Improvement of ablative margins by the intraoperative use of CEUS-CT/MR image fusion in hepatocellular carcinoma
Li et al. BMC Cancer
Improvement of ablative margins by the intraoperative use of CEUS-CT/MR image fusion in hepatocellular carcinoma
Kai Li 0
Zhong-Zhen Su 0
Er-Jiao Xu 0
Jin-Xiu Ju 0
Xiao-Chun Meng 1
Rong-Qin Zheng 0
0 Department of Medical Ultrasonics, Third Affiliated Hospital of Sun Yat-Sen University , 600 Tianhe Road, Guangzhou 510630, Guangdong Province , PR China
1 Department of Radiology, Third Affiliated Hospital of Sun Yat-Sen University , 600 Tianhe Road, Guangzhou 510630, Guangdong Province , PR China
Background: To assess whether intraoperative use of contrast-enhanced ultrasound (CEUS)-CT/MR image fusion can accurately evaluate ablative margin (AM) and guide supplementary ablation to improve AM after hepatocellular carcinoma (HCC) ablation. Methods: Ninety-eight patients with 126 HCCs designated to undergo thermal ablation treatment were enrolled in this prospective study. CEUS-CT/MR image fusion was performed intraoperatively to evaluate whether 5-mm AM was covered by the ablative area. If possible, supplementary ablation was applied at the site of inadequate AM. The CEUS image quality, the time used for CEUS-CT/MR image fusion and the success rate of image fusion were recorded. Local tumor progression (LTP) was observed during follow-up. Clinical factors including AM were examined to identify risk factors for LTP. Results: The success rate of image fusion was 96.2 % (126/131), and the duration required for image fusion was 4.9 ± 2.0 (3-13) min. The CEUS image quality was good in 36.1 % (53/147) and medium in 63.9 % (94/147) of the cases. By supplementary ablation, 21.8 % (12/55) of lesions with inadequate AMs became adequate AMs. During follow-up, there were 5 LTPs in lesions with inadequate AMs and 1 LTP in lesions with adequate AMs. Multivariate analysis showed that AM was the only independent risk factor for LTP (hazard ratio, 9.167; 95 % confidence interval, 1.070-78.571; p = 0.043). Conclusion: CEUS-CT/MR image fusion is feasible for intraoperative use and can serve as an accurate method to evaluate AMs and guide supplementary ablation to lower inadequate AMs.
Hepatocellular carcinoma; Ablative margin; Image fusion; Intraoperative; Contrast-enhanced ultrasound
Percutaneous ablation is one of the most frequently
used methods for hepatocellular carcinomas (HCCs)
that are not suitable for resection or liver
transplantation. Compared with resection, percutaneous
radiofrequency ablation (RFA) has a higher rate of local tumor
progression (LTP) [
], and the LTP rate contributes
to long-term survival [
]. The ablative margin (AM) is
an independent factor affecting LTP [
]. Several studies
have reported different methods to evaluate AM,
including MR with impaired clearance of ferucarbotran [
MR with gadolinium ethoxybenzyl diethylene triamine
pentaacetic acid [
], CT-CT image fusion [
MRMR image fusion  and ultrasound-CT/MR image
]. In these studies, none of the methods were
applied intraoperatively. Theoretically, if the AM could be
assessed intraoperatively, supplementary ablation could be
performed to increase the number of adequate AMs and
reduce the probability of LTP.
Ultrasound has the advantages of real-time guidance,
accessibility and non-invasiveness, and contrast-enhanced
ultrasound (CEUS) has greatly improved the accuracy of
ultrasound in liver tumor diagnosis and the evaluation of
local ablation treatment [
]. Compared with CT/MR and
the new imaging methods mentioned above, CEUS is
more suitable for intraoperative usage. However, the
sensitivity of CEUS within 1 h after ablation has been variable
in many different studies [
] and can be as low as
25 % [
] due to interference by peripheral hyperemia or
gas in the ablative area. Furthermore, AMs can not be
accurately evaluated by routine CEUS.
