Received: 13 April 2022
DOI: 10.1111/hepr.13793- Revised: 1 May 2022

Accepted: 6 May 2022

ORIGINAL ARTICLE

Comparison of modified CEUS LI‐RADS with sonazoid andCT/MRI LI‐RADS for diagnosis of hepatocellular carcinoma
Katsutoshi Sugimoto1 | Kazuhiro Saito2 | Natsuhiko Shirota2 |Naohisa Kamiyama3 | Kentaro Sakamaki4 | Hiroshi Takahashi1 | Takuya Wada1 |Tatsuya Kakegawa1 | Yusuke Tomita1 | Masakazu Abe1 | Yu Yoshimasu1 |Hirohito Takeuchi1 | Takao Itoi1
1

Department of Gastroenterology andHepatology, Tokyo Medical University,
Tokyo, Japan

Abstract
Aim: To compare the diagnostic performance based on the modified CEUS Liver2

Department of Radiology, Tokyo Medical
University, Tokyo, Japan

Imaging Reporting and Data System (LI‐RADS), which includes Kupffer‐phase3

findings as a major imaging feature, with that of CT and MRI (CT/MRI) LI‐RADS

Ultrasound General Imaging, GE Healthcare,Hino, Tokyo, Japan4for liver nodules in patients at high risk of HCC.

Center for Data Science, Yokohama City
University, Yokohama, Japan

Methods: A total of 120 patients with 120 nodules were included in this retro-

Correspondence

14.0–30.8 mm). Of these lesions, 90.0% (108 of 120) were confirmed as HCCs, 6.7%

Katsutoshi Sugimoto, Department of
Gastroenterology and Hepatology, Tokyo
Medical University, 6‐7‐1 Nishishinjuku,
Shinjuku‐ku, Tokyo 160‐0023, Japan
Email: sugimoto@tokyo-med.ac.jp(8 of 120) were intrahepatic cholangiocarcinomas, 1.7% (2 of 120) were metastases,

spective study. The median size of the lesions was 20.0 mm (interquartile range,

and 1.7% (2 of 120) were dysplastic nodules. All nodules were diagnosed histopathologically. Each nodule was categorized according to the modified CEUS
LI‐RADS and CT/MRI LI‐RADS version 2018. The diagnostic performance and inter‐

Funding information

modality agreement of each criterion was compared.

Tokyo Medical University Cancer Research
Foundation (2021)

Results: The inter‐modality agreement for the modified CEUS LI‐RADS and CT/MRI
LI‐RADS was slight agreement (kappa = 0.139, p = 0.015). The diagnostic accuracies
of HCCs for the modified CEUS LR‐5 and CT/MRI LR‐5 were 70.0% (95% confidence interval [CI]: 61.0%, 78.0%) versus 70.8% (95% CI: 61.8%, 78.8%) (p = 0.876),
respectively. The diagnostic accuracies of non‐HCC malignancies for the modified
CEUS LR‐M and CT/MRI LR‐M were 84.2% (95% CI: 76.4%, 90.2%) versus 96.7%(95% CI: 91.7%, 99.1%) (p = 0.002), respectively.
Conclusions: The diagnostic performance for HCCs on the modified CEUS LR‐5 andCT/MRI LR‐5 are comparable. In contrast, CT/MRI LR‐M has better diagnostic
performance for non‐HCC malignancy than that of the modified CEUS LR‐M.
KEYWORDS

contrast media, hepatocellular carcinoma, LI‐RADS, sonazoid, ultrasound-Abbreviations: CEUS, Contrast‐Enhanced Ultrasound; CI, Confidence interval; DN, Dysplastic nodule; EOB‐MRI, Gadoxetic acid‐enhanced magnetic resonance imaging; HCC, hepatocellular
carcinoma; ICC, Intrahepatic cholangiocarcinoma; LI‐RADS, Liver Imaging Reporting and Data System.

Hepatology Research. 2022;1–9.

wileyonlinelibrary.com/journal/hepr© 2022 Japan Society of Hepatology.

1

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SUGIMOTO ET AL.

