High Pathological Risk of Recurrence After Surgical

Resection for Hepatocellular Carcinoma: An Indication

for Salvage Liver Transplantation
Margarita Sala,1 Josep Fuster,2 Josep M. Llovet,1 Miquel Navasa,1 Manel Sole,3
Mara Varela,1 Fernando Pons,1 Antoni Rimola,1 Juan Carlos Garca-Valdecasas,2
Concepcio Bru,4 and Jordi Bruix1 for the
Barcelona Clnic Liver Cancer (BCLC) Group
Surgical resection and liver transplantation offer a 5-year
survival greater than 70% in patients with hepatocellular
carcinoma, but the high recurrence rate impairs long-term
outcome after resection. Pathological data such as vascular invasion and detection of additional nodules predict
recurrence and divide patients into high and low risk
prole. Based on this, we proposed salvage liver transplant
to resected patients in whom pathology evidenced high
recurrence risk even in the absence of proven residual
disease. From January 1995 to August 2003 we have evaluated 1,638 patients. Resection was indicated in 77
patients, but only 17 (22%) (all cirrhotics, 14 hepatitis C
virus) were optimal candidates for both resection and
transplantation. Of them, 8 exhibited a high risk prole at
pathology and were offered transplantation. Among the 8
high risk patients, 7 presented recurrence, compared with
only 2 of the 9 at low risk (P .012). Two of the high risk
patients refused transplant and developed multifocal disease during follow-up. The other 6 were enlisted and all
but 1 had tumor foci in the explant. Only 1 presented
extrahepatic dissemination early after transplant and died
4 months later. The others are free of disease after a
median follow-up of 45 months. Two recurrences were
detected in low risk patients, 1 of them being transplanted
18 months after surgery. These data in a small series of
patients conrm that pathological parameters identify
patients at higher risk of recurrence, which allow them to

Abbreviations: HCC, hepatocellular carcinoma; LT, liver transplantation.

From the 1Liver Unit, 2Surgery Department, 3Pathology Department, and 4Radiology Department, Institut dInvestigacions Biome`diques August Pi i Sunyer (IDIBAPS), Hospital Clnic, University of
Barcelona, Catalonia, Spain.
Supported by a grant from Instituto de Salud Carlos III (grant
number C03/02); a contract from Programa Ramon y Cajal
(IDIBAPS, Ministerio de Ciencia y Tecnologa) (to J.M.L.); and a
research grant from the Hospital Clnic of Barcelona (to M.V. and M.
Sala); a grant from de Instituto de Salud Carlos III (Ministerio de
Sanidad y Consumo) (to M. Sala).
Address reprint requests to Jordi Bruix, BCLC Group, Liver Unit,
Hospital Clnic i Provincial, Villarroel 170, 08036-Barcelona, Catalonia, Spain. Telephone: 34-3-2279803; FAX: 34-93-2275792; E-mail:
bruix@ub.edu
Copyright 2004 by the American Association for the Study of
Liver Diseases
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/lt.20202

1294

be listed for liver transplantation without proven malignant disease. In conclusion, this policy is clinically effective and could further improve the outcome of resected
patients. (Liver Transpl 2004;10:12941300.)

epatocellular carcinoma (HCC) is the 5th most

common cancer worldwide and the 3rd most
common cause of cancer-related death.1 Radical treatments for early hepatocellular carcinoma are surgical
resection, liver transplantation (LT), and percutaneous
treatments.2 However, there are no randomized control
trials (RCTs) comparing these treatments, and the best
option depends on the results obtained in observational
studies. LT is the best option in patients with decompensated cirrhosis and single HCC 5 cm or showing
up to 3 nodules, each of them 3 cm. However, there
is a major controversy in cirrhotic patients with preserved liver function and solitary tumors. Survival after
surgical resection in Child Pugh A patients without
signicant portal hypertension and normal bilirubin is
similar to that obtained with LT,3 and the main difference lies in the higher tumor recurrence rate after resectionabove 70% at 5 years vs. 15% after LT.3 5 This is
the major argument used by some authors to support
LT as the rst treatment option.
Several studies have shown that the risk of recurrence might be predicted by the presence of microvascular invasion or additional nodules.3,6 10 and, therefore, both parameters could be used to divide already
resected patients into those with low recurrence risk and
those with high risk. Interestingly, the recurrence rate in
transplanted patients who present a high risk prole in
the explanted liver is slightly increased. However, it is
not prohibitive,3,4,11,12 and this suggests that this subgroup of patients would have been better served by
transplantation.
In our Unit, surgical resection is the rst option
offered to HCC patients without signicant portal
hypertension and normal bilirubin. Following the
above reasoning, we proposed in 1995 that it could be
worthwhile to propose enlisting for LT to those patients

