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© 2004 by the American Institute of Ultrasound in Medicine
J Ultrasound Med 23:1557-1568 • 0278-4297

Real-time Imaging With the Sonographic Contrast Agent SonoVue

Differentiation Between Benign and Malignant Hepatic Lesions

Alexandra von Herbay, MD, Christoph Vogt, MD, Reinhard Willers, PhD and Dieter Häussinger, MD

Department of Medicine, University of Tübingen, Tübingen, Germany (A.v.H.); and Department of Medicine (A.v.H., C.V., D.H.) and Computer Center (R.W.), University of Düsseldorf, Düsseldorf, Germany.

Address correspondence and reprint requests to Alexandra von Herbay, MD, Department of Gastroenterology, Hepatology, and Infectiology, Clinic of Internal Medicine 1, University of Tübingen, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective. We investigated the ability of contrast-enhanced sonography with SonoVue (Altana Pharma, Konstanz, Germany), a sulfur hexafluoride microbubble contrast agent, to reveal differences between benign and malignant focal hepatic lesions. Methods. One hundred twenty-six lesions in 124 patients with focal hepatic lesions detected by B-mode sonography (hepatocellular carcinoma, n = 36; metastasis, n = 25; cholangiocellular carcinoma, n = 1; lymphoma, n = 2; focal nodular hyperplasia, n = 9; adenoma, n = 4; regenerative cirrhotic nodule, n = 13; hemangioma, n = 29; and focal hyposteatosis, n = 7) were examined in a prospective study. After intravenous injection of 2.4 mL of SonoVue, the liver was examined continuously for 3 minutes by low–mechanical index pulse inversion sonography. Results. For the discrimination of malignant versus benign liver lesions, SonoVue-enhanced sonography improved sensitivity from 78% to 100% and specificity from 23% to 92% compared with baseline sonography. Receiver operating characteristic analysis revealed a significant improvement in this discrimination (area under the receiver operating characteristic curve, 0.510 ± 0.054 [SD] at baseline sonography, 0.998 ± 0.003 with SonoVue-enhanced sonography; P < .001). The following flow patterns in the early phase were diagnosis specific: early central starlike pattern for focal nodular hyperplasia, peripheral globular-nodular pattern for hemangioma, and diffuse arterial enhancement for malignant lesions. Homogeneous enhancement in the late phase was predictive for benign lesions (P < .001). Conversely, 93% of patients without contrast enhancement in the late phase had malignant lesions (P < .001). Conclusions. SonoVue-enhanced sonography has greater specificity and sensitivity than baseline sonography for the differentiation of benign and malignant liver lesions.

Key Words: contrast media • hemangioma • hepatocellular carcinoma • liver • metastasis • sonography • SonoVue

Abbreviations: Az, area under the receiver operating characteristic curve • CT, computed tomography • FNH, focal nodular hyperplasia • HCC, hepatocellular carcinoma • MI, mechanical index • MR, magnetic resonance • ROC, receiver operating characteristic


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Sonography is usually the first line of investigation in the detection of focal hepatic lesions. However, differentiation between benign and malignant lesions is difficult in many cases. Whereas the use of contrast agents has been established for other imaging techniques, for example, computed tomography (CT) and magnetic resonance (MR) imaging,1 the value of contrast agents in sonographic examinations is under clinical investigation. A major advance for sonographic examinations with contrast agents is the development of pulse inversion sonography. Pulse inversion sonography is a technique that works by sending 2 separate pulses, 180° out of phase, and summing the reflected echoes to form the final sonographic signal.2–5 The linear echoes reflected from the tissue nullify, whereas the nonlinear echoes reflected from the contrast medium produce a detectable signal.

