Imaging for the Diagnosis of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis - AASLD
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A MERICAN A SSOCIATION FOR
T HE STUDY OF LIVER D I S E ASES
HEPATOLOGY, VOL. 67, NO. 1, 2018
Imaging for the Diagnosis
of Hepatocellular Carcinoma: A
Systematic Review and Meta-analysis
Lewis R. Roberts ,1 Claude B. Sirlin,2 Feras Zaiem,3 Jehad Almasri,3 Larry J. Prokop,3 Julie K. Heimbach,1
M. Hassan Murad,3 and Khaled Mohammed3
Multiphasic computed tomography (CT) and magnetic resonance imaging (MRI) are both used for noninvasive diagnosis
of hepatocellular carcinoma (HCC) in patients with cirrhosis. To determine if there is a relative diagnostic benefit of one
over the other, we synthesized evidence regarding the relative performance of CT, extracellular contrast–enhanced MRI,
and gadoxetate-enhanced MRI for diagnosis of HCC in patients with cirrhosis. We also assessed whether liver biopsy ver-
sus follow-up with the same versus alternative imaging is best for CT-indeterminate or MRI-indeterminate liver nodules
in patients with cirrhosis. We searched multiple databases from inception to April 27, 2016, for studies comparing CT
with extracellular contrast–enhanced MRI or gadoxetate-enhanced MRI in adults with cirrhosis and suspected HCC. Two
reviewers independently selected studies and extracted data. Of 33 included studies, 19 were comprehensive, while 14
reported sensitivity only. For all tumor sizes, the 19 comprehensive comparisons showed significantly higher sensitivity
(0.82 versus 0.66) and lower negative likelihood ratio (0.20 versus 0.37) for MRI over CT. The specificities of MRI versus
CT (0.91 versus 0.92) and the positive likelihood ratios (8.8 versus 8.1) were not different. All three modalities performed
better for HCCs 2 cm. Performance was poor for HCCs
ROBERTS ET AL. HEPATOLOGY, January 2018 elsewhere.(8) Also of fundamental importance is pretest with some, but not all, of the hallmark features of probability: patients with cirrhosis have a high pretest HCC. The differential diagnosis for such nodules probability of HCC and a low pretest probability of includes HCC, non-HCC malignancy, and nonmalig- nonmalignant nodules that may resemble HCC at nant entities. Because imaging does not establish a imaging. In such patients, nodules with the hallmark specific diagnosis in such cases, prior clinical practice imaging features of HCC can be reliably diagnosed as guidelines by the American Association for the Study HCC.(9) of Liver Diseases recommended biopsy for all liver While the imaging features distinctive of HCC can lesions >1 cm initially detected by surveillance ultra- be observed both by multiphasic CT and MRI, MRI sound and interpreted as indeterminate by diagnostic offers a number of additional imaging sequences that call-back CT and MRI.(9,13) The evidence supporting can be helpful in HCC diagnosis, including T2- this recommendation was not provided, however. Due weighted sequences, diffusion-weighted imaging, and, to the limitations of biopsy(2,14) and the complexities in combination with the use of a partially extracellular of working up suspected HCC, alternative strategies and partially hepatocellular contrast agent such as such as follow-up or alternative imaging may be prefer- gadoxetate disodium, the ability to distinguish even able in individual cases. relatively small and subtle lesions by hypointensity in We conducted this systematic review and meta- the hepatobiliary phase.(10-13) MRI has important analysis to synthesize the existing evidence about the diagnostic disadvantages, however, including greater comparative performance of multiphasic CT and MRI technical complexity, higher susceptibility to artifacts, with extracellular or gadoxetate contrast in the diagno- and less consistent image quality. In particular, MRI sis of HCC in patients with underlying cirrhosis. quality may be compromised in patients with difficulty While a number of systematic reviews and meta- breath-holding, trouble keeping still, or large-volume analyses have examined the performance of CT and/or ascites. Also, although noncontrast MRI may detect MRI in the diagnosis of HCC,(15-24) relatively few tumor nodules, such sequences rarely provide sufficient studies have examined these imaging modalities in specificity to enable noninvasive diagnosis of HCC. comparative studies in which CT was directly com- Thus, while noncontrast MRI may provide useful pared to either extracellular or partially extracellular information, it does not reliably permit definitive diag- and partially hepatocellular contrast agent MRI. A nosis and staging of HCC in most patients. For these number of the publications included studies that were reasons, the comparative diagnostic performance of not directly comparative,(15,17-19,21,22) and some did multiphasic CT and MRI in real-life practice remains not include more recent studies.(16,20) Two studies uncertain. published since our analyses were performed provide Another area of controversy is the optimal manage- some complementary information and are reviewed in ment of patients in whom CT or MRI detects a nodule the Discussion.(22,23) Also, we examined the available ARTICLE INFORMATION: From the 1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN; 2Liver Imaging Group, Department of Radiology, University of California San Diego, San Diego, CA; 3Evidence-Based Practice Center, Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic College of Medicine and Science, Rochester, MN. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: Lewis R. Roberts, M.B. Ch.B., Ph.D. San Diego, CA Division of Gastroenterology and Hepatology E-mail: csirlin@ucsd.edu Mayo Clinic College of Medicine and Science or Rochester, MN M. Hassan Murad, M.D., M.P.H. E-mail: Roberts.Lewis@mayo.edu Evidence-Based Practice Center, Mayo Clinic Robert D. Tel: 11-507-284-4823 and Patricia E. Kern Center for the Science of Health Care or Delivery Claude B. Sirlin, M.D. Mayo Clinic College of Medicine and Science Liver Imaging Group, Department of Radiology Rochester, MN University of California San Diego E-mail: Murad.Mohammad@mayo.edu 402
HEPATOLOGY, Vol. 67, No. 1, 2018 ROBERTS ET AL.
