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Chapter 5
that only 25–30% of transplant candidates have
a potential donor. It has the advantage of being
performed rapidly, so avoiding drop-out on the
waiting lists. The number of LDLT in Western
countries has however decreased recently and the
trend is to favour cadaveric transplantation through
changes in allocation policies.
• New rules of graft allocation have been
implemented, initially in the USA and subsequently
in Europe. In the USA, the Model of End-stage
Liver Disease (MELD) organ allocation policy
implemented in 2002 has given priority to
candidates with HCC within the Milan criteria.
Waiting times have shortened, obviating the need
for LDLT. Similar policies have been applied in
other countries, such as France and the UK.
• Treatment of the tumour by resection, ablation or
chemoembolisation is widely used while the patient
is on the waiting list to avoid tumour progression
beyond the oncological criteria. There is some
evidence that these treatments may reduce drop-out
rates on the waiting lists, but it is not clear if the
outcome is the same for patients within or beyond
the Milan criteria. The impact of these treatments
on downstaging and post-transplantation survival
is similarly uncertain. A specific advantage of
resection over ablation or chemoembolisation is
that it provides pathological details of the tumours.
However, it is still unclear if the presence of poor
prognostic factors should encourage or discourage
transplantation.
Liver transplantation is the key treatment option
for patients with HCC who fulfil the Milan criteria.
• Reducing drop-out rates on the waiting list is
dependent on changes in graft allocation policies
and on treatment of the HCC while the patient is
on the waiting list.
• Living donor liver transplantation can be proposed
for HCC if the waiting list is expected to be so
long that there is a high risk of drop-out because
of tumour progression.
vascularity, such as the diaphragmatic or mammary
arteries, that should also be embolised to achieve
adequate control. Injection of iodised oil has been
combined to improve the efficacy of embolisation.
Iodised oil (Lipiodol), which is hyperdense on CT,
is cleared from the normal hepatic parenchyma
but retained in malignant tumours for periods
ranging from several weeks to over a year. This
accumulation, which is not associated with
significant adverse effects, may be used for targeting
cytotoxic drugs and increasing their concentration
in the tumour cells. Recently, drug-eluting beads
(DC-Beads) loaded with doxorubicin have been
developed. This technique is much more expensive
than conventional TACE but preliminary results
show superior treatment response and delayed
tumour progression.
anti-angiogenic treatments is under evaluation.
58
Combination of TACE and
59
Contraindications
TACE should not be performed in patients with liver
decompensation, biliary obstruction, bilioenteric
anastomosis and impaired kidney function. Portal
vein thrombosis is also a contraindication unless it
is limited to a section of the liver only and TACE
can be performed in a highly selective manner on a
limited tumour volume.
Morbidity and mortality
Mortality is less than 1% if these contraindications
are applied. Overall, more than 75% of patients
develop a post-embolisation syndrome characterised
by fever, abdominal pain, nausea and raised serum
transaminase levels. These symptoms, which are
not prevented by antibiotics or anti-inflammatory
drugs, are self-limiting and last for less than
1 week. More severe complications occur in less
than 5% of patients and include, in decreasing
order of frequency: cholecystitis or gallbladder
infarction, gastric or duodenal wall necrosis, and
acute pancreatitis. These, along with the postembolisation syndrome, have become less frequent
with the use of supraselective embolisation. Hepatic
abscess formation is rare, occurring in 0.3%, but is
associated with high mortality. The main risk factors
are a previous history of bilioenteric anastomosis,
large tumours and portal thrombosis.
Transarterial chemoembolisation (TACE)
Technique
HCC, in contrast to the liver parenchyma, receives
almost 100% of its blood supply from the artery.
When the feeding artery is obstructed, the tumour
experiences an ischaemic insult that results in
extensive necrosis. With the development of more
supraselective embolisation, greater attention is paid
to accessory arteries that may contribute to tumour
The efficacy of TACE is assessed by CT (usually at
1month) as the disappearance of the arterial vascular
supply to the tumour and a decrease in its diameter.