Several studies showed that contrast-enhanced sonography with high–mechanical index (MI) techniques6–11 could improve the differentiation between benign and malignant focal hepatic lesions. However, contrast agents of the first generation, for example, Levovist (SH U 508A; Schering AG, Berlin, Germany), are based on the destruction of microbubbles caused by insonation at high MI (>0.7).12 Therefore, the examination cannot be performed with real-time sonography, and complex techniques, such as "intermittent imaging,"4,12–15 are required. Contrast agents of the second generation, for example, SonoVue (Altana Pharma, Konstanz, Germany), are of diagnostic value even at very low transmission power (MI <0.3) because of their physical behavior during insonation. Therefore, continuous real-time sonography can be performed without destruction of the microbubbles,16,17 which is a benefit for the dynamic analysis of contrast enhancement in the early phase.

These microbubbles circulate in vessels, crossing the pulmonary and systemic capillary circulation.16,17 During low-MI imaging, the SonoVue microbubbles have a much higher nonlinear behavior than native tissue, resulting in detectable echoes.

The aim of this study was to determine whether the analysis of the SonoVue enhancement in early and late phases after injection allows differentiation between benign and malignant focal liver lesions. Furthermore, the question was addressed whether the dynamic analysis of the early arrival pattern of SonoVue is of differential diagnostic value.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
In a prospective study, 126 lesions in 124 patients with focal hepatic lesions (65 men and 59 women; mean age, 59 ± 14 [SD] years) were examined. The protocol was approved by the Institutional Review Board of the University of Düsseldorf. Before the sonographic examination was started, the purpose of the study was explained to each patient, and oral informed consent was obtained according to the ethical guidelines from Helsinki.18

Patients
The study population was recruited from patients who underwent abdominal sonography in the University Hospital Ultrasound Department. Final diagnosis was confirmed by liver biopsy, CT, MR imaging, or scintigraphy (Table 1Go), performed as part of the clinical workup of the patients.


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  		Table 1. Final Diagnoses in 126 Lesions in 124 Patients by Histologic Examination, CT, MR Imaging, and Scintigraphy
 
In 64 patients, malignant liver lesions were diagnosed as hepatocellular carcinoma (HCC; n = 36), metastasis (n = 25), cholangiocellular carcinoma (n = 1), and non-Hodgkin lymphoma (n = 2). In 62 patients, benign lesions were diagnosed as focal nodular hyperplasia (FNH; n = 9), adenoma (n = 4), hemangioma (n = 29), regenerative cirrhotic nodules (n = 13), and focal steatosis (n = 7).

Contrast Agent
SonoVue is a contrast agent of the second generation that contains phospholipid-stabilized microbubbles filled with sulfur hexafluoride with a diameter of less than 8 µm (mean, 2.5 µm).16,17 Contrast agents filled with perfluorocarbon vapor resist ultrasonic acoustic power better than air-filled sonographic contrast agents.16–20 SonoVue is a "blood pool" contrast agent. In addition to the early vascular phase (arterial and portal phase), SonoVue also has a late parenchymal phase (1–3 minutes after injection) due to accumulation in very small parenchymal vessels.21

Study Design
All examinations were performed with a Sonoline Elegra sonography unit (Siemens, Erlangen, Germany) using a 3.5C40 multifrequency transducer (Siemens). We screened the liver for focal lesions in both native and tissue harmonic imaging modes and documented the number and location of focal lesions. Pulse inversion sonography was performed with Ensemble contrast harmonic imaging software (Siemens). SonoVue was administered as a bolus using an intravenous catheter having at least a 21-gauge diameter followed by 10 mL of a 0.9% saline bolus. Scanning was performed in real time for 3 minutes starting directly after the SonoVue injection.

The equipment settings for the contrast imaging were set to contrast harmonic imaging mode, frequency of 2.0 to 2.5 MHz, parallel processing turned on, persistence turned off, and low (<0.2) MI. Photopic software (Siemens) was used to improve the visualization of the B-mode imaging in the background, resulting in clear visualization of the lesion even with 3% power. All examinations were stored on magnetic optical disks and on S-VHS videotapes.

