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1 Department of Gastroenterology and Hepatology, Kinki University School of
Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
2 Present address: Department of Ultrasound, The Second Affiliated Hospital, Sun
Yat-sen University, 107 Yanjiangxi Rd., Guangzhou 510120, China.
3 Present address: Department of Ultrasound, The Third Affiliated Hospital, Sun
Yat-sen University, Shipai, Guangzhou 510630, China.
4 Present address: Department of Ultrasound, Zhongshan Hospital, Shanghai,
China.
5 Present address: Department of Ultrasound, Wuhan General Hospital of Guangzhou
Military Area, Wuhan 430070, China.
6 Abdominal Ultrasound Unit, Kinki University School of Medicine, Osaka-Sayama,
Osaka 589-8511, Japan.
Received July 18, 2003;
accepted after revision September 26, 2003.
Address correspondence to M. Kudo
(m-kudo{at}med.kindai.ac.jp).
Abstract
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SUBJECTS AND METHODS. Using a microbubble contrast agent we performed coded harmonic angio in 163 patients with 192 hepatic tumor nodules: 153 hepatocellular carcinomas, 13 metastases, 14 hemangiomas, eight dysplastic nodules, and four focal nodular hyperplasias. After injecting Levovist, we performed real-time scanning, interval-delay fast low-angle shot imaging, and sweep scanning in the early arterial phase, late vascular phase, and postvascular phase, respectively.
RESULTS. On contrast-enhanced coded harmonic angio, the typical hemodynamic pattern of hepatocellular carcinomas was shown as abundant tumor vessels supplied from the periphery to the center of the tumor and dense parenchymal tumor staining with fast washout (sensitivity, 92.8%; specificity, 92.3%). The characteristic hemodynamic pattern of metastases was peripheral tumor vessels with a rim parenchymal stain in the vascular phase followed by a perfusion defect in the postvascular phase (sensitivity, 69.2%; specificity, 100%). Hemangiomas were hypovascular in the early arterial phase with gradual spotty or cottonwool pooling continuing to the late vascular phase (sensitivity, 92.9%; specificity, 100%). Dysplastic nodules were shown as having no early arterial supply with isovascularity in the late vascular phase (sensitivity, 75%; specificity, 100%). Focal nodular hyperplasias were shown to have a spoked wheel pattern of blood vessels accompanied by dense staining in interval-delay scanning (sensitivity, 100%; specificity, 100%).
CONCLUSION. Contrast-enhanced coded harmonic angio is a promising method to provide useful information for the differential diagnosis of hepatic tumors.
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Contrast agents are widely used in assessing nodular hepatic tumors in radiologic studies. Recently, IV contrast agents for sonographic imaging have also become available for routine clinical use [6, 7]. The use of microbubble contrast agents has improved the detection and characterization of the intranodular vascularity of hepatic lesions on conventional color Doppler imaging and power Doppler imaging [8, 9]. However, contrast-enhanced color Doppler imaging and power Doppler imaging have relatively poor signal resolution from the microbubbles, resulting in an insufficient ability to depict intratumoral vascular information in addition to abundant artifacts [810].
To improve the detectability of the enhanced microbubble signals, researchers have studied using the behavior of microbubbles in blood flow and developed new sonographic technology [7, 1119]. Phase- or pulse-inversion harmonic imaging is one of the new imaging techniques. It produces high-quality contrast-enhanced images that are superior to second harmonic imaging or conventional Doppler imaging [14, 19]. Coded harmonic angio (General Electric Medical Systems) is a further improved technology that combines phase- or pulse-inversion harmonic imaging with a "coded excitation technique," which transmits coded pulse sequences, decoding them on receipt. Theoretically, it can provide high sensitivity and resolution to the enhanced blood signals. In this study, we used coded harmonic angio with a microbubble contrast agent in nodular hepatic lesions to investigate its ability to characterize hepatic tumors.
