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1 Department of Radiology, Samsung Medical Center, 50 Ilwon-dong, Kangnam-ku,
Seoul, Korea 135-710.
2 Biostatistics Unit, Samsung Biomedical Research Institute, Sungkyunkwan
University School of Medicine, Seoul 135-710, Korea.
Received August 6, 2001;
accepted after revision January 11, 2002.
Address correspondence to J. H. Lim.
Abstract
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SUBJECTS AND METHODS. One hundred thirteen patients with 131 hepatocellular carcinomas underwent triple-phase helical CT. The diagnosis was established by pathologic examination after surgical resection in all patients. For triple-phase helical CT, hepatic arterial, portal venous, and delayed phase scanning began 30, 60, and 180 sec, respectively, after the injection of 120 mL of iodinated contrast material. Dual-phase helical CT excluding delayed phase and triple-phase helical CT images were reviewed independently by three radiologists on a segment-by-segment basis. Diagnostic accuracy was assessed using receiver operating characteristic analysis in 330 resected segments. Sensitivities and specificities were calculated. The value of the delayed phase images in the characterization of hepatocellular carcinoma was also assessed.
RESULTS. The diagnostic accuracy of triple-phase helical CT including delayed phase (area under the curve [Az], 0.973) was significantly higher than that of dual-phase helical CT (Az, 0.954). The mean sensitivity of triple-phase CT (89%) was also significantly higher than that of dual-phase CT (86%). The mean specificities of triple-phase CT (99%) and dual-phase CT (99%) were equal. Delayed phase images were helpful in the characterization of hepatocellular carcinoma in 14% of patients.
CONCLUSION. The addition of delayed phase imaging to dual-phase helical CT is valuable for the detection and characterization of hepatocellular carcinoma.
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Regarding the value of portal venous phase versus delayed phase scanning, Choi et al. [8] reported that portal venous CT is equal to delayed phase CT in the detection of hypervascular hepatocellular carcinoma. However, a considerable number of hypovascular hepatocellular carcinomas and premalignant nodules such as dysplastic nodules are seen in cirrhotic livers [7, 10]. Several articles described delayed phase CT as more useful for the diagnosis of hypovascular tumors than arterial and portal venous phase CT [5, 7, 10, 11]. However, many cases of hepatocellular carcinoma described in these articles were not confirmed at histopathology, and the comparisons of diagnostic performance were not assessed by receiver operating characteristic (ROC) analysis. The purpose of our study was to determine the value of adding delayed phase imaging to arterial and portal phase CT for the detection and characterization of hepatocellular carcinoma.
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Three hundred thirty hepatic segments were resected, and 131 hepatocellular carcinomas in 125 segments were confirmed pathologically. Hepatocellular carcinomas ranged from 0.5 to 14.0 cm in diameter (mean, 4.1 cm). There were 93 men and 20 women, 26-78 years old (mean, 52.9 years). This study was approved by the institutional review board of our hospital, and written informed consent was obtained from all patients. Ninetyeight patients in the study had liver cirrhosis as a result of either hepatitis B (n = 64), hepatitis C (n = 28), Budd-Chiari syndrome (n = 1), or alcoholism (n = 5). The remaining 15 patients had hepatitis B (n = 13) or C (n = 2) without cirrhosis.
Triple-Phase Helical CT
CT was performed with a helical scanner (HiSpeed Advantage; General
Electric Medical Systems, Milwaukee, WI). Scanning parameters were 120 kVp,
180 mAs, 7-mm section collimation, and 7mm/sec table speed during a single
breath-hold helical acquisition of 25-30 sec, depending on liver size. Images
were obtained in a craniocaudal direction and reconstructed every 7 mm to
provide contiguous or overlapping sections. The hepatic arterial phase, portal
venous phase, and delayed phase images were obtained with delays of 30, 60,
and 180 sec, respectively, after injection of 100 mL of nonionic iodinated
contrast material (Iopamiro 300 [iopamidol], Bracco, Milano, Italy; Ultravist
300 [iopromide], Schering, Berlin, Germany) through the antecubital vein at a
rate of 3 mL/sec.