Image Analysis
The analysis of the baseline sonograms and the contrast-enhanced studies was performed by the consensus of 2 independent observers. The reviewers did not know the final diagnosis at the time of analysis. For interpretation of the results, a 5-point grading system was used for baseline and contrast-enhanced images with the following scores: 1, definitely benign; 2, probably benign; 3, indeterminate; 4, probably malignant; and 5, definitely malignant.

The analysis of the grading was performed for both baseline B-mode and contrast-enhanced sonography. A subjective evaluation of the lesion was used for rating the lesions at baseline sonography.22 This evaluation included consideration of echogenicity, shape, and location of the lesions relative to neighboring vessels. Hyperechoic lesions next to veins and lesions suggestive of having a central star were suspected as benign. Lesions with a hypoechoic rim or with polygonal edges were suspected as malignant.

Assessment of the postcontrast imaging was performed according to the following parameters: (1) arrival time and arrival pattern of SonoVue in the early phase after intravenous injection (central starlike, peripheral globular-nodular followed by centripetal fill-in, flushlike, diffuse stippled, or no enhancement); and (2) contrast enhancement in the late phase after intravenous injection (60–180 seconds). The SonoVue arrival patterns are shown in Figure 1Go.



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  		Figure 1. Analysis of SonoVue arrival pattern in the early phase after SonoVue injection. The arrival pattern was analyzed according to the following classification, from left to right: no enhancement, peripheral globular-nodular followed by centripetal fill-in, diffuse stippled, central starlike, and flushlike.

 
On the basis of prior experience from studies using the high-MI technique with Levovist,6–11 lesions with homogeneous bright enhancement in the late phase were given benign ratings, whereas lesions without enhancement in the late phase were given higher ratings for malignancy. Lesions that could not be classified as benign or malignant were classified as score 3. Lesions with central starlike enhancement were classified as FNH; lesions with peripheral globular-nodular enhancement were classified as hemangioma; lesions with early flushlike enhancement were classified as unclear; and lesions with early diffuse enhancement were classified as suggestive of malignancy.

Statistical Analysis
A mean rating score was provided by the consensus of 2 independent readers. For the calculation of sensitivity and specificity, a score of 3 or higher was counted as a positive test result. Our rationale for treating a score of 3 (indeterminate) as malignant was to avoid missing any malignant lesions. Receiver operating characteristic (ROC) curves were obtained for baseline and contrast-enhanced sonography according to the 5-point system (1, definitely benign; 2, probably benign; 3, indeterminate; 4, probably malignant; and 5, definitely malignant) described above. Comparison of ROC curves was performed with LABMRMC software (University of Chicago, Chicago, IL).23,24 The laboratory–multiple readers–multiple treatments algorithm (LABMRMC) uses jackknifing and analysis of variance techniques to test the difference between baseline and contrast-enhanced sonography. The statistical significance between patients with certain diagnoses was calculated by the {chi}2 test. P < .05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The rating scores of the observers for the 64 malignant and 62 benign lesions are summarized in Table 2Go. Baseline B-mode sonography detected 14 (23%) of 62 benign lesions and 50 (78%) of 64 malignant lesions on the basis of a mean score of 3 or higher, with specificity of 23% and sensitivity of 78%. Contrast-enhanced sonography detected 64 (100%) of 64 malignant lesions on the basis of a mean score of 3 or higher, with specificity of 92% and sensitivity of 100%. Homogeneous contrast enhancement in the late phase was found in benign lesions (Figures 2Go and 3Go) but also in 1 patient with HCC. However, because of the early arterial contrast enhancement in the edge of this particular lesion, this lesion was classified as unclear. On baseline sonography, 22 patients were rated as indeterminate (score of 3) because classification as benign or malignant was not possible; in the early phase of contrast enhancement, 35 patients were rated as indeterminate; and in the late phase of contrast-enhanced imaging, only 2 patients were rated as indeterminate. Receiver operating characteristic curves are presented in Figure 4Go. The areas under the fitted curve for early contrast-enhanced sonography (Az, 0.932 ± 0.023 [SD]) and for the combination of early and late contrast-enhanced sonography (Az, 0.998 ± 0.003) were significantly higher than that for baseline sonography (Az, 0.510 ± 0.054; P < .001).