These features do not necessarily evolve in parallel. A
decrease in tumour size may, for example, be associated
with persistent vascularisation (i.e. residual tumour),
whereas compact Lipiodol uptake without residual
vascularisation may indicate complete tumour necrosis
despite no significant decrease in size (
92
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Monitoring
Fig.5.5).
Primary malignant tumours of the liver
a b
Figure5.5 • HCC treated with microbeads chemoembolisation. (a) Pre-treatment; (b) 2weeks after chemoembolisation:
note the presence of necrosis. (c) 2years after chemoembolisation: the image of the tumour remains, but it is avascular,
indicating complete local control.
Efficacy
There is grade A evidence that TACE improves
survival.
60
One of the largest studies is a prospective
Japanese nationwide survey reporting median and
1-, 3-, 5- and 7-year survivals of 34months, 82%,
47%, 26% and 16%, respectively, with a TACErelated mortality of 0.5%. Independent predictors
of survival were, by decreasing order of influence:
the degree of liver damage, portal vein invasion,
maximum tumour size and number of lesions, and
AFP levels. Two recent randomised controlled studies
from Asia have reported data that are strongly
supportive of surgical resection over TACE
sequential TACE and radiofrequency ablation
61
62
or
patients with multiple tumours.
• TACE is one of the two non-curative
treatment options (with sorafenib [Nexavar®]) that
can improve survival.
• TACE should be recommended as first-line
palliative treatment for non-surgical patients with
compensated Child–Pugh A and with large or
multifocal HCC, without portal vein thrombosis or
extrahepatic metastasis (so-called BCLC stage B).
energy into heat via a needle electrode (15–18G),
positioned in the tumour while the patient is made
into an electric circuit by grounding pads applied to
their thighs. The radiofrequency emitted from the
tip causes ionic agitation and frictional heat, which
leads to cell death from coagulation necrosis. The
objective is to maintain a temperature of 55–100°C
throughout the entire target volume for a sufficient
period of time. Monitoring the impedance is
important because excessive heating results in tissue
charring, increased tissue impedance and decreased
energy absorption.
in
RFA is the first-line ablation technique. All
randomised controlled trials comparing percutaneous
ethanol injection (PEI) and RFA have suggested that
the actuarial probability of local recurrence was
significantly lower with RFA compared to PEI, and
that RFA required fewer treatment sessions to
achieve comparable anti-tumoural effects.
Advantages and drawbacks
These ablative methods are minimally invasive,
c
63,64
preserve the uninvolved liver parenchyma, have no
Percutaneous local ablative therapy
Technique
Locoregional therapies are percutaneous treatment
modalities that allow the injection of a damaging
agent or the application of an energy source directly
into the tumour. Damaging agents include chemicals
such as ethanol or acetic acid. Energy sources either
aim at increasing temperature by radiofrequency,
microwave or interstitial laser photocoagulation
or, alternatively, at decreasing temperature
(cryoablation). Irreversible electroporation is a
new non-thermal ablation therapy that uses a highvoltage direct electrical current to create nanopores
in the cellular membrane that results in cell death
via apoptosis. Radiofrequency ablation (RFA) has
emerged as the most effective of these techniques.
It exploits the conversion of electromagnetic
systemic side-effects, and avoid the mortality and
morbidity of major hepatic surgery. On the other
hand, only tumours <
5 cm are likely to be treated
successfully and the smaller the diameter, the
greater the probability of complete local control.
The presence of multiple tumours (more than three)
is also a limitation because of the need for repeated
punctures. In addition, multiple tumours are either
the result of multifocal carcinogenesis or vascular
extension, and therefore a focal treatment is unlikely
to be very effective. A key requirement is also the
need to clearly visualise the tumour by US and
access it safely. Hence, isoechoic HCC or tumours
located in the upper part of segments 4, 7 and 8 or
at the edge of the left lateral section if it extends
behind the spleen may occasionally be unsuitable
for treatment. Finally, whichever technique is used,
the needle should not enter the tumour directly
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93
Chapter 5
but pass through the hepatic parenchyma so as
to prevent intraperitoneal bleeding or seeding of
tumour cells. This may prove impossible for some
superficial or protruding tumours. An experienced
group reported that up to one-third of patients who
were theoretically good candidates for ablation
could not be treated due to non-visibility of the
HCC on US, risk of thermal injury or absence of
a safe path.
