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1 Department of Radiology, Yamanashi Medical University, 1110 Shimokato, Tamaho,
Nakakoma, Yamanashi 409-3815, Japan.
2 First Department of Internal Medicine, Yamanashi Medical University, Yamanashi
409-3815, Japan.
Received September 4, 2001;
accepted after revision March 12, 2002.
Address correspondence to T. Ichikawa.
Abstract
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MATERIALS AND METHODS. Double arterial phase images with multidetector CT were evaluated using quantitative, qualitative, and receiver operating characteristic analyses for 59 patients with 78 hepatocellular carcinomas. Early and late arterial phase (double arterial phase) CT scans were obtained at a fixed time of 25 and 40 sec, respectively, after administration of contrast material. Total dose and injection rate of contrast material were 100 mL and 3 mL/sec, respectively.
RESULTS. On the basis of the receiver operating characteristic curves, the mean area under the curve values of the late (0.98) and combined arterial phase CT scans (0.98) were equivalent, and both were significantly greater than the mean of the early arterial phase CT scans (0.842) for detecting hepatocellular carcinoma (p < 0.05). The mean relative sensitivity values obtained with the late (69/78, 88%) and combined arterial phase CT scans (70/78, 90%) were also equivalent and were significantly greater than those obtained with the early arterial phase CT scans (52/78, 67%; p < 0.001).
CONCLUSION. Double arterial phase CT with multidetector CT showed no significant improvement in effectiveness compared with single late arterial phase CT used alone for detecting hypervascular hepatocellular carcinoma in the cirrhotic liver.
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Multidetector CT scanners have been recently developed and successfully introduced in many areas of radiology to replace conventional helical CT scanners with single-row detector arrays. Several studies have emphasized that multidetector CT scanners have potential advantages for lesion detection and characterization based on the patterns of lesion enhancement in the liver [9,10,11]. As a result, the volume coverage was markedly improved using multidetector CT scanners, and the entire scanning of the liver was completed in 10 sec or less, which may be short enough for scanning the entire liver during the optimal hepatic arterial phase.
Moreover, an excellent scanning speed allows acquisition of two separate sets of hepatic CT scans within the time regarded as the hepatic arterial phase. Murakami et al. [11] reported that double arterial phase imaging of the liver with multidetector CT is effective for improving the detectability of hypervascular hepatocellular carcinoma. However, radiologists should recognize that the application of double arterial phase imaging to the liver may have crucial disadvantages for patients and radiology systems, such as increased radiation dose to patients, larger number of images requiring a workstation for interpretation, or overload to the X-ray tube of a CT scanner. Therefore, great care is necessary to double-check conclusions before applying double arterial phase imaging to the liver for the detection of hypervascular hepatocellular carcinoma. The purpose of our study was to apply double arterial phase imaging with multidetector CT to the liver and to determine whether this technique is effective for detecting hypervascular hepatocellular carcinoma on the basis of quantitative and qualitative analyses.
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All patients underwent both CT during arterial portography and CT hepatic arteriography. Combined imaging was used as the gold standard modality at our institution for diagnosing the 16 lesions with no pathology confirmation. Indeed, numerous studies [12,13,14,15,16,17] have reported that CT during arterial portography may be the most reliable technique for determining the numbers of hepatocellular carcinoma without pathology confirmation. However, a lesion that is positive for abnormalities on CT during arterial portography alone but has no evidence of a hypervascular nature may not be diagnosed as hepatocellular carcinoma with great confidence because other diagnoses, such as a dysplastic nodule, may not be excluded. Therefore, CT hepatic arteriography, which has been described not only as a sensitive technique similar to CT during arterial portography for detecting hepatocellular carcinoma but also as the most confident technique for determining the hypervascular nature of a hepatic lesion [12], was used in addition to CT during arterial portography as the gold standard. Moreover, all patients included in this study underwent CT with iodized oil (Lipiodol; Andre-Gelbe Laboratory, Aulnay-sous-Bois, France), which is also recognized as one of the most sensitive techniques for detecting hypervascular hepatocellular carcinoma [13, 14], after transcatheter arterial chemoembolization was performed under digital subtraction angiography. Thus, all 78 lesions, including the 16 lesions with no pathology confirmation, were diagnosed with a combination of CT during arterial portography and CT hepatic arteriography on the basis of previously reported criteria for these imaging modalities (on CT during arterial portography, rounded low attenuation [12, 15,16,17]; on CT hepatic arteriography, rounded hyperattenuation [12]). The lesions were also confirmed from the nodular deposition of iodized oil on follow-up CT with iodized oil [13, 14, 18], which was performed 2-4 weeks after the iodized oil was administered. That is, a possibly hypovascular lesion that was positive for abnormalities on CT during arterial portography but was negative on both CT hepatic arteriography and CT with iodized oil was not included in this study.
