Ultrasound contrast agents for hepatic imaging with nonlinear modes

Ultrasound Contrast Agents for Hepatic Imaging with Nonlinear Modes Edward Leen, MD, FRCR and Paul Horgan, PhD, FRCS

Conventional unenhanced ultrasonography is well recognized to be limited in the detection and characterization of focal liver lesions compared with contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI). However, the true value of ultrasound scanning is underestimated because previous comparative studies had been made against contrast-enhanced as opposed to -unenhanced CT/MRI scans. The fact is that the sensitivity of unenhanced CT is similar or even worse than that of unenhanced ultrasound scanning. The need for contrast agents is clear. The diagnostic capabilities of any modality are improved, because it is the differential distribution of the contrast agent between the normal tissue and a lesion that makes the abnormality more visible and easier to characterize. Recent advances in nonlinear imaging modes and development of new generation of ultrasound contrast agents have led to increasing interest in their clinical application; however, there is some uncertainty with regard to within which clinical settings they should be used and more importantly how to optimally use them given there are different classes of agents and that the improvements in imaging have been so rapid. In this article the different generations of contrast agents, their behavior and optimal ultrasound equipment settings, as well as their application in specific clinical settings are reviewed.

Classes of Ultrasound Contrast Agents The ideal ultrasound contrast agent for hepatic imaging should be safe, stable in the vascular From the Departments of Radiology and Surgery, Royal Infirmary, Alexandra Parade, Glasgow, United Kingdom Reprint requests: Edward Leen, MD, FRCR, Radiology Department, Alexandra Parade, Glasgow, G31 2ER, United Kingdom. E-mail: [email protected]. Curr Probl Diagn Radiol 2003;32:66. © 2003 Mosby, Inc. All rights reserved. 0363-0188/2003/$35.00 ⫹ 0 55/1/120001 doi:10.1067/mdr.2003.120001

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system to survive pulmonary capillary circulation, and be capable of modifying the acoustic properties of the regions of interest within the liver. Most of the current contrast agents satisfy these criteria to some degree. They consist of microbubbles that measure between 2 to 8 ␮m in diameter and are well recognized to be the most effective backscatterers. Ultrasound contrast agents are sometimes labeled as first, second, or third generations; first-generation agents consist of those that trap air and have short persistence time whereas second-generation agents contain insoluble gases such as perfluorocarbons with prolonged longevity. Stability of these microbubbles is provided in the form of a shell, made of denatured albumin, lipid or surfactant layers. In contrast third-generation agents use polymer shells and contain either air or perfluorocarbons with much longer persistence time. However, from the point of view of liver imaging, classification according to whether the agents have added sinusoidal or late phase liver uptake or not may be more appropriate (Tables 1 and 2). Earlier agents were primarily designed to be blood pool agents and have been shown to be highly effective in enhancing spectral/color/power Doppler signals within the macro vasculature on fundamental modes, lasting up to 7 minutes after an intravenous bolus administration and approximately up to 15 to 20 minutes after an infusion. Newer agents such as NC100100 (Nycomed Amersham, Oslo) and SHU 563A (Schering AG, Berlin) have additional tissue specific properties. They are selectively taken up by the Kupffer cells of the reticuloendothelial system after the vascular phase and may enhance the normal hepatic parenchyma for up to an hour on either fundamental or harmonic, gray-scale or Doppler modes depending on the dosage used. The advantage of such type of contrast is that lesions, which are deficient of Kupffer cells or associated with Kupffer

Curr Probl Diagn Radiol, March/April 2003

TABLE 1. Ultrasond contrast agents: no sinusoidal or latephase liver uptake confirmed as yet Trade Code Licensee Composition Name Name Acusphere

A1700

Point Biomedical

BiSphere

PB127

Amersham Health

Optison

FS069

Schering AG

Imavist

AFO-150

Polylactic-co-glycolic, polycaprolactone, co- polymers; perfluorocarbon gas Double-walled gelatin/polymer spheres filled with air Perfluoropropane filled Albumin microspheres Surfactant shell containing perfluorohexane vapor in nitrogen gas

Application/Status Myocardial Perfusion Phase II/III

Myocardial Perfusion Phase II/III Left ventricular opacification/ endocardial border delineation. Marketed in Europe and USA Left ventricular opacification/ endocardial border delineation. (NDA filed USA) Myocardial perfusion: Phase II Non-cardiac: Phase II

TABLE 2. Ultrasound contrast: sinusoidal or latephase liver uptake confirmed Trade Licensee Code Name Composition Name Schering AG

Levovist*

SHU 508A

Schering AG

Sonavist

SHU 563A

Bracco Spa

BR14

Bracco Spa

SonoVue

BR1

Bristol Myers Squibb Medical Imaging Inc

Definity

MRX-115

Amersham Health

Sonazoid

NC 100100

Suspension of galactose microparticles and Palmitic acid in water PolyButylCyanoAcrylate microspheres containing air Phospholipid shell containing Perfluorobutane Phospholipid stabilized SF6 gas

Phospholipid coated microbubbles of Perfluoropropane/air with gas filled lipid bi-layers Perfluorobutane gas encapsulated in lipid shell

cells dysfunction, do not retain the contrast agent thereby improving the lesion-to-tissue contrast ratio (Figs 1 and 2). Levovist (Schering AG, Berlin), which was primarily designed as a blood pool agent, has also been shown to have a delayed liver-specific phase (5 minutes after bolus intravenous injection) with enhancement of normal liver parenchyma in gray scale on pulse inversion or wideband harmonic modes or in mosaic colors through stimulated acoustic emission on fundamental color/power Doppler modes. Other agents such as SonoVue or Imavist, although primarily designed to be blood pool agents, were also subsequently found by chance to have the so-called “sinusoidal phase” because the agents are believed to be trapped or slowed in the hepatic sinusoids.1 This specific phase may last up to 6 minutes. This characteristic is useful for both detection and characterization

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Applications/Status LVO/EBD & Non cardiac Marketed in Europe Non-cardiac Phase II Europe Liver: Phase I, II Europe Non-cardiac; marketed in Europe, Phase II/III in USA LVO/EBD NDA filed USA and Europe. Myocardial perfusion: Phase II LVO/EBD: marketed in USA Noncardiac: Phase II/III in USA

LVO/EBD, NDA submitted in USA, Non-Cardiac: Phase II/III

because malignant tumors are deficient of sinusoids, and they therefore appear as filling defect surrounded by the enhanced normal liver parenchyma.