HEPATOLOGY RESEARCHINTRODUCTION

modified CEUS LI‐RADS is that the former includes late and mild
washout as a major imaging feature while the latter includes Kupffer‐

Hepatocellular carcinoma (HCC) is the only type of cancer diagnosed

phase hypoenhancement as a major imaging feature.

noninvasively in high‐risk patients based on typical imaging features

To the best of our knowledge, there has been no report toof CT, MRI, or contrast‐enhanced ultrasound (CEUS) often without

compare CT/MRI LI‐RADS and the modified CEUS LI‐RADS. Thus,

biopsy.1,2 Because many methods of imaging diagnostic criteria havethe purpose of this study was to compare CT/MRI LI‐RADS version

been proposed, this may lead to some confusion among radiologists,

2018 and the modified CEUS LI‐RADS for the categorization per-hepatologists, and surgeons, who are responsible for the manage-

formance for patients at high risk of HCC.

ment of patients at risk for or with HCC.
Recently, to overcome the situation, the American College ofRadiology developed the Liver Imaging Reporting and Data System

MATERIALS AND METHODS(LI‐RADS) at CT or MRI in patients at risk for HCC in 2011,3 which
has been refined and updated to version 2018.4 In contrast, CEUS

This study was reviewed and approved by the Tokyo Medical Uni-

has unique advantages over CT and MRI, since it offers pure vascularversity ethics review board. The requirement to obtain written

images, real‐time dynamic images, and excellent safety for patients

informed consent was waived for this retrospective study.

with impaired renal function or allergies to iodine or gadolinium.5
American College of Radiology (ACR) also established the CEUS LI‐RADS in 20166 and further revised it in 2017.7 Comparison be-

Patients

tween CT/MRI LI‐RADS and CEUS LI‐RADS for categorization has
been previously performed and reported.8–10

A clinical/pathological database was used to retrospectively identify

The US contrast agents currently available are categorized into

patients with risk factors for HCC who underwent contrast‐

two types: pure blood pool contrast agents, such as Lumason (Braccoenhanced CT (CECT) or gadoxetic acid (Gd‐EOB‐DTPA) enhanced

Diagnostics, Monroe Township, NJ, USA) and Definity (Lantheus

MRI, abbreviated as EOB‐MRI, and CEUS at our institution between

Medical Imaging, Billerica, MA, USA) and combined blood pool andMarch 2017 and December 2021 (Figure 1). Liver histology, including

Kupffer cell contrast agents, such as Sonazoid (GE Healthcare, Oslo,

US‐guided biopsy and surgical pathology, served as the standard

Norway). Unfortunately, the current version of CEUS LI‐RADS

reference. If the patients had multiple nodules, only one nodule which(version 2017) is applicable only to the pure blood pool contrast

was histopathologically diagnosed was included. The inclusion

agents but not to the combined blood pool and Kupffer cell agents.

criteria were (1) age 20 years or older; (2) nodules detected by CECT/

To overcome the gap those using Sonazoid in daily clinical

EOB‐MRI and US; (3) nodules with pathological diagnosis; and (4) anpractice (clinicians in many Asian countries, e.g.,), a modified CEUS LI‐

interval of less than 4 weeks between CECT/EOB‐MRI and CEUS

RADS that is also applicable to Sonazoid was developed.11–13 The

examinations. The patients with the following criteria were excluded:

main difference between CEUS LI‐RADS (version 2017) and the(1) cirrhosis due to a vascular disorder such as Budd‐Chiari syndrome

FIGURE 1

Flow diagram of study

HEPATOLOGY RESEARCHSUGIMOTO ET AL.

- 3

or cardiac congestion; (2) diffuse HCC; and (3) poor image quality forimages (T1WI) included in‐phase and opposed‐phase images. The

any reason.