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Between March 2000 and July 2001, 570 consecutive patients with liver tumors detected on screening sonography were studied with contrast-enhanced coded harmonic angio using an IV contrast agent, Levovist. Of the 570 patients, 403 had extrahepatic diseases or treated hepatic tumors and were excluded from this group. No other exclusion criteria were present. Thus, 167 consecutive patients were included in this study: 104 men and 59 women, ranging in age from 33 to 83 years (mean, 63 years). Contrast-enhanced coded harmonic angio was performed on 192 nodular hepatic lesions: 153 hepatocellular carcinomas, 13 metastases (nine gastrointestinal cancers, one lung cancer, and three breast cancers), 14 hemangiomas, eight dysplastic nodules, and four focal nodular hyperplasias. Intranodular vascularity could be evaluated in all 192 nodules.
The maximal diameters of the 192 hepatic nodules were as follows: hepatocellular carcinomas, 0.714 cm (mean, 2.7 cm); metastases, 0.84.5 cm (mean, 3.0 cm); hemangiomas, 0.89.1 cm (mean, 3.9 cm); dysplastic nodules, 1.02.9 cm (mean, 2.0 cm); and focal nodular hyperplasias, 1.24.0 cm (mean, 2.5 cm). Histologic diagnosis was obtained at sonographically guided percutaneous biopsy or surgery in 34 hepatocellular carcinomas, all the dysplastic nodules, four metastases, one hemangioma, and all the focal nodular hyperplasias. The other 158 tumors were diagnosed on the basis of tumor-marker factors and a combination of imaging findings on dynamic CT (X-vigor, Toshiba Medical Systems), MRI (Visart-Hyper, Toshiba), CT arteriography, CT arterioportography, or hepatic angiography (DHF-158CX, Hitachi Medical). All 153 hepatocellular carcinomas received integrative treatment. The other nine metastases without histologic diagnosis were followed up for more than 6 months, and all the benign lesions were followed up for more than 12 months.
Contrast Medium
Levovist, the contrast agent used in this study, is an IV microbubble agent
consisting of 99.9% D-galactose and 0.1% palmitic acid. Before
injection, we mixed 5 mL of sterile water with 2.5 g of Levovist
microparticles according to the manufacturer's instructions and obtained a
suspension of 400 mg/mL. This was injected as a bolus at a speed of 1 mL/sec
via a 20-gauge cannula placed in the antecubital vein and then flushed with 10
mL of normal saline.
Imaging
The sonographic study was performed with the Logiq 700 Expert series
(General Electric Medical Systems) and a convex-arrayed wideband transducer
was used at a frequency of 24 MHz. Before starting the
contrast-enhanced study, fundamental B-mode imaging was performed. A
representative plane was selected for each nodule to clearly show the lesion
and the surrounding liver parenchyma. Coded harmonic angio was performed with
a mechanical index of 0.60.8, and the dynamic range was fixed at 72
decibels. The main gain of coded harmonic angio was maintained at 40 G, and a
single focus point was set at the deepest edge of the nodule.
The complete contrast-enhanced coded harmonic angio procedure was classified into three phases: early arterial phase, from 10 to 60 sec after Levovist administration; late vascular phase, from 1 to 5 min; postvascular phase, 5 min after Levovist administration.
During contrast-enhanced coded harmonic angio, the patients were asked to hold their breath from 10 sec after the Levovist administration (when the first enhanced signal appeared in the liver) to diminish the motion artifacts and avoid losing the targeted tumor. Then, real-time imaging was performed for 2030 sec to detect the supply pattern of the blood vessels in the early arterial phase and for 10 sec in the late vascular phase. A gradual change in the scanning plane was needed to observe the entire nodule. After storing the still pictures by reviewing the cine-loop memory, automatic intermittent (23 sec) or manual interval-delay (510 sec) fast low-angle shot (FLASH) echo imaging was performed three or four times to show tumor parenchymal staining in the late vascular phase. In the postvascular phase, real-time sweep scanning was performed. When a hemangioma was suspected by B-mode imaging, long (12 min) interval-delay scanning was applied to show the specific vascular pattern. For multiple nodules in the liver, coded harmonic angio was performed repeatedly after the injection of another vial of Levovist with an injection time interval of more than 10 min.
All patients underwent three-phase dynamic CT using an MDCT system. A total of 100 mL of Iopamiron (Iopamidol, Nihon Schering) was injected IV with an iodine concentration of 370 mg/mL. Dynamic acquisition was performed in the early arterial phase (30 sec), portal phase (60 sec), and delayed phase (180 sec).
