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Toniutto et al. Hepatoma Res 2020;6:50 I http://dx.doi.org/10.20517/2394-5079.2020.40 Page 5 of 21

The American College of Radiology developed the Liver Imaging Reporting and Data System (LI-RADS)
[24]
to standardize the acquisition, interpretation, reporting, and data collection of liver imaging . LI-RADS
is being increasingly adopted in clinical practice for patients at high risk of HCC, thereby enabling the
categorization of observations from LR-1 (definitely benign) to LR-5 (definitely HCC) based on the
[25]
level of suspicion for HCC. However, a recent meta-analysis derived from 14 studies showed that the
performance of LI-RADS for diagnosing HCC has a sensitivity of 67% and specificity of 92%. These data
confirm previous reports indicating that radiologic imaging alone inaccurately stages as many as 20%-25%
of patients undergoing LT for HCC [26-28] .

Histological factors
To increase the prognostic accuracy of the predictive models of HCC recurrence based exclusively on
morphological data, some authors explored using the histological characteristics of HCC obtained by
[26]
nodule biopsy performed before LT. Cillo et al. selected 33 patients with HCC for LT based on tumor
grading obtained by liver biopsy. Patients with moderately to well-differentiated HCC had a 5-year post-LT
survival of 75% despite approximately one-third of them failing to meet the Milan criteria at explanted liver
[28]
examination. With respect to MVI, Shah et al. . evaluated 155 patients with confirmed HCC after LT that
satisfied the Milan criteria, then assessed the presence of MVI via pathological analysis. The presence of
MVI was significantly associated with both the number and size of the nodules and, more importantly, 68%
of patients who developed HCC recurrence were positive for MVI. Despite the undoubted diagnostic value
of pre-LT pathological assessment of tumor grading and MVI, routine tumor biopsy is often unfeasible
[29]
either due to the presence of multiple nodules or the risk of cancer cells seeding .

To overcome these limitations, a recent approach to non-invasively detect the presence of MVI in HCC
is the application of 18F-FDG PET/CT imaging . In HCC, the growth rate and activity of glycolytic
[30]
[31]
enzymes are related . Thus, contrary to what occurs in well-differentiated HCC, poorly differentiated
[32]
HCC cells exhibit low glucose-6 phosphatase activity and high 18F-FDG uptake . Recent studies appear
to confirm that maximum standardized uptake values of 18F-FDG PET/CT imaging are strongly correlated
with the histological characteristics of HCC, such as MVI and tumor grade [33-35] . The optimal cutoff values
for the SUVmax of HCC (SUVmax T) and SUVmax of the normal liver (SUVmax L) in predicting MVI
have been identified as 3.80 and 1.49, respectively . Moreover, in a study that enrolled 34 HCC liver
[36]
[37]
transplanted patients, none of the patients with a SUVmax L/T ratio > 1.5 had well-differentiated HCC .
A further improvement in the radiological detection of MVI in patients with HCC was derived from the
application of gadoxetic acid-enhanced MRI and 18F-FDG PET/CT examinations. With the application
of these radiological techniques, the presence of peritumoral enhancement and the ratio of SUVmax T/
SUVmean L ≥ 1.2 had a statistically significant association with MVI, with an odds ratios of 10.6 and 14.2,
[38]
respectively . When both MRI and PET/CT imaging techniques have been applied in combination, the
[30]
sensitivity and specificity for the prediction of MVI were 78.6 and 80% respectively . Recent experiences
have demonstrated how the combination of 18F-FDG PET/CT can represent valid help in selecting LT
[39]
patients with HCC who exceed the Milan criteria. A Japanese study that enrolled 182 living donor
liver transplanted (LDLT) patients with HCC demonstrated that, in patients exceeding the Milan criteria
with negative 18F-FDG PET/CT and alpha-fetoprotein (AFP) serum levels < 115 ng/mL, the 5-year HCC
recurrence rate was not statistically different from those fulfilling the Milan criteria (19% compared to 7%,
P = 0.1). Similar results have been obtained in a Korean study involving LDLT, wherein patients exceeding
either the Milan or UCSF criteria, but with negative 18F-FDG PET/CT, had 5-year HCC-free survival rates
[40]
after LT of 73.3 and 72.8%, respectively . However, these encouraging results require extensive validation
in Western populations, in patients with different etiologies of liver disease, and in LT performed using
cadaveric donors. Undoubtedly, the combined use of 18F-FDG PET/CT could represent a new and more
accurate system to non-invasively assess the morphological and histological features of HCC in the near
future, which could guide the selection of patients for LT.