Ultrasound-CT/MR image fusion combines the
advantages of ultrasound and CT/MR and expands the use of
both imaging methods, including the localization,
identification and ablation of lesions that are not visible with
B-mode ultrasound in the liver [
] as well as
prostate gland . The AM can be accurately evaluated by
a precise comparison of the size and location of the
tumor with the ablative area using CEUS and CT/MR
image fusion one month after ablation [
whether CEUS-CT/MR image fusion can be applied
intraoperatively to evaluate AM has not been reported.
We hypothesized that if we combined the CEUS of the
ablative area with the CT/MR image of the HCC before
ablation, the AM could be evaluated intraoperatively. If
the location of the inadequate AM could be identified,
supplementary ablation could be performed. The aim of
this study was to assess whether CEUS-CT/MR image
fusion could be applied intraoperatively to evaluate the
AM and guide supplementary ablation to facilitate the
achievement of adequate AMs and, accordingly, reduce
the rate of LTP.
This prospective study was approved by The Institute
Research Medical Ethics Committee of the Third Affiliated
Hospital of Sun Yat-Sen University. All human studies
were performed in accordance with the ethical standards
established by the 1964 Declaration of Helsinki and its
subsequent amendments. Informed consent was obtained
from all patients prior to their inclusion in the study.
Patients and lesions
The patients in this study were part of the
ultrasoundCT/MR image fusion research program and were
continuously enrolled every other week. From September
2009 to June 2012, all patients were enrolled who were
diagnosed with HCC and scheduled to receive
percutaneous ablation treatment in our department. All lesions
were diagnosed based on the clinical criteria from the
American Association for the Study of Liver Diseases [
Patients were excluded from the study if they met the
following criteria: 1) patient was scheduled to receive
other surgeries along with RFA that might affect
ultrasound-CT/MR image fusion, such as liver resection,
laparoscopic cholecystectomy or splenectomy; 2)
ultrasound and CT/MR images could not be successfully fused;
3) patient was allergic to the ultrasound contrast agent; or
4) patient did not receive a CT/MR examination 1–2
months after ablation.
The Cool-Tip Radiofrequency System (Covidien, Mansfield,
MA, USA) and single electrode with 3 cm long exposed tip
were used. The ablation was performed under endotracheal
anesthesia. Patients with lesions larger than 3 cm in
diameter and/or with multiple lesions would receive
transcatheter arterial chemoembolization (TACE) 1–2 weeks before
RFA. All lesions were ablated according to a previously
determined plan, and effort was made to ablate the whole
tumor as well as the 5-mm AM. If the lesion was located
within 5 mm of a blood vessel (portal vein or hepatic vein)
less than 2 mm in diameter, effort would be made to ablate
the lesion as well as the vessel to achieve an adequate AM.
If the lesion was within 5 mm of a blood vessel larger than
2 mm in diameter, we attempted to ablate the entire
normal hepatic parenchyma between the lesion and the vessel.
If the HCC lesion was within 5 mm of critical structures
such as the diaphragm or gastrointestinal tract, artificial
ascites or pleural effusion was applied by injecting normal
saline into the abdominal or pleural cavity to avoid injury
to the critical structures. Supplementary ablation was
applied if an adequate AM (5 mm) was not achieved after the
previously planned ablation. Supplementary ablation was
not performed if the inadequate AM was caused by large
vessels (diameter >2 mm) or supplementary puncture was
too risky or difficult.
Evaluation of the AM by intraoperative CEUS-CT/MR image fusion
The MyLab Twice (Esaote, Italy) ultrasound unit and
convex array transducer CA431 (4–10 MHz) were used. The
ultrasound unit was equipped with the program Virtual
Navigator, and the real-time contrast-tuned imaging
technique (CnTI, MI < 0.05). SonoVue (Bracco, Italy) was used
as the contrast agent. During each application, 2.4 ml of
the contrast agent was administered into the antecubital
vein followed by 5 ml of normal saline.