T1WI parameters (in‐phase and opposed‐phase) were as follows:
TR/TE, 4.2/2.57, 1.34 msec; flip angle, 10°; 1 averaging; matrix, 320
� 168; parallel acquisition technique (PAT) factor 3 with a gener-

CEUS

alizedautocalibrating

partiallyparallelacquisition(GRAPPA)algorithm; slice thickness, 2 mm and acquisition time, 18 s. Fat‐
US images were obtained by an Aplio i800 diagnostic US system

suppressed respiratory‐triggered T2‐weighted images parameters(Canon Medical Systems, Otawara, Tochigi, Japan) equipped with awere as follows: TR/TE, 3840/85 msec; flip angle, 100°; echo train

3.5 MHz convex transducer (PVT‐475BT), pulse inversion harmonic

length, 28; matrix, 320 � 320; slice thickness, 5 mm; 1 averaging;

imaging mode, mechanical index 0.14–0.2 and a dynamic range ofand PAT factor 3 with the GRAPPA algorithm. Diffusion weighted

45 dB, or by a LOGIQ E10 diagnostic US system (GE Healthcare,

images (DWI) were obtained under free breath. DWI parameters

Wauwatosa, WI, USA) equipped with a 3.5 MHz convex transducer

were as follows: TR/TE, 6600/46 msec; flip angle, 90°; matrix, 360(C1‐6‐D), amplitude modulation imaging mode, mechanical index

� 460; slice thickness, 5 mm; 3 averaging and b‐values 200 and

0.16–0.2 and a dynamic range of 63 dB. If the lesion was observed with

800 s/mm2.

poor conspicuity on B‐mode US, the fusion imaging technique of CT/

A total of 0.025 mmol/kg of Gd‐EOB‐DTPA was injected via the

MRI with US was used. The size, location and echogenicity of lesions

antecubital vein at a rate of 2 ml/sec, followed by 40 ml of physi-

were assessed. The second‐generation US contrast agent Sonazoid

ological saline. A three‐dimensional (3D) volumetric interpolated(GE Healthcare) was injected as a 0.5‐ml bolus into an antecubital vein

breath‐hold examination (3D‐VIBE) was performed. The 3D‐VIBE

via a 21‐gauge peripheral intravenous cannula, followed by a 10‐mlparameters were as follows: TR/TE, 2.8/0.93 msec; flip angle, 9°;saline flush at a rate of 1.0‐ml/s using a dedicated injector (Sonazoid

matrix, 480 � 248; PAT factor, 2; slice thickness, 3 mm; andShot: Nemoto, Bunkyo‐ku, Tokyo, Japan). A timer was started at theacquisition time, 20 s. A monitoring scan technique (the Care Bolus

time of contrast agent injection. Images were recorded continuously as

method) was used to obtain the optimal arterial phase. In additiona cine clip for a period of 60 s immediately after injection of theto a pre‐contrast acquisition, the dynamic datasets covered thecontrast agent (for evaluation of the vascular phase), after which thearterial phase with acquisitions at 9 and 19 s after contrast media

scan was frozen. After a waiting period of approximately 10 min fromarriving at aortic arch. The portal phase and hepatobiliary phasethe time of contrast agent injection to permit pooling of the agent inimages were obtained at 70 s and 20 min respectively. In addition,

the liver parenchyma, enhancement of the lesion was observed using aan acquisition was obtained at 240 s after injection of contrast

sweep scan and images were recorded (for evaluation of the Kupffer

agent.

phase or post‐vascular phase). If missed to assess arterial phaseenhancement in the first injection of Sonazoid, we performed anothercontrast injection in the Kupffer phase (i.e., “defect reperfusion im-

CEUS imaging assessment

aging”) to ensure whether arterial hyperenhancement or not. The
sequence that was followed in the CEUS protocol is shown else-

One hepatologist with more than 15 years of experience in liver

where.11 The examination was performed by three hepatologists with

CEUS, who was blinded to the reference standard results and othermore than 5 years of CEUS experience.

imaging findings for the liver nodules, reviewed the CEUS examinations and assigned each nodule to a category according to themodified CEUS LI‐RADS,11,12 which is based on CEUS LI‐RADS (2017CT

version).14 Briefly, the main difference between CEUS LI‐RADS(2017 version) and the modified CEUS LI‐RADS is that former in-

CT was performed with 64 or 256 multidetector CT. Iodine contrast

cludes late and mild washout as a major imaging feature, while themedia with a concentration of 600 mgI/kg was injected throughlatter includes Kupffer phase findings as a major imaging feature.

the antecubital vein during 30 s. Timing of the arterial phase was

The other criteria in the modified CEUS LI‐RADS are the same asdetermined by monitoring the scan. The arterial phase scan was

those in CEUS LI‐RADS (2017 version).14

started at 20 s after reaching more than 100 HU in the abdominal
aorta. The portal phase was 20 s after the arterial phase, and theequilibrium phase was 180 s after the arterial phase.