Microbubble Behavior and Imaging Modes The interaction between the insonating ultrasound beam and the microbubbles is very complex; basic understanding of their behavior under various sound fields has been fundamental to the development of improved methods of visualizing and displaying the contrast agents. On insonation at low amplitude (0 to 100 kPa), microbubbles behave as linear backscatterers, alternatively contracting and expanding according to the positive and negative pressures of the sinusoidal

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FIG 1. A, Sonazoid enhanced Pulse Inversion Harmonic Imaging shows metastatic deposit appearing as filling defect with slight rim enhancement in the late phase. B, Sonazoid-enhanced Power Pulse Inversion Harmonic Imaging shows smaller metastatic deposit appearing as color-free defect adjacent to the gallbladder in the late phase.

sound waves. As the incident pressure increases (100 kPA to 1 MPa) they begin to show nonlinear characteristics with emission of harmonics (ie, on the negative portion of the sound waves, the bubbles can become quite large but on the positive portion there is a limit to which they can contract), and this asymmetry is what constitutes the harmonic emissions. With

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further increase in the peak pressure of the incident ultrasound field, the shell of the microbubbles is disrupted; during this process a transient, strong nonlinear echo is emitted (stimulated acoustic emission/ loss of correlation), and the microbubbles are destroyed. Fundamental color/power Doppler modes and the newer harmonic modes (tissue, pulse/phase inver-

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FIG 2. Sonavist enhanced Pulse Inversion Harmonic Imaging shows multiple metastatic deposits appearing as filling defect with rim enhancement in the late phase

sion) use the microbubbles⬘ nonlinear and transient scattering properties to enhance signals from the contrast over those of background tissue. Ultrasound contrast agents are indeed very effective in enhancing fundamental spectral/color/power Doppler signals within the macro-circulation of the liver. However, blooming of the color/power Doppler signals and shadowing artefacts may mar enhancement of the blood pool, and further degradation may arise from the respiratory and cardiac motion artefacts on the fundamental modes. Adjustment of the color/power Doppler gain counteracts the benefit of using the contrast agents. Fortunately, the use of harmonic modes effectively displays the microbubbles signals while suppressing the tissue motion artefacts. Unlike computed tomography (CT) and magnetic resonance imaging (MRI) contrast agents, most ultrasound agents on fundamental gray scale mode are not depicted in the microcirculation and do not enhance the liver parenchyma at clinical doses. The echo from the tissue is still far too strong, compared with that from the small volume of contrast within the microcirculation of the tissue itself. The simplest method of displaying the signals from the microbubbles in the microcirculation over those of tissue is to destroy the microbubbles in the microcirculation at high ultrasound output (above mechanical index (MI) of 1.0) by use of fundamental color/power Doppler modes (stimulated acoustic emissions/loss of correlation imaging). This method emits the strongest signals; furthermore Doppler modes are ideal because they are very sensitive. A mosaic of color Doppler signals and color enhancement are displayed on color/power Doppler

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mode, respectively. Gray-scale enhancement is also achieved effectively as a result of the same destructive process, by use of the harmonic imaging modes. However, these fundamental Doppler and tissue harmonic modes are inherently limited by poorer resolution and lack of penetration. Destruction of the microbubbles results in transience of the effect unless there is replenishment of the new microbubbles in the scan plane. Therefore only microbubbles, which can perfuse the imaging space between frames, may be visible. In clinical practice the contrast enhancement is seen only on one frame (the first frame) because scanning is performed at a frame rate at which the interval between frames far exceeds the time for new microbubbles to perfuse the scanning plane. In the liver microcirculation, it takes approximately 8 seconds for the contrast agent to fill this scan plane. This forms the basis for interval delay imaging, or intermittent imaging. Short or long delay times can also be used to emphasize vascular or tissue contrast, respectively. More importantly, this technique can accentuate the differential perfusion kinetics between normal liver tissue and tumors, which may be used to improve tissue characterization.2 This destructive technique is a highly effective method of displaying contrast in the microcirculation, irrespective of whether the microbubbles are in motion. It is particularly relevant with respect to agents with late liver parenchymal phase uptake, such as Levovist. However, this destructive method is limited because it only produces transient displays of contrast; this may be partially resolved by use of repeated or higher doses of contrast agents, but the resulting

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inhomogeneous echogenicity, especially in the near field, as well as shadowing artefacts from the larger vessels carrying higher concentration of the contrast agents, are limiting factors. Newer methods such as pulse/phase pulse inversion harmonic imaging have had quite an impact in displaying contrast enhancement of the liver parenchyma. In pulse inversion imaging, a sequence of 2 ultrasound pulses is transmitted instead of 1 single pulse. The first pulse is an in-phase pulse, and the second is a mirror image of the first. For any linear target, the response to the second pulse is an inverted copy of the response from first pulse. These are then summated, and all linear echoes are canceled. However, for a nonlinear target such as microbubbles, the responses to positive and negative pulses are different and therefore do not cancel each other on summation. The fundamental components of the echo are canceled, whereas the even harmonic components are added resulting in twice the harmonic level of a single pulse. They allow the use of broader transmit and receive bandwidths, with improved resolution and increased sensitivity to contrast, thereby overcoming some of the limitations of the simple harmonic modes. These advantages also permit the use of much lower nondestructive output power level for continuous imaging thus obviating the need for intermittent/interval delay imaging; at such low mechanical index, the background tissue appears quite dark, and this can be compensated by increasing the gain setting. More recent improvements now allow adequate visualization of deep-seated lesions (10 to 15 cm), which was previously problematic.

