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Page 8 of 21 Toniutto et al. Hepatoma Res 2020;6:50 I http://dx.doi.org/10.20517/2394-5079.2020.40

discriminatory function with respect to time to HCC recurrence. A low MoRAL score (cutoff ≤ 314.8)
was associated with significantly longer recurrence-free (vs. > 314.8) and overall survival in the cohort
exceeding the Milan criteria. The 5-year recurrence-free and overall survival rates of patients exceeding the
Milan criteria with a low MoRAL score were as high as 66.3% and 82.6%, respectively. Moreover, patients
within the Milan criteria with a high MoRAL score showed a higher risk of recurrence than patients
exceeding the Milan criteria with a low MoRAL score.

[72]
Only one retrospective study combining AFP and DCP serum levels to predict HCC recurrence was
performed outside of Asia, in the US. The authors demonstrated that AFP ≥ 250 ng/mL and DCP ≥ 7.5 ng/mL
were associated with a higher risk of HCC recurrence. When AFP and DCP were combined with the Milan
criteria, the hazard ratio increased from 2.6 for outside the Milan criteria to 8.6 for outside the Milan
criteria and AFP ≥ 250 ng/mL, and to 7.2 for outside the Milan criteria and DCP ≥ 7.5 ng/mL.

Systemic inflammation biomarkers
The option of considering inflammatory markers as elements associated with greater HCC invasiveness or
with more frequent recurrence after LT arises from certain studies conducted on C-reactive protein (CRP).
CRP is a protein synthesized by hepatocytes in response to systemic inflammation and has been implicated
[73]
in the prognosis of HCC . Some Asian studies have demonstrated that in patients outside the Milan
criteria, high serum CRP levels were significantly associated with a higher risk of HCC recurrence [74,75] .

Besides CRP, recent studies have identified NLR and PLR as two inflammation markers involved in the
[41]
prognosis of HCC . Halazun et al. reported that in patients within the Milan criteria, an NLR ≥ 5 was
[76]
associated with worse recurrence-free survival after LT than in patients with an NLR < 5 (25% vs. 75%).
These observations led the authors to propose a risk model for predicting HCC recurrence that includes
NLR and tumor size > 3 cm in diameter. Further studies have been conducted to assess the real impact of
NLR on the independent risk of HCC recurrence along with MVI and the size and number of nodules.
Recent meta-analyses have highlighted that the cutoff value of NLR is rather heterogeneous among different
studies, which is justified since the results obtained were not comparable. By applying an NLR cutoff value
of 4, the majority of studies have indicated that a high NLR value is associated with MVI and a lower HCC
recurrence-free survival after LT [77,78] .

Regarding PLR, high PLR has been associated with a significant increase in HCC recurrence after LT .
[79]
Notably, the prognostic value of PLR in determining the risk of HCC recurrence should be evaluated with
caution. Moreover, some reports indicate that the absolute platelet count seems to be as important as PLR.
9
In patients with a platelet count ≥ 75 × 10 /L on the day before transplant, the HCC recurrence rate was
significantly higher than in patients with a platelet count < 75 × 10 /L (28.2% vs. 13.2%) ; interestingly the
[80]
9
former group of patients presented more frequently with poorly differentiated HCC, MVI, and bile duct
invasion compared to the latter group.
Many hypotheses have been proposed in an attempt to explain the pathophysiological mechanisms
involved in determining the influence of NLR and PLR in HCC recurrence after LT. Both neutrophils and
platelets are implicated in promoting vascular invasion and the development of metastasis of tumors by
increasing the production of vascular endothelial growth factor (VEGF) [81,82] . Furthermore, platelets may
promote the establishment of HCC metastases by blocking tumor cell removal [83,84] . Since high NLR and
PLR are determined by low lymphocyte numbers, it may be hypothesized that the reduction in lymphocyte
numbers could result in impaired immune surveillance against HCC . While existing studies conducted
[41]
on inflammatory markers have provided interesting results, they also have several limitations. Specifically,
the retrospective nature of the studies and the small number of cases represent the major limitations.
Moreover, the different cutoffs applied to NLR and PLR make adoption of these models for predicting the
risk of HCC recurrence in the clinical practice unvalidated.