Annals of Internal Medicine
Imaging Techniques for the Diagnosis of Hepatocellular Carcinoma
A Systematic Review and Meta-analysis
Roger Chou, MD; Carlos Cuevas, MD; Rongwei Fu, PhD; Beth Devine, PhD, PharmD, MBA; Ngoc Wasson, MPH;
Alexander Ginsburg, MA; Bernadette Zakher, MBBS; Miranda Pappas, MA; Elaine Graham, MLS; and Sean D. Sullivan, PhD
Background: Several imaging modalities are available for diag-
nosis of hepatocellular carcinoma (HCC).
Purpose: To evaluate the test performance of imaging modali-
ties for HCC.
Data Sources: MEDLINE (1998 to December 2014), the Co-
chrane Library Database, Scopus, and reference lists.
Study Selection: Studies on test performance of ultrasonogra-
phy, computed tomography (CT), or magnetic resonance imag-
ing (MRI).
Data Extraction: One investigator abstracted data, and a sec-
ond investigator conrmed them; 2 investigators independently
assessed study quality and strength of evidence.
Data Synthesis: Few studies have evaluated imaging for HCC
in surveillance settings. In nonsurveillance settings, sensitivity for
detection of HCC lesions was lower for ultrasonography without
contrast than for CT or MRI (pooled difference based on direct
comparisons, 0.11 to 0.22), and MRI was associated with higher
sensitivity than CT (pooled difference, 0.09 [95% CI, 0.07 to 12]).
For evaluation of focal liver lesions, there were no clear differ-
H epatocellular carcinoma (HCC) is the most com-
mon primary malignant neoplasm of the liver, usu-
ally developing in persons with chronic liver disease.
Worldwide, it is the fth most common type of cancer
and the third most common cause of death from cancer
(1). There were 25 000 deaths attributed to liver and
intrahepatic bile duct cancer in the United States in
2011 (2). Common causes of HCC are hepatitis C virus
infection, hepatitis B virus infection, and alcohol abuse,
although a substantial proportion of cases have no
identiable cause (35).
Imaging modalities for HCC include ultrasonogra-
phy, computed tomography (CT), and magnetic reso-
nance imaging (MRI). Although CT and MRI provide
higher-resolution images than ultrasonography, they
are also more costly and, in the case of CT, are associ-
ated with radiation exposure (5). Because HCC is typi-
cally a hypervascular lesion, CT and MRI are performed
with arterial-enhancing contrast agents. Microbubble-
enhanced ultrasonography can also be performed, al-
though agents are not yet approved by the U.S. Food
and Drug Administration for this purpose, and micro-
bubbles are present in the liver for only a limited dura-
tion (6). Other technical, patient, and tumor factors may
also affect test performance (712).
This article reviews the test performance of ultra-
sonography, MRI, and CT for detection of HCC and for
evaluation of focal liver lesions. This was conducted as
part of a larger review commissioned by the Agency for
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REVIEW
ences in sensitivity among ultrasonography with contrast, CT,
and MRI. Specicity was generally 0.85 or higher across imaging
modalities, but this item was not reported in many studies. Fac-
tors associated with lower sensitivity included use of an ex-
planted liver reference standard, and smaller or more well-
differentiated HCC lesions. For MRI, sensitivity was slightly higher
for hepatic-specic than nonspecic contrast agents.
Limitations: Only English-language articles were included,
there was statistical heterogeneity in pooled analyses, and costs
were not assessed. Most studies were conducted in Asia and
had methodological limitations.
Conclusion: CT and MRI are associated with higher sensitivity
than ultrasonography without contrast for detection of HCC; sen-
sitivity was higher for MRI than CT. For evaluation of focal liver
lesions, the sensitivities of ultrasonography with contrast, CT, and
MRI for HCC are similar.
Primary Funding Source: Agency for Healthcare Research and
Quality. (PROSPERO: CRD42014007016)
Ann Intern Med. 2015;162:697-711. doi:10.7326/M14-2509 www.annals.org
For author afliations, see end of text.
Healthcare Research and Quality (AHRQ) on HCC imag-
ing (13).
METHODS
Scope of the Review
The protocol was developed by using a standard-
ized process with input from experts and the public
and was registered in the PROSPERO database
(CRD42014007016) (14). The review protocol included
key questions on the comparative test performance of
imaging for detection of HCC and for evaluation of
focal liver lesions.
Detailed methods and data for the review, includ-
ing search strategies, inclusion criteria, and abstraction
and quality ratings tables, are available in the full re-
port, which also includes further key questions, full sen-
sitivity and subgroup analyses, and an additional imag-
ing modality (positron emission tomography) (13).
Data Sources and Searches
A research librarian searched multiple electronic
databases, including MEDLINE (1998 to December
2013 for the full report; the update search for the re-
See also:
Web-Only
CME quiz
Annals of Internal Medicine Vol. 162 No. 10 19 May 2015 697
 REVIEW
view in this article was performed in December 2014),
the Cochrane Library, and Scopus. Additional studies
were identied by reviewing reference lists and from
peer review suggestions.
Study Selection
Two investigators independently evaluated each
study at the title/abstract and full-text article stages to
determine inclusion eligibility (Appendix Table 1, avail-
able at www.annals.org). We included studies on
the test performance of ultrasonography, CT, or MRI
against a reference standard for detection of HCC in
surveillance or nonsurveillance settings (for example,
imaging performed in patients undergoing treatment
for liver disease or in whom HCC was previously diag-
nosed) or for further evaluation of focal liver lesions.
Reference standards were histopathologic examination
based on explanted liver or nonexplant histologic spec-
imens, imaging plus clinical follow-up (for example, le-
sion growth), or a combination of these.
We selected studies of ultrasonography (with or
without contrast) and contrast-enhanced CT and MRI
that met minimum technical criteria (non-multidetector
or multidetector spiral CT, or 1.5- or 3.0-T MRI) (7). We
excluded studies published before 1998 and those in
which imaging began before 1995, unless the imaging
methods met minimum technical criteria; studies of MRI
with contrast agents no longer commercially produced
(for example, superparamagnetic iron oxide [ferumox-
ides or ferucarbotran] or mangafodipir); and studies of
CT arterial portography, CT hepatic angiography, and
intraoperative ultrasonography. We included studies of
ultrasonography microbubble contrast agents because
they are commercially available and commonly used
outside the United States, and efforts to obtain ap-
proval from the U.S. Food and Drug Administration are
ongoing (1517).
We excluded studies of diagnostic accuracy for
non-HCC malignant lesions, including liver metastases.
We included studies that reported results for HCC and
cholangiocarcinoma together if cholangiocarcinoma le-
sions comprised less than 10% of the total. Studies on
the accuracy of imaging for distinguishing HCC from a
specic type of liver lesion (such as hemangioma or
pseudolesion) and on the accuracy of imaging tests
used in combination are addressed in the full report
(13).
We excluded studies published only as conference
abstracts and included only English-language articles.
The literature ow diagram is shown in Appendix
Figure 1 (available at www.annals.org).
Data Abstraction and Quality Rating
One investigator abstracted details on the study
design, dates of imaging and publication, patient pop-
ulation, country, sample size, imaging method and as-
sociated technical factors (Appendix Table 2, available
at www.annals.org), and results. Two investigators inde-
pendently applied the approach recommended in the
AHRQ Methods Guide for Medical Test Reviews to as-
sess risk of bias as high, moderate, or low (18, 19).
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Imaging Techniques for Diagnosis and Staging of Hepatocellular Carcinoma
Data Synthesis
We conducted meta-analysis with a bivariate logis-
tic mixed random-effects model that incorporated the
correlation between sensitivity and specicity, using
SAS software, version 9.3 (SAS Institute) (20). We as-
sumed bivariate normal distributions for sensitivity and
specicity. Statistical heterogeneity was measured with
the random-effect variance (2). We calculated positive
and negative likelihood ratios by using the summarized
sensitivity and specicity (21, 22).
We analyzed data separately for each imaging mo-
dality; ultrasonography with and without contrast were
also analyzed separately. We also separately analyzed
studies in which imaging was performed for detection
of HCC and for evaluation of focal liver lesions; studies
on HCC detection were further stratied by setting (sur-
veillance or nonsurveillance). We separately analyzed
test performance by using patients with HCC or by us-
ing HCC lesions (one patient can have multiple lesions)
as the unit of analysis. Other sensitivity and subgroup
analyses were conducted on the reference standard,
factors related to risk of bias, country, technical factors
(Appendix Table 2), tumor factors (such as HCC lesion
size or degree of tumor differentiation), and patient
characteristics (for example, severity of underlying liver
disease, underlying cause of liver disease, and body
mass index).
We performed separate analyses on the subset of
studies that directly compared 2 or more imaging mo-
dalities or techniques in the same population against a
common reference standard (23). We used the same
bivariate logistic mixed-effects model as described
above, with an added indicator variable for imaging
modalities. We also performed meta-analyses for
within-study comparisons on lesion size, degree of tu-
mor differentiation, and (when data were available)
technical factors.
We graded the strength of each body of evidence
as high, moderate, low, or insufcient on the basis of
the aggregate risk of bias, consistency, precision, and
directness (24).
Role of the Funding Source
This research was funded by the AHRQ Effective
Health Care Program. Investigators worked with AHRQ
staff to develop and rene the review protocol. The
AHRQ staff had no role in conducting the review, and
the investigators are solely responsible for the content
of the manuscript and the decision to submit for
publication.
RESULTS
Of the 5202 citations identied at the title and ab-
stract level, 890 articles seemed to meet inclusion cri-
teria and were selected for further full-text review. After
full-text review, 241 studies (Appendix Table 3, avail-
able at www.annals.org) met inclusion criteria for the
key questions and imaging modalities addressed in this
review (Appendix Figure 1).
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 Imaging Techniques for Diagnosis and Staging of Hepatocellular Carcinoma REVIEW

Table 1. Test Performance of Imaging Modalities for HCC

Imaging Modality Unit of Sensitivity (95% CI) Studies, n Specicity (95% CI) Studies, n Positive LR Negative LR
Analysis
Detection of HCC
Surveillance settings
US without contrast Patient 0.78 (0.600.89) 4 0.89 (0.800.94) 3 6.8 (4.211) 0.25 (0.130.46)
CT Patient 0.84 (0.590.95) 2 0.99 (0.860.999) 2 60 (5.9622) 0.16 (0.060.47)
US without contrast Lesion 0.60 (0.240.87) 1 No data
CT Lesion 0.62 (0.460.76) 1 Insufcient data
Nonsurveillance
settings
US without contrast Patient 0.73 (0.460.90) 8 0.93 (0.850.97) 6 11 (5.421) 0.29 (0.130.65)
CT Patient 0.83 (0.760.88) 17 0.91 (0.840.95) 12 9.1 (5.116) 0.19 (0.130.27)
MRI Patient 0.86 (0.790.91) 14 0.89 (0.820.93) 12 7.7 (4.613) 0.16 (0.100.24)
US without contrast Lesion 0.59 (0.420.74) 11 0.83 (0.530.95) 2 3.4 (1.29.4) 0.50 (0.370.66)
US with contrast Lesion 0.75 (0.570.88) 9 0.97 (0.840.999) 1
CT Lesion 0.76 (0.720.80) 80 0.89 (0.840.93) 21 7.1 (4.711) 0.26 (0.220.32)
MRI Lesion 0.83 (0.800.86) 82 0.87 (0.790.93) 20 6.5 (3.811) 0.20 (0.160.24)

Evaluation of focal liver

lesions
US without contrast Patient 0.78 (0.690.86) 1 No data
US with contrast Patient 0.87 (0.790.92) 12 0.91 (0.830.95) 8 9.6 (5.118) 0.14 (0.090.23)
CT Patient 0.86 (0.750.92) 8 0.88 (0.760.95) 5 7.4 (3.317) 0.16 (0.090.30)
MRI Patient 0.75 (0.660.83) 5 0.82 (0.600.93) 5 4.1 (1.89.2) 0.31 (0.230.40)
US without contrast Lesion 0.62 (0.180.93) 4 0.92 (0.840.96) 3 8.1 (3.618) 0.41 (0.121.4)
US with contrast Lesion 0.87 (0.800.92) 21 0.91 (0.850.95) 10 9.8 (5.717) 0.14 (0.090.23)
CT Lesion 0.79 (0.670.87) 13 0.90 (0.370.99) 6 7.7 (0.7184) 0.24 (0.150.38)
MRI Lesion 0.82 (0.740.88) 15 0.92 (0.780.97) 12 10 (3.629) 0.20 (0.140.28)
CT = computed tomography; HCC = hepatocellular carcinoma; LR = likelihood ratio; MRI = magnetic resonance imaging; US = ultrasonography.

Sixty-eight studies evaluated ultrasonography (Ap-
pendix Table 3), 131 evaluated CT (25153), and 125
evaluated MRI (Appendix Table 3). Almost all studies
reported sensitivity, but specicity was available in only
139 studies.
We rated 5 studies as having low risk of bias (56,
99, 128, 132, 154), 199 as having moderate risk of bias,
and 89 as having high risk of bias (13). One hundred
twenty-ve studies avoided use of a case control de-
sign, 160 used blinded design, and 75 were prospec-
tive. More studies were conducted in Asia (190 studies)
than in Australia, Canada, the United States, or Europe
(95 studies in total for these regions). In 166 studies,
imaging began in or after 2003 (13).
Twenty-eight studies evaluated CT using methods
that met minimum technical specications (8-row mul-
tidetector CT; contrast rate 3 mL/s; at least arterial,
portal venous, and delayed-phase imaging; delayed-
phase imaging performed >120 s after administration
of contrast; and enhanced imaging section thickness
5 mm), and 67 studies evaluated MRI using methods
that met minimum technical specications (1.5- or 3.0-T
MRI; at least arterial, portal venous, and delayed-phase
imaging; delayed-phase imaging performed >120 s af-
ter administration of contrast; and enhanced imaging
section thickness 5 mm). Seventy-three MRI studies
evaluated use of hepatic-specic contrast (for example,
gadoxetic acid or gadobenate). Forty-seven ultra-
sonography studies evaluated use of microbubble con-
trast agents.
Six studies (34, 47, 134, 140, 155, 156) of imaging
for detection of HCC were conducted in surveillance
settings, and 191 studies were conducted in nonsur-
www.annals.org
veillance settings. Fifty-six studies evaluated imaging
for identication of HCC in patients with focal liver
lesions.
Detection of HCC
Surveillance Settings
Few studies evaluated imaging for HCC in surveil-
lance settings (strength of evidence, low to insufcient).
Sensitivity of ultrasonography without contrast for HCC
lesions was 0.78 (95% CI, 0.60 to 0.89; 4 studies) and
specicity was 0.89 (CI, 0.80 to 0.94; 3 studies), for a
positive likelihood ratio of 6.8 (CI, 4.2 to 11) and a neg-
ative likelihood ratio of 0.25 (CI, 0.13 to 0.46) (Table 1
and Appendix Figure 2, available at www.annals.org).
For CT, 2 studies reported sensitivity of 0.84 (CI, 0.59 to
0.95) and specicity of 0.99 (CI, 0.86 to 0.999) (34, 140).
No study evaluated ultrasonography with contrast or
MRI in surveillance settings.
Nonsurveillance Settings
Most studies on detection of HCC were performed
in nonsurveillance settings (strength of evidence, low to
moderate). The sensitivity of ultrasonography without
contrast for identication of patients with HCC was 0.73
(CI, 0.46 to 0.90; 8 studies), and specicity was 0.93 (CI,
0.85 to 0.97; 6 studies) (Appendix Figure 3, available at
www.annals.org). For CT, sensitivity was 0.83 (CI, 0.75
to 0.89; 17 studies) and specicity was 0.91 (CI, 0.86 to
0.96; 11 studies) (Figure 1).
For MRI, sensitivity was 0.86 (CI, 0.79 to 0.91; 14
studies) and specicity was 0.89 (CI 0.83 to 0.93; 12
studies) (Figure 2).
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 REVIEW Imaging Techniques for Diagnosis and Staging of Hepatocellular Carcinoma

Figure 1. Test performance of computed tomography for detection of patients with hepatocellular carcinoma in
nonsurveillance settings.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Trojan et al, 1999 (138) 0.93 (0.661.00) Trojan et al, 1999 (138)
Khan et al, 2000 (72) 0.90 (0.680.99) Khan et al, 2000 (72)
Lim et al, 2000 (94) 0.80 (0.520.96) Lim et al, 2000 (94) 0.96 (0.801.00)
Peterson et al, 2000 (120) 0.59 (0.430.74) Peterson et al, 2000 (120)
Mortel et al, 2001 (108) 0.82 (0.570.96) Mortel et al, 2001 (108) 1.00 (0.901.00)
Nakayama et al, 2001 (114) Nakayama et al, 2001 (114) 0.93 (0.840.98)
Libbrecht et al, 2002 (92) 0.50 (0.010.99) Libbrecht et al, 2002 (92) 0.77 (0.490.95)
de Ldinghen et al, 2002 (38) 0.81 (0.580.95) de Ldinghen et al, 2002 (38) 0.85 (0.550.98)
Burrel et al, 2003 (32) 1.00 (0.871.00) Burrel et al, 2003 (32) 0.95 (0.761.00)
Freeny et al, 2003 (46) 0.65 (0.430.84) Freeny et al, 2003 (46) 0.93 (0.760.99)
Teefey et al, 2003 (136) 0.63 (0.240.91) Teefey et al, 2003 (136) 0.72 (0.450.92)
Kim et al, 2006 (81) 0.89 (0.750.96) Kim et al, 2006 (81)
Rizvi et al, 2006 (125) 0.65 (0.380.86) Rizvi et al, 2006 (125) 1.00 (0.161.00)
Ronzoni et al, 2007 (127) 0.83 (0.700.93) Ronzoni et al, 2007 (127) 0.77 (0.620.89)
Denecke et al, 2009 (39) 1.00 (0.891.00) Denecke et al, 2009 (39)
Kim et al, 2009 (73) 0.87 (0.760.94) Kim et al, 2009 (73)
Yu et al, 2011 (146) 0.76 (0.680.82) Yu et al, 2011 (146) 0.92 (0.860.96)
Combined 0.83 (0.750.89) Combined 0.91 (0.860.96)
2 = 0.60; P = 0.01 2 = 0.63; P = 0.02
Total: N = 541; TP = 435 Total: N = 511; TN = 473
0.0 1.0 0.2 1.0
Sensitivity (95% CI) Specificity (95% CI)

TN = true negative; TP = true positive.

