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Borzio et al. Hepatoma Res 2019;5:15 I http://dx.doi.org/10.20517/2394-5079.2019.11 Page 9 of 16

none of the non-malignant hepatocellular nodules fell into LR5 category making the LI-RADS specificity
for HCC diagnosis close to 100%. The high specificity of LI-RADS criteria was further emphasized in a
[67]
recent systematic review in which data from 2,760 patients were analysed . The authors found that only
3% of observations categorized as LR5 were non-malignant giving a 97% overall specificity of LI-RADS
[68]
for malignancy. To overcome the low sensitivity of LI-RADS, the most recent version (v2018) provides
updated criteria for small (10-19 mm) LR-5 observations and a simplified definition for threshold growth. In
this version, in order to align LI-RADS criteria with AASLD/EASL criteria of HCC and increase simplicity,
a 10-19 mm nodule with arterial phase hyperenhancement and non-peripheral “washout” is definitely
categorized as LR-5.

According to LI-RADS v2018, hypointensity in the HE-phase and DWI hyperintensity are considered as
[66]
ancillary features but they should not allow upgrading a suspected malignant lesion (LR-4) to LR-5 . In
order to significantly increase the diagnostic efficacy of the MRI LI-RADS criteria it has been suggested that
they should be modified (mLI-RADS) by incorporating hypointensity in the HE-phase and hyperintensity at
[68]
diffusion restriction among the major MRI features of malignancy .

A further progress in the diagnostic accuracy small HCCs comes from the recently released Contrast-
Enhanced Ultrasound LI-RADS (CEUS LI-RADS v2017) which provides a refined definition of the
[69]
typical CEUS pattern of HCC . According to CEUS LI-RADS criteria, a nodule showing a rapid arterial
enhancement and a delayed wash out (> 60 s) can be classified as definite HCC (LR-5) regardless its size.
These criteria were recently validated in a series of 1086 well-defined lesions detected in cirrhosis and studied
by CEUS. Applying CEUS LI-RADS criteria 58.5 % of HCCs were correctly classified as LR-5 with a PPV of
[70]
98.5% and only 3% of non-malignant nodules were erroneously classified as HCC . Thus, LR-5 CEUS is an
extremely reliable criteria for HCC, given its excellent PPV, without misdiagnosis for other malignancies.
[70]
Using CEUS LI-RADS criteria most of LG and HG-DN were classified al LR-3 and LR-4 . These results are
extremely important and support the use of CEUS in clinical practice not only for the definite diagnosis of
HCC when other imaging is inconclusive but also for monitoring indeterminate lesions at risk of neoplastic
transformation considering that it is cheaper and more accessible than MRI.

NATURAL HISTORY OF PRENEOPLASTIC LESIONS
Although preneoplastic lesions have been described several years ago, their natural history has been
clarified only recently by prospective studies carried out on cirrhotic patients undergoing US surveillance
for early detection of HCC. Early small series from Japan [71-73] collected in a pre-dynamic imaging era,
and including ultrasonically detected non malignant lesions classified according to different histologic
criteria, provided preliminary evidence of the preneoplastic role of adenomatous/dysplastic nodules. More
robust and convincing data derived from two successive prospective studies [5,74] comparing the natural
history of different non-malignant lesions detected by ultrasounds in cirrhosis and categorized according
to IWP classification. These studies confirmed that HG-DN were the true precursors of HCC with a risk
of neoplastic transformation significantly higher as compared to LG-DN and LRN. Similar conclusions
[75]
emerged from a single centre study on 66 LRNs and 20 DNs with a 28-years follow-up by Sato et al. .
However, in these studies, the overall rate of malignant evolution of HG-DN nodules was relatively low
ranging from 9% to 31% and neoplastic evolution could be documented in large regenerative/LG-DN as well
albeit at a lower rate [5,74] [Table 2]. In addition, transforming progression of HG-DNs was hardly predictable
in terms of elapsing time from US detection to HCC transformation. In fact, some HG-DNs remained stable
over a long time (20% to 50%), often exceeding the follow-up time suggested by AASLD/EASL guidelines (18
months), and some disappeared during follow-up. These data rise concern on the low PPV of morphology as
a unique tool for the correct identification of nodules at risk of transformation when applied to small samples
supporting a “watchful waiting” policy based on a strict radiologic surveillance. Conversely, Iavarone et al. [76]
in a retrospective-prospective study carried out on 36 non-malignant nodules histologically classified as