A MERICAN A SSOCIATION FOR
T HE STUDY OF LIVER D I S E ASES

HEPATOLOGY, VOL. 63, NO. 3, 2016

Prospective Validation of Ab Initio Liver
Transplantation in Hepatocellular
Carcinoma Upon Detection of Risk
Factors for Recurrence After Resection
Joana Ferrer-F abrega,1,2* Alejandro Forner,2,3* Alexandre Liccioni,2 Rosa Miquel,2–4 V ıctor Molina,1 Miquel Navasa,3,5
Constantino Fondevila,1,3 Juan Carlos Garc ıa-Valdecasas,1,3** Jordi Bruix,2,3 and Josep Fuster1–3
A decade ago we proposed to enlist for transplantation those patients with resected hepatocellular carcinoma in whom
pathology registered pejorative histological markers (microvascular invasion and/or satellites; ab initio indication) and not
wait for the appearance of recurrence. This study evaluates the outcome of this approach. From 1995 to 2012, 164 patients
with hepatocellular carcinoma underwent resection. Eighty-five patients were potential candidates for liver transplantation
and were considered for it upon detection of pejorative histological markers. Patients without these markers were followed,
and salvage liver transplantation was considered upon development of tumor recurrence/liver function impairment. Thirtyseven patients were at high risk and 48 at low risk of recurrence at pathology. Twenty-three out of 37 high-risk patients
recurred during follow-up, but in nine of them the tumor burden extent contraindicated liver transplantation. Seventeen
were finally transplanted: 10 of them presented recurrence at imaging/explant. After a median posttransplant follow-up of
50.9 months, hepatocellular carcinoma had recurred in two patients and five patients had died, the 5-year survival being
82.4%. Twenty-six of the 48 low-risk patients developed recurrence, and 11 of them were transplanted. After a median
posttransplant follow-up of 59 months, two patients developed recurrence and five died, their 5-year survival being 81.8%.
Conclusion: Enlistment of patients at high risk of HCC recurrence after resection but before recurrence development seems
a valid strategy and is associated with excellent long-term outcome; as early (<6 months) recurrence reflects an aggressive
tumor behavior leading to tumor extent exceeding transplant criteria, we propose to wait at least 6 months before enlistment; however, once included on the waiting list, priority strategies should be implemented in order to reach effective
transplantation prior to the appearance of recurrence. (HEPATOLOGY 2016;63:839-849)

H

epatocellular carcinoma (HCC) is the most
common primary tumor of the liver. The
incidence of HCC is increasing in the
United States and Europe, and it is currently the third
leading cause of cancer-related death globally.(1,2) Liver

transplantation (LT) is theoretically the treatment of
choice because it allows removal not only of the tumor
but also of the underlying cirrhosis. It offers a high survival rate and a low recurrence rate in well-selected
cases.(3,4) Although Spain has the highest rate of

Abbreviations: AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; LR, liver resection; LT, liver transplantation; MR, magnetic resonance; US,
abdominal ultrasound.
Received June 19, 2015; accepted November 9, 2015.
Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.28339/suppinfo.
*These authors have contributed equally to this work.
**Director, Liver Transplant program.
Supported by the Instituto de Salud Carlos III (funding of CIBERehd and grants PI13/01229 and PI14/00962, to A.F. and J.B.). The Association
Llavaneres contra el C 
ancer supported the work of J.F.
C 2015 by the American Association for the Study of Liver Diseases.
Copyright V
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hep.28339
Potential conflict of interest: Dr. Bruix consults, advises, and has received grants from Bayer. He consults and advises Novartis and Biocompatibles.
He consults and has received grants from Arqule and Daiichi. He consults for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Kowa, Lilly, and
Roche.

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ET AL.

