Hepatocellular carcinoma (HCC) is the most common primary malignant liver neoplasm, more frequent in patients with HCV- and HBV-related cirrhosis, alcoholic cirrhosis, or hemochromatosis.

In the last 20 years, the incidence has risen sharply, so HCC represents the fifth most common cancer in the world and the third leading cause of death for neoplasm [4]. Except for the limited percentage of “de novo” HCC arising in noncirrhotic patients, the genesis of HCC is a “multistep” process including regenerating nodules and low- and high-grade dysplastic nodules up to overt HCC. During carcinogenesis process, liver vascularization becomes irregular and mostly arterial, with progressive reduced portal supply [5, 6]. Therefore, at CEUS, HCC occurs, in its typical form, as inhomogeneously hypervascular in the arterial phase, with more or less rapid washout in the extended portal-venous phase with hypoechoic appearance (“washout” sign) sometimes associated with a peripheral hypervascular halo (pseudocapsule) in the extended portal venous phase. However, according to the degree of differentiation, HCC may present different aspects. In fact, well-differentiated HCC, although hypervascular in the arterial phase, cannot be hypoechoic in the extended portal-venous phase causing misunderstanding at CEUS [7]. Moreover, CEUS allows the differentiation between HCC from regenerative and low-grade dysplastic nodules since these latter are not hypervascular in the arterial phase and are mainly indistinguishable from the remaining liver parenchyma in the extended portal-venous phase [8].

Being a real-time imaging modality, CEUS can be considered as problem-solving technique when CT or MR are not able to definitively characterize a nodule in cirrhotic patients allowing a better delineation of contrast enhancement behavior especially in the arterial phase when CT or MRI fails to show it because of incorrect arterial-phase timing [9, 10].

Nevertheless, CEUS has important limitations in surveillance programs of these patients because the short duration of the arterial phase does not allow to detect possible new hypervascular foci in all liver segments except with multiple contrast agent injections, but this is not feasible during daily clinical practice [11].