Image Analysis
Dual-phase helical CT scans (excluding delayed phase scans) and
triple-phase helical CT scans were evaluated independently by three
gastrointestinal radiologists unaware of the results of the pathologic
examination. The observers reviewed the scans at separate sessions at 4-week
intervals. All images were evaluated on a 2000 x 2000 PACS (picture
archiving and communication system) monitor (General Electric Medical Systems
Integrated Imaging Solutions, Mount Prospect, IL) with adjustment of the
optimal window setting in each case. The image review was conducted on a
segment-by-segment basis, but the observers were asked to interpret the images
of the whole livers without information about the resected part of the liver.
Hepatic segmentation was based on the Couinaud numbering system.
Three hundred thirty segments were resected in the 113 patients. In 15 of these segments, two segments were totally occupied by a single hepatocellular carcinoma and were considered to be a single segment. Therefore, a total of 315 segments (125 with at least one hepatocellular carcinoma and 190 without hepatocellular carcinoma) were finally entered into the ROC analysis. Six segments contained two hepatocellular carcinomas. Seven segments each with a hepatocellular carcinoma had 11 dysplastic nodules. Two segments without hepatocellular carcinoma had dysplastic nodules, and two other segments without hepatocellular carcinoma had a hemangioma in each segment.
Each observer recorded the location (Couinaud's segment) and size of each focal lesion and the presence or absence of hepatocellular carcinoma. A nodule showing enhancement through hepatic arterial supply and lack of portal venous supply (i.e., homogeneous or variegated enhancement with visualization of intratumoral arteries on hepatic arterial phase, iso- or low attenuation on portal venous phase, and low attenuation on delayed phase; mixed attenuation on hepatic arterial and portal venous phase and low attenuation on delayed phase) [4, 12,13,14] was regarded as a hepatocellular carcinoma. In addition, a nodule with a discrete capsule on arterial and delayed phases [15], with mosaic appearance on portal and delayed phases [15,16,17], and larger than 2 cm showing predominantly low attenuation on all three phases [12] was regarded as hepatocellular carcinoma. Observers assigned one of five confidence scores to their observations: 1, definitely absent; 2, probably absent; 3, possibly present; 4, probably present; and 5, definitely present. When a lesion invaded two or more segments, the observers were asked to determine only the segment that was mainly involved and to evaluate the probability of another lesion in the other segments.
As a subjective analysis, three observers recorded nodules in which delayed phase images were helpful in the characterization of hepatocellular carcinoma by depiction of a capsule or mosaic pattern. When a partial or complete thin rim of high attenuation was seen on delayed phase, a capsule was present; when there were heterogeneous areas in a mass, a mosaic pattern was present [15,16,17].
An ROC curve area of each observer was estimated by using a nonparametric method for the presence of clustered data [18]. To compare the accuracies of two imaging modalities in each observer, we tested the equality of these two correlated ROC curve areas using a nonparametric method and taking into account the covariance between the two estimated areas. Averaged ROC curve areas of all observers were computed for each imaging modality, and the statistical significance of the difference between the averaged areas under the ROC curves for the two imaging modalities was calculated by computing covariances between the estimated areas according to a nonparametric method [18]. The number of hepatocellular carcinomas correctly allocated as possibly present (score, 3), probably present (score, 4), or definitely present (score, 5) by each observer was regarded as the number of hepatocellular carcinomas correctly diagnosed. Sensitivity and specificity were calculated for each observer and for each imaging modality, and the statistical significance of any of the differences was assessed using the method for clustered data [19, 20]. We programmed with Fortran language for statistical analyses using Fortran Powerstation 4.0 (Microsoft, Redmond, WA). A p value of less than 0.05 indicated a statistically significant difference. Interobserver agreement for the detection of hepatocellular carcinoma with each imaging modality was assessed with kappa statistics. Kappa values greater than 0.80 indicated excellent agreement [21].
