamic 3D-CEUS allows a reliable assessment of early treatment efcacy and prediction of
response after anti-angiogenic and targeted therapy by using
immunohistochemistry result of pathology as a reference [7]
(Fig.14.5).
In addition, dynamic 3D-CEUS can be used to measure
the necrotic portion and compare the necrosis rate in the treat-
a
Fig. 14.3 A case of focal nodular hyperplasia (FNH). It showed spoke-wheel arteries (a) and hyperenhancement (a, b) in the arterial phase on
three-dimensional contrast enhanced ultrasound (3D-CEUS) image
b
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J.-Y. Cao et al.
a
Fig. 14.4 A hepatocellular carcinoma (HCC) lesion can be detected
clearly in arterial phase (22s after injection of contrast agent) on twodimensional contrast enhanced ultrasound (2D-CEUS) (a). On three-
a
b
dimensional contrast enhanced ultrasound (3D-CEUS), the feeding
arteries can be further displayed (b)
b
c
Fig. 14.5 A hyperechoic hepatocellular carcinoma (HCC) lesion (a)
was enhanced in a heterogeneous hyper-enhancement pattern before (b,
c) and 1d post-transarterial chemoembolization (TACE) on threedimensional contrast enhanced ultrasound (3D-CEUS) images (e, f). It
d
showed heterogeneous hyper-intensity on contrast MRI (d). PI of TIC
from 3D-CEUS obviously decreased from 1.6 (c) to 0.3 (f) after TACE
treatment
14 Dynamic Three-Dimensional Contrast Enhanced Ultrasound withQuantication ofFocal Liver Lesions
265
e
Fig. 14.5 (continued)
a
f
b
c
Fig. 14.6 There is a small necrotic area in hepatocellular carcinoma
(HCC) lesion (a). The feeding artery is exhibited more clearly on threedimensional contrast enhanced ultrasound (3D-CEUS) than its twodimensional contrast enhanced ultrasound (2D-CEUS) (b). On
ment of liver tumors [6]. Figure14.6 shows an example of
calculating tumor volume and non-enhanced portion
volume.
However, dynamic 3D-CEUS has technical limitations
imposed by the difculty involved in the relatively slow
d
3D-CEUS, tumor size was calculated as 20.68ml (c), whereas the nonenhanced portion size was 0.37ml (d). Therefore, the necrotic ratio is
1.79%
frame rate, it is difcult to capture every detail of the contrast process of liver tumors. In addition, scan-blind areas
(e.g., located close to the diaphragm) still exist, though a
larger scanning range can be obtained via 3D-CEUS than
2D-CEUS [8].
266
J.-Y. Cao et al.
3D-CEUS not only has the unique display advantage in
comparison of local treatment response, but also can guide
and improve the specic implementation of needle layout
scheme before multipolar radiofrequency ablation (RFA) of
large liver tumors.
References
1. Ferraioli G, Meloni MF.Contrast-enhanced ultrasonography of the
liver using SonoVue. Ultrasonography. 2018;37:25–35.
2. Cao J, Dong Y, Fan P, Mao F, Wang W.Feasibility of dynamic three-
dimensional contrast-enhanced ultrasound in focal liver lesions:
image quality evaluation and correlation of quantication with
two-dimensional contrast-enhanced ultrasound. Clin Hemorheol
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3. Song Y, Cheng J, Zhang R.Contribution of 3-dimensional contrast-
enhanced ultrasonography (CEUS) compared with 2- dimensional
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4. Cao J, Dong Y, Mao F, Wang W. Dynamic three-dimensional
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5. Beyer LP, Wassermann F, Pregler B, Michalik K, Rennert J,
Wiesinger I, Stroszczynski C, et al. Characterization of focal
liver lesions using CEUS and MRI with liver-specic contrast
media: experience of a single radiologic center. Ultraschall Med.
2017;38:619–25.
6. Nam K, Stanczak M, Lyshchik A, Machado P, Kono Y, Forsberg F,
Shaw CM, etal. Evaluation of hepatocellular carcinoma transarterial chemoembolization using quantitative analysis of 2D and 3D
real-time contrast enhanced ultrasound. Biomed Phys Eng Express.
2018;4:035039.