evidence supporting biopsy or additional imaging for DATA EXTRACTION
indeterminate lesions in patients with cirrhosis.
We extracted the following variables from each
study: study characteristics including primary author,
Materials and Methods time period of study/year of publication and country of
study; patient baseline characteristics including coun-
We followed a predefined protocol developed by the
try, age, lesion number, lesion size, alpha-fetoprotein
HCC clinical practice guideline writing and systematic
level, Child-Pugh score, and cause of cirrhosis; index
review committees of the American Association for the
and reference test characteristics; outcomes of interest.
Study of Liver Diseases. We reported this systematic
We extracted true-positive, false-positive, false-
review according to the Preferred Reporting Items for
negative, and true-negative values of the index tests
Systematic Reviews and Meta-Analyses statement.(25)
(MRI versus CT). Data extraction was done in
duplicate.
ELIGIBILITY CRITERIA
Two questions were identified by the American METHODOLOGICAL QUALITY
Association for the Study of Liver Diseases practice
guidelines committee. Table 1 describes detailed inclu-
AND RISK OF BIAS ASSESSMENT
sion and exclusion criteria for the two questions of We used the Quality Assessment of Diagnostic
interest. For question 1, we included studies that Accuracy Studies 2 tool(26) to assess the risk of bias
enrolled adults diagnosed with cirrhosis and suspected and applicability of diagnostic accuracy studies. We
HCC and compared multiphasic CT versus MRI with assessed the following domains: patient selection,
and without extracellular contrast or gadoxetate diso- index test, reference standard, flow, and timing. Qual-
dium. For question 2, we included studies that enrolled ity of evidence was evaluated using the Grading of
adults with cirrhosis and indeterminate hepatic lesion Recommendations Assessment, Development, and
and compared biopsy, repeated imaging, or alternative Evaluation approach.(27)
imaging for the diagnostic evaluation.
SEARCH STRATEGY STATISTICAL ANALYSIS
A comprehensive search of several databases from We calculated measures of diagnostic test accuracy
each database inception to April 27, 2016, in any lan- (sensitivity, specificity, likelihood ratios, and diagnostic
guage was conducted. The databases included Ovid odds ratios) using a bivariate regression model, allow-
Medline In-Process & Other Non-Indexed Citations, ing for correlation between sensitivity and specificity.
Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane I2 >50% suggests high heterogeneity. Summary re-
Central Register of Controlled Trials, and Scopus. ceiver operating characteristic curves were also esti-
The search strategy was designed and conducted by an mated. Statistical analyses were conducted using Stata
experienced librarian with input from the primary version 13 (StataCorp, College Station, TX). We cal-
investigators. Supporting Tables S1 and S2 demon- culated an interaction P value to estimate the statistical
strate the detailed search strategy for questions 1 and significance between the accuracy measures of the two
2, respectively. index tests (MRI versus CT). A separate analysis of
studies that only reported detection rates (without a
2 3 2 diagnostic table) was performed. In this subset
STUDY SELECTION
of studies we pooled the detection rate with 95% confi-
Using an online reference management system (Dis- dence intervals (CIs) using Jeffreys method. We
tillerSR; Evidence Partners, Inc.), two reviewers inde- pooled log-transformed event rates with DerSimonian
pendently screened the titles and abstracts for potential and Laird random-effect models. We assessed publica-
eligibility. Full text versions of the included abstracts tion bias by examining funnel plot asymmetry and
were retrieved and screened in duplicate. Disagree- Egger’s regression test. Subgroup and sensitivity analy-
ments were harmonized by consensus and, if not pos- ses were done based on the cohort enrollment date
sible by consensus, through arbitration by a third (
ROBERTS ET AL. HEPATOLOGY, January 2018
TABLE 1. Inclusion and Exclusion Criteria
Q1 Q2
Population Adults with cirrhosis and suspected HCC Adults with cirrhosis and an indeterminate nodule
after contrast-enhanced CT or MR or CEUS
Intervention versus comparison Diagnosis and staging of HCC with contrast- Repeat imaging after observation period 2-3
enhanced, multiphasic CT versus MR with and months versus biopsy versus repeat alternative
without extracellular contrast or gadoxetate imaging technique
disodium
Outcomes Accuracy of identifying and staging HCC Survival, cost-effectiveness, stage at diagnosis,
patient tolerance
Study design Comparative studies Comparative studies
Exclusions Noncomparative studies that included either MRI or Noncomparative studies, reviews, case reports,
CT only; reviews, case reports, and studies with and studies with fewer than 5 patients
fewer than 5 patients
Abbreviation: CEUS, contrast-enhanced ultrasonography.