CT/MRI imaging assessment
One radiologist with more than 9 years of experience in liver CT/

MRI

MRI, who was blinded to the reference standard results and otherimaging findings for the liver nodules, reviewed the CT/MRI exami-

MRI was performed with 3T MRI system (MAGNETOM Vida or

nations and assigned each nodule to a category according to the CT/

MAGNETOM Skyra, Siemens, Erlangen, Germany). T1‐weighted

RMI LI‐RADS (2018 version).15 For patients who received both CECT4-

SUGIMOTO ET AL.

HEPATOLOGY RESEARCH

and EOB‐MRI examinations, the nodules were classified accordingused for the evaluation of inter‐modality agreement. All statisticalto EOB‐MRI.

analyses were performed using SAS software, version 9.4 (SASInstitute). Values of p < 0.05 were considered as statisticallysignificant.

Statistical analysis
Qualitative data are presented as numbers and percentages, and

RESULTS

quantitative data are presented as median and interquartile range(IQR). The per‐lesion sensitivity, specificity, positive predictive

Patients and liver nodule characteristics

value (PPV), negative predictive value (NPV), and accuracy with
the 95% confidence interval (CI) of both the modified CEUS

A total of 120 patients 120 nodules (male: 90, female: 30; median age

LI‐RADS and CT/RMI LI‐RADS (2018 version) were compared byand interquartile range; 73 years and 67–80 years) were finallyusing the McNemar test. Categorical variables were compared

included in this study. The median size of the lesions was 20.0 mm

using the paired chi‐square test. The Cohen's kappa coefficient was(interquartile range, 14.0–30.8 mm). Of these lesions, 90.0% (108 of120) were confirmed as HCCs including 28.7% (31 of 108): well‐

TABLE 1

differentiated HCC; 60.2% (65 of 108): moderately differentiatedBaseline characteristics

HCC; 11.1% (12 of 108): poorly differentiated HCC, 6.7% (8 of 120)

Characteristics

Value

No. of patients

120

metastases, and 1.7% (2 of 120) were dysplastic nodules. A total ofMedian age (y)a73 (67–80)

112 nodules were confirmed by biopsy and 8 nodules were confirmed

were intrahepatic cholangiocarcinomas (ICCs), 1.7% (2 of 120) wereby surgical pathology. The most common cause of liver disease wasSexhepatitis C virus infection (34.2% [41 of 120], and 80.0% (90 of 120)

Male

90

Female30

istics of the participants and the targeted nodules are described in

96 (80.0%)

Table 1.

HCV

41 (34.2%)

Alcohol

33 (27.5%)

Distribution of the modified CEUS LI‐RADS and CT/
MRI categories

HBV

30 (25.0%)

NASH

14 (11.7%)

AIH

2 (1.7%)

Presence of cirrhosisof participants had cirrhosis. The clinical and pathologic character-

Liver disease etiology

No. of lesions
Lesion size (mm)a(Table 2) and the distributions were different form each other20.0 (14.0–30.8)(p < 0.0001). Inter‐modality agreement for the modified CEUS LI‐RADS and CT/MRI LI‐RADS was slight agreement (kappa = 0.139

Biopsy112 (93.3%)

Surgery

8 (6.7%)

Histopathologic analysis

modified CEUS LI‐RADS and CT/MRI LI‐RADS for the nodules andpathological diagnosis are shown in Table 3 and the distributions

108 (90.0%)

Well‐differentiated31 (28.7%)

Moderately differentiated65 (60.2%)

Poorly differentiated12 (11.1%)

ICC

8 (6.7%)

Metastasis

2 (1.7%)DN

2 (1.7%)

Data in parentheses are interquartile range.

[95%CI: 0.003, 0.275], p = 0.015). The results of classification by thewere also different form each other (p < 0.0001).

