1. PERSPECTIVES
OPINION
Hepatocellular carcinoma—resection
or transplant?
Sheung Tat Fan
Abstract | Resection and liver transplantation are considered effective treatments
for early-stage hepatocellular carcinoma (HCC). As data from randomized trials are
lacking, the choice of technique is controversial. Retrospective analyses suggest that
for patients with suboptimal liver function, transplantation is the preferred treatment.
For patients with preserved liver function and HCC within the Milan criteria, the overall
survival rate is similar for both techniques; therefore resection is the preferred
treatment. For tumours beyond the Milan criteria but within acceptable expanded
criteria, transplantation has a more favourable outcome than resection. As liver grafts
are in short supply, resection followed by transplantation once intrahepatic recurrence
is detected would spare patients with favourable or very aggressive tumours from
transplantation and enable patients with moderately aggressive tumours to undergo
timely transplantation. Currently, resection and transplantation are considered
complementary in the management of HCC. Expanding the transplantation and
resection criteria of HCC needs to be investigated.
Fan, S. T. Nat. Rev. Gastroenterol. Hepatol. 9, 732–737 (2012); published online 11 September 2012;
doi:10.1038/nrgastro.2012.158
Introduction
Hepatocellular carcinoma (HCC) is the
fifth most common malignancy globally and its incidence is rising worldwide.
Each year, about 500,000–1,000,000 new
cases are reported and approximately
600,000 patients die globally from the
disease. 1 Hepatectomy (resection) and
liver transplantation are considered effective treatments. How to choose between
resection and transplantation for an individual patient is controversial. To date, no
randomized trial has been conducted to
show that one treatment is superior to the
other. The choice depends on the extent
of comorbidities and the liver function of
the patient, availability of a liver graft and
transplant service, and the technical skill of
the surgical team. The long-term outcome
of hepatectomy or transplantation depends
on, among many other factors, the biological behaviour of the tumour, which
varies greatly between patients. The aim
of this article is to provide a perspective on
the outcomes after treatment of HCC by
Competing interests
The author declares no competing interests.
732 | DECEMBER 2012 | VOLUME 9
transplantation or resection and the future
development of surgical treatment of HCC.
Biology of HCC
HCC evolves from a monoclonal focus
into a low-grade dysplastic nodule, a highgrade dysplastic nodule, an early cancer,
and, finally, an advanced HCC.2 A few years
might be required for the high-grade dysplastic nodule to progress to HCC. Stromal
invasion in the portal tract is characteristic of malignancy in early HCC.2 Tumours
>2 cm tend to grow expansively; a fibrous
capsule might form around the tumour as a
host defence against tumour growth.3 The
capsule is eventually ineffective because
the tumour can grow across the capsule
to form microsatellites. Thereafter, the
tumour grows by replacing and destroying
neighbouring liver cells. HCC might also
show a sinusoidal growth pattern (cancer
cells infiltrate the sinusoids at the tumour
boundaries, engulfing hepatocytes4), which
is observed mostly in poorly differentiated,
undifferentiated and sarcomatous HCC.
Venous permeation occurs in the early
development of a tumour and is found in
27% of small and distinctively nodular HCC
(2 cm).4 As the tumour grows, invasion
into the portal vein and hepatic vein leads
to dissemination into the adjacent liver and
systemic circulation, respectively. Tumour
invasion into the peripheral bile duct is
common but is not clinically important
until the tumour grows into the common
bile duct. Rapid growth of the tumour
might result in intratumoural bleeding,
sudden expansion of the tumour and spontaneous rupture in about 10% of patients.5
Massive bleeding and dissemination of
cancer cells into the peritoneal cavity as a
result of tumour rupture lead to rapid mortality. HCC tends to be multicentric, which
could be attributable to portal vein invasion
but could also be the result of malignant
transformation of hepatocytes occurring in
different parts of the liver either simultaneously or sequentially. Simultaneous malignant transformation of many hepatocytes
probably accounts for the diffuse type of
HCC, which is the most malignant form
of HCC, for which neither resection nor
transplantation is effective.