Contrast Agent Kinetic Distribution Understanding the kinetic profiles of these contrast agents after a bolus intravenous injection in pathologic tissues and the normal liver parenchyma is key to improved detection and differentiation between benign and malignant lesions. In that respect the kinetic profiles of echo-enhancers within the hepatic artery, portal vein, and liver parenchyma are not too dissimilar from those obtained during CT or MRI examinations, with the exception that echo-enhancers are truly intravascular agents whereas CT or MRI agents diffuse into the extravascular space to enter the equilibrium phase, which starts at about 90 seconds. Therefore unlike CT or MRI there is no true “equilibrium phase” for echo-enhancers, and the urgency in having to complete the imaging scan within the 90-second

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limit as set for CT does not really apply. Beyond the 90 seconds there is still fairly good contrast difference between the normal liver and even small (⬍0.5 cm) liver tumors to enable their depiction on contrastenhanced ultrasonography. In addition with ultrasound imaging, the kinetic changes of contrast distribution is visualized in real time at the rate of approximately 15 to 25 frames per second, and the sensitivity in depicting the contrast agents is far superior, taking into account the small volume of contrast used (1 or 2 mL); the arrival of contrast agent within the liver is seen at a much earlier stage, with the hepatic arterial and portal venous phases being approximately 5 to 10 seconds earlier compared with those of CT or MRI. Primary and secondary neoplasms of the liver demonstrate wide variability in their vascularity, which is dependent to some extent on the size and the growth stage of the tumor. It is now generally accepted that when the tumor is small (about 1 mm) the main blood supply is via the portal vein. As the tumor grows, a new arterial system develops and becomes the predominant blood supply.3 Tumor identification is improved with contrast agents because of increased difference in echogenicity between normal and diseased areas of the hepatic parenchyma. Contrast agents are first delivered to the liver via the branches of the hepatic artery proper. This occurs by approximately 15 to 20 seconds after a bolus contrast injection in the peripheral vein. Most tumors are supplied almost exclusively by the hepatic artery, whereas only 20% to 25% of the blood supply to the liver originates from the hepatic artery and the remainder from the portal vein. The relative echogenicity between the liver and the tumor may not change significantly, although hypervascular lesions may show early enhancement at this stage. This is defined as the arterial phase, which ranges between 15 to 25 seconds from the time of administration. As blood is then delivered to the liver from the portal vein, the echo signal intensity of the liver rises rapidly. In malignant tumors the contrast agent from the arterial phase usually washes out fairly rapidly. The difference in the echogenicity between the liver and the tumor is therefore accentuated during this phase. This is defined as the portal venous phase, and the peak of the enhancement difference during this phase lies between 35 to 90 seconds. All contrast agents will display such arterial and portal phases. However, beyond the vascular phases, some agents such as Optison clear out of the circulation fairly rapidly, whereas other agents such

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FIG 3. Optison-enhanced Pulse Inversion Harmonic imaging shows multiple hepatocellular carcinomas in cirrhotic liver

SonoVue are held in the sinusoids for up to 5 to 6 minutes from the time of the bolus injection, and this specific phase can be called the “sinusoidal phase” (Fig 3, A and B).4 On the other hand echo-enhancers, which are taken up by the Kupffer cells of the reticuloendothelial system such as Sonazoid, liver parenchymal enhancement continues beyond the 5 minutes and may last for up to an hour depending on the dose use (Fig 4).

Optimization of Equipment Settings and Current Scanning Strategy for Detection and Characterization In the detection and characterization of focal liver tumors, the ultrasound equipment settings first consist of the selection of any of the nonlinear imaging modes

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(pulse inversion harmonic [ATL, Bothel, Washington, USA] or phase inversion harmonic [Siemens, Erlangen, Germany] and coherent contrast imaging [Acuson, Erlangen, Germany]), set at low MI (0.1 to 0.2) for agents such as SonoVue, Definity, Optison, Sonazoid, and Imavist. The MI and receiver gain can be adjusted according to the patient⬘s body habitus but the MI should be kept as low as possible. If, however, the image remains too dark in spite of receiver gain compensation and the anatomic landmarks are lost, it may be worth increasing the MI up to 0.35 to 0.4, and as soon as the arrival of the contrast agent is seen, it can be adjusted down to 0.2. The focal zone, if singular, should be set low down the screen (usually 4/5). Persistence setting, which refers to the temporal smoothing that the scanner performs in displaying images, should also be minimized. There are other

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FIG 4. Sonazoid-enhanced Power Pulse Inversion Harmonic Imaging showing very small metastatic deposit appearing as filling defect with rim enhancement in the late phase

TABLE 3. Equipment settings Acuson Sequoia 6.0 & 7.0 Cadence CCI

Siemens Elegra 6.0 & 7.0 Ensemble ECI

Transducer: 4C1 MultiHertz: Frequency H3.0 (for 6.0) P1.5 (for 7.0) Power: ⫺0.21 dB MI: ⫺.20 Focus: 4 dynamic (for 6.0) 2 dynamic (for 7.0) 70dB for 6.0 80dB for 7.0 Edge: 0 Persistence: 3 Delta 3 for 6.0 Delta 4 for 7.0 Post processing: 3 for 6.0; 4 for 7.0 CPS Map: M2 for 7.0

Transducer: 3.5C40 or CX5-2 Frequency select: 2.0

Transducer: C5-2

Power: 1% MI: 0.1 Focus: Auto with 1 zone

MI: 0.1 Focus: Multiple or single

B mode 70dB

70dB

Edge: Medium Persistence: 3 Photopic: 54dB

Persistence: Low Compression: C2

Post processing: Color Map Gray

parameters such as dynamic range/compression and line density, which would also affect microbubble destruction and contrast display sensitivity, but these would already have been optimized by the equipment manufacturer, and the user is best advised to adopt the default setting for the individual contrast agent (Table 3). For detection, standardization of the scanning protocol is important to ensure coverage of the whole liver. In our unit, the left lobe and then the right lobe are scanned axially as 2 separate sweeps followed by sagittal sweeps. Oblique sweeps through the 3 right intercostal spaces are also performed to complete the examination. This sequence of scanning is repeated