Analysis
All the sonographic data were recorded on videotape from the beginning of
B-mode scanning. The still images were stored on the hard disk of the unit by
reviewing the cine-loop memory. By replaying the videotapes, at least three
observers evaluated the intranodular hemodynamics and classified them into
seven patterns (type Itype VII), which will be fully described in the
Results section, without knowledge of the findings on other imaging techniques
or the pathologic or clinical data. In cases of discrepancy, the tapes were
discussed and reevaluated to reach agreement. The intranodular vascularity on
contrast-enhanced coded harmonic angio was assessed as hypervascular,
isovascular, or hypovascular by comparing the intranodular vessels and
parenchymal staining with those of the surrounding liver parenchyma. The
enhancement patterns in different phases were evaluated.
The contrast enhancement on dynamic CT was reviewed by three radiologists without knowledge of the contrast-enhanced coded harmonic angio results. On comparison with the surrounding liver parenchyma, high attenuation, isoattenuation, and low attenuation of the hepatic nodules were considered to be hypervascular, isovascular, and hypovascular, respectively.
The indication of hypervascularity and isovascularity was defined as a positive depiction of intranodular vascularity. The data were analyzed with the chi-square test. A p value less than 0.05 was considered significant.
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The intranodular hemodynamic patterns of the nodular hepatic lesions were classified as follows (Fig. 1): type I (hepatocellular carcinoma pattern), abundant tumor vessels appeared as a basketlike or irregular branching pattern from the periphery infiltrating the center, with dense tumor parenchymal staining with fast washout; type II (metastasis pattern), linear tumor vessels in the marginal area with rimlike or peripheral parenchymal staining with perfusion defects in the post-vascular phase; type III (hemangioma pattern), spotty pooling or a cotton- or woollike appearance with a gradual fill-in over time that persisted until the postvascular phase, as shown by long interval-delay scanning (interval time, 12 min); type IV (dysplastic nodule pattern), no intranodular vessels in the early arterial phase and isovascular staining with interval-delay scanning in the late vascular phase; type V (focal nodular hyperplasia pattern), central arterial supply with centrifugal radiation in the early arterial phase accompanied by dense parenchymal staining by interval-delay scanning; type VI (atypical pattern), different tumor vessels and parenchymal staining from those described above; and type VII (hypovascular pattern), no tumor vessels and no parenchymal staining during any phase.
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Hepatocellular Carcinoma
Contrast-enhanced coded harmonic angio detected intratumoral vascularity in
96.7% (148/153) of the hepatocellular carcinomas although it showed no blood
signal in the remaining 3.3% (5/153). In contrast, 150 hepatocellular
carcinoma nodules (98.0%) showed hyper- or isovascularity on dynamic CT. The
detection rates of intratumoral vascularity between contrast-enhanced coded
harmonic angio and CT had no significant difference (p >
0.05).
Of the 148 hypervascular hepatocellular carcinomas, 142 appeared as type I (hepatocellular carcinoma pattern) (Figs. 1 and 2A, 2B, 2C) on contrast-enhanced coded harmonic angio, and six showed an atypical pattern of hemodynamics. In the 142 hepatocellular carcinoma nodules, 18 (12.7%) had peripheral small tumor vessels; however, dense tumor parenchymal staining was present within the entire tumor, followed by fast washout in the postvascular phase. Five nodules (3.5%) showed moderate blood vessels in the early arterial phase and heterogeneous tumor parenchymal staining in the late vascular phase with perfusion defects in the postvascular phase. In the other eight hepatocellular carcinomas (5.6%), abundant tumor blood vessels were shown in the early arterial phase on contrast-enhanced coded harmonic angio although tumor parenchymal staining was detected in only part of the nodule. In the remaining 111 nodules (78.2%), moderate or abundant blood vessels were detected, accompanied by dense tumor staining within the entire tumor, as well as perfusion defects in the postvascular phase.
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Above all, in the 142 hypervascular hepatocellular carcinomas, contrast-enhanced coded harmonic angio showed tumor vessels appearing from the periphery and infiltrating the center of the tumor with irregular branches. Most of the 142 hepatocellular carcinomas showed heterogeneous or homogeneous tumor parenchymal staining, which was hyperechoic on the gray-scale background when compared with the surrounding liver parenchyma. Perfusion defects in the postvascular phase due to fast washout from the nodule were another characteristic of these hepatocellular carcinomas.
