Contrast-enhanced ultrasound (CEUS) using microbubble contrast agents are useful for the diagnosis of the nodules in liver cirrhosis. CEUS can be used as a problem-solving method for indeterminate nodules on computed tomography (CT) or magnetic resonance imaging (MRI) or as an initial diagnostic test for small newly detected liver nodules. CEUS has unique advantages over CT and MRI including no renal excretion of contrast, real-time imaging capability, and purely intravascular contrast. Hepatocellular carcinoma (HCC) is characterized by arterial-phase hypervascularity and later washout (negative enhancement). Benign nodules such as regenerative nodules or dysplastic nodules are usually isoechoic or slightly hypoechoic in the arterial phase and isoechoic in the late phase. However, there are occasional HCC lesions with atypical enhancement including hypovascular HCC and hypervascular HCC without washout. Cholangiocarcinomas are infrequently detected during HCC surveillance and mostly show rim-like or diffuse hypervascularity followed by rapid washout. Hemangiomas are often found at HCC surveillance and are easily diagnosed by CEUS. CEUS can be effectively used in the diagnostic work-up of small nodules detected at HCC surveillance. CEUS is also useful to differentiate malignant and benign venous thrombosis and to guide and monitor the local ablation therapy for HCC.

Ultrasound (US) is most commonly used for imaging surveillance for hepatocellular carcinoma (HCC) in high-risk patients[1]. Once a focal hepatic nodule is detected during HCC surveillance, a diagnostic imaging test is performed. The assessment of tumor vascularity is most important in the differential diagnosis of the nodules. Doppler US techniques have been used to detect vascularity in liver tumors; however, these techniques lack sensitivity to detect tumor vascularity. Contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) is most commonly used to characterize liver masses. Contrast-enhanced ultrasound (CEUS) using a microbubble contrast agent is a relatively new imaging technique and has been proved to be useful for characterizing liver tumors. CEUS enables a real-time demonstration of continuous hemodynamic changes of liver tumors after injection of the contrast material.

Recent practice guidelines for HCC provided recommendations for the diagnostic algorithm for newly detected nodules at HCC surveillance[1-3]. The application of the imaging test varies depending on the size of the nodules. For very small lesions (< 1 cm in size), follow-up with US scan is usually recommended in 3 mo as further imaging tests may not be reliable for the diagnosis. For lesions same or larger than 1 cm, the performance of multiphasic contrast-enhanced CT, MRI or CEUS is a reasonable next step. There has been a controversy on the use of CEUS because intrahepatic cholangiocarcinoma can be misdiagnosed as HCC and CEUS has been subsequently excluded from the diagnostic tests for HCC in updated AASLD practice guidelines[1]. However, it has been argued that intrahepatic cholangiocarcinoma is relatively rare in liver cirrhosis and CEUS can depict suggestive findings of cholangiocarcinoma[4]. As the imaging diagnosis of small nodules with 1-2 cm in size can be particularly challenging, a multi-modality approach is often needed. Biopsy is performed only when imaging findings are inconclusive.

In this article, we explain the technical aspects of CEUS and its differences from CT and MRI. Then CEUS imaging findings of HCC and other cirrhosis-related nodules and the role of CEUS in diagnosing tumor thrombosis and monitoring local ablation therapy for HCC are reviewed.

CEUS uses intravenous microbubble contrast agents that are small (3-5 μm) enough to pass through the pulmonary circulation. Microbubble contrast agents are approved for radiologic use in more than 50 countries and have excellent safety record with lower rate severe adverse reactions than CT contrast[5]. There are a few different types of microbubble contrast agents that are commercially available. Presently Definity (Lantheus Medical Imaging) and SonuVue (Bracco) are most widely used. These are purely intravascular contrast agents that show strong vascular enhancement after bolus injection and slowly diffuse into the blood over about 5 min. Therefore, the contrast agent can be repeatedly injected with about 5-min intervals as needed. Sonazoid (Daiichi), which is most actively used in Japan, shows similar vascular enhancement and is taken up by Kupffer cells in the late phase.