7. Wang Z, Wang W, Liu GJ, Yang Z, Chen LD, Huang Y, Li W,
etal. The role of quantitation of real-time 3-dimensional contrastenhanced ultrasound in detecting microvascular invasion: an invivo
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8. Lee JC, Yan K, Lee SK, Yang W, Chen MH.Focal liver lesions:
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Future Prospects
Wen-PingWang, Bei-JianHuang, andYiDong
15
15.1 Early Diagnosis ofSmall
Hepatocellular Carcinoma
Substantial progress have been achieved in the treatment of
hepatocellular carcinoma (HCC), early and accurate diagnosis through surveillance of patients at high risk is of vital
importance for successful treatment. Since HCC has a high
incidence of recurrence following surgery therapy, secondary surveillance after treatment is regarded as an important
part of disease management. On contrast enhanced ultrasound, secondary surveillance includes assessment of the
entire liver for evaluation of new nodules. The presence of
hyperenhancement during arterial phase is highly suspicious
characteristic of recurrence on CEUS.Meanwhile, the presence of wash-out is not always necessary to make diagnose
HCC residual or recurrence.
Early detection of HCC is important since multiple treatment options are available for small HCC including curative
surgical resection, liver transplantation, or tumor ablation.
Advances in liver imaging techniques have facilitated the
detection of small malignant liver lesions at an early stage,
including borderline hepatic nodules in hepatocarcinogenesis [1, 2].
Since the hyperenhancement during arterial phase of
CEUS is the hallmark of malignancy and essential to diagnosis conrmation [3]. Currently, the reported overall diagnostic accuracy of CEUS in FLLs≤ 10mm (n = 62) was 80.6%,
with 92.7% positive predictive value and 85.7% negative
predictive value was [4]. Sonazoid-enhanced CEUS was
reported to precisely evaluate not only tumor enhancement,
but also the tumor vessel patterns [5]. The tumor vessel patterns observed during arterial phase of CEUS may be useful
for differentiating regenerative nodulars (RN) from high-
W.-P. Wang (*) · B.-J. Huang · Y. Dong
Department of Ultrasound, Zhongshan Hospital, Fudan University,
Shanghai, China
e-mail: huang.beijian@zs-hospital.sh.cn;
dong.yi@zs-hospital.sh.cn
grade degenerative nodulars (HGDN) and early HCC in
patients with chronic liver hepatitis or cirrhosis. On
Sonazoid-enhanced CEUS, most of the early HCC and
HGDN lesions showed a peripheral vessel pattern during
arterial phase [5].
15.2 Improved Liver Metastasis Detection (Sonazoid)
CEUS is accurate in characterization of hepatocellular nodules, but is limited in the detection of small hepatocellular
nodule, especially if nodules cannot be detected with conventional ultrasound. In clinical practice, sweeps through the
whole liver are performed during late phase to nd additional
conspicuous wash-out areas. Since prolonged continuous
scanning might cause destruction of microbubbles, the
sweeps of the whole liver should be performed quickly.
Sonazoid is peruorobutane microbubbles in a phospholipid shell. Its microbubbles are phagocytosed intact by
Kupffer cells and retained within the reticuloendothelial
system. CEUS performed with Sonazoid allows liver-specic Kupffer phase imaging for at least 60min. Thus, any
malignant liver tissue with markedly fewer or absent Kupffer
cells shows a signal defect on CEUS images during Kupffer
phase [6].
15.3 Machine Learning Algorithm
andRadiomics Approach
inPredicting Microvascular Invasion
or Tumor Recurrence
Although there have been great advances in therapeutic
modalities of HCCs, the 5-year survival rates and 5-year
recurrence rate have been reported to be 30–50% and
70–85%, respectively. The prognosis of poorly differentiated
HCC is especially unfavorable. Since disease recurrence
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021
W.-P. Wang et al. (eds.), Contrast-Enhanced Ultrasound Imaging of Hepatic Neoplasms,
https://doi.org/10.1007/978-981-16-1761-4_15
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W.-P. Wang et al.
following curative-intent ablations occurs in approximately
50% of patients within 2 years and in 70% of patients within
5 years [7]. It is of vital importance to make appropriate clinical management. The earlier the recurrence is detected, the
better the disease control might be.