contrast material used (gadoxetate-enhanced versus bias for the remaining 14 studies that reported detec-
extracellular contrast–enhanced). tion rate only was considered low to moderate (Fig.
2B). Detailed assessment of the methodological quality
of the studies is provided in Table 3.
Results
Our search strategy identified 2,256 citations. After
Pooled Analysis of Diagnostic Accuracy
screening titles and abstracts, a total of 433 were Nineteen studies(3,28-45) compared the diagnostic
deemed eligible for full text retrieval. We eventually accuracy of MRI versus CT in detecting HCC. Com-
included 33 studies. Figure 1 demonstrates the study pared to CT, MRI with an extracellular agent, or MRI
selection process. with gadoxetate disodium showed a significantly
higher sensitivity (0.82; 95% CI, 0.75-0.87; I2 5
Q1: WHAT IS THE DIAGNOSTIC 80.74; versus 0.66; 95% CI, 0.60-0.72; I2 5 72.53)
and lower negative likelihood ratio (0.20; 95% CI,
ACCURACY OF MULTIPHASIC CT
0.15-0.28; versus 0.37; 95% CI, 0.30-0.44) in diagno-
VERSUS MULTIPHASIC MRI IN sis of HCC lesions. No significant difference was
ADULTS WITH CIRRHOSIS AND found for the pooled specificity, positive likelihood
SUSPECTED HCC? ratio, or diagnostic odds ratio. Figures 3 and 4 illus-
trate sensitivity and specificity forest plots of CT and
Nineteen studies(3,28-45) reported true-positive,
MRI, respectively. Analysis of the receiver operating
false-positive, false-negative, and true-negative values,
characteristic area under the curve (Fig. 5) showed that
while 14 studies(5,46-58) reported only detection rate
accuracy of MRI for detection of HCC was 0.91 (95%
(sensitivity rate). Table 2 describes the detailed base-
CI, 0.89-0.93) compared to 0.80 (95% CI, 0.77-0.83)
line characteristics of the included studies.
for CT. Sensitivity analysis was done to exclude two
cohorts(39,44) that enrolled patients before 2000; no
Methodological Quality change in the results was found. Table 4 shows the
of the Included Studies diagnostic accuracy of CT versus MRI for diagnosis of
The overall risk of bias of the 19 studies (Fig. 2A) HCC.
that reported all diagnostic accuracy values was low to
moderate. Almost 50% of the studies were judged to
Subgroup Analysis
have low risk of bias in terms of patient selection, index Subgroup analysis was done based on the type of
test, reference standard, flow, and timing. The majority MRI contrast material. Eight studies(28,31,33,34,38,41,43,45)
of the studies were considered to have a low risk of bias evaluated gadoxetate-enhanced MRI versus CT, and 11
on applicability to clinical practice in terms of reference studies(3,29,30,32,35-37,39,40,42,44) evaluated extracellular
standard, index test, and patient selection. The risk of contrast–enhanced MRI versus CT in detecting HCC.
404
HEPATOLOGY, Vol. 67, No. 1, 2018 ROBERTS ET AL. Pooled analysis demonstrated that both gadoxetate- 94.6; versus 0.48; 95% CI, 0.34-0.62; I2 5 52). No enhanced MRI and extracellular contrast–enhanced differences were found in the pooled specificity, nega- MRI provided significantly higher sensitivity and lower tive likelihood ratio, positive likelihood ratio, and diag- negative likelihood ratio than CT. No significant differ- nostic odds ratio. Also, no differences were identified ence was noticed in the pooled specificity, positive likeli- in pooled performance characteristics between MRI hood ratio, and diagnostic odds ratio. Figures 6 and 7 with an extracellular agent and CT for 1-2 cm HCCs illustrate the forest plots of sensitivity and specificity of or between MRI with gadoxetate and CT for 2 cm (0.88; 95% CI, enhanced CT versus extracellular contrast MRI was 0.80-0.93; I2 5 70.5; versus 0.79; 95% CI, 0.70-0.86; 0.61 versus 0.75, with a P value of 0.006. The negative I2 5 88.2) and
TABLE 2. Characteristics of the Included Studies
406
Study Design/ CT Imaging MRI Patients Male Age No. of Tumor Size AFP Level Child-Pugh Gold Cause of
Reference Country Description fDescription (n) (n) (Years) Lesions (cm) (ng/mL) Score Standard Cirrhosis
Chen et al.(28) Retrospective/ Dynamic Gadoxetate 139 101 68 6 11 139 0.05-3 NR NR Pathology (115) NR
Japan contrast- disodium– Benign imaging fea-
enhanced CT enhanced MRI tures with >1 year
follow- up (24)
ROBERTS ET AL.