CT
All CT examinations were performed using a commercially available
multidetector CT scanner (Aquillion; Toshiba Medical, Tokyo, Japan) with a
0.5-sec gantry rotation speed. The detector configuration was 2.0 x 4.0
mm, in which four interspaced helical data sets were obtained from 16 detector
rows of 0.5 mm each. The table speed was 11 mm (pitch, 5.5). In addition, all
CT examinations were performed at 120 kVp and 150 mAs. For the reconstructed
transverse double arterial phase images, we used a 5-mm slice thickness and a
5-mm interval. All scans were acquired in a cephalocaudal direction. Before
contrast-enhanced multiphasic CT, a scout view was obtained, and then
unenhanced CT scans were obtained with a 5-mm section thickness. The first
unenhanced CT scan was obtained of the top of the liver. The unenhanced CT
series were programmed to include the entire liver. The upper and lower
contrast-enhanced CT scanning levels were decided from these unenhanced CT
scans.
All patients received a fixed dose of 100 mL of nonionic contrast material (iomeprol 350 [350 mg I/mL]; Bracco-Eisai, Tokyo, Japan) IV by means of a power injector (Autoenhance-50; Nemotokyorindo, Tokyo, Japan). The contrast material was administered at a rate of 3 mL/sec, with a monophasic rate of injection in all patients. The clearest advantage of double arterial phase scanning is to increase the detection of hypervascular hepatocellular carcinoma against the optimal scaning delay caused by the variation in the circulation time of patients, even if a bolus tracking technique, which may be too troublesome to always perform in routine clinical work, is not used in the arterial phase CT protocol. Therefore, we tried to use fixed scanning delays in our double arterial phase protocol.
Determination of the Fixed Delays for the Double Arterial Phase
Protocol
In previous studies
[4,5,6,7,8],
scanning delays ranging from 20 to 40 sec were used in arterial phase imaging.
Kopka et al. [8] stated that
the arterial phase starts 15-33 sec (mean, 21 sec) after the beginning of the
contrast material injection when a bolus tracking program (SmartPrep; General
Electric Medical Systems, Milwaukee, WI) is used to optimize the scanning
delay for arterial phase imaging. However, they also emphasized that the start
of arterial phase imaging was too early in five (17%) of 30 patients when a
fixed scanning delay of 20 sec was chosen. They mentioned that the portal
venous phase started 43-63 sec (mean, 50 sec) after the beginning of the
contrast material injection when the bolus tracking program was used to
optimize the scanning delay for portal venous phase imaging. On the basis of
both their results and ours, optimal duration of the hepatic arterial phase is
considered to range from approximately 25 sec to approximately 50 sec in most
patients.
We investigated the attenuation conspicuity (mean contrast-enhanced lesion attenuation minus mean contrast-enhanced liver attenuation in Hounsfield units) of 95 hypervascular hepatocellular carcinomas on the basis of the data previously obtained with single-detector helical CT in our institute to determine the fixed scanning delays in the double arterial phase protocol. Parameters in the injection protocol were the same as those of double arterial phase CT in our study. The accurate scanning time for each lesion on the arterial phase imaging could be estimated according to the location of the scan (image number) and the scanning delay (25 sec after the beginning of the contrast material injection). As a result, the acquisition time of each lesion ranged widely from 25.0 to 47.5 sec because of the long scanning time for the entire liver with a single-detector helical CT unit. The results showed that attenuation conspicuity of the lesions tended to increase until 47.5 sec after the beginning of the contrast material injection (Fig. 1). However, some lesions showed early increase of the attenuation conspicuity 25-30 sec after the beginning of the contrast material injection.
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Considering our results and those of Kopka et al. [8], we determined that each arterial phase image with the double arterial phase protocol in our study was started after a fixed scanning delay of 25 sec for the early arterial phase images and 40 sec for the late arterial phase images after initiating infusion of contrast material. The double arterial phase protocol included two scans of the entire liver during a single breath-hold acquisition if the patients tolerated the procedure. The acquisition time for one scan was 8-11 sec, and the breath-hold time for the double arterial phase image was 23-26 sec. As a result, 63 (80%) of the 78 lesions that were present at the upper half of the liver were scanned during the first half of the early (25-30 sec) and late (40-45 sec) arterial phase imaging (group 1). The remaining 15 lesions (20%) were present in the lower half of the liver (segment V or VI) and therefore were scanned during the later half of the early (30-35 sec) and late (45-50 sec) arterial phase imaging (group 2).