Abbreviations: AIH, autoimmune hepatitis; DN, dysplastic nodule; HBV,
hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus;
ICC, intrahepatic cholangiocarcinoma; NASH, non‐alcoholicsteatohepatitis; y, year.
amodified CEUS LI‐RADS were 9.2%, 6.7%, 61.7%, and 22.5%, and for
CT/MRI LI‐RADS, 6.7%, 20.8%, 60.8%, and 11.7%, respectively

120

Diagnosis method

HCC

The percentages of nodules in LR‐3, LR‐4, LR‐5, and LR‐M for the

T A B L E 2 Comparison between CEUS and CT/MRI
classification
CEUS (n = 120)category

CT (n = 52)/MRI (n = 68) category
3

4

5

M

Total

3

2 (2)

8 (7)

1 (1)

0

11 (10)

4

0

3 (2)

5 (5)

0

8 (7)

5

6 (6)

13 (13)53 (53)2 (1)74 (73)

M

0

1 (1)

14 (14)

12 (3)

27 (18)8 (8)25 (23)73 (73)14 (4)

120 (108)

Total

Note: Data in parentheses are number of HCCs.

HEPATOLOGY RESEARCH- 5

SUGIMOTO ET AL.

Modified CEUS LI‐RADS and CT/MRI LI‐RADS
categories and degree of histopathologic
differentiation of HCC(95% CI: 61.0%, 78.0%) versus 70.8% (95% CI: 61.8%, 78.8%)

The relationship between the modified CEUS LI‐RADS categories anditive, likely due to the imbalance between number of HCCs andthe degree of HCC differentiation and between the CT/MRI LI‐RADS

others.

25.5% (95% CI: 13.9%, 40.3%); and the accuracies were 70.0%(p = 0.876), respectively. However, some of these p‐values
could not be calculated because the Hessian matrix was not pos-

categories and the degree of HCC differentiation are shown in

The diagnostic performances for non‐HCC malignancies of theTable 4. On the modified CEUS LI‐RADS categories, all poorly

modified CEUS LI‐RADS and CT/MRI LI‐RADS are also shown in

differentiated HCCs were classified as LR‐M, resulting in a statisti-

Table 5. The sensitivities for the modified CEUS LR‐M and CT/MRI

cally significant difference among the distribution. In contrast, there

LR‐M were 90.0% (95% CI: 55.5%, 99.7%) versus 100% (95% CI:

was no statistically significant difference among the distribution on

58.7%, 100%); the specificities were 83.6% (95% CI: 75.4%, 90.0%)

the CT/MRI LI‐RADS categories.

versus 96.4% (95% CI: 91.0%, 99.0%) (p = 0.001); the PPVs were33.3% (95% CI: 16.5%, 54.0%) versus 71.4% (95% CI: 41.9%, 91.6%);
the NPVs of HCCs were 98.9% (95% CI: 94.2%, 100%) versus 100%

The diagnostic performance of the modified CEUS LI‐RADS and CT/MRI LI‐RADS(95% CI: 94.9%, 100%); and the accuracies were 84.2% (95% CI:
76.4%, 90.2%) versus 96.7% (95% CI: 91.7%, 99.1%) (p = 0.002),
respectively. However, some of these p‐values could not be calcu-

The diagnostic performances for HCCs of the modified CEUS LI‐

lated because the Hessian matrix was not positive, likely due to the

RADS and CT/MRI LI‐RADS are shown in Table 5. The sensitiv-

imbalance between number of HCCs and others.

ities for the modified CEUS LR‐5 and CT/MRI LR‐5 were 67.6%(95% CI: 57.9%, 76.3%) versus 67.6% (95% CI: 57.9%, 76.3%)(p = 1.000); the specificities were 91.7% (95% CI: 61.5%, 99.8%)

DISCUSSION

versus 100% (95% CI: 64.0%, 100%); the PPVs were 98.6%(95% CI: 97.2%, 100%) versus 100% (95% CI: 92.7%, 100%); theOur study results demonstrated that both the modified CEUS LR‐5

NPVs of HCCs were 23.9% (95% CI: 12.6%, 38.8%) versus

and CT/MRI LI‐RADS had a high specificity (91.7% and 100%) andPPV (98.6%, 100%) for the diagnosis of HCC, respectively. In