Across modalities, positive likelihood ratios ranged
from 7.7 to 11 and negative likelihood ratios from 0.16
to 0.29, with overlapping CIs (Table 1). For ultrasonog-
raphy without contrast, restricting the analysis to stud-
ies that avoided a case control design decreased sen-
sitivity (0.54 [CI, 0.38 to 0.70]; 6 studies). For CT,
studies with a contrast rate of 3 mL/s or greater re-
ported a higher sensitivity (0.86 [CI, 0.78 to 0.92]; 9
studies) than studies with a contrast rate less than 3
mL/s (0.71 [CI, 0.53 to 0.84]; 4 studies), and studies with
delayed-phase imaging reported somewhat higher
sensitivity (0.89 [CI, 0.81 to 0.94]; 7 studies) than stud-
ies without delayed-phase imaging (0.79 [CI, 0.68 to
0.87]; 8 studies).
The sensitivity of ultrasonography without contrast
for HCC lesions was 0.59 (CI, 0.42 to 0.74; 11 studies),
and specicity was 0.83 (CI, 0.53 to 0.95; 2 studies)
(Appendix Figure 4, available at www.annals.org). For
ultrasonography with contrast, sensitivity was 0.75 (CI,
0.57 to 0.88; 9 studies); only 1 study reported specic-
ity (Appendix Figure 5, available at www.annals.org). In
7 of 9 studies, the ultrasonography contrast agent was
perubutane. For CT, sensitivity was 0.76 (CI, 0.72 to
0.80; 80 studies) and specicity was 0.90 (CI, 0.84 to
0.93; 21 studies) (Appendix Figure 6, available at www
.annals.org). For MRI, sensitivity was 0.83 (CI, 0.80 to
0.86; 82 studies) and specicity was 0.88 (CI, 0.79 to
0.93; 20 studies) (Appendix Figure 7, available at www
.annals.org). The likelihood ratios were somewhat
700 Annals of Internal Medicine Vol. 162 No. 10 19 May 2015
weaker for ultrasonography without contrast (positive
likelihood ratio, 3.4 [CI, 1.2 to 9.4]; negative likelihood
ratio, 0.50 [CI, 0.37 to 0.66]) than for CT or MRI (positive
likelihood ratios, 7.1 and 6.5; negative likelihood ratios,
0.26 and 0.20, respectively). (157164)
Direct Comparisons
Within-study comparisons provide more direct evi-
dence on comparative test performance (strength of
evidence, moderate). Two studies that directly com-
pared ultrasonography with versus without contrast in
nonsurveillance settings found no difference in sensitiv-
ity for detection of HCC lesions (difference, 0.04 [CI,
0.11 to 0.04]) (Table 2) (165, 166).
Sensitivity was lower for ultrasonography without
contrast than CT or MRI. Compared with CT, the differ-
ence in sensitivity for HCC lesions was 0.11 (CI, 0.17
to 0.04; 3 studies); compared with MRI, the difference
was 0.22 (CI, 0.31 to 0.14; 3 studies). Findings
were similar for identication of patients with HCC.
Ultrasonography with contrast was also associated
with lower sensitivity than CT (difference, 0.16 [CI,
0.32 to 0.01]; 3 studies). The difference between
the sensitivity of ultrasonography with contrast and that
of MRI was smaller and not statistically signicant
(0.08 [CI, 0.19 to 0.02]; 3 studies).
When HCC lesions were used as the unit of analy-
sis, MRI was associated with higher sensitivity for HCC
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 Imaging Techniques for Diagnosis and Staging of Hepatocellular Carcinoma
lesions than CT (difference, 0.09 [CI, 0.07 to 0.12]; 32
studies). Findings were similar when studies were strat-
ied according to use of non hepatic-specic or
hepatic-specic contrast. The difference in sensitivity
was more pronounced for HCC lesions smaller than 2
to 3 cm (difference, 0.17 [CI, 0.13 to 0.21]; 22 studies),
particularly in studies that used hepatic-specic MRI
contrast agents (difference, 0.25 [CI, 0.19 to 0.31]; 14
studies).
Two studies of ultrasonography with contrast ver-
sus CT were performed in surveillance settings and re-
ported results that were consistent with the overall nd-
ings (34, 140). Other direct comparisons of imaging
modalities were performed in nonsurveillance settings.
In trials of MRI that directly compared test perfor-
mance using different contrast agents, use of hepatic-
specic contrast agents (gadoxetic acid or gado-
benate) was associated with higher sensitivity than
non hepatic-specic contrast agents (gadopentetate or
gadodiamide) (difference, 0.13 [CI, 0.07 to 0.18]; 9
studies), with no difference in specicity. The difference
was somewhat greater for HCC lesions smaller than 2
cm (difference, 0.15 [CI, 0.08 to 0.22]; 7 studies). There
was no difference in sensitivity between MRI with
diffusion-weighted and contrast-enhanced imaging
and contrast-enhanced MRI without diffusion-weighted
imaging for HCC lesions, including lesions smaller than
2 cm.
One trial found no clear difference between the
test performance of spectral versus standard CT (101).
REVIEW
Evaluation of Focal Liver Lesions
For evaluation of focal liver lesions, strength of ev-
idence ranged from low to moderate. Sensitivity of ul-
trasonography with contrast for identication of pa-
tients with HCC was 0.87 (CI, 0.79 to 0.92; 12 studies),
and specicity was 0.92 (CI, 0.83 to 0.95; 8 studies)
(Appendix Figure 8, available at www.annals.org). For
CT, sensitivity was 0.86 (CI, 0.75 to 0.92; 8 studies) and
specicity was 0.88 (CI, 0.76 to 0.95; 5 studies) (Appen-
dix Figure 9, available at www.annals.org). For MRI,
sensitivity was 0.75 (CI, 0.65 to 0.83; 5 studies) and
specicity was 0.83 (CI, 0.61 to 0.93; 5 studies) (Appen-
dix Figure 10, available at www.annals.org). The posi-
tive likelihood ratio was somewhat stronger for ultra-
sonography with contrast (9.6 [CI, 5.1 to 18]) than for
CT or MRI (7.4 and 4.1, respectively); the negative like-
lihood ratio ranged from 0.14 to 0.31 (Table 1).
Sensitivity of ultrasonography with contrast for HCC
lesions was 0.87 (CI, 0.80 to 0.92; 23 studies), and spec-
icity was 0.91 (CI, 0.85 to 0.95; 11 studies) (Appendix
Figure 11, available at www.annals.org). For CT, sensi-
tivity was 0.79 (CI, 0.67 to 0.87; 13 studies) and speci-
city was 0.90 (CI, 0.37 to 0.99; 6 studies) (Appendix
Figure 12, available at www.annals.org). For MRI, sensi-
tivity was 0.81 (CI, 0.73 to 0.88; 15 studies) and speci-
city was 0.92 (CI, 0.78 to 0.97; 12 studies) (Appendix
Figure 13, available at www.annals.org). Across modal-
ities, the positive likelihood ratio ranged from 7.7 to 10
and the negative likelihood ratio from 0.14 to 0.24, with
overlapping CIs.

Figure 2. Test performance of magnetic resonance imaging for detection of patients with hepatocellular carcinoma in
nonsurveillance settings.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Krinsky et al, 2001 (157) 0.55 (0.230.83) Krinsky et al, 2001 (157)
Krinsky et al, 2002 (158) 0.88 (0.680.97) Krinsky et al, 2002 (158)
Libbrecht et al, 2002 (92) 0.70 (0.350.93) Libbrecht et al, 2002 (92) 0.82 (0.570.96)
de Ldinghen et al, 2002 (38) 0.90 (0.700.99) de Ldinghen et al, 2002 (38) 1.00 (0.751.00)
Burrel et al, 2003 (32) 1.00 (0.881.00) Burrel et al, 2003 (32) 0.95 (0.761.00)
Teefey et al, 2003 (136) 0.50 (0.160.84) Teefey et al, 2003 (136) 0.75 (0.480.93)
Lauenstein et al, 2007 (159) 0.89 (0.710.98) Lauenstein et al, 2007 (159) 0.98 (0.921.00)
Seil et al, 2008 (160) 0.86 (0.570.98) Seil et al, 2008 (160) 0.83 (0.590.96)
Yu et al, 2011 (146) 0.85 (0.770.91) Yu et al, 2011 (146) 0.87 (0.790.93)
Park et al, 2012 (161) 0.88 (0.720.97) Park et al, 2012 (161) 0.84 (0.600.97)
Hanna et al, 2014 (162) 0.74 (0.610.85) Hanna et al, 2014 (162) 0.93 (0.770.99)
Hwang et al, 2014 (154) 0.94 (0.840.99) Hwang et al, 2014 (154) 1.00 (0.751.00)
Maiwald et al, 2014 (163) 0.92 (0.750.99) Maiwald et al, 2014 (163) 0.75 (0.530.90)
Yu et al, 2014 (164) 0.87 (0.750.94) Yu et al, 2014 (164) 0.80 (0.610.92)
Combined 0.86 (0.790.91) Combined 0.89 (0.830.93)
2 = 0.43; P = 0.02 2 = 0.54; P = 0.02
Total N = 490.5; TP = 418.5 Total N = 388; TN = 344
0.2 1.0 0.5 1.0
Sensitivity (95% CI) Specificity (95% CI)

TN = true negative; TP = true positive.

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Table 2. Pooled Direct (Within-Study) Comparisons of Test Performance of Imaging for HCC

Imaging Modality Unit of Analysis* Sensitivity A (95% CI) Sensitivity B (95% CI) Difference (95% CI)
Detection of HCC
US with contrast (A) vs. US without contrast (B) Lesion (1), liver 0.79 (0.72 to 0.76) 0.81 (0.76 to 0.86) 0.04 (0.11 to 0.04)
segment (1)
US without contrast (A) vs. CT (B) Patient 0.68 (0.54 to 0.80) 0.80 (0.68 to 0.88) 0.12 (0.20 to 0.03)
US without contrast (A) vs. CT (B) Lesion 0.55 (0.43 to 0.66) 0.66 (0.54 to 0.76) 0.11 (0.18 to 0.04)
US with contrast (A) vs. CT (B) Lesion 0.58 (0.37 to 0.77) 0.74 (0.54 to 0.87) 0.16 (0.32 to 0.01)
US without contrast (A) vs. MRI (B) Patient 0.61 (0.48 to 0.74) 0.81 (0.69 to 0.89) 0.19 (0.30 to 0.08)
US without contrast (A) vs. MRI (B) Lesion 0.57 (0.42 to 0.71) 0.79 (0.67 to 0.88) 0.22 (0.31 to 0.14)
US with contrast (A) vs. MRI (B) Lesion 0.65 (0.41 to 0.84) 0.73 (0.50 to 0.88) 0.08 (0.19 to 0.02)
MRI (A) vs. CT (B) Patient 0.88 (0.64 to 0.97) 0.82 (0.52 to 0.95) 0.06 (0.03 to 0.16)
MRI (A) vs. CT (B) Lesion 0.81 (0.76 to 0.84) 0.71 (0.66 to 0.76) 0.09 (0.07 to 0.12)
HCC lesions <2 cm Lesion 0.72 (0.65 to 0.79) 0.56 (0.47 to 0.63) 0.17 (0.13 to 0.21)
Nonhepatic-specic MRI contrast Lesion 0.61 (0.44 to 0.75) 0.55 (0.38 to 0.70) 0.06 (0.00 to 0.13)
Hepatic-specic contrast Lesion 0.76 (0.69 to 0.82) 0.51 (0.42 to 0.60) 0.25 (0.19 to 0.31)
MRI with gadoxetic acid or gadobenate (A) vs. Lesion 0.83 (0.76 to 0.89) 0.71 (0.61 to 0.79) 0.13 (0.07 to 0.18)
gadopentetate or gadodiadmide (B)
HCC lesions <2 cm Lesion 0.77 (0.68 to 0.84) 0.62 (0.52 to 0.71) 0.15 (0.08 to 0.22)
Diffusion-weighted imaging plus contrast- Lesion (3), 0.86 (0.77 to 0.91) 0.84 (0.78 to 0.89) 0.01 (0.04 to 0.07)
enhanced imaging (A) vs. contrast- patient (1)
enhanced imaging alone (B)
HCC lesions <2 cm Lesion 0.78 (0.67 to 0.86) 0.75 (0.63 to 0.84) 0.04 (0.02 to 0.09)

Evaluation of focal liver lesions

US with contrast (A) vs. US without contrast (B) Lesion 0.89 (0.83 to 0.93) 0.39 (0.32 to 0.47) 0.50 (0.41 to 0.58)
US without contrast (A) vs. CT (B) Patient 0.78 (0.70 to 0.85) 0.89 (0.84 to 0.95) 0.12 (0.21 to 0.02)
US with contrast (A) vs. CT (B) Patient 0.91 (0.85 to 0.94) 0.88 (0.81 to 0.92) 0.03 (0.02 to 0.08)
US with contrast (A) vs. CT (B) Lesion 0.92 (0.88 to 0.96) 0.89 (0.83 to 0.93) 0.04 (0.02 to 0.09)
HCC lesions <2 cm Lesion 0.78 (0.61 to 0.89) 0.71 (0.52 to 0.85) 0.07 (0.01 to 0.15)
US with contrast (A) vs. MRI (B) Patient 0.79 (0.65 to 0.94) 0.83 (0.69 to 0.97) 0.03 (0.24 to 0.17)
US with contrast (A) vs. MRI (B) Lesion 0.79 (0.65 to 0.94) 0.83 (0.69 to 0.97) 0.03 (0.24 to 0.17)
HCC lesions <2 cm Lesion 0.53 (0.28 to 0.76) 0.68 (0.43 to 0.86) 0.16 (0.30 to 0.02)
MRI (A) vs. CT (B) Patient 0.81 (0.70 to 0.92) 0.74 (0.62 to 0.87) 0.06 (0.10 to 0.23)
MRI (A) vs. CT (B) Lesion 0.84 (0.76 to 0.92) 0.62 (0.52 to 0.72) 0.22 (0.09 to 0.35)
HCC lesion <2 cm Lesion 0.65 (0.04 to 0.99) 0.50 (0.02 to 0.98) 0.15 (0.002 to 0.30)
CT = computed tomography; HCC = hepatocellular carcinoma; MRI = magnetic resonance imaging; US = ultrasonography.
* Numbers in parentheses are the numbers of studies.

Direct Comparisons more pronounced for ultrasonography with contrast

Two studies found ultrasonography with contrast to
be associated with higher sensitivity than ultrasonogra-
phy without contrast (difference, 0.50 [CI, 0.41 to 0.58])
(Table 2) (167, 168). Sensitivity was very similar for ul-
trasonography with contrast versus CT (4 to 5 studies).
Ultrasonography with contrast was associated with
lower sensitivity than MRI for HCC lesions smaller than
2 cm, on the basis of 3 studies (difference, 0.16 [CI,
0.30 to 0.02]).
One study found no clear difference between MRI
versus CT in test performance for identication of pa-
tients with HCC (132), but another study found MRI to
have higher sensitivity (difference, 0.22 [CI, 0.09 to
0.35]) and lower specicity (difference, 0.36 [CI,
0.58 to 0.15]) for HCC lesions (49). Sensitivity was
also lower for HCC lesions smaller than 2 to 3 cm, but
the difference was of borderline statistical signicance
(difference, 0.15 [CI, 0.00 to 0.30]; 3 studies) (49, 71,
128).
Effects of a Reference Standard
Across imaging modalities, sensitivity was lower
when an explanted liver was used as the reference stan-
dard than when other reference standards were used
(Appendix Table 4, available at www.annals.org;
strength of evidence, moderate). The difference was
702 Annals of Internal Medicine Vol. 162 No. 10 19 May 2015
(sensitivity for HCC lesions, 0.34 with explanted liver vs.
0.72 to 0.75 with other reference standards) and less
pronounced for CT and MRI (sensitivity, 0.67 and 0.70,
respectively, for explanted liver and 0.80 to 0.88 for
other reference standards). A similar pattern was ob-
served for ultrasonography without contrast when pa-
tients with HCC lesions were used as the unit of
analysis.
Effects of Patient and Tumor Characteristics
Across imaging modalities, sensitivity increased
with larger tumor sizes (Appendix Table 5, available at
www.annals.org; strength of evidence, moderate). Dif-
ferences in sensitivity for lesions larger than 20 mm ver-
sus those 10 to 20 mm ranged from 0.17 to 0.37; for
lesions 10 to 20 mm versus those smaller than 10 mm,
differences in sensitivity ranged from 0.28 to 0.42. Sen-
sitivity was also higher for moderately or poorly differ-
entiated versus well-differentiated tumors (difference,
0.34 to 0.40).
Effects of other tumor characteristics and patient
factors on test performance were not well-studied
(strength of evidence, insufcient to low). For ultra-
sonography, lesion depth and body mass index had no
effect on estimates of sensitivity (169 171). For MRI, 3
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 Imaging Techniques for Diagnosis and Staging of Hepatocellular Carcinoma REVIEW

Table 2Continued

Studies, n Specicity A (95% CI) Specicity B (95% CI) Difference (95% CI) Studies, n

2 0.98 (0.96 to 0.997) 0.92 (0.89 to 0.95) 0.06 (0.02 to 0.10) 1

6 0.92 (0.84 to 0.96) 0.94 (0.87 to 0.97) 0.01 (0.05 to 0.02) 5

3 0.83 (0.65 to 0.93) 0.93 (0.83 to 0.98) 0.10 (0.20 to 0.008) 2
3 No data No data
3 0.94 (0.87 to 0.97) 0.82 (0.66 to 0.91) 0.13 (0.03 to 0.22) 3
3 0.75 (0.66 to 0.82) 0.78 (0.700.85) 0.03 (0.13 to 0.06) 2
3 No data No data
5 0.83 (0.68 to 0.92) 0.90 (0.79 to 0.95) 0.07 (0.15 to 0.01) 5
32 0.86 (0.78 to 0.91) 0.91 (0.85 to 0.95) 0.05 (0.10 to 0.002) 7
22 0.91 (0.84 to 0.95) 0.91 (0.84 to 0.95) 0.002 (0.05 to 0.04) 5
6 0.77 (0.64 to 0.86) 0.74 (0.61 to 0.84) 0.03 (0.13 to 0.19) 1
14 0.92 (0.85 to 0.96) 0.94 (0.87 to 0.97) 0.01 (0.06 to 0.04) 4
9 0.87 (0.78 to 0.92) 0.88 (0.80 to 0.93) 0.02 (0.09 to 0.05) 6

7 0.93 (0.82 to 0.98 0.91 (0.79 to 0.97) 0.02 (0.05 to 0.09) 2

4 0.88 (0.74 to 0.95) 0.76 (0.62 to 0.86) 0.11 (0.01 to 0.02) 4

7 0.92 (0.76 to 0.98) 0.89 (0.70 to 0.96) 0.03 (0.04 to 0.11) 4

2 1.0 (1.01.0) 0.94 (0.85 to 1.0) 0.06 (0.02 to 0.15) 1

1 No data No data
5 0.93 (0.87 to 0.96) 0.94 (0.88 to 0.97) 0.01 (0.06 to 0.05) 2
4 No data No data
7 0.87 (0.62 to 0.97) 0.94 (0.77 to 0.98) 0.06 (0.15 to 0.03) 4
1 0.79 (0.68 to 0.90) 0.75 (0.64 to 0.87) 0.04 (0.12 to 0.20) 1
1 0.79 (0.68 to 0.90) 0.75 (0.64 to 0.87) 0.04 (0.12 to 0.20) 1
3 0.95 (0.85 to 0.98) 0.98 (0.91 to 0.99) 0.03 (0.08 to 0.02) 3
1 0.85 (0.72 to 0.99) 0.81 (0.66 to 0.96) 0.04 (0.16 to 0.24) 1
1 0.36 (0.200.52) 0.72 (0.58 to 0.87) 0.36 (0.58 to 0.15) 1
3 0.93 (0.21 to 0.998) 0.98 (0.48 to 0.9996) 0.05 (0.23 to 0.13) 3