65
Contraindications and limitations
Contraindications to ablation procedures include
gross ascites, which favours intraperitoneal
bleeding, coagulopathy that cannot be corrected,
previous history of bilioenteric anastomosis or
endoscopic sphincterotomy associated with bile
bacterial contamination and therefore a risk of
abscess formation. Additional contraindications
(more specific to ablative techniques than ethanol
injection) are the proximity of the tumour
to the colon, duodenum, stomach or biliary
confluence which may be injured or perforated
by the heating process. RFA, unlike microwave
ablation (MWA), is as a rule contraindicated in
patients with a pacemaker. The efficacy of RFA
also seems to be more impacted by the proximity
of a vascular pedicle (the so-called cooling
effect) than MWA. Whereas PEI is a short and
very cheap procedure performed under light
sedation, RFA is more costly, prolonged (20–90
minutes) and painful, and therefore generally
performed under general anaesthesia. MWA is
also performed under general anaesthesia but
the procedure is quicker.
Mortality following ablation is less than 1%
and morbidity less than 10% The most frequent
complications are pleural effusion and segmental
intrahepatic dilatation, which have no or limited
impact. Severe complications include abscess
formation, perforation of adjacent organs and
intraperitoneal bleeding. Tumour seeding occurs
in less than 5% of patients. Risk factors include
subcapsular location and poor histological
differentiation of the tumour. Coagulating the
needle tract while removing the needle may reduce
this risk.
Methods and margins
Ablation should not only target the tumour but
also aim to achieve a safety margin so as to control
satellite nodules. The incidence of these satellite
nodules, as well as their distance from the main
tumour increases as the main tumour enlarges and
with poorly differentiated tumours. This safety
margin should be 5 mm at least; hence, for an
HCC measuring 3 cm in diameter, the diameter of
the ablation should be 4 cm. This is best achieved
with thermal rather than chemical ablation.
Methods to further improve tumour and margin
control include multipolar ablation (several probes
are placed around the tumour) and combining
ablation with TACE.
66
Treatment response is
assessed by CT or MRI at least 1month after the
procedure. RFA may result in a rim of fibrotic
tissue (hypervascular on late phase MRI or CT)
at the periphery of the tumour and should not be
mistaken for residual tumour tissue. Follow-up
thereafter relies on imaging studies at 3-monthly
intervals to ensure that there is no recurrence of
contrast enhancement.
Indication
Percutaneous ablative therapies have initially been
performed in patients who were unsuitable for
resectional surgery as recommended by EASL and
AASLD. It has thereafter been used as neoadjuvant
treatment in liver transplant candidates and for
treatment of recurrence after liver resection.
As the results of ablation improve, due to
improved technology and patient selection, it may
also be considered as an alternative to surgery or
even as a first-line treatment in selected situations.
A large multicentre phase II trial reported a 97%
sustained complete response rate and 68% actuarial
5-year survival following ablation in patients with
2 cm.67 The results of two RCTs comparing
HCC <
ablation and resection in patients with early HCC
demonstrated no difference.
RFA is now considered by some centres as the
first-line treatment for single nodules <2 cm in
diameter.
68,69
However, meta-analyses still favour surgery
compared to ablation in terms of 3-year survival
and local control.
is that both in the USA
70,71
One additional concern
72
and in Italy73 there
has been a recent temporal trend of increased
use of ablation as a treatment for HCC with a
simultaneous decrease in survival following this
treatment, unlike what has been observed for
other treatments. These observations suggest that
the extension of indications for ablation should be
strictly evaluated.
Other palliative treatments
Conventional systemic chemotherapy
Systemic chemotherapy has had very limited
value in the past as only a very small number of
patients obtained partial response or meaningful
palliation using conventional drugs. Therefore,
there is no rationale for using chemotherapy
in patients with unresectable HCC outside of
clinical trials.
