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monitoring and tumors are often large with possible vascular involvement. In these patients, performing
a liver biopsy is often necessary for diagnostic confirmation. A second, frequently, is that of patients with
[1]
chronic liver disease (cirrhosis or advanced fibrosis) under regular ultrasound surveillance . The goal of
[2]
surveillance and screening is to reduce mortality . For the aforementioned reasons HCC meets the criteria for
developing a surveillance program and the use of ultrasound as a screening tool is accepted by major scientific
[3-5]
societies . In many studies the 3-year survival rate varies between 50.8% and 45.6% in patients under
surveillance and 27.9% and 28.8% in those not screened. Even after correction for lead time bias, the three-year
survival is better in patients undergoing ultrasound surveillance: 39.7% vs. 29.1%. It is likely that the increased
survival in patients undergoing surveillance is linked to an increase in early detection of HCC in patients
[5]
screened (OR of 2.11; 95% CI, 1.88-2.33) and therefore of the use of curative treatments (61.8% vs. 38.2%) .

ULTRASONOGRAPHY AND CONTRAST-ENHANCED ULTRASONOGRAPHY
Efficacy of detection of HCC with ultrasound varies widely and in cirrhotic patients presents with a
[7]
[6]
sensitivity of 33%-96% while specificity reach over 90% . The identification of small HCC nodules in
cirrhotic liver with a coarse parenchymal pattern is not easy, therefore a skilled operator must work with
adequate equipment, preferably in dedicated centers. In gray-scale ultrasound small HCCs typically appear
as a hypoechoic lesion. In some cases increased echogenicity may be present due to adipose degeneration.
Sometimes the hypoechoic nodule may present a hyperechoic focus which is suggestive of development of
[8]
HCC within a dysplastic nodule (nodule in nodule phenomenon) .

But not all nodules identified with ultrasound in patients with chronic liver disease (cirrhosis or advanced
fibrosis) undergoing surveillance are HCCs. In this context, the role of imaging is to differentiate the
nodules of HCC from other malignant lesions (intrahepatic cholangiocarcinoma and metastasis) and non-
malignant (e.g., regenerative nodules, low and high grade dysplastic nodules, confluent fibrosis, angiomas,
etc.) that can be found in the cirrhotic liver. In oncology, the diagnosis of cancer generally requires
histological assessment; from this point of view HCC is an exception since a non-invasive diagnosis can
be achieved with imaging alone in these high-risk populations. The peculiar angiographic behavior of the
HCC nodules in a cirrhotic liver characterized by the presence of the wash-in during the arterial phase
and by the wash-out during the venous and late phases, represents the diagnostic hallmarks of HCC.
These characteristics are able to provide a reliable diagnosis of HCC in high-risk patients affected by liver
cirrhosis or with advanced fibrosis, and represent the background for the development, by Western and
Asian scientific societies, of different algorithms for non-invasive diagnosis of HCC [3,4,9,10] . The recommended
imaging methods are computed tomography (CT) and MRI with contrast agents. Diagnostic algorithms
of American Association for the Study of Liver Diseases (AASLD) and European Association for the Study
of the Liver (EASL) guidelines adopt a strategy dependent on the size of the lesion. Nodules smaller than 1
cm are considered too small to be characterized and both guidelines recommend ultrasound monitoring
every three (AASLD) or four months (EASL). As for the diagnosis of nodules with a diameter greater than
2 cm, both guidelines recommend only one imaging method. For nodules with a diameter of 1-2 cm, the
statements differ, as the American guidelines recommend the same approach used for lesions larger than
2 cm (only one contrast method is sufficient), while the European guidelines contemplate the concordance of
two consecutive images if these cases are not followed in centers with substantial “expertise”.

Consequently, in cirrhotic patients, biopsy is indicated only in cases where nodules do not present
contrasting features typical of HCC. However, the increasing knowledge about the immunohistochemical
and molecular characteristics of HCC may bring biopsy to the forefront in order to select patients who could
[11]
gain the most benefit from target-driven HCC treatments .
In conclusion, the identification of a liver focal lesion greater than 1 cm in the course of surveillance of
patients at risk with ultrasonography imposes the study of the nodule vascularization through the use of