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1 All authors: Department of Cancer Survey, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3, Nakamichi, Higashinari, Osaka, 537-8511 Japan.
Received January 2, 2001;
accepted after revision April 17, 2001.
Supported in part by a grant from the Foundation for Promotion of Cancer
Research.
Abstract
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SUBJECTS AND METHODS. The subjects were 107 patients with focal liver lesions that initially had been found on conventional sonograms. The final diagnoses for the lesions were hepatocellular carcinoma in 60 patients, cholangiocellular carcinoma in six, metastatic carcinoma in 24, hemangioma in 10, and focal fat-spared region in seven.
The pulse inversion harmonic imaging mode and a galactose-based contrast agent (Levovist) were used. Dynamic sonography was designed to obtain vascular-phase (composed of the arterial phase and the portal phase) images of the focal lesion and liver-parenchymal-phase images of the whole liver in a series obtained after a bolus injection of the contrast agent.
RESULTS. If the whole-tumor or mosaic enhancement patterns (arterial phase) and/or the reticular enhancement (parenchymal phase) are regarded as positive findings for hepatocellular carcinoma, the sensitivity, specificity, and positive predictive value of dynamic sonography in our study were 92%, 96%, and 96%, respectively. If a ring enhancement (arterial to portal phase) or a clear defect (parenchymal phase) or both are regarded as positive findings for cholangiocellular carcinoma or metastasis, the sensitivity, specificity, and positive predictive value were 90%, 95%, and 88%, respectively. If puddle enhancement (portal phase) is regarded as a positive finding for hemangioma, the figures for sensitivity, specificity, and positive predictive value were 60%, 100%, and 100%, respectively. Also, the tumors that showed no focal sign in the liver parenchymal phase were all benign lesions, such as hemangiomas or focal fat-spared regions.
CONCLUSION. Dynamic sonography in a protocol combining pulse inversion harmonic imaging and an IV bolus injection of the contrast agent proved to be an effective tool in characterizing liver tumors.
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Since the development of color-flow Doppler imaging, radiologists have used sonography to collect vascular data with which to characterize hepatic tumors [5, 6]. IV contrast agents suitable for use in sonography recently have been developed [7, 8]. Using such a contrast agent, researchers found that a hypervascular hepatocellular carcinoma nodule was enhanced as a color-filled pattern on color-flow Doppler images [9]. However, with color-flow Doppler imaging, the change in intralesional contrast agent distribution over time cannot be accurately detected because of the modality's low spatial resolution.
Recently, second harmonics, a kind of nonlinear echo component, began to be used in sonographic imaging [10]. The enhancement effect on hepatic tumors with this technique was first studied in animals [11, 12]. Then Wilson et al. [13] reported the enhancement effect of harmonic imaging on human liver tumors using a contrast agent composed of fluorocarbon, but the change in enhancement over the course of time was not described.
More recently, along with improvements in the sonographic equipment, a pulse inversion harmonic imaging technique has made sonography more sensitive by allowing detection of the low-intensity second harmonics caused by microbubbles [14]. Moreover, one particular galactose-based sonographic contrast agent (Levovist; Schering, Berlin, Germany) has the unique characteristic of remaining within liver parenchyma even after blood-pool clearance [15]. Harvey et al. [16] reported that liver-parenchymal-phase images obtained by pulse inversion harmonic imaging were effective in revealing subcentimeter metastases. With the combination of this contrast agent and pulse inversion harmonic imaging, dynamic sonography, like dynamic CT, is now regarded as a possible means for the characterization of hepatic tumors.
The purpose of this study was to propose a dynamic sonography protocol with which the vascular-phase images of the tumor and the liver-parenchymal-phase images of the whole liver could be obtained in a series after one-shot IV injection of the galactose-based contrast agent. This study also was performed to evaluate the effectiveness of dynamic sonography for the characterization of human hepatic tumors.
