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Zhang et al. Late recurrence of hepatocellular carcinoma

seen in cases of late recurrence. [23,32] The lungs are to identify those patients with the potential for late
the most common site of extrahepatic involvement, recurrence.
followed by bone involvement. In our late recurrence
patients, 4 out of 5 had extrahepatic involvement. Our This study is limited by its small sample size and
one case of continued survival after late recurrent small number of identified cases of late recurrence,
HCC (currently over 44 months) had just hepatic which renders it difficult to identify trends and factors
involvement. This could potentially be a case of de that may predispose a patient to develop recurrent
novo HCC developing in the transplanted liver, the HCC. However, our study provides detailed clinical
mechanism of which may differ from the biological information characterizing five cases of late HCC
mechanisms involved in early HCC recurrence. recurrence after LT, in the hopes that it may benefit
other researchers in elucidating the characteristics
Treatment of HCC recurrence after transplant involves associated with this fortunately infrequent post-LT
surgical resection when possible as it has been complication. A notable observation from this study
shown to be associated with a survival advantage. [4,33] was that not all of the late recurrences occurred in
Unfortunately, in many cases, patients present the liver. This is notable because all the patients
with disseminated disease and surgery is not underwent LT of primary treatment of HCC. Thus,
feasible. Other options for treatment include TACE, it can be inferred that the patients experiencing
RFA, high-intensity focused ultrasound ablation, extrahepatic recurrences did so as a consequence of
stereotactic body radiation therapy, and modulation indolent metastases present at the time of transplant.
of immunosuppressants. [34] Sorafenib, a multikinase In the 2 cases with intrahepatic recurrence, it is not
inhibitor that improves progression-free and overall possible to conclude whether the recurrences were
survival in patients with advanced HCC, has also in fact, new tumors arising in the transplanted liver.
shown promising results in treatment of HCC However, in both cases, patients had difficult to
recurrence post-LT with a modest survival benefit control-viral hepatitis and it is possible that hepatitis
and manageable adverse effects. [35,36] Combination and fibrosis predisposed them to recurrent HCC in the
therapy with sorafenib and an mTOR inhibitor such liver. Because nearly one-third of our post-LT patients
as everolimus has also been used in practice, though with recurrent HCC experienced recurrence more than
longer follow-up studies are needed to assess the 5 years after LT, our study highlights the importance of
benefits versus increased toxicity of such a regimen long-term follow-up with imaging every 6-12 months
in recurrent HCC. [37,38] Our 5 patients with late and the need for biomarkers to identify patients who
recurrence were treated with various combinations may be at risk for late recurrences. We encourage
of resection, RFA, sorafenib, and everolimus. Our future studies to further characterize patients with late
single surviving patient had undergone ablation, has recurrence of HCC and perhaps molecular studies
been on everolimus/sorafenib, and had resolution of a could help better identify those patients at greatest
previously seen intrahepatic lesion. risk for recurrence to allow physicians to monitor
these patients more vigilantly.
Once a patient develops recurrence, survival is
rather dismal despite efforts to treat these patients. Authors’ contributions
Median survival for patients with recurrence has been Study design: S.A. Kwee, L.L .Wong
reported to be between 8.7 months to 18.3 months Data analysis: J.A. Zhang
from time of recurrence. [4,18,25,33] Our 5 late recurrence Manuscript preparation: J.A. Zhang, L.L .Wong
cases ranged greatly in survival time after diagnosis Critical review of manuscript: S.A. Kwee
of recurrence (2 months-over 44 months).
Financial support and sponsorship
Efforts have been made to better identify molecular This study was supported by NIH grant 2 P30
factors that predict recurrence after liver resection for CA071789-13.
HCC. Kim et al. [39] in a cohort of 72 patients in Korea
performed gene expression studies on archived tissue
samples. They identified a 233 gene signature that Conflicts of interest
was significantly associated with late recurrence after Dr. Wong is on the speaker bureau for Bayer
liver resection. From this, they also developed and Healthcare. Dr. Kwee and Ms. Zhang have no conflicts
validated a 4 and 20 gene predictors from the full 233 of interest to report.
gene predictors, however this was in a population of
primarily hepatitis B HCC. Perhaps similar molecular Patient consent
studies are needed, especially in transplant patients This is a retrospective study and the Institutional
64 Hepatoma Research ¦ Volume 3 ¦ April 10, 2017