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Page 2 of 9 Giorgio et al. Hepatoma Res 2019;5:20 I http://dx.doi.org/10.20517/2394-5079.2019.05

of this kind of tumor. HCC is the most frequent primary epitelial malignant tumor of the liver . The main
[1]
feature of this tumor is that it arises mainly in patients with cirrhosis trough the transformation of normal
regenerating nodules in displastic nodules and finally overt HCC . For non cirrhosis HBV patients, it is
[1-5]
via HBV-DNA integration into the host genome, which occurs at early steps of clonal tumor expansion
and induces both genomic instability and direct insertional mutanegesis. Therefore, patients with cirrhosis
represent a high risk population for developing HCC and should undergo a 6 months surveillance with
ultrasound (US) to allow the detection of the tumor at an early stage [6-13] . In clinical practice, CECT and
CEMRI are not recommended in the surveillance programs. Viceversa, when US examination shows a new
nodule, CECT and/or CEMRI are reccomended for the staging of the disease.

VASCULAR CHANGES IN HEPATOCARCINOGENESIS AND CEUS
It is well known that in the case of HCC arising on cirrhosis the normal vascular support is reversed: while
in normal subjects the vascular support of the liver is provided by the portal venous system up to 75%, in
HCC the blood supply of the nodule is only arterial.

The process of hepatocarcinogenesis in cirrhosis includes the progression from Low Grade Displastic
nodule to High Grade Displastic nodule (HGDN) and overt HCC. During this process, unpaired arteries
progressively substitute tumoral portal tracts so that overt HCC blood supply is only arterial. This
pathological phenomenon explains the arterial hyperenhancement of typical HCC nodules on dynamic
imaging modalities such as CECT, CEMRI and CEUS [14,15] .

In recent years, CEUS has gained significant popularity in the characterization of focal liver lesions. CEUS
has shown to have a great capability in distinguishing between benign or malignant hepatic nodules on the
basis of characteristic patterns of blood supply of the lesions . The 2nd generation contrast agent SonoVue
[16]
is a pure blood stream agent formed by micro bubbles with inert gas sulphur- hexafluoride and a palmitic
acid shell. After Intra venam injection of 2.4 mL of SonoVue, in real time and second by second, the arterial
phase appearance of contrast agent distribution within the nodule’s vessels (duration 10-30 s after contrast
injection) can be studied and recorded, followed by the portal phase (30-60 s after injection ) and the late or
sinusoidal phase (60-240 s) [16,17] . The typical CEUS pattern of HCC in cirrhosis is reported in Figures 1-5 [18,19] .

HCC DIAGNOSIS IN CIRRHOSIS AND ROLE OF CEUS
US surveillance of HCC in cirrhosis and CEUS
It is well known that conventional US, although a unique tool for surveillance, has a great sensitivity but a
very low specificity in the characterization of HCC in cirrhosis . CEUS has shown to significantly improve
[16]
US accuracy [16,20] . CEUS using SonoVue easily show the characteristics of liver nodules blood supply and
therefore allow the characterization of malignant nodules .
[17]
CEUS has determined a real revolution by eliminating the low specificity of conventional US in diagnosing
and managing HCC after recognition of a new nodule in a cirrhotic liver: this is due to the immediate and real
time visualization of its vascular supply . Other advantages of CEUS are the absence of ionizing radiation,
[16]
the low cost, repeatability, safety and, more important, the possibility to be performed in patients with renal
insufficiency [16,21] . Moreover, it has been reported that CEUS add significant diagnostic information in the
characterization of atypical or indistinctive lesions on conventional US [21,22] .

The main limitation of CEUS using pure blood stream contrast agents is based on the fact that only one lesion
at a time can be studied and characterized, due to the very short duration of the arterial phase (see later).
Consequently, CECT and/or CEMRI are the only dynamic imaging modalities to be used for the staging of
the tumor. For the same reasons, CEUS with pure blood stream agents such as sulphur hexafluoride cannot
be used for surveillance, unlike Sonazoid which is a new US contrast agent using perflubutane (see later).