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The final diagnoses of the lesions studied were hepatocellular carcinoma in 60 patients, cholangiocellular carcinoma in six, metastatic adenocarcinoma in 24, hemangioma in 10, and a focal fat-spared region in seven. Sixty hepatocellular carcinomas, six cholangiocellular carcinomas, 21 metastatic adenocarcinomas, and one focal fat-spared region were histologically diagnosed after surgical resection (61 lesions), sonographically guided biopsy (24 lesions), or autopsy (three lesions). For the remaining lesions, diagnoses were confirmed by dynamic MR imaging or dynamic CT or both. Sonographic follow-ups of the patients were performed more than 6 months after their initial examinations (Table 1).
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In the 24 cases of metastatic cancer, the primarily affected organ was the colon in 11 patients and the pancreas in nine patients; the gallbladder, breast, stomach, or lung was the primarily affected organ in one patient each. The size of the focal lesions ranged from 0.9 to 8.0 cm (median size, 2.0 cm; mean ± 2 SDs, 2.2 ± 1.5 cm). The size of each kind of tumor ranged from 1.2 to 8.0 cm for hepatocellular carcinoma, 2.0 to 4.0 cm for cholangiocellular carcinoma, 1.8 to 8.0 cm for metastasis, 0.8 to 4.0 cm for hemangioma, and 1.5 to 3.0 cm for focal fat-spared region.
Method of Dynamic Sonography
Galactose-based microbubbles (Levovist) were injected as a bolus into an
antecubital vein at 300 mg/mL x 0.1 mL/kg of body weight, followed by an
injection of 5 mL of saline solution. We used a sonographic scanner (HDI-5000;
ATL Ultrasound, Bothell, WA) with a 5-2-MHz curved array probe and the pulse
inversion harmonic imaging mode. With this software unit, alternate pulses,
180° out of phase, are transmitted with each sonographic pulse. At
summation, the fundamental pulses are canceled, and the nonlinear echo
component caused mainly by vibration or disruption of the microbubbles can be
selectively received.
The protocol of our dynamic hepatic sonography is shown in Figure 1. Before injection of the contrast agent, we determined the best scanning section in which the tumor and the nearest portal branch could be clearly visualized. During the first 1.5 min after contrast agent injection, the vascular-phase images of the tumor and the adjacent portion of liver were continuously observed. To minimize microbubble disruption, the vascular-phase images were taken at a rather low mechanical index of 0.4 and a low frame rate of 1-2 per sec, with the imaging being triggered by an electrocardiograph. After a 6.5-min pause, the liver parenchymal-phase images were obtained by a sweep scan of the whole liver, including the tumor, at a high mechanical index setting of 1.2 or 1.3 by which the remaining bubbles were disrupted instantaneously. All images from the beginning to the end of the examination were recorded on videotape as video signals, and key sequences were also recorded as digital signals in a personal computer (HDI-Lab system; ATL Ultrasound).
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Image Analysis
The vascular phase, which was the first 1.5-min component of the imaging,
was divided into two parts: the arterial phase and the portal phase. The time
period up to the beginning of the portal branch enhancement was defined as the
arterial phase, and the period after that was defined as the portal phase.
The enhancement pattern of focal lesions in the vascular phase was classified according to the modified enhanced pattern classification proposed by Nino-Murcia et al. [17] for use with CT. We found the following five types of patterns: whole enhancement (the whole tumor area is enhanced in the arterial phase, Fig. 2B), mosaic enhancement (as in a mosaic, only some parts of the tumor area are enhanced during the arterial phase, Fig. 3B), ring enhancement (a ringlike enhancement appears in the peripheral area of the tumor from the arterial phase through the portal phase, Figs. 4A and 4B), puddle enhancement (a puddlelike or patchy enhancement appears in the portal phase, Fig. 5), and no focal sign (similar to the surrounding liver).
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The findings observed in the liver parenchymal phase were also classified into five types: a clear defect (a well-defined hypoechoic region, Fig. 4C), an obscure defect (an ill-defined hypoechoic region with an obscure margin, Fig. 2D), a reticular enhancement (a netlike enhancement in the tumor area, Fig. 3D), a regional enhancement (a positive enhancement of the focal lesion), and no focal sign (same as the surrounding liver, Fig. 6B).