T A B L E 3 Comparison of histopathologic results and category
between CEUS and CT/MRI
Category

CEUS (n = 120)

CT (n = 52)/MRI (n = 68)

contrast, the result of this study showed that the inter‐modality
agreement for the LI‐RADS category between CEUS and CT/MRI
was slight agreement (kappa = 0.139). This means that CEUS and CT/
MRI may see different characteristic features on HCC. Thus, both

Pathology

3

4

5

M

Total

3

4

5

M

Total

HCC

10

7

73

18

108

8

23

73

4

108

The discordance between CEUS and CT/MRI for LR‐3 was

ICC

0

0

1

7

8

0

0

0

8

8

analyzed in this study. LR‐3 is assigned to findings that have an in-

Metastasis

0

0

0

2

2

0

0

0

2

2

DN

1

1

0

0

2

0

2

0

0

2

Total

11

8

74

27

120

8

25

73

14

120

CT/MRI LR‐3, among which 6 HCCs were reclassified as the modified

Abbreviations: DN, dysplastic nodule; HCC, hepatocellular carcinoma;
ICC, intrahepatic cholangiocarcinoma.

CEUS LR‐5 (Figure 2). We can attribute this improvement in the

TABLE 4

CEUS and CT/MRI should be necessary for diagnosing HCC correctly.

termediate malignant probability. In this study, 10 HCCs were classified as the modified CEUS LR‐3, among which only 1 HCC wasreclassified as CT/RMI LR‐5. In contrast, 8 HCCs were classified assuperiority of CEUS to detect arterial phase hyperenhancement

Comparison of histopathologic differentiation of HCC and category between CEUS and CT/MRI

Category

CEUS (n = 120)

Histopathologic differentiation of HCC

3

4

5

M

Total

3

4

5

M

Total

Well‐differentiated

9

4

18

0

31

4

11

15

1

31

Moderately differentiated

1

3

55

6

65

4

11

48

2

65

Poorly differentiated

0

0

0

12

12

0

1

10

1

12

Total

10

7

73

18

108

8

23

73

4

108

Abbreviation: HCC, hepatocellular carcinoma.
CEUS: p < 0.0001.
CT/MRI: Not significant

CT (n = 52)/MRI (n = 68)

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SUGIMOTO ET AL.

TABLE 5HEPATOLOGY RESEARCH

Comparison of diagnostic performance of LR‐5 and LR‐M categories between CEUS and CT/MRI
HCC

VariableSensitivity (%)

Specificity (%)

PPV (%)NPV (%)

Accuracy (%)

CEUS LR‐5

Non‐HCC malignancy
CT/MRI LR‐5

67.6

67.6

73/108 (57.9, 76.3)

73/108 (57.9, 76.3)

91.7

100.0

11/12 (61.5, 99.8)

12/12 (64.0, 100.0)

98.6

100.0

73/74 (97.2, 100.0)

73/73 (92.7, 100.0)

23.9

25.5

11/46 (12.6, 38.8)

12/47 (13.9, 40.3)

70.0

70.8

84/120 (61.0, 0.780)

85/120 (61.8, 78.8)

p value
1.000

n.c

a

n.c

a

n.c

a

0.876

a

a

CEUS LR‐M

CT/MRI LR‐M

p value

90.0

100.0

n.ca

9/10 (55.5, 99.7)

10/10 (58.7, 100.0)

83.6

96.4

92/110 (75.4, 90.0)

106/110 (91.0, 99.0)

33.3

71.4

9/27 (16.5, 54.0)

10/14 (41.9, 91.6)

98.9

100.0

92/93 (94.2, 100.0)

106/106 (94.9, 100.0)

84.2

96.7

101/120 (76.4, 90.2)

116/120 (91.7, 99.1)

0.001an.ca

n.ca

0.002aNote: Data in parentheses are 95% confidence interval.
Abbreviations: HCC, hepatocellular carcinoma; n.c, not calculated; NPV, negative predicted value; PPV, positive predicted value.
a

McNemar test.