donation (35 liver donations per million inhabitants),(5) the number of available livers is still exceeded
by the number of potential recipients.(6) This situation
has led to an increase in the time from the decision to
transplant until the transplantation itself. During this
time, the HCC may progress, leading to dropout from
the waiting list, thus impairing the outcome according
to intention-to-treat analysis.(7) Taking into account
this organ scarcity, liver resection (LR) is considered
the preferred treatment option for those solitary
tumors arising from a normal liver or in a patient with
cirrhosis and very well-preserved liver function. In
expert hands, this is a safe procedure with low morbidity and mortality, allowing 5-year survival rates after
LR in those optimal candidates of around 70%, very
similar to that obtained after LT.(7) However, the 5year recurrence rate may exceed 70%, representing an
“Achilles heel” of the resection option. In an attempt
to promote LR as the first-line treatment with curative
intention, salvage transplantation following LR in
cases of disease recurrence has been widely
adopted.(8,9) The initial reports by Majno et al.(10) and
Poon et al.(11) were followed by several contributions.(12-25) Initial concerns regarding the technical
difficulties of LT after LR were discarded,(26,27) and a
recent meta-analysis evaluating the outcomes of this
strategy confirmed that salvage LT following primary
LR is a highly applicable strategy with long-term survival outcomes that are comparable to upfront LT.(28)
Disease recurrence after resection might be predicted by pathological findings such as differentiation
degree, presence of satellites/multifocality, and the
existence of microvascular invasion.(24,29-31) Due to the
high risk of recurrence, a decade ago we proposed to
enlist HCC patients initially treated with LR in whom
these major predictors of recurrence were detected in

HEPATOLOGY, March 2016

the surgical specimen before the recurrence was
identified.(32)
This strategy (ab initio indication) was based on the
high probability of excessive tumor burden beyond the
criteria accepted for offering LT once recurrence was
identified, limiting the possibility of salvage transplantation. This policy has been recently proposed by other
groups.(24) As microvascular invasion has been identified as one of the strongest prognostic variables associated with tumor recurrence and survival after LT,(33) it
could be argued that the use of this parameter to enlist
patients would translate to high recurrence rates and
dismal outcomes. If this were the case, enlistment
because of risk should not be recommended.
However, our preliminary study in 2004(32)
reported that this strategy could be highly effective as
it offered increased access to LT for those in
need, while sparing the use of the limited number of
organs for those who would not benefit. The survival
figures were also promising, and in the present
study we prospectively analyzed in a larger cohort of
patients the intention-to-treat long-term outcome of
patients initially resected but in whom a high risk of
recurrence based on pathology prompted their enlistment for LT.

Patients and Methods
From January 1995 to December 2012, 164 patients
with HCC were initially treated with LR. Among the
total resected patients, 85 patients with HCC were
suitable for either LR or LT, but according to the Barcelona Clinic Liver Cancer group schedule,(8,9,34) they
were treated by LR. These patients offered LR as a
first option constitute the target population of this

ARTICLE INFORMATION:
From the 1HepatoBilioPancreatic Surgery and Transplant Unit, Department of Surgery, and 2Barcelona Clinic Liver Cancer (BCLC)
Group, Liver Unit, Hospital Clinic Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain; 3Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Madrid, Spain; 4Department of Pathology, Hospital Clinic Barcelona, University of Barcelona, Barcelona, Spain; 5Liver Transplantation Unit, Liver Unit, Hospital Clinic
Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain

ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Josep Fuster and Jordi Bruix
BCLC Group
HBP Surgery and Transplant Unit
Hospital Clinic Barcelona, IDIBAPS
University of Barcelona
Carrer Villarroel 170, 08036 Barcelona

840

Spain.
E-mail: jfuster@clinic.ub.es and
jbruix@clinic.ub.es
Tel: 134 932275718
Fax: 134 932275589.

  
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HEPATOLOGY, Vol. 63, No. 3, 2016

