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1 Hepatobiliary Imaging Ricci et al. Sonography of Benign Liver Lesions Paolo Ricci 1 Andrea Laghi Vito Cantisani Pasquale Paolantonio Sara Pacella Elisa Pagliara Federico Arduini Valerio Pasqualini Francesca Trippa Marzia Filpo Roberto Passariello Ricci P, Laghi A, Cantisani V, et al. Received April 19, 2004; accepted after revision July 1, All authors: Dipartimento di Scienze Radiologiche, Policlinico Umberto I Università La Sapienza, V. le Regina Elena, Rome , Italy. Address correspondence to P. Ricci (paolo.ricci@uniroma1.it). AJR 2005;184: X/05/ American Roentgen Ray Society Original Report Contrast-Enhanced Sonography with SonoVue: Enhancement Patterns of Benign Focal Liver Lesions and Correlation with Dynamic Gadobenate Dimeglumine Enhanced MRI OBJECTIVE. Contrast-enhanced real-time low-mechanical-index sonography is a new diagnostic technique for the assessment of macro- and microcirculation. The purpose of our article is to describe contrast-enhancement patterns of different benign focal liver lesions using the second-generation contrast agent SonoVue and to compare these findings with those of gadobenate dimeglumine enhanced MRI. CONCLUSION. SonoVue-enhanced real-time low-mechanical-index sonography provides specific contrast-enhancement patterns of different benign focal liver lesions, allowing accurate characterization. Findings on SonoVue-enhanced sonography correlate well with those obtained on gadobenate dimeglumine enhanced MRI. haracterization of focal liver lesions still remains a challenge for C diagnostic radiology, the aim of which is to avoid invasive procedures (i.e., liver biopsy), especially for the diagnosis of benign lesions. Sonography, because it is safe, inexpensive, quick, and easily accessible, is the first-line imaging technique for liver evaluation. However, baseline sonographic examination has several limitations in lesion characterization, requiring the need for second-level diagnostic studies (helical CT, MRI) [1, 2]. Color Doppler sonography shows promises of better diagnostic performance with the analysis of Doppler sonography spectra in or around tumors, although artifacts represented by respiratory or cardiac activity limit the diagnostic accuracy [1, 3]. IV sonographic contrast agents, consisting of tiny microbubbles confined to intravascular spaces and not leaking through the vessel wall, can enhance Doppler sonography signals and overcome these limitations [4]. Although these contrast agents increase the reflectivity of blood and enhance spectral and color Doppler signals, even contrast-enhanced color Doppler sonography is associated with artifacts such as color blooming and oversaturation. Moreover, overlapping between color Doppler patterns of benign and malignant lesions has been shown [5]. Harmonic sonography is a new technique that uses microbubble contrast agents and produces fewer artifacts. Tanaka et al. [6] reported that the combination of Levovist (SH U 508A, Schering) and second harmonic imaging software (the so-called intermittent imaging) allows a dynamic sonography protocol with which the contrast-enhancement patterns of different liver lesions can be assessed. Recently, the development of second-generation contrast agents and dedicated software AJR:184, March

Ricci et al. allows real-time examination and easier definition of enhancement patterns [7 9].

Microbubbles can survive multiple capillary passages after IV injection, giving significant contrast enhancement in the left heart and the arterial system and in the venous system after the second

The aim of our study was to evaluate the dynamic pattern of enhancement of real-time sonography using a second-generation contrast agent (SonoVue, Bracco) in a population of patients with focal liver

Sonographic findings of enhancing patterns were compared with findings of dynamic contrast-enhanced MRI performed after the IV injection of gadobenate dimeglumine.