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  		Table 2. Rating of Focal Hepatic Lesions in 126 Lesions
 




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  		Figure 2. Focal nodular hyperplasia in a 42-year-old woman. A, Native B-mode sonogram shows a hypoechoic lesion in the left liver lobe (arrows). B, Contrast-enhanced early phase inversion sonogram shows central starlike enhancement 15 seconds after intravenous injection of 2.4 mL of SonoVue (arrows). C, Contrast-enhanced early phase inversion sonogram shows flushlike contrast enhancement 30 seconds after intravenous injection of 2.4 mL of SonoVue (arrows).

 



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  		Figure 3. Benign hepatocellular adenoma in a 55-year-old woman. A, Native B-mode sonogram shows a hyperechoic lesion in the right liver lobe, which is difficult to localize (arrow). B, Contrast-enhanced early phase inversion sonogram 10 seconds after intravenous injection of SonoVue. Short flushlike enhancement is detectable in the location of the adenoma (arrow).

 


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  		Figure 4. Receiver operating characteristic curve shows differentiation of malignant from benign lesions on contrast-enhanced sonography in the late phase of contrast enhancement. We set the cutoff value at 3. Note that the sensitivity and specificity of contrast-enhanced sonography for differentiation between benign and malignant lesions were significantly higher than those for B-mode sonography.

 
Analysis of the SonoVue Enhancement in Early and Late Phases After Injection
Table 3Go summarizes the 2 observers’ consensus classification of the enhancement patterns in the lesions in our study population. Ninety-eight percent of the patients with homogeneous enhancement within the hepatic lesion in the late phase had benign lesions (Figures 2Go and 3Go; P < .001). Among the lesions that clearly demarcated during the late phase of contrast-enhanced sonography, 93% were malignant (Figures 5Go and 6Go; P < .001).


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  		Table 3. Low-MI Pulse Inversion Sonography in Early and Late Phases of SonoVue Administration in 126 Lesions
 



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  		Figure 5. Hepatocellular carcinoma in a 51-year-old patient. A, Native B-mode sonogram shows inhomogeneous parenchyma in the right lobe of the liver in a patient with liver cirrhosis. B, SonoVue-enhanced late phase sonogram (120 seconds after injection) shows diffuse demarcation of carcinoma (arrows) surrounded by SonoVue-enhanced liver parenchyma (arrows).

 



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  		Figure 6. Metastasis in an 82-year-old patient. A, Native B-mode sonogram shows a hypoechoic lesion in the right liver lobe (arrow). B, SonoVue-enhanced late phase sonogram (120 seconds after injection) shows clear demarcation of the metastatic lesion surrounded by enhanced liver parenchyma (arrow).

 
Additional lesions that were not visible at baseline imaging were detected during the late phase of contrast-enhanced sonography in 9 patients with HCC and 6 patients with metastatic disease. No additional lesions were found during contrast-enhanced imaging of patients with benign disease. Thus, the finding of lesions on contrast-enhanced sonography that were occult on baseline imaging was 100% specific for malignancy (P < .001).

Malignant Lesions (n = 64)
Forty-seven percent of the 36 patients with HCC had diffuse contrast enhancement in the early arterial phase (<20 seconds), and 14% had flushlike enhancement. In contrast, 25% of the patients with HCC had early contrast enhancement comparable with that of the liver parenchyma, but 6% showed clear demarcation of the lesion even in the first 20 seconds after SonoVue injection. In 3% of the patients, the contrast enhancement was diffusely reduced compared with the surrounding liver parenchyma.