cohort. They had single tumors, absence of clinically
significant portal hypertension, and normal bilirubin
levels. Patients with clinically significant portal hypertension, abnormal bilirubin levels, or two or three nodules  3 cm and without severe associated diseases were
considered for LT.
The preoperative diagnosis and staging of HCC
included abdominal ultrasound (US), dynamic computed tomography, and/or magnetic resonance (MR)
imaging. Diagnosis was established by biopsy if noninvasive diagnostic criteria were not met in accordance
with the then available practice guideline for HCC
management.(8,9,35,36) Additionally, a preoperative
hemodynamic study with hepatic venous pressure gradient measurement was performed in order to exclude
clinically significant portal hypertension.
The surgical procedure comprised intraoperative US
to exclude additional nodules, localize the tumor, and
perform an anatomical resection with a macroscopicfree margin. Resected liver specimens were serially cut
in 0.5-cm-thick slices and fixed in formalin. Representative samples of tumor, nontumoral tissue, and surgical margins were embedded in paraffin for microscopic
examination. Tumor number and size were confirmed
on gross inspection, and microscopic analysis determined the presence of vascular invasion, microscopic
tumor satellites, tumor differentiation (worst grade if
heterogeneous), and status of the resected margin.
According to pathological criteria,(32) the patients were
divided into two groups, those with a high risk of
recurrence if they exhibited microvascular invasion
and/or additional nodules or satellites and those with a
low risk of recurrence if they did not exhibit any of
these parameters.
Patients in the high-risk group were evaluated for
inclusion on the waiting list for LT. In both groups,
the imaging follow-up was as follows: US 1 month
after LR, MR (or computed tomography if contraindication for MR) at 3 months and then MR every 6
months during the first 2 years and, if recurrence was
not detected, regular US surveillance every 6 months
after 2 years from LR. For those patients included on
the waiting list the follow-up was every 3 months,
alternating MR and US. From 1995 to June 2007
organ allocation for HCC patients was based on the
strict order of entry on the waiting list. Since July
2007, the Model of End-Stage Liver Disease has been
used for organ allocation. Model of End-Stage Liver
Disease exception points were applied in HCC
patients if baseline tumor size by initial imaging assessment was >3 cm, there were multiple tumors within

Milan criteria, the alpha-fetoprotein (AFP) level was
>200 ng/mL, and/or treatment failed or tumor
recurred. Such cases receive 19 points, with 1 extra
added every 3 months.

STATISTICAL ANALYSIS
Patient baseline characteristics are expressed as
median (range) and percentages. Comparisons
between groups were made using the Student t test for
quantitative variables and the v2 test or the Fisher test
for qualitative variables. A P value <0.05 was considered to indicate statistical significance.
Survival was calculated from the time of LR or
the time of LT to death or the end of follow-up
at March 31, 2015. Time to recurrence was calculated from the time of LR until the development
of recurrence by imaging before LT or the day of
LT if recurrence was detected in the explant analysis. Both survival and time to recurrence analyses
were done with the Kaplan-Meier method. Comparison between low-risk and high-risk patients
was done by the log rank test. Data were collected
and analyzed with SPSS statistical software (SPSS
20.0, 1989-1995; Chicago, IL).

Results
Figure 1 shows a flowchart of the 164 patients
included in this study. Seventy-nine patients (48.2%)
treated with LR were not suitable for LT because of
advanced age (n 5 57), bridging resection to LT (n 5
1), or tumor was beyond Milan criteria (n 5 21). In
this population, after a median follow-up of 58.6
months, 32 patients died and the 1-year, 3-year, 5year, and 10-year survival rates were 96.1%, 84.1%,
65.1%, and 54.9%, respectively, with a recurrence
probability at 5 years of 65%. The remaining 85
patients (51.8%) were potential candidates for both LR
and LT, and they constitute the target population of
this study. The main patient characteristics of that
cohort are summarized in Table 1. The median tumor
size was 2.6 cm (range 1-5), and 71.9% had a tumor
smaller than 3 cm at imaging. Ten patients experienced major postoperative morbidity according to
Dindo-Clavien classification (two type IVa, four type
IIIa, and four type IIIb)(37); in nine patients these
complications were completely resolved with no consequences, but one patient died after 2.8 months secondary to complications related to surgical resection. R0
resection with tumor-free surgical margins was

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HEPATOLOGY, March 2016

                                                                                                                                       

FIG. 1. Flowchart of patients included in the study. Abbreviation: MC, Milan criteria.
                                                                                                                                       

achieved in all patients, but in three cases there was no
safety margin between the resected tumor and the liver
parenchyma (these three cases also displayed pathological markers of high risk of recurrence). Pathological
assessment showed that 57.6% of the HCCs were
moderately differentiated, 41.2% exhibited microvascular invasion, and 23.5% presented satellites. After a
median follow-up of 61.1 months (range 2.7-236.7),
28 out of 85 patients (32.9%) received LT.
According to the pathological study of the resected
specimen, the 85 patients were divided into two
groups: patients with high risk of recurrence (n 5 37,
43.5%) and patients with low-risk of recurrence (n 5
48, 56.5%). Tumor size was the sole parameter that
was significantly different between the high-risk and
low-risk subgroups both at imaging (median size 3 cm
versus 2.3 cm, respectively, P 5 0.003) and at pathology (median size 3 cm versus 2.4 cm, respectively; P 5
0.002). High-risk HCC was also less frequently well
differentiated when compared to the low-risk group
(21.6 versus 39.6%, P 5 0.04).

