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Page 6 of 10 Simsek et al. Hepatoma Res 2020;6:11 I http://dx.doi.org/10.20517/2394-5079.2019.51

HCC recurrence after LT was 427 days, ranging from 34 to 1502 days. The site of HCC recurrence was
intrahepatic in 8 (31%), extrahepatic in 14 (54%), and both intra- and extrahepatic in 4 (15%) patients.
Overall, 31% of recipients had intrahepatic HCC recurrence following LT when compared to 69% with
extrahepatic recurrence. Twenty-two percent of the patients who had extrahepatic involvement had
concomitant liver involvement. The most common sites of extrahepatic involvement were the lungs (44.4%)
and bones (44.4%) (spine, rib, pelvis, and humerus), followed by mediastinum (27.8%), brain (22.2%),
portal lymph nodes (11.1%), gastro-hepatic ligament (5.6%), adrenal gland (5.6%), pleura (5.6%), and
peritoneum (5.6%).

A range of different treatment modalities was used for recurrences [Table 3]. Six (21.4%) of the 26 patients
were managed with supportive care. The remaining 20 cases received various treatment modalities
including locoregional therapy (transarterial chemoembolization in 3, Y 90 in 1, and radiofrequency
ablation in 1), external radiation in 10, and surgical resections in 8 (brain 4, spine 2, bone 1, and Whipple
surgery in 1). Nine (32%) patients received combination therapies of the above-mentioned modalities.
Seven patients (27%) received sorafenib. An additional two patients received chemotherapy regimens other
than sorafenib [Table 3]. Recurrence-free survival and overall survival are shown in Figure 3. Patients who
developed HCC recurrence following LT had an extremely poor overall survival (7.7%). In total, 19% of
patients died within one year following LT. Overall, 24 out of 26 (92.3%) patients died throughout the four-
year follow-up period. Timing of death relevant to the time of LT is shown in Table 3.

DISCUSSION
In this series, we report a rate of 15% HCC recurrence following deceased donor LT at our transplant
[13]
program. This rate is consistent with the literature report of 15%-20% post-LT HCC recurrence . It is well
known that the patients who are outside of MC prior to LT have higher rates of tumor recurrence following
[1]
LT, compared to those within the MC . Although all of the patients within our series were thought to be
within MC radiographically prior to LT, according to radiology findings, only 34% were within the criteria
by reviewing the explant. When including an additional four (15%) patients who were downstaged, in total
49% were within MC based on pathology. This discrepancy between radiology and pathology has been
[13]
previously described by other groups in the literature .

[8]
Our sites of recurrence findings are very similar to the recent reports . In a systematic review of post-LT
HCC recurrence, extrahepatic site was the most common site of recurrence in 67% of cases, compared to
[8]
intrahepatic in 33% . The extrahepatic sites of involvement included: bone, pulmonary, adrenal, lymph
nodes, and brain .
[8]
Within our series, 54% of the HCC recurrences were diagnosed within 1 year post-OLT, while 81% and
96% of recurrences occurred within 2 and 3 years following OLT, respectively. The average time to HCC
recurrence within our series was 427 days (range 34-1502 days). It is shown by others that early versus
[14]
late recurrence is a predictor of post-LT survival . The patients with early HCC recurrence, defined as
[14]
recurrence within 24 months post-LT, have a worse prognosis . There are a few potential theories for early
HCC recurrence post-LT: (1) biologically rapid growing, aggressive tumors; (2) lack of high-quality pre-LT
imaging or overlooking intra- or extrahepatic imaging ; (3) extrahepatic microscopic viable HCC cells that
[8]
could not be detected by conventional imaging prior to LT; and (4) presence of circulating tumor cells that
seed to other sites. The mechanism by which the late recurrence occurs is unclear . Presence of pre-LT HCCs
[15]
that are biologically slow growing, or development of de novo HCC recurrence in the liver allograft could
be the cause. Within our series, we did not have any cases who had HCC recurrence that occurred or were
diagnosed beyond five years following LT.

The selection of an ideal treatment for post LT HCC recurrence is a matter of debate, and the evidence is
mainly based on expert opinion and non-randomized cohort studies . The treatment modality will vary
[9]