studies found that sensitivity decreased as ChildPugh
class increased (154, 172, 173).
DISCUSSION
The key ndings of this review, including detailed
strength of evidence grades, are summarized in Ap-
pendix Table 6 (available at www.annals.org). For de-
tection of HCC, too few studies were conducted in sur-
veillance settings to draw strong conclusions, although
2 head-to-head studies found that ultrasonography
without contrast had lower sensitivity than CT (34, 140).
In nonsurveillance settings, on the basis of within-study
comparisons, sensitivity for HCC lesions was lower for
ultrasonography without contrast than for CT or MRI
(difference, 0.11 to 0.22) and sensitivity of MRI was
higher than that of CT (difference, 0.09 [CI 0.07 to 12]).
There were no differences between ultrasonography
with versus without contrast for detection of HCC in
patients not undergoing evaluation of focal liver lesions
(165, 166); this nding is consistent with the short du-
ration that microbubble contrast is present within the
liver (12). For evaluation of focal liver lesions, there
were no clear differences in sensitivity among ultra-
sonography with contrast, CT, and MRI, except that ul-
trasonography with contrast was associated with lower
sensitivity than MRI for small HCC lesions.
www.annals.org
Across imaging modalities, specicity was gener-
ally 0.85 or higher, but many studies did not report
specicity and pooled estimates were frequently impre-
cise. Most likelihood ratios were in or near the moder-
ately useful range (positive likelihood ratio of 5 to 10
and negative likelihood ratio of 0.1 to 0.2) (174).
Across imaging modalities, factors associated with
lower estimates of sensitivity were an explanted liver as
the reference standard, HCC lesions (rather than pa-
tients with HCC) as the unit of analysis, and smaller or
more well-differentiated HCC lesions. For CT, higher
contrast rates and use of delayed-phase imaging were
associated with higher sensitivity in subgroup analyses.
For MRI, within-study comparisons found hepatic-
specic contrast agents to be associated with slightly
higher sensitivity than non hepatic-specic contrast
agents, particularly for smaller lesions. Other sensitivity
and stratied analyses, including analyses based on
technical factors, resulted in no clear differences.
Our ndings differ from those of previously pub-
lished reviews that found no clear differences in test
performance among ultrasonography, CT, and MRI
(175178). Some features of our review that might ex-
plain these discrepancies include inclusion of more
studies, and performance of separate analyses based
on reason for imaging and unit of analysis. In addition,
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 REVIEW
we found differences in the sensitivity of imaging mo-
dalities for detection of HCC in direct (within-study)
comparisons that were not observed in indirect (across-
study) comparisons. This is consistent with research
showing that results of diagnostic test reviews based on
direct comparisons often differ from those of reviews
based on indirect comparisons (23).
Some factors might affect the applicability of our
ndings. Over one half of the studies were conducted
in Asia, although stratication of studies by country had
no clear effects on estimates. Some studies excluded
nonhypervascular HCC lesions, but estimates were sim-
ilar when we excluded such studies. Because imaging
techniques are evolving, we restricted our review to
studies published since 1998 and to imaging methods
that met minimal technical criteria, and performed ad-
ditional sensitivity and subgroup analyses on technical
factors. Almost all studies on detection of HCC were
performed in nonsurveillance settings, most of which
evaluated high-prevalence populations.
Our review has limitations. Substantial statistical
heterogeneity was present in most pooled analysesa
situation common in meta-analyses of diagnostic accu-
racy (179 181). Because of anticipated heterogeneity,
we used a random-effects model to pool studies,
performed stratied and subgroup analyses, and per-
formed separate analyses based on within-study com-
parisons. In addition, we restricted inclusion to English-
language articles and did not formally assess for
publication bias by using statistical or graphical meth-
ods for small sample effects, because such methods
can be misleading for diagnostic studies (182, 183). We
did not identify unpublished studies through searches
on clinical trial registries and regulatory documents, al-
though the usefulness of such methods for diagnostic
studies may be limited.
Although test performance can provide useful in-
formation about the accuracy of diagnostic tests (Ap-
pendix Table 7, available at www.annals.org), the ef-
fects on clinical outcomes depend on whether they
lead to more optimal use of effective interventions, bal-
anced against harms from performing the test or sub-
sequent tests and interventions. As described in the full
report (13), the only study on the effects of surveillance
(with ultrasonography and -fetoprotein) versus no sur-
veillance on clinical outcomes found a decreased risk
for liver-specic mortality, but it was conducted in
China and had methodological shortcomings (184). No
study measured downstream harms related to false-
positive or false-negative test results, anxiety or label-
ing due to imaging, or subsequent work-up after imag-
ing. Although the risk for serious imaging-related direct
harms appears to be low (185188), potential harms
include serious cardiopulmonary events with micro-
bubble contrast agents (189 191) and long-term ef-
fects of radiation exposure with CT (192). Factors other
than test performance, such as convenience or cost,
that depend on the imaging modality and specic
technical factors (such as the type of contrast and im-
aging machine), frequency of imaging, and need for
704 Annals of Internal Medicine Vol. 162 No. 10 19 May 2015
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Imaging Techniques for Diagnosis and Staging of Hepatocellular Carcinoma
follow-up testing, may also affect the choice of imaging
modalities and techniques.
In conclusion, CT and MRI are associated with
higher sensitivity than ultrasonography without contrast
for detection of HCC; sensitivity is higher for MRI than
for CT. For evaluation of focal liver lesions, the sensitiv-
ities of ultrasonography with contrast, CT, and MRI for
HCC seem to be similar. Across imaging modalities,
sensitivity was low for small and well-differentiated le-
sions. Research is needed to understand the effects of
test performance differences on clinical outcomes.
From Pacic Northwest Evidence-based Practice Center, Ore-
gon Health & Science University, Portland, Oregon; University
of Washington Centers for Comparative and Health Systems
Effectiveness (CHASE) Alliance, Seattle, Washington; and
Mayo Medical School, Rochester, Minnesota.
Disclaimer: The ndings and conclusions in this document are
those of the authors, who are responsible for its content, and
do not necessarily represent the views of the Agency for
Healthcare Research and Quality (AHRQ). No statement in this
report should be construed as an ofcial position of AHRQ or
of the U.S. Department of Health and Human Services.
Grant Support: By the Agency for Healthcare Research and
Quality (contract 290-2007-10057-I, task order 8).
Acknowledgment: The authors thank Tracy Dana, MLS, for as-
sistance with literature search strategy development; Monica
Daeges, BA, and Sara Grusing, BS, for manuscript and library
assistance; Leah Williams, BS, for editorial support; and AHRQ
Task Order Ofcer Nahed El-Kassar, MD, PhD.
Disclosures: Dr. Chou reports grants from AHRQ during the
conduct of the study. Dr. Cuevas reports grants from AHRQ
during the conduct of the study and has received grants from
National Institutes of Health (NIH R21: Minimally Invasive Ab-
lative Therapies for Pancreatic Mucinous Cystic Neoplasms)
outside the submitted work. Dr. Fu reports funds from Ore-
gon Health & Science University during the conduct of the
study. Ms. Graham reports funds from AHRQ during the con-
duct of the study. Dr. Zakher reports funds from AHRQ during
the conduct of the study. Authors not named here have dis-
closed no conicts of interest. Disclosures can also be viewed
at www.acponline.org/authors/icmje/ConictOfInterestForms
.do?msNum=M14-2509.
Requests for Single Reprints: Roger Chou, MD, Oregon
Health & Science University, Mail Code BICC, 3181 Southwest
Sam Jackson Park Road, Portland, OR 97239-3098; e-mail,
chour@ohsu.edu.
Current author addresses and author contributions are avail-
able at www.annals.org.
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 Current Author Addresses: Dr. Chou: The Pacic Northwest
Evidence-based Practice Center, Oregon Health & Science
University, Mail Code BICC, 3181 Southwest Sam Jackson
Park Road, Portland, OR 97239-3098.
Dr. Cuevas: Department of Radiology, University of Washing-
ton, Box 357115, 1959 NE Pacic Street, Seattle, WA
98195-7115.
Drs. Fu and Zakher, Ms. Wasson, Ms. Pappas, and Ms. Gra-
ham: The Pacic Northwest Evidence-based Practice Center,
Department of Medicine, Department of Medical Informatics
and Clinical Epidemiology, Oregon Health & Science Univer-
sity, Mail Code BICC, 3181 Southwest Sam Jackson Park
Road, Portland, OR 97239-3098.
Dr. Devine: University of Washington, Department of Phar-
macy, Box 357630, 1959 NE Pacic Street, Seattle, WA
98195-7630.
Mr. Ginsburg: Mayo Medical School, 200 First Street SW,
Rochester, MN 55905.
Dr. Sullivan: School of Pharmacy, University of Washington,
Box 357631, 1959 NE Pacic Street, Seattle, WA 98195-7631.
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Author Contributions: Conception and design: R. Chou, C.
Cuevas, E. Graham, S.D. Sullivan.
Analysis and interpretation of the data: R. Chou, C. Cuevas, R.
Fu, B. Devine, N. Wasson, A. Ginsburg, B. Zakher, S.D.
Sullivan.
Drafting of the article: R. Chou, N. Wasson.
Critical revision of the article for important intellectual con-
tent: R. Chou, C. Cuevas, R. Fu, B. Devine, N. Wasson, A. Gins-
burg, B. Zakher, S.D. Sullivan.
Final approval of the article: R. Chou, C. Cuevas, R. Fu, B.
Devine, N. Wasson, M. Pappas, E. Graham, S.D. Sullivan.
Provision of study materials or patients: C. Cuevas, N. Wasson.
Statistical expertise: R. Chou, R. Fu.
Obtaining of funding: R. Chou, E. Graham, S.D. Sullivan.
Administrative, technical, or logistic support: R. Chou, N. Was-
son, A. Ginsburg, M. Pappas, E. Graham.
Collection and assembly of data: R. Chou, C. Cuevas, B.
Devine, N. Wasson, A. Ginsburg, B. Zakher, M. Pappas, E. Gra-
ham, S.D. Sullivan.
Annals of Internal Medicine Vol. 162 No. 10 19 May 2015
 Appendix Table 1. Inclusion and Exclusion Criteria

Key Questions Inclusion Criteria Exclusion Criteria

All key questions
Interventions Ultrasonography (with or without contrast)
Contrast-enhanced spiral CT (including nonmultidetector or
multidetector CT, and CT using dual-energy and spectral methods)
Contrast-enhanced MRI using a 1.5- or 3.0-T scanner
Diffusion-weighted MRI
PET or PET/CT (including use of 18F-uorodeoxyglucose ,
18
F-uorothymidine, 11C-acetate, and 11C-choline tracers)
Comparisons For studies of diagnostic accuracy (comparative test performance):
Reference standard comparators: histopathologic examination
(based on explanted liver specimens or biopsy), clinical follow-up,
and imaging follow-up
Imaging comparators: alternative imaging tests or strategies
For studies of comparative effectiveness:
No imaging, or an alternative imaging strategy
Timing No restrictions
Setting All care settings (e.g., primary and secondary care)
Study design Controlled randomized and nonrandomized trials
Cohort studies on effects of imaging on diagnostic thinking or clinical
decision making
Studies of diagnostic accuracy
Outdated imaging techniques (e.g.,
conventional, nonspiral/nonmultidetector CT,
MRI using a 1.0-T scanner)
CT and MRI without contrast, with the exception
of studies of diffusion-weighted MRI without
contrast
CT arterial portography and CT hepatic
arteriography
C-arm CT
Intraoperative ultrasonography
MRI with ferucarbotran, ferumoxides, or
mangafodipir contrast
Does not meet inclusion criteria
None
None
Studies of diagnostic accuracy that did not
report the reference standard used, or in
which the reference standard included the
results of the test being investigated
Case reports, case series, letters to the editor,
and nonsystematic reviews
Studies published before 1998 or in which
imaging was performed before 1995, unless
technical details were reported and studies
met minimum technical criteria as described in
the Interventions section above

Key questions 1 and 2

Populations Key question 1: Patients with cholangiocarcinoma, unless they
Patients at high risk for HCC undergoing surveillance, including: comprised <10% of the study population
Asian male HBV carriers aged >40 y, Asian female HBV carriers Patients with nonprimary (metastatic) lesions to
aged >50 y, HBV carriers with a family history of HCC, African/North the liver
American black HBV carriers, all individuals with cirrhosis (including Patients undergoing imaging to evaluate
alcoholic cirrhosis), HBV or HCV carriers with cirrhosis, and patients response to ablative or other treatments
with stage 4 primary biliary cirrhosis Children
Other high-risk patients undergoing surveillance, as dened by the
primary studies
Patients enrolled in studies designed to determine detection rates
of imaging for HCC, including patients who underwent liver
transplantation or surgery for HCC or other reasons
Key question 2:
Patients in whom a suspicious lesion for HCC has been detected by
surveillance or by other means, including patients who underwent
liver transplantation for HCC or other reasons
Patients enrolled in studies designed to distinguish HCC from
another type of liver lesion (benign or malignant)
Outcomes Diagnostic outcomes: test performance, types of HCC lesions Nonclinical and nondiagnostic outcomes
detected
Intermediate outcomes: effects on diagnostic thinking, effects on
clinical decision making
Clinical and patient-centered outcomes: overall mortality or survival;
recurrence of HCC, including rates of seeding by ne-needle
aspiration; quality of life, as measured with scales such as the Short
Form Health Survey or EuroQol-5D; and psychosocial effects of
diagnostic testing on patients, patients' caregivers, and other family
members
Resource utilization and patient burden (e.g., costs associated with
the imaging procedure, number of imaging procedures, and other
procedures performed)
Harms: adverse effects or harms associated with the imaging
techniques (e.g., test-related anxiety, adverse events secondary to
venipuncture, contrast allergy, exposure to radiation) and adverse
effects or harms associated with test-associated diagnostic work-up
(e.g., harms of biopsy or harms associated with work-up of other
incidental tumors discovered on imaging)
CT = computed tomography; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; MRI = magnetic resonance
imaging; PET = positron emission tomography.

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 Appendix Figure 1. Summary of evidence search and selection.

Records identified (n = 5202)

Records after duplicates removed (n = 5124)

Records screened (n = 5124) Records excluded (n = 4234)

Full-text articles excluded (n = 592)

Full-text articles assessed
Background: 87
for eligibility (n = 890)*
Systematic review: 12
Wrong population: 162
Wrong intervention: 69
Wrong comparator: 11
Wrong outcome: 189
Studies evaluating research Wrong setting: 2
questions not covered by Wrong study design: 6
this publication (n = 57)* Wrong publication type: 9
Not English language: 7
Imaging before 1995: 6
Studies included (n = 241) Inadequate reference standard: 32

* Studies of positron emission tomography; effects on clinical decisions, clinical outcomes, or staging; and accuracy for distinguishing hepatocel-
lular carcinoma lesions from another specic type of liver lesion are addressed in the full report (13).

Appendix Table 2. Technical Factors Abstracted, by

Imaging Modality
Imaging Modality Technical Factors Abstracted
Ultrasonography Use of contrast
Type of contrast
Ultrasonography operator (technician, physician,
or other)
Transducer frequency
Use of Doppler

CT Use of multidetector scanner and number of rows

Imaging sequences with timing
Contrast rate
Section thickness for contrast-enhanced images
Use of dual-energy or spectral CT techniques

MRI MRI unit type (number of Teslas)

Imaging sequences with timing
Type of contrast
Section thickness
Use of diffusion-weighted imaging sequences
Spatial resolution
CT = computed tomography; MRI = magnetic resonance imaging.

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 Appendix Table 3. References to Articles That Met the Inclusion Criteria

Article Study Diagnostic

Number Tests Studied
1 Addley HC, Grifn N, Shaw AS, Mannelli L, Parker RA, Aitken S, et al. Accuracy of hepatocellular carcinoma detection on CT
multidetector CT in a transplant liver population with explant liver correlation. Clin Radiol. 2011;66:349-56. [PMID:
21295772]
2 Ahn SS, Kim M-J, Lim JS, Hong H-S, Chung YE and Choi J-Y. Added value of gadoxetic acid-enhanced hepatobiliary MRI
phase MR imaging in the diagnosis of hepatocellular carcinoma. Radiology. 2010;255:459-66. [PMID: 20413759]
3 Akai H, Kiryu S, Matsuda I, Satou J, Takao H, Tajima T, et al. Detection of hepatocellular carcinoma by CT
Gd-EOB-DTPA-enhanced liver MRI: comparison with triple phase 64 detector row helical CT. Eur J Radiol.
2011;80:310-5. [PMID: 20732773]
4 Alaboudy A, Inoue T, Hatanaka K, Chung H, Hyodo T, Kumano S, et al. Usefulness of combination of imaging modalities US, CT, MRI
in the diagnosis of hepatocellular carcinoma using Sonazoid(R)-enhanced ultrasound, gadolinium
diethylene-triamine-pentaacetic acid-enhanced magnetic resonance imaging, and contrast-enhanced computed
tomography. Oncology. 2011;81 Suppl 1:66-72. [PMID: 22212939]
5 An C, Park MS, Jeon HM, Kim YE, Chung W-S, Chung YE, et al. Prediction of the histopathological grade of MRI
hepatocellular carcinoma using qualitative diffusion-weighted, dynamic, and hepatobiliary phase MRI. Eur Radiol.
2012;22:1701-8. [PMID: 22434421]
6 An C, Park MS, Kim D, Kim YE, Chung WS, Rhee H, et al. Added value of subtraction imaging in detecting arterial MRI
enhancement in small (<3 cm) hepatic nodules on dynamic contrast-enhanced MRI in patients at high risk of
hepatocellular carcinoma. Eur Radiol. 2013;23:924-30. [PMID: 23138382]
7 Baccarani U, Adani GL, Avellini C, Lorenzin D, Curro G, Beltrami A, et al. Comparison of clinical and pathological staging CT
and long-term results of liver transplantation for hepatocellular carcinoma in a single transplant center. Transplant
Proc. 2006;38:1111-3. [PMID: 16757280]
8 Baek CK, Choi JY, Kim KA, Park MS, Lim JS, Chung YE, et al. Hepatocellular carcinoma in patients with chronic liver CT, MRI
disease: a comparison of gadoxetic acid-enhanced MRI and multiphasic MDCT. Clin Radiol. 2012;67:148-56. [PMID:
21920517]
9 Baird AJ, Amos GJ, Saad NF and Benson MD. Retrospective audit to determine the diagnostic accuracy of MRI
Primovist-enhanced MRI in the detection of hepatocellular carcinoma in cirrhosis with explant histopathology
correlation. J Med Imaging Radiat Oncol. 2013;57:314-20. [PMID: 23721140]
10 Bartolozzi C, Donati F, Cioni D, Crocetti L and Lencioni R. MnDPDP-enhanced MRI vs dual-phase spiral CT in the CT
detection of hepatocellular carcinoma in cirrhosis. Eur Radiol. 2000;10:1697-702. [PMID: 11097390]
11 Bennett GL, Krinsky GA, Abitbol RJ, Kim SY, Theise ND and Teperman LW. Sonographic detection of hepatocellular US
carcinoma and dysplastic nodules in cirrhosis: correlation of pretransplantation sonography and liver explant
pathology in 200 patients. AJR Am J Roentgenol. 2002;179:75-80. [PMID: 12076908]
12 Bhattacharjya S, Bhattacharjya T, Quaglia A, Dhillon AP, Burroughs AK, Patch DW, et al. Liver transplantation in cirrhotic CT
patients with small hepatocellular carcinoma: an analysis of pre-operative imaging, explant histology and prognostic
histologic indicators. Dig Surg. 2004;21:152-9. [PMID: 15166485]
13 Burrel M, Llovet JM, Ayuso C, Iglesias C, Sala M, Miquel R, et al. MRI angiography is superior to helical CT for detection CT
of HCC prior to liver transplantation: an explant correlation. Hepatology. 2003;38:1034-42. [PMID: 14512891]
14 Catala V, Nicolau C, Vilana R, Pages M, Bianchi L, Sanchez M, et al. Characterization of focal liver lesions: comparative US
study of contrast-enhanced ultrasound versus spiral computed tomography. Eur Radiol. 2007;17:1066-73. [PMID:
17072617]
15 Cereser L, Furlan A, Bagatto D, Girometti R, Como G, Avellini C, et al. Comparison of portal venous and delayed phases MRI
of gadolinium-enhanced magnetic resonance imaging study of cirrhotic liver for the detection of contrast washout of
hypervascular hepatocellular carcinoma. J Comput Assist Tomogr. 2010;34:706-11. [PMID: 20861773]
16 Chalasani N, Horlander JC, Sr., Said A, Hoen H, Kopecky KK, Stockberger SM, Jr., et al. Screening for hepatocellular US
carcinoma in patients with advanced cirrhosis. Am J Gastroenterol. 1999;94:2988-93. [PMID: 10520857]
17 Cheung TT, Ho CL, Lo CM, Chen S, Chan SC, Kenneth SHC, et al. 11C-acetate and 18F-FDG PET/CT for clinical staging CT
and selection of patients with hepatocellular carcinoma for liver transplantation on the basis of milan criteria:
Surgeon's perspective. J Nucl Med. 2013;54:192-200. [PMID: 23321459]
18 Choi D, Kim SH, Lim JH, Cho JM, Lee WJ, Lee SJ, et al. Detection of hepatocellular carcinoma: combined T2-weighted MRI
and dynamic gadolinium-enhanced MRI versus combined CT during arterial portography and CT hepatic
arteriography. J Comput Assist Tomogr. 2001;25:777-85. [PMID: 11584240]
19 Choi SH, Lee JM, Yu NC, Suh K-S, Jang J-J, Kim SH, et al. Hepatocellular carcinoma in liver transplantation candidates: MRI
detection with gadobenate dimeglumine-enhanced MRI. AJR Am J Roentgenol. 2008;191:529-36. [PMID: 18647927]
20 Chou C-T, Chen R-C, Chen W-T and Lii J-M. Characterization of hyperintense nodules on T1-weighted liver magnetic MRI
resonance imaging: comparison of Ferucarbotran-enhanced MRI with accumulation-phase FS-T1WI and
gadolinium-enhanced MRI. J Chin Med Assoc. 2011;74:62-8. [PMID: 21354082]
21 Chung S-H, Kim M-J, Choi J-Y and Hong H-S. Comparison of two different injection rates of gadoxetic acid for arterial MRI
phase MRI of the liver. J Magn Reson Imaging. 2010;31:365-72. [PMID: 20099350]
22 Chung J, Yu J-S, Kim DJ, Chung J-J, Kim JH and Kim KW. Hypervascular hepatocellular carcinoma in the cirrhotic liver: MRI
diffusion-weighted imaging versus superparamagnetic iron oxide-enhanced MRI. Magn Reson Imaging.
2011;29:1235-43. [PMID: 21907517]
23 Colagrande S, Fargnoli R, Dal Pozzo F, Bindi A, Rega L and Villari N. Value of hepatic arterial phase CT versus lipiodol CT
ultrauid CT in the detection of hepatocellular carcinoma. J Comput Assist Tomogr. 2000;24:878-83. [PMID:
11105704]
24 Dai Y, Chen MH, Fan ZH, Yan K, Yin SS and Zhang XP. Diagnosis of small hepatic nodules detected by surveillance US, CT
ultrasound in patients with cirrhosis: Comparison between contrast-enhanced ultrasound and contrast-enhanced
helical computed tomography. Hepatol Res. 2008;38:281-90. [PMID: 17908168]
25 de Ledinghen V, Laharie D, Lecesne R, Le Bail B, Winnock M, Bernard P-H, et al. Detection of nodules in liver cirrhosis: CT, MRI
spiral computed tomography or magnetic resonance imaging? A prospective study of 88 nodules in 34 patients. Eur J
Gastroenterol Hepatol. 2002;14:159-65. [PMID: 11981340]
Continued on following page