Golfieri et al.(30) Prospective/ Quadruple-phase Dynamic 3D MRI 63 53 63.3 123 1-3 NR A 46 Transplant (10) HBV 5 22,
Italy MDCT with performed following B 13 Resection (6) HCV 5 32
contrast administration of C4 Liver (8) biopsy Alcoholic 5 9
gadopentetate 2-year follow-up (9)
dimeglumine
Granito et al.(46) Prospective/ Quadruple-phase Gadoxetate 33 25 70 48 1.8 7 A5 22 Radiology HCV 5 19
Italy MDCT using a disodium– (48-84) (0.1-3) (1.8-375) A6 6 Biopsy HBV 5 6
helical CT enhanced MRI B7 4 Cryptogenic 5 4
scanner, B8 1 NASH 5 2
contrast- Alcohol 5 1 P
enhanced BC 5 1
Hassan, et al.(32) Retrospective/ MDCT triphasic MRI with contrast 61 37 46.5 95 0.52 NR NR Biopsy NR
Kuwait imaging with (gadodiamide) (19-74) (0.04-1) Radiological and
nonionic iodinated clinical follow-up
contrast agent
Haradome et al.(31) Retrospective/ MDCT scanner with Gd-EOB-DTPA- 75 60 54.7 86 1.74 6 0.6 NR A 48 Pathologic HCV (23),
multicenter 16 detector rows; all enhanced (42-67) B5 specimens: HBV (14),
patients received MRI C1 surgical HCV1HBV (4), alco-
intravenous nonionic resection holic (10), and cryp-
contrast medium (19) or fine togenic (3)
needle biopsy (41)
Hayashida et al.(47) Retrospective/ A multidetector row Dynamic MRI 38 23 72 NR
TABLE 2. Continued
Study Design/ CT Imaging MRI Patients Male Age No. of Tumor Size AFP Level Child-Pugh Gold Cause of
Reference Country Description fDescription (n) (n) (Years) Lesions (cm) (ng/mL) Score Standard Cirrhosis
Jung et al.(50) Prospective/ Biphasic contrast- Nonenhanced and 40 29 66.4 41 5.5 (1.5-12) NR A 14 Pathological NR
Germany enhanced spiral Gd-EOB-DTPA- (36-82) B7 diagnosis
CT enhanced MRI C 1,
and
unknown 5
9
Kasai et al.(34) Retrospective/ Dynamic enhanced Gd-EOB-DTPA MRI 47 35 65.4 6 9.1 112 NR NR NR All available NR
Japan CT images with clinical information
nonionic contrast (including US, CT,
HEPATOLOGY, Vol. 67, No. 1, 2018
material MRI findings;
laboratory data;
histopathological
findings; and
radiologic
follow-up
examinations)
Kawada et al.(51) Retrospective/ A 64-channel MDCT Dynamic MRI with 13 10 67 15408
TABLE 2. Continued
Study Design/ CT Imaging MRI Patients Male Age No. of Tumor Size AFP Level Child-Pugh Gold Cause of
Reference Country Description fDescription (n) (n) (Years) Lesions (cm) (ng/mL) Score Standard Cirrhosis
Maiwald et al.(38) Prospective/ Multiphase-64-slice 3-Tesla MRI with 50 42 60.6 NR NR NR A 27 Biopsy Alcoholic 5 26,
Germany contrast- Gd-EOB-DTPA (29-84) B 16 HBV 5 2,
ROBERTS ET AL.