Liver Transplantation, Vol 10, No 10 (October), 2004: pp 1294 1300

Liver Transplantation After Surgical Resection

with solitary HCC who were treated by surgical resection and in whom the pathological assessment evidenced parameters of a high risk of recurrence. This
novel policy differs from that applied by most of the
groups who follow resected patients and consider salvage transplantation upon detection of recurrence.13 19
The present study describes the results we have
obtained with this strategy.

Patients and Methods

Between January 1995 and August 2003, 1,638 patients with
HCC were diagnosed, staged, and treated in our Liver Unit
following a previously published schedule.20 Cirrhotic
patients with early HCC (single tumors 5 cm or 3 nodules 3 cm each) are considered for radical therapies. Resection is indicated for patients with single tumors, absence of
signicant portal hypertension, and normal bilirubin.
Patients with signicant portal hypertension, abnormal bilirubin, or 3 nodules 3 cm are considered for LT (if younger
than 65 years old and without severe associated diseases).
Percutaneous treatments are applied when surgery is precluded. For patients in an intermediate stage, the rst option
is arterial chemoembolization, and those diagnosed at an
advanced stage are considered for phase II-IV trials. Finally,
end stage patients (Okuda III,21 Performance status 3-422)
receive symptomatic treatment.
During this period of time, 77 cirrhotic patients with
HCC were suitable for surgical resection, but only 17 (22%)
were optimal candidates for both resection (rst option) and
LT ( 65 years old without severe associated conditions).
These patients were offered resection as a rst option and
constitute the population of this cohort analysis to assess the
efcacy of the above mentioned salvage strategy.
Sixteen patients were male, mean age was 55 7 years,
and the etiology of underlying cirrhosis was hepatitis C virus
in 14 cases. All patients had a preserved liver function (all
belonged to Child Pugh A group) and did not have signicant
portal hypertension. According to preoperative staging, all
had single tumors that in 9 patients were 30 mm and in 8
ranged between 30 and 50 mm. The mean tumor size was
30 9 mm (range 15 50 mm) (Table 1).
Diagnosis of HCC was performed by needle biopsy in 12
cases and by noninvasive criteria in 5 cases (2 coincidental
imaging techniques or 1 imaging technique with increased
alpha-fetoprotein). Preoperative staging included abdominal
ultrasound, dynamic computed tomography, and/or magnetic resonance imaging. Additionally, a preoperative hemodynamic study with measurement of hepatic venous pressure
gradient was also performed in order to exclude patients with
signicant portal hypertension (hepatic venous pressure gradient 10 mmHg).
Surgical technique included intraoperative ultrasound to
exclude additional nodules, localize the tumor, and perform
an anatomical resection.

1295

Resected liver specimens were serially sliced in .5 cm thick

slices and xed in formalin. Representative samples of tumor,
nontumoral tissue, and surgical margins were embedded in
parafn for microscopic examination. Tumor number and
size were conrmed on gross inspection, and microscopic
analysis determined the presence of vascular invasion, microscopic tumor satellites, tumor differentiation, and status of
the resection margin.
According to the pathological criteria, the patients were
divided into 2 groups: patients with high risk of recurrence if
they had microvascular invasion and/or additional nodules or
satellites and patients with low risk of recurrence if they did
not have any of these parameters (Table 1). Patients of the
high risk group were offered enlistment for liver transplantation even in the absence of tumoral disease and followed every
3 months after enlistment by means of clinical examination,
alpha-fetoprotein, abdominal ultrasound and computed
tomography scan. Patients of the low risk group were advised
to attend regular follow-up every 6 months. Additional diagnostic techniques were performed upon suspicion of recurrence to conrm malignancy, stage the disease, and indicate
treatment, which is based on the same strategy as depicted for
the primary tumor.

