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

The new 2017 Japanese guidelines on management of HCC stated that CEUS sensitivity is similar to dynamic
CT or dynamic MRI in diagnosis of HCC and therefore CEUS is able to characterize nodules detected
on sonography. The US contrast agent indicated in these guidelines is Sonazoid, which is a US contrast
agent phagocytized by Kupffer cells . In the past, controversies arose over the possibility of misdiagnosis
[24]
between small (< 3 cm) Intrahepatic Cholangiocarcinoma (ICC) arising in cirrhosis and HCC. In such cases,
CEUS was considered unable to distinguish between these two entities in cirrhotic livers because, in the
experience of Spanish authors, CEUS washout patterns of ICC can mimic those of HCC . As of today, it is
[25]
well established that the differential diagnosis between small < 3 cm ICC in cirrhosis and small HCC is no
longer a problem. It is well known that, at CEUS, small ICC can present an intense (as HCC) arterial phase
hyperenhancement, but a more rapid and marked washout in the portal phase (always < 42 s), differently
from the mild and very late wash-out (> 60 s) of HCC in the sinusoidal phase, avoiding any pitfalls [26,27] .
Therefore, the old diatribe that for several years has labelled CEUS not able to distinguish between small
HCC and ICC nodules arisen in a cirrhotic liver is now to be considered surpassed [25-31] . Nevertheless, we
should consider that small HCC nodules (< 2 cm) can present with hyperenhancement in the arterial phase
followed by isovascularity in the portal and sinusoidal phases in more than 50% of cases (as is shown in
Figure 4 and Giorgio’s 2011 results .as reported below.

CEUS LI-RADS and HCC
A so-called CEUS LI-RADS was proposed by the American College of Radiology based on the Liver Imaging
Reporting and Data System (LI-RADS) using CECT and CEMRI patterns for HCC in cirrhotic livers. LI-
RADS was originally developed for CECT and CEMRI, but expanded to include CEUS. Based on CEUS
features, focal liver lesions (“observations” in radiologic terminology) detected in a cirrhotic liver can be
classified in 5 major classes ranging from “definitely benign” (LR-1) to “definitely HCC” (LR-5) . Sonovue is
[32]
included in the CEUS LI- RADS version 2017 . The 5 major categories (LR-1-LR-5) are classified according
[32]
to the diameter of the lesions and their contrast enhancement patterns.
The CEUS pattern characterized by the presence of rapid, intense and homogeneous hyperenhancement in
the arterial phase (APHE) followed by mild and late (> 60 s) wash-out is termed as CEUS LI-R 5. When a
hepatic nodule discovered in a cirrhotic liver presents with the CEUS LR-5 pattern, the nodule can managed
as HCC and there is no need for biopsy. This classification is applied to nodules > 10 mm [32-35] .

Very recently, Terzi et al. reported very interesting data that strongly influenced the last 2018 EASL guidelines
[36]
in diagnosis of HCC. In a multicentre retrospective study, these authors evaluated CEUS patterns of 1,006
nodules in 848 patients with chronic liver disease at risk for HCC. Median size of nodules was small: 2 cm.
Five hundred twenty one (52%) out of all nodules showed APHE and a mild, late wash-out. The 17% of nodules
showed APHE and isoechogenicity in the portal and late phase, while 16% of nodules were iso-enhancing in
the arterial and portal-late phases. The most important data was that 512 (98.5%) of all nodules classified as
CEUS LR-5 were HCC. When authors included in their analysis 3 other CEUS LR-5 cases that were judged
underdiagnosed and that resulted HGDN at biopsy, the rate of HCC diagnosis became 99%. In their study,
Terzi et al. did not report any case of misdiagnosis with ICC.
[36]

Moreover, studies on inter-observer agreement suggest that the classification of small hepatic nodules (< 2 cm)
with LI-RADS-CEUS is reproducible with good consistency in patients with chronic liver disease [37-39] .

CEUS arterial hyper enhancement and early HCC
Some authors studied the interobserver agreement for CEUS-based standardized algorithms in diagnosis of
HCC in high-risk patients. The interobserver agreement was good for arterial phase hyper enhancement,
which is the key diagnostic feature for HCC nodules in a cirrhotic liver . For what has been said so far,
[39]
although it is evident that HCC diagnosis on CEUS relies also on the washout findings (type and time),