94
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Primary malignant tumours of the liver
Anti-angiogenic targeted therapies
• One trial using molecularly targeted agents
has, for the first time, demonstrated an improved
overall survival in this disease and set a new
standard as a first-line treatment of advanced
HCC. These new agents target angiogenesis and
epidermal growth factor (EGF) receptor pathways.
• Sorafenib (Nexavar®) is therefore recommended
as first-line palliative option in patients not eligible
for resection, liver transplantation, percutaneous
ablation or TACE, if they still have preserved liver
function.
Sorafenib exerts an anti-angiogenic effect by targeting
the tyrosine kinases vascular endothelial growth factor
(VEGF) receptors 2 and 3, and the platelet-derived
growth factor receptor β. In an initial phase III trial,
the median overall survival of Child–Pugh A cirrhotic
patients with histologically proven and advanced
HCC was 10.7 months in the treated group versus
7.9 months in the placebo double-blinded controlled
arm of the study (P = 0.00058) and the median times
to tumour progression were 24weeks and 12weeks,
respectively (P
= 0.000007).74 This efficacy in
advanced HCC (unresectable or metastatic) has been
confirmed in an Asian randomised placebo-controlled
trial that included mostly patients with HBV-related
75
and in a large phase IV study with more
HCC
than 3000 patients.
76
Side-effects included diarrhoea
(39%), hand–foot syndrome (21%), anorexia (14%)
and alopecia (14%). The anti-tumour effect, the
pharmacokinetic profile and safety profile were similar
in Child–Pugh A and B. These results have established
sorafenib as the standard of treatment for advanced
HCC in patients with Child–Pugh A (or B). Several
trials assessing strategies including combination or
sequential treatments are underway.
Other agents with comparable action pathways
have been evaluated in phase II trials and include
bevacizumab and sunitinib. Anti-EGF receptor
agents, such as elotinib (Tarceva®) and cetuximab,
also show promising results. Contraindications to
these treatments include coronary artery disease,
cardiac failure, systemic hypertension and Child B
or C cirrhosis.
Radioembolisation
External beam radiation therapy has been of limited
value in treating HCC because the normal liver
parenchyma is very radiosensitive. Greater interest
has therefore been placed on injecting radioisotopes
such as
131
iodine-iodised oil or 90Yttrium (90Y)labelled microspheres directly into the hepatic artery
(radioembolisation), which offers the advantage of
increased delivery within the tumour and decreased
toxicity. The former agent has an efficacy comparable
to that of chemoembolisation in patients with HCC
not complicated by portal thrombosis but is superior
in patients with tumour portal extension. The use of
90
Y microspheres is recent and has been shown in a
phase II trial to be safe and effective, in particular in
patients with portal vein thrombosis.
90
Y-radioembolisation over TACE is that it may
of
77
One advantage
be indicated in patients with portal vein thrombosis,
while TACE has been usually considered as a
contraindication. These results have been reproduced
in several studies, but without randomised controlled
trials comparing
90
Y-labelled microspheres, TACE
or other established treatments. To date, none of the
retrospective studies have demonstrated an impact of
radioembolisation on survival.
78
Other treatments
Antiandrogenic, antioestrogenic and somatostatin
analogues, once proposed, are currently considered
ineffective.
anti-angiogenics are promising, particularly in patients
with vascular tumour invasion. The additional efficacy
of radioembolisation over TACE, or of anti-angiogenics
over no-treatment, requires strict assessment in the
context of limited financial resources.
25
New treatments such as radioembolisation and
Defining a treatment strategy
Uncomplicated HCC associated with
chronic liver disease
Treatment algorithms need to take account of availability of treatments.
• Liver transplantation, when available, is
considered first and attention is therefore paid
to the extent of liver disease, patient age and
presence or absence of associated conditions.
If a long waiting time (>
resection, ablation or TACE are considered prior
to liver transplantation.
• If transplantation is not available or not
indicated, resection should be considered.
Limiting factors are the number of nodules
(ideally there should be only one) and the severity
of underlying liver disease (patients should be
Child–Pugh A and have neither cytolysis, portal
hypertension nor impaired ICG tests). If a right
hepatectomy is considered it should be preceded
by PVE (with or without TACE).