Statistical Analysis
Baseline characteristics of the patients are expressed as
mean SD. Comparison between groups was done by using
the Students t-test for quantitative variables, and the 2 test
or the Fisher test for qualitative variables. Follow-up length is
expressed as median (range). Follow-up was computed as
starting from the resection date for all patients and was maintained until death or last visit before December 15, 2003.
The calculations were done by the SPSS package (SPSS
10.0, 1989 1995, Chicago, IL).

Results
According to the pathological study of the resected
specimen, patients were divided into 2 groups: patients
with high risk of recurrence (n 8) if they had additional nodules and/or microvascular invasion and
patients with low risk of recurrence when these 2
parameters were absent (n 9) (Fig. 1). The characteristics of both groups are depicted in Table 1. The resection border was tumor-free in all cases.
High Risk Patients
Amongst the 8 patients with high risk of recurrence, 6
patients accepted to be enlisted for LT and 2 refused. Of
the 6 patients enlisted, 2 developed tumor recurrence
while waiting. One patient presented a single tumor at
12 months, and percutaneous ethanol injection was

1296

Sala et al.

Table 1. Characteristics of the Patients

Variables
Age (years)
Gender (M/F)
Etiology of cirrhosis
HCV
HBV
Alcohol
Other
AFP (ng/mL; 10/11 100/101 400/400)
Bilirubin (mg/dL)
Prothrombin activity (%)
Albumin (g/dL)
AST (IU/L)
ALT (IU/L)
HVPG (mmHg)
Mean tumor size (mm)
30 mm
31 50 mm
Pathologic characteristics
Mean tumor size (mm)
Differentiation degree
Well
Moderate
Poor
Microvascular invasion
Yes
No
Additional nodules
Yes
No

Overall (n 17)

Low Risk (n 9)

High Risk (n 8)

55 7
16/1

54 8.5
8/1

56 5
8/0

ns
ns
ns

14
1
1
1
10 / 1 / 5 / 1
.9 .1
88 10
43 4
67 40
100 65
6.3 2.5
30 9
9
8

6
1
1
1
6/1/2/0
.9 .1
89 11
43 3
73 51
107 84
5.5 2.5
29 12
5
4

4/0/3/1
.8 .1
88 10
43 4
61 24
92 36
7.5 2
30 6
4
4

32 13

29 13

35 12

6
10
1

5
4

1
6
1

7 / 10
10

7
1

3
14

3
5

ns
ns
ns
ns
ns
ns
ns
ns

ns
ns

As per design

As per design

Abbreviations: HCV, hepatitis C virus; HBV, hepatitis B virus; AFP, alpha-fetoprotein; AST, aspartate aminotransferase; ALT, alanine
aminotransferase; HVPG, hepatic venous pressure gradient; ns, not statistically signicant.
NOTE: Numbers expressed as mean standard deviation.

applied as adjuvant treatment. This patient was transplanted 4 months after. The other patient developed
multifocal tumor recurrence 6 months after resection
and is currently still waiting for LT. The resected specimen of this patient showed a single HCC 40 mm in
size, with microvascular invasion and without additional nodules. Recurrence was not suspected prior to
LT in the other 4 patients enlisted because of risk
(median time from resection to LT: 12 months, range
9 19). Median time elapsed between imaging studies
and LT was 53 days (range 14 93).
Characteristics of the explanted liver in the 5 high risk
patients that have been transplanted are depicted in Table
2. Only 1 patient had no tumoral recurrence in the
explanted liver. This patient was transplanted 9 months
after resection and presented both adverse pathological
ndings. The remaining 4 patients presented tumor recurrence. The patient whose tumor recurrence was treated by
percutaneous ethanol injection showed viable tumor in

the treated foci and 1 additional tumor nest. The other 3

patients were transplanted without any evidence of tumor
recurrence, but the explanted liver showed recurrent
tumor foci less than 2 cm, associated with microvascular
invasion in 2 patients.
At the end of follow-up (median follow-up 26
months, range 4 84), 2 of the transplanted patients
had died. One patient (the 1 without tumor nests in the
explanted liver) died 7 years after LT because of recurrent hepatitis C virus cirrhosis without HCC recurrence. The other patient, whose explanted liver showed
multiple foci of HCC and microvascular invasion, died
4 months after LT due to peritoneal dissemination of
HCC and intrahepatic spread.
Finally, the 2 patients who refused enlistment for LT
developed a large multinodular recurrence not amenable for radical therapies at 4.5 and 50 months, respectively. They died at 10 and 18 months after recurrence
due to tumor progression.

