Background: Current practice guidelines recommend the use of ultrasound (US) as an initial surveillance tool for hepatocellular carcinoma (HCC) in patients with liver cirrhosis. Patients with liver cirrhosis, however, frequently have coarse liver parenchyma, masking the presence of tiny nodules during B-mode US. Contrast-enhanced US (CEUS) with Sonazoid has a long-lasting, stable Kupffer phase, which makes it possible to scan the entire liver to depict small lesions. In addition, defect reperfusion imaging (reinjection imaging) enables to determine whether the detected nodule is HCC or not. This prospective, multicenter, randomized, controlled trial was conducted to demonstrate the usefulness of Kupffer phase surveillance in the detection of small HCC compared to B-mode US. Methods: A total of 23 institutions joined this study. In total, 656 patients with hepatitis B- or C-related liver cirrhosis were randomized either to the B-mode US surveillance group (n = 313) or the Kupffer phase CEUS with Sonazoid surveillance group (n = 309). The primary endpoint was the maximum size of HCC at the time of the first detection. Secondary endpoints included time to HCC detection, number of tumors, and Barcelona Clinic Liver Cancer stage at the first detection, and sensitivity, specificity, and accuracy of each method in the diagnosis, and the cumulative detection rate of HCC. Results: The mean HCC size at the first detection was significantly smaller in the CEUS (13.0 ± 4.1 mm; n = 28) than in the B-mode US group (16.7 ± 4.1 mm; n = 26) (p = 0.011). Of the 38 patients with HCV cirrhosis diagnosed with HCC by US alone, mean tumor size at the first detection was significantly smaller in the 20 patients diagnosed by CEUS alone than in the 18 diagnosed by B-mode US alone (12.7 ± 3.1 vs. 17.6 ± 7.0 mm, p = 0.012). In contrast, among the 16 patients with HBV cirrhosis diagnosed by US alone, mean tumor size at the first detection was similar in the 8 patients diagnosed by CEUS alone and the 8 diagnosed by B-mode US (13.6 ± 6.0 vs. 14.5 ± 2.7 mm, p = 0.715). Conclusion: Kupffer phase CEUS surveillance with Sonazoid is extremely useful for the early detection and confirmation of HCC using a reinjection technique. Kupffer phase CEUS with Sonazoid contrast combined with the reinjection technique is, therefore, recommended as first-line screening tool for HCC in patients with liver cirrhosis, especially those with very coarse liver parenchyma.

1.
Galle
PR
,
Forner
A
,
Llovet
JM
,
Mazzaferro
V
,
Piscaglia
F
,
Raoul
JL
, et al.;
European Association for the Study of the Liver. Electronic address: [email protected]
;
European Association for the Study of the Liver
.
Management of hepatocellular carcinoma
.
J Hepatol
.
2018
Jul
;
69
(
1
):
182
236
.
[PubMed]
0168-8278
2.
Marrero
JA
,
Kulik
LM
,
Sirlin
CB
,
Zhu
AX
,
Finn
RS
,
Abecassis
MM
, et al.
Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases
.
Hepatology
.
2018
Aug
;
68
(
2
):
723
50
.
[PubMed]
0270-9139
3.
Kokudo
N
,
Hasegawa
K
,
Akahane
M
,
Igaki
H
,
Izumi
N
,
Ichida
T
, et al.
Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines)
.
Hepatol Res
.
2015
Jan
;
45
(
2
):
123
7
.
[PubMed]
1386-6346
4.
Omata
M
,
Cheng
AL
,
Kokudo
N
,
Kudo
M
,
Lee
JM
,
Jia
J
, et al.
Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update
.
Hepatol Int
.
2017
Jul
;
11
(
4
):
317
70
.
[PubMed]
1936-0533
5.
Kudo
M
,
Matsui
O
,
Izumi
N
,
Iijima
H
,
Kadoya
M
,
Imai
Y
, et al.;
Liver Cancer Study Group of Japan
.
JSH Consensus-Based Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma: 2014 Update by the Liver Cancer Study Group of Japan
.
Liver Cancer
.
2014
Oct
;
3
(
3-4
):
458
68
.
[PubMed]
2235-1795
6.
Hatanaka
K
,
Kudo
M
,
Minami
Y
,
Ueda
T
,
Tatsumi
C
,
Kitai
S
, et al.
Differential diagnosis of hepatic tumors: value of contrast-enhanced harmonic sonography using the newly developed contrast agent, Sonazoid
.
Intervirology
.
2008
;
51
Suppl 1
:
61
9
.
[PubMed]
0300-5526
7.
Kudo
M
,
Hatanaka
K
,
Maekawa
K
.
Newly developed novel ultrasound technique, defect reperfusion ultrasound imaging, using sonazoid in the management of hepatocellular carcinoma
.
Oncology
.
2010
Jul
;
78
Suppl 1
:
40
5
.
[PubMed]
0030-2414
8.
Kudo
M
.
Defect Reperfusion Imaging with Sonazoid®: A Breakthrough in Hepatocellular Carcinoma
.
Liver Cancer
.
2016
Feb
;
5
(
1
):
1
7
.
[PubMed]
2235-1795
9.
Claudon
M
,
Dietrich
CF
,
Choi
BI
,
Cosgrove
DO
,
Kudo
M
,
Nolsøe
CP
, et al.;
World Federation for Ultrasound in Medicine
;
European Federation of Societies for Ultrasound
.
Guidelines and good clinical practice recommendations for Contrast Enhanced Ultrasound (CEUS) in the liver - update 2012: A WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS
.
Ultrasound Med Biol
.
2013
Feb
;
39
(
2
):
187
210
.
[PubMed]
0301-5629
10.
Hatanaka
K
,
Kudo
M
,
Minami
Y
,
Maekawa
K
.
Sonazoid-enhanced ultrasonography for diagnosis of hepatic malignancies: comparison with contrast-enhanced CT
.
Oncology
.
2008
;
75
Suppl 1
:
42
7
.
[PubMed]
0030-2414
11.
Ahmed Mohammed
HA
,
Yang
JD
,
Giama
NH
,
Choi
J
,
Ali
HM
,
Mara
KC
, et al.
Factors Influencing Surveillance for Hepatocellular Carcinoma in Patients with Liver Cirrhosis
.
Liver Cancer
.
2017
Feb
;
6
(
2
):
126
36
.
[PubMed]
2235-1795
12.
Kudo
M
.
Management of Hepatocellular Carcinoma in Japan as a World-Leading Model
.
Liver Cancer
.
2018
May
;
7
(
2
):
134
47
.
[PubMed]
2235-1795
13.
Kudo
M
,
Hatanaka
K
,
Kumada
T
,
Toyoda
H
,
Tada
T
.
Double-contrast ultrasound: a novel surveillance tool for hepatocellular carcinoma
.
Am J Gastroenterol
.
2011
Feb
;
106
(
2
):
368
70
.
[PubMed]
0002-9270
14.
Nakashima
O
,
Sugihara
S
,
Kage
M
,
Kojiro
M
.
Pathomorphologic characteristics of small hepatocellular carcinoma: a special reference to small hepatocellular carcinoma with indistinct margins
.
Hepatology
.
1995
Jul
;
22
(
1
):
101
5
.
[PubMed]
0270-9139
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.