• If resection is not considered due to the severity
of the underlying liver disease and the nodule is
single (or if there are fewer than three nodules),
6 months) is expected,
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95
Chapter 5
ablation is the treatment of choice provided the
tumour is <
RFA is becoming a first-line treatment, as an
alternative to resection.
• If neither resection nor RFA is considered, TACE
is performed provided there is no ascites or liver
failure (and in particular that serum bilirubin
is <
50 μmol/L) and that the tumour burden
is not too extensive (no vascular invasion or
extrahepatic metastases).
• Remaining patients are currently considered
for anti-angiogenic treatments provided there is
neither liver failure nor vascular disease.
According to this algorithm, it may be considered
that the proportion of HCC patients who are
candidates for transplantation is less than 5%, for
resection 10–15%, for ablation 15–20% and for
TACE 30–40%.
5 cm. For single tumours <2 cm,
Treatment of complicated HCC
• HCC with macroscopic portal vein invasion is
a contraindication for liver transplantation and
ablative treatments. Traditionally TACE was
also contraindicated (because of the risk of liver
necrosis); it is today occasionally performed
provided the thrombus is limited to a section of
the liver and that embolisation is highly selective,
with reduced doses and partial (rather than total)
arterial occlusion as the endpoint. If thrombus
does not extend into the main portal vein, surgical
resection can be considered. Radioembolisation
and anti-angiogenic therapy is otherwise
indicated.
• HCC with macroscopic invasion of hepatic
veins seems to carry an even worse prognosis
as the tumour thrombus will extend into the
inferior vena cava. When the thrombus is
confined to the hepatic vein, resection if possible
can be proposed. There is, however, a very high
risk of pulmonary metastases developing within
6–12months of surgery. Extension into the
inferior vena cava or the right atrium is usually
beyond any treatment.
• Ruptured HCC should be actively treated unless
it occurs as a terminal presentation in patients
with multiple tumours, portal thrombosis and
end-stage liver failure. The primary aim of
treatment is to stop bleeding, ideally by arterial
embolisation. Subsequent hepatectomy can
be associated with long-term survival. Indeed,
(i) bleeding is not necessarily due to tumour
rupture, but occasionally due to rupture of an
artery at the junction of the tumour and the
adjacent parenchyma and (ii) even if the tumour
has ruptured, this is not always associated with
peritoneal seeding of tumour cells.
Fibrolamellar carcinoma
(FLC)
FLC is a rare variant of HCC, defined as welldifferentiated polygonal hepatic tumour cells with
an eosinophilic granular cytoplasm surrounded
by a fibrous lamellar stroma. It is most frequently
observed in the Western hemisphere, where it
accounts for approximately 1% of all HCCs. These
tumours occur at a younger age than HCC (20–
35 years), preferentially in women, and classically
do not arise on a background of chronic liver
disease.
• FLC are usually large at the time of diagnosis
(8–10 cm), and the common revealing symptoms
are a palpable mass, abdominal pain, weight
loss, malaise and anorexia.
• Prognosis is better than that of HCC overall. Fiveyear survival following resection is 50–75%.
• Resection is preferred to transplantation as the
latter has very little or no place.
On imaging, FLC presents as a large solitary
hypervascular heterogeneous liver mass with a central
hypodense region due to central necrosis or fibrosis.
On MRI, the central scar has low attenuation on T2
images, whereas the central scar of focal nodular
hyperplasia has high attenuation. They have welldefined margins and calcification is present in
68%. Histology demonstrates deeply eosinophilic,
polygonal neoplastic cells surrounded by a dense,
layered fibrous stroma.
AFP levels are raised in less than 10% of patients.
Lymph node invasion within the hepatic pedicle
is frequent (60%) and if resection is considered,
simultaneous lymphadenectomy is recommended.
There is a significant risk of recurrence, not only
within the liver but also as lymph node or distant
metastases. Close long-term follow-up is mandatory
since recurrence and death beyond 5 years are
common. Repeat surgery is a reasonable option in
this younger patient population due to the relatively
indolent course of the disease and the relative
inefficacy of non-surgical treatments.