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The videotapes of the studies of all patients were reviewed by three medical doctors specializing in sonography who were unaware of the final diagnoses of the tumors. For each tumor, the enhancement patterns in the vascular phase and the liver parenchymal phase were classified according to the criteria just described. There were no instances in which the three reviewers indicated three different enhancement patterns for the same tumor; judgments on classifications were reached by adopting the classification on which two or more of the reviewers agreed.
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The findings in the liver parenchymal phase are summarized in Table 3. Twenty-two (92%) of the 24 lesions classified as showing a clear defect were cholangiocellular carcinomas or metastases. All 12 lesions classified as showing a reticular enhancement were hepatocellular carcinomas. All 16 lesions that exhibited no focal sign were benign—nine hemangiomas and seven focal fat-spared regions.
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Enhancement Patterns of Focal Hepatic Lesions
The enhancement patterns of each of the focal liver lesions are as
follows.
Hepatocellular carcinoma.—In the arterial phase, the
enhancement of the tumor first appeared near the feeding artery
(Fig. 2A) and gradually
extended to become whole-tumor enhancement
(Fig. 2B) in 24 (40%) of the 60
hepatocellular carcinomas and mosaic enhancement
(Fig. 3B) in 29 (48%) of the 31
hepatocellular carcinomas. Thereafter, in the portal phase, the surrounding
liver was gradually enhanced, and the echo level of the tumor area decreased
compared with that of the surrounding liver tissue (Figs.
2C and
3C). There were seven
hepatocellular carcinomas (12%) in which no focal finding was observed in the
vascular phase. Three of these carcinomas were histologically
well-differentiated hepatocellular carcinomas, and neither dynamic CT nor
hepatic arterial CT revealed the lesions. The remaining four hepatocellular
carcinomas were located deep within the body
surface.
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In the liver parenchymal phase, the whole of the liver was strongly enhanced, and the tumor was observed as an obscure defect (Fig. 2D) in 37 patients (63%) and as reticular enhancement (Fig. 3D) in 12 patients (20%). Of the 12 patients with hepatocellular carcinomas that showed a reticular enhancement, surgical resection was performed on nine. All of these carcinomas were accompanied by a fibrous capsule and septa, as shown in Figure 3E.
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Cholangiocellular carcinoma and metastases.—In the arterial phase, ring enhancement (Fig. 4A) appeared in the periphery of the tumor and lasted until the portal phase (Fig. 4B) in five (83%) of the six cholangiocellular carcinomas and in 19 (79%) of the 24 metastases. In the parenchymal phase, a clear defect (Fig. 4C) was observed in five (83%) of the cholangiocellular carcinomas and 17 (71%) of the metastases.
Hemangioma.—In the arterial phase, no particular enhancement was seen in the tumor area in any of the patients, but in the portal phase, puddle enhancement (Fig. 5) was observed in six (60%) of the 10 hemangiomas. In the liver parenchymal phase, no focal sign was observed in nine (90%) of the hemangiomas.
Focal fat-spared region.—In all cases, the echo level of the focal region gradually increased during the portal phase, but it was low compared with that of the surrounding liver. In the parenchymal phase, the whole of the liver, including the focal area, was strongly enhanced, and no focal sign could be distinguished (Fig. 6B).
Diagnostic Accuracy
If whole-tumor enhancement or mosaic enhancement in the arterial phase
and/or reticular enhancement in the parenchymal phase are regarded as positive
findings for hepatocellular carcinoma, the sensitivity, specificity, and
positive predictive value of dynamic sonography in our study were 92%, 96%,
and 96%, respectively (Table
4). If ring enhancement seen from the arterial phrase to portal
phase or a clear defect seen in the parenchymal phase or both are regarded as
positive findings for either cholangiocellular carcinoma or metastasis, the
sensitivity, specificity, and positive predictive value of the modality were
90%, 95%, and 88%, respectively. If puddle enhancement occurring in the portal
phase is regarded as a positive finding for hemangioma, the sensitivity was
60%, and both the specificity and the positive predictive value were 100%.
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By applying our protocol in patients with focal liver lesions, we have proven that dynamic sonography has high diagnostic value in characterizing hepatic tumors.