The other six hepatocellular carcinoma nodules showed tumor vessels only in the marginal area with partial tumor parenchymal staining (atypical pattern), and five were hypovascular on contrast-enhanced coded harmonic angio. All six nodules were proven to be well-differentiated hepatocellular carcinomas at sonographically guided biopsy.
Contrast-enhanced coded harmonic angio, therefore, showed most of the hepatocellular carcinomas as having the characteristic hemodynamic pattern of hepatocellular carcinoma. The sensitivity and specificity of this hepatocellular carcinoma pattern were 92.8% (142/153) and 92.3% (36/39), respectively. The positive and negative predictive values of this finding were 97.9% (142/145) and 76.6% (36/47), respectively.
Metastasis
Contrast-enhanced coded harmonic angio detected blood signals in 12 (92.3%)
of 13 metastases, compared with dynamic CT that showed 11 (84.6%) of the 13
metastases as having positive tumor vascularity, although no significant
difference (p > 0.05) was observed.
Of the 12 hypervascular metastases, contrast-enhanced coded harmonic angio showed peripheral tumor vessels and marginal rimlike parenchymal staining in nine nodules. In the other three metastases, tumor vessels and weak parenchymal staining were detected in all the tumors. However, the 13 metastases were all shown as perfusion defects in the postvascular phase with sweep scanning. By combining the three phases of the Levovist study, contrast-enhanced coded harmonic angio showed the metastases with findings compatible with type II (metastasis pattern) (Figs. 1 and 3A, 3B) with a sensitivity and specificity of 69.2% (9/13) and 100% (179/179), respectively. The positive and negative predictive values of this finding were 100% (9/9) and 97.8% (179/183), respectively.
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Hemangioma
On contrast-enhanced coded harmonic angio, all the hemangiomas were shown
to have hypervascularity, and the typical hemodynamic patterns (Figs.
1 and
4A,
4B,
4C,
4D) of hemangioma were shown
in 13 nodules, with spotty pooling vessels detected in the vascular phase.
Gradual fill-in and globular tumor parenchymal pooling in the late vascular
phase were shown with long interval-delay scanning (12 min), which
persisted until the postvascular phase (type III). The sensitivity and
specificity of this finding were 92.9% (13/14) and 100% (178/178),
respectively, and the positive and negative predictive values of this finding
were 100% and 99.4%, respectively. In the remaining hemangioma of 0.8-cm
maximal diameter, tumor vessels and dense parenchymal pooling were detected in
the early arterial phase with real-time scanning, which was difficult to
distinguish from the hemodynamic pattern of hepatocellular carcinoma. However,
the tumor blood pooling continued to the postvascular phase suggesting a
diagnosis of hemangioma. The typical findings of hemangioma on T2-weighted MRI
were shown, and no change in the nodule was observed at the 6-month
follow-up.
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Contrast-enhanced coded harmonic angio showed the same sensitivity (100%) in the detection of intratumoral vascularity as that on dynamic CT.
Dysplastic Nodule
Contrast-enhanced coded harmonic angio showed no blood vessels in any of
the eight dysplastic nodules in the early arterial phase. In the late vascular
phase and postvascular phase, contrast-enhanced coded harmonic angio showed
isovascular staining in six nodules and hypervascular staining in one,
suggesting a portal venous supply to the nodule. However, the remaining nodule
showed a hypovascular pattern. In these nodules, portal venous flow was shown
on CT arterioportography. The sensitivity and specificity of type IV
(dysplastic nodule pattern) (Figs.
1 and
5A,
5B,
5C,
5D,
5E) were 75% (6/8) and 100%
(184/184), respectively, and the positive and negative predictive values were
100% (6/6) and 98.9% (184/186), respectively. In contrast, dynamic CT detected
low attenuation in the arterial phase in all the dysplastic nodules
accompanied by isoattenuation in six of the nodules in the portal and delayed
phases. The detection of dysplastic nodule intranodular vascularity by
contrast-enhanced coded harmonic angio and dynamic CT was not significantly
different (p > 0.05).