1297

Liver Transplantation After Surgical Resection

Figure 1. Results of the proposed decision policy for HCC patients treated by surgical resection after stratifying them
according to the risk of recurrence based on pathology. TACE, transarterial chemoembolization; PEI, percutaneous
ethanol injection; mo, months.

Low Risk Patients

According to our strategy, these 9 patients were not
offered to be enlisted for LT after resection because of
their low recurrence risk. However, 2 of them had
recurrence during follow-up. One patient, initially having a solitary HCC of 4 cm encapsulated and well
differentiated, developed a multinodular HCC 19
months after resection and was treated by transarterial
chemoembolization. He is alive 55 months after resec-

tion. The 2nd patient, operated on because of a solitary

HCC of 2 cm without capsule and moderately differentiated, developed a solitary tumor recurrence and was
enlisted 18 months after resection. LT was performed 9
months later and he is alive and free of recurrence 28
months after LT (55 months after resection).
The remaining 7 patients are alive and without
HCC recurrence with a median follow-up of 55
months (range 19 103).

Table 2. Characteristics of the High Risk Transplanted Patients

Resected HCC
No.
Patient
1
2
3
4
5

Size
(mm)
30
40
35
25
20

Vascular
Invasion

Additional
Nodules

Yes
Yes
No
Yes
Yes

No
No
Yes
Yes
Yes

Explanted Liver
Time
(months)*
19
12
9
16
9

Tumor

Size
(mm)

Vascular
Invasion

Additional
Nodules

Recurrence

FollowUp
(months)

Yes
Yes
Yes
Yes
No

5
12
9
18

Micro
Micro
Micro
No

Yes
No
No
Yes

Yes
No
No
No
No

4
65
26
18
84

Abbreviations: HCC: hepatocellular carcinoma.

*Time from resection to liver transplantation.
Recurrence after liver transplantation.
Time from liver transplant to the end of follow-up.
Patient with tumor recurrence after liver transplantation who died 4 months after.

Patient treated percutaneously before liver transplantation.

Patient with high risk of recurrence in whom explanted liver did not show tumor recurrence. This patient died 84 months after liver
transplantation due to recurrent HCV cirrhosis.
NOTE: The sixth patient is still awaiting liver transplantation.

1298

Sala et al.

Discussion
Tumor recurrence is the major drawback after surgical
resection of HCC, and this is used by some authors to
support LT as the rst therapeutic option for these
patients.19,23,24 However, transplantation applicability
and outcomes are curtailed by the shortage of donors.
This creates a waiting time during which the HCC may
progress and, when analyzed according to intention to
treat the survival of the patients, might be less than that
offered by surgical resection.3,25,26 Because of this, most
of the groups consider resection as the rst treatment
approach for patients who would be candidates for both
resection and LT.13 18,20 In such a scenario, the main
issue is how to manage the risk of recurrence and to treat
its development. Despite some encouraging results with
Interferon,27 acyclic retinoids,28 radiation,29 and adoptive immunotherapy,30 there is no effective therapy to
prevent tumor relapse.31 Thus, in the majority of centers the established clinical practice is to carefully follow
the resected patients and, upon detection of recurrence,
consider the potential indication of so-called salvage
LT.15 This approach has been heavily criticized for
years because initial studies suggested that LT after
resection would offer poorer results,19 but the data
recently published by Belghiti et al.13 indicate that the
survival after salvage LT is not signicantly lower. The
explanation for this discrepancy might be related to the
biological selection process that the patients have
undergone until reaching LT. This does not refer to a
better identication of candidates by imaging techniques in order to exclude desperate patients with
extensive multifocal recurrence, but to the fact that only
those patients with a less aggressive recurrence would
become candidates for salvage LT. It is well known that
there are 2 major pathways leading to recurrence: tumor
dissemination prior to operation and de novo tumor
development in an oncogenic cirrhotic liver.32 40
In most cases, recurrence will be related to the rst
mechanism (dissemination) and will very likely appear
early during follow-up as a multifocal involvement.32,39,41 43 This dissemination nature of recurrence and its faster progression mean that patients will
not be candidates for salvage surgery. In fact, if enlisted
upon detection of recurrence, they will experience a
higher rate of exclusion while waiting, and even if they
do reach transplantation, their outcome will be dismal.
By contrast, those infrequent patients in whom dissemination has not taken place will most likely develop
solitary de novo tumors and in that way become candidates for successful salvage therapy. While the retrospective analysis of the database by Poon et al. suggests