2 Ricci et al. allows real-time examination and easier definition of enhancement patterns [7 9]. These microbubble agents use insoluble gases such as sulfur hexafluoride or perfluoropropane to achieve better stabilization of microbubbles in vivo. Microbubbles can survive multiple capillary passages after IV injection, giving significant contrast enhancement in the left heart and the arterial system and in the venous system after the second capillary passage. The aim of our study was to evaluate the dynamic pattern of enhancement of real-time sonography using a second-generation contrast agent (SonoVue, Bracco) in a population of patients with focal liver lesions characterized as benign on gadobenate dimeglumine enhanced MRI. Sonographic findings of enhancing patterns were compared with findings of dynamic contrast-enhanced MRI performed after the IV injection of gadobenate dimeglumine. A Subjects and Methods Patient Population Between January and September 2003, we examined 43 patients (21 men, 22 women; median age, 55 years, range, years) who had focal liver lesions detected as benign on contrast-enhanced dynamic MRI, who could actively cooperate, and who required no sedation. Forty-eight lesions were detected: 27 hemangiomas (measuring cm in maximum diameter), 17 focal nodular hyperplasias (measuring cm in diameter), and four adenomas (measuring 2 5 cm in diameter). MRI was considered the gold standard for the diagnosis of hemangioma and focal nodular hyperplasia. Diagnostic criteria for hemangiomas were the combination of a markedly hyperintense signal on T2-weighted images; a specific contrast-enhancement pattern on dynamic studies, represented by globular enhancement during the arterial phase and progressive fill-in during B C D Fig year-old man with hepatic hemangioma. A and B, Contrast-enhanced sonograms show globular peripheral enhancement of lesion during arterial phase (A) and incomplete filling-in during portal and late phases (B). C and D, Gadobenate dimeglumine enhanced MR images show lesion presenting same contrast behavior. 822 AJR:184, March 2005

3 Sonography of Benign Liver Lesions the portal venous phase; and a hypointense signal on the hepatobiliary phase images. Diagnostic criteria for focal nodular hyperplasia were, first, an iso- or slightly hypointense signal on T1-weighted images and an iso- or slightly hyperintense signal on T2-weighted images and second, a dynamic contrast-enhancement pattern showing marked hypervascularity on the arterial phase with rapid washout and isointensity on portal venous and delayed phase images. In addition, hyperintensity compared with surrounding liver parenchyma on the hepatobiliary phase images was considered pathognomonic. In all four liver adenomas, sonographically guided biopsy was obtained for diagnostic confirmation. After the study was approved by the institutional review board, we obtained written consent from Fig year-old woman with focal nodular hyperplasia. A, Contrast-enhanced sonogram shows early homogeneous enhancement during arterial phase. B and C, Contrast-enhanced sonograms show lesion appears slightly hyperechoic and hysoechoic (having same enhancement as surrounding liver parenchyma in portal and late phases) during portal (B) and late (C) phases. (Fig. 2 continues on next page) each patient before contrast-enhanced sonography was performed. Sonography Protocol Patients were examined using an Esatune scanner (Esaote) equipped with dedicated software (CnTI Contrast Tuned Imaging, Esaote) and C530 convex or PA420 phased-array probes (Esaote). The sonographic examinations included conventional gray-scale imaging to identify anatomic landmarks and real-time low-mechanicalindex ( ) continuous scanning after the administration of a bolus of SonoVue. Contrastenhancement patterns were assessed twice during a 30-min interval. SonoVue was administered as an IV fast bolus of 2.4 ml, followed by 3 ml of saline flush. A single marker lesion was identified, measured, and evaluated. When more lesions were identified on conventional sonography, a single marker lesion, the larger and more conspicuous one, was considered for characterization. When different lesions revealed similar dimensions and conspicuity, the more superficial was selected. Patients with more lesions were evaluated on a lesion-by-lesion basis. During contrast-enhanced evaluations, the entire vascular phase was continuously studied, consisting of an arterial phase (15 45 sec after the injection), a portal venous phase (50 90 sec), and a late phase (90 sec to 4 5 min). Our scanning technique was stationary in the region of the lesion, allowing the visualization of macro- and microcirculation of the lesion, as a result of the blood pool characteristics of SonoVue. In some cases, we performed flash A B C AJR:184, March

, high-mechanical-index fast scanning), which allows microbubble destruction, to evaluate reperfusion during the arterial phase in lesions showing strong enhancement and during the portal phase only

All examinations were digitally recorded and subsequently analyzed off-line. MRI Protocol MRI was performed in all patients within 7 days before contrast-enhanced sonography with a 1.