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Focal Nodular Hyperplasia
All four focal nodular hyperplasias showed a central arterial supply with a
centrifugal radiating flow to the periphery (spoked wheel pattern) in the
early arterial phase, accompanied by dense parenchymal staining in the late
vascular and postvascular phases (type V) (Figs.
1 and
6A,
6B,
6C). Both the sensitivity and
specificity of this finding were 100%. In contrast, on dynamic CT, the spoked
wheel focal nodular hyperplasia pattern was not shown in any of the four, and
only hypervascularity was shown.
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Sonography is most widely used to depict hepatic tumors during clinical follow-up because of its noninvasiveness and ease of use. However, conventional sonography, including Doppler techniques, cannot provide satisfactory information on intratumoral vascularity because color Doppler imaging and power Doppler imaging lack the sensitivity to detect slow flow. Since Kudo et al. [25] attempted to use an intraarterial CO2 microbubble contrast agent in sonography to detect the intratumoral hemodynamics, the differential diagnosis of hepatic tumors has become possible with contrast-enhanced sonography from the characteristic tumor vascularity. Recently, less invasive techniques, such as IV sonographic contrast studies, have become available in the clinical setting, although conventional color Doppler imaging and power Doppler imaging do not work well with contrast agents because of the drawbacks of Doppler-related artifacts such as blooming, bubble noise, or high susceptibility to tissue motion [610].
Various gases or shells have been studied for use as sonographic contrast agents [7], and Levovist is the most widely studied microbubble agent. The small size of the Levovist microbubbles allows safe passage through the pulmonary capillaries. In addition, a small amount of palmitic acid, which acts as a surfactant, improves the intravascular stability of the microbubbles by preserving the low surface tension, resulting in an enhancement effect lasting for several minutes. Previous studies [6, 26] showed that the microbubbles move in a complex manner in the blood flow. When they are exposed to an acoustic field, the microbubbles undergo nonlinear movement and produce nonlinear signals, known as harmonic components. With sudden exposure to a sonographic beam with high acoustic power after several seconds' suspension of transmission, a high-intensity, but momentary, echo can be obtained in the first frame image, known as a "FLASH echo image" or interval-delay image [11, 26].
On the basis of knowledge about the behavior of microbubbles in the blood flow, different sonographic technologies have been developed [1119, 27]. Phase- or pulse-inversion harmonic imaging is a new microbubble-specific technology that transmits two pulses of sonographic waves in rapid succession with a 180¡ phase change. The scanner receives the echo from the sum of the two inverted pulses. As a result, phase- or pulse-inversion harmonic imaging detects signals from the microbubbles, but fewer from the tissue. This is superior to second harmonic imaging and conventional Doppler imaging in showing the vascularity of hepatic tumors because of its high sensitivity and resolution [19].
Coded harmonic angio is a newly developed advanced technology using phase- or pulse-inversion harmonic imaging. It combines phase- or pulse-inversion harmonic imaging with coded technology that boosts weak microbubble signals and suppresses tissue signals by transmitting coded pulse sequences and decoding them on receipt [28]. Coded technology uses a code and decode pulse sequence system, so-called digitally encoded sonographic technology, to enhance the signals from the contrast agent and, at the same time, suppress unwanted background, fundamental, and harmonic signals from the tissue.
In this study, contrast-enhanced coded harmonic angio was continuously performed using Levovist to show the tumor blood vasculature in the early arterial phase. Intermittent or interval-delay scanning, which allows time for microbubbles to flow into the tumor blood space, was performed to show tumor parenchymal staining. Furthermore, sweep scanning in the postvascular phase was used to show the findings after washout of the microbubbles from the vascular space, which is believed to be taken up by Kupffer's cells [7]. In this study, promising results were obtained in depicting the characteristic hemodynamic patterns in various hepatic tumors.
