Literature Search
Through our electronic search, 406 studies were initially identified, and 70 of these were duplicates. Fifty-one studies were relevant after reading titles and abstracts. After scrutinizing the full text, 12 articles[12–16, 10, 17–22] with sufficient detail that meet our research design were included (Fig. 1). Details of the excluded studies are showed in Appendix 1, See Fig. 1 for the study selection process.
Characteristics Of The Included Studies
The important characteristics of the finally included studies are listed in Table 1. A total of 5275 patients with 5739 lesions were evaluated in this article (Table 2). All studies were full-text publications that contain enough data and details to analyze. All included studies except for one[20] had been carried out in a single center. Most of these studies had a retrospective design, only two prospective studies. And in these retrospective studies, 1 study[16] was a case-control design. Liver nodules were analyzed according to LI-RADS v.2017 in 9 studies[14, 12, 16, 10, 22, 17, 21, 15, 19], and v.2016 in the other 3 articles[18, 20, 13].
The studies mostly were conducted in Asia, in which China and South Korea account for the majority; 1 in Italy[20], 1 in German[18]. In 3 of the 12 available studies, the publication was English, and the rest was Chinese[13, 12, 14].
Table 1
Characteristic of Included Studies
Study
|
Country
|
Study design
|
Multicentric
|
No. of patients
|
Age (y)
(mean ± SD) or range
|
Male (%)
|
CEUS contrast
|
LI-RADS version
|
Reference standards for HCC
|
Reference standards for Non-HCC malignancy
|
Reference standards for Benign
|
Zheng 2020
|
China
|
retrospective
|
No
|
1826
|
54 (44, 62)
|
90.0
|
SonoVue
|
2017
|
Pathology or CCRS
|
Pathology or CCRS
|
Pathology or CCRS
|
Chen
2019
|
China
|
retrospective
|
No
|
210
|
55 ± 10
|
77.6
|
SonoVue
|
2017
|
Pathology
|
Pathology
|
N/A
|
Huang 2020
|
China
|
retrospective
|
No
|
172
|
51.8 ± 10.8
|
79.1
|
SonoVue
|
2017
|
Pathology
|
Pathology
|
CCRS
|
Li
2019
|
China
|
retrospective
|
No
|
1366
|
52.3 (12.0)
|
80.3
|
SonoVue
|
2017
|
Pathology
|
Pathology
|
pathology
|
Schellhaas 2017
|
Germany
|
prospective
|
No
|
100
|
66.1 (42–85)
|
85.0
|
SonoVue
|
2016
|
Pathology or CCRS
|
Pathology or CCRS
|
Pathology or CCRS
|
Tan
2020
|
Singapore
|
retrospective
|
No
|
45
|
63.1 (34–84)
|
32.0
|
SonoVue
|
2017
|
Pathology or CCRS
|
Pathology or CCRS
|
Pathology or CCRS
|
Terzi
2018
|
Italy
|
retrospective
|
Yes
|
848
|
70 (31–89)
|
54.0
|
SonoVue
|
2016
|
Pathology or CCRS
|
Pathology or CCRS
|
Pathology or CCRS
|
Wang
2020
|
China
|
retrospective
|
No
|
258
|
52 ± 11
|
77.5
|
SonoVue
|
2017
|
Pathology or CCRS
|
Pathology or CCRS
|
Pathology or CCRS
|
Han
2017
|
China
|
retrospective
|
No
|
129
|
59.6 ± 10.8
|
78.3
|
SonoVue
|
2016
|
Pathology or CCRS
|
Pathology or CCRS
|
Pathology or CCRS
|
Wu
2018
|
China
|
retrospective
|
No
|
178
|
52.1 ± 11.7
|
86.0
|
SonoVue
|
2017
|
Pathology
|
Pathology
|
Pathology
|
Liu
2019
|
China
|
retrospective
|
No
|
82
|
58.15 ± 10.97
|
74.4
|
SonoVue
|
2017
|
Pathology or CCRS
|
Pathology or CCRS
|
Pathology or CCRS
|
Kang
2020
|
China
|
prospective
|
No
|
43
|
63.3(50–76)
|
86.0
|
SonoVue
|
2017
|
Pathology or imaging
|
Pathology or CCRS
|
follow up
|
CCRS: composite clinical reference standard |
NA not available. |
Table 2
Number of HCC and Malignancy Observations per LI-RADS Category per Study
Study
|
Observations
n
|
Observations size (mm)
|
HCC
n
|
Non-HCC malignancy, n
|
Benign, n
|
Zheng 2020
|
2020
|
N/A
|
1514
|
138
|
368
|
Chen 2018
|
210
|
N/A
|
105
|
105
|
0
|
Huang 2020
|
175
|
16.1 ± 3.4
|
105
|
3
|
67
|
Li 2019
|
1366
|
47 (35)
|
985
|
139
|
242
|
Schellhaas2017
|
100
|
52.2 ± 78.9
|
87
|
6
|
7
|
Tan 2020
|
46
|
N/A
|
37
|
9
|
0
|
Terzi 2018
|
1,006
|
20 (5–150)
|
820
|
53
|
133
|
Wang 2020
|
355
|
25
|
115
|
5
|
235
|
Han 2017
|
148
|
N/A
|
68
|
36
|
44
|
Wu 2018
|
197
|
29 ± 16
|
170
|
17
|
10
|
Liu 2019
|
82
|
37.04 ± 30.69
|
48
|
1
|
33
|
Kang 2020
|
34
|
21 (20–35)
|
12
|
1
|
21
|
Data are mean or median value, mean ± SD and data in parentheses are range. |
Methodological Quality
Our evaluation of study quality with the QUADAS-2 tool is reported in Appendix 2. Overall, these included studies were considered to be at high risk of bias and high concerns about applicability. Only one study presented low bias in all four domains and applicability concerns[15]. The major risk of bias and applicability concerns were related to patient selection, reference standard. 2 articles[16, 22] selectively enrolled study subjects (1[16] was case-control). This was considered high risk because it may affect the prevalence of HCC in the study by the authors.
