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Borzio et al. Hepatoma Res 2019;5:15 I http://dx.doi.org/10.20517/2394-5079.2019.11 Page 7 of 16

appear as iso- or even hyper-intense nodules. These contrast agents are therefore potentially able to
[35]
distinguish differently progressed lesions . Although the full potential of liver-specific-contrast media
needs to be fully assessed in prospective studies, the use of these agents is now considered mandatory in this
[36]
setting since they provide better diagnostic accuracy than the vascular contrast media . Recent data on
histologically well characterized small atypical nodules in cirrhosis, confirmed the high diagnostic accuracy
of Gd EOB DTPA MRI to correctly distinguish eHCC from premalignant nodules. Ninety-seven percent
of iso/hypovascular nodules were correctly classified as premalignant or malignant in HE-phase with a
specificity of 100% for malignancy when hypointensity in HP phase was coupled with hypervascularity in
[32]
[38]
[37]
arterial phase . These data are well in keeping with those of Choi et al. . In a recent prospective study
carried out on 111 small nodules defined as atypical at CEUS or dynamic CT and histologically classified
as eHCCs or dysplastic, either LG-DN and HG-DN, emerged that HE-phase hypointensity by itself using
Gd-EOB-DTPA was the strongest predictor of malignancy superior to vascular-based hallmarks and T2w
behaviour. All hypointense nodules at HE phase were malignant/premalignant (overt HCC or eHCC/HG-
DN) and hypointensity captured 45/51 malignant nodules either hyper- or hypovascular, with a sensitivity
of 88% and specificity of 97% reaching 100% when associated with arterial enhancement. In this study, all
benign nodules (large regenerative or LG-DN) displayed iso-hyperintensity at HE-phase. However, it could
be outlined that a very low rate (roughly 3%) of well-differentiated hepatocellular carcinomas (wdHCCs), are
hyper vascularized at arterial phase but are iso-hyperintense on HE-phase mainly because they retain still
functioning hepatocytes [39-43] . It is wise to consider nodules with arterial enhancement but hyperintense in
HE as highly suspicious of incipient malignant transition.

The differential diagnosis between HG-DN and eHCC still remains difficult even by Gd-EOB-DTPA MRI
since HG-DN show variable behaviour on HE-phase being frequently hypointense like eHCC [38,44-48] . Indeed,
the specificity of hypointensity on HE-phase as a unique hallmark of malignancy, is suboptimal ranging
from 33% to 97% [38,49] . It has been recently outlined that coupling Gd-EOB-DTPA MRI with diffusion-
weighted imaging (DWI) may result in increased accuracy for diagnosis of overt HCC and also for the
differential diagnosis of eHCC and HG-DN [44,45] . DWI is based on the simple assumption that water diffusion
in the extracellular compartment is influenced by cellular density which, in turn, reduces the width of
interstitial spaces and water diffusion [50,51] . Water diffusion can be quantified by a mathematical index called
apparent diffusion coefficient (ADC); low ADC values mean low diffusivity, namely hypercellularity and,
as previously stated, hypercellularity progressively increases from HG-DN, to eHCC reaching maximum
expression in progressed HCC. Unfortunately, DWI as a unique tool for assessing hepatic lesions is
inaccurate due to the considerable overlap between benign and malignant lesions and normal liver tissue [52,53] .
In addition, DWI images are highly influenced by artefacts of liver motion due to respiration and artefacts
in the left lobe derived from the heart beating [54,55] . Therefore, DWI should be used in conjunction to the
[56]
other conventional imaging features. Renzulli et al. reported data from a prospective study evaluating the
imaging criteria of HCC, early HCC and HG-DNs using gadoxetic acid-enhanced liver MRI in 228 patients
prospectively enrolled with 480 small nodules detected under surveillance for cirrhosis. Using three MRI
findings: HE-phase hypointensity, arterial hyperintensity and diffusion-weighted imaging (DWI) the authors
designed an algorithm which yielded an overall sensitivity of 96.6% and a specificity of 92.7% and a very high
sensitivity (94.7%) and specificity (99.3%) in classifying HG-DN. Although some technical aspects need to
be fully standardized (type of MRI machine, breath old method, b value for DWI), gadoxetic acid-enhanced
MRI including DWI analysis as part of a diagnostic algorithm, may represent a promising approach to better
defining those small lesions still atypical at vascular and HE phases being eHCC hyperintense and HG-DN
isointense al DWI. DWI behaviour is currently part of ancillary features for liver nodules characterization in
[57]
Liver Imaging Reporting and Data System (LI-RADS) v17 system (see above) .

These advances on MRI prompted JHS and APASL guidelines to incorporate gadoxetic acid-enhanced MRI
for definition of atypical nodules before performing biopsy [18,19] . Conversely, the late version of guidelines
from the Western world [58,59] , still endorse a diagnostic algorithm for HCC that have remained the same for