The growth rate of HCC varies from
patient to patient. The average time it takes
for the HCC to double in size (up to around
3 cm) ranges from 3 months to 6 months.6
Slow-growing HCCs are frequently welldifferentiated, whereas fast-growing HCCs
are often poorly differentiated. The growth
rate of HCC might be accelerated if nonsurgical treatments, such as transcatheter
arterial chemoembolization, cannot induce
complete tumour necrosis because the
residual cancer cells might be activated and
become more aggressive.7 The behaviour
of the HCC might also be altered by liver
injury 8 and immunosuppression.9
Resection of HCC
Conventionally, major hepatectomy (resection of three or more Couinaud’s liver segments) is indicated for HCC confined to
one lobe of the liver. Accumulated experience and innovations of surgical techniques
in the past two decades have enabled an
expansion of indications to include resection of additional nodules in the contra­
lateral lobe, extraction of tumour thrombus
in the portal vein, inferior vena cava or bile
duct and resection of major blood vessels in
conjunction with the tumour followed by
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2. PERSPECTIVES
reconstruction. The hospital mortality rate
is low (3%) and transfusion requirement is
minimal (10%) if the patient has preserved
liver function (Child–Pugh class A or indocyanine green retention rate 14%), minimal
intraoperative blood loss, nontumorous
liver volume and function preserved, and
has received optimum care during and after
surgery. 10 The minimum remnant liver
volume that enables safe major hepatectomy
is 20% for patients with normal liver, 30% for
patients with chronic hepatitis and 40% for
patients with cirrhosis.11 In case the remnant
liver volume is insufficient and the liver is
normal or mildly cirrhotic, the contra­
lateral liver can be induced to hyper­ rophy
t
by ipsilateral portal vein embolization 12
or Yttrium‑90 radioembolization.13
Major hepatectomy is contraindicated
in patients with portal hypertension.
However, if these patients have a tumour
that is confined to one liver segment and
have controllable ascites (by diuretics), they
could survive a minor hepatectomy if portal
hypertension is not aggravated by division
of collaterals in the subcutaneous tissues and
umbilical ligament, if only minimal blood
volume is lost and if maximal non­tumorous
liver is preserved.14
After resection, tumours recur in about
40% of patients within the first year.10 Such
recurrence can be intrahepatic, extra­hepatic
or both. Intrahepatic recurrence might be
detected in the rest of the liver as new primaries or near to the resection margin,
which indicates that regional dissemination
from the original tumour via the portal vein
or its branches has not been totally eradicated. Molecular profiling can be used to
differentiate a new primary from intra­
hepatic spread. 15 Clinically, intra­ epatic
h
recurrences that occur more than 2 years
after hepatectomy are considered de novo
or new primaries.16 As a result of the evermutating nature of hepatocytes affected by
viral hepatitis, new primaries can occur any
time after hepatectomy. Extrahepatic recurrences are related to circulating tumour
cells or cancer stem cells.17 These cells are
deposited in extra­ epatic organs and even
h
in the liver remnant itself to grow into
tumours when a favourable microenvironment for tumour growth is present. Thus,
post­ perative complications that induce a
o
systemic inflammatory response and hence
a favourable microenvironment for tumour
growth are associated with an increased
incidence of tumour recurrence.18
Owing to the high incidence of recurrence after hepatectomy, the 5‑year
disease-free survival rate is low. The 5‑year
disease-free survival rates for tumour-nodemetastasis (TNM) stage I, II, IIIA and IVA
are 50%, 55%, 25% and 13%, respectively.
About 17% of patients might survive
for 10 years without tumour recurrence
(S. T. Fan, unpublished work). The 5‑year
overall survival rates for TNM stage I, II,
IIIA and IVA are 82%, 77%, 44% and 28%,
respectively.10 The higher overall survival
rate than disease-free survival rate despite
a high tumour recurrence rate is attributable to the fact that after hepatectomy,
patients are under close surveillance and
prompt treatment of small recurrences is
generally effective. About 25% of patients
might survive for 10 or more years after
hepatectomy (S. T. Fan, unpublished work).