True FLC should be differentiated from mixed
FLC–HCC, defined as conventional HCC displaying
some distinct area with FLC features.
be an alternative option in selected cases and
survival rates of 48% can be obtained in patients
transplanted for FLC–HCC.
81
79
80
LT may
79
96
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Primary malignant tumours of the liver
Intrahepatic
cholangiocarcinoma (ICCA)
ICCA, also known as peripheral cholangiocarcinoma,
is the second most frequent primary tumour of
the liver after HCC. It arises from the peripheral
intrahepatic biliary radicles, which differentiates
them from hilar (Klatskin) tumours and common
bile duct cholangiocarcinoma.
Until the very end of the 1980s there lacked
immunohistological markers that could pinpoint the
biliary origin of adenocarcinoma and ICCA were
therefore probably frequently considered as being the
liver metastasis of an adenocarcinoma of unknown
origin. The diagnosis is currently ascertained through
immunostaining.
This tumour has a poor prognosis overall and resection, sometimes at any cost, was the only therapeutic
option. However, the recent implementation of a
specific staging system and evidence that chemotherapy
is effective pave the way for improved management.
Incidence
In the Western world, the incidence of ICCA is 0.3–3
per 100 000 per million, 10 times less than HCC.
Recent reports suggest the incidence is increasing,
particularly in the USA, UK, France, Italy, Japan and
Australia. Although this increase may be real, it is
probably mainly explained by improved identification
of this tumour and changing rules on how they should
be coded according to the International Classification
of Diseases for Oncology (ICD).
Risk factors
The traditional risk factors for cholangiocarcinoma
include chronic biliary inflammation such as primary
sclerosing cholangitis, chronic choledocholithiasis,
hepatolithiasis, parasitic biliary infestation, Caroli’s
disease and choledochal cyst. However, in most
patients with ICCA (more than 95%) none of these
risk factors can be identified. The exception occurs
in some areas of Asia and in particular north-eastern
Thailand where the parasite Opisthorcis viverrini is
particularly prevalent.
New risk factors are emerging, including chronic
non-alcoholic liver disease, HBV infection, HCV
infection, diabetes and the metabolic syndrome.
However, in contrast to HCC, most ICCAs develop
without a background of liver disease. In surgical
series, 75% of patients have normal livers, 16% have
chronic hepatitis/liver fibrosis and 9% have cirrhosis.
Classification and staging
The Liver Cancer Study Group of Japan proposed
a gross classification of ICCA into three types
82
83
on macroscopic finding: mass-forming, which is
by far the commonest type (75% in Asian series
and probably more in the West); periductalinfiltrating, which spreads along the bile ducts; and
intraductal-growth type with intraluminal spread.
However, tumours may have mixed components,
in particular a combination of mass-forming and
periductal-infiltrating.
Whereas previously ICCA were staged using a
similar system as HCC, the AJCC implemented
a specific classification for ICCA in 2010.
staging takes into account the number of tumours
and vascular invasion (the presence of either defines
T2), rather than tumour size. The reason for this is
that it is very unusual to diagnose ICCA early and size
does not independently impact survival in published
surgical series. T3 tumours are those perforating the
visceral peritoneum or involving local extrahepatic
structures by direct invasion, although this is fairly
rare. The T staging also aims to take into account
the periductal-infiltrating pattern of ICCA and, when
present, defines T4. However, this infiltrating pattern
may be difficult to identify on imaging studies or
even on pathological specimens and there is no
standardised definition yet. Lymph node involvement
has a major impact on survival and when present,
defines TNM stage III. Prevalence of lymph node
extension is high and therefore lymphadenectomy
should be routinely performed to achieve accurate
staging. Median survival of patients with stage I is
greater than 5years (but these patients are very rare),
whereas that of patients with stage II is 53months
and that of patients with stage III is 16months.
84
Pathology and progression
analysis
Two distinct conditions that precede invasive
cholangiocarcinoma have been identified. The
first is a flat or micropapillary growth of atypical
biliary epithelium, which has been called biliary
dysplasia or biliary intraepithelial neoplasia.