enhanced CT C7 HCV 5 3,
Hemochromatosis 5
3,
Budd-Chiari-
syndrome 5 1,
NASH 5 1,
Cryptogenic 5 14
Di Martino et al.(29) Prospective/ Multiphasic CT MRI with gadobenate 140 104 66 254 >2 cm, NR A 71 Pathological NR
Italy using a dimeglumine (23-82) 1-2 cm,TABLE 2. Continued
Study Design/ CT Imaging MRI Patients Male Age No. of Tumor Size AFP Level Child-Pugh Gold Cause of
Reference Country Description fDescription (n) (n) (Years) Lesions (cm) (ng/mL) Score Standard Cirrhosis
Rode et al.(40) Prospective/ Noncontrast MRI with 43 30 51 (27-65) 59 1.24 NR NR Pathological HBV 5 4
France spiral CT gadolinium HCV 5 19
Alcoholism 5 14
Biliary
disease 5 2
Autoimmune
hepatitis 5 1
Wilson disease 5 1
Cryptogenic 5 1
HEPATOLOGY, Vol. 67, No. 1, 2018
Sangiovanni et al.(3) Prospective/ A 64-row MDCT Dynamic MRI with 64 47 65 (44-80) 67 2 5 2
Sano et al.(41) Retrospective/ A 16–detector row Gadoxetate 64 47 67 6 9.3 108 0.4-2 NR A 54 Pathologic NR
Japan dynamic contrast disodium– B 10 diagnosis
material–enhanced enhanced MRI
CT
Serste et al.(42) Case-only, Multidetector, Dynamic MRI 74 58 60 56 1-2 8 (1-413) NR Biopsy HCV 5 33
observational multiphasic CT (38-88) HBV 5 20
study/France before and after No cirrhosis 5 13
contrast
medium
Sugimoto et al.(56) Retrospective/ Helical with Dynamic 27 13 71.5 6 5.99 27ROBERTS ET AL. HEPATOLOGY, January 2018
Abbreviations: AFP, alpha-fetoprotein; Gd-EOB-DTPA, gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid HBV, hepatitis B virus; HCV, hepatitis C virus; MDCT, multidetector CT; NASH, nonalcoholic steatohepa-
gadoxetate-enhanced MRI was 0.28 versus 0.13, with
cirrhosis 5 186
a P value of 0.01, while the sensitivity of contrast-
Cause of
Cirrhosis
fibrosis 5 66
NR
NR
HCV 5 251
HBV and/or
enhanced CT versus extracellular contrast MRI was
PBC 5 9
Alcoholic
Liver 0.45 versus 0.29, with a P value of 0.002.
Analysis of Studies That Reported
gold standard if the
follow-up findings
Angiographic and
were used as the
Standard
not confirmed
Detection Rate Only
Gold
histologically
NR
lesion was
Biopsy
Fourteen studies(5,46-58) compared MRI versus CT
and reported only detection/sensitivity rate. Pooled
Child-Pugh
Score
analysis (Fig. 8) showed that detection/sensitivity rate
NR
NR
NR
and heterogeneity of CT, extracellular contrast–
enhanced MRI, and gadoxetate-enhanced MRI were
0.70 (95% CI, 0.63-0.77; I2 5 80.5%; P < 0.001;
AFP Level
(ng/mL)
NR
NR
NR
0.79; 95% CI, 0.67-0.93; I2 5 93.3%; P < 0.001; and
0.86; 95% CI, 0.81-0.92; I2 5 48.9%; P 5 0.057,
respectively). Stratified analyses based on the size of
1.9 (0.5-3)
hepatic lesions and the degree of HCC differentiation
Tumor Size
(cm)
NR
NR
are shown in Supporting Figs. S9-S13.
Publication Bias
Lesions
No. of
61
Visual inspection of the funnel plot suggests possible
NR
NR
TABLE 2. Continued
publication bias (Supporting Fig. S14), which is con-
sistent with the results of Egger’s regression test (P 5
0.04).
(29-84)
(48-83)
(Years)
54.6
Age
NR
67
Quality of Evidence
The quality of evidence (i.e., certainty in the esti-
Male
28
385
(n)
NR
mates) is considered low to moderate, downgraded due
to the methodological limitations of the included stud-
included in
analysis)
Patients
50 (42
512
ies and possible publication bias.
(n)
the
39
Q2: ADULTS WITH CIRRHOSIS
dime- glumine
enhanced MRI
gadopentetate
fDescription
AND AN INDETERMINATE
dynamic or
Dynamic MRI
disodium–
MRI
enhanced
Gadolinium-
titis; NR, not reported; PBC, primary biliary cirrhosis; US, ultrasound.
Gadoxetate
HEPATIC NODULE UNDERGO A
MRI
BIOPSY, REPEATED IMAGING, OR
ALTERNATIVE IMAGING FOR
contrast material
Triphasic CT with
CT Imaging
Description
CT with contrast
Helical CT with
THE DIAGNOSTIC EVALUATION
Noncontrast
contrast
then spiral
spiral CT,
No studies were found eligible to answer this
population, intervention, comparison, and outcomes
Study Design/
question.
Retrospective/
Country
Prospective/
Japan
China
Japan
Discussion
Yamashita et al.(5)
MAIN FINDINGS
Ueda et al.(44)
Xing et al.(45)
Reference
We identified 33 studies in this systematic review
which evaluated the performance of multiphasic
410HEPATOLOGY, Vol. 67, No. 1, 2018 ROBERTS ET AL.
TABLE 3. Risk of Bias Assessment
Risk of Bias Applicability
Are there
Are there concerns that
Could the Could the concerns that Are there the target
conduct or reference the included concerns that condition as
Could the interpretation standard, its Could the patients and the index defined by the
selection of of the index conduct, or its patient flow setting do not test, its conduct, reference
patients have test have interpretation have match the or interpretation standard does
introduced introduced have introduced introduced review differ from the not match the
Reference bias? bias? bias? bias? question? review question? question?