A flow diagram of intraoperative AM assessment and
management is shown in Fig. 1. The fusion was performed
10–15 min after ablation to decrease the interference of
gas in the ablative area. First, one CT/MR portal or
delayed phase series in DICOM format was transferred into
the navigation system in MyLab Twice, which could be
performed before ablation. The navigation system
automatically generated the three-dimensional (3D) data and
displayed the reconstructed 3D-CT/MR images. The
index tumor and 5-mm AM were outlined in different
colors (Fig. 2). For co-registration, the axial section of the
medial line of the body between the CT/MR and the
primary ultrasound scan was used. Vascular structures, such
as bifurcations or confluences of the portal and hepatic
veins, were frequently chosen as anatomical landmarks.
After planar registration, additional refinement was
performed to enable more precise fusion. All co-registrations
and refinements were performed at the end of expiration,
which was controlled by a breathing machine. Image
fusion was only achieved at the area around the index lesion
rather than the whole liver.
After ultrasound-CT/MR image fusion, CEUS was
performed in the overlapped mode of CT/MR with
CEUS. The patient’s breath was stopped at the end of
expiration, and during the arterial, portal and delayed
phase, the probe was moved across the entire ablative
area to determine whether the non-enhanced ablative
area encompassed the tumor as well as the AM. The
CEUS-CT/MR image fusion images and clips were
stored on a disk.
The time used to generate the CEUS-CT/MR image
fusion (CT/MR data upload to the US machine not
included) and the success rate of CEUS-CT/MR image
fusion were recorded. The CEUS image quality and the
CEUS-CT/MR image fusion for evaluating the AM were
assessed intraoperatively by 2 independent assessors,
who then conferred and arrived at a consensus. The
CEUS image quality was classified as “good”, “medium”
or “poor”. A CEUS image of an ablative area of good
quality was defined based on the presence of clear and
sharp margins. If the margin of the ablative area in the
CEUS image could not be clearly visualized, it was
defined as “poor”. An image quality between “good” and
“poor” was defined as “medium”.
If the CEUS-CT/MR image fusion showed that the
ablative area covered the whole tumor, it was defined as
complete ablation. If the CEUS-CT/MR image fusion
showed that the ablative area covered the whole AM, it
was defined as adequate AM. If the ablative area just
covered the whole tumor but not the AM, it was defined
as an inadequate AM. The space around the index
tumor was equally divided into 8 quadrants, designated
1–8, by three orthogonal transverse, coronal and sagittal
planes crossing the center of the tumor. The occurrence
of an adequate AM and the quadrant containing an
inadequate AM were recorded. The reasons for an
inadequate AM were categorized as blood vessel-related
(diameter larger than 2 mm) and non-vessel-related. If
the blood vessel was within 5 mm of the lesion and
remained intact after ablation, it was considered blood
vessel-related; otherwise, it was designated as
non-vesselrelated. After supplementary ablation, another CEUS-CT/
MR image fusion was performed.
One month after ablation, all patients received
contrastenhanced CT/MR as the standard for complete ablation.
Complications related to ablation were also recorded.
Patients with residual tumors would receive further
treatment, and their patient data would not be used for
the LTP evaluation. For patients with complete ablation,
follow-up was performed using CEUS and serum AFP
examination at 2-month intervals and CT/MR at
6month intervals. If LTP was suspected by CEUS, CT/MR
was performed. The imaging criteria for LTP on CT/MR
included the presence of a characteristic enhancement
pattern (hypervascularization in the arterial phase and a
wash-out pattern in the portal and delayed phases)
adjacent to the ablative area. The complete ablation rate and
the occurrence and location of LTP were recorded.
Univariate analysis and multivariate analysis were
performed. For univariate analysis, we divided all of the
tumors into 2 groups according to each variable that
could potentially be related to LTP: (1) age (<70 years or
>70 years), (2) sex (male or female), (3) etiology
(hepatitis B/C positive or negative), (4) liver cirrhosis (yes or
no), (5) Child–Pugh grade (A or B), (6) AFP (<20 ng/ml
or >20 ng/ml), (7) number of tumors at the time of RFA
(1 or >1), (8) tumor diameter (<20 mm or ≥20 mm), (9)
past history of HCC (yes or no), (10) located in the
hepatic dome (defined as within 10 mm beneath the
diaphragm) (yes or no), (11) TACE before ablation (yes or
no), and (12) AM (adequate or inadequate). The
cumulative LTP rates of these 2 groups for each factor were
estimated using the Kaplan–Meier method, and the
statistical significance was assessed using the log–rank test.