Factors that determine survival of
patients after a hepatectomy are TNM stage,
the volume of blood lost during surgery,
complications after surgery, tumour nodule
number, microvascular invasion and positive resection margins.10 Genomic changes
in the nontumorous liver rather than the
tumour itself might be more important in
prognostication.19 Clinically, of all the risk
factors, a positive resection margin has the
most profound influence on long-term
survival. These findings demonstrate the
need for a meticulous technique to attain
a tumour-free resection margin while
retaining sufficient nontumorous liver.
Radiofrequency ablation is increasingly
used instead of resection of HCC for its simplicity of application. It is applicable to HCC
located in difficult positions for resection.
However, the 5‑year disease-free survival
rate of patients treated with radiofrequency
ablation (33.9%) is lower than with resection (54.8%) and radiofrequency ablation is
not applicable to large tumours.20
Transplantation for HCC
Currently, patients with early-stage HCC
and Child–Pugh class B or C liver function are selected for liver transplantation.
The Milan criteria (solitary tumour ≤5 cm
in diameter, or ≤3 tumours, each ≤3 cm in
diameter) was adopted as a gold standard
for selection because it was shown that the
disease-free survival rates at 4 years for
patients whose tumour status exceeded or
was within the Milan criteria were 59% and
92%, respectively.21 The low survival rate
for patients with tumour status beyond the
Milan criteria argues against liver transplantation for these patients because the rate is
lower than that of patients without HCC.
Therefore, allocation of deceased donor
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© 2012 Macmillan Publishers Limited. All rights reserved
grafts to patients beyond the Milan criteria
would jeopardize the survival of patients
without HCC who are on the waiting list.
However, subsequent studies have demonstrated that the Milan criteria might be
too restrictive.22 Modest expansion of the
selection criteria (for example, University
of California, San Francisco criteria) results
in survival comparable to that of patients
with tumour status within the Milan criteria (Table 1).22 In China, where no national
organ allocation system is available, recruitment of patients with HCC for liver transplantation is liberal. A study performed
under such a liberal policy has shown that
liver transplantation could be extended to
patients with total tumour diameter 8 cm,
if the tumour is well or moderately differentiated and associated with a preoperative
α‑fetoprotein level 400 μg/l.23 The 5‑year
survival rate of such patients was 72%.23
These results have been corroborated by a
Canadian study.24
The use of living donor grafts eliminates the consideration of collective and
societal benefits of liver transplantation
using deceased donor grafts and enables
early transplantation. Living donor liver
transplantation (LDLT) for HCC is frequently used in some centres with the argument that LDLT can maximize individual
patient benefit and a patient’s choice. A
further argument is that even though the
outcome of all types of liver transplantation for patients with tumour status
beyond the Milan criteria is less favourable than patients within the Milan criteria,
the outcome is still much better than with
resection. In a large-volume centre, LDLT
was extended to patients in whom the
largest tumour was ≤5 cm in diameter and
≤6 tumours were present. The overall 5‑year
survival rate was 76%.25 How widely LDLT
can be expanded is not known. In view of
potential living donor morbidity (15%)
and mortality (0.5%),26 the acceptance of
patients with HCC for LDLT should not be
too liberal.
A trend exists towards worse outcome
with LDLT compared with deceased donor
liver transplantation (DDLT) for patients
with tumour status beyond the Milan and
University of California, San Francisco
criteria; however, it is not known why this
trend exists.27 The benchmark of a 5‑year
overall survival rate of 70% for transplant
recipients should be adopted to avoid donor
dissatisfaction and, more importantly, loss
of confidence in the transplant team within
the community. The dilemma is how to
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3. PERSPECTIVES
Table 1 | Expanded selection criteria of transplantation for hepatocellular carcinoma
Study
Criteria
Additional patients benefitted
compared with Milan criteria (%)
University of California,
San Francisco22
One tumour ≤6.5 cm; up to three tumours each ≤4.5 cm, total tumour diameter ≤8 cm
30
Kyoto45
Tumour number ≤10, all ≤5 cm and PIVKA-II ≤400 mAu/ml
11
Tokyo
≤5 nodules, each ≤5 cm
6
Seoul25
Tumour number ≤6, largest ≤5 cm
10
Hangzhou
Total tumour diameter ≤8 cm, or total tumour diameter 8 cm with histopathologic grade I/II
and AFP 400 μg/l
37.5
Toronto24
No tumour size or number restrictions; no systemic symptoms; not poorly differentiated
(beyond Milan tumours only)
46.6
46
23
Abbreviations: AFP, α‑fetoprotein; PIVKA-II, proteins induced by vitamin K absence II.