Chen et al.(28) High Low Low Low Low Low low
Golfieri et al.(30) Low Unclear High High Low Low low
Granito et al.(46) Low Low Unclear Unclear Low Low low
Haradome High Low Low Low Low Low unclear
et al.(31)
Hassan et al.(32) Unclear Unclear High High High High unclear
Hayashida Low Unclear High Unclear Low Low low
et al.(47)
Hidaka et al.(33) High Unclear Low Unclear Low Low low
Hori et al.(48) Low Unclear High High Low Unclear unclear
Inoue et al.(49) High Unclear Low Low Low Low low
Jung et al.(50) High Low Low Low Low Low low
Kasai et al.(34) Low Unclear High High Low Low low
Kawada et al.(51) Unclear Unclear Low Low High Low low
Khalili et al.(35) Low Low Low Low Low Low low
Leoni et al.(36) Low Low Unclear Unclear Low Low low
Libbrecht et al.(37) High Unclear Low Low Low Low low
Maiwald et al.(38) Low Low High High Low Low low
Di Martino Low Unclear Low Low Low Low low
et al.(29)
Mita et al.(52) High Unclear Low Low Low Low low
Onishi et al.(53) High Low High High Low Low unclear
Park et al.(54) High Low Low Low Low Low low
Pitton et al.(55) Low Unclear High Unclear Low Low low
Puig et al.(39) Low Low Unclear Unclear Low Low low
Rode et al.(40) Low Unclear Low Low Low Low low
Sangiovanni Low Low Low Low Low Low low
et al.(3)
Sano et al.(41) High Low Low Low Low Low low
Serste et al.(42) High Low Low Low Low Low low
Sugimoto et al.(56) High Unclear Low Low Low Low low
Sun et al.(43) Low Low Low Low Low Low low
Toyota et al.(57) High Low Low Low Low Low unclear
Tsurusaki Low High Low Low Low Low low
et al.(58)
Ueda et al.(44) High Unclear High High Low Low unclear
Xing et al.(45) Unclear Unclear Unclear Unclear Unclear Unclear unclear
Yamashita et al.(5) Low Unclear Low High Low Low high
cross-sectional contrast CT in comparison to con- a significantly lower negative likelihood ratio (0.20
trast MRI performed with extracellular contrast versus 0.37) for MRI over CT. However, the specif-
agent or with the partially extracellular/partially icity was 0.91 for MRI versus 0.92 for CT, and the
hepatocellular agent gadoxetate. Nineteen of the positive likelihood ratios of 8.8 for MRI versus 8.1
studies assessed all parameters for determining the for CT were not different (Table 4). Overall, the
diagnostic accuracy of the tests, while 14 reported summary receiver operating characteristic curves
only the detection rate or sensitivity of the tests. showed a higher area under the curve of 0.91 for
Pooled analysis of the 19 studies that compared the MRI versus 0.80 for CT. The results were similar
diagnostic accuracy of MRI to CT showed a signifi- when considering only the 17 studies started in the
cantly higher sensitivity (0.82 versus 0.66) as well as year 2000 or later (Table 4).
411ROBERTS ET AL. HEPATOLOGY, January 2018 FIG. 2. The Quality Assessment of Diagnostic Accuracy Studies 2 results showing methodological quality of the studies included. In subgroup analyses by type of MRI contrast mate- studies comparing CT to gadolinium ethoxybenzyl rial, similar observations were made with an absolute contrast, potentially suggestive of an unknown system- 14% increase in sensitivity for gadoxetate-enhanced atic bias in these studies. MRI and for extracellular contrast–enhanced MRI In subgroup analyses by lesion size, MRI showed higher over CT (Table 5). There was an unexplained better per-lesion sensitivity for 2 cm performance of cross-sectional imaging overall in the HCCs but not for 1-2 cm HCCs or for
HEPATOLOGY, Vol. 67, No. 1, 2018 ROBERTS ET AL.