4 Ricci et al. scanning (i.e., high-mechanical-index fast scanning), which allows microbubble destruction, to evaluate reperfusion during the arterial phase in lesions showing strong enhancement and during the portal phase only in lesions showing contrast enhancement during this phase. Reperfusion after flash scanning during the portal phase must be considered pathognomonic for focal nodular hyperplasia. All examinations were digitally recorded and subsequently analyzed off-line. MRI Protocol MRI was performed in all patients within 7 days before contrast-enhanced sonography with a 1.5-T MR unit (Magnetom Vision Plus; Siemens Medical D F Solutions) using a phased-array multicoil as a receiver coil. The MRI protocol included axial breath-hold T2-weighted (TR/TE, infinite/90; flip angle, 150 ; acquisiton time, 25 sec; slice thickness, 6 mm; interslice gap, 0.25%; matrix, ; field of view, 350 mm), half-fourier singleshot turbo spin-echo (HASTE), and unenhanced and gadobenate dimeglumine enhanced spoiled T1-weighted (TR/TE, 170/4.6; flip angle, 80 ; number of excitations, 1; acquisition time, 20 sec; slice thickness, 6 mm; interslice gap, 0.25%; matrix, ; field of view, 350 mm) fast low-angle shot (FLASH) sequences. A triphasic dynamic contrast-enhanced study was obtained after the administration of an IV bolus of 0.1 mmol/kg of gadobenate dimeglumine (MultiHance, Bracco) Fig. 2. (continued) 28-year-old woman with focal nodular hyperplasia. D and E, Gadobenate dimeglumine enhanced MR images reveal that lesion appears markedly hyperintense during arterial phase (D) and hysointense during portal (E) and late phases. F, Gadobenate dimeglumine enhanced MR image after 1 hr (hepatobiliary phase) shows that lesions remain isointense compared with liver parenchyma. flushed by 20 ml of sterile saline solution using an automatic MR-compatible injector. The scanning delay for triphasic dynamic gradient-recalled echo imaging was 14 sec, 50 sec, and 3 min after initiating contrast injection, representing the hepatic arterial, portal venous, and equilibrium phases, respectively. The dynamic study was followed by a delayed, hepatospecific phase obtained 1 hr after the injection of contrast material, as recommended by the manufacturer. Previous studies have shown that liver enhancement with gadobenate dimeglumine is relatively stable during this period [10]. Image Analysis Sonographic digital records were analyzed offline, in consensus, by two radiologists who were E 824 AJR:184, March 2005

Sonography of Benign Liver Lesions both experienced in contrast sonography of the liver and who were blinded to clinical and other imaging data.

5 Sonography of Benign Liver Lesions both experienced in contrast sonography of the liver and who were blinded to clinical and other imaging data. MR images were reviewed by two gastrointestinal radiologists experienced in both liver sonography and MRI. Images were analyzed at different consensus conferences to describe size, baseline appearance, and dynamic contrast-enhancement behavior of the different lesions. Sonographic findings were eventually compared with MRI findings Results All lesions were successfully studied during the arterial, portal, and late phases on both sonography and MRI. No clinically significant side effects related to the sonographic contrast agent were experienced by patients. No patients were excluded from the study because of the inability to cooperate, and the studies were considered to be of sufficient diagnostic quality in all cases. Hemangioma Twenty-seven hemangiomas were detected in 24 patients. On baseline sonography, all the hemangiomas were inhomogeneous with posterior acoustic enhancement: Fifteen were hyperechoic, three hyper- and isoechoic, and nine hypoechoic. The contrast-enhancement patterns were as follows: specific globular enhancement (Fig. 1A) with progressive complete (n = 12) and incomplete (n = 13) (Fig. 1B) wash-in in 25 lesions. In the remaining two lesions, a rapid wash-in, with late washout, characteristic of a capillary hemangioma, was observed. On unenhanced MRI, all the lesions were hypointense on T1-weighted and markedly hyperintense on T2-weighted images. On contrast-enhanced studies, 25 lesions showed a globular enhancement pattern during the arterial phase (Fig. 1C) with progressive centripetal filling (complete in 12 lesions and incomplete in 13 [Fig. 1D]) during the portal venous and equilibrium phases. During the 1-hr hepatobiliary phase, all lesions showed a hypointense signal compared with liver parenchyma. In the remaining two lesions, characterized as capillary hemangiomas, the contrast-enhancement pattern presented rapid wash-in during the arterial phase, with persistent enhancement during the portal venous and equilibrium phases. Hypointense signal compared with surrounding liver parenchyma was observed during the hepatobiliary phase. Dynamic enhancement patterns on MRI completely correlated with those on contrast-enhanced sonography. Focal Nodular Hyperplasia Seventeen focal nodular hyperplasias were detected in 15 asymptomatic women with no history of chronic hepatic disease. On baseline sonography, the lesions appeared slightly hyperechoic, with evidence of a central hypoechoic area in seven cases. During the contrast-enhanced study, the lesions showed an extremely rapid homogeneous contrast uptake during the arterial phase (Fig. 2A), with mild hyperechogenicity or isoechogenicity relative to surrounding enhanced liver parenchyma during the portal and late phases (Figs. 2B and 2C). A central scar was evident on the portal and late phases in seven cases. A specific diagnostic clue in the characterization of focal nodular hyperplasia was the evidence of revascularization during the portal and late phases after microbubble disruption as a result of the flash scanning application. On unenhanced MRI, all the lesions were isointense on T1-weighted images and iso- to slightly hyperintense on T2-weighted images. MR images showed homogeneous contrast enhancement during the arterial phase (Fig. 2D), with isointensity during the portal (Fig. 2E) and equilibrium phases. During the 1-hr hepatobiliary phase, all lesions showed isointense to slightly hyperintense signal compared with liver parenchyma (Fig. 2F). A central scar (hyperintense on both the T2- weighted images and on the portal and late phases of contrast-enhanced T1-weighted images) was observed in five cases. A B Fig year-old woman with hepatocellular adenoma. A and B, Contrast-enhanced sonograms show early, intense, and homogeneous wash-in during arterial phase (A) followed by fast washout during portal phase (B). (Fig. 3 continues on next page) AJR:184, March