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Philips ATL 5000 10.5 Pulse Inversion PIH

Post processing: X-Res

systematically over and over throughout the hepatic arterial, portal venous and sinusoidal or late phases depending on the contrast agent used. The whole examination should be recorded on SVHS video or digitally on extended cine-loop archived on hard drive for further review. The hepatic arterial phase may be too short to complete a full liver coverage to specifically detect all the hypervascular malignant tumors; however, for these lesions, the contrast washout is usually fast, and the portal phase may be long enough for them to be depicted. Irrespective of the tumor vascularity, most lesions, if not all, should be detectable with the standardized protocol described earlier. Unlike CT or MRI, there is in fact no need to

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especially scan at these specific phases. It is, however, important to understand the temporal changes in the echogenicity of the lesions, which may occur during these phases for the purpose of characterization. Agents with “sinusoidal or late phase uptake” have the advantage that there is ample scanning time and are ideally suited for the purpose of detection. For agents with no such “sinusoidal or late phase uptake” (Optison), the use of smaller doses may be preferable to curtail the overlap between the arterial and portal phases as some of the hypervascular lesions may disappear during that period. However, repeat injections of these smaller doses is feasible for a more complete examination of the liver. In the characterization of focal liver tumors, a standardized scanning protocol is also useful to evaluate the tumoral vascular structure during the arterial and portal phase and the relative contrast entrapment/ uptake within the tumor compared with the surrounding normal liver parenchyma in the sinusoidal or late phase depending on the type of contrast used. Because it is now possible to scan at very low MI and visualize the temporal changes of the lesional enhancement and its vascular structure in real time, there is in fact no need for any “interval delay scanning technique” to accentuate the differential vascularity between the tumor and normal liver tissue. After the administration of the contrast agent, gentle sweeps to cover the whole lesion is recommended instead of maintaining the same scanning plane continuously; although there is minimal destruction when scanning at low MI, significant microbubble destruction still occurs when the probe is kept at the same scan plane. In addition when sweeping through the lesion, a 3-dimensional perspective of the lesional vascular structure is obtained. These sweeps can be repeated over the whole vascular phase and into the sinusoidal/late phase. However, for suspected benign hemangiomas the protocol needs to be tailored to demonstrate the centripetal progression of the peripheral nodular enhancement by progressively increasing the delays between sweeps to allow for the accumulation of agent throughout the lesion, because there is always some degree of microbubble destruction, even at such low MI. However, the equipment settings and scanning protocols are different for agents such as Levovist and Sonavist because they are best displayed with nonlinear imaging modes set at high MI (over 1.0). Specific imaging modes, Agent Detection Imaging (ADI)

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available on both Acuson and ATL5000 are specifically designed for using Levovist and are highly effective in displaying contrast by use of color map with high resolution (Figs 5 and 6). The scanning protocol for detection is as follows: the left lobe and then the right lobe is scanned axially or sagittally at 4 to 5 minutes post Levovist or Sonavist injection. Oblique scans at the intercostal spaces can also be performed to complete the right lobe examination. Because this is a destructive mode, the contrast display with Levovist is transient; the first sweep through each lobe will provide the best and possibly the only chance to visualize tissue enhancement. Precontrast scan planning is therefore essential to ensure complete coverage of the whole liver. If the examination is incomplete after the first injection, repeated contrast administration is possible. With the transience of the contrast display, biopsy of newly identified lesions is almost impossible with this agent. For characterization, single sweeps through the lesion can be performed at the hepatic arterial (15 to 20 seconds) and portal venous (60 to 90 seconds) phases at high MI to demonstrate the lesion vascular structure and then in the late phase to demonstrate the amount of contrast uptake within the lesion. During the vascular phase after Levovist administration, the sweeps over the lesion should not be repeated as often as in the case of low MI technique because it will spoil the late phase imaging. However, with Sonavist, in spite of the destructive high MI mode being used, repeated sweeps are possible to complete the liver exam in the vascular and late phases; this is most likely because of the much higher dose of Sonavist used (Fig 2).

Characterisation of Focal Liver Lesions The findings of the above-mentioned techniques used in the imaging of focal liver lesions have been fairly consistent in our own experience with improved specificity, particularly for lesions such as hemangioma, focal nodular hyperplasia, hepatocellular carcinoma, and metastasis.4 Hemangiomas are the most common benign tumors of the liver and are incidentally found. They consist of a large network of endothelium-lined vascular spaces. The sonographic features of hemangiomas are nonspecific. They usually occur as solitary homogenous echogenic mass and may be associated with posterior acoustic enhancement. Although very vascular the blood flow with these tumors is very sluggish and appear as hypovascular lesions on unenhanced fundamental Doppler

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FIG 5. A, Levovist-enhanced ADI mode showing liver metastases as filling defects in the late phase. B, Levovist-enhanced ADI mode show FNH, which is isoechoic to liver; central stellate scar stands out as filling defect.

ultrasound. However, after contrast agent administration on pulse/phase inversion harmonic (PIH) imaging, they demonstrate the same characteristic progressive peripheral nodular centripetal enhancement as seen on CT or MRI. Even during the early arterial phase, peripheral hyperechoic nodular areas may be seen, becoming more numerous and gradually filling in the lesion either partially or almost completely over several minutes (Fig 7). The baseline hyperechogenicity of the hemangiomas is typically reversed to become hypoechoic in the central areas, which have not yet been filled with contrast

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during the arterial phase. Delayed imaging with agents with sinusoidal/late phase liver parenchymal uptake also demonstrate delayed partial peripheral or complete enhancement as a result of sluggish flow. With these findings a definitive diagnosis can now be made. However, in a small percentage, rapid homogenous enhancement of the whole lesion may be seen simulating hypervascular metastases or the progressive centripetal enhancement or late uptake may not be present, especially in smaller lesions; correlative imaging modality or even biopsy must be considered in these circumstances.