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 Appendix Table 3Continued

Article Study Diagnostic

Number Tests Studied
26 Denecke T, Grieser C, Froling V, Steffen IG, Rudolph B, Stelter L, et al. Multislice computed tomography using a CT
triple-phase contrast protocol for preoperative assessment of hepatic tumor load in patients with hepatocellular
carcinoma before liver transplantation. Transpl Int. 2009;22:395-402. [PMID: 19000231]
27 Di Martino M, Marin D, Guerrisi A, Baski M, Galati F, Rossi M, et al. Intraindividual comparison of gadoxetate US, CT, MRI
disodium-enhanced MR imaging and 64-section multidetector CT in the Detection of hepatocellular carcinoma in
patients with cirrhosis. Radiology. 2010;256:806-16. [PMID: 20720069]
28 Di Martino M, De Filippis G, De Santis A, Geiger D, Del Monte M, Lombardo CV, et al. Hepatocellular carcinoma in US, CT, MRI
cirrhotic patients: prospective comparison of US, CT and MR imaging. Eur Radiol. 2013;23:887-96. [PMID: 23179521]
29 Donati OF, Hunziker R, Fischer MA, Raptis DA, Breitenstein S and Patak MA. MRI for characterization of primary tumors MRI
in the non-cirrhotic liver: added value of Gd-EOB-DTPA enhanced hepatospecic phase. Eur J Radiol.
2014;83:1074-9. [PMID: 24816085]
30 D'Onofrio M, Rozzanigo U, Masinielli BM, Caffarri S, Zogno A, Malago R, et al. Hypoechoic focal liver lesions: US
characterization with contrast enhanced ultrasonography. J Clin Ultrasound. 2005;33:164-72. [PMID: 15856516]
31 Doyle DJ, O'Malley ME, Jang H-J, Jhaveri K. Value of the unenhanced phase for detection of hepatocellular carcinomas CT
3 cm or less when performing multiphase computed tomography in patients with cirrhosis. J Comput Assist Tomogr.
2007;31:86-92. [PMID: 17259838]
32 Egger C, Goertz RS, Strobel D, Lell M, Neurath MF, Knieling F, et al. Dynamic contrast-enhanced ultrasound (DCE-US) US
for easy and rapid evaluation of hepatocellular carcinoma compared to dynamic contrast-enhanced computed
tomography (DCE-CT)a pilot study. Ultraschall Med. 2012;33:587-92. [PMID: 23154871]
33 Forner A, Vilana R, Ayuso C, Bianchi L, Sole M, Ayuso JR, et al. Diagnosis of hepatic nodules 20 mm or smaller in US, CT, MRI
cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.[Erratum appears
in Hepatology. 2008 Feb;47(2):769]. Hepatology. 2008;47:97-104. [PMID: 18069697]
34 Fracanzani AL, Burdick L, Borzio M, Roncalli M, Bonelli N, Borzio F, et al. Contrast-enhanced Doppler ultrasonography in US
the diagnosis of hepatocellular carcinoma and premalignant lesions in patients with cirrhosis. Hepatology.
2001;34:1109-12. [PMID: 11731999]
35 Freeman RB, Mithoefer A, Ruthazer R, Nguyen K, Schore A, Harper A, et al. Optimizing staging for hepatocellular US
carcinoma before liver transplantation: A retrospective analysis of the UNOS/OPTN database. Liver Transpl.
2006;12:1504-11. [PMID: 16952174]
36 Freeny PC, Grossholz M, Kaakaji K and Schmiedl UP. Signicance of hyperattenuating and contrast-enhancing hepatic CT
nodules detected in the cirrhotic liver during arterial phase helical CT in pre-liver transplant patients:
radiologic-histopathologic correlation of explanted livers. Abdom Imaging. 2003;28:333-46. [PMID: 12719903]
37 Furuse J, Maru Y, Yoshino M, Mera K, Sumi H, Sekiguchi R, et al. Assessment of arterial tumor vascularity in small US
hepatocellular carcinoma. Comparison between color doppler ultrasonography and radiographic imagings with
contrast medium: dynamic CT, angiography, and CT hepatic arteriography. Eur J Radiol. 2000;36:20-7. [PMID:
10996754]
38 Gaiani S, Celli N, Piscaglia F, Cecilioni L, Losinno F, Giangregorio F, et al. Usefulness of contrast-enhanced perfusional US
sonography in the assessment of hepatocellular carcinoma hypervascular at spiral computed tomography. J Hepatol.
2004;41:421-6. [PMID: 15336445]
39 Gambarin-Gelwan M, Wolf DC, Shapiro R, Schwartz ME and Min AD. Sensitivity of commonly available screening tests in US
detecting hepatocellular carcinoma in cirrhotic patients undergoing liver transplantation. Am J Gastroenterol.
2000;95:1535-8. [PMID: 10894592]
40 Gatto A, De Gaetano AM, Giuga M, Ciresa M, Siciliani L, Miele L, et al. Differentiating hepatocellular carcinoma from MRI
dysplastic nodules at gadobenate dimeglumine-enhanced hepatobiliary-phase magnetic resonance imaging. Abdom
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41 Giorgio A, Ferraioli G, Tarantino L, De Stefano G, Scala V, Scarano F, et al. Contrast-enhanced sonographic appearance US, CT
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42 Giorgio A, De Stefano G, Coppola C, Ferraioli G, Esposito V, Di Sarno A, et al. Contrast-enhanced sonography in the US. MRI
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43 Goleri R, Marini E, Bazzocchi A, Fusco F, Trevisani F, Sama C, et al. Small ( 3 cm) hepatocellular carcinoma in cirrhosis: CT, MRI
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44 Goshima S, Kanematsu M, Matsuo M, Kondo H, Kato H, Yokoyama R, et al. Nodule-in-nodule appearance of MRI
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45 Goto E, Masuzaki R, Tateishi R, Kondo Y, Imamura J, Goto T, et al. Value of post-vascular phase (Kupffer imaging) by US
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46 Guo L, Liang C, Yu T, Wang G, Li N, Sun H, et al. 3 T MRI of hepatocellular carcinomas in patients with cirrhosis: does MRI
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47 Hanna RF, Ward TJ, Chow DS, Lagana SM, Moreira RK, Emond JC, et al. An evaluation of the sensitivity of MRI at MRI
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48 Haradome H, Grazioli L, Tinti R, Morone M, Motosugi U, Sano K, et al. Additional value of gadoxetic MRI
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49 Hardie AD, Kizziah MK and Boulter DJ. Diagnostic accuracy of diffusion-weighted MRI for identifying hepatocellular MRI
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Continued on following page

