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Zanetto et al. Hepatoma Res 2018;4:70 I http://dx.doi.org/10.20517/2394-5079.2018.102 Page 9 of 16

explain their apparently higher risk (3.1 vs. 1.1/100 per years). In another meta-analysis conducted on 24
[62]
studies , the factors associated with recurrent HCC included a history of HCC recurrence, and a shorter
interval between HCC complete response and DAA initiation. This led the authors to recommend delaying
DAA treatment for at least 6 months after HCC treatment, thus enabling a longer immune surveillance of
existing microscopic HCC clones. Delaying DAA treatment could also allow more time to assess HCC treat-
ment response, thereby minimizing the chances of misclassification bias. Such a delay was merely a precau-
tionary (not evidence-based) suggestion, said the authors, that might be adopted in clinical practice while we
wait for this HCC-DAA issue to be solved. Even though we still need more long-term evidences to discon-
firm the possible role of DAA-mediated viral eradication in enhancing HCC recurrence, which is supported
also by the lack of those immune-modulating properties held by IFN, current available evidences are not
supporting this hypothesis. To help further evidences clarify this issue, clinicians should always document
correct assessment of response after HCC treatments, possibly shortly before DAA start, and estimate recur-
rence risk on tumors’ features and patients’ related risk factors. Additionally, when comparing DAAs-treated
patients with those treated with IFN, adjustments for disease stages should always be conducted as baseline
risks have different reference ranges.

HCC PATTERN
Occurrence
[63]
Nakao et al. investigated the pattern of de novo HCC, reporting 6 cases of pathologically-confirmed HCC
in patients with a SVR after treatment with DAAs. All these patients’ tumors were single nodules, moderate-
ly differentiated and growing rapidly: these unconventional features (when compared with previous series)
[35]
might overlap with the unexpected early tumor recurrence as described by Reig et al. . In our own experi-
[42]
ence, with the northern Italian cohort , we found what seemed to be a more aggressive pattern of HCC
presentation: among 16 patients developing HCC (29.1% of the sample), 8 (14.5%) presented with multiple
nodules of various size, 8 (14.5%) with an infiltrative diffuse HCC, 6 (10.9%) with portal thrombosis, and 4
[64]
(7.2%) with extrahepatic metastases. Given the clinical importance of these findings, Renzulli et al. aimed
specifically to examine the radiological features of microvascular invasion (MVI) in a retrospective analysis
of 344 consecutive patients with HCV-related cirrhosis treated with DAAs and followed up for 48-74 weeks.
After DAA treatment, HCC developed in 29 patients (11/29, 38% multi-nodular); forty-one HCC nodules
were detected (27 of them recurrent), with imaging suggestive of MVI in 29/41 (70.7%) nodules, even in 17/29
(58.6%) nodules 10-20 mm in diameter. On the other hand, MVI was only present in 17/51 (33.3%) of the
HCC nodules developing before any DAA treatment (P = 0.0007). These surprising data come from different
cohorts and cannot be attributed simply to a lack of surveillance, because patients were strictly followed up.
That said, it is important to remember that all these alarming findings came from small cohorts, and often
from retrospective single-center experiences. The picture they paint contrasts with the report on the large
[65]
historical French cohort , in which cancer presented as a single nodule in 69.6% of cases, as 2 or 3 nodules
in 19.8%, and was infiltrative or with more than 3 nodules in only 10.8%.

Recurrence
[35]
Reig et al. reported not only on a higher incidence of HCC recurrence, but also on a possibly more aggres-
sive neoplastic pattern in recurrences after DAA treatment: 25% of the recurrences in the original Spanish
cohort were multi-nodular, and 20% of them had an infiltrative pattern, despite the fact that the majority
of the HCCs included in this analysis were at low risk of recurrence (judging from nodule size, Barcelona
Clinic Liver Cancer stage, and histopathology of the resected tumor in patients who had surgery). In the
[58]
previously-mentioned study by Cabibbo et al. , the pattern of recurrence varied: 28 patients developed
intrahepatic growths, and 24 of them had a nodular profile, while 5 (one with MVI) developed infiltrative
HCC. None of the patients developed extrahepatic metastases.

Very little information is available regarding the characteristics of recurrent tumors, however, so that it is
almost impossible to draw any conclusions.