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FIG 6. Levovist-enhanced ADI mode shows VIPOMA appearing as filling defect lying above the aorta and inferior vena cava in the subcapsular area.

Focal nodular hyperplasias (FNHs) occur more commonly in young women, with an increased incidence in those taking oral contraceptives. They are most often asymptomatic and are usually incidentally detected. They are well circumscribed, nonencapsulated, and usually solitary. They have no malignant potential; hemorrhage into the lesion is rare, and management is therefore conservative. FNHs are made up of normal hepatocytes, Kupffer cells, bile duct elements, and fibrous connective tissue. They consist of multiple nodules separated by fibrous bands radiating from a central scar. The central or eccentric stellate scar contains fibrous tissue, bile ducts, and thin-walled blood vessels. On unenhanced ultrasonography they are often isoechoic and difficult to delineate, but they may also be hypoechoic compared to normal liver. The scar usually appears as a stellate or linear hypoechoic or anechoic area. FNHs are very vascular lesions and on continuous scanning using contrast enhanced PIH modes, the lesional vessels are typically of the “stellate” or “spoke wheel” configuration (Fig 8, A and B). The lesion becomes hyperechoic during both arterial and portal phase (Fig 8, B and C). The central scar easily stands out as a hypoechoic or anechoic area within the hyperechoic lesion. When agents with sinusoidal/late liver parenchymal uptake are used, there is always marked uptake of the contrast in the

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late phase, and again the central scar is easily depicted within the hyperechoic tumor (Fig 8, D). Given the clinical history, a definitive diagnosis can be made in most patients. The main differential diagnosis would be a fibrolamellar hepatocellular carcinoma. Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It usually arises in previously damaged livers, most commonly in patients with alcoholic cirrhosis, hepatitis B and C or hemochromatosis. It is usually solitary but may be multifocal or diffuse. HCCs may be hypoechoic or hyperechoic or have mixed echogenicity depending on the size of the tumor, the fat content, degree of differentiation, scarring or necrosis. They may either have irregular margins with or without the halo sign or have well-defined smooth echogenic rim corresponding to presence of pseudocapsule; the latter is not uncommonly seen, especially in the well-differentiated tumors. A characteristic feature is presence of tumor extension into the biliary tree or portal or hepatic veins. Venous invasion is commonly seen in the larger advanced tumors. HCCs are characteristically hypervascular. On continuous low MI scanning with contrast enhanced PIH, chaotic peritumoral and intralesional tortuous “corkscrew”/s-shaped vessels may be clearly depicted in the arterial phase when the lesions become hyperechoic (Fig 9, A and B). Vascular

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FIG 7. A, Hyperechoic hemangioma at baseline. B, SonoVue-enhanced Pulse Inversion Harmonic Imaging of hemangioma shows peripheral nodular enhancement during the arterial phase. C, SonoVue-enhanced Pulse Inversion Harmonic Imaging of hemangioma shows progressive peripheral nodular enhancement during the portal venous phase. D, SonoVue-enhanced Pulse Inversion Harmonic Imaging of haemangioma shows complete filling-in of contrast in the sinusoidal phase.

lakes subsequently appear as dense focal areas of increased echogenicity. In the presence of cirrhosis, the portal phase may be delayed, and the liver parenchymal enhancement may appear less intense. Delayed imaging after administration of agents with sinusoidal/liver parenchymal uptake, HCCs appear as echo-poor filling defects in a background of bright liver (Fig 9, C and D). A hyperechoic rim enhancement replacing the halo sign may be seen. In a small percentage of cases, there may be significant contrast uptake within the lesions, especially in the welldifferentiated tumors with agents such as Levovist;

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contrast uptake within the liver parenchymal may also be nonuniform in the presence of cirrhosis, which may limit the usefulness of the technique. However, these lesional uptake and inhomogenities in cirrhosis have not been observed with agents such as SonoVue. Metastatic disease of the liver is about 20 times more common than any of the primary hepatic neoplasms. Hepatic metastases typically appear as multiple focal discrete lesions, but solitary lesions may also occur. Diffuse infiltrative hepatic involvement may be seen in breast cancer or lymphoma. On fundamental B mode ultrasonography, a metastasis may appear as

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FIG 7. Continued.

discrete hypoechoic, hyperechoic, or of mixed echogenicity, and some look like target lesions. These appearances are nonspecific in determining the primary site. Contrast-enhanced ultrasound appearance of metastasis is variable depending on the size and vascularity of the tumor and the degree of necrosis. Metastases of same cellular type (eg, colon) may vary in their enhancement characteristics and metastases of different cellular types (breast and colon) may produce identical appearances. Most commonly hepatic metastases from colon and lung carcinomas are hypovascular. On continuous scanning at low MI with contrastenhanced PIH imaging, these lesions usually show few

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peritumoral vessels and are of the same echogenicity as the liver during the arterial phase; during the portal phase, they typically appear as hypoechoic filling defects surrounded by a brighter liver parenchyma and rim enhancement (Fig 10). For lesions, which are hyperechoic at baseline, there is a characteristic reversal of the echogenicity to become hypoechoic. However, the vascularity of the smaller colorectal liver metastases may differ, and there may be a more uniform display of the intralesional vessels during the arterial phase. However, during the portal phase, the liver parenchyma enhances and the metastasis may appear as echo-poor filling defects with or without rim

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FIG 8. A, SonoVue-enhanced Ensemble Contrast Imaging of FNH during the early arterial phase shows central artery. B, SonoVue-enhanced Ensemble Contrast Imaging of FNH during the arterial phase shows lesional enhancement characteristic central scar as stellate arterial configuration. C, SonoVue-enhanced Ensemble Contrast Imaging of FNH during the portal venous phase shows similar lesional enhancement. D, SonoVue-enhanced Ensemble Contrast Imaging of FNH during the sinusoidal phase shows isoechogenicity of lesion and normal liver with an accentuated central scar.