842

HIGH-RISK PATIENTS
All 37 high-risk patients were considered for LT
upon the resected specimen analysis. Four patients
refused to be enlisted, one was lost of follow-up,
and four were not considered for LT because of
medical reasons. Accordingly, 28 patients were considered for enlistment. Nine patients experienced
tumor recurrence beyond Milan criteria and were
discarded for LT, 17 patients had been transplanted
after a median waiting time of 12.6 months (range
2.5-21.7), and two were still on the waiting list.
The main pathological characteristics and outcome
of the 20 high-risk patients finally not transplanted
are described in Supporting Table S1. Very interestingly, in those nine patients with recurrence that
precluded LT, the median time from LR to recurrence was 6.5 months (range 1.6-29.6), and we
identified two different patterns of recurrence
appearance: those with early recurrence within 6
months after LR (five patients with recurrence at

  
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HEPATOLOGY, Vol. 63, No. 3, 2016

TABLE 1. Characteristics of the Patients*
Variables
Age (years)
Gender, n (%)
Male
Female
Etiology cirrhosis, n (%)
HCV
HBV
Alcohol
NASH
Hemochromatosis
No cirrhosis
AFP (ng/mL)†
<10
11-100
101-400
>400
Bilirubin (mg/dL)
HVPG (mm Hg)
Median tumor size (cm)
 3.0
3.1-5.0
Pathologic characteristics
Median tumor size (cm)
 3.0 cm
3.1-5.0 cm
 5.1 cm
Differentiation degree
Well
Moderate
Poor
Microvascular invasion
Yes
No
Additional nodules
Yes
No
Satellitosis
Yes
No
Capsula
Yes
No
Recurrence
Yes
No
Liver transplant
Yes
No

Overall (n 5 85)

Low Risk (n 5 48)

High Risk (n 5 37)

58 (31-68)

56 (40-68)

59 (31-68)

70 (82.4%)
15 (17.6%)

38 (79.2%)
10 (20.8%)

32 (86.5%)
5 (13.5%)

58
15
8
1
2
1
7

34
9
3
1
1

P
ns
ns

ns

0.8
7
2.6
61
24

(68.2%)
(17.6%)
(9.4%)
(1.2%)
(2.4%)
(1.2%)
(1-10,724)
45
20
7
3
(0.3-2.6)
(1.5-14)
(1-5)
(71.9%)
(28.2%)

(70.8%)
(18.8%)
(6.3%)
(2.1%)
(2.1%)
0
7 (2-175) (no data: 8)
26
11
3
0
0.7 (0.3-2.2)
6.8 (2.5- 14)
2.3 (1-5)
40 (83.3%)
8 (16.7%)

24 (64.9%)
6 (16.2%)
5(13.5%)
0 (0%)
1 (2.7%)
1 (2.7%)
8 (1-10,724) (no data: 2)
19
9
4
3
0.8 (0.4-2.6)
7.0 (1.5-12.5)
3.0 (1.4-5)
21 (56.8%)
16 (43.2%)

2.5
57
24
4

(1-7.5)
(67.1%)
(28.2%)
(4.7%)

2.4 (1-4.5)
37 (77.1%)
11 (22.9%)
0

3.0
20
13
4

27 (31.8%)
49 (57.6%)
9 (10.6%)

19 (39.6%)
27 (56.3%)
2 (4.2%)

8 (21.6%)
22 (59.5%)
7 (18.9%)

35 (41.2%)
50 (58.8%)

0
48

35 (94.6%)
2 (5.4%)

7 (8.2%)
78 (91.8%)

0
48

7 (18.9%)
30 (81.1%)

20 (23.5%)
65 (76.5%)

0
48

20 (54.1%)
17 (45.9%)

42 (49.4%)
43 (50.6%)

22 (45.8%)
26 (54.2%)

20 (54.1%)
17 (45.9%)

46 (54.1%)
39 (45.9%)

26 (54.2%)
22 (45.8%)

20 (54.1%)
17 (45.9%)

28 (32.9%)
57 (67.1%)

11 (22.9%)
37 (77.1%)

17(45.9%)
20(54.1%)

(1.4-7.5)
(54.1%)
(35.1%)
(10.8%)

ns

ns
ns
0.003

0.002

0.040

Per design

Per design

Per design

ns

ns

0.036

*Quantitative variables expressed as median (range). Median follow-up (n 5 85): 61.1 months (range 2.7-236.7).
†
Ten patients with no data.
Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; HVPG, hepatic venous pressure gradient; NASH, nonalcoholic steatohepatitis; ns, not significant.