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Table 2 shows the mean sensitivities and the sensitivities for each observer and for dual-phase and triple-phase CT. The mean sensitivity of triple-phase CT (89%) was significantly higher than that of dual-phase CT (86%; p = 0.011, McNemar test). All hepatocellular carcinomas missed on dual-phase and triple-phase CT were less than 3 cm, and the numbers of missed hepatocellular carcinomas were greater on dual-phase CT than on triple-phase CT for all observers (Table 3). Regarding 30 small hepatocellular carcinomas less than 2 cm, the mean sensitivity of triple-phase CT (70%) was also significantly higher than that of dual-phase CT (61%; p = 0.009). However, for 68 large hepatocellular carcinomas measuring 2 cm or greater, the mean sensitivities of triple-phase and dual-phase CT were 95% and 93%, respectively. The difference was not statistically significant (p = 0.073). A 1.0-cm hepatocellular carcinoma was not detected on dual-phase CT by any of the observers but was detected on triple-phase CT by all observers (Fig. 2A,2B,2C). On dual-phase CT, only one observer interpreted a 1.2-cm well-differentiated hepatocellular carcinoma as a possible hepatocellular carcinoma (score, 3). On triple-phase CT, this finding was interpreted as a probable hepatocellular carcinoma (score, 4) by all observers (Fig. 3A,3B,3C). Of the 30 interpretations of 10 well-differentiated hepatocellular carcinomas, 16 were detected on dual-phase CT by three observers, whereas 19 were detected on triple-phase CT (mean sensitivity of dual-phase CT, 53%; mean sensitivity of triple-phase CT, 63%; p = 0.350).
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The mean specificities and the specificities for each observer are also shown in Table 2. The mean specificities of triple-phase CT (99%) and dual-phase CT (99%) were equal (p = 1.000). Three observers interpreted seven false-positive results on dual-phase CT and triple-phase CT. Additional false-positive CT results were attributed to two hemangiomas and one dysplastic nodule (Fig. 4A,4B,4C). Another dysplastic nodule in the segment without hepatocellular carcinoma was not detected on either dual-phase CT or triple-phase CT. The kappa values among the three observers showed excellent agreement with dual-phase and triple-phase CT (Table 4). Three observers assessed 18 (14%), 16 (12%), and 21 (16%) of 131 hepatocellular carcinomas with added value for characterization by delayed phase imaging (Fig. 5A,5B,5C).
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Hepatocellular carcinoma reportedly enhances in proportion to the degree of contrast material uptake. Most of them can be detected on arterial phase images as high-attenuation nodules, but some hepatocellular carcinomas are low attenuation on arterial phase CT [4, 7, 30]. The degree of tumor enhancement depends on the hepatic arterial supply, whereas that of the surrounding hepatic parenchyma is dependent on the portal venous supply. When the arterial supply to a tumor is not sufficient to enhance the tumor more than the surrounding parenchyma, the tumor will be low attenuating. Moderately or poorly differentiated hepatocellular carcinoma is almost solely supplied by the hepatic arteries because the portal tracts in the tumor disappear [26, 31,32,33]. In some cases of moderately or poorly differentiated hepatocellular carcinoma in which the hepatic artery supply is not sufficient to increase the degree of the attenuation more than the surrounding parenchyma, the nodule will present as persistently low attenuation on arterial, portal, and delayed phases [4, 7]. Those nodules possessing the same degree of hepatic artery supply and slightly decreased portal vein supply compared with the surrounding liver parenchyma may be isoattenuating on arterial and portal phase [11] because the contrast enhancement through the hepatic artery may continue into the portal venous phase but wash out on the delayed phase. Thus, these hepatocellular carcinomas will be manifest as low-attenuation nodules only on delayed phase CT images [2, 5, 7, 10, 11].
Hwang et al. [7] explained that peak enhancement of hepatic parenchyma on delayed phase imaging due to portal hypertension in cirrhotic patients maximizes the contrast between the relatively hypovascular hepatocellular carcinomas and the surrounding hepatic parenchyma. In general, small hepatocellular carcinomas, such as well-differentiated hepatocellular carcinomas or early hepatocellular carcinomas, are not hypervascular. Well-differentiated hepatocellular carcinomas have a normal or slightly increased hepatic artery supply with a decreased portal supply, and these nodules can be seen only on delayed phase images [2, 34]. Takayasu et al. [27] described the enhancement pattern of early hepatocellular carcinoma as showing isoattenuation on both early and delayed phases images, therefore not detected in half (46%) the cases; as showing iso- or low attenuation on early phase; and as showing low attenuation on delayed phase (41%). Thus, Takayasu et al. suggested that delayed CT images are more important than arterial phase images in the detection of early hepatocellular carcinoma. Incomplete development of tumor vessels (unpaired arteries) in early hepatocellular carcinoma or well-differentiated hepatocellular carcinoma can be a possible explanation for iso- or low attenuation only on arterial phase CT images [27].