Image Interpretation and Analysis
Quantitative measurements of CT enhancement (in Hounsfield units) were made
of all patients. For this purpose, one radiologist placed regions of interest
(ROIs) over the aorta and normal liver parenchyma at the level of the celiac
trunk and the lesions on the unenhanced and double arterial phase CT scans.
The ROI for each lesion was carefully placed in the confines of the entire
lesion. As a rule, for heterogeneous lesions, the ROIs were placed to include
the entire lesion, without excluding various components with differing
attenuation. However, when calcifications or cystic foci were noted in a
lesion or in the liver parenchyma, such regions were avoided in the ROI
analysis. CT attenuation measurements were performed three times and averaged
for each lesion. Mean enhancement of the aorta, normal liver parenchyma, and
lesions was calculated by subtracting unenhanced attenuation from respective
contrast-enhanced attenuation. The liver-to-lesion contrast was also
calculated for double arterial phase CT images with the following equation:
liver-to-lesion attenuation ratio equals mean contrast-enhanced liver
attenuation divided by mean contrast-enhanced lesion attenuation.
To investigate the possibility that fixed scanning delays occurring after the injection of contrast material for each arterial phase image may affect lesion detectability, we also plotted the attenuation conspicuity of the lesion (the attenuation conspicuity of the lesion equals mean contrast-enhanced lesion attenuation minus mean contrast-enhanced liver attenuation in Hounsfield units) against delay time for each arterial phase CT scan in all patients. The accurate scanning time for each lesion on each arterial phase image could be estimated according to the location of the scan (image number) and the scanning delay.
For conducting the receiver operating characteristic (ROC) analysis, two radiologists serving as study coordinators initially reviewed CT during arterial portography, CT hepatic arteriography, and CT with iodized oil with knowledge of the clinicopathologic and radiologic findings. On the basis of the clinicopathologic and radiologic findings previously described, they attempted to determine the number and location of the lesions and to anatomically correlate these pathologically confirmed lesions with imaging as accurately as possible to allow detection of false-positive interpretations. Therefore, in cases in which reviewers identified lesions other than the lesions indicated by the study coordinators, the study coordinators considered those lesions to be false-positive lesions. For the ROC analysis, the study coordinators also attempted to select 78 CT slices that showed no abnormalities from CT scans in patients with no hepatocellular carcinoma (who were different from the 59 patients with hepatocellular carcinoma nominated for this study) on the basis of the findings of CT during arterial portography, CT hepatic arteriography, and other follow-up imaging. When the study coordinators selected these patients whose findings were negative for hepatocellular carcinoma, they noted the image quality, scan location, degree of contrast enhancement of the liver and the intrahepatic vessels, patient age, and sex matched to those of the patients included in the study whose findings were positive for hepatocellular carcinoma. For the blinded review, the study coordinators reprinted the images for all patients included in this study and cut the films as each image was separated. All CT scans were then interpreted independently and in random order by the three reviewers.
First, the reviewers were asked to evaluate the early arterial phase CT scans alone. Second, they interpreted the late arterial phase CT scans alone. The interval for each set of interpretations was at least 1 week. Two weeks after these interpretations, the reviewers also evaluated both the early and the late arterial phase CT scans together (combined arterial phase CT). The reviewers were aware that all CT examinations were performed in each patient for the purpose of evaluating possible hepatocellular carcinoma. However, reviewers were unaware of patient identity, clinical history, results of other imaging examinations, and histopathologic evaluations.
For all CT scans, each reviewer graded the presence (or absence) of lesions on a 5-point confidence scale (1, definitely absent; 2, probably absent; 3, equivocal; 4, probably present; 5, definitely present). If a lesion was considered to be present in the liver on any kind of CT, the number, location, and attenuation compared with normal liver parenchyma were recorded.
Statistical Analysis
For the calculated mean enhancement of the aorta, liver, and lesions; the
attenuation ratio of the liver and lesions; and the attenuation conspicuity of
the lesions with double arterial phase CT, we used Wilcoxon's signed rank test
to determine whether there were significant differences in each value between
early and late arterial phase CT or between group 1 and group 2.