enhancement. In contrast hypervascular metastases (such as the carcinoids, islet cell, melanoma breast, renal or thyroid malignancies) become hyperechoic during the arterial (Fig 10). In the portal phase, contrast washes out of the lesion relatively rapidly, and they become hypoechoic to the surrounding liver with improved delineation. In the case of breast and colonic metastases, there may be a combination of both hypervascular and hypovascular lesions; some of the hypervascular lesions may become isoechoic to surrounding liver parenchyma during the arterial phase but can still be recognized by virtue of the microbubbles haphazard movement within the hypervascular lesion. Delayed imaging with sinusoidal/ liver specific agents, both hypervascular or hypovascular metastases characteristically appear as hypoechoic le-

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sions with or without rim enhancement in a background of bright liver. Their enhancement characteristics during the hepatic arterial, portal venous and sinusoidal/late phases are summarized in Table 4.

Clinical Perspectives Because of its relative low cost, safety, and availability, conventional ultrasound remains the most widely used cross-sectional imaging modality in routine clinical practice worldwide. Recent advances in nonlinear imaging together with a whole new generation of echo-enhancing agents have improved the clinical applications of ultrasound scanning. Indeed there are now increasing reports of single- and multicenter studies confirming improved

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FIG 8. Continued.

detection and characterization of focal liver lesions with contrast-enhanced ultrasound scanning.4 – 8 In a study comparing unenhanced versus contrast-enhanced ultrasound scanning in the detection of liver metastases, the average number of confirmed metastases increased from 3.06 to 5.42 after contrast administration; the sensitivity for detecting individual metastases significantly improved from 63% to 91%. More importantly subcentimeter lesions were identified in more than 92% of confirmed cases after contrast compared with 54% at baseline.5 In a multicenter study of 123 patients evaluating unenhanced versus contrast-enhanced ultrasound scanning in the detection of liver metastases, similar results were observed with the sensitivity for detection of individual lesions improving significantly from 71% to

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87% after contrast administration. Furthermore, the specificity also improved significantly from 60% to 88%.9 In a more recent multicenter study of 157 patients, off-site blinded readers showed improved sensitivity for detection of individual lesions from 38% to 67% after contrast injection, and the characterization of the lesions was also improved with none of the metastases showing contrast uptake in the late phase.10 However, all the above studies have used contrast-enhanced 2-phase CT and MRI scanning as the standard of reference, and it remains to be seen whether contrast-enhanced ultrasongraphy is as sensitive or more accurate than CT or MRI alone. In spite of the significant improvement of contrastenhanced ultrasound scanning in obtaining images of the liver, there is some debate with regard to its

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FIG 9. A, Heterogenous liver with poorly delineated lesions at baseline. B, SonoVue enhanced Pulse Inversion Harmonic Imaging during the arterial phase with marked enhancement of the HCCs and improved delineation. C, SonoVue-enhanced Pulse Inversion Harmonic Imaging during the portal venous phase with the HCCs appearing as dark filling defects after rapid contrast washout. D, SonoVue-enhanced Pulse Inversion Harmonic Imaging during the sinusoidal phase with HCCs still appearing as dark filling defects.

implementation in routine clinical practice. Clearly it is highly unlikely that it would replace CT or MRI; however, it should be used as a complementary tool in specific clinical scenarios.

Incidental Lesions in Normal Livers Benign hepatic tumors or tumorlike conditions occur more frequently than anticipated in the general population. In a consecutive necropsy study of 95 men, benign lesions were identified in 52% of the cases.11 The most common tumors were small bile duct tumors followed by

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cavernous hemangiomas detected in 26 (27%) and 19 (20%) men, respectively. Multiple lesions were present in 46% of the bile duct tumors and in 50% of the hemangiomas. In another autopsy series of 95 men, half of whom had history of alcohol abuse, preneoplastic nodules (hyperplastic and dysplastic nodules) were identified in 19% of the cases.12 Small hepatic lesions are indeed frequently detected on routine imaging studies. In a contrastenhanced abdominal CT scan review of 1454 patients, Jones et al13 reported the presence of a

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FIG 9. Continued.

hepatic lesion measuring 15 mm or less in 254 (17%) patients. Of these, 130 (51%) were judged to be benign, 56 (22%) were judged to be malignant, and the remaining 68 (27%) could not be classified. Eighty-two percent of the patients with small lesions were also known to have a malignant primary tumor, and in 51% of these patients the lesions were classified as benign. None of patients without a known malignant primary cancer had a small hepatic lesion that was classified as malignant. Multi-

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ple small hepatic lesions were more likely to represent malignancy than solitary small lesions. More recently, in a CT report review of 2978 patients with cancer, small lesions measuring 1 cm or less were identified in 378 (12.7%) patients14; of these patients, the small lesions were classified as being metastases in 59 (15.6%) cases. In contrast in 303 (80.2%) patients, the lesions were judged to be benign, and in the remaining patients the lesions were judged as indeterminate. Among the 3 most common primary

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FIG 10. A, SonoVue-enhanced Pulse Inversion Harmonic Imaging during the arterial phase shows hypervascular metastasis enhancement. B, SonoVue-enhanced Pulse Inversion Harmonic Imaging during the portal venous phase with the metastasis appearing as a dark filling defect after rapid contrast washout with bright rim enhancement. C, SonoVue-enhanced Pulse Inversion Harmonic Imaging during the sinusoidal phase with the metastasis still appearing as a dark filling defect with bright rim enhancement

tumors in the study, that is lymphoma, colorectal and breast, small lesions were metastases in 4%, 14%, and 22%, respectively. The authors concluded that although small hepatic lesions in patients with cancer are more likely to be benign than malignant, these lesions represent metastases in 11.6% of patients. Studies carried out by Jones et al13 and Schwartz et al14 used CT scanners in the nonhelical mode. Clearly more liver lesions would be detected with biphasic injection of contrast media, thinner collimation and helical CT scanning; the true incidence for small hepatic lesions is therefore underestimated. The widespread use of new generations of imaging modalities has led to an increase in the frequency of

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detecting coincidental focal liver lesions in patients with no symptomatic evidence of liver disease. Differentiation between the benign and malignant lesions is usually not difficult when they are large, but when they are small, characterization is clearly problematic because they do not display enough characteristic features, and biopsy can be very difficult if not impossible. In patients without known cancer, nearly all of these lesions will be benign and are now usually evaluated with serial follow-up imaging scans. However, in patients with known cancer where knowledge of stage and progression is crucial in determining prognosis and therapeutic management, the relevance of urgent accurate characterization of these small

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FIG 10. Continued.