F I G U R E 2 A moderately differentiated HCC in S7 is categorized as the modified CEUS LR‐5 and CT/MRI LR‐3 by EOB‐MRI in a 70‐year‐
old man with alcoholic cirrhosis. (a, pink circle) B‐mode US image with portal‐venous phase EOB‐MRI fusion image shows 2.0‐cm ill‐definedobservation. CEUS: (b, pink circle) shows arterial phase hyper enhancement, (c, pink circle) followed by hypo‐enhancement in 10 minutes after
contrast injection, or Kupffer phase. EOB‐MRI: (d, arrow) shows hypo‐intense in the pre‐contrast T1 weighted image, (e, arrow) shows iso‐enhancement in the arterial phase, (f, arrow) washout in the portal venous phase, (g arrow) hyper‐intense in the hepato‐biliary phase

HEPATOLOGY RESEARCHSUGIMOTO ET AL.

- 7(APHE) compared to that of CT or MRI.16 Thus, for CT/MRI LR‐3 andclassified as the modified CEUS LR‐M, among which 18 nodules (67%;

LR‐4 nodules which show no APHE, CEUS examination should be

18/27) were histopathologically diagnosed as HCCs (Figure 3). In

performed to ensure whether those nodules are truly hypo‐vascular

contrast, 14 nodules were classified as CT/MRI LR‐M, among which

or not.

only 4 nodules (29%; 4/14) were histopathologically diagnosed as

The discordance CEUS and CT/MRI for LR‐M was also analyzed

HCCs. Accordingly, compared with the modified CEUS LR‐M, CT/MRI

in this study. LR‐M is assigned to findings that are probably or defi-

LR‐M had higher diagnostic performance for non‐HCC malignancies.

nitely malignant but not HCC specific. In this study, 27 nodules were

The main reason for this was that some HCCs were more likely to

F I G U R E 3 A poorly differentiated HCC in S7 is categorized as the modified CEUS LR‐M and CT/MRI LR‐5 by CECT in a 71‐year‐old man
with alcoholic cirrhosis. (a, arrow) B‐mode US image shows 2.7‐cm hypo‐echoic observation. CEUS: (b, arrow) shows arterial phase hyper
enhancement, (c, arrow) followed by washout at 42 s after contrast agent injection, (d, arrow) contrast defect in 10 minutes after contrast
injection, or Kupffer phase. (e, arrow) Pre‐contrast CT image shows hypo‐dense observation. CECT: (f, arrow) shows arterial phase hyper
enhancement, (g, arrow) washout in the portal venous phase, (h, arrow) washout in the delayed phase. (i) Grossly, the HCC presents as a simple
nodular type with extranodular growth. (j) The HCC shows solid growth pattern (HE, � 200)

8-SUGIMOTO ET AL.

HEPATOLOGY RESEARCH

present an enhancement pattern of “early washout” on CEUS.

sensitivity is also required. Thus, in order for CEUS LI‐LADS toMoreover, these nodules which showed early washout on CEUS were

become widely used in Japan, it may be necessary to revise CEUS

composed of 12 poorly differentiated HCCs (100%; 12/12), six

LI‐LADS and adapt it to Japanese medical care.

moderately differentiated HCCs (9.2%; 6/65) and no well‐

There are several limitations in the study: First, a prospective

differentiated HCCs (0%; 0/31). In contrast, one poorly differenti-

and multicenter study is needed to validate the inter‐modality

ated HCC was classified as CT/MRI LR‐M.

agreement and diagnostic performance between the modified CEUS

Although the early washout feature on CEUS for poorly differ-

LI‐RADS and CT/MRI LI‐RADS. Second, although all nodules in thisentiated HCCs decreased the diagnostic performance of HCC, thisstudy were diagnosed by histopathologically, almost all (93.3%) was

finding is actually advantageous because poorly differentiated HCCs

made by needle biopsy and especially this may be concerned when

have higher malignant potential than other types of HCCs and are

diagnosing differentiation of HCCs. Third, the relatively small number

essentially similar to metastasis.