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 Appendix Table 3Continued

Article Study Diagnostic

Number Tests Studied
50 Hardie AD, Kizziah MK and Rissing MS. Can the patient with cirrhosis be imaged for hepatocellular carcinoma without MRI
gadolinium?: Comparison of combined T2-weighted, T2*-weighted, and diffusion-weighted MRI with
gadolinium-enhanced MRI using liver explantation standard. J Comput Assist Tomogr. 2011;35:711-5. [PMID:
22082541]
51 Hardie AD, Nance JW, Boulter DJ and Kizziah MK. Assessment of the diagnostic accuracy of T2*-weighted MR imaging MRI
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21112710]
52 Hatanaka K, Kudo M, Minami Y, Ueda T, Tatsumi C, Kitai S, et al. Differential diagnosis of hepatic tumors: value of US
contrast-enhanced harmonic sonography using the newly developed contrast agent, Sonazoid. Intervirology. 2008;51
Suppl 1:61-9. [PMID: 18544950]
53 Hecht EM, Holland AE, Israel GM, Hahn WY, Kim DC, West AB, et al. Hepatocellular carcinoma in the cirrhotic liver: MRI
gadolinium-enhanced 3D T1-weighted MR imaging as a stand-alone sequence for diagnosis. Radiology.
2006;239:438-47. [PMID: 16641353]
54 Hidaka M, Takatsuki M, Okudaira S, Soyama A, Muraoka I, Tanaka T, et al. The expression of transporter OATP2/OATP8 CT, MRI
decreases in undetectable hepatocellular carcinoma by Gd-EOB-MRI in the explanted cirrhotic liver. Hepatology
International. 2012:1-7.
55 Higashihara H, Osuga K, Onishi H, Nakamoto A, Tsuboyama T, Maeda N, et al. Diagnostic accuracy of C-arm CT during CT
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biphasic, dynamic MDCT. Eur Radiol. 2012;22:872-9. [PMID: 22120061]
56 Hirakawa M, Yoshimitsu K, Irie H, Tajima T, Nishie A, Asayama Y, et al. Performance of radiological methods in CT, MRI
diagnosing hepatocellular carcinoma preoperatively in a recipient of living related liver transplantation: comparison
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57 Hori M, Murakami T, Oi H, Kim T, Takahashi S, Matsushita M, et al. Sensitivity in detection of hypervascular CT
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58 Hori M, Murakami T, Kim T, Tsuda K, Takahashi S, Okada A, et al. Detection of hypervascular hepatocellular carcinoma: CT, MRI
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59 Hwang J, Kim SH, Lee MW and Lee JY. Small ( 2 cm) hepatocellular carcinoma in patients with chronic liver disease: CT, MRI
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60 Hwang J, Kim YK, Kim JM, Lee WJ, Choi D and Hong SS. Pretransplant diagnosis of hepatocellular carcinoma by MRI
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61 Iannaccone R, Laghi A, Catalano C, Rossi P, Mangiapane F, Murakami T, et al. Hepatocellular carcinoma: role of CT
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62 Iavarone M, Sangiovanni A, Forzenigo LV, Massironi S, Fraquelli M, Aghemo A, et al. Diagnosis of hepatocellular US, CT, MRI
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63 Ichikawa T, Kitamura T, Nakajima H, Sou H, Tsukamoto T, Ikenaga S, et al. Hypervascular hepatocellular carcinoma: can CT, MRI
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64 Ichikawa T, Saito K, Yoshioka N, Tanimoto A, Gokan T, Takehara Y, et al. Detection and characterization of focal liver CT, MRI
lesions: a Japanese phase III, multicenter comparison between gadoxetic acid disodium-enhanced magnetic
resonance imaging and contrast-enhanced computed tomography predominantly in patients with hepatocellular
carcinoma and chronic liver disease. Invest Radiol. 2010;45:133-41. [PMID: 20098330]
65 Imamura M, Shiratori Y, Shiina S, Sato S, Obi S, Okudaira T, et al. Power Doppler sonography for hepatocellular US
carcinoma: factors affecting the power Doppler signals of the tumors. Liver. 1998;18:427-33. [PMID: 9869398]
66 Inoue T, Kudo M, Hatanaka K, Takahashi S, Kitai S, Ueda T, et al. Imaging of hepatocellular carcinoma: Qualitative and US, CT, MRI
quantitative analysis of postvascular phase contrast-enhanced ultrasonography with sonazoid. Oncology.
2008;75:48-54. [PMID: 19092272]
67 Inoue T, Kudo M, Maenishi O, Komuta M, Nakashima O, Kojiro M, et al. Value of liver parenchymal phase US, CT, MRI
contrast-enhanced sonography to diagnose premalignant and borderline lesions and overt hepatocellular carcinoma.
AJR Am J Roentgenol. 2009;192:698-705. [PMID: 19234266]
68 Inoue T, Kudo M, Komuta M, Hayaishi S, Ueda T, Takita M, et al. Assessment of Gd-EOB-DTPA-enhanced MRI for HCC US, CT, MRI
and dysplastic nodules and comparison of detection sensitivity versus MDCT. J Gastroenterol. 2012;47:1036-47.
[PMID: 22526270]
69 Iwazawa J, Ohue S, Hashimoto N, Abe H, Hamuro M and Mitani T. Detection of hepatocellular carcinoma: comparison of US, CT, MRI
angiographic C-arm CT and MDCT. AJR Am J Roentgenol. 2010;195:882-7. [PMID: 20858813]
70 Jang HJ, Lim JH, Lee SJ, Park CK, Park HS and Do YS. Hepatocellular carcinoma: are combined CT during arterial CT
portography and CT hepatic arteriography in addition to triple-phase helical CT all necessary for preoperative
evaluation? Radiology. 2000;215:373-80. [PMID: 10796910]
71 Jang HJ, Kim TK and Wilson SR. Small nodules (1-2 cm) in liver cirrhosis: characterization with contrast-enhanced CT
ultrasound. Eur J Radiol. 2009;72:418-24. [PMID: 18834687]
72 Jang HJ, Kim TK, Khalili K, Yazdi L, Menezes R, Park SH, et al. Characterization of 1- to 2-cm liver nodules detected on CT
hcc surveillance ultrasound according to the criteria of the american association for the study of liver disease: Is
quadriphasic CT necessary? AJR Am J Roentgenol. 2013;201:314-21. [PMID: 23883211]
73 Jeng C-M, Kung C-H, Wang Y-C, Wu C-Y, Lee W-Y, Fan C-K, et al. Spiral biphasic contrast-enhanced computerized CT
tomography in the diagnosis of hepatocellular carcinoma. J Formos Med Assoc. 2002;101:588-92. [PMID: 12440092]
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Number Tests Studied
74 Jeong WK, Byun JH, Lee SS, Won HJ, Kim KW, Shin YM, et al. Gadobenate dimeglumine-enhanced liver MR imaging in MRI
cirrhotic patients: quantitative and qualitative comparison of 1-hour and 3-hour delayed images. J Magn Reson
Imaging. 2011;33:889-97. [PMID: 21448954]
75 Jin Y, Nah S, Lee J, Jeong S, Lee DH, Kim YS, et al. Utility of Adding Primovist Magnetic Resonance Imaging to Analysis MRI
of Hepatocellular Carcinoma by Liver Dynamic Computed Tomography. Clin Gastroenterol Hepatol. 2013;11:187-92.
[PMID: 23142203]
76 Kakihara D, Nishie A, Harada N, Shirabe K, Tajima T, Asayama Y, et al. Performance of gadoxetic acid-enhanced MRI for MRI
detecting hepatocellular carcinoma in recipients of living-related-liver-transplantation: Comparison with dynamic
multidetector row computed tomography and angiography-assisted computed tomography. J Magn Reson Imaging.
2014 [PMID: 24259437]
77 Kang BK, Lim JH, Kim SH, Choi D, Lim HK, Lee WJ, et al. Preoperative depiction of hepatocellular carcinoma: CT
ferumoxides-enhanced MR imaging versus triple-phase helical CT. Radiology. 2003;226:79-85. [PMID: 12511672]
78 Kawada N, Ohkawa K, Tanaka S, Matsunaga T, Uehara H, Ioka T, et al. Improved diagnosis of well-differentiated CT, MRI
hepatocellular carcinoma with gadolinium ethoxybenzyl diethylene triamine pentaacetic acid-enhanced magnetic
resonance imaging and Sonazoid contrast-enhanced ultrasonography. Hepatol Res. 2010;40:930-6. [PMID:
20887598]
79 Kawaoka T, Aikata H, Takaki S, Uka K, Azakami T, Saneto H, et al. FDG positron emission tomography/computed CT
tomography for the detection of extrahepatic metastases from hepatocellular carcinoma. Hepatol Res.
2009;39:134-42. [PMID: 19208034]
80 Kawata S, Murakami T, Kim T, Hori M, Federle MP, Kumano S, et al. Multidetector CT: diagnostic impact of slice CT
thickness on detection of hypervascular hepatocellular carcinoma. AJR Am J Roentgenol. 2002;179:61-6. [PMID:
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81 Khalili K, Kim TK, Jang H-J, Haider MA, Khan L, Guindi M, et al. Optimization of imaging diagnosis of 1-2 cm US, CT, MRI
hepatocellular carcinoma: an analysis of diagnostic performance and resource utilization. J Hepatol. 2011;54:723-8.
[PMID: 21156219]
82 Khan MA, Combs CS, Brunt EM, Lowe VJ, Wolverson MK, Solomon H, et al. Positron emission tomography scanning in CT
the evaluation of hepatocellular carcinoma. J Hepatol. 2000;32:792-7. [PMID: 10845666]
83 Kim CK, Lim JH and Lee WJ. Detection of hepatocellular carcinomas and dysplastic nodules in cirrhotic liver: Accuracy US
of ultrasonography in transplant patients. J Ultrasound Med. 2001;20:99-104.]
84 Kim SK, Lim JH, Lee WJ, Kim SH, Choi D, Lee SJ, et al. Detection of hepatocellular carcinoma: comparison of dynamic CT
three-phase computed tomography images and four-phase computed tomography images using multidetector row
helical computed tomography. J Comput Assist Tomogr. 2002;26:691-8. [PMID: 12439300]
85 Kim T, Murakami T, Hori M, Takamura M, Takahashi S, Okada A, et al. Small hypervascular hepatocellular carcinoma CT
revealed by double arterial phase CT performed with single breath-hold scanning and automatic bolus tracking. AJR
Am J Roentgenol. 2002;178:899-904. [PMID: 11906869]
86 Kim YK, Kim CS, Kwak HS and Lee JM. Three-dimensional dynamic liver MR imaging using sensitivity encoding for MRI
detection of hepatocellular carcinomas: comparison with superparamagnetic iron oxide-enhanced mr imaging. J
Magn Reson Imaging. 2004;20:826-37. [PMID: 15503325]
87 Kim YK, Kim CS, Lee YH, Kwak HS and Lee JM. Comparison of superparamagnetic iron oxide-enhanced and MRI
gadobenate dimeglumine-enhanced dynamic MRI for detection of small hepatocellular carcinomas. AJR Am J
Roentgenol. 2004;182:1217-23. [PMID: 15100122]
88 Kim SH, Choi D, Kim SH, Lim JH, Lee WJ, Kim MJ, et al. Ferucarbotran-enhanced MRI versus triple-phase MDCT for the CT
preoperative detection of hepatocellular carcinoma. AJR Am J Roentgenol. 2005;184:1069-76. [PMID: 15788575]
89 Kim YK, Kim CS, Chung GH, Han Y-M, Lee SY, Chon SB, et al. Comparison of gadobenate dimeglumine-enhanced MRI
dynamic MRI and 16-MDCT for the detection of hepatocellular carcinoma. AJR Am J Roentgenol. 2006;186:149-57.
[PMID: 16357395]
90 Kim YK, Kwak HS, Kim CS, Chung GH, Han YM and Lee JM. Hepatocellular carcinoma in patients with chronic liver MRI
disease: comparison of SPIO-enhanced MR imaging and 16-detector row CT. Radiology. 2006;238:531-41. [PMID:
16371577]
91 Kim YK, Kwak HS, Han YM and Kim CS. Usefulness of combining sequentially acquired gadobenate MRI
dimeglumine-enhanced magnetic resonance imaging and resovist-enhanced magnetic resonance imaging for the
detection of hepatocellular carcinoma: comparison with computed tomography hepatic arteriography and computed
tomography arterioportography using 16-slice multidetector computed tomography. J Comput Assist Tomogr.
2007;31:702-11. [PMID: 17895780]
92 Kim SJ, Kim SH, Lee J, Chang S, Kim Y-S, Kim SH, et al. Ferucarbotran-enhanced 3.0-T magnetic resonance imaging CT
using parallel imaging technique compared with triple-phase multidetector row computed tomography for the
preoperative detection of hepatocellular carcinoma.[Erratum appears in J Comput Assist Tomogr. 2008
Jul-Aug;32(4):615]. J Comput Assist Tomogr. 2008;32:379-85. [PMID: 18520541]
93 Kim YK, Lee YH, Kim CS and Han YM. Added diagnostic value of T2-weighted MR imaging to gadolinium-enhanced MRI
three-dimensional dynamic MR imaging for the detection of small hepatocellular carcinomas. Eur J Radiol.
2008;67:304-10. [PMID: 17714904]
94 Kim YK, Lee YH, Kim CS, Han YM and Hwang SB. Double-dose 1.0-M gadobutrol versus standard-dose 0.5-M MRI
gadopentetate dimeglumine in revealing small hypervascular hepatocellular carcinomas. Eur Radiol. 2008;18:70-7.
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95 Kim KW, Lee JM, Klotz E, Park HS, Lee DH, Kim JY, et al. Quantitative CT color mapping of the arterial enhancement CT
fraction of the liver to detect hepatocellular carcinoma. Radiology. 2009;250:425-34. [PMID: 19188314]
96 Kim SH, Kim SH, Lee J, Kim MJ, Jeon YH, Park Y, et al. Gadoxetic acid-enhanced MRI versus triple-phase MDCT for the MRI
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Number Tests Studied
97 Kim YK, Kim CS, Han YM, Kwak HS, Jin GY, Hwang SB, et al. Detection of hepatocellular carcinoma: gadoxetic CT
acid-enhanced 3-dimensional magnetic resonance imaging versus multi-detector row computed tomography. J
Comput Assist Tomogr. 2009;33:844-50. [PMID: 19940648]
98 Kim YK, Kim CS, Han YM and Park G. Detection of small hepatocellular carcinoma: can gadoxetic acid-enhanced MRI
magnetic resonance imaging replace combining gadopentetate dimeglumine-enhanced and superparamagnetic
iron oxide-enhanced magnetic resonance imaging? Invest Radiol. 2010;45:740-6. [PMID: 20644488]
99 Kim YK, Kim CS, Han YM, Park G, Hwang SB and Yu HC. Comparison of gadoxetic acid-enhanced MRI and MRI
superparamagnetic iron oxide-enhanced MRI for the detection of hepatocellular carcinoma. Clin Radiol.
2010;65:358-65. [PMID: 20380933]
100 Kim TK, Lee KH, Jang H-J, Haider MA, Jacks LM, Menezes RJ, et al. Analysis of gadobenate dimeglumine-enhanced MR MRI
ndings for characterizing small (1-2-cm) hepatic nodules in patients at high risk for hepatocellular carcinoma.
Radiology. 2011;259:730-8. [PMID: 21364083]
101 Kim YK, Kim CS, Han YM and Lee YH. Detection of liver malignancy with gadoxetic acid-enhanced MRI: is addition of MRI
diffusion-weighted MRI benecial?.[Erratum appears in Clin Radiol. 2011 Oct;66(10):1006]. Clin Radiol.
2011;66:489-96. [PMID: 21367403]
102 Kim YK, Kim CS, Han YM, Yu HC and Choi D. Detection of small hepatocellular carcinoma: intraindividual comparison of MRI
gadoxetic acid-enhanced MRI at 3.0 and 1.5 T.[Erratum appears in Invest Radiol. 2011 Sep;46(9):600]. Invest Radiol.
2011;46:383-9. [PMID: 21467946]
103 Kim AY, Kim YK, Lee MW, Park MJ, Hwang J, Lee MH, et al. Detection of hepatocellular carcinoma in gadoxetic MRI
acid-enhanced MRI and diffusion-weighted MRI with respect to the severity of liver cirrhosis. Acta Radiol.
2012;53:830-8. [PMID: 22847903]
104 Kim DJ, Yu JS, Kim JH, Chung JJ and Kim KW. Small hypervascular hepatocellular carcinomas: value of MRI
diffusion-weighted imaging compared with "washout" appearance on dynamic MRI. Br J Radiol. 2012;85:e879-86.
[PMID: 22573299]
105 Kim M-J, Lee M, Choi J-Y and Park YN. Imaging features of small hepatocellular carcinomas with microvascular invasion MRI
on gadoxetic acid-enhanced MR imaging. Eur J Radiol. 2012;81:2507-12. [PMID: 22137613]
106 Kim PN, Choi D, Rhim H, Rha SE, Hong HP, Lee J, et al. Planning ultrasound for percutaneous radiofrequency ablation to US
treat small ( 3 cm) hepatocellular carcinomas detected on computed tomography or magnetic resonance imaging: a
multicenter prospective study to assess factors affecting ultrasound visibility. J Vasc Interv Radiol. 2012;23:627-34.
[PMID: 22387030]
107 Kim MY, Kim YK, Park HJ, Park MJ, Lee WJ and Choi D. Diagnosis of focal liver lesions with gadoxetic acid-enhanced MRI
MRI: is a shortened delay time possible by adding diffusion-weighted imaging? J Magn Reson Imaging.
2014;39:31-41. [PMID: 24115329]
108 Kim YK, Kim YK, Park HJ, Park MJ, Lee WJ and Choi D. Noncontrast MRI with diffusion-weighted imaging as the sole MRI
imaging modality for detecting liver malignancy in patients with high risk for hepatocellular carcinoma. Magn Reson
Imaging. 2014;32:610-8. [PMID: 24702980]
109 Kitamura T, Ichikawa T, Erturk SM, Nakajima H, Sou H, Araki T, et al. Detection of hypervascular hepatocellular CT
carcinoma with multidetector-row CT: single arterial-phase imaging with computer-assisted automatic bolus-tracking
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110 Kondo H, Kanematsu M, Itoh K, Ito K, Maetani Y, Goshima S, et al. Does T2-weighted MR imaging improve preoperative MRI
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111 Korenaga K, Korenaga M, Furukawa M, Yamasaki T and Sakaida I. Usefulness of Sonazoid contrast-enhanced US
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112 Koushima Y, Ebara M, Fukuda H, Morimoto N, Sugiura N, Yoshikawa M, et al. Small hepatocellular carcinoma: MRI
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113 Krinsky GA, Lee VS, Theise ND, Weinreb JC, Rofsky NM, Dio T, et al. Hepatocellular carcinoma and dysplastic nodules MRI
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114 Krinsky GA, Lee VS, Theise ND, Weinreb JC, Morgan GR, Dio T, et al. Transplantation for hepatocellular carcinoma and MRI
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115 Kumano S, Uemura M, Haraikawa T, Hirata M, Kikuchi K, Kim T, et al. Efcacy of double arterial phase dynamic magnetic CT
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116 Kunishi Y, Numata K, Morimoto M, Okada M, Kaneko T, Maeda S, et al. Efcacy of fusion imaging combining US
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117 Kwak H-S, Lee J-M and Kim C-S. Preoperative detection of hepatocellular carcinoma: comparison of combined MRI
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118 Kwak H-S, Lee J-M, Kim Y-K, Lee YH and Kim C-S. Detection of hepatocellular carcinoma: comparison of MRI
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119 Kwon S, Kim YK, Park HJ, Jeong WK, Lee WJ and Choi D. Is gadoxetic acid-enhanced MRI limited in tumor MRI
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120 Laghi A, Iannaccone R, Rossi P, Carbone I, Ferrari R, Mangiapane F, et al. Hepatocellular carcinoma: detection with CT
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Number Tests Studied
121 Lauenstein TC, Salman K, Morreira R, Heffron T, Spivey JR, Martinez E, et al. Gadolinium-enhanced MRI for tumor MRI
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122 Lee J-M, Kim I-H, Kwak H-S, Youk J-H, Han Y-M and Kim C-S. Detection of small hypervascular hepatocellular CT
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123 Lee J, Won JL, Hyo KL, Jae HL, Choi N, Park MH, et al. Early hepatocellular carcinoma: Three-phase helical CT features CT
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124 Lee DH, Kim SH, Lee JM, Park HS, Lee JY, Yi N-J, et al. Diagnostic performance of multidetector row computed CT
tomography, superparamagnetic iron oxide-enhanced magnetic resonance imaging, and dual-contrast magnetic
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125 Lee JY, Kim SH, Jeon YH, Lee J, Kim MJ, Choi D, et al. Ferucarbotran-enhanced magnetic resonance imaging versus MRI
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initial experience. J Comput Assist Tomogr. 2010;34:127-34. [PMID: 20118735]
126 Lee MW, Kim YJ, Park HS, Yu NC, Jung SI, Ko SY, et al. Targeted sonography for small hepatocellular carcinoma CT,MRI
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127 Lee CH, Kim KA, Lee J, Park YS, Choi JW and Park CM. Using low tube voltage (80kVp) quadruple phase liver CT for the MRI
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128 Lee JE, Jang JY, Jeong SW, Lee SH, Kim SG, Cha S-W, et al. Diagnostic value for extrahepatic metastases of CT
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129 Li CS, Chen RC, Tu HY, Shih LS, Zhang TA, Lii JM, et al. Imaging well-differentiated hepatocellular carcinoma with CT
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130 Li R, Guo Y, Hua X, He Y, Ding J, Guo A, et al. Characterization of focal liver lesions: comparison of pulse-inversion CT
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131 Libbrecht L, Bielen D, Verslype C, Vanbeckevoort D, Pirenne J, Nevens F, et al. Focal lesions in cirrhotic explant livers: US, CT, MRI
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132 Lim JH, Kim CK, Lee WJ, Park CK, Koh KC, Paik SW, et al. Detection of hepatocellular carcinomas and dysplastic nodules CT
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133 Lim JH, Choi D, Kim SH, Lee SJ, Lee WJ, Lim HK, et al. Detection of hepatocellular carcinoma: value of adding delayed CT
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134 Lim JH, Kim SH, Lee WJ, Choi D and Lim HK. Ultrasonographic detection of hepatocellular carcinoma: Correlation of US
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135 Lin M-T, Chen C-L, Wang C-C, Cheng Y-F, Eng H-L, Wang J-H, et al. Diagnostic sensitivity of hepatocellular carcinoma CT, MRI
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136 Liu WC, Lim JH, Park CK, Kim MJ, Kim SH, Lee SJ, et al. Poor sensitivity of sonography in detection of hepatocellular US
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137 Liu YI, Kamaya A, Jeffrey RB and Shin LK. Multidetector computed tomography triphasic evaluation of the liver before CT
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138 Liu YI, Shin LK, Jeffrey RB and Kamaya A. Quantitatively dening washout in hepatocellular carcinoma. AJR Am J CT
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139 Lu CH, Chen CL, Cheng YF, Huang TL, Tsang LLC, Ou HY, et al. Correlation between imaging and pathologic ndings in CT
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140 Luca A, Caruso S, Milazzo M, Mamone G, Marrone G, Miraglia R, et al. Multidetector-row computed tomography CT
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141 Luo BM, Wen YL, Yang HY, Zhi H, Ou B, Ma JH, et al. Differentiation between malignant and benign nodules in the liver: US
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142 Luo W, Numata K, Kondo M, Morimoto M, Sugimori K, Hirasawa K, et al. Sonazoid-enhanced ultrasonography for US
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143 Luo W, Numata K, Morimoto M, Kondo M, Takebayashi S, Okada M, et al. Focal liver tumors: characterization with 3D CT
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144 Luo W, Numata K, Morimoto M, Nozaki A, Nagano Y, Sugimori K, et al. Three-dimensional contrast-enhanced CT
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145 Lv P, Lin XZ, Chen K and Gao J. Spectral CT in patients with small HCC: investigation of image quality and diagnostic CT
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Number Tests Studied
146 Maetani YS, Ueda M, Haga H, Isoda H, Takada Y, Arizono S, et al. Hepatocellular carcinoma in patients undergoing CT
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147 Maiwald B, Lobsien D, Kahn T and Stumpp P. Is 3-Tesla Gd-EOB-DTPA-Enhanced MRI with Diffusion-Weighted Imaging CT
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148 Marin D, Catalano C, De Filippis G, Di Martino M, Guerrisi A, Rossi M, et al. Detection of hepatocellular carcinoma in MRI
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149 Marin D, Di Martino M, Guerrisi A, De Filippis G, Rossi M, Ginanni Corradini S, et al. Hepatocellular carcinoma in patients MRI
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150 Marrero JA, Hussain HK, Nghiem HV, Umar R, Fontana RJ and Lok AS. Improving the prediction of hepatocellular MRI
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151 Matsuo M, Kanematsu M, Itoh K, Ito K, Maetani Y, Kondo H, et al. Detection of malignant hepatic tumors: comparison of MRI
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152 Mita K, Kim SR, Kudo M, Imoto S, Nakajima T, Ando K, et al. Diagnostic sensitivity of imaging modalities for US, CT
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153 Mok TSK, Yu SCH, Lee C, Sung J, Leung N, Lai P, et al. False-negative rate of abdominal sonography for detecting US
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154 Monzawa S, Ichikawa T, Nakajima H, Kitanaka Y, Omata K and Araki T. Dynamic CT for detecting small hepatocellular CT
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155 Mori K, Yoshioka H, Takahashi N, Yamaguchi M, Ueno T, Yamaki T, et al. Triple arterial phase dynamic MRI with MRI
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156 Moriyasu F and Itoh K. Efcacy of perubutane microbubble-enhanced ultrasound in the characterization and detection US, CT
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157 Mortele KJ, De Keukeleire K, Praet M, Van Vlierberghe H, de Hemptinne B and Ros PR. Malignant focal hepatic lesions CT
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158 Murakami T, Kim T, Takamura M, Hori M, Takahashi S, Federle MP, et al. Hypervascular hepatocellular carcinoma: CT
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159 Murakami T, Kim T, Kawata S, Kanematsu M, Federle MP, Hori M, et al. Evaluation of optimal timing of arterial phase CT
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160 Nagaoka S, Itano S, Ishibashi M, Torimura T, Baba K, Akiyoshi J, et al. Value of fusing PET plus CT images in CT
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161 Nakamura H, Ito N, Kotake F, Mizokami Y and Matsuoka T. Tumor-detecting capacity and clinical usefulness of SPIO-MRI MRI
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162 Nakamura Y, Tashiro H, Nambu J, Ohdan H, Kakizawa H, Date S, et al. Detectability of hepatocellular carcinoma by CT, MRI
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163 Nakayama A, Imamura H, Matsuyama Y, Kitamura H, Miwa S, Kobayashi A, et al. Value of lipiodol computed tomography CT
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164 Noguchi Y, Murakami T, Kim T, Hori M, Osuga K, Kawata S, et al. Detection of hypervascular hepatocellular carcinoma CT
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165 Noguchi Y, Murakami T, Kim T, Hori M, Osuga K, Kawata S, et al. Detection of hepatocellular carcinoma: comparison of CT, MRI
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166 Numata K, Fukuda H, Miwa H, Ishii T, Moriya S, Kondo M, et al. Contrast-enhanced ultrasonography ndings using a US
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167 Onishi H, Kim T, Imai Y, Hori M, Nagano H, Nakaya Y, et al. Hypervascular hepatocellular carcinomas: detection with CT, MRI
gadoxetate disodium-enhanced MR imaging and multiphasic multidetector CT. Eur Radiol. 2012;22:845-54. [PMID:
22057248]
168 Ooi C-C, Low S-C, Schneider-Kolsky M, Lombardo P, Lim S-Y, Abu Bakar R, et al. Diagnostic accuracy of US
contrast-enhanced ultrasound in differentiating benign and malignant focal liver lesions: a retrospective study. J Med
Imaging Radiat Oncol. 2010;54:421-30. [PMID: 20958940]
169 Ooka Y, Kanai F, Okabe S, Ueda T, Shimofusa R, Ogasawara S, et al. Gadoxetic acid-enhanced MRI compared with CT MRI
during angiography in the diagnosis of hepatocellular carcinoma. Magn Reson Imaging. 2013;31:748-54 Epub 2012
Dec 5. [PMID: 23218794]
170 Park G, Kim YK, Kim CS, Yu HC and Hwang SB. Diagnostic efcacy of gadoxetic acid-enhanced MRI in the detection of MRI
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20682591]
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 Appendix Table 3Continued

Article Study Diagnostic

Number Tests Studied
171 Park Y, Kim SH, Kim SH, Jeon YH, Lee J, Kim MJ, et al. Gadoxetic acid (Gd-EOB-DTPA)-enhanced MRI versus MRI
gadobenate dimeglumine (Gd-BOPTA)-enhanced MRI for preoperatively detecting hepatocellular carcinoma: an
initial experience. Korean J Radiol. 2010;11:433-40. [PMID: 20592927]
172 Park JH, Kim SH, Park HS, Kim GH, Lee JY, Lee JM, et al. Added value of 80 kVp images to averaged 120 kVp images in CT
the detection of hepatocellular carcinomas in liver transplantation candidates using dual-source dual-energy MDCT:
results of JAFROC analysis. Eur J Radiol. 2011;80:e76-85. [PMID: 20875937]
173 Park M-S, Kim S, Patel J, Hajdu CH, Do RKG, Mannelli L, et al. Hepatocellular carcinoma: detection with MRI
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2012;56:140-8. [PMID: 22370974]
174 Park MJ, Kim YK, Lee MW, Lee WJ, Kim YS, Kim SH, et al. Small hepatocellular carcinomas: improved sensitivity by MRI
combining gadoxetic acid-enhanced and diffusion-weighted MR imaging patterns. Radiology. 2012;264:761-70.
[PMID: 22843769]
175 Park VY, Choi J-Y, Chung YE, Kim H, Park M-S, Lim JS, et al. Dynamic enhancement pattern of HCC smaller than 3 cm in MRI
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176 Paul SB, Gulati MS, Sreenivas V, Madan K, Gupta AK, Mukhopadhyay S, et al. Evaluating patients with cirrhosis for US
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Suppl 1:117-23. [PMID: 18087192]
177 Pauleit D, Textor J, Bachmann R, Conrad R, Flacke S, Layer G, et al. Hepatocellular carcinoma: detection with US
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178 Peterson MS, Baron RL, Marsh JW, Jr., Oliver JH, 3rd, Confer SR and Hunt LE. Pretransplantation surveillance for CT
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179 Petruzzi N, Mitchell D, Guglielmo F, O'Kane P, Deshmukh S, Roth C, et al. Hepatocellular carcinoma likelihood on MRI MRI
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180 Piana G, Trinquart L, Meskine N, Barrau V, Beers BV and Vilgrain V. New MR imaging criteria with a diffusion-weighted MRI
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181 Pitton MB, Kloeckner R, Herber S, Otto G, Kreitner KF and Dueber C. MRI versus 64-row MDCT for diagnosis of MRI
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182 Pozzi Mucelli RM, Como G, Del Frate C, Iuri D, Furlan A, Al-Grhiw E, et al. Multidetector CT with double arterial phase CT
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183 Pugacheva O, Matsui O, Kozaka K, Minami T, Ryu Y, Koda W, et al. Detection of small hypervascular hepatocellular CT
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184 Quaia E, Alaimo V, Baratella E, Medeot A, Midiri M and Cova MA. The added diagnostic value of 64-row multidetector US, CT
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185 Quaia E, Bertolotto M, Calderan L, Mosconi E and Mucelli RP. US characterization of focal hepatic lesions with US
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186 Rickes S, Schulze S, Neye H, Ocran KW and Wermke W. Improved diagnosing of small hepatocellular carcinomas by US
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187 Rimola J, Forner A, Tremosini S, Reig M, Vilana R, Bianchi L, et al. Non-invasive diagnosis of hepatocellular carcinoma MRI
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188 Rizvi S, Camci C, Yong Y, Parker G, Shrago S, Stokes K, et al. Is post-Lipiodol CT better than i.v. contrast CT scan for early CT
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189 Rode A, Bancel B, Douek P, Chevallier M, Vilgrain V, Picaud G, et al. Small nodule detection in cirrhotic livers: evaluation US, CT, MRI
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190 Ronzoni A, Artioli D, Scardina R, Battistig L, Minola E, Sironi S, et al. Role of MDCT in the diagnosis of hepatocellular CT
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191 Sangiovanni A, Manini MA, Iavarone M, Romeo R, Forzenigo LV, Fraquelli M, et al. The diagnostic and economic impact US, CT, MRI
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192 Sano K, Ichikawa T, Motosugi U, Sou H, Muhi AM, Matsuda M, et al. Imaging study of early hepatocellular carcinoma: MRI
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193 Schima W, Hammerstingl R, Catalano C, Marti-Bonmati L, Rummeny EJ, Montero FT, et al. Quadruple-phase MDCT of CT
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195 Seitz K, Strobel D, Bernatik T, Blank W, Friedrich-Rust M, Herbay Av, et al. Contrast-Enhanced Ultrasound (CEUS) for the US, CT
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 Appendix Table 3Continued