Next, multivariate analysis using the step-wise Cox
proportional hazard model was performed for the variables
with P < 0.20 in the univariate analysis to investigate
independent risk factors for LTP.
The statistical analysis was performed using SPSS for
Microsoft Windows (version 11.0.1; SPSS Inc. Chicago,
IL, USA). Measurement data are presented as the
mean ± standard deviation or the median. Counted data
are expressed as cases or lesion numbers and percentages.
P < 0.05 was considered statistically significant.
Ninety-eight patients with 126 HCC lesions were
enrolled in the analysis. The clinical characteristics of the
patients and lesions are listed in Table 1. Ultrasound and
CT/MR images could not be successfully fused in 3 patients
with 5 HCC lesions because of anatomical deformation,
and these 3 patients were excluded. The rate of successful
image fusion was 96.2 % (126/131), and the duration
required for image fusion (time for transferring CT/MR
image data into the ultrasound machine was not
included) was 4.9 ± 2.0 (3–13) min. Artificial ascites and
pleural effusion were used in 16 and 6 patients,
respectively, and the median volume of normal saline used was
600 ml (400–1000 ml) and 400 ml (300–600 ml),
respectively. Image fusion was successful in all lesions
with artificial ascites or pleural effusion. Altogether,
147 contrast agent injections were applied, and the
CEUS image quality was good in 36.1 % (53/147) and
medium in 63.9 % (94/147) of the cases.
After ablation according to the predetermined plan,
CEUS-CT/MR image fusion detected 55 lesions that did
not achieve adequate AMs in 208 quadrants. Inadequate
AMs were caused by blood vessels in 142 (68.3 %)
quadrants and by non-vessels in 66 (31.7 %) quadrants.
Supplementary ablation was applied in 18 lesions. In 12 of
the 18 lesions, an inadequate AM in all quadrants
resulted from non-vessel-related causes. In the other 6
lesions, inadequate AM in some quadrants resulted from
non-vessel-related causes and in some other quadrants
from blood vessel-related causes. In the 18 lesions,
supplementary ablation was only applied to 44 quadrants with
an inadequate AM due to non-vessel-related causes. After
supplementary ablation, the inadequate AMs in the 44
quadrants became adequate AMs (Fig. 3). Because of
supplementary ablation, 21.8 % (12/55) of the lesions with
inadequate AMs achieved adequate AMs and 21.2 % (44/
208) of the quadrants with inadequate AMs achieved
adequate AMs. Finally, 43 lesions that did not achieve
adequate AMs in 164 quadrants, including 142 quadrants
(86.6 %) for blood vessel-related reasons and 22 quadrants
(13.4 %) for non-vessel-related reasons (Table 2).
One month after ablation, all patients received CT/MR,
with 1 residue tumor detected. The success rate of
CEUSCT/MR image fusion for detecting complete ablation was
99.2 % (125/126). The lesion that was not completely
ablated had indistinct boundaries and was assessed as
having an adequate AM by CEUS-CT/MR image
fusion. This patient later received TACE and was not
included in further analyses in the present study. There
was only 1 patient with a hemothorax after ablation,
and catheterization was performed. The catheter was
removed 6 days later, and the patient recovered.
The median follow-up periods for lesions with adequate
AMs and inadequate AMs were 23 months (6–37 months)
and 25 months (4–37 months), respectively, and there was
no significant difference between the follow-up periods of
the 2 groups (p = 0.778). During follow-up, 6 LTPs were
detected, and the rate of LTP was 4.8 % (6/125). One LTP
occurred in a lesion with an adequate AM at 6 months
after ablation, and the rate of LTP in this group was 1.2 %
(1/82). This patient concomitantly presented multiple
intrahepatic occurrences and subsequently received TACE.