Before the ROC analysis, interobserver agreement for image interpretation for each arterial phase CT scan was assessed for establishing the reliability of the imaging interpretation in our study. The degree of interobserver agreement between each combination of two reviewers was calculated with chance-corrected kappa statistics. In general, a kappa statistic greater than 0.75 is considered excellent agreement beyond chance; 0.4-0.75, good agreement; and less than 0.4, poor agreement [19].
For the ROC analysis, composite ROC curves were created for early, late, and combined arterial phase CT. Composite ROC curves used to represent the performance of the three reviewers as a group were calculated by averaging the binormal parameter values of the individual curves. The findings were analyzed by means of maximum likelihood estimation of binormal ROC curve grading data [20]. The diagnostic accuracy of each imaging technique for each reviewer was evaluated by calculating the area under the ROC curve (Az). Factors with Az values greater than 0.80 were considered to have good diagnostic accuracy on the basis of the findings of a previous study that used ROC analysis [20]. The Az value of each imaging technique was compared using the jackknife method [21].
When a lesion was assigned grade 4 or grade 5 (probably or definitely hepatocellular carcinoma), it was regarded as positive for the presence of hepatocellular carcinoma. Our findings cannot indicate the absolute sensitivity of each imaging technique for the detection of hepatocellular carcinoma because this study included only representative hepatocellular carcinoma and did not include other kinds of liver diseases. Therefore, the term "sensitivity" used in this article means relative sensitivity. The significant differences in the proportion of the sensitivity of early, late, and combined arterial phase CT were estimated by the paired chi-square test for dependent sample proportions (McNemar test) [22].
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The attenuation conspicuity of the lesion on each arterial phase image is individually plotted in Figure 2. The mean attenuation conspicuity of the lesion on late arterial phase CT (36.7 H) was significantly higher than that on early arterial phase CT (13.8 H) (p < 0.001). The attenuation conspicuity of the lesions increased on late arterial phase CT compared with that on early arterial phase CT in most (73/78, 94%) of the lesions. All the remaining five lesions (6%) that showed a decrease of attenuation conspicuity on the late arterial phase CT compared with that revealed on the early arterial phase CT scans were in group 1. In these five lesions, the change of attenuation conspicuity of the lesion between both arterial phase CT examinations might be considered minor (>10 H; range, 1.8-7.8 H) in four and definite in one (21.4 H). However, all five lesions were assigned the same grades for lesion conspicuity by all three reviewers in the qualitative assessment.
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Qualitative Assessment
The chance-corrected kappa values indicating the confidence levels for the
image interpretation of the ROC analysis between the three reviewers are
summarized in Table 2. The
kappa values were excellent (
> 0.75, for late arterial phase CT
scans between radiologists 1 and 2 and for late and combined arterial phase CT
scans between radiologists 1 and 3) or good (
= 0.4-0.75 for early and
combined arterial phase CT scans between radiologists 1 and 2; for early,
late, and combined arterial phase CT scans between radiologists 2 and 3; and
for early arterial phase CT scans between radiologists 1 and 3) for
interpretation of all types of images.
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ROC Analysis
The findings of the ROC curves and the Az values with
early, late, and combined arterial phase CT scans are shown in
Table 3 and
Figure 3. The mean
Az values of late (0.98) and combined arterial phase CT
(0.98) were equivalent, and both were significantly higher than the mean of
early arterial phase CT (0.842) for detecting hepatocellular carcinoma
(p < 0.05).
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Sensitivity for Tumor Detection
The sensitivity values obtained with early, late, and combined arterial
phase CT scans are shown in Table
4. The sensitivity values obtained with late (for each reviewer:
69/78, 70/78, 69/78 lesions; 88%, 90%, 88%, respectively) and combined
arterial phase (for each reviewer: 70/78, 68/78, or 71/78 lesions; 90%, 87%,
or 91%, respectively) CT were equivalent with no significant differences and
were significantly higher than those obtained with early arterial phase CT
(for each reviewer: 46/78, 53/78, or 56/78 lesions, 59%, 68%, or 72%,
respectively; p < 0.001) (Fig.
4A,4B).
No significant difference was seen in sensitivity values obtained with early,
late, and combined arterial phase CT between group 1 and group 2.
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Regarding lesion detection with double arterial phase CT, 24 lesions that were assigned grades of 4 or 5 were detected by radiologist 1, 18 lesions by radiologist 2, and 14 lesions by radiologist 3 only on late arterial phase images. Only one lesion, which was in group 1, was detected on early arterial phase images by all reviewers. This lesion already showed a washout of contrast material and isoattenuation compared with the peripheral liver parenchyma on late arterial phase CT, although it might have been retrospectively identified because of the appearance of an enhanced tumor capsule (Fig. 5A,5B).