Ninety-seven percent of the patients with HCC showed clear demarcation of the lesion in the late phase (>60 seconds after injection; Figure 5Go). However, in the 1 patient with histologically proved HCC, early SonoVue enhancement was found in a small part of the edge of the lesion, accompanied by homogeneous enhancement in the late phase. Therefore, this particular lesion was classified as unclear.

Sixty-eight percent of the 25 patients with liver metastases showed no specific contrast enhancement. In contrast, 12% of the patients had diffuse contrast enhancement, and 4% had flushlike contrast enhancement in the early phase (<20 seconds). However, 16% of the patients had clear demarcation of the lesion even in the first 20 seconds after injection. All patients with liver metastases showed clear demarcation of the lesion in the late phase (Figure 6Go).

The patient with cholangiocellular carcinoma showed diffuse early arterial contrast enhancement followed by sharp demarcation of the lesion in the late phase. Neither of the 2 patients with lymphatic infiltration of the liver showed early contrast enhancement. In 1 patient, demarcation of the lymphatic infiltration started even in the first 20 seconds after injection. In the late phase, both patients had clear demarcation of the lesion.

Analysis of the early phase showed that the arrival pattern of diffuse arterial enhancement was the only pattern that was specific for malignant lesions. Early diffuse SonoVue arrival as a sign of malignant lesions had sensitivity of 33%, specificity of 98%, a positive predictive value of 95%, and a negative predictive value of 59% (P < .001).

Benign Lesions (n = 62)
Seventy-two percent of the 29 patients with hemangioma showed peripheral globular-nodular enhancement starting in the early phase, followed by centripetal fill-in of the lesion in 83% of these patients (Figure 7Go). Seventeen percent of the patients had no signs of specific SonoVue enhancement; 7% showed early demarcation of the lesion; and 1 patient showed early arterial flushlike enhancement followed by clear demarcation of the lesion in the late phase. In this patient, the diagnosis of hemangioma was confirmed by liver biopsy. In the late phase, 62% of the patients with hemangioma showed hyperechoic enhancement due to the centripetal fill-in of SonoVue; 21% of the patients had enhancement within the hepatic lesion comparable with that of the surrounding liver parenchyma; and 17% showed sharp demarcation of the lesion. Peripheral globular-nodular enhancement as a sign of hemangioma had sensitivity of 72%, specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 92% (P < .001).






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  		Figure 7. Hemangioma of the liver in a 44-year-old woman. A, Native B-mode sonogram showing a hyperechoic lesion in the right liver lobe (arrow). B, SonoVue-enhanced early phase sonogram (30 seconds after injection) showing peripheral globular-nodular enhancement in the hemangioma (arrow). C, SonoVue-enhanced early phase sonogram (60 seconds after injection) showing peripheral globular-nodular enhancement in the hemangioma with progress of centripetal fill-in (arrow). D, SonoVue-enhanced late phase sonogram (180 seconds after injection) showing contrast enhancement in the total lesion (arrow).

 
Eighty-nine percent of the FNH lesions showed central starlike arterial SonoVue enhancement in the early phase (<20 seconds after injection; Figure 2Go). In the remaining 11% of the patients, early flushlike enhancement was found. Early central starlike enhancement as a sign of FNH had sensitivity of 89%, specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 99% (P < .001).

Seventy-five percent of the patients with histologically proved benign adenoma had early flushlike SonoVue enhancement (<20 seconds after injection), which appeared for less than 20 seconds, followed by contrast enhancement comparable with that of the surrounding liver parenchyma in the late phase (Figure 3Go). Early flushlike enhancement in the early phase was not specific for adenoma and also occurred in patients with other benign lesions, such as FNH and hemangioma, and in malignant lesions, such as HCC and metastasis. However, flushlike enhancement followed by homogenous enhancement in the late phase was specific for benign lesions (P < .001).

