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at least 16 years not giving due relevance to the above discussed imaging innovation. Furthermore, western
guidelines erroneously consider CT as equivalent to MRI in diagnostic accuracy even though recent meta-
analyses [60-61] , one of which conducted by the same authors who contributed to the last version of AASLD
guidelines, confirmed, the superiority of the latter. Other hepato-specific contrast media as Sonazoid for
CEUS (s-CEUS) or Super paramagnetic iron oxide agents for MRI (SPIO-MRI) showed promising results
but they are not available worldwide and the experience with these compounds is limited to Eastern
countries [18,19] . Sonazoid (GE Healthcare, Waukesha, WI, USA), is a second-generation contrast agent
available in Japan, South Korea, and Norway (August 2015). The microbubbles of this agent are captured
in the liver parenchyma by reticuloendothelial (Kupffer) cells and, therefore, s-CEUS provides information
in both haemodynamic-phase and accumulated-phase images. Because malignant tumours contain few
or no Kuppfer cells, they appear as perfusion defects in late phase of s-CEUS. Conversely, non-neoplastic
nodules with preserved or only minimally reduced reticuloendothelial system lack wash-out in the late-
phase. Sonazoid proved to be particularly accurate for characterization of small lesions in cirrhosis. In a
[62]
literature review covering 10 years experience with Sonazoid , s-CEUS emerged as accurate as gadoxetic
acid-enhanced MRI in differentiating benign nodules from wdHCC. Furthermore, s-CEUS provides a
[63]
better characterization of some small lesions at contrast-enhanced CT or MRI. Takahashi et al. in a
study comparing s-CEUS and gadoxetic acid-enhanced MRI on characterization of small < 3 cm lesions in
cirrhosis reported that 27% of indeterminate hypo-vascular lesions at MRI turned out to be hyper-enhancing
at s-CEUS and were histologically diagnosed as HCC. For these reasons s-CEUS is currently included by
Japanese and APASL guidelines in the diagnostic algorithm for indeterminate lesions discovered in cirrhosis
during surveillance.

LI-RADS CRITERIA
In 2011 the American College of Radiology issued a new system of liver imaging reporting (LI-RADS) aimed
at providing a precisely defined terminology for interpreting and reporting contrast-enhancing CT and MRI
[64]
examination of nodules detected in cirrhosis . This system also included guidance for the interpretation
of data obtained by MRI with hepato-specific agents. According to LI-RADS, lesions detected at dynamic
CT or MRI in patients at high risk of having HCC (cirrhotic patients under surveillance), are categorized as
definitively benign (LR-1), probably benign (LR-2), intermediate probability of being HCC (LR-3), probably
HCC (LR-4) and definitively HCC (LR-5). This system would provide more guidance to clinicians to adopt
proper clinical decisions such as accelerated follow-up, biopsy or even treatment of small lesions in cirrhosis.
According to criteria proposed by LI-RADS the great majority of dysplastic nodules are categorized as LR-3
[64]
and LR-4. LR-3 lesions should be strictly monitored and LR-4 lesions require biopsy .
LI-RADS system was strongly encouraged by the US regulatory agency for liver transplantation (UNOS)
to avoid or minimize futile transplants for false positive cases. Indeed, LI-RADS criteria proposed by LI-
[57]
RADS v2014 and by the updated 2017 version (v2017) for diagnosis of HCC are more restrictive than
those proposed by AASLD-EASL and do not accept the diagnosis of definitive-HCC (LR-5) for lesions sized
1-2 cm even in presence of wash in and washout. In these cases a 50% growth in at least 6 months is needed
for definite classification as LR-5. These stringent criteria would limit de facto the early diagnosis of HCC
in the group of 1-2 cm nodules. These limits were emphasized by a prospective study comparing LI-RADS
classification with AASLD criteria for HCC on 133 small (< 2 cm) newly detected nodules in cirrhosis
[65]
studied by MRI . In this study 21 histologically proven eHCCs were erroneously subcategorized as LR-4
according to LI-RADS criteria even though they were hyper-enhancing at arterial phase with late wash-out.
In addition, 29 small HCCs fell into LR-3 category making the overall sensitivity of LI-RADS for HCC 43%,
[66]
relevantly lower than the sensitivity of AASLD criteria (58.6%). Similar results were obtained by Ronot et al. in a
prospective study on 595 nodules < 3 cm in cirrhosis, where specificity of LI-RADS criteria for diagnosis
of HCC relevantly increased and became better than AASLD criteria when LR-4 and LR-5 categories
were considered in combination. On the other hands and more important, in the study by Darnell et al. [65]