Nino-Murcia et al. [17]
suggested a classification for the enhancement patterns of focal liver lesions
seen in the arterial phase of dynamic CT. The enhancement pattern in the
vascular phase of our dynamic sonography corresponds well to their findings
for dynamic CT. However, one potential difficulty has been reported with the
sequential observation of the whole liver using dynamic CT: determining the
length of the delay (between the injection of the contrast medium and the
start of the scanning) that provides optimal contrast enhancement
[18]. On the other hand,
sonography is highly useful in revealing focal hepatic tumors even without the
use of a contrast agent. So, in our series of dynamic sonography, we could
continuously observe the lesion of interest throughout the vascular phase
without risk of missing the optimal observation timing. As a result, the
detailed enhancement process could be obtained like a single-level dynamic CT
study
[19].
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Liver-parenchymal-phase imaging has already been reported to be useful for the detection of metastases because metastasis is shown as a clear defect area [18]. However, to our knowledge, no report to date has described the liver-parenchymal-phase images of hepatic tumors other than images of metastases. In this study, we described the liver parenchymal-phase images of various kinds of liver tumors. We found that a reticular enhancement pattern was a highly specific finding for hepatocellular carcinoma. The pharmacodynamics of our chosen contrast agent after blood-pool clearance have not yet been clearly elucidated, but the function of the reticuloendothelial system or other mechanisms—such as the slowly moving microbubbles in the liver sinusoids or attachment to sinusoidal endothelial lining cells—are likely to be involved [16]. In our series, a reticular enhancement pattern was observed only in hepatocellular carcinomas, and most of those carcinomas were accompanied by a fibrous capsule or septa. Also, the observed reticular pattern corresponded well to the shape of the fibrous capsule and septa as shown in Figures 3D and 3E. Indications are that the bubbles remaining in the blood space within the fibrous capsule or septa possibly caused the reticular enhancement seen in the liver parenchymal phase.
Moreover, all of the malignant tumors in our series showed some focal sign in the liver parenchymal phase. The focal lesions, which disappeared in the liver parenchymal phase, were all found to be benign tumors, such as focal fat-spared regions or hemangiomas (unexpectedly, other benign tumors such as focal nodular hyperplasia or liver cell adenoma were not found among the lesions we studied). Therefore, we believe that whole-liver scanning in the liver parenchymal phase provides additional information useful in the detection of malignant tumors.
Regarding the differential diagnosis of hepatocellular carcinoma, we note that regenerative nodules found in the cirrhotic liver are very confusing on routine sonographic examinations. However, histologic examinations confirmed that no regenerative nodules were among our subject lesions. Because only those lesions clearly revealed on ordinary sonograms were selected for study, regenerative nodules and some borderline malignancies may have been excluded. Further study will be necessary to find methods of differentiating borderline malignancies from regenerative nodules.
In four hepatocellular carcinomas, located deep within the body surface, no focal sign could be observed in the vascular phase, possibly because of the attenuation of sound. Deep attenuation is one of the weak points of this method. However, even the deep areas could be covered if liver-parenchymal-phase imaging were performed on a high mechanical index setting.
As for the safety of the contrast agent, no side effects were observed in any patients in this series. Unlike the contrast agents used for CT imaging, Levovist is noniodine, and the injected volume is at most 10 mL, so possible side effects, such as an allergic reaction to iodine or renal or cardiac overload, are less likely to occur.
In our series, we found that dynamic hepatic sonography has many advantages over dynamic CT, such as convenience, the probability of fewer side effects, no exposure to radiation, and no risk of missing the optimal time for observation. To verify this method as a substitute for dynamic CT, a detailed comparison of findings obtained with each modality in the same group of patients must be performed. In conclusion, our study showed that, using a protocol combining pulse inversion harmonic imaging and IV injection of Levovist, dynamic hepatic sonography proved to be effective in characterizing hepatic tumors.
Acknowledgments
We thank Ryoko Uchimoto of Nippon Schering and Paul Kalman of ATL
Ultrasound for providing technical advice; Tomohiro Tanaka for providing
editorial assistance; and Kiyomi Yamamoto, Hiroko Ono, Sayako Miyazaki, and
Yumiko Ueda for providing additional assistance.
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