Eighty-five percent of the 11 patients with regenerative cirrhotic nodules had no specific SonoVue enhancement in the early phase. One patient showed demarcation of the lesion starting 20 seconds after injection, which disappeared 20 seconds later, followed by homogeneous SonoVue enhancement. One patient with a histologically proved dysplastic cirrhotic nodule showed early demarcation followed by homogenous enhancement in the late phase. All patients with regenerative cirrhotic nodules had homogeneous contrast enhancement in the late phase after SonoVue injection. All 7 patients with focal hyposteatosis showed SonoVue enhancement comparable with that of the surrounding liver parenchyma.

Analysis of the late phase showed that homogeneous enhancement in the late phase was found only in benign lesions (P < .001), despite 1 patient with HCC, in whom homogeneous enhancement was also found in the late phase. However, according to the combined analysis of early and late phases, the lesion in this particular patient was classified as malignant because of the early arterial diffuse enhancement.

Demarcation of the lesion in the late phase as a sign of malignant lesions had sensitivity of 98%, specificity of 92%, a positive predictive value of 93%, and a negative predictive value of 98% (P < .001).

Contrast enhancement in the early phase comparable with that of the surrounding liver was found in both benign and malignant lesions, without significant differences between both groups. In contrast, homogeneous or hyperechoic enhancement in the late phase as a sign of benign lesions had sensitivity of 92%, specificity of 98%, a positive predictive value of 98%, and a negative predictive value of 93% (P < .001).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of this study show that SonoVue improves sensitivity and specificity in discrimination between benign and malignant focal liver lesions when compared with baseline B-mode sonography. The late phase of SonoVue enhancement is superior to the early phase of enhancement in discrimination between benign and malignant focal liver lesions.

Demarcation of the lesion in the late phase is a parameter for malignant lesions, whereas homogeneous SonoVue enhancement in the late phase is a parameter for benign lesions. Homogeneous enhancement of the lesion in the late phase was found in benign cirrhotic nodules, focal hyposteatosis, FNH, and benign adenoma.

The results in the late phase of SonoVue enhancement found in this study are comparable with findings reported in studies with other contrast agents, such as Levovist.6,14,15 However, the analysis of the late phase enhancement alone allows no characterization of the final diagnosis, despite patients with hemangioma having centripetal fill-in of the contrast agent.

Therefore, the analysis of the early phase enhancement is important for characterization of the final diagnosis. Because of the real-time examination with SonoVue, the analysis of arrival patterns in the early phase is improved in comparison with that for the interval delay imaging performed with Levovist.15

Central starlike enhancement is predictive for FNH, which was found in 89% of the FNH lesions in the present study. These results are comparable with results from studies performed with SonoVue low-MI imaging by other groups, which found central starlike enhancement in 96% of patients,25 and with findings for high-MI imaging using the contrast agent Levovist, which showed central starlike enhancement in 67% of patients with FNH.15 In comparison with Levovist, SonoVue has the advantage that its microbubbles are stable against the ultrasound beam, which allows analysis of the contrast enhancement under real-time conditions. In contrast, analysis of Levovist enhancement has to be performed with the interval delay technique because the rupture of Levovist microbubbles does not allow real-time scanning. In this study, we found central starlike enhancement in 89% of the FNH lesions, which is a higher percentage than that found by Hohmann et al,21 who reported central starlike enhancement in 45% of patients with FNH examined with SonoVue and an early arterial flush in an additional 36% of patients. The lower percentage of patients with central starlike enhancement could be due to the fact that this finding is detectable for only a few seconds, followed by flushlike enhancement in the total lesion.

Peripheral globular-nodular enhancement is predictive for hemangioma and was found in 72% of hemangioma cases in this study. This parameter is comparable with the peripheral globular-nodular enhancement found on CT.1 The finding of peripheral globular-nodular enhancement in hemangioma in this study is comparable with findings reported by other groups, which found this specific type of SonoVue enhancement in 88%,25 91%,21 and 100% (only 6 patients) of patients with hemangioma.26 However, the results observed with real-time examination of SonoVue are better than findings reported with Levovist, which showed peripheral globular-nodular enhancement in only 18%,17 44%,4 and 60%,27 of patients with hemangioma. The higher sensitivity of SonoVue is due to the advantages of the low-MI real-time examination with a second-generation contrast agent.