Article Study Diagnostic

Number Tests Studied
196 Seitz K, Bernatik T, Strobel D, Blank W, Friedrich-Rust M, Strunk H, et al. Contrast-enhanced ultrasound (CEUS) for the US, MRI
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197 Serste T, Barrau V, Ozenne V, Vullierme M-P, Bedossa P, Farges O, et al. Accuracy and disagreement of computed CT, MRI
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198 Shah SA, Tan JC, McGilvray ID, Cattral MS, Cleary SP, Levy GA, et al. Accuracy of staging as a predictor for recurrence MRI
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199 Simon G, Link TM, Wortler K, Doebereiner F, Schulte-Frohlinde E, Daldrup-Link H, et al. Detection of hepatocellular MRI
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200 Singh P, Erickson RA, Mukhopadhyay P, Gopal S, Kiss A, Khan A, et al. EUS for detection of the hepatocellular US, CT
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201 Sofue K, Tsurusaki M, Kawasaki R, Fujii M and Sugimura K. Evaluation of hypervascular hepatocellular carcinoma in CT
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202 Strobel D, Raeker S, Martus P, Hahn EG and Becker D. Phase inversion harmonic imaging versus contrast-enhanced US
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203 Sugimoto K, Moriyasu F, Shiraishi J, Saito K, Taira J, Saguchi T, et al. Assessment of arterial hypervascularity of US, MRi
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204 Suh YJ, Kim M-J, Choi J-Y, Park YN, Park M-S and Kim KW. Differentiation of hepatic hyperintense lesions seen on MRI
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205 Suzuki S, Iijima H, Moriyasu F, Sasaki S, Yanagisawa K, Miyahara T, et al. Differential diagnosis of hepatic nodules using US, MRI
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206 Tanaka S, Ioka T, Oshikawa O, Hamada Y and Yoshioka F. Dynamic sonography of hepatic tumors. AJR Am J US
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207 Tanaka O, Ito H, Yamada K, Kubota T, Kizu O, Kato T, et al. Higher lesion conspicuity for SENSE dynamic MRI in MRI
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208 Tang Y, Yamashita Y, Arakawa A, Namimoto T, Mitsuzaki K, Abe Y, et al. Detection of hepatocellular carcinoma arising in MRI
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209 Tanimoto A, Yuasa Y, Jinzaki M, Nakatsuka S, Takeda T, Kurata T, et al. Routine MR imaging protocol with breath-hold MRI
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210 Teefey SA, Hildeboldt CC, Dehdashti F, Siegel BA, Peters MG, Heiken JP, et al. Detection of primary hepatic malignancy US, CT, MRI
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211 Toyota N, Nakamura Y, Hieda M, Akiyama N, Terada H, Matsuura N, et al. Diagnostic capability of gadoxetate MRI
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212 Trojan J, Schroeder O, Raedle J, Baum RP, Herrmann G, Jacobi V, et al. Fluorine-18 FDG positron emission tomography CT, US
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213 Tsurusaki M, Semelka RC, Uotani K, Sugimoto K, Fujii M and Sugimura K. Prospective comparison of high- and CT
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214 Valls C, Cos M, Figueras J, Andia E, Ramos E, Sanchez A, et al. Pretransplantation diagnosis and staging of CT
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2004;182:1011-7. [PMID: 15039179]
215 Van Thiel DH, Yong S, Li SD, Kennedy M and Brems J. The development of de novo hepatocellular carcinoma in US, CT
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216 Wagnetz U, Atri M, Massey C, Wei AC and Metser U. Intraoperative ultrasound of the liver in primary and secondary CT, MRI
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217 Wang J-H, Lu S-N, Hung C-H, Chen T-Y, Chen C-H, Changchien C-S, et al. Small hepatic nodules ( 2 cm) in cirrhosis US
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218 Wang ZL, Tang J, Weskott HP, Li JL, Wang W, Luo YK, et al. Undetermined focal liver lesions on gray-scale ultrasound in US
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219 Xiao X-g, Han X, Shan W-d and Li A-y. Multi-slice CT angiography by triple-phase enhancement in preoperative CT
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220 Xu H-X, Xie X-Y, Lu M-D, Liu G-J, Xu Z-F, Zheng Y-L, et al. Contrast-enhanced sonography in the diagnosis of small US
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 Appendix Table 3Continued

Article Study Diagnostic

Number Tests Studied
221 Xu P-J, Yan F-H, Wang J-H, Lin J and Ji Y. Added value of breathhold diffusion-weighted MRI in detection of small MRI
hepatocellular carcinoma lesions compared with dynamic contrast-enhanced MRI alone using receiver operating
characteristic curve analysis. J Magn Reson Imaging. 2009;29:341-9. [PMID: 19161186]
222 Xu HX, Lu MD, Liu LN, Zhang YF, Guo LH, Xu JM, et al. Discrimination between neoplastic and non-neoplastic lesions in US
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223 Yamamoto K, Shiraki K, Deguchi M, Sugimoto K, Sakai T, Ohmori S, et al. Diagnosis of hepatocellular carcinoma using US, CT
digital subtraction imaging with the contrast agent, Levovist: comparison with helical CT, digital subtraction
angiography, and US angiography. Oncol Rep. 2002;9:789-92. [PMID: 12066210]
224 Yan FH, Shen JZ, Li RC, Zeng MS, Wu D, Zhou KR, et al. Enhancement patterns of small hepatocellular carcinoma shown CT, MRI
by dynamic MRI and CT. Hepatobiliary Pancreat Dis Int. 2002;1:420-4. [PMID: 14607719]
225 Yoo SH, Choi JY, Jang JW, Bae SH, Yoon SK, Kim DG, et al. Gd-EOB-DTPA-enhanced MRI is better than MDCT in CT, MRI
decision making of curative treatment for hepatocellular carcinoma. Ann Surg Oncol. 2013;20:2893-900. [PMID:
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226 Yoshioka H, Takahashi N, Yamaguchi M, Lou D, Saida Y and Itai Y. Double arterial phase dynamic MRI with sensitivity MRI
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12205581]
227 Youk JH, Lee JM and Kim CS. MRI for detection of hepatocellular carcinoma: comparison of mangafodipir trisodium and MRI
gadopentetate dimeglumine contrast agents. AJR Am J Roentgenol. 2004;183:1049-54. [PMID: 15385303]
228 Yu JS, Lee JH, Chung JJ, Kim JH and Kim KW. Small hypervascular hepatocellular carcinoma: limited value of portal and MRI
delayed phases on dynamic magnetic resonance imaging. Acta Radiol. 2008;49:735-43. [PMID: 18608015]
229 Yu JS, Chung JJ, Kim JH and Kim KW. Small hypervascular hepatocellular carcinomas: value of "washout" on MRI
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230 Yu NC, Chaudhari V, Raman SS, Lassman C, Tong MJ, Busuttil RW, et al. CT and MRI improve detection of hepatocellular US, CT, MRI
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231 Yu MH, Kim JH, Yoon JH, Kim HC, Chung JW, Han JK, et al. Role of C-arm CT for transcatheter arterial CT
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232 Yu MH, Kim JH, Yoon J-H, Kim H-C, Chung JW, Han JK, et al. Small (<1-cm) hepatocellular carcinoma: diagnostic MRI
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233 Yukisawa S, Okugawa H, Masuya Y, Okabe S, Fukuda H, Yoshikawa M, et al. Multidetector helical CT plus CT
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234 Zacherl J, Pokieser P, Wrba F, Scheuba C, Prokesch R, Zacherl M, et al. Accuracy of multiphasic helical computed CT
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what is the truth? Ann Surg. 2002;235:528-32. [PMID: 11923609]
235 Zhang X-Y, Luo Y, Wen T-F, Jiang L, Li C, Zhong X-F, et al. Contrast-enhanced ultrasound: Improving the preoperative US
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236 Zhou K-R, Yan F-H, Tu B-W. Arterial phase of biphase enhancement spiral CT in diagnosis of small hepatocellular CT
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237 Zhao H, Zhou K-R and Yan F-H. Role of multiphase scans by multirow-detector helical CT in detecting small CT
hepatocellular carcinoma. World J Gastroenterol. 2003;9:2198-201. [PMID: 14562377]
238 Zhao H, Yao JL, Han MJ, Zhou KR and Yan FH. Multiphase hepatic scans with multirow-detector helical CT in detection CT
of hypervascular hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2004;3:204-8. [PMID: 15138110]
239 Zhao H, Yao J-L, Wang Y and Zhou K-R. Detection of small hepatocellular carcinoma: comparison of dynamic CT, MRI
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Gastroenterol. 2007;13:1252-6. [PMID: 17451209]
240 Zhao XT, Li WX, Chai WM and Chen KM. Detection of small hepatocellular carcinoma using gadoxetic acid-enhanced MRI
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241 Zheng X-H, Guan Y-S, Zhou X-P, Huang J, Sun L, Li X, et al. Detection of hypervascular hepatocellular carcinoma: CT
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CT = computed tomography; MRI = magnetic resonance imaging; US = ultrasonography.

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 Appendix Figure 2. Test performance of ultrasonography without contrast for detection of patients with hepatocellular
carcinoma in surveillance settings.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Chalasani et al, 1999 (16) 0.59 (0.390.78) Chalasani et al, 1999 (16) 0.93 (0.890.96)
Mok et al, 2004 (153) 0.86 (0.640.97) Mok et al, 2004 (153) 0.82 (0.720.89)
Van Thiel et al, 2004 (215) 0.60 (0.360.81) Van Thiel et al, 2004 (215) 0.94 (0.860.98)
Paul et al, 2007 (176) 0.92 (0.810.98) Paul et al, 2007 (176)
Combined 0.78 (0.600.89) Combined 0.89 (0.800.94)
2 = 0.52; P = 0.108 2 = 0.26; P = 0.164
Total N = 120; TP = 94 Total N = 420; TN = 382
0.4 1.0 0.7 1.0
Sensitivity (95% CI) Specificity (95% CI)

Reference numbers are those in Appendix Table 3. TN = true negative; TP = true positive.

Appendix Figure 3. Test performance of ultrasonography without contrast for detection of patients with hepatocellular
carcinoma in nonsurveillance settings.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Trojan et al, 1999 (212) 1.00 (0.771.00) Trojan et al, 1999 (212)
Gambarin-Gelwan et al, 2000 (39) 0.58 (0.330.80) Gambarin-Gelwan et al, 2000 (39) 0.94 (0.870.98)
Kim et al, 2001 (83) 0.38 (0.150.65) Kim et al, 2001 (83) 0.92 (0.780.98)
Bennett et al, 2002 (11) 0.30 (0.140.50) Bennett et al, 2002 (11) 0.97 (0.930.99)
Libbrecht et al, 2002 (131) 0.40 (0.160.68) Libbrecht et al, 2002 (131) 1.00 (0.891.00)
Teefey et al, 2003 (210) 0.89 (0.521.00) Teefey et al, 2003 (210) 0.73 (0.450.92)
Lim et al, 2006 (134) 0.94 (0.880.98) Lim et al, 2006 (134)
Yu et al, 2011 (230) 0.64 (0.550.72) Yu et al, 2011 (230) 0.96 (0.930.98)
Combined 0.73 (0.460.90) Combined 0.93 (0.850.97)
2 = 2.35; P = 0.024 2 = 0.78; P = 0.123
Total N = 341; TP = 238 Total N = 634; TN = 605
0.1 1.0 0.4 1.0
Sensitivity (95% CI) Specificity (95% CI)

Reference numbers are those in Appendix Table 3. TN = true negative; TP = true positive.

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 Appendix Figure 4. Test performance of ultrasonography without contrast for detection of hepatocellular carcinoma lesions
in nonsurveillance settings.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Immaura et al, 1998 (65) 0.64 (0.570.71) Immaura et al, 1998 (65)
Trojan et al, 1999 (212) 1.00 (0.871.00) Trojan et al, 1999 (212)
Kim et al, 2001 (83) 0.33 (0.130.59) Kim et al, 2001 (83)
Rode et al, 2001 (189) 0.46 (0.190.75) Rode et al, 2001 (189) 0.95 (0.850.99)
Bennett et al, 2002 (11) 0.21 (0.090.36) Bennett et al, 2002 (11)
Liu et al, 2003 (136) 0.27 (0.160.42) Liu et al, 2003 (136)
Lim et al, 2006 (134) 0.64 (0.560.72) Lim et al, 2006 (134)
Yu et al, 2011 (230) 0.46 (0.390.53) Yu et al, 2011 (230)
Kim et al, 2012 (106) 0.75 (0.720.78) Kim et al, 2012 (106)
Kunishi et al, 2012 (116) 0.78 (0.670.86) Kunishi et al, 2012 (116)
Di Martino et al, 2013 (28) 0.72 (0.640.79) Di Martino et al, 2013 (28) 0.63 (0.520.73)
Combined 0.59 (0.420.74) Combined 0.83 (0.530.95)
2 = 1.21; P = 0.005 2 = 3.35; P = 0.075
Total N = 1828; TP = 1221 Total N = 147; TN = 110
0.1 1.0 0.5 1.0
Sensitivity (95% CI) Specificity (95% CI)

Reference numbers are those in Appendix Table 3. TN = true negative; TP = true positive.

Appendix Figure 5. Sensitivity of ultrasonography with contrast for detection of hepatocellular carcinoma lesions in
nonsurveillance settings.

Study, Year (Reference) Sensitivity (95% CI)

Zhou et al, 2002 (236) 0.68 (0.540.79)

Inoue et al, 2008 (66) 0.98 (0.910.99)
Iavarone et al, 2010 (62) 0.34 (0.230.46)
Kawada et al, 2010 (78) 0.67 (0.410.85)
Alaboudy et al, 2011 (4) 0.72 (0.580.83)
Kunishi et al, 2012 (116) 0.83 (0.730.89)
Sugimoto et al, 2012 (203) 0.85 (0.730.92)
Numata et al, 2014 (166) 0.33 (0.210.46)
Zhang et al, 2014 (235) 0.89 (0.810.94)
Mixed-effects model overall 0.75 (0.570.88)
2 = 1.53; P = 0.006

0 0.5 1.0
Sensitivity (95% CI)

Reference numbers are those in Appendix Table 3.

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 Appendix Figure 6. Test performance of computed tomography for detection of hepatocellular carcinoma lesions in
nonsurveillance settings.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Hori et al, 1996 (57) 0.68 (0.590.76) Hori et al, 1996 (57)
Bartolozzi et al, 2000 (10) 0.80 (0.700.88) Bartolozzi et al, 2000 (10)
Jang et al, 2000 (70) 0.95 (0.870.98) Jang et al, 2000 (70)
Lim et al, 2000 (132) 0.71 (0.480.89) Lim et al, 2000 (132)
Nakamura et al, 2000 (161) 0.62 (0.530.71) Nakamura et al, 2000 (161)
Murakami et al, 2001 (158) 0.86 (0.780.93) Murakami et al, 2001 (158)
Nakayama et al, 2001 (163) 0.87 (0.790.93) Nakayama et al, 2001 (163)
Rode et al, 2001 (189) 0.54 (0.250.81) Rode et al, 2001 (189) 0.93 (0.800.98)
Hori et al, 2002 (58) 0.71 (0.570.83) Hori et al, 2002 (58)
Ichikawa et al, 2002 (63) 0.90 (0.810.95) Ichikawa et al, 2002 (63)
Jeng et al, 2002 (73) 0.89 (0.840.94) Jeng et al, 2002 (73)
Kawata et al, 2002 (80) 0.75 0.650.84) Kawata et al, 2002 (80)
Kim et al, 2002 (85) 0.92 (0.840.97) Kim et al, 2002 (85) 0.92 (0.800.98)
Noguchi et al, 2002 (164) 0.48 (0.360.61) Noguchi et al, 2002 (164)
Yan et al, 2002 (224) 0.68 (0.570.79) Yan et al, 2002 (224)
Zacherl et al, 2002 (234) 0.75 (0.610.86) Zacherl et al, 2002 (234)
Zhou et al, 2002 (236) 0.91 (0.790.97) Zhou et al, 2002 (236)
de Ledinghen et al, 2002 (25) 0.52 (0.380.66) de Ledinghen et al, 2002 (25) 0.74 (0.560.87)
Burrel et al, 2003 (13) 0.61 (0.490.73) Burrel et al, 2003 (13) 0.67 (0.410.87)
Freeny et al, 2003 (36) 0.60 (0.410.77) Freeny et al, 2003 (36) 0.50 (0.350.65)
Laghi et al, 2003 (120) 0.89 (0.820.93) Laghi et al, 2003 (120)
Lee et al, 2003 (122) 0.58 (0.450.71) Lee et al, 2003 (122) 0.97 (0.940.99)
Noguchi et al, 2003 (165) 0.66 (0.560.75) Noguchi et al, 2003 (165)
Zhao et al, 2003 (237) 0.98 (0.921.00) Zhao et al, 2003 (237)
Bhattacharjya et al, 2004 (12) 0.63 (0.480.77) Bhattacharjya et al, 2004 (12) 0.87 (0.730.95)
Valls et al, 2004 (214) 0.79 (0.690.87) Valls et al, 2004 (214)
Zhao et al, 2004 (238) 1.00 (9.941.00) Zhao et al, 2004 (238)
Kim et al, 2005 (88) 0.92 (0.840.97) Kim et al, 2005 (88) 0.96 (0.910.99)
Xiao et al, 2005 (219) 0.97 (0.901.00) Xiao et al, 2005 (219)
Zheng et al, 2005 (241) 0.94 (0.870.98) Zheng et al, 2005 (241)
Kim et al, 2006 (89) 0.79 (0.650.89) Kim et al, 2006 (89)
Kim et al, 2006 (90) 0.78 (0.650.87) Kim et al, 2006 (90)
Schima et al, 2006 (193) 0.96 (0.900.99) Schima et al, 2006 (193)
Monzawa et al, 2007 (154) 0.94 (0.830.99) Monzawa et al, 2007 (154) 0.83 (0.710.91)
Ronzoni et al, 2007 (190) 0.73 (0.650.81) Ronzoni et al, 2007 (190)
Yukisawa et al, 2007 (233) 0.75 (0.620.86) Yukisawa et al, 2007 (233) 0.93 (0.880.96)
Zhao et al, 2007 (239) 0.93 (0.810.99) Zhao et al, 2007 (239)
Kitamura et al, 2008 (109) 0.94 (0.790.99) Kitamura et al, 2008 (109)
Maetani et al, 2008 (146) 0.87 (0.800.92) Maetani et al, 2008 (146) 0.75 (0.480.93)
Denecke et al, 2009 (26) 0.82 (0.710.90) Denecke et al, 2009 (26) 0.71 (0.510.87)
Kim et al, 2009 (95) 0.72 (0.610.81) Kim et al, 2009 (95)
Kim et al, 2009 (96) 0.89 (0.800.95) Kim et al, 2009 (96) 0.96 (0.860.99)
Kim et al, 2009 (97) 0.72 (0.600.81) Kim et al, 2009 (97)
Kumano et al, 2009 (115) 0.66 (0.530.77) Kumano et al, 2009 (115)

0.1 1.0 0.3 1.0

Sensitivity (95% CI) Specificity (95% CI)

(Continued)

Reference numbers are those in Appendix Table 3. TN = true negative; TP = true positive.