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In the study by Murakami et al. [11], a double arterial phase technique was useful for improving the detection rate of hypervascular hepatocellular carcinoma. First, they used a preliminary minibolus technique with generation of a timeattenuation curve before determining the injection-to-scanning delay. We believe that the clearest advantage of double arterial phase scanning is to increase detection of hypervascular hepatocellular carcinoma with various optimal scanning delays in patients. This may also mean possible omission of any bolus-tracking techniques for optimizing scanning delay for arterial phase images, which are too troublesome to be routinely performed. For these reasons, we attempted to use fixed scanning delays for double arterial phase scanning. In our study, attenuation conspicuity (lesion attenuation minus liver attenuation) on early arterial phase CT (mean, 13.8 H) was significantly lower than that on late arterial phase CT (mean, 36.7 H) in most lesions (73/78, 94%). These results may indicate that late arterial phase CT is a phase of the optimal or maximal period of tumor enhancement for most hypervascular hepatocellular carcinomas, and late arterial phase imaging alone is enough to detect them. Moreover, the significance of early arterial phase imaging might be underestimated by our discouraging results, including the minor difference of attenuation conspicuity and invariable qualitative results between early and late arterial phase CT. Further studies are needed about the usefulness of double arterial phase CT for detecting hypervascular hepatocellular carcinoma because one lesion was not detected by single late arterial phase CT alone in our study, and patterns of enhancement of hepatocellular carcinoma may be variable.
Second, Murakami et al. [11] used a larger dose of contrast material (2 mL/kg) and a faster injection rate (5 mL/sec) than those used in our study. The maximal dose and the injection rate of contrast material influence peak liver enhancement and width of the temporal window [8]. Although 100 mL of contrast material is less than the dose that most institutes currently use for hepatic CT, it may be acceptable in our study because of the body weight of the patients (range, 38-64 kg; mean, 54 kg). Faster injection rates of contrast material may improve hypervascular hepatic lesion detection because of the significantly increased enhancement of the aorta (including the hepatic artery) on hepatic arterial phase CT scans [25,26,27,28,29,30]. However, enhanced false-positive lesions, for which small arterialportal venous shunts may play a major role, may increase on hepatic arterial phase CT in the cirrhotic liver [31]. In our experience, there is no significant difference in diagnostic performance for hypervascular hepatocellular carcinoma underlying the cirrhotic liver between the contrast injection rates of 3 and 5 mL/sec on the basis of the ROC analysis, because the faster the injection rate of contrast material, the more hypervascular hepatocellular carcinoma and enhanced false-positive lesions can be detected on arterial phase CT.
Our present study contained several significant limitations. First, the study population was small, and a minority of the lesions had no pathology confirmation. However, all patients had confirmatory imaging examinations, including CT during arterial portography and CT hepatic arteriography followed by several follow-up sonograms, contrast-enhanced dynamic CT, and CT with iodized oil as a gold standard. A second criticism could be that our study included patients whose findings were negative for abnormalities but did not include other hypervascular hepatic lesions such as hemangioma, hepatic adenoma, or focal nodular hyperplasia as controls. If these abnormal conditions had been intermixed in our study, it would have been more realistic. Double arterial phase scanning has a potential advantage in the liver for improving not only lesion detection but also lesion characterization on the basis of the analysis of the enhancement patterns shown on each arterial phase image [10]. In addition, there was also an obvious bias in this retrospective study because all reviewers knew that each subject with an abnormal condition had only hypervascular hepatocellular carcinoma.
In conclusion, the use of the double arterial phase showed no significant usefulness compared with single late arterial phase imaging alone for detecting hypervascular hepatocellular carcinoma if fixed scanning delays were used. Even with double arterial phase scanning, some kind of bolus-tracking technique may be needed to compensate for patient-related (cardiovascular status) or lesion-related (tumor vascularity or permeability) variables and definite hemodynamic changes occurring in the circulation of the cirrhotic liver. For confirming the necessity and usefulness of a bolus-tracking technique, we compared the single arterial phase scanning technique with an automatic bolus-tracking techniquethat is, the SmartPrep technique [32] with a double arterial phase scanning technique in the same patient group.
Acknowledgments
We thank Michael P. Federle for his valuable advice.
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1.5 cm) malignant hepatic neoplasms.
AJR
1995;164:879
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