Seventy-five percent of the patients with hepatocellular adenoma examined in this study showed short early arterial flushlike enhancement for less than 20 seconds, followed by homogeneous SonoVue enhancement of the lesion in the late phase. In contrast, the enhancement in the late phase of Levovist is variable putatively because of variable reticuloendothelial system content in different hepatocellular adenomas.6,28

Regenerative cirrhotic nodules and focal hyposteatosis show the same enhancement as the surrounding liver parenchyma, comparable with the results found with Levovist.15,27 In 1 patient with a cirrhotic nodule, we found early demarcation of the lesion in the arterial phase, followed by homogeneous enhancement starting in the portal-venous phase lasting until the end of the late phase, indicating a local change of microvasculature.

Early diffuse arterial enhancement is predictive for malignant lesions and may occur not only in HCC but also in metastases or cholangiocellular carcinoma. Sixty-one percent of patients with HCC had early arterial enhancement in this study. Diffuse early enhancement in HCC in more than 90% of patients has been reported by other groups.21,27,29,30 However, early flushlike enhancement can also occur in benign lesions, such as FNH, adenoma, and hemangioma.21,25,31 The demarcation of HCC lesions in the late phase of SonoVue is comparable with the findings reported with Levovist.4,6,7,32 Hohmann et al21 reported 1 patient with HCC who had homogeneous SonoVue enhancement in the late phase comparable with that of the surrounding liver tissue. In this particular patient, the diagnosis of HCC was made on the basis of the early arterial enhancement of the lesion. These findings are comparable with our findings in 1 patient with HCC and early diffuse contrast enhancement followed by homogeneous contrast enhancement in the late phase.

Eighty-four percent of the metastases examined in this study had no signs of hypervascular enhancement in the early phase. In the late phase, all metastases showed sharp demarcation of the lesions. Demarcation of metastases in the late phase of SonoVue was comparable with the findings of Hohmann et al,21 who reported clear demarcation of lymphoma, metastases, and cholangiocellular carcinoma in all cases. In our study, metastases, cholangiocellular carcinoma, and lymphoma showed the same demarcation in the late phase of SonoVue enhancement as has been reported in studies performed with Levovist.4,6,14,26,27,33,34

Additional demarcation of malignant lesions, which had not been diagnosed during B-mode sonography, was found in 23% of the patients with malignant lesions but in none of the patients with benign lesions. This percentage was lower than in studies performed with Levovist, in which additional malignant lesions were found in 30% to 60% of the patients with malignant lesions.6,14,33,35 However, comparison of both methods in the same patient population will be necessary in the future to clarify whether both contrast agents are equivalent in the detection of occult malignant liver lesions in late phase imaging.

The data from this study show that analysis of SonoVue enhancement using low-MI imaging in real-time sonography allows the correct sonographic differentiation between benign and malignant liver lesions in 95% of patients. Furthermore, the analysis of the arrival pattern in the early phase allows the correct diagnosis in 89% of patients with FNH and in 72% of patients with hemangioma. Whereas late phase imaging is important for differentiation between benign and malignant lesions, early phase imaging is important for characterizing certain diagnoses of the lesions.


   Footnotes
 
Received April 23, 2004, from the Department of Medicine, University of Tübingen, Tübingen, Germany (A.v.H.); and Department of Medicine (A.v.H., C.V., D.H.) and Computer Center (R.W.), University of Düsseldorf, Düsseldorf, Germany. Revision requested May 14, 2004. Revised manuscript accepted for publication August 17, 2004.

This study was supported by the Freunde und Förderer der Heinrich-Heine-Universität Düsseldorf and by the Deutsche Krebshilfe.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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