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 Appendix Figure 6Continued.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Lee et al, 2009 (124) 0.49 (0.380.61) Lee et al, 2009 (124)
Marin et al, 2009 (148) 0.84 (0.740.91) Marin et al, 2009 (148)
Marin et al, 2009 (149) 0.61 (0.490.73) Marin et al, 2009 (149)
Pitton et al, 2009 (181) 0.76 (0.690.82) Pitton et al, 2009 (181)
Di Martino et al, 2010 (27) 0.69 (0.580.78) Di Martino et al, 2010 (27)
Iavarone et al, 2010 (62) 0.52 (0.390.65) Iavarone et al, 2010 (62)
Ichikawa et al, 2010 (64) 0.57 (0.510.63) Ichikawa et al, 2010 (64)
Iwazawa et al, 201 (69) 0.62 (0.520.71) Iwazawa et al, 2010 (69)
Lu et al, 2010 (139) 0.84 (0.760.90) Lu et al, 2010 (139)
Luca et al, 2010 (140) 0.43 (0.340.52) Luca et al, 2010 (140) 0.93 (0.800.98)
Addley et al, 2011 (1) 0.72 (0.570.84) Addley et al, 2011 (1) 0.68 (0.490.83)
Akal et al, 2011 (3) 0.78 (0.650.89) Akal et al, 2011 (3) 0.90 (0.680.99)
Haradome et al, 2011 (48) 0.70 (0.570.81) Haradome et al, 2011 (48) 0.95 (0.830.99)
Hirakawa et al, 2011 (56) 0.47 (0.360.68) Hirakawa et al, 2011 (56)
Lin et al, 2011 (135) 0.82 (0.760.87) Lin et al, 2011 (135)
Pugacheva et al, 2011 (183) 0.40 (0.300.51) Pugacheva et al, 2011 (183)
Sano et al, 2011 (192) 0.63 (0.530.73) Sano et al, 2011 (192) 0.98 (0.951.00)
Wagnetz et al, 2011 (216) 0.98 (0.911.00) Wagnetz et al, 2011 (216)
Yu et al, 2011 (230) 0.65 (0.580.72) Yu et al, 2011 (230)
Baek et al, 2012 (8) 0.77 (0.650.86) Baek et al, 2012 (8)
Higashihara et al, 2012 (55) 0.65 (0.550.74) Higashihara et al, 2012 (55)
Hwang et al, 2012 (59) 0.59 (0.460.72) Hwang et al, 2012 (59)
Inoue et al, 2012 (68) 0.67 (0.560.77) Inoue et al, 2012 (68)
Lee et al, 2012 (127) 0.85 (0.740.93) Lee et al, 2012 (127)
Liu et al, 2012 (137) 0.81 (0.540.96) Liu et al, 2012 (137)
Lv et al, 2012 (145) 0.84 (0.660.95) Lv et al, 2012 (145)
Onishi et al, 2012 (167) 0.44 (0.330.57) Onishi et al, 2012 (167)
Cheung et al, 2013 (17) 0.55 (0.420.68) Cheung et al, 2013 (17)
Di Martino et al, 2013 (28) 0.72 (0.640.79) Di Martino et al, 2013 (28) 0.87 (0.780.93)
Hidaka et al, 2012 (54) 0.56 (0.350.75) Hidaka et al, 2012 (54)
Liu et al, 2013 (138) 0.93 (0.661.00) Liu et al, 2013 (138) 0.97 (0.841.00)
Nakamura et al, 2013 (162) 0.55 (0.430.67) Nakamura et al, 2013 (162)
Toyota et al, 2013 (211) 0.91 (0.810.97) Toyota et al, 2013 (211)
Yoo et al, 2013 (225) 0.44 (0.330.55) Yoo et al, 2013 (225) 0.95 (0.771.00)
Numata et al, 2014 (166) 0.21 (0.110.35) Numata et al, 2014 (166)
Park et al, 2014 (175) 0.61 (0.490.73) Park et al, 2014 (175)

Combined 0.76 (0.720.80) Combined 0.90 (0.840.93)

2 2 = 0.92; P = 0.00
= 0.91; P = 0.00
0.1 1.0 Total: N = 6534; TP = 4756 0.3 1.0 Total: N = 1404; TN = 1264
Sensitivity (95% CI) Specificity (95% CI)

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 Appendix Figure 7. Test performance of magnetic resonance imaging for detection of hepatocellular carcinoma lesions in
nonsurveillance settings.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Hori et al, 1998 (57) 0.76 (0.680.83) Hori et al, 1998 (57)
Tang et al, 1999 (208) 0.94 (0.880.98) Tang et al, 1999 (208)
Nakamura et al, 2000 (161) 0.94 (0.840.98) Nakamura et al, 2000 (161)
Krinsky et al, 2002 (113) 0.55 (0.320.77) Krinsky et al, 2002 (113)
Matsuo et al, 2001 (151) 0.70 (0.570.82) Matsuo et al, 2001 (151)
Rode et al, 2001 (181) 0.77 (0.460.95) Rode et al, 2001 (181) 0.57 (0.430.70)
Krinsky et al, 2002 (114) 0.33 0.250.42) Krinsky et al, 2002 (114)
Pauliet et al, 2002 (177) 0.90 (0.810.95) Pauliet et al, 2002 (177)
Tanimoto et al, 2022 (209) 0.91 (0.810.97) Tanimoto et al, 2022 (209)
Yan et al, 2002 (224) 0.83 (0.730.91) Yan et al, 2002 (224)
Yoshioka et al, 2002 (226) 0.92 (0.780.98) Yoshioka et al, 2002 (226)
de Ledinghen et al, 2002 (52) 0.61 (0.470.74) de Ledinghen et al, 2002 (52) 0.88 (0.730.97)
Burrel et al, 2003 (13) 0.76 (0.650.85) Burrel et al, 2003 (13) 0.75 (0.530.90)
Noguchi et al, 2003 (165) 0.64 (0.540.73) Noguchi et al, 2003 (165)
Kim et al, 2004 (87) 0.92 (0.800.98) Kim et al, 2004 (87)
Kondo et al, 2005 (110) 0.79 (0.640.91) Kondo et al, 2005 (110)
Kwak et al, 2005 (118) 0.90 (0.800.96) Kwak et al, 2005 (118)
Mori et al, 2005 (155) 0.65 (0.550.75) Mori et al, 2005 (155)
Simon et al, 2005 (199) 0.94 (0.870.98) Simon et al, 2005 (199) 0.15 (0.020.45)
Tanaka et al, 2005 (2007) 0.65 (0.480.79) Tanaka et al, 2005 (2007)
Hecht et al, 2006 (53) 0.68 (0.430.87) Hecht et al, 2006 (53) 0.63 (0.450.79)
Kim et al, 2006 (89) 0.94 (0.840.99) Kim et al, 2006 (89)
Kim et al, 2007 (91) 0.90 (0.800.96) Kim et al, 2007 (91)
Lauenstein et al, 2007 (121) 0.78 (0.610.90) Lauenstein et al, 2007 (121)
Zhao et al, 2007 (239) 0.88 (0.740.96) Zhao et al, 2007 (239)
Choi et al, 2008 (19) 0.83 (0.680.93) Choi et al, 2008 (19)
Kim et al, 2008 (93) 0.85 (0.770.90) Kim et al, 2008 (93)
Kim et al, 2008 (94) 0.94 (0.810.99) Kim et al, 2008 (94)
Tsurusaki et al, 2008 (213) 1.00 (0.661.00) Tsurusaki et al, 2008 (213)
Kim et al, 2009 (96) 0.94 (0.860.98) Kim et al, 2009 (96) 0.98 (0.891.00)
Kim et al, 2009 (97) 0.90 (0.810.96) Kim et al, 2009 (97)
Kumano et al, 2009 (115) 0.74 (0.610.84) Kumano et al, 2009 (115)
Marin et al, 2009 (149) 0.67 (0.550.78) Marin et al, 2009 (149)
Pitton et al, 2009 (181) 0.98 (0.940.99) Pitton et al, 2009 (181)
Xu et al, 2009 (221) 0.85 (0.710.94) Xu et al, 2009 (221)
Yu et al, 2009 (229) 0.49 (0.370.61) Yu et al, 2009 (229)
Ahn et al, 2010 (2) 0.90 (0.820.96) Ahn et al, 2010 (2) 0.93 (0.770.99)
Di Martino et al, 2010 (27) 0.85 (0.760.92) Di Martino et al, 2010 (27)
Iavarone et al, 2010 (62) 0.48 (0.350.62) Iavarone et al, 2010 (62)
Ichikawa et al, 2010 (64) 0.60 (0.540.66) Ichikawa et al, 2010 (64)
Kim et al, 2010 (99) 0.84 (0.720.92) Kim et al, 2010 (99)
Kim et al, 2010 (98) 0.91 (0.840.95) Kim et al, 2010 (98)

0.1 1.0 0.0 1.0

Sensitivity (95% CI) Specificity (95% CI)
(Continued)

Reference numbers are those in Appendix Table 3.

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 Appendix Figure 7Continued.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Lee et al, 2010 (125) 1.00 (0.911.00) Lee et al, 2010 (125)
Lu et al, 2010 (139) 0.76 (0.670.83) Lu et al, 2010 (139)
Park et al, 2010 (170) 0.86 (0.750.94) Park et al, 2010 (170)
Park et al, 2010 (171) 0.81 (0.580.95) Park et al, 2010 (171)
Akal et al, 2011 (3) 0.87 (0.740.94) Akal et al, 2011 (3) 0.93 (0.810.99)
Haradome et al, 2011 (48) 0.87 (0.750.94) Haradome et al, 2011 (48) 0.92 (0.790.98)
Hardle et al, 2011 (51) 0.83 (0.650.94) Hardle et al, 2011 (51) 0.63 (0.380.84)
Hirakawa et al, 2011 (56) 0.63 (0.520.73) Hirakawa et al, 2011 (56)
Kim et al, 2011 (100) 0.89 (0.770.96) Kim et al, 2011 (100)
Kim et al, 2011 (101) 1.00 (0.801.00) Kim et al, 2011 (101)
Plana et al, 2011 (180) 0.60 (0.500.69) Plana et al, 2011 (180)
Pugacheva et al, 2011 (183) 0.40 (0.300.51) Pugacheva et al, 2011 (183)
Sano et al, 2011 (192) 0.96 (0.890.99) Sano et al, 2011 (192) 0.96 (0.910.98)
Wagnetz et al, 2011 (216) 0.92 (0.750.99) Wagnetz et al, 2011 (216)
Yu et al, 2011 (230) 0.72 (0.650.79) Yu et al, 2011 (230)
Baek et al, 2012 (8) 0.89 (0.800.95) Baek et al, 2012 (8)
Guo et al, 2012 (46) 0.85 (0.760.92) Guo et al, 2012 (46)
Hwang et al, 2012 (59) 0.88 (0.770.95) Hwang et al, 2012 (59)
Inoue et al, 2012 (68) 0.77 (0.660.85) Inoue et al, 2012 (68)
Kim et al, 2012 (103) 0.82 (0.770.87) Kim et al, 2012 (103)
im et al, 2012 (105) 0.76 (0.630.86) im et al, 2012 (105)
Lee et al, 2012 (127) 0.94 (0.850.98) Lee et al, 2012 (127)
Onishi et al, 2012 (167) 0.68 (0.560.79) Onishi et al, 2012 (167)
Park et al, 2012 (174) 0.93 (0.880.96) Park et al, 2012 (174) 0.98 (0.941.00)
Sugimoto et al, 2012 (203) 0.80 (0.670.89) Sugimoto et al, 2012 (203)
Baird et al, 2013 (9) 0.43 (0.270.59) Baird et al, 2013 (9) 1.00 (0.781.00)
Di Martino et al, 2013 (28) 0.87 (0.810.92) Di Martino et al, 2013 (28) 0.91 (0.830.96)
Hidaka et al, 2012 (54) 0.59 (0.390.78) Hidaka et al, 2012 (54)
Nakamura et al, 2013 (162) 0.69 (0.570.79) Nakamura et al, 2013 (162)
Ooka et al, 2013 (169) 0.94 (0.870.98) Ooka et al, 2013 (169) 0.97 (0.950.99)
Petruzzi et al, 2013 (179) 0.78 (0.560.93) Petruzzi et al, 2013 (179) 0.91 (0.710.99)
Toyota et al, 2013 (211) 0.96 (0.881.00) Toyota et al, 2013 (211)
Yoo et al, 2013 (225) 0.48 (0.260.70) Yoo et al, 2013 (225) 0.87 (0.600.98)
Yu et al, 2013 (213) 0.87 (0.810.92) Yu et al, 2013 (213)
Hanna et al, 2014 (47) 0.81 (0.720.88) Hanna et al, 2014 (47)
Hwang et al, 2014 (60) 0.79 (0.700.86) Hwang et al, 2014 (60) 0.93 (0.820.99)
Kim et al, 2014 (108) 0.95 (0.900.98) Kim et al, 2014 (108) 0.79 (0.620.91)
Park et al, 2014 (174) 0.83 (0.720.91) Park et al, 2014 (174)
Yu et al, 2014 (232) 0.70 (0.610.77) Yu et al, 2014 (232)
Zhao et al, 2014 (240) 0.86 (0.700.95) Zhao et al, 2014 (240) 0.60 (0.360.81)

Combined 0.83 (0.800.86) Combined 0.88 (0.79 0.93)

2 = 0.76; P = 0.00 2 = 1.56; P = 0.00
0.1 1.0 0.0 1.0
Total: N = 6296 Total: N = 1246
Sensitivity (95% CI) Specificity (95% CI)

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 Appendix Figure 8. Test performance of ultrasonography with contrast in evaluation of focal liver lesions for identication of
patients with hepatocellular carcinoma.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Fracanzani et al, 2001 (34) 0.95 (0.751.00) Fracanzani et al, 2001 (34) 0.71 (0.480.89)
Quaia et al, 2003 (185) 0.87 (0.600.98) Quaia et al, 2003 (185)
Gaiani et al, 2004 (38) 0.90 (0.810.96) Gaiani et al, 2004 (38)
Wang et al, 2006 (217) 0.72 (0.470.90) Wang et al, 2006 (217) 0.83 (0.520.98)
Catala et al, 2007 (14) 0.91 (0.790.98) Catala et al, 2007 (14)
Forner et al, 2008 (33) 0.52 (0.380.65) Forner et al, 2008 (33) 0.93 (0.770.99)
Jang et al, 2009 (71) 0.87 (0.690.96) Jang et al, 2009 (71) 1.00 (0.881.00)
Luo et al, 2009 (143) 0.93 (0.850.98) Luo et al, 2009 (143) 0.89 (0.780.95)
Luo et al, 2009 (144) 0.98 (0.891.00) Luo et al, 2009 (144) 0.94 (0.800.99)
Seitz et al, 2009 (195) 0.85 (0.700.94) Seitz et al, 2009 (195) 0.96 (0.910.99)
Seitz et al, 2010 (196) 0.79 (0.600.92) Seitz et al, 2010 (196) 0.79 (0.660.89)
Egger et al, 2012 (32) 0.84 (0.600.97) Egger et al, 2012 (32)
Combined 0.87 (0.790.92) Combined 0.92 (0.830.95)
2 = 0.59; P = 0.0046 2 = 0.62; P = 0.037
Total: N = 482; TP = 407 Total: N = 354; TN = 320
0.4 1.0 0.5 1.0
Sensitivity (95% CI) Specificity (95% CI)

Reference numbers are from Appendix Table 3. TN = true negative; TP = true positive.

Appendix Figure 9. Test performance of computed tomography in evaluation of focal liver lesions for identication of
patients with hepatocellular carcinoma.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Fracanzani et al, 2001 (34) 0.95 (0.751.00) Fracanzani et al, 2001 (34) 0.81 (0.580.95)
Catala et al, 2007 (14) 0.87 (0.730.95) Catala et al, 2007 (14)
Golfieri et al, 2009 (43) 0.61 (0.470.74) Golfieri et al, 2009 (43) 0.56 (0.210.86)
Luo et al, 2009 (142) 0.93 (0.850.98) Luo et al, 2009 (142) 0.94 (0.840.98)
Moriyasu and Itoh, 2009 (156) 0.89 (0.820.94) Moriyasu and Itoh, 2009 (156)
Seitz et al, 2009 (195) 0.70 (0.530.83) Seitz et al, 2009 (195) 0.95 (0.890.98)
Egger et al, 2012 (32) 1.00 (0.821.00) Egger et al, 2012 (32)
Serste et al, 2012 (197) 0.74 (0.600.86) Serste et al, 2012 (197) 0.81 (0.620.94)
Combined 0.86 (0.750.92) Combined 0.88 (0.760.95)
2 = 0.65; P = 0.036 2 = 0.64; P = 0.083
Total: N = 423; TP = 353 Total: N = 233; TN = 210
0.5 1.0 0.2 1.0
Sensitivity (95% CI) Specificity (95% CI)

Reference numbers are those in Appendix Table 3. TN = true negative; TP = true positive.

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 Appendix Figure 10. Test performance of magnetic resonance imaging in evaluation of focal liver lesions for identication of
patients with hepatocellular carcinoma.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Forner et al, 2008 (33) 0.62 (0.480.74) Forner et al, 2008 (33) 0.97 (0.821.00)
Golfieri et al, 2009 (43) 0.81 (0.690.91) Golfieri et al, 2009 (43) 0.33 (0.070.70)
Seitz et al, 2010 (196) 0.83 (0.640.94) Seitz et al, 2010 (196) 0.75 (0.620.86)
Serste et al, 2012 (197) 0.81 (0.670.91) Serste et al, 2012 (197) 0.85 (0.660.96)
Donati et al, 2014 (29) 0.58 (0.280.85) Donati et al, 2014 (29) 0.87 (0.600.98)
Combined 0.75 (0.650.83) Combined 0.83 (0.610.93)
Q = 10.21; P = 0.04 Q = 19.07; P = 0.00
2 = 0.12; P = 0.040 2 = 0.13; P = 0.000
Total: N = 203; TP = 151 Total: N = 134; TN = 107
0.3 0.9 0.1 1.0
Sensitivity (95% CI) Specificity (95% CI)

Reference numbers are those in Appendix Table 3. TN = true negative; TP = true positive.

Appendix Figure 11. Test performance of ultrasonography with contrast for evaluation of focal liver lesions for identication of
hepatocellular carcinoma lesions.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Tanaka et al, 2001 (206) 0.92 (0.820.97) Tanaka et al, 2001 (206) 0.96 (0.861.00)
Yamamoto et al, 2002 (223) 0.91 (0.780.97) Yamamoto et al, 2002 (223)
Rickes et al, 2003 (186) 0.89 (0.790.96) Rickes et al, 2003 (186)
Strobel et al, 2003 (202) 0.92 (0.641.00) Strobel et al, 2003 (202)
Gaiani et al, 2004 (38) 0.91 (0.840.96) Gaiani et al, 2004 (38)
Giorgio et al, 2004 (41) 0.97 (0.911.00) Giorgio et al, 2004 (41)
Suzuki et al, 2004 (205) 0.90 (0.770.97) Suzuki et al, 2004 (205) 0.91 (0.591.00)
DOnofrio et al, 2005 (30) 0.93 (0.760.99) DOnofrio et al, 2005 (30)
Luo et al, 2005 (140) 1.00 (0.871.00) Luo et al, 2005 (140)
Catala et al, 2007 (14) 0.91 (0.790.98) Catala et al, 2007 (14)
Giorgio et al, 2007 (42) 0.77 (0.630.88) Giorgio et al, 2007 (42) 0.96 (0.801.00)
Li et al, 2007 (130) 0.89 (0.780.95) Li et al, 2007 (130)
Dai et al, 2008 (24) 0.91 (0.800.97) Dai et al, 2008 (24) 0.87 (0.740.95)
Hatanaka et al, 2008 (52) 0.97 (0.930.99) Hatanaka et al, 2008 (52) 0.94 (0.860.98)
Wang et al, 2008 (218) 0.75 (0.190.99) Wang et al, 2008 (218)
Xu et al, 2008 (220) 0.80 (0.660.90) Xu et al, 2008 (220) 0.93 (0.820.98)
Luo et al, 2009 (141) 0.61 (0.510.70) Luo et al, 2009 (141) 0.90 (0.820.95)
Quaia et al, 2009 (184) 0.89 (0.790.95) Quaia et al, 2009 (184) 0.67 (0.520.80)
Mita et al, 2010 (152) 0.68 (0.490.83) Mita et al, 2010 (152)
Ooi et al, 2010 (168) 0.84 (0.710.94) Ooi et al, 2010 (168)
Sangiovanni et al, 2010 (191) 0.26 (0.130.44) Sangiovanni et al, 2010 (1910) 1.00 (0.841.00)
Khalili et al, 2011 (81) 0.53 (0.350.70) Khalili et al, 2011 (81) 0.91 (0.820.97)
Xu et al, 2012 (222) 0.89 (0.820.94) Xu et al, 2012 (222) 1.00 (0.891.00)
Combined 0.87 (0.800.92) Combined 0.91 (0.850.95)
2 = 1.19; P < 0.0001 2 = 0.51; P = 0.012
Total: N = 1156; TP = 975 Total: N = 495; TN = 445

0.1 1.0 0.5 1.0

Sensitivity (95% CI) Specificity (95% CI)

Reference numbers are those in Appendix Table 3. TN = true negative; TP = true positive.

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 Appendix Figure 12. Test performance of computed tomography in evaluation of focal liver lesions for identication of
hepatocellular carcinoma lesions.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Colagrande et al, 2000 (23) 0.94 (0.870.98) Colagrande et al, 2000 (23)
Yamamoto et al, 2002 (223) 0.93 (0.810.99) Yamamoto et al, 2002 (223)
Giorgio et al, 2004 (41) 0.92 (0.830.97) Giorgio et al, 2004 (41)
Iannaccone et al, 2005 (61) 0.93 (0.890.96) Iannaccone et al, 2005 (61)
Catala et al, 2007 (14) 0.87 (0.730.95) Catala et al, 2007 (14)
Li et al, 2007 (130) 0.84 (0.720.92) Li et al, 2007 (130) _
Dai et al, 2008 (24) 0.80 (0.680.90) Dai et al, 2008 (24) 0.98 (0.891.00)
Golfieri et al, 2009 (43) 0.62 (0.510.72) Golfieri et al, 2009 (43) 0.72 (0.550.86)
Quaia et al, 2009 (184) 0.72 (0.600.82) Quaia et al, 2009 (184) 0.71 (0.570.83)
Mita et al, 2010 (152) 0.53 (0.350.70) Mita et al, 2010 (152)
Sangiovanni et al, 2010 (191) 0.44 (0.270.62) Sangiovanni et al, 2010 (191) 1.00 (0.841.00)
Khalili et al, 2011 (81) 0.53 (0.350.70) Khalili et al, 2011 (81) 0.99 (0.921.00)
Jang et al, 2013 (72) 0.58 (0.410.74) Jang et al, 2013 (72) 0.99 (0.931.00)
Combined 0.79 (0.670.87) Combined 0.90 (0.370.99)
2 = 0.97; P = 0.001 2 = 4.39; P = 0.110
Total: N = 924; TP = 725 Total: N = 294; TN = 267

0.3 1.0 0.4 1.0

Sensitivity (95% CI) Specificity (95% CI)

Reference numbers are those in Appendix Table 3. TN = true negative; TP = true positive.