achieve a comparable result with expanded
indications. As the outcome of liver transplantation depends on the biological behaviour of the tumour, which cannot be altered,
surgical techniques to reduce dissemination of cancer cells during surgery and
complications that might induce systemic
inflammatory responses and subsequent
tumour recurrences should be the appropriate approach until an effective adjuvant
treatment is found.
In my opinion, liver transplantation is
the best treatment for patients with earlystage HCC because the tumour itself and
the liver harbouring the potential recurrent foci are removed, and complications
of liver failure and portal hypertension
are eliminated. The 5‑year overall survival rates for TNM stage I, II, IIIA and
IVA are 94%, 83%, 83% and 74%, respectively (S. T. Fan, unpublished work). The
5‑year disease-free survival rates for TNM
stage I, II, IIIA and IVA are 94%, 80%, 84%
and 73%, respectively (S. T. Fan, unpublished work). Recurrence occurs in about
15% of patients, presumably as a result of
engraftment of circulating tumour cells.28
The recurrence might manifest as long as
6 years after transplantation. Most patients
succumb to recurrence rapidly because
the cancer cells are resistant to treatment.28 Some concern exists that a living
donor graft that is small-for-size sustains
more graft injury and might harbour more
tumour recurrence than a deceased donor
graft, but a study published in 2011 showed
that the outcome of LDLT was similar to
that of DDLT.27
Risk factors for HCC recurrence after
LDLT are related to tumour stage and to
previous treatments that failed to control
the HCC (and thus the indication for liver
transplantation).29 In this situation (salvage
transplantation), multiple unsuccessful
734 | DECEMBER 2012 | VOLUME 9
treatments might have resulted in the most
malignant cancer cells, which have a high
metastatic potential, remaining in the
patient. In our series, after taking out the
patients who underwent salvage transplantation, the outcome of LDLT as the primary
treatment for HCC was comparable with
that of DDLT.30 Primary transplantation
for HCC is therefore preferred if a liver
graft is available. For predicting the longterm survival after DDLT, the risk factor
of microvascular invasion seems to not be
as important as it is in patients undergoing
resection. 23,24,31 Rather, tumour differentiation grade is the most important predictor of survival.32 Evaluation of tumour
biopsy samples taken before transplant
for microvascular invasion is therefore
not necessary. Thus, if a tumour biopsy is
performed, information regarding tumour
cell differentiation would be more valuable for selecting patients with advanced
but well or moderately differentiated HCC
for transplantation.24
Apart from tumour recurrence, the
underlying viral disease might recur and
adversely affect the survival of transplant
recipients. Fortunately, the use of new antiviral agents almost eliminates recurrence
of hepatitis B.33 Thus, long-term survival is
not affected by a patient’s hepatitis B status.
For hepatitis C, a study published in 2011
indicated that the long-term outcome of
patients with HCC who undergo a liver
transplantation is not seriously affected by
their hepatitis C status.34
Resection versus transplantation
In selecting resection or transplantation for
an individual patient, the following factors
have to be taken into consideration: comorbid illness; liver function; extent of tumour
growth; graft availability; and long-term
results of the treatment modality.
For hepatectomy, the age of the patient
is not a limiting factor as long as the
physical condition of the patient means
that he or she is not suffering from renal
failure.35 For transplantation, many centres
have set an arbitrary age limit of 65 years
because an elderly patient’s organ function reserve might not tolerate the transplant operation. These patients are also at
an increased risk of complications related
to immuno­ uppression, such as dia­
s
betes mellitus, cardiovascular disease and
opportunistic infections.