that the majority of patients with recurrence could

become candidates for salvage LT, this is not supported
at all by the few available data in clinical practice3,13,14,16,18,19,44 and even by their own previous publications.39,45 As a whole, less than 20% of the patients
are candidates for salvage surgery,46 56 and this low
applicability was the major criticism of the Markov
analysis on salvage LT performed by Majno et al. who
considered an 80% applicability rate upon recurrence
detection.15
According to all these comments, it is clear that the
policy to wait for recurrence to develop and then indicate treatment is less than optimal. The risk of recurrence can be accurately predicted by pathologic examination of the resected tissue. Microvascular invasion
and presence of satellites or additional intrahepatic neoplastic sites are thought to be related to unrecognized
tumor spread prior to resection, and interestingly, those
transplanted patients in whom pathology examination
depicts these pathologic high risk parameters do not
present a prohibitive rate of disease recurrence during
follow-up.11,12 Therefore, for these patients LT should
be considered the best primary treatment.
Following this reasoning, we proposed a more active
attitude offering enlistment for LT to those patients
who after initial HCC resection would prove to bear
this pathologic high risk prole. The results of this
study demonstrate the efcacy of this novel policy.
During the period of the investigation, we operated on
77 patients and 17 of them qualied as candidates both
for resection and LT. According to our treatment strategy, they were offered resection as primary treatment,
and based on the pathologic ndings, 8 patients were
classied at high risk and 9 at low risk. All but 1 of those
at high risk showed recurrence either prior to LT (n
2) or in the explanted liver in the absence of disease on
imaging techniques (n 3). Unfortunately, 2 patients
did not accept to be enlisted, and when recurrence was
detected, it was recognized as multifocal and LT could
not be indicated as a salvage procedure. These 2 subjects
support the aforementioned concept suggesting that
recurrence due to dissemination is very unlikely to be
detected at a stage when salvage LT might be feasible. In
addition, we have also evidenced that this policy offers
an adequate long-term outcome. Only 1 patient developed massive or extensive tumor dissemination after LT
and died 4 months after the operation. The other 4
patients have been followed for a median of 45 months
and show no tumor recurrence, there being only 1
death at 84 months because of recurrent hepatitis C
virus cirrhosis.
On the other hand, the outcome of patients classi-

Liver Transplantation After Surgical Resection

ed as low risk has also been encouraging. Only 2 out of

the 9 patients in this group have recurrence. One of
them was amenable to be enlisted for LT (successfully
performed after 9 months waiting time), while the
other was discarded due to multifocal disease and was
treated by transarterial chemoembolization. The
remaining 7 patients are all alive and free of disease after
a median follow-up of 55 months. They may develop
recurrence during follow-up, but this will very likely be
the result of a de novo tumor in the cirrhotic liver.
Accordingly, this group of patients will benet from a
conservative approach with regular surveillance that
allows them to skip or delay the risks associated to LT.
If HCC occurs, they will become optimal candidates
for salvage LT.
It could be argued that the number of patients in
which the need of LT is avoided is very limited, and
therefore, it makes no sense to maintain resection as the
rst option. However, any effort to optimize the use of
the limited pool of cadaveric donors is worth undertaking.
In the future, the availability of effective adjuvant
therapies may effectively prevent recurrence, and/or
molecular proling57 will rene the risk assessment
even prior to tumor resection. While these advancements take place, our active salvage transplantation policy according to risk appears to be an effective treatment
policy for patients with surgical HCC. Obviously, conrmation of our data by other groups should be available prior to unequivocally recommending this policy
in conventional clinical practice.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

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