The other 5 LTPs occurred in lesions with inadequate
AMs at 4, 6, 9, 10 and 12 months after ablation, and the
rate of LTP in this group was 11.6 % (5/43). The rate of
LTP in inadequate AM quadrants due to blood
vesselrelated and non-vessel-related causes were 2.1 % (3/142)
and 9.1 % (2/22), respectively, and this difference was not
significant (p = 0.134). The positions of LTP matched the
positions of inadequate AMs, as detected by CEUS-CT/
MR image fusion (Fig. 4).
In the univariate analysis, the potential factors
contributing to LTP with p < 0.20 were liver cirrhosis (p = 0.150),
tumor diameter (p = 0.118) and AM (p = 0.014) (Table 3).
The multivariate analysis showed that the only
independent risk factor for LTP was AM (hazard ratio, 9.167; 95 %
confidence interval, 1.070-78.571; p = 0.043).
The results of the present study support the feasibility
of the clinical use of CEUS-CT/MR image fusion for
evaluating AM intraoperatively after HCC ablation
based on several features. First, image fusion between
ultrasound and CT/MR could be achieved within 5 mins,
which would not obviously prolong the operational time.
Of course, the performance of this technique would
require a learning curve. Based on our experience,
approximately 30 practice repetitions would greatly shorten the
Fig. 4 a1 and a2 show the CEUS-CT fused image. a1 shows the
overlapped image of CEUS and CT. The HCC lesion and 5-mm AM
are outlined in blue and yellow, respectively. The ablative area in
CEUS was anechoic and is outlined with a dotted line (arrowhead).
In a1, the ablative area just covers the tumor, and part of the AM is
not covered by the ablative area (arrow). Thus, the CEUS-CT fused
image shows that this HCC lesion has an inadequate AM at the site
indicated by the arrow. In the CT image in a2, the HCC lesion and
5-mm AM are outlined in blue and yellow, respectively. One month
after ablation, the CT revealed complete ablation of the lesion, and
the serum AFP fell to a normal level. However, 9 months after ablation,
the serum AFP again increased. LTP was shown by CEUS (b) and CT (c)
at the same site with an inadequate AM as in a1 (arrow)
Second, a high success rate was obtained for
CEUSCT/MR image fusion. In previous studies, 3DCEUS-CT/
MR image fusion [
] had a relatively low technical
success rate (81.6 %), whereas in the present study, a much
higher rate of successful image fusion was achieved
(96.2 %). This difference might be explained by an ability
of 2-dimensional CEUS-CT/MR image fusion to reduce
the influence of narrow intercostal spaces or the location
of the lesion [
]. Patients who were scheduled to receive
liver resection, laparoscopic cholecystectomy or
splenectomy were excluded from the analysis because these
procedures would lower the successful rate of image
fusion. In our study, we maintained accurate image fusion
around the index lesion rather than the whole liver, so that
anatomical changes caused by artificial ascites or pleural
effusion would not affect the image fusion. Additionally,
the breath of the patient was well controlled using a
breathing machine for as long as 2 min, which would
greatly facilitate co-registration.
Third, the image quality of the intraoperative CEUS was
sufficient for further evaluation. The gas caused by
ablation would affect the image quality of CEUS;
consequently, we waited 10–15 min until the hyperechogenicity
around the ablative area decreased. Attentive observation
of the echogenicity caused by gas and microbubbles might
improve interpretation of the CEUS image. The
echogenicity caused by gas was present before arrival of the
contrast agent and was not displaced. In contrast, the
chogenicity caused by microbubbles was displayed due to
their presence in the blood vessels.
In clinical cases, the AM is not verifiable by pathology;
therefore, the LTP rate has been chosen to test the
accuracy of the evaluated AM [
10, 11, 13
]. In the present
study, the AM was the only independent factor affecting
LTP, which indicated that CEUS-CT/MR image fusion
provided an accurate evaluation of the AM. Compared
with other studies [
], a much lower LTP rate
(4.8 %) was obtained in the present analysis. This
difference might be explained by the much higher rate of
adequate 5-mm AMs in this study compared with other
studies. The high rate of adequate AMs resulted in part
from intraoperative supplementary ablation, such that
approximately 20 % of the inadequate AMs were
effectively reduced. The other reason for the high rate of
adequate AMs was that effort was made to ablate the
tumor as well as the 5-mm AM. In the previous studies
] the authors did not describe their efforts to
ablate the AMs. We also tried to ablate the vessel near
the lesion if its diameter was less than 2 mm, which
reduced the rate of inadequate AMs due to blood
In the case of an inadequate AM due to
non-vesselrelated causes, CEUS-CT/MR image fusion was more
useful because it could not only detect the inadequate
AM but also guide supplementary ablation. All of the
inadequate AMs resulting from non-vessel-related
causes were transformed into adequate AM after
supplementary ablation, indicating that these types of AMs
could be improved. For lesions in which supplementary
ablation was not applied due to the presence of nearby
critical structures such as the gallbladder and
gastrointestinal tract, ethanol injection could be applied at
the risky location.