The results of our study have several practical implications in the treatment of patients with hepatocellular carcinoma. First, delayed phase imaging is important, especially for the detection of small hepatocellular carcinomas less than 2 cm. Small hepatocellular carcinomas can be treated either by surgical resection or nonsurgical methods such as radiofrequency ablation or alcohol injection. If we detect an additional small hepatocellular carcinoma in the other lobe of the liver that might have been missed on dual-phase CT, we choose a nonsurgical method of treatment because hepatocellular carcinomas in both lobes of the liver exclude surgical resection. Second, delayed phase imaging is valuable in confirming or increasing the confidence level in the detection of equivocal nodules on arterial or portal venous phase images because those nodules are usually more conspicuous on delayed phase than on portal venous phase imaging (Fig. 3A,3B,3C) or are detected only on delayed phase CT (Fig. 2A,2B,2C). Third, triple-phase CT, including delayed phase imaging, has additional value in the characterization of hepatic masses because of better visualization of a capsule (Fig. 5A,5B,5C) or the mosaic pattern of hepatocellular carcinoma than with dual-phase CT [10, 15]. Delayed peripheral enhancement of cholangiocarcinoma and "filling-in" patterns of hemangioma are well-known signs in the differential diagnosis of hepatic masses.
One may question the benefit of triple-phase CT, considering the added radiation dose to the patients and the increased scanning time compared with dual-phase CT [8]. The most important implication of our study is that triple-phase helical CT is better than dual-phase CT for the detection of small hepatocellular carcinomas. Small hepatocellular carcinomas are much easier to treat at surgery or by local ablation therapy, and when treated, the prognosis of those patients is much better than that of patients with hepatocellular carcinomas larger than 2 cm [35,36,37]. During follow-up imaging of cirrhotic patients, the initial presentation of hepatocellular carcinoma is usually a small nodule less than 2 cm, but there may be multiple small nodules in patients with advanced cirrhosis, such as regenerative nodules or dysplastic nodules, which must be differentiated from hepatocellular carcinoma. Delayed phase imaging is helpful in the differential diagnosis of those small nodules. Additionally, in advanced liver cirrhosis, small arterioportal shunts mimic hepatocellular carcinoma on hepatic arterial phase imaging. Delayed phase imaging is valuable in excluding hepatocellular carcinoma because those arterioportal shunts will be isoattenuating on the delayed phase. Patients with advanced liver cirrhosis require a more thorough examination at the cost of radiation hazard and more time and work for radiologists.
In the evaluation of the sensitivities of hepatic arterial phase and portal venous phase versus delayed phase imaging in hepatocellular carcinoma detection, our method has some bias because hepatic arterial phase and portal venous phase images were available for review during the delayed phase image interpretation. Because delayed phase images would rarely be interpreted without hepatic arterial phase and portal venous phase images in clinical practice, the purpose of our study was to determine whether delayed phase images provide information in addition to hepatic arterial phase and portal venous phase images in the detection of hepatocellular carcinoma. The importance of this study is that one can detect or confirm additional nodules on delayed phase images that would not or would hardly be detected on hepatic arterial and portal venous phase images.
In conclusion, delayed phase CT is useful in the detection and characterization of hepatocellular carcinoma, especially for the detection of small hepatocellular carcinomas, and should be included in a multiphasic helical CT examination.
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1.5 cm) malignant hepatic neoplasms. AJR
1995;164:879
-884
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) (area under ROC curve [Az] = 0.954
± 0.012) and triple-phase helical CT (
) (Az
= 0.793 ± 0.009). Difference in mean areas under curves was
statistically significant (p<0.001).