17,18

Thus, we recommend that inof benign lesions and non‐HCC malignancies hindered the general-clinical practice when we encounter LR‐M nodules on CEUS due toization of our results. Fourth, CT and MRI were not analyzed

early washout, firstly we should perform CT or MRI to rule out the

separately due to the relatively small number of nodules. Finally,

possibility of non‐HCC malignancies and then the nodule was clas-

although we mentioned HCC is the only type of cancer diagnosed

sified as CT/MRI LR‐5, which has high probability of poorly differ-

non‐invasively in high‐risk patients based on the typical imaging

entiated HCC. In that case, we may take more radial therapy such asfeatures of CT, MRI, or CEUS, we performed tumor biopsy as aliver resection rather that local ablation therapy.17,18

routine clinical practice. It seems paradoxical, but we make it a rule toIn this study, we used the modified CEUS LI‐RADS using Kupffer‐perform tumor biopsy with informed consent before percutaneous

phase hypoenhancement as a major imaging feature for LR‐5 instead

local ablation therapy to obtain pathological evidence, which may beof using late phase mild washout. There may be concern about

acceptable especially in the academic center.

whether the hypoenhancement in Kupffer‐phase findings can be used

In conclusion, the modified CEUS LI‐RADS criteria is reasonable

as an alternative to “washout”. The same concern was raised forfor non‐invasive diagnosis of liver nodules in patients at high risk of

EOB‐MRI about whether hypointensity observed in the hepatobiliary

HCC. The modified CEUS and CT/MRI LR‐5 corresponds to compa-

phase (HBP) findings can be used as an alternative to “washout” forrable positive predictive values of HCC. For LR‐3 and LR‐4 nodules

the noninvasive diagnosis of HCC. In this regard, Joo et al. exploredcategorized by CT/MRI, CEUS should be performed. CT/MRI LR‐M

the question and demonstrated that the criterion of “hypointensity

has better diagnostic performance for non‐HCC malignancies thanon the portal‐venous‐phase (PVP)” of EOB‐MRI resulted in the highthe modified CEUS LR‐M.

specificity of 97.9%, while the criteria of “hypointensity on the PVP
and/or transitional phase (TP), and/or HBP” resulted in lower speci-

A C K N OW L E D G E M E N T S

ficities of 86.3% and 48.4%, respectively. Thus, they concluded that

This study was supported by the Cancer Research Grant afforded by

washout should be assessed in the PVP alone rather than combined

the Tokyo Medical University Cancer Research Foundation (2021).

with the TP or HBP for a more specific diagnosis of HCC on EOB‐
MRI.19 Based on this, EOB‐MRI as well as CT and MRI using extra-

C O N F L I C T OF I NT E R E S T

cellular agents has been incorporated with CT/MRI LI‐RADS in the

The authors declare no conflict of interest.

same manner.
Does this also apply to Sonazoid? Takahashi et al. explored thequestion and demonstrated that after 5 min of Sonazoid injection, 38

ETHICAL STATEMENT
This study was reviewed and approved by the Tokyo Medical Uni-out of 52 HCCs (73.1%) showed washout, while after 10 min, the so‐versity ethics review board. The requirement to obtain written

called Kupffer‐phase, 47 out of 52 HCCs (90.4%) showed washout,informed consent was waived for this retrospective study.

resulting in higher sensitivity and accuracy without reducing specificity when using Kupffer phase findings as major imaging feature.

R E F E R E NC E S

Thus, they concluded that washout should be assessed in the Kupffer1.

phase.

12

In this article, we addressed the usefulness of LI‐RADS especiallythe modified CEUS LI‐RADS. However, one question may arise: If
Sonazoid‐enhanced CEUS is applicable in Japan, will CEUS LI‐RAD2.

become widely used in Japan? CEUS LI‐RADS may help standardize
CEUS procedure and the classification of hepatic nodules in cirrhotic
liver, facilitating communication between hepatologists, sonologists,

3.

radiologists, and surgeons. However, the feature of LI‐RADS is toenhance specificity rather than sensitivity because liver transplantation is one of the major treatment options in Western countries. In contrast, since there are few liver transplants in Japan, high4.

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How to cite this article: Sugimoto K, Saito K, Shirota N,
Kamiyama N, Sakamaki K, Takahashi H, et al. Comparison ofmodified CEUS LI‐RADS with sonazoid and CT/MRI LI‐RADS
for diagnosis of hepatocellular carcinoma. Hepatol Res.
2022;1–9. https://doi.org/10.1111/hepr.13793