1.6, 2.8, 3.4, 4.5, and 6.5 months) and those with
late recurrence beyond 6 months (four patients at
7.5, 15.1, 29.4, and 29.6 months). The outcomes of
the 17 patients finally transplanted are described in
Table 2. Seven among 17 high-risk transplanted
patients developed tumor recurrence at imaging

prior to LT after a median time of 8.9 months
(range 2.3-18.9) after LR. Two of them developed
post-LT recurrence after 3.5 months and 107.4
months and died due to cancer progression at 3.7
months and 107.8 months after LT, respectively. In
the remaining 10 high-risk patients, tumor

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HEPATOLOGY, March 2016

TABLE 2. Characteristics of the High-Risk Transplanted Patients
Resected HCC

Explanted HCC

Size (cm)

VI

AN

S

LR-LT*
(Months)

1

2

1

1 (33)

1

9.43

2

3

1

2

1

19.10

3

3.5

1

2

2

2.43

4

3.2

1

2

2

12.57

5

3.5

2

1 (32)

1

9.07

6

2.5

1

1 (33)

1

16.57

2 HCC (1.8 1 0.3 cm),
lymphoma marginal zone§

7

3

1

2

2

19.23

No HCC

No

8

2.2

1

2

2

15.83

HCC (1.5 cm), no VI§

No

9

1,4

1

2

2

12.53

HCC (1 cm)§

No

10

2.0

1

2

2

19.27

No HCC§,k

No

11

3.5

1

2

1

21.73

2 HCC (0.8 1 1 cm), no VI§

No

12

3

1

2

2

3.70

No HCC

No

13

1.9

1

2

2

13.00

2 HCC (1.2 1 0.2 cm)§

No

14

2.0

1

2

1

16.43

No

15

3.1

1

2

1

5.37

4 HCC
(2 1 1.8 1 0.8 1 0.4 cm), VI
No HCC

16

4.0

1

2

2

5.43

No HCC

No

17

5.0

1

2

1

5.57

No HCC

No

Tumor
No HCC

Multinodular HCC
(0.5 cm), VI§

Recurrence
Post-LT

Follow-Up
(Months)†,‡

No

Dead
(HCV cirrhosis)
84.17/93.60
Dead
(Tumor recurrence)
3.67/22.76
Dead
(HCV cirrhosis and leukemia)
11.07/13.60
Alive
202.07/214.63
Alive
163.27/172.33
Dead
(Tumor recurrence)
107.77/124.33
Alive
113.77/133
Alive
115.03/130.86
Alive
70.27/82.80
Alive
51.70/70.96
Alive
48.97/70.70
Alive
58.27/61.96
Alive
36.17/49.16
Alive
30.23/46.66
Dead
(lymphoma)
10.50/15.86
Alive
41.73/47.16
Alive
24.47/30.03

Yes
3.50 months

No HCC

No

Multinodular HCC (1.2 cm)

No

HCC (0.9 cm), VI

No
Yes
107.40 months

No

*Time (months) from tumor resection to LT.
†
Time (months) from LT to the end of follow-up.
‡
Time (months) from tumor resection to the end of follow-up.
§
Recurrence while on waiting list.
k
Recurrence as single nodule of 24 mm 14.6 months after resection and treated with radiofrequency ablation during time on the waiting list. In explant, complete necrosis.
Abbreviations: AN, additional nodules; HCV, hepatitis C virus; S, satellitosis; VI, vascular invasion.

recurrence was not detected prior to LT; but in
three cases, the explant analysis demonstrated recurrent tumor foci. None of these 10 patients developed tumor recurrence after LT.
After a median follow-up following LR for the 37
high-risk patients of 44.7 months (range 2.8-211.6),
16 patients died, 12 of them related to HCC recurrence; and the 1-year, 3-year, 5-year, and 10-year
patient survival rates were 89.2%, 69.9%, 60.2%, and

844

51.6%, respectively (Fig. 2A). Survival was significantly
superior in those patients finally transplanted compared to nontransplanted patients (1-year, 3-year, and
5-year patient survival of 100%, 82.4%, and 82.4%
compared to 80%, 59.1%, and 38%, respectively; P 5
0.033) (Fig. 2B). Taking into account those patients
finally transplanted, after a median follow-up of 50.9
months, five patients died and the 5-year survival from
LT was 82.4%.