Regarding the index test, 1 study used CEUS and the CT/MRI[22], which may be a source of bias. The reference standard was a potential risk of bias because these articles used different reference standards to diagnose liver nodes. For example, only using pathology would be appropriate to exclude some patients[23]. Most studies did not report whether or not the assessment of the index test was blinded to the reference standard. On the other hand, the Flow and Timing domain in most articles was not reported, so the risk of bias was unclear.
Diagnostic Performance Of Ceus Lirads
The overall per-lesion sensitivity and specificity of CEUS LR-5 for the diagnosis of HCCs from 12 studies were 70% (95% CI, 65%-74%) and 94% (95% CI, 91%-96%), respectively (Appendix 3). The pooled estimate of diagnostic odds ratio (DOR) was 61.12 (95% CI 34.81-107.32). The summary of ROC is provided in Appendix 5.
The overall per-lesion sensitivity and specificity of LR-M as a predictor of non-HCC malignancy from 10 studies were 83% (95% CI, 71%-91%) and 94% (95% CI, 88%-97%), respectively (Appendix 4).
Meta-regression Analysis
We explored potential heterogeneity using the nation of publication, study design, subject enrollment, LI-RADS version, imaging reviewer, and reference standard as covariates. For LI-RADS category 5, all these factors, except for imaging reviewers, significantly influenced sensitivities or specificities. And for LI-RADS M, only reference standard had a significant impact on the pooled sensitivity (P༜0.01). The result was summarized in Table 3 and Table 4.
Proportions of HCC and overall malignancies for each LI-RADS category
The forest plot data of the percentages of HCC and overall malignancies for each LI-RADS category in each study are provided in Appendix 6. The pooled percentages of HCC and overall malignancy, respectively, were 0% (95% CI, 0–2%) and 0% (0–2%) for LR-1, 1% (95% CI 0–6%) and 1% (0–6%) for LR-2, 20% (9–34%) and 23% (10–37%) for LR-3, 78% (67–88%) and 82% (72–91%) for LR-4, 97% (94–99%) and 99% (98–100%) for LR-5, 40% (23–58%) and 97% (87–99%) for LR-M, and 100% (93–100%) and 100% (93–100%) for LR-TIV (Fig. 2). Meta-regression was performed for each category (Appendix 7).
Publication Bias
The linear regression test of funnel plot asymmetry indicated no significant publication bias (P = 0.50).
Table 3
Results of meta-regression analysis of the sensitivity and specificity of LI-RADS category 5 for diagnosing HCC
|
Sensitivity
|
P value
|
Specificity
|
P value
|
Nation of publication
|
|
༜0.01
|
|
༜0.01
|
Asian(n = 10)
|
71(67–75)
|
|
95(92–98)
|
|
Non-Asian(n = 2)
|
66(57–74)༉
|
|
91(81–100)
|
|
Study design
|
|
0.04
|
|
0.03
|
Prospective study(n = 2)
|
59(44–75)
|
|
86(70–100)
|
|
Retrospective study(n = 10)
|
70(66–75)
|
|
95(92–97)
|
|
Subject enrollment
|
|
༜0.01
|
|
0.63
|
Consecutive(n = 10)
|
72(68–75)
|
|
94(91–97)
|
|
Selective(n = 2)
|
53(40–66)
|
|
96(92–100)
|
|
LI-RADS version
|
|
0.01
|
|
0.08
|
2017(n = 9)
|
72 (69–76)
|
|
95(92–98)
|
|
2016(n = 3)
|
64 (58–70)
|
|
94(88–100)
|
|
Imaging reviewer
|
|
0.28
|
|
0.33
|
Inexperienced(n = 1)
|
76(63–88)
|
|
94(87–100)
|
|
experienced(n = 11)
|
69(65–73)
|
|
94(92–97)
|
|
Reference standard
|
|
0.02
|
|
༜0.01
|
Pathology(n = 2)
|
75(67–82)
|
|
86(83–90)
|
|
Pathology or CCRS(n = 10)
|
68(64–73)
|
|
96(95–97)
|
|
Table 4
Results of meta-regression analysis of the sensitivity and specificity of LI-RADS category M for diagnosing HCC
|
Sensitivity
|
P value
|
Specificity
|
P value
|
Nation of publication
|
|
0.16
|
|
0.72
|
Asian(n = 8)
|
86(77–95)
|
|
92(87–98)
|
|
Non-Asian(n = 2)
|
73(47–98)
|
|
97(92–100)
|
|
Study design
|
|
0.18
|
|
0.08
|
Prospective study(n = 2)
|
59(13–100)
|
|
98(95–100)
|
|
Retrospective study(n = 8)
|
86(78–93)
|
|
92(87–97)
|
|
Subject enrollment
|
|
0.11
|
|
0.21
|
Consecutive(n = 8)
|
82(73–91)
|
|
94(91–98)
|
|
Selective(n = 2)
|
96(90–100)
|
|
87(70–100)
|
|
LI-RADS version
|
|
0.47
|
|
0.93
|
2017(n = 7)
|
81(65–98)
|
|
97(93–100)
|
|
2016(n = 3)
|
83(70–95)
|
|
91(85–97)
|
|
Reference standard
|
|
༜0.01
|
|
0.39
|
Pathology(n = 2)
|
65(49–80)
|
|
91(80–100)
|
|
Pathology or CCRS(n = 8)
|
87(82–93)
|
|
94(90–99)
|
|