TABLE 4. Summary of findings with nonlinear imaging Tumor types HCCs Hypervascular Metastases Hypovascular Metastases Haemangiomas FNHs

Characteristi c features “s” shaped vessels and vascular lakes Rim enhancement Rim enhancement Progressive peripheral nodular enhancement Stellate central scar, which remains anechoic

Continuous low MI Imaging Arterial Phase

Portal Phase

Hyper-echoic

Hyper-/hypo-/isoechoic: dose dependent Iso- or Hypoechoic: dose dependent Hypoechoic

Hyper-echoic No change in echo Centripetal Filling-in Hyper-echoic

lesions is therefore an important issue. Contrast-enhanced nonlinear imaging is of particular value in that respect; it is ideally suited for the characterization of these small focal liver lesions because real-time visualization of tumoral vessels and tissue enhancement is now possible with relatively minute amount of contrast.

Screening and Surveillance for Hepatocellular Carcinoma Hepatocellular carcinoma is the fifth most common cancer in the world with the lowest incidence in Northern Europe and Northern America. Screening and surveillance for hepatocellular carcinoma remains a clinical challenge. In spite of the lack of concrete

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Agents with Sinusoidal/late phase uptake No contrast uptake No contrast uptake No contrast uptake

Significant contrast update Hyperechoic

Marked contrast uptake

evidence of any true survival benefit or cost effectiveness, it is now becoming widely accepted among hepatologists that it should be routine in the management of patients with end-stage liver disease. Nevertheless some of the rationales for screening and surveillance are compelling. The worldwide incidence is increasing but more noticeably in North America and Europe; it is now believed that the rise in the latter continents which is progressively affecting younger patients, is mainly attributed to the rise in hepatitis C viral infection, whereas the rates associated with alcoholic cirrhosis and hepatitis B virus infection have remained stable.15 The disease is extremely lethal with median survival rates of untreated symptomatic cases ranging between

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4 to 6 months. Patients with even small tumors also carry a significant mortality rate, because less than 50% will survive 5 years in spite of undergoing apparently curative resection. The target population for screening and surveillance for hepatocellular carcinoma is readily identifiable. Chronic hepatitis B and C virus infections are well recognized to increase the risk of hepatocellular carcinoma. In Europe approximately 28% of liver cancer has been attributed to chronic hepatitis B virus infection and 21% to hepatitis C virus infection, and the risk is greatest in the presence of coinfection with both hepatitis B and C virus.16 Cirrhosis is another major risk factor irrespective of the cause. The annual risk for development of HCC in cirrhosis ranges between 1% and 6%.17,18 The risk is higher in patients with cirrhosis caused by viral infection compared with nonviral causes. Although cirrhosis is a major risk factor irrespective of cause, up to 56% of patients with hepatocellular carcinoma have previously undiagnosed cirrhosis.19 Cirrhosis may be easily diagnosed by any cross-sectional imaging modality if characteristic features such as nodular hepatic contour, ascites, or varices are present. But in the early stages of the disease, it may be impossible to differentiate between stage III fibrosis and cirrhosis. If the presence of cirrhosis alone were to be used to define the target population, these patients would not have been recruited into the screening or surveillance program. Zaman et al19 also showed that those patients with occult cirrhosis were predominantly HbsAg-seropositive. Therefore patients with chronic viral hepatitis, as well as those with overt cirrhosis, have to be included in any screening or surveillance program. Serum alpha-fetoprotein levels (AFP) and conventional ultrasonography have been the most commonly used screening tests for hepatocellular carcinoma with low morbidity rates. The ideal screening tests should also have high sensitivity and specificity. But the performance of AFP has been poor in that respect, with a sensitivity of 39% to 64%, a specificity of 76% to 91% and a positive predictive value of 9% to 32%.20 –22 In addition, a rise in levels of AFP is not specific for hepatocellular carcinoma, and it may also increase transiently, persistently, or intermittently with flares of active hepatitis. In contrast within the context of screening healthy HbsAg carriers, as well as patients with cirrhosis, ultrasound scanning has been shown to have a sensitivity of 71% and 78%, respectively, a specificity of 93%, but a positive predictive

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value of 14% and 73%, respectively.21,22 These results could be improved further with the administration of ultrasound contrast agents. There are as yet no studies to determine the best recall policy. However, at the consensus meeting of the European Association for the Study of Liver in Barcelona in 2000, it was suggested that patients with cirrhosis should undergo 6-monthly ultrasound scanning and AFP levels assessment; patients who have no nodule on ultrasound scanning but have increasing AFP levels should undergo spiral CT of their liver; for those patients with a nodule of less than 1 cm, 3-monthly ultrasound scanning is recommended on the basis that these lesions are far too small to characterize accurately, and at least 50% of these subcentimeter lesions will not be hepatocellular carcinomas; patients with a nodule more than 2 cm should have AFP levels greater than 400 ng/mL, and CT, MRI, or angiography evidence of lesional hypervascular before hepatocellular carcinoma can be confirmed.23 If the nodule is less than 2 cm, diagnosis can be made with noninvasive criteria (if biopsy is not an option), which had been defined as radiologic criteria (2 coincidental imaging techniques that show arterial hypervascularization for lesions larger than 2 cm) and combined criteria (1 imaging modality that shows arterial hypervascularization associated with AFP levels over 400 ng/mL). Biopsy may be another option in some centers but remains controversial; in some North American and European centers, biopsy would prelude hepatic resection or transplantation because of the risk of tumor seedlings along the needle tracks. Furthermore, a negative biopsy result of a lesion visible on imaging techniques in a cirrhotic liver does not necessarily rule out malignancy completely. Therefore within the context of the patient with cirrhosis, hepatocellular carcinoma can be diagnosed noninvasively with the abovementioned criteria. Clearly there are several stages in this algorithm whereby administration of ultrasound contrast might be more effective, namely, in the 6 monthly recalls to improve detection, the characterization of the lesions measuring less than 2 cm, and as the second modality in demonstrating the hypervascularity of the lesion in the noninvasive diagnosis of the hepatocellular carcinoma.