TABLE 4. Accuracy of Contrast-Enhanced CT Versus MRI for Diagnosis of HCC
Sensitivity Specificity 1 Likeli- – Likeli- Diagnostic
Studies (95% CI) (95% CI) hood Ratio hood Ratio Odds Ratio
Modality (n) I2 (%) P I2 (%) P (95% CI) P (95% CI) P (95% CI) P
All studies irrespective of cohort year
Contrast- 19 0.66 0.0003 0.92 0.83 8.1 0.86 0.37 0.001 22 0.24
enhanced CT (0.60-0.72) (0.84-0.96) (4.1-16.2) (0.30-0.44) (10-50)
I2 5 72.53 I2 5 86.74
MRI with and without 19 0.82 0.91 8.8 0.20 43
contrast (0.75-0.87) (0.82-0.95) (4.6-16.9) (0.15-0.28) (20-92)
I2 5 72.90 I2 5 89.81
All cohorts started in the year 2000 or later
Contrast- 17 0.69 0.002 0.94 0.82 11.9 0.96 0.32 0.01 37 0.3
enhanced CT (0.63-0.76) (0.87-0.98) (5.1-27.7) (0.26-0.40) (15-90)
I2 5 73.9 I2 5 88.93
MRI 17 0.84 0.93 12.3 0.17 73
(0.77-0.90) (0.84-0.97) (5.1-29.5) (0.11-0.25) (29-181)
I2 5 86.18
Moreover, although the sensitivity of MRI forROBERTS ET AL. HEPATOLOGY, January 2018 FIG. 4. Sensitivity and specificity forest plots of MRI studies for diagnosis of HCC. FIG. 5. Summary receiver operating characteristic curves showing performance of CT and MRI for diagnosis of HCC. Abbreviations: AUC, area under the curve; SROC, summary receiver operating characteristic. 414
HEPATOLOGY, Vol. 67, No. 1, 2018 ROBERTS ET AL.
FIG. 6. Sensitivity and specificity forest plots from the eight studies comparing contrast-enhanced CT versus gadoxetate-enhanced
MRI in diagnosis of HCC.
FIG. 7. Sensitivity and specificity forest plots from the 11 studies comparing contrast-enhanced CT versus extracellular contrast–
enhanced MRI in diagnosis of HCC.
415TABLE 5. Accuracy of Contrast-Enhanced CT Versus MRI in Diagnosis of HCC (Subgroup Analysis)
416
Specificity
Sensitivity (95% CI) (95% CI) 1 Likelihood Ratio – Likelihood Ratio Diagnostic Odds Ratio
Variable Modality Studies (n) I2 (%) P I2 (%) P (95% CI) P (95% CI) P (95% CI) P
Subgroup analysis based on type of MRI contrast material
Gadoxetate contrast Contrast-enhanced CT 8 0.73 0.02 0.96 0.47 18.0 0.77 0.28 0.01 65 0.41
ROBERTS ET AL.
only MRI (0.64-0.81) (0.90-0.98) (7.2-45.4) (0.20-0.38) (23-179)
I2 5 76.35 I2 5 80.31
Gadoxetate MRI 8 0.87 0.94 15.3 0.13 115
(0.79-0.93) (0.90-0.97) (8.3-28.3) (0.08-0.22) (47-278)
I2 5 78.12 I2 5 60.07
Extracellular contrast Contrast-enhanced CT 11 0.61 0.006 0.87 0.91 4.5 0.73 0.45 0.002 10 0.31
only MRI (0.54-0.67) (0.73-0.94) (2.2-9.3) (0.38-0.54) (4-23)
I2 5 57.77 I2 5 84.84
Extracellular contrast MRI 11 0.75 0.86 5.5 0.29 19
(0.67-0.82) (0.68-0.95) (2.3-13.1) (0.23-0.36) (8-45)
I2 5 73.67 I(2) 5 90.04
Subgroup analysis based on size of hepatic lesion
1-2 cm Contrast CT 6 0.64 0.15 0.88 0.78 6.2 0.89 0.45 0.47 13 0.78
(0.58-0.70) (0.82-0.92) (1.83-20.86) (0.39-0.54) (4.8-39.6)
I2 5 61.79 I2 5 90.89
Extracellular MRI 6 0.70 0.87 5.5 0.39 17
(0.64-0.75) (0.81-0.91) (1.6-18.3) (0.27-0.55) (5.1-62.4)
I2 5 80.4 I2 5 92.1
>2 cm Contrast CT 3 0.79 0.09 0.9 0.71 6.46 0.99 0.26 0.5 25.79 0.47
(0.70-0.86) (0.76 - 0.97) (2.72-15.32) (0.07-0.95) (2.8-237.96)
I2 5 88.2 I2 5 0 I2 5 0 I2 5 88.8 I2 5 65.1
Extracellular MRI 3 0.88 0.87 6.48 0.15 64.66
(0.80-0.93) (0.73-0.96) (2.98-14.07) (0.05-0.5) (19.13-218.55)
I2 5 70.5 I2 5 0 I2 5 0 I2 5 78.3 I2 5 0HEPATOLOGY, Vol. 67, No. 1, 2018 ROBERTS ET AL.