 HEPATOLOGY, Vol. 63, No. 3, 2016

                                                                  

FIG. 2. (A) Survival of high-risk patients (n 5 37) after surgical
resection according to intention-to-treat analysis. (B) Survival of
high-risk patients (n 5 37) after surgical resection. Continuous
line corresponds to those finally transplanted, and dotted line
represents those finally not transplanted. Survival was significantly
superior in those finally transplanted (P 5 0.033).
                                                                  

LOW-RISK PATIENTS
Forty-eight patients were not offered enlistment for
LT after resection because of their low recurrence risk
according to pathology criteria. After a median followup of 71.8 months (range 7.4-236.7), 26 patients
(54.2%) developed tumor recurrence and were considered for salvage LT.
Two patients with tumor recurrence after 30.6
months and 49.9 months refused to be enlisted; three
patients were excluded for advanced age, two because of
medical reasons, and five because of recurrence beyond
Milan criteria; and finally, in two patients with very

 
FERRER-FABREGA
ET AL.

well-preserved liver function and late recurrence (after
46.4 and 50.8 months) a new resection was considered.
The characteristics of the nontransplanted low-risk
patients with recurrence (n 5 15) are depicted in Supporting Table S2. Accordingly, 12 out of 26 patients
with tumor recurrence were included on the waiting list.
At the end of the follow-up, 11 out of 12 patients
enlisted were finally transplanted after a median waiting
time of 6 months and the remaining patient is still on
the waiting list. The main clinical and pathological characteristics of these 11 low-risk patients finally transplanted are summarized in Table 3. Seven patients
received some treatment prior to transplantation. In 10
cases, an HCC focus was detected on the explant. After
a median follow-up after LT of 59 months, two patients
developed post-LT tumor recurrence at 59.9 and 38
months and died at 70.7 and 42.8 months, respectively.
During the follow-up, 14 low-risk patients died, with a
median survival of 139.5 months (95% confidence interval 73.1-206), and the 1-year, 3-year, 5-year, and 10year patient survival rates for these 48 low-risk patients
from LR were 97.9%, 95.8%, 90.3%, and 59.9%, respectively. The survival was not different in those patients
finally transplanted compared to nontransplanted
patients (1-year, 3-year, and 5-year patient survival of
100%, 90.9%, and 81.8% compared to 97.3%, 97.3%,
and 93.4%, respectively; P 5 0.909).

OUTCOME OF THE WHOLE
COHORT
After a median follow-up of 61.1 months (range
2.76-236.7), the survival rates at 1 year, 3 years, 5
years, and 10 years of the 85 patients treated with LR
and evaluated for LT according to pathological findings were 94.1%, 84.5%, 77.1%, and 54.9%, respectively. According to the pathological findings after LR,
survival was significantly superior in the low-risk group
(n 5 48) compared to the high-risk group (n 5 37):
survival at 1 year, 3 years, 5 years, and 10 years of
97.9% versus 89.2%, 95.8% versus 69.9%, 90.3% versus 60.2%, and 59.9% versus 51.6%, respectively (P 5
0.039) (Fig. 3). Considering only those patients finally
transplanted (n 5 28), the survival from LR at 1 year,
3 years, 5 years, and 10 years was 100%, 85.7%, 81.4%,
and 65.5%, respectively, and from LT it was 81.8%,
81.8%, 71.4%, and 45.9%, respectively. More interestingly, there were no statistically significant differences
in survival in those patients finally transplanted according to the baseline pathological findings; the 1-year, 3year, 5-year, and 10-year patient survival rates from the

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HEPATOLOGY, March 2016

TABLE 3. Characteristics of the Low-Risk Transplanted Patients
Resected
HCC
Size (cm)

Time to
Recurrence*
(months)

1

3.5

50.10

2

2

17.73

3

1.1

56.93

4

1

74.60

5

1.1

42.50

6

3.1

7

Time From
Recurrence
to LT

LR-LT†
(months)