Currently, liver transplantation is
restricted to patients with HCC who have
expected favourable outcomes. Although
expanded criteria have been attempted
in some centres, large tumours (8 cm)
and HCC with portal vein, hepatic vein
or inferior vena cava invasion are generally contraindicated for transplantation. However, such patients are readily
accepted for hepatectomy, which might
be their only chance of a cure. Therefore,
primary liver transplantation could benefit
about 2% of patients with HCC, whereas
primary resection could be performed in
about 25% of patients with HCC (S. T. Fan,
unpublished work).
Hepatectomy can be performed readily
without incurring major expenses, whereas
the timing of liver transplantation depends
on the availability of a liver graft, and the
transplant workup and operations are
expensive. Moreover, a stay in the intensive care unit is mandatory after a transplant, whereas nearly all patients who have
undergone a hepatectomy can be cared for
in a general ward. As a tumour might grow
and disseminate whilst a patient is waiting
for a liver graft, the opportunity for timely
treatment might be lost. Thus, the longterm outcome of patients listed for liver
transplantation is not different from that of
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4. PERSPECTIVES
a
b
c
Figure 1 | Salvage transplantation.
a | A patient with left-liver hepatocellular
carcinoma (arrows) and portal vein invasion
(single arrowhead) underwent left
hepatectomy and portal vein tumour
thrombus extraction. The patient survived the
hepatectomy despite the fact that he had
portal hypertension and varices (double
arrowhead). b | 5 months after the
hepatectomy, the patient had recurrence in
the right liver and the residual tumour was
resistant to chemoembolization (arrow).
c | The patient underwent right-liver living
donor liver transplantation. The patient has
remained disease-free for 5 years after the
transplantation.
those who underwent resection. Resection
might also be associated with better results
than transplantation for patients with earlystage HCC and low Model for End-stage
Liver Disease (MELD) score who are listed
for transplantation.36
Liver function status remains the most
important determinant of selection of
a treatment modality. Although some
centres have advocated liver transplantation to patients with Child–Pugh class A
liver function or normal liver, most centres
offer transplantation only to patients with
Child–Pugh class B or C liver function or
a MELD score 14 for whom hepatectomy
cannot be performed safely.28
Despite the major differences in patients’
liver function, both resection and transplantation can be performed with a low hospital mortality rate (3%).10,28 The reported
long-term outcomes of the two techniques
are vastly different.28 Liver transplantation
results in a much lower recurrence rate and
a longer overall survival rate than resection.
However, the excellent results for transplantation are artefactual because only patients
with an early-stage tumour and anticipated
favourable outcomes are allowed to receive
the scarce resource of a transplanted liver,
whereas many patients with advanced TNM
stage undergo hepatectomy. When patients
with the same early-stage tumour status
(for example, within the Milan criteria)
are compared, the overall survival rate of
the patients undergoing hepatectomy was
not different from that of those undergoing
liver transplantation.28 The major difference, though, was a higher tumour recurrence rate among patients undergoing
hepatectomy than in those who received
a transplant. However, treatment of small
recurrence is effective in patients who have
undergone resection, but not in patients
who have undergone transplantation. 28
Immunosuppression is perhaps the major
reason accounting for the difference.
For patients with more advanced tumours
(for example, up‑to‑7 criteria, that is, HCC
with seven as the sum of the size of the
largest tumour [in cm] and the number of
tumors37), the advantage of liver transplantation starts to emerge. The 5‑year disease-free
survival rate of patients with microvascular
invasion who have undergone liver transplantation is twice as good as that of patients
with microvascular invasion who have
undergone resection (88.2% versus 41.2%).35
In comparing the results among patients
with late TNM stages, the difference is also
obvious. These findings might imply that a
more liberal policy could be adopted, which
would enable more patients with HCC to
undergo transplantation. However, given the
current restricted organ allocation policy in
most countries around the world, it is diffi­
cult to show the superiority of DDLT over
resection for advanced tumours. Centres
that perform large numbers of LDLT might
have accumulated sufficient data to validate
such an approach.
Resection then transplantation
Salvage transplantation can be considered when the intrahepatic recurrence
NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY
© 2012 Macmillan Publishers Limited. All rights reserved
after hepatectomy cannot be treated with
resection because of a difficult location or
cannot be treated with nonsurgical therapy
as a result of deteriorated liver function.
