Contrast‐enhanced ultrasound: Emerging modality for liver lesion characterization

The characterization of focal liver lesions has traditionally been difficult on ultrasound, with a low specificity of approximately 50%.1 The emergence of contrast-enhanced ultrasound (CEUS) in the past decade has allowed much more accurate characterization of both benign and malignant liver lesions, with sensitivity of up to 96% and specificity of 90%.2,3 The article by Wang et al. in the current issue of the Journal of Gastroenterology and Hepatology confirms the findings of previous publications, highlighting the utility of CEUS in clinical practice in assisting in the diagnosis of lesions in a fatty liver, a commonly encountered scenario.4 Currently, the mainstay of investigation for undifferentiated focal liver lesions is contrast-enhanced computed tomography (CE-CT) or magnetic resonance imaging (MRI). Typically CE-CT requires a four-phase study in arterial, portal, venous and delayed phases; this allows characterization of the vascularity of the liver lesion. CE MRI characterization of liver lesions also involves dynamic contrast enhancement, as well as assessment of the T1 and T2 features. The advantages of CT are its speed and availability, but its disadvantages include radiation exposure and contraindication in patients with renal failure. The advantages of MRI include the absence of radiation exposure and excellent soft tissue contrast resolution, but it is a relatively lengthy examination. Contraindications to MRI include a range of implantable devices (which may be affected by the strong magnetic field), and the recently recognized uncommon but serious complication of nephrogenic systemic fibrosis; the latter follows certain gadolinium-based contrast agents in patients with renal failure.5 The development of second-generation microbubble contrast agents, which are purely intravascular agents, has created the ability for ultrasound to show the enhancement features of a liver lesion comparable to that of contrast-enhanced CT or MRI.6 The microbubble agents are low-solubility gases, enveloped in a shell which is more stable compared with previous first-generation microbubble agents. The newer agents are therefore better suited to clinical practice.7 Several second-generation CE-US agents are already widely used in Europe, Asia and Canada for imaging liver lesions, as well for other applications. The second-generation agents include sulfur hexafluoride in a phospholipid shell (SonoVue, Bracco, Italy), and perflutren-filled lipid microspheres (Definity; Lantheus Medical Imaging, Billerica, MA, USA). Definity was recently approved for use in Australia for liver, renal and cardiac applications, and has been used in some countries for several years. One major advantage of microbubble contrast agents is that they can be safely used in patients with known renal failure. Another advantage is the ability to immediately characterize an indeterminate liver lesion detected during clinical ultrasound examination, without necessarily requiring referral for a second investigation such as CE-CT. A study by Wilson et al. in 2007 found that recommendations for further investigations of liver lesions decreased from 99.7% to 18% following CEUS.3 The main limitations of CEUS are patients with large body habitus, small lesions which are located deep within the liver, typically with a depth of greater than 10 cm and the inability to obtain a good acoustic window for lesional assessment.8 Their use should be avoided in some patients with cardiac disease, for example, those with right to left shunts and unstable myocardial ischemic disease, as well as in patients with respiratory failure and pulmonary hypertension due to risk of sudden cardiac death. The technique of CEUS exploits pulse inversion imaging, a relatively new contrast-specific technique which suppresses the background echoes from the liver parenchyma, thus allowing better visualization of the microbubbles when insonated using low acoustic power.1,7 The examination is carried out and assessed in real time, with continuous observation of the microbubbles from the time they enter the area of interrogation. During this time, the lesion is assessed in the arterial phase (0–40 s) and during an extended portal venous phase, from 40 s to decrease of contrast enhancement (which is 4–5 min). The timing of the peak arterial enhancement of contrast (‘wash-in’ phase) and time of the disappearance of the bubbles (‘washout’ phase) and the lesion vascular morphology are assessed.9 Cine clips of the whole examination are obtained for all CEUS studies to allow off-line review and analysis at a later stage, if required. The accuracy of assessment of the morphology of the vascular supply of the lesion and enhancement kinetics for characterization has again been demonstrated by Wang et al. in this issue.4 Arterial phase enhancement is seen in both benign and malignant lesions. In real-time imaging, lesions which have typically been hypovascular on CT or MR imaging, for example metastases, have been demonstrated to show some arterial enhancement using CEUS.10 The technique is therefore more sensitive for depicting blood flow than CE-CT or MRI. It has been shown that the washout time of enhancement has the highest positive predictive value for accurately characterizing a lesion.10 The timing of the contrast washout assists in distinguishing benign from malignant lesions. Benign tumors tend to have sustained enhancement into the extended portal venous phase, with malignant tumors demonstrating washout in the early portal venous and sometimes late arterial phase.9 There is also a correlation between the degree of cellular differentiation with the timing of washout, particularly in primary hepatocellular carcinoma (HCC).11,12 Well-differentiated primary HCC tends to have later washout compared with moderately to poorly differentiated tumors, which have washout in the late arterial or early portal venous phase.13 The strength of CEUS compared with CT and MRI is the ability to assess the pattern of vascularity in real time, which can accurately characterize certain liver lesions. This has been illustrated by Wang et al.4 in this issue of the Journal, confirming that this is a technique which can be used in routine clinical practice. Some benign lesions have characteristic patterns of enhancement which are diagnostic. Peripheral, nodular enhancement which progresses centripetally is diagnostic for a hemangioma. Focal nodular hyperplasia has centrifugal enhancement with a central feeding artery which tends to branch in a radial ‘spoke-wheel’ pattern. Malignant lesions show a dysmorphic pattern of vascular enhancement. Primary HCC classically has arterial phase enhancement, progressing rapidly to diffuse filling due to hepatic arterial supply, whereas metastatic lesions classically demonstrate rim or sparse central enhancement.9 The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB)14 has provided a series of guidelines which describe the areas where CEUS of the liver can have a clear-cut clinical impact. These include: Characterization of focal lesions incidentally detected in patients with no known chronic liver disease. Characterization of focal lesions in surveillance programs of chronic liver disease. Staging and follow up of cancer patients. Focal lesions with inconclusive MRI/CT or cytology/histology results. Characterization of portal vein thrombosis. In conclusion, the article by Wang et al. further supports the evidence that contrast enhanced ultrasound is a safe imaging modality which has the ability to characterize indeterminate liver lesions in real time. The advantage of immediately characterizing a lesion detected on unenhanced ultrasound is potentially time and cost saving because further investigations can be averted. This may also avoid unnecessary patient anxiety. CEUS also provides an option where CT or MR imaging is either contraindicated or yields equivocal findings. As with any new modality, there is a learning curve, and there is also the issue of the relative ‘operator dependence’ of ultrasound. Nevertheless, with increasing experience with the use of CEUS in more centers there is no doubt that CEUS will gain increasing value in routine clinical practice for the evaluation of focal liver lesions.

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