Ricci et al. Fig. 3. (continued) 40-year-old woman with hepatocellular adenoma.

E, Gadobenate dimeglumine enhanced MR image after 1 hr (hepatobiliary phase) shows lesions (arrow) appear hypointense compared with liver parenchyma.

All lesions were characterized by early homogeneous contrast enhancement during the arterial phase (Fig. 3A), with subsequent rapid washout during the portal phase (Fig. 3B).

6 Ricci et al. Fig. 3. (continued) 40-year-old woman with hepatocellular adenoma. C and D, Gadobenate dimeglumine enhanced MR images show same contrast behavior during arterial (C) and portal (D) phases. Arrow indicates lesion. E, Gadobenate dimeglumine enhanced MR image after 1 hr (hepatobiliary phase) shows lesions (arrow) appear hypointense compared with liver parenchyma. Adenoma Four adenomas were evaluated in four women with histories of chronic use of oral contraceptives. All four lesions appeared as rounded, iso- to hyperechoic lesions. All lesions were characterized by early homogeneous contrast enhancement during the arterial phase (Fig. 3A), with subsequent rapid washout during the portal phase (Fig. 3B). On unenhanced examination, the lesions were hypointense on T1-weighted images and slightly hyperintense on T2-weighted images. MR images showed homogeneous and intense contrast enhancement during the arterial phase (Fig. 3C), with rapid washout during the portal venous and equilibrium phases C D (Fig. 3D) and no evidence of either a central scar or a pseudocapsule. During the 1-hr hepatobiliary phase, all lesions showed a hypointense signal compared with liver parenchyma. Dynamic MRI findings correlated well with contrast-enhanced sonographic features in all patients (Fig. 3E). Discussion SonoVue is a new blood pool sonographic contrast agent that consists of a stabilized aqueous suspension of sulfur hexafluoride microbubbles with a phospholipidic shell. The mean diameter of SonoVue bubbles is 2.5 mm, which allows both transpulmonary and transinusoidal passage. These bubbles have a strong wideband harmonic response at low mechanical index, which is ideal for vascular phase imaging, allowing clear depiction of the arterial, portal, and late phases and visualization of both macro- and microvasculature of hepatic lesions. Unlike CT or MRI contrast agents, which diffuse into the extravascular space to enter the equilibrium phase, Sono- Vue is a blood pool agent and therefore does not have a true equilibrium phase. Scans are obtained by either moving the transducer over the entire liver to visualize the vascular phases in real-time or remaining in the region of interest to study the changes of enhancement over time in that area. To date only few reports have been published on the clinical E 826 AJR:184, March 2005