The early and accurate prediction of local tumor responses
to the rst TACE session has a critical clinical impact on the
overall management of HCCs. An emerging computerassisted technology, radiomics based on ultrasound images
can provide comprehensive quantications of large amounts
of high output image features, which has the potential to
reveal disease characteristics that be impossible to be appreciated by human eyes. One initial study proved that deep
learning based radiomics model combining CEUS examination holds good potential for beneting TACE candidates in
the clinical practice [8].
Radiomics algorithm based on multi-modal ultrasound
images could be helpful in diagnosis, differential diagnosis,
and prediction of clinical prognosis of liver tumors [9].
Radiomics analysis based on ultrasound original radio frequency (ORF) signals data combined with signal analysis
and processing technology can effectively predict microvascular invasion (MVI) in HCC patients [10]. Radiomic algorithm based on grayscale ultrasound images has potential
clinical application value for non-invasively preoperative
prediction of MVI in HCC patients. The gross-tumoral
region radiomic signature was proved to be useful in further
discriminating between M1 and M2 levels among MVIpositive patients [11].
15.4 Next Generation Contrast Imaging
Technologies
Compared to current clinical practice, recent advancements
in ultrasound system and transducer provide improved spatial and temporal imaging resolution. With improved spatial
resolution and temporal resolution, new CEUS technologies
enables microvascular imaging and ow visualization, which
will be put into reality in the next decades.
Superharmonic imaging is a brand new contrast-enhanced
technique with improved resolution. It takes unique advantage of excitation of microbubbles at low frequencies, and
detection of the broadband harmonics at high frequencies.
The superharmonic imaging can be performed with very
high bandwidth ultrasound transducers [12]. When performed with 3D CEUS, the real-time microvascular imaging
is referred to as acoustic angiography. It can enable visualization of dynamic microvascular perfusion with high temporal resolution in the liver, enabling visualization of
suspected microvascular invasion.
Superresolution contrast-enhanced ultrasound, also be
called ultrasound localization microscopy, is an extension of high frame rate plane wave imaging. This technology exploits the stochastic blinking of specific
fluorescent sources and localizes the center of each separable source [13].
When be performed with ultrasound, the position of each
moving bubble is approximated by estimation of the center
of the signal it returns. As a result, a reconstructed microbubble ow image could be depicted with extremely high
resolution [14]. Currently the super-resolution contrast
enhanced ultrasound still requires huge and signicant postprocessing to acquire the 3D volume.
15.5 Emerging Application ofCEUS
fortheInterventional Procedure
CEUS during interventional procedure guidance can not
only depict lesions, but also provide post-procedure assessment of treatment response. Depending on the unique physical properties of ultrasound microbubble contrast agents, it is
possible to amend them as therapeutic vehicles for future
therapeutic innovations, such as drug delivery, vascular ow
augmentation, and thrombolysis.
In previous studies, intra-arterial CEUS with direct
administration of microbubble contrast agents during transarterial liver tumor interventions to assess tumor vascular
supply. By identifying additional tumor feeding vessels or
resulting in a change in catheter position, intra-arterial CEUS
changed the treatment plan in most patients. Intraarterial
CEUS could increase the accuracy of TACE by clearly delineating the vascular supply. Intra-arterial CEUS could also
potentially decrease the amount of iodinated contrast material required during TACE procedure, especially for patients
with renal impairment.
Therapeutic uses of CEUS microbubble agents have
potential applications in tumor-targeted therapy and mechanochemical thrombolysis.
There are several possible mechanisms for microbubbles
to circumvent drug delivery barriers to tumors: (a) permeability change of transient cell membrane; (b) therapeutic extravasation increased by microvessel poration (enlarging
endothelial gap junctions); (c) diffusive transport of the therapeutic agent through the interstitium caused by interstitial
pressure modulation; and (d) cellular uptake caused by sonoporation of the target cell membrane. Until now, several phase
I studies have explored the use of microbubbles for drug
delivery to tumors. Recent research hotpots focus on exploring the use of microbubbles to enhance tumor oxygenation,
increasing radiation sensitivity and tumoricidal efcacy [15].
15 Future Prospects
269
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