2 nodules of HCC
(1.5 cm and 1 cm)
3 nodules of HCC

14.83

64.93

14.60

32.33

13.93

70.87

10.63

85.23

13.53

56.03

33.10

3 nodules of HCC
(1.6 cm, 1.7 cm,
1.1 cm)
3 nodules of HCC
(1.8 cm, 1.3 cm,
and 1.3 cm)
2 nodules of HCC
(2.5 cm and 1.4 cm)
Nodule of 1.5 cm

15.60

48.70

2.4

13.60

Nodule of 0.5 cm

9.10

22.70

8

2

16.83

Nodule of 0. 8 cm

13.93

30.77

9

4

3.70

Nodule of 1.4 cm

7.83

11.53

Multiple HCCs with portal
invasion,
tumor mass of 5.5 cm
4 HCCs (3 cm, 0.1 cm,
0.1 cm, 1.4 cm)
2 HCCs (1.2 cm and 1.8
cm)
3 HCCs (1.1 cm, 0.3
cm, 1.7 cm),
dysplastic nodule (0.7
cm)
Necrotic area of 2.3 cm
with HCC areas
(1.5 cm), necrotic
nodule 4.5 cm
No HCC

10
11

3.8
1.3

Nodule of 0.9 cm
2 nodules of HCC
(1.9 cm and 1.6 cm)

2.90
9.00

9.53
70.90
(LDLT)

HCC (1.1 cm), VI
2 HCCs (1.9 cm and 1.6
cm)

6.63
61.90

Form of
Recurrence

Explanted HCC
4 HCCs (3.6 cm, 1.3
cm, 1 cm, 1.5 cm), VI
3 HCCs (1 cm, 1.3 cm,
0.5 cm)
6 HCCs, no VI

Recurrence
Post-LT
No
No
Solid mass of 5.5 cm on
segment 4, liver TACE
59.87 months
No

No
No
No

No

Peritoneal
carcinomatosis
37.97 months
No
No

*Time (months) from LR to recurrence.
†
Time (months) from LR to LT.
Abbreviations: HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; TACE, transarterial chemoembolization;
VI, vascular invasion.

time of LR for low-risk (n 5 11) versus high-risk
patients (n 5 17) were 100% versus 100%, 90.9% versus 82.4%, 81.8% versus 82.4%, and 62.3% versus
68.6%, respectively (P 5 0.773) (Fig. 4).

Discussion
Our results validate that enlistment of patients at
high risk of recurrence after resection before recurrence
development is a valid strategy and is associated with
excellent long-term outcome. In those patients, with
single HCC and with well-preserved liver function
with no clinically relevant portal hypertension, LR followed by salvage transplantation in case of identification of pathological parameters of high risk of
recurrence (ab initio indication) or identification of
recurrence during the follow-up in those with no pathological parameters of risk offers an excellent longterm outcome (5-year survival of 77.1% from the

846

moment of LR), figures comparable to those offered
with upfront LT.(4) The major advantage of this strategy is the reduction of the number of transplants
required, saving a relevant number of grafts and
decreasing the number of enlisted patients.(10)
In our cohort of high-risk patients, 19 out of 28
patients considered for LT developed tumor recurrence
during follow-up, 12 of them appearing within the first
year; and in nine patients the recurrence was multifocal, exceeding the criteria for considering LT. Our
findings are in accordance with those reported by Fuks
et al.(24): in this retrospective study 90 out of 112
resected patients experienced tumor recurrence, and
salvage transplantation was feasible in only 39 cases; in
30 patients the recurrence was outside Milan criteria,
impeding the salvage LT. Microvascular invasion is
the hallmark of our high-risk population, and as
expected, this feature has a relevant impact on the risk
of tumor recurrence. In our cohort, microvascular invasion was present in 35 out of 85 patients (41.2%),

 HEPATOLOGY, Vol. 63, No. 3, 2016

                                                                  