As shown on angiography, CO2 sonographic angiography, and CT arteriography, hepatocellular carcinoma is characterized by its hypervascularity, which appears as an early arterial supply with dense tumor staining [8, 20, 21, 25]. In this study, contrast-enhanced coded harmonic angio showed that 92.8% (142/153) of the hepatocellular carcinomas had early arterial supply from the periphery, infiltrating the center of the nodules with irregular branches, and heterogeneous or homogeneous tumor parenchymal staining similar to that on dynamic CT. Corresponding to the high velocity of draining flow and fast washout [29], the hepatocellular carcinoma nodules had perfusion defects in the postvascular phase. By combining the findings in the three kinetic phases of Levovist, contrast-enhanced coded harmonic angio can provide an excellent depiction of the intratumoral hemodynamics characteristic of hepatocellular carcinoma.
On contrast-enhanced coded harmonic angio, nine of the 13 metastases were shown to have peripheral linear tumor vessels with rim enhancement between the nonenhanced portion of the lesion and the enhanced surrounding parenchyma. This pattern of enhancement is never seen in other liver tumors and corresponds highly to the appearance on dynamic CT. Furthermore, all the metastases appeared as perfusion defects in the postvascular phase. However, in four of the 13 metastases, different hemodynamic patterns were detected, resulting in the relatively low sensitivity of the metastasis pattern. This might have been caused by the different characteristics of the original tumors.
On contrast-enhanced coded harmonic angio, a typical spotty pooling pattern in the early arterial phase followed by globular or cottonwool pooling was detected in the hemangiomas, but not in the other hepatic tumors. Furthermore, even in the small-sized hemangioma that was an atypical pattern of tumor vessels and parenchymal staining, tumor parenchymal pooling continuing over a long time period showed a characteristic specific to hemangioma and important in distinguishing hemangioma from hypervascular hepatocellular carcinoma.
As many studies have described, a dysplastic nodule is characterized by its portal supply and arterial hypovascularity [2124]. In this study, contrast-enhanced coded harmonic angio detected six dysplastic nodules without an arterial supply in the early arterial phase followed by isoechoic staining probably due to the presence of portal flow in the late vascular phase. The isoechoic pattern in the postvascular phase might also have been due to the presence of Kupffer's cells in the nodules. This finding shows a high specificity and positive predictive value, although the sensitivity is low. It is sometimes very difficult to confirm the diagnosis of dysplastic nodules especially for nodules that contain malignant foci within the dysplastic nodule.
Surprisingly, contrast-enhanced coded harmonic angio clearly showed the typical central arterial supply and spoke-wheel appearance in all the focal nodular hyperplastic nodules, corresponding exactly to the pathologic studies and CO2 sonographic angiography [25, 30]. The sensitivity and specificity were both 100%.
Although we have given the sensitivity and specificity of contrast-enhanced sonography in the diagnosis of metastasis, hemangioma, dysplastic nodule, and focal nodular hyperplasia, it must be pointed out that the numbers of these diseases were relatively low for statistical purposes.
Obviously, several intrinsic limitations in contrast-enhanced coded harmonic angio exist. First, it may not be as helpful as CT or MRI, which can perform both lesion detection and characterization. Second, this method cannot be applied to nodules which cannot be detected on B-mode sonography. In these respects, this method may be inferior to CT or MRI. Apart from this limitation, contrast-enhanced coded harmonic angio showed a comparable detectability of hypervascularity to that of three-phase dynamic CT in hepatic tumors. Furthermore, in its depiction of the tumor vessels in real time, it is superior to dynamic CT, if a sonographically detectable nodule can be imaged. Therefore, it may replace some of the roles of dynamic CT or MRI in the differential diagnosis of hepatic tumors, especially for benign tumors. Once a benign tumor, such as hemangioma or focal nodular hyperplasia, is confirmed, additional studies will not be needed, avoiding unnecessary exposure to X rays or invasive examinations. Because dynamic CT is superior to sonography in detecting hypervascular lesions in the whole liver, sonography and dynamic CT have complementary roles in lesion detection and characterization.
In conclusion, with the use of a microbubble contrast agent, Levovist, coded harmonic angio is a promising approach in the noninvasive characterization of hepatic tumors on the basis of showing the characteristic appearance of each hepatic tumor sensitively and specifically. We believe this highly advanced technology is extremely useful in the differential diagnosis of hepatic tumors. When this method becomes widely available, it may change the diagnostic strategy for hepatic tumors because of its complementary role with CT or MRI.
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