Blood vessels near the lesion were the most common
reason for an inadequate AM in our study, which is in
agreement with previous studies [
]. Although no
significant differences were observed, the rate of LTP related to
inadequate AMs due to non-vessel-related causes (9.1 %,
2/22) was higher than that due to blood vessel-related
causes (2.1 %, 3/142). This finding might be because, if the
lesion was within 5 mm of a blood vessel, we attempted to
ablate all of the normal hepatic parenchyma between the
lesion and the vessel. This procedure could reduce the
heat sink effect caused by blood flow, and micro-satellite
nodules around the original tumor might also be treated,
in turn lowering the rate of LTP [
CEUS-CT/MR image fusion could also be used to
evaluate complete ablation by observing whether the
ablative area covered the entire tumor. The comparison
of HCC before ablation and the ablative area after
ablation was more objective than routine CEUS and more
suitable for less experienced operators. This finding
might explain why CEUS-CT/MR image fusion
demonstrated a higher rate of detecting complete ablation
(99.2 %) than routine CEUS (96.6 %) [
]. One residual
lesion was recorded as an adequate AM. This lesion had
an indistinct boundary, and it is possible that the area of
the lesion had been underestimated. Whether CEUS-CT/
MR image fusion could eventually improve the complete
ablation rate requires further study.
This study had some limitations. First, the results of
CEUS-CT/MR image fusion could only show whether
the necrotic area covered the 5-mm thickness of the
normal liver parenchyma around the HCC lesion. It
could not offer biological evidence for the absence of
viable tumor cells at the margin. Second, the difference
in the occurrence of LTP occurrence was the only
evaluating indicator, which might partially explain why
a lesion with an adequate AM developed LTP.
Theoretically, the type of tumor differentiation and the results
of TACE before ablation might also influence LTP. A
well designed clinical study or experimental study is
needed to further evaluate CEUS-CT/MR image fusion
for assessing AM. Third, supplementary ablation could
potentially increase the rate of complications. Thus,
future studies are needed to assess whether the AM
should be covered in all lesion types to decrease LTP,
such as lesions with a complete pseudocapsule.
In conclusion, these present findings demonstrated the
feasibility of intraoperative evaluation of the AM using
CEUS-CT/MR image fusion after HCC ablation.
Supplementary ablation could be guided by CEUS-CT/MR image
fusion, leading to improved AMs. The failure to establish
a 5-mm AM was the only significant risk factor associated
with concordant LTP, thus demonstrating the accuracy of
CEUS-CT/MR image fusion for evaluating AMs. This
study describes a new method to evaluate and improve
AMs, which might help decrease the rate of LTP.
Availability of supporting data
The datasets supporting the conclusions of this article
are presented in the main manuscript.
HCC: hepatocellular carcinoma; CEUS: contrast-enhanced ultrasound;
LTP: local tumor progression; RFA: radiofrequency ablation; AM: ablative
margin; 3D: three-dimensional.
The authors declare that they have no competing interests.
K L and ZZ S contributed equally to this work. Together, they designed this
prospective study and were responsible for the data analysis. EJX and JXJ
were responsible for gathering data. XCM was responsible for CT/MRI image
interpretation. RQZ was the supervisor of this clinical research. All authors
read and approved the final manuscript.
This work was supported by the National Natural Science Foundation of
China (No. 81301931, No. 81271669 and No. 81430038) and Research
Cooperation Project of Guangdong Province (No. 2013B090200020).
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