Staging and Follow-up of Patients with Cancer Accurate cancer staging is crucial in determining the optimal therapeutic management of the patients

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and is highly dependent on imaging studies. The liver is the most common target organ for metastasis for many primary cancers. There are therefore clinically distinct tasks in liver imaging, which includes first the assessment of whether there is any space-occupying lesion in the liver, second the characterization of the lesion, and third the staging of the tumor in the liver for resection, that is, to determine the extent of the intrahepatic disease, the involvement of surgically critical areas such as porta hepatis, major bile ducts, inferior vena cava, and the presence of extrahepatic disease. Imaging strategies for the liver will also differ, depending on the clinical setting. Different techniques are required depending on the primary tumor types, evaluation before resection of the primary, for surveillance of patients who had undergone apparently curative resection of the primary cancer, follow-up examinations for patients with known liver metastases to assess therapeutic response, and evaluations before surgical hepatic resection in which more rigorous study is required to locate all hepatic lesions. For example, a single imaging modality such as ultrasound scanning, CT, or MRI may be adequate to screen for the presence or absence of metastases or for assessment of metastasis response to treatment, but multiple imaging studies (multiphasic contrast-enhanced CT, MRI, or intraoperative ultrasound scanning) are often required when liver resection of metastases is being considered. In many centers, hepatic ultrasonography remains the primary imaging modality of choice in imaging the liver for suspected metastases from primary tumors such as breast, melanoma, esophagus, stomach, pancreas, and lung. This practice is merely historical, readily available, and cheap (compared with CT or MRI) and is usually triggered by the finding of abnormal liver function test results; the identification of liver metastasis is also simply used as a prognostic indicator of poor outcome. For these tumor types, in contrast to colorectal cancer, “global detection” of hepatic metastasis, that is, whether metastasis is present, is the most important issue rather than “the actual number and localization” of the metastasis because liver resection is usually not an option. In that respect, ultrasound sensitivity may in fact be improved with the use of echo-enhancers. For patients who undergo apparently curative resection of the primary cancer, there are centers that undertake a formal or semiformal type of surveillance

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program for early detection of recurrence on the premise that if it were detected early, these patients would stand a better chance for prolonged survival or even cure. However, similar to the screening programs for hepatocellular carcinoma, there is as yet no evidence to suggest that surveillance for recurrence is cost-effective or actually improves survival. Recent studies have highlighted the lack of consensus among surgeons on the value of routine follow-up after curative resection for the primary cancer. This is particularly so for colorectal cancer given it is the second most common cause of cancer-related death in the Western world.24,25 However, most studies have focused on the early detection of local recurrence amenable to surgery, but these are clearly based on a false premise, and there is increasing evidence that this approach is ineffective and costly.26 In contrast surveillance programs designed to detect asymptomatic liver metastases may be more effective. Indeed more recently Howell et al27 have shown that an intensive liver imaging follow-up program with 3-monthly ultrasound scanning and yearly CT identified 88% of patients with development of liver metastases in an asymptomatic stage and were amenable to liver resection or chemotherapy. It is worth noting that the 5-year survival rate of patients undergoing liver resection is about 35% and the mortality rate is usually less than 5%.28 Furthermore, recent studies have shown that patients with disseminated disease receiving systemic chemotherapy at an asymptomatic stage had higher response rates, better quality of life, and improved survival rates compared with those in whom the administration of chemotherapy was delayed until symptoms developed.29 The question of imaging in follow-up programs and its intensity should therefore be readdressed. Although CT may be effective for detection of both local and hepatic recurrences, it is also more expensive and less readily available compared with ultrasound scanning, but the latter is limited in the detection of local recurrence in routine practice. However, local recurrence usually occurs within the first 6 months of the primary resection; follow-up program could therefore be tailored to use of ultrasound scanning beyond the first 6 months. Contrast-enhanced ultrasound scanning may be a more cost-effective modality in the detection of liver metastases given the constraints of current health resources. Intraoperative ultrasound scanning remains the most sensitive imaging modality relative to current multiphasic contrast CT or MRI in the detection of

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FIG 11. Intraoperative SonoVue enhanced Pulse Inversion Harmonic Imaging during the sinusoidal phase shows metastasis as focal defect.

hepatic metastasis and is routinely used before liver resection by most liver surgeons. CT is, however, still required to rule out any extrahepatic disease before liver resection is contemplated. It is commonly known that the 5-year survival rate of patients undergoing liver resection for metastases ranges between 25% to 40% at best; most of the patients ultimately succumb to residual disease or “occult” metastases, which remained undetectable to conventional imaging modalities at the time of resection. There is early indication from a preliminary study in our unit that intraoperative contrast-enhanced ultrasonography is even more sensitive and accurate than unenhanced intraoperative ultrasonography, with up to 50% of cases leading to a change in surgical management (Fig 11). It remains to be seen whether these results are reproduced by other centers.

Summary The continuing development of nonlinear imaging, as well as a whole new generation of contrast agents, holds out great prospects in improving liver imaging. Optimization of the equipment settings for different classes of contrast agents is essential in the detection and characterization of focal liver lesions. On the basis of the preliminary results of multicenter clinical trials, it is reasonable to assume that their application in specific clinical settings will impact favorably on patient management.

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