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Shimizu et al. Hepatoma Res 2020;6:12 I http://dx.doi.org/10.20517/2394-5079.2019.48 Page 7 of 9

reported that HCC incidence was 3.73 HCC/100 person-years in 1123 cirrhotic patients treated with
interferon (IFN)-free regimens and 72 patients developed HCC within a median of 10.3 months after
starting antiviral treatment. Although some large-cohort studies and systemic reviews revealed that there
were no significant differences in hepatocarcinogenesis after achieving SVR between patients treated with
IFN and those treated with DAAs, there are still unknown mechanisms involved in the increased risk of
[22]
HCC emergence in IFN-free regimens. Yoshimasu et al. reported that the HCC occurrence rate after
DAA treatment was very low and the recurrence rate was lower than that in previous IFN reports.

The AFP level and AFP-L3% were identified as important factors in predicting the occurrence/recurrence of
[23]
HCC; thus, patients with such levels are still at risk of developing cancer after SVR. Villani et al. reported
that DAA administration induced an early increase in serum vascular endothelial growth factor (VEGF)
[24]
and a change in the inflammatory pattern, coinciding with HCV clearance. Debes et al. identified a set
of 12 immune mediators whose levels were significantly higher in serum before DAA treatment of patients
who eventually developed de novo HCC compared to controls. A panel of nine cytokines, measured in
serum before treatment (MIG, IL22, TRAIL, APRIL, VEGF, IL3, TWEAK, SCF, and IL21), identified
patients who developed de novo HCC with an area under the receiver operating characteristic curve value
higher than 0.8. Further analyses of the mechanism also provide important information about HCV-
induced carcinogenesis and the effects of DAAs. In this study, we focused on the HCV status; however,
HCC recurrence and overall survival are associated with multiple factors including liver fibrosis, immune
status, life style, and comorbidities.

Several studies revealed that the ADC value was a predictive factor of the histological grade of HCC [25-27] .
However, in this study, we could not find a significant difference in ADC values between DAA-SVR
and HCV-positive HCC. In contrast to these studies that included patients who received resection or
transplantation, our patients had a smaller size of HCC, which led to inaccurate quantification values due
to technical error.

There are some limitations in this study. The sample size was small and this study was conducted in a
single center. DAA-SVR HCC patients received HCC screening within six months before administration of
DAAs; however, the imaging modality was not uniform, including CT, MRI, or ultrasound. Therefore, we
could not definitely exclude the possibility that small hepatic nodules that could be detected only by HPB
of EOB-MRI were missed in some patients before DAA treatment. Tumor biopsy was performed only when
the patients agreed to the procedure and the location of the tumor was not near large vessels, liver surface,
and other organs. Therefore, the correlation between pathological and MRI features should be evaluated in
a large cohort in which patients received liver resection.

Our study is the first to reveal the significant differences in MRI findings between DAA-SVR and HCV-
positive HCC. According to our results, HCC that develop within one year after the end of DAA treatment
would have unique imaging features that may be linked to malignant phenotype if not found and treated
early. Today, most patients with HCV infection can achieve viral eradication with DAA therapy. However,
in high-risk patients such as those with cirrhosis, the surveillance of HCC should be done at early
time points after SVR to diagnose HCC at an early stage and curatively treat it with resection, RFA, or
microwave ablation, which may lead to better OS in these patients.

DECLARATIONS
Acknowledgments
We really appreciate the meaningful suggestion from Dr. Utaroh Motosugi (Yamanashi university) and
valuable pathological comments from Dr. Kotaro Matsunaga (St. Marianna University school of Medicine).