Appendix Figure 13. Test performance of magnetic resonance imaging in evaluation of focal liver lesions for identication of
hepatocellular carcinoma lesions.

Study, Year (Reference) Sensitivity (95% CI) Study, Year (Reference) Specificity (95% CI)

Kim et al, 2004 (86, 87) 0.91 (0.760.98) Kim et al, 2004 (86, 87)
Youk et al, 2004 (227) 0.88 (0.790.93) Youk et al, 2004 (227)
Marrero et al, 2005 (150) 0.91 (0.810.97) Marrero et al, 2005 (150) 0.97 (0.821.00)
Giorgio et al, 2007 (42) 0.90 (0.770.97) Giorgio et al, 2007 (42) 0.88 (0.690.97)
Golfieri et al, 2009 (43) 0.84 (0.740.91) Golfieri et al, 2009 (43) 0.36 (0.210.54)
Chung et al, 2010 (21) 0.90 (0.680.99) Chung et al, 2010 (21)
Sangiovanni et al, 2010 (191) 0.44 (0.270.62) Sangiovanni et al, 2010 (191) 1.00 (0.841.00)
Chung et al, 2011 (22) 0.94 (0.870.98) Chung et al, 2011 (22) 0.84 (0.600.97)
Khalili et al, 2011 (81) 0.62 (0.440.78) Khalili et al, 2011 (81) 1.00 (0.951.00)
Kim et al, 2011 (100) 0.77 (0.610.88) Kim et al, 2011 (100) 0.95 (0.870.98)
Suh et al, 2011 (204) 0.88 (0.620.98) Suh et al, 2011 (204) 0.81 (0.640.93)
Gatto et al, 2013 (40) 0.69 (0.410.89) Gatto et al, 2013 (40) 0.64 (0.350.87)
Kim et al, 2012 (104) 0.73 (0.630.81) Kim et al, 2012 (104) 1.00 (0.691.00)
Rimola et al, 2012 (187) 0.58 (0.480.68) Rimola et al, 2012 (187) 0.96 (0.881.00)
Combined 0.81 (0.730.88) Combined 0.92 (0.780.97)
P = 0.00 P = 0.00

0.3 1.0 Total: N = 1023 0.2 1.0 Total: N = 920

Sensitivity (95% CI) Specificity (95% CI)

Reference numbers are those in Appendix Table 3.

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 Appendix Table 4. Test Performance of Imaging Modalities for Detection of Hepatocellular Carcinoma Lesions, Stratied by
the Reference Standard Used
Imaging Modality and Sensitivity Studies, n Specicity Studies, n Positive LR Negative LR
Reference Standard (95% CI) (95% CI)
US without contrast
Explanted liver 0.34 (0.220.47) 5 Insufcient data
Histopathologic, nonexplant 0.75 (0.580.86) 3 Insufcient data
Mixed histologic and imaging/clinical criteria 0.72 (0.460.88) 1 Insufcient data

CT
Explanted liver 0.67 (0.590.75) 23 0.82 (0.740.88) 12 3.8 (2.65.6) 0.40 (0.310.50)
Histopathologic, nonexplant 0.86 (0.780.91) 12 0.95 (0.880.98) 3 19 (7.149) 0.15 (0.100.23)
Imaging/clinical 0.65 (0.430.83) 3 Insufcient data
Mixed histologic and imaging/clinical 0.80 (0.750.84) 34 0.92 (0.830.96) 4 11 (5.321) 0.22 (0.170.27)

MRI
Explanted liver 0.70 (0.620.77) 20 0.86 (0.730.93) 10 5.0 (2.59.8) 0.35 (0.270.44)
Histopathologic, nonexplant 0.88 (0.820.93) 11 0.97 (0.880.99) 3 29 (7.3117) 0.12 (0.080.19)
Imaging/clinical reference standard 0.86 (0.670.95) 2 Insufcient data
Mixed histologic and imaging/clinical 0.85 (0.810.88) 33 0.84 (0.540.96) 3 5.2 (1.518) 0.18 (0.130.24)
CT = computed tomography; LR = likelihood ratio; MRI = magnetic resonance imaging; US = ultrasonography.

Appendix Table 5. Diagnostic Accuracy of Imaging for Hepatocellular Carcinoma, by Lesion Size and Degree of Differentiation

Imaging Modality, Lesion Size, Sensitivity Studies, n Specicity Studies, n Positive LR Negative LR
and Differentiation (95% CI) (95% CI)
US without contrast
<10 mm 0.09 (0.02 to 0.29) 4 0.93 (0.79 to 1.0) 1 1.3 0.98
1020 mm 0.50 (0.23 to 0.78) 4 0.60 (0.46 to 0.74) 1 1.2 0.83
>20 mm 0.88 (0.66 to 0.96) 4 0.53 (0.35 to 0.71) 1 1.9 0.23
Difference between >20 mm 0.37 (0.18 to 0.57) 4 0.33 (0.53 to 0.14) 1
and 1020 mm
Difference between 1020 mm 0.41 (0.19 to 0.63) 4 0.06 (0.29 to 0.16) 1
and <10 mm

US with contrast
1020 mm 0.64 (0.33 to 0.87) 3 1.0 (26/26) 1
>20 mm 0.91 (0.71 to 0.98) 3 1.0 (2/2) 1
Difference 0.26 (0.04 to 0.48) 3 0.0 1
Moderately or poorly differentiated 0.83 (0.55 to 0.95) 3 No data
Well differentiated 0.43 (0.15 to 0.76) 3 No data
Difference 0.40 (0.17 to 0.64) 3 No data

CT
<10 mm 0.32 (0.25 to 0.41) 21 0.69 (0.52 to 0.82) 2 1.0 (0.59 to 1.8) 0.99 (0.77 to 1.3)
1020 mm 0.74 (0.67 to 0.80) 23 0.86 (0.74 to 0.93) 2 5.3 (2.8 to 10) 0.30 (0.23 to 0.40)
>20 mm 0.95 (0.92 to 0.97) 20 0.90 (0.73 to 0.97) 1 9.5 (3.2 to 28) 0.06 (0.04 to 0.09)
Difference between >20 mm 0.21 (0.15 to 0.26) 20 0.04 (0.10 to 0.18) 2
and 1020 mm
Difference between 1020 mm 0.42 (0.36 to 0.48) 21 0.17 (0.004 to 0.35) 1
and <10 mm
Moderately or poorly differentiated 0.81 (0.67 to 0.90) 6 No data
Well differentiated 0.47 (0.29 to 0.65) 6 No data
Difference 0.34 (0.23 to 0.46) 6 No data

MRI
<10 mm 0.51 (0.41 to 0.62) 22 0.89 (0.56 to 0.98) 4 4.6 (0.92 to 23) 0.55 (0.42 to 0.72)
1020 mm 0.80 (0.72 to 0.86) 23 0.95 (0.75 to 0.992) 4 17 (2.9 to 99) 0.21 (0.15 to 0.30)
>20 mm 0.97 (0.95 to 0.98) 20 0.98 (0.82 to 0.998) 3 42 (4.8 to 373) 0.03 (0.02 to 0.05)
Difference between >20 mm 0.28 (0.21 to 0.35) 20 0.07 (0.05 to 0.18) 4
and 1020 mm
Difference between 1020 mm 0.17 (0.11 to 0.24) 20 0.02 (0.03 to 0.08) 3
and <10 mm
Moderately or poorly differentiated 0.77 (0.55 to 0.90) 4 No data
Well differentiated 0.42 (0.21 to 0.67) 4 No data
Difference 0.36 (0.20 to 0.51) 4 No data
CT = computed tomography; LR = likelihood ratio; MRI = magnetic resonance imaging; US = ultrasonography.

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 Appendix Table 6. Strength of Evidence
Test Performance Unit of Analysis Imaging Modality Studies, n Risk of Consistency Directness Precision Patients or Strength of
or Comparison Bias* Lesions, n Evidence

Surveillance
Surveillance settings Patients with HCC US without contrast Sens: 4 Moderate Inconsistent Indirect Imprecise Sens: 540 Sens: Low
Spec: 3 Spec: 488 Spec: Low
Surveillance settings Patients with HCC CT Sens: 2 Moderate Consistent Indirect Imprecise Sens: 385 Sens: Low
Spec: 2 Spec: 385 Spec: Low
Surveillance settings Patients with HCC MRI No evidence Insufcient

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Surveillance settings HCC lesions US without contrast Sens: 1 Moderate Sens: Inconsistent Indirect Sens: Imprecise Sens: 42 Sens: Low
Spec: 0 Spec: No studies Spec: No studies Spec: Spec: Insufcient
Surveillance settings HCC lesions CT Sens: 1 Moderate Sens: Single study Indirect Sens: Imprecise Sens: 42 Sens: Low
Spec: 0 Spec: No studies Spec: No studies Spec: Spec: Insufcient
Surveillance settings HCC lesions MRI No evidence Insufcient
Nonsurveillance settings Patients with HCC US without contrast Sens: 8 Moderate Inconsistent Indirect Imprecise Sens: 975 Sens: Low
Spec: 6 Spec: 858 Spec: Low
Nonsurveillance settings Patients with HCC CT Sens: 17 Moderate Inconsistent Indirect Precise Sens: 1327 Sens: Moderate

Annals of Internal Medicine Vol. 162 No. 10 19 May 2015

Spec: 12 Spec: 1145 Spec: Moderate
Nonsurveillance settings Patients with HCC MRI Sens: 14 Moderate Inconsistent Indirect Precise Sens: 1332 Sens: Moderate
Spec: 12 Spec: 1240 Spec: Moderate
Nonsurveillance settings HCC lesions US without contrast Sens: 11 Moderate Inconsistent Indirect Sens: Precise Sens: 1996 Sens: Moderate
Spec: 2 Spec: Imprecise Spec: 323 Spec: Low
Nonsurveillance settings HCC lesions US with contrast Sens: 9 Moderate Sens: Inconsistent Indirect Sens: Imprecise Sens: 443 Sens: Low
Spec: 1 Spec: Single study Spec: Imprecise Spec: Spec: Insufcient
Nonsurveillance settings HCC lesions CT Sens: 80 Moderate Inconsistent Indirect Precise Sens: 8145 Sens: Moderate
Spec: 21 Spec: 2948 Spec: Moderate
Nonsurveillance settings HCC lesions MRI Sens: 82 Moderate Inconsistent Indirect Precise Sens: 7162 Sens: Moderate
Spec: 20 Spec: 2472 Spec: Moderate
Direct (within-study) comparisons of Patients with HCC US without contrast Sens: 6 Moderate Inconsistent Direct Precise Sens: 899 (US) Sens: Moderate
imaging modalities vs. CT Spec: 5 Sens: 838 (CT) Spec: Moderate
Spec: 885 (US) For the 2 studies in
Spec: 824 (CT) surveillance
settings, the
strength of
evidence is low for
sensitivity and
specicity.
Direct (within-study) comparisons of Patients with HCC US without contrast Sens: 3 Moderate Consistent Direct Precise Sens: 712 (US) Sens: Moderate
imaging modalities vs. MRI Spec: 3 Sens: 712 (MRI) Spec: Moderate
Spec: 712 (US)
Spec: 712 (MRI)
Direct (within-study) comparisons of Patients with HCC MRI vs. CT Sens: 5 Moderate Inconsistent Direct Precise Sens: 318 (MRI) Sens: Moderate
imaging modalities Spec: 5 Sens: 484 (CT) Spec: Moderate
Spec: 318 (MRI)
Spec: 534(CT)
Direct (within-study) comparisons of HCC lesions US without contrast Sens: 3 Moderate Inconsistent Direct Precise Sens: 535 (US) Sens: Moderate
imaging modalities vs. CT Spec: 2 Sens: 539 (CT) Spec: Moderate
Spec: 323 (US)
Spec: 323 (CT)
Direct (within-study) comparisons of HCC lesions US without contrast Sens: 3 Moderate Consistent Direct Precise Sens: 660 (US) Sens: Moderate
imaging modalities vs. MRI Spec: 2 Sens: 660 (MRI) Spec: Moderate
Spec: 323 (US)
Spec: 323 (MRI)

Continued on following page

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Appendix Table 6Continued
Test Performance Unit of Analysis Imaging Modality Studies, n Risk of Consistency Directness Precision Patients o r Strength of
or Comparison Bias* Lesions, n Evidence

Direct (within-study) comparisons of HCC lesions US with contrast vs. Sens: 4 Moderate Sens: Inconsistent Direct Sens: Precise Sens: 217 (US) Sens: Moderate
imaging modalities CT Spec: 0 Spec: No studies Spec: No studies Sens: 217 (CT) Spec: Insufcient
Spec:
Direct (within-study) comparisons of HCC lesions US with contrast vs. Sens: 3 Moderate Sens: Consistent Direct Sens: Imprecise Sens: 172 (US) Sens: Moderate

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imaging modalities MRI Spec: 0 Spec: No studies Spec: No studies Sens: 170 (MRI) Spec: Insufcient
Spec:
Direct (within-study) comparisons of HCC lesions MRI vs. CT Sens: 32 Moderate Inconsistent Direct Precise Sens: 3002 (MRI) Sens: Moderate
imaging modalities Spec: 7 Sens: 3288 (CT) Spec: Moderate
Spec: 874 (MRI)
Spec: 842 (CT)

Diagnosis
Evaluation of focal liver lesion Patients with HCC US with contrast Sens: 12 Moderate Inconsistent Indirect Precise Sens: 836 Sens: Moderate
Spec: 8 Spec: 678 Spec: Moderate
Evaluation of focal liver lesion Patients with HCC US without contrast Sens: 1 Moderate Sens: Consistent Indirect Sens: Imprecise Sens: 93 Sens: Low
Spec: 0 Spec: No studies Spec: No studies Spec: Spec: Insufcient
Evaluation of focal liver lesion Patients with HCC CT Sens: 8 Moderate Inconsistent Indirect Sens: Precise Sens: 656 Sens: Moderate
Spec: 5 Spec: Imprecise Spec: 471 Spec: Low
Evaluation of focal liver lesion Patients with HCC MRI Sens: 5 Moderate Consistent Indirect Imprecise Sens: 337 Sens: Low
Spec: 5 Spec: 337 Spec: Low
Evaluation of focal liver lesion HCC lesions US with contrast Sens: 21 Moderate Inconsistent Indirect Precise Sens: 1652 Sens: Moderate
Spec: 10 Spec: 1175 Spec: Moderate
Evaluation of focal liver lesion HCC lesions CT Sens: 13 Moderate Inconsistent Indirect Precise Sens: 1196 Sens: Moderate
Spec: 6 Spec: 591 Spec: Moderate
Evaluation of focal liver lesion HCC lesions MRI Sens: 15 Moderate Inconsistent Indirect Precise Sens: 1214 Sens: Moderate
Spec: 12 Spec: 1043 Spec: Moderate
Direct (within-study) comparisons of Patients with HCC US without contrast Sens: 1 Moderate Sens: Single study Direct Sens: Imprecise Sens: 121 Sens: Low
imaging modalities vs. CT Spec: 0 Spec: No studies Spec: No studies Spec: 0 Spec: Insufcient
Direct (within-study) comparisons of Patients with HCC US with contrast vs. Sens: 5 Moderate Consistent Direct Sens: Precise Sens: 956 Sens: Moderate
imaging modalities CT Spec: 2 Spec: Imprecise Spec: 586 Spec: Low
Direct (within-study) comparisons of Patients with HCC MRI vs. CT Sens: 1 Moderate Single study Direct Imprecise Sens: 74 Sens: Low
imaging modalities Spec: 1 Spec: 74 Spec: Low
Direct (within-study) comparisons of HCC lesions US with contrast vs. Sens: 4 Moderate Sens: Inconsistent Direct Sens: Imprecise Sens: 446 Sens: Moderate
imaging modalities CT Spec: 0 Spec: No studies Spec: No studies Spec: 0 Spec: Insufcient
Direct (within-study) comparisons of HCC lesions US with contrast vs. Sens: 1 Moderate Single study Direct Imprecise Sens: 162 Sens: Low
imaging modalities MRI Spec: 1 Spec: 162 Spec: Low
Direct (within-study) comparisons of HCC lesions MRI vs. CT Sens: 1 Moderate Single study Direct Imprecise Sens: 123 Sens: Low
imaging modalities Spec: 1 Spec: 123 Spec: Low

CT = computed tomography; HCC = hepatocellular carcinoma; MRI = magnetic resonance imaging; Sens = sensitivity; Spec = specicity; US = ultrasonography.
* Low, moderate, or high.
Consistent or inconsistent.
Direct or indirect.
Precise or imprecise.
High, moderate, low, or insufcient.

Annals of Internal Medicine Vol. 162 No. 10 19 May 2015

 Appendix Table 7. Post test Probability of HCC With Different Imaging Modalities in Detection of HCC or for Evaluation of
Focal Liver Lesions for HCC
Imaging Modality Unit of Analysis Pretest Positive Post test Negative Post test
Probability, % LR (95% CI) Probability of LR (95% CI) Probability of
HCC After a HCC After a
Positive Test Negative Test
Result, % Result, %
Detection of HCC
US without contrast* Patient with HCC 1 6.8 (4.211) 6.4 0.25 (0.130.46) 0.25
5 26 1.3
US without contrast Patient with HCC 1 11 (5.421) 10 0.29 (0.130.65) 0.29
5 37 1.5
CT Patient with HCC 1 9.1 (5.116) 8.4 0.19 (0.130.27) 0.19
5 32 0.99
CT HCC lesion 1 7.1 (4.711) 6.7 0.26 (0.220.32) 0.26
5 27 1.3
MRI Patient with HCC 1 7.7 (4.613) 7.2 0.16 (0.100.24) 0.16
5 29 0.84
MRI HCC lesions 1 6.5 (3.811) 6.2 0.20 (0.160.24) 0.20
5 25 1.0

Evaluation of focal liver lesions

US with contrast Patient with HCC 10 9.6 (5.118) 52 0.14 (0.090.23) 1.5
25 76 4.5
US with contrast HCC lesion 10 9.8 (5.717) 52 0.14 (0.090.23) 1.5
25 77 4.5
CT Patient with HCC 10 7.4 (3.317) 45 0.16 (0.090.30) 1.7
25 71 5.1
CT HCC lesion 10 7.7 (0.7184) 46 0.24 (0.150.38) 2.6
25 72 7.4
MRI Patient with HCC 10 4.1 (1.89.2) 31 0.31 (0.230.40) 3.3
25 58 9.4
MRI HCC lesion 10 10 (3.629) 53 0.20 (0.140.28) 2.2
25 77 6.2
CT = computed tomography; HCC = hepatocellular carcinoma; LR = likelihood ratio; MRI = magnetic resonance imaging; Sens = sensitivity;
Spec = specicity; US = ultrasonography.
* Based on studies conducted in surveillance settings.
Based on studies conducted in nonsurveillance settings.

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 CORRECTION: IMAGING TECHNIQUES FOR THE DIAGNOSIS OF
HEPATOCELLULAR CARCINOMA
In Figure 2 of a recent article (1), the bottom of the
right side of the forest plot is the true negative total, not
the true positive total.
In the rst paragraph, the number of deaths attributed
to liver and intrahepatic bile duct cancer in the United States
in 2011 was incorrect; the correct estimate is 25 000, not
156 940.
This has been corrected in the online version.

Reference
1. Chou R, Cuevas C, Fu R, Devine B, Wasson N, Ginsburg A, et al. Imaging
techniques for the diagnosis of hepatocellular carcinoma. A systematic review
and meta-analysis. Ann Intern Med. 2015;162:697-711. doi:10.7326/M14-
2509

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