Salvage transplantation is also considered
when repeated nonsurgical treatments
fail to control the recurrent tumour; the
5‑year survival rate of these patients after
transplantation is about 40%. 38 Salvage
transplantation is also adopted as the
intention-­ o-treat policy, so that patients
t
with a tumour status within the Milan criteria and good liver function are offered resection as the first-line treatment followed by
transplantation in case of recurrence. The
5‑year survival rate of the transplant recipients is about 70%.39 In an intention-to-treat
analysis, the long-term outcome of salvage
transplantation is similar to that of primary
transplantation.40 This policy assumes that
the patient is suitable for transplantation
when recurrence is detected and that recurrence is mainly intrahepatic. However, in a
survey by Fuks et al.,40 about 20% of recurrences were extrahepatic and the transplantability was only 28%. The reasons for
the exclusion from salvage transplantation
were advanced age, acquired comorbidities
and recurrence beyond the Milan criteria.
After hepatectomy, increased vigilance
during surveillance could increase the
transplantability rate by detecting early
recurrence.41 The fact that some HCCs are
more aggressive than others implies that not
every patient is suitable for transplantation.
Despite the low transplantability rate, the
policy of resection first followed by transplantation is still advantageous, as patients
with favourable tumour biology (and thus
no recurrence, which accounts for 20% of
patients) and those with very aggressive
cancer behaviour (and thus rapid recurrence beyond the Milan criteria, which
accounts for 27% of patients) could be
spared from liver transplantation, whereas
those with moderate tumour aggressiveness
(53% of patients) could benefit from timely
transplantation. 40 However, uncertainty
exists regarding the influence of the original
tumour status and the time interval between
resection and recurrence on the results of
salvage transplantation. Perhaps, for the
patient’s benefit, he or she should be eligible
for transplantation as long as the recurrence
is within the acceptable criteria (Figure 1).
Another approach is ‘pre-emptive’ liver
transplantation, that is, transplantation
is carried out soon after resection before
recurrence is detected.42,43 The selection of
patients for pre-emptive transplantation
VOLUME 9 | DECEMBER 2012 | 735

5. PERSPECTIVES
is based on finding features of high risk
of recurrence in the resected HCC. These
features include microvascular invasion,
microsatellites and poor differentiation
of the tumour. Among these features,
only microvascular invasion and micro­
satellites are chosen because patients
with poorly differentiated HCC have uniformly poor outcomes after transplantation. Implementation of pre-emptive liver
transplantation, however, could be difficult because the patient might not accept
a second operation after experiencing the
trauma of the first one. In addition, in
some regions, a liver graft might not be
readily available because the local organ
allocation policy restricts graft allocation
to patients with presence of tumours or
deteriorated liver function. Moreover, as
tumours might develop while the patient is
waiting for a deceased donor graft, unless
a graft is readily available (for example,
from a living donor), the ultimate efficacy
of pre-emptive liver transplantation is not
different from the wait-and-see protocol.
Therefore, to implement pre-emptive liver
transplantation effectively, consideration
should be given to changing the organ
allocation policy.
Conclusions
In my opinion, liver transplantation is
without doubt the best treatment for HCC.
In the ideal situation of sufficient and
prompt graft supply, liver transplantation
should be the first choice, as primary transplantation might be more cost-effective
than salvage transplantation.44 However,
in real practice—because of graft shortage—primar y resection followed by
transplantation for recurrence should be
the protocol for patients with preserved
liver function. Rather than considering
resection and transplantation as mutually
exclusive, resection and transplantation
should be considered as complementary
in helping our patients to struggle through
the battle against HCC. Instead of restricting patients’ access to transplantation, the
transplant community should strive to
expand the criteria for transplantation such
that many more patients can benefit from
this procedure. Before the era of sufficient
graft supply arrives, liver surgeons should
continue to develop innovations that can
expand the resectability of HCC.
Department of Surgery, The University of Hong
Kong, Queen Mary Hospital, 102 Pok Fu Lam
Road, Hong Kong.
stfan@hku.hk
736 | DECEMBER 2012 | VOLUME 9
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