Page 178 - Read Online

Page 6 of 16 Borzio et al. Hepatoma Res 2019;5:15 I http://dx.doi.org/10.20517/2394-5079.2019.11

At imaging using the so-called extracellular contrast media, mature HCC shows a typical vascular pattern
characterized by homogeneous and intense contrast uptake in the arterial phase known as “wash in” followed
by a progressive washout of contrast in venous or late phases. Opposite, regenerative nodules, being a simple
hypertrophic inflammatory growth of normal hepatocytes, maintain a normal vascular supply and share the
same contrast uptake as the surrounding cirrhotic parenchyma during arterial and venous phases. Dysplastic
nodules, either LG-DN or HG-DN lack a well- developed neoangiogenesis and maintain normal or partially
normal portal inflow appearing as non-enhancing or partially enhancing nodules. Conventional dynamic
imaging “per se” cannot differentiate LG-DN from HG-DN. Diagnostic difficulties are also represented by
those incipient eHCCs with still poorly developed neoangiogenesis which usually appear as non-enhancing
lesions (the so-called hypovascular HCC) and, therefore, hardly distinguishable from HG-DNs.

According to all the international guidelines [16-20] arterial wash-in and late washout, when present, are
sufficient for the diagnosis of HCC and histologic confirmation is not necessary even for small lesions. This
paradigm served to design the non-invasive diagnostic algorithm for nodules detected in cirrhotic patients
under surveillance proposed by AASL-EASL-ERTOC guidelines [16-17] . According to this algorithm, new
lesions < 1 cm should be strictly monitored without biopsy. Nodules > 1 cm showing definite hallmarks
of malignancy by a single enhancing imaging do not require confirmation by a second one and diagnosis
of HCC is accepted. In case of equivocal/inconclusive results by the first imaging, a second one should
be sequentially performed. If uncertainty still persists after two dynamic techniques, lesion should be
categorized as indeterminate or atypical and biopsy is recommended [16,29] .

This sequential strategy demonstrated high specificity and almost absolute PPV for diagnosis of HCC and,
in clinical practice, proved to be cost-effective and useful for minimizing the number of futile biopsies [9,22] .

Although specificity and positive predictive value of radiologic hallmarks of malignancy (wash in and
late washout) are close to 100%, their sensitivity in small lesions is suboptimal (71%) [30,31] . According to
vascular-based imaging modalities one-third of small nodules discovered under surveillance remain indeed
indeterminate or atypical even by dynamic MRI. Indeterminate/atypical lesions include approximately 30%
of hypovascular eHCCs [7,22,32] and the large majority of pre-neoplastic lesions (the one-third rule: one-third of
small lesions are indeterminate and one-third of them are HCCs).

Premalignant nodules are usually detected by standard US as hypo- or, less frequently, as hyper-echoic small
nodules. Hence, standard US cannot be used for differential diagnosis being dysplastic nodules completely
indistinguishable from well-established HCC. On dynamic imaging these nodules appear as non- or weakly
enhancing lesions on arterial phase and hypo/iso-enhancing on venous/delayed phases (hypovascular
nodules). Therefore, they fall into the group of indeterminate/atypical lesions and, as recommended by
AASLD/EASL guidelines, they should require histologic diagnosis. In this setting however, the role of
biopsy is still debated (see above). The differentiation between DN and eHCC is challenging on conventional
dynamic imaging. The recent introduction of MRI hepato-specific post-vascular contrast media has
represented a relevant diagnostic advance in the characterization of small nodules in cirrhosis [33,34] .
Gadolinium-chelate agents as gadolinium ethoxybenzyl diethylenetiamine pentaacetic acid (Gd EOB DTPA,
©
©
Primovist ) or gadobenate dimeglumine (Gd-BOPTA, MultiHance ) enter the hepatocyte by the organic
anion transporter polypeptide 1 (OATP1) and are excreted in the bile canaliculi by MRP2,3,4 protein
transporters. These agents make possible to achieve information not only on the vascular profile of a given
lesion (dynamic phase) but also on specific hepatocyte functions in the so-called hepatobiliary phase (HE
phase). During carcinogenetic process, proteins responsible of uptake and excretion of gadolinium-chelates
[35]
are progressively lost and this derangement may precede changes on vascular profile . Most eHCCs and
veHCCs, are in fact no longer able to incorporate gadolinium-chelates and appear hypo-intense on HE
phase. Opposite, LG-DN and most HG-DN maintain still preserved uptake function and consequently