CEUS requires a contrast specific imaging technique that is now widely available in most commercially available ultrasound systems. Low mechanical index (MI) contrast-specific mode is used to visualize the microbubbles continuously while suppressing signals from tissue. A dual-imaging mode, which enables simultaneous real-time display of gray-scale and contrast-specific mode, is essential for scanning small liver lesions. High MI frames can be used to disrupt microbubbles and the enhancement pattern of refilling the scanning plane can be evaluated. This is called disruption-replenishment technique and is useful to visualize vascular morphology within the tumor of enhancement pattern of rapidly-enhancing lesions, especially when it is used with maximum-intensity projection method[6].

CEUS has several advantages over CT or MRI. Firstly, microbubbles can be safely injected in patients with renal failure as there is no renal excretion of the contrast[5]. CEUS is therefore a useful problem-solving method for characterizing liver masses when CT or MRI is contraindicated due to renal failure (Figure 1). There is no need of blood test for renal function before contrast injection. Secondly, CEUS allows real-time assessment of arterial-phase enhancement, eliminating the issue of appropriate arterial-phase timing. CEUS often detects arterial-phase hypervascularity when CT or MRI fails to show it because of incorrect arterial-phase timing (Figure 2)[7]. Real-time evaluation also enables a detailed assessment of arterial-phase filling pattern and vascular morphology within the liver lesion which are often critical for differential diagnosis of rapidly enhancing hypervascular liver lesions[8]. Thirdly, washout phenomenon (negative enhancement of liver lesion relative to the liver in the late phase) in malignant liver lesions is more consistently seen on CEUS than CT/MRI. This is due to the different properties of the contrast material. Microbubbles in CEUS are purely intravascular and show washout in malignant tumors in the late phase; however, CT or MRI may not show washout in malignant tumors with high vascular permeability and large extracellular interstitial space because the contrast agent can leak into the interstitium[7,9]. Fourth, CEUS is relatively inexpensive and very well tolerated by the patients who are claustrophobic. CEUS can be easily repeated in short intervals if needed without the risk of ionizing radiation. Lastly, CEUS can be performed immediately when a new liver nodule is identified, allowing an immediate characterization of benign liver nodules such as hemangiomas and avoiding additional imaging tests[10].

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Figure 1 A 61-year-old man with hepatocellular carcinoma and renal failure. A: Gray-scale ultrasound shows a hypoechoic mass (arrow) within the cirrhotic liver. There is a large amount of ascites surrounding the liver. Contrast-enhanced computed tomography or magnetic resonance scan could not be performed because of renal failure; B: Contrast-enhanced ultrasound (CEUS) image in the arterial phase shows hypervascularity of the mass (arrow) relative to the liver; C: The mass (arrow) shows washout in the portal venous phase. The diagnosis of hepatocellular carcinoma was made based on imaging findings of CEUS without biopsy.

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Figure 2 A 63-year-old man with moderately-differentiated hepatocellular carcinoma. A: Computed tomography scan in the arterial phase shows a small exophytic nodule (arrow) which shows similar attenuation to the liver; B: The nodule (arrow) is slightly hypoattenuating to the liver in the delayed phase; C: Contrast-enhanced ultrasound (CEUS) in the arterial phase clearly demonstrates hypervascularity of the nodule (arrow); D: CEUS in the portal venous phase shows washout of the nodule (arrow).

On the other hand, CEUS is operator-dependent and requires extensive hands-on experience. There are sonographically difficult regions in the liver such as high right subphrenic area. CEUS is not an appropriate staging modality for HCC as it only images some part of the liver with each contrast injection. CT or MRI is always needed for proper tumor staging once HCC diagnosis is made. However, CEUS can be effectively used as a useful problem-solving method utilizing its unique advantages when CT or MRI is indeterminate or contraindicated (Figures 1 and 2)[10].

CEUS is an excellent imaging technique with several unique advantages over CT or MRI, including safe usage in renal failure patients, better detection of arterial-phase hypervascularity due to real-time imaging capability, consistent demonstration of washout in malignant lesions, and excellent patient’s compliance. Therefore CEUS can be effectively used in the diagnostic algorithms of new liver nodules detected during HCC surveillance and pre- or post-RFA evaluation for HCC.