maintaining similar specificity.(18-23) The one meta-
0.9
P
analysis published since our analysis was performed
Diagnostic Odds Ratio
included studies in which there was no direct compari-
son between CT and MRI and is therefore complemen-
(95% CI)
(1-137)
(2-104)
tary to ours.(23) The major distinguishing feature of this
14
14
study was the inclusion of only those studies that
directly compared CT with MRI, thus reducing poten-
tially substantial biases in studies without direct perfor-
mance comparisons. In particular, the reported accuracy
0.37
P
of imaging for HCC diagnosis depends on multiple fac-
– Likelihood Ratio
tors that may vary across studies, including population
(0.30-0.72)
(0.14-0.69)
characteristics (e.g., severity of cirrhosis, degree of portal
(95% CI)
0.47
0.31
hypertension, and frequency of obesity) and applied ref-
erence standard (e.g., follow-up imaging, biopsy, hepa-
tectomy pathology). Restricting our analysis to articles
reporting within-study performance helps mitigate the
0.7
P
confounding effects of these variables. Other distin-
1 Likelihood Ratio
guishing features of our study compared to some meta-
analyses(15-17,20,21,23) were the inclusion of CT, extracel-
(95% CI)
(1-43.6)
(1-20.5)
6.6
4.4
lular agent MRI, and gadoxetate-MRI and the subanal-
yses by contrast material and lesion size.
STRENGTHS AND LIMITATIONS
TABLE 5. Continued
0.7
P
While multiphasic MRI appears to be marginally more
(0.60-0.99)
(0.43-0.97)
Specificity
(95% CI)
I2 5 81.5
I2 5 92
I2 (%)
sensitive than CT in the pooled analysis of comparative
0.91
0.83
studies, examination of the data suggested possible publi-
cation bias, and the quality of the evidence was considered
to be low to moderate, with particular concerns including
P
0.2
the methodological limitations of the studies and incon-
Sensitivity (95% CI)
sistencies across studies. Consequently, the differences in
pooled diagnostic performance are considered insufficient
(0.44-0.70)
(0.50-0.89)
I2 5 86.28
I2 5 61.6
I2 (%)
0.58
0.74
to definitively recommend MRI over CT. Key factors
driving this conclusion include the overall low quality of
the evidence, practical concerns about generalizability to
nonacademic settings, and recognition that multiple fac-
Studies (n)
tors beyond diagnostic accuracy inform the optimal selec-
tion of imaging modalities in individual patients.
4
4
Compared to multiphasic CT, multiphasic MRI has
the advantages of providing greater soft tissue contrast,
more detailed evaluation of nodule and background liver
tissue characteristics, and absence of exposure to ionizing
Modality
radiation. However, MRI also has important disadvan-
Contrast CT
tages, including greater cost, higher technical complex-
ity, longer scan times, increased tendency to artifact, and
MRI
less consistent image quality due to patient factors such
1 cm 1ROBERTS ET AL. HEPATOLOGY, January 2018 FIG. 8. Sensitivity/detection rate of contrast-enhanced CT, gadoxetate-enhanced MRI, and extracellular contrast–enhanced MRI in detection of HCC from the 14 studies reporting only sensitivity/detection rates. In contrast, CT is more readily available and faster consequences including the incompletely understood and, due to more wide open scanner bores, less likely to long-term effects of exposure to ionizing radiation provoke claustrophobia but has the shortcoming of (CT) and gadolinium deposition (MRI). Because exposing patients to radiation. Both CT and MRI those risks are difficult to quantify and predict, individ- require intravenous access and contrast agents, the use ual patient preferences should be considered. Addi- of which may be problematic in patients with acute kid- tionally, MRI with gadolinium-based agents may be ney injury or chronic renal failure. preferable in patients with mild to moderate chronic The choice between CT and MRI also depends on kidney disease due to the reduced risk of contrast- patient safety preferences as both modalities are associ- induced nephrotoxicity, while patients with end-stage ated with potential downstream adverse health kidney disease on dialysis should probably undergo CT 418
HEPATOLOGY, Vol. 67, No. 1, 2018 ROBERTS ET AL.
with iodinated agents to prevent the rare development may be compromised. In such patients, extracellu-
of nephrogenic systemic fibrosis (NSF). Contrast- lar contrast agent MRI or CT may be preferable.
enhanced imaging should be rescheduled for patients 4. Contrast agent contraindications: CT and MRI con-
with acute kidney injury if possible. In regard to the trast agents may be contraindicated in some
risk of NSF from use of MRI contrast agents in patients due to safety concerns, while other patients
patients with chronic renal failure, while there have may refuse contrast agents or have inadequate intra-
been some publications suggesting that newer MRI venous access. In such patients, noncontrast MRI
contrast agents may be associated with increased risk may be best. Contrast-enhanced ultrasound is
of NSF, there is insufficient evidence from well- another option in patients in whom CT or MRI is
controlled studies to address this question. A prospec- contraindicated for safety considerations; but this
tive, multicenter, nonrandomized phase 4 study of modality has only recently been approved in the
gadoxetate disodium including patients with moderate United States, and the requisite expertise for its
(n 5 193) and severe (n 5 85) renal impairment did application is not yet widespread.
not raise any clinically significant safety concern, and Finally the choice may depend on the preferred sensi-
no NSF cases were observed. tivity/specificity trade-off:
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