7 Sonography of Benign Liver Lesions use of contrast-enhanced sonography with SonoVue in characterization of focal liver lesions [7 9]. Leen et al. [7] showed that the administration of SonoVue improves the Doppler display of tumoral vascularization with reduced interobserver variability and is a useful tool in characterization of focal liver lesions. Quaia et al. [8, 11] and Hohmann et al. [9] reported that low-mechanical-index real-time sonography with SonoVue markedly improves the characterization of focal hepatic lesions in comparison with unenhanced sonography. As shown in our study, contrast-enhanced sonography is useful in providing specific contrast-enhancement patterns during realtime evaluation of liver lesions, without any risk of missing the optimal phase of observation. This is equivalent to MRI, but at a lower cost and with better patient compliance. Regarding hemangiomas, a typical feature is evidence of globular enhancement, with progressive in-filling, which was observed in 25 of our patients. This is particularly useful in the presence of atypical hemangiomas, which appear on baseline examinations as hypo- or hysoechoic (having the same echogenicity as the surrounding liver parenchyma, commonly with a thin hypoechoic peripheral rim) lesions, as seen in our study in nine patients. However, when a different contrast behavior during the arterial phase was observed, the detection of late washout led to the diagnosis of capillary hemangioma [12]. Focal nodular hyperplasias showed an early strong and homogeneous enhancement during the arterial phase. During the portal phase, the lesions appeared mildly hyperechoic over the normal parenchyma because of their portal supply, whereas the lesions appeared hysoechoic (having the same enhancement as the surrounding enhanced liver parenchyma in the late phase) during the late phase. Key points in the characterization of focal nodular hyperplasias are early and homogeneous enhancement during the arterial phase, presence of portal supply, evidence of a hypoechoic scar, and lack of a pseudocapsule. These features are helpful in differentiating focal nodular hyperplasia from hepatocellular carcinoma and adenoma. The association of a history of chronic use of oral contraceptives with the presence of a rounded and well-marginated lesion showing early homogeneous enhancement during the arterial phase and rapid washout during the portal phase may lead to the diagnosis of adenoma. An important point in differentiating adenoma from focal nodular hyperplasia is the absence of portal supply. A clue to discriminate hepatocellular carcinoma from adenoma is the slow and more heterogeneous arterial enhancement and the frequent presence of a pseudocapsule. All contrast-enhanced sonographic findings correlated well with those of MRI. As shown in our study, contrast-enhanced sonography with SonoVue is a useful tool in the characterization of focal liver lesions. This technique is characterized by high cost-effectiveness, high patient compliance, and high accuracy in providing specific contrast-enhancement patterns that are roughly comparable to those obtained on MRI. Although our study population was limited, especially regarding the few cases of adenomas and the absence of regenerative nodules, our results show that in the workup (follow-up and diagnosis) of patients with benign focal liver lesions, sonography should be performed with second-generation contrast agents and new technologies such as Contrast Tuned Imaging. References 1. Wilson SR, Burns PN, Muradali DM, Wilson JA, Lai X. Harmonic hepatic US with microbubble contrast agent: initial experience showing improved characterization of hemangioma, hepatocellular carcinoma, and metastasis. Radiology 2000;215: Ros PR, Mortele KJ. Hepatic imaging: an overview. Clin Liver Dis 2002;6: Leen E. The role of contrast-enhanced ultrasound in the characterization of focal liver lesions. Eur Radiol 2001;11 [suppl 3]:E27 E34 4. Tanaka S, Kitamra T, Yoshioka F, et al. Color Doppler sonography of hepatic tumors with a galactose-based contrast agent: correlation with angiographic findings. Ultrasound Med Biol 1995;21: Hosten N, Puls R, Bechstein WO, Felix R. Focal liver lesions: Doppler ultrasound. Eur Radiol 1999;9: Tanaka S, Ioka T, Oshikawa O, Hamada Y, Yoshioka F. Dynamic sonography of hepatic tumors. AJR 2001;177: Leen E, Angerson WJ, Yarmenitis S, et al. Multicentre clinical study evaluating the efficacy of SonoVue (BR1), a new ultrasound contrast agent in Doppler investigation of focal hepatic lesions. Eur J Radiol 2002;41: Quaia E, Bertolotto M, Calderanl L, Mosconi E, Mucelli RP. US characterization of focal hepatic lesions with intermittent high-acoustic-power mode and contrast material. Acad Radiol 2003;10: Hohmann J, Skrok J, Puls R, Albrecht T. Characterization of focal liver lesions with contrast-enhanced low MI real time ultrasound and SonoVue [in German]. Rofo 2003;175: Petersein J, Spinazzi A, Giovagnoni A. Focal liver lesions: evaluation of the efficacy of gadobenate dimeglumine in MR imaging a multicenter phase III clinical study. Radiology 2000;215: Quaia E, Degobbis F, Tona G, Mosconi E, Bertolotto M, Pozzi Mucelli R. Differential patterns of contrast enhancement in different focal liver lesions after injection of the microbubble US contrast agent SonoVue. Radiol Med (Torino) 2004;107: Vilgrain V, Boulos L, Vuillerme M-P, et al. Imaging of atypical hemangiomas of the liver with pathologic correlation. RadioGraphics 2000;20: AJR:184, March

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