FIG. 3. Survival of the whole cohort from the time of surgical
resection according to the pathological findings. Dotted line corresponds to high-risk patients (n 5 37), and continuous line represents low-risk patients (n 5 48). Survival was significantly
superior in low-risk patients (P 5 0.039).
                                                                  

figures superior to those reported in the Metroticket
study in those patients within Milan criteria
(10.9%)(33) but similar to those in more recent reports
specifically evaluating the prognostic value of this finding.(24,38,39) Because microvascular invasion has been
identified as an important predictor of tumor recurrence and overall survival after LT, the inclusion on
the waiting list of those patients with this very unfavorable feature according to the ab initio indication might
be associated with an inadmissible rate of tumor recurrence and impaired survival. Our results confirm that
long-term survival is excellent in those patients finally
transplanted. However, in a relevant proportion of
patients the tumor recurred during the evaluation for
inclusion on the LT waiting list and during the waiting
time. It is notable that, despite the high probability of
tumor recurrence and dropout during the waiting time,
the 5-year survival of this high-risk population according to the intention-to-treat principle is 60.2%, a figure
similar to those derived from the Metroticket calculator if microvascular invasion is considered.(33)
As described, 19 out 28 high-risk patients considered for ab initio LT developed tumor recurrence
during the follow-up, and in nine of those patients the
recurrence impeded their access to LT. More interestingly, in five cases the recurrence appeared within 6
months after LR. On the contrary, in three cases, the

 
FERRER-FABREGA
ET AL.

recurrence was detected beyond 1 year after LR (at
15.1, 29.4, and 29.6 months). Based on our experience, we propose a waiting time of at least 6 months
prior to study enlistment. During this period, we will
be able to identify the patients with biologically less
aggressive tumors, thus avoiding transplanting those
patients with aggressive tumors associated with a high
risk of post-LT recurrence and impaired survival.
However, once the patient is enlisted, exception points
should be assigned for transplantation prior to any
recurrence appearance.
In our study we did not identify increased AFP as a
useful independent marker to predict early recurrence.
The selection of patients with single HCC probably
explains why we have only three patients with
increased AFP >400 ng/mL, all of them classified as
high risk because of the pathological profile. Two of
them presented a dismal evolution with recurrence
within 6 months after resection, while the remaining
one was transplanted 12.57 months after resection,
with tumor recurrence identified on explant, and that
patient was free of disease 17 years later. The study by
Fuks et al. also failed to identify AFP as a useful tool.(24)
As known, AFP is a marker of more advanced disease
that may have been potentially understaged in some
                                                                  

FIG. 4. Survival of those patients finally transplanted (n 5 28)
from the moment of resection. Dotted line corresponds to highrisk patients (n 5 17), and continuous line represents low-risk
patients (n 5 11). There were no statistically significant differences
in survival (P 5 0.77).
                                                                  

847

  
FERRER-FABREGA
ET AL.

studies covering several years during which the imaging
technology has improved significantly. Similarly, we
have not identified an independent predictive value of
differentiation degree as opposed to the data by others,
such as Cillo et al.(40) Seven out of the nine patients with
poor differentiation degree showed pathological predictors of recurrence; thus, differentiation degree alone does
not improve the prediction of recurrence. It is important
to note that we have registered the worst differentiation
degree in case of heterogeneous tumor pattern. Hence, if
assessed by tumor biopsy, the accuracy of the parameter
may be suboptimal and the very encouraging results by
Colecchia et al. should be validated.(41)
Nowadays, in accordance with the implemented
policy in various countries (e.g., Spain, USA,
France),(42) those small resected HCCs will never have
priority for LT unless they exhibit recurrence. The key
point is that, during this time, an aggressive recurrence
could arise, putting at risk transplant success. In that
regard, in our study the two patients with recurrence
after LT had developed recurrence while on the waiting list with times between LR and LT of 19.1 months
and 16.6 months. Accordingly, we suggest that priority
should be given to enlisted patients in order to avoid
the later emergence of a too advanced recurrent disease
ultimately leading to post-LT recurrence.
In conclusion, our study supports the recommendation
that, for those patients with solitary lesions and an
absence of portal hypertension, LR constitutes an effective, potential curative treatment approach. In these
patients, transplant may not offer survival benefit. On the
contrary, LT should be offered to those patients with
microvascular invasion and/or satellites in the resected
specimen, there being no benefit in waiting for recurrence
recognition by imaging. In order to avoid aggressive disease recurrence with dismal prognosis, we propose that a
waiting time of at least 6 months between resection and
enlistment for transplant should be in place. Beyond this
time point, priority strategies based on preoperative
imaging should allow patients to be effectively transplanted. Such a policy offers optimal outcomes and optimizes the use of the currently limited pool of donors.

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Supporting Information
Additional Supporting Information may be found at
onlinelibrary.wiley.com/doi/10.1002/hep.28339/suppinfo.

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