The second is an intraductal papillary neoplasm
of the bile duct characterised by the prominent
papillary growth of atypical biliary epithelium with
distinct fibrovascular cores and frequent mucin
overproduction. These preneoplastic conditions
have mainly been analysed in hepatolithiasis and
are observed more frequently in large bile ducts as
hilar tumours than in small septal–interlobular bile
ducts such as with ICCA. The dysplasia–carcinoma
sequence therefore appears more obvious for hilar
lesions than peripheral lesions. This suggests that
an alternative source of ICCA could be the canals
of Hering or hepatic progenitor cells, which are a
target cell population for carcinogenesis in chronic
liver disease.
The T
85
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97
Chapter 5
Clinical presentation and
laboratory tests
As a rule, ICCA tend to be diagnosed at an advanced
stage because the tumour remains clinically silent
for a long time. Symptoms, when present, include
abdominal pain, malaise, night sweats, asthenia,
nausea and weight loss. When they appear, the
tumour is frequently unresectable.
ICCA typically occur with equal frequency in
men or women between the age of 55 and 75years.
Liver function tests are non-specific even though
an increase in liver enzymes (in particular GGT)
may be the only initial finding in some patients.
Although ICCA by definition excludes tumours
arising from the biliary confluence or first-order
branches, jaundice may be present if the tumour
compresses or invades the biliary confluence.
Serum markers lack sensitivity and specificity.
Carcinoembryonic antigen (CEA) exceeds 20 ng/
mL in 15% and carbohydrate antigen (CA) 19–9
300 U/mL in 40% of cases. AFP exceeds 200 ng/
is >
mL in only 6% of patients.
Imaging studies
The main characteristic of mass-forming ICCA is
that it is a fibrous tumour and therefore displays
no enhancement on the arterial phase and delayed
enhancement during the late phase. This may be
seen both on CT and MRI. On MRI, lesions are
hypointense on T1-weighted images and moderately
to markedly hyperintense on T2-weighted images
Fig.5.6). They are typically large, non-encapsulated,
(
heterogeneous, associated with narrowing of adjacent
portal veins and retraction of the liver capsule. As the
tumour grows, satellite nodules frequently develop
in the vicinity of the tumour, and subsequently in the
contralateral lobe (
satellite nodules may not be visible on imaging. There
Fig. 5.7). When superficial, these
is a high propensity for lymph node invasion (present
in 40% of resected patients if lymphadenectomy
is performed routinely), but imaging studies have a
sensitivity of only 50% and a specificity of 75% to
predict this.
Diagnosis
The main differential diagnoses of ICCA are other
fibrous tumours and in particular metastases from
colorectal cancer. Both tumours may easily be
confused on imaging studies. The diagnosis relies on
a biopsy that shows an adenocarcinoma of biliary
phenotype (CK7+ CK20−). Colorectal metastases
are in contrast CK7–CK20 + .
Treatment
Surgical resection is the only curative treatment.
Unlike HCC, there is currently no place for liver
transplantation.
As the tumour is usually diagnosed at an advanced
stage, has ill-defined borders and occasionally extends
to major portal branches or hepatic veins, surgery is
frequently extensive. A major hepatectomy is required
in 75–80%, with extension to segment 1 in 30% of
cases and including the common bile duct in 20% of
cases to achieve a complete resection. This surgery is
therefore associated with significant postoperative
mortality. This is estimated to be 6%, higher than
following surgery for colorectal metastases and
almost comparable to that of surgery for HCC despite
the usual absence of chronic liver disease.
There is a significant risk (20–30%) that, despite
adequate preoperative imaging, contraindications
to a curative resection are identified at laparotomy.
Staging laparoscopy has been advocated, but
is also associated with high false-negative rates
and, as a consequence, patients should be warned
a
Figure5.6 • Vascular kinetics of a small cholangiocarcinoma on MRI (arrowed). Note that the lesion is spontaneously
hypointense (a) that the uptake of vascular contrast is more pronounced in the late phase (c) than in the arterial phase
(b) and that there is a retraction of the capsule.
b
c
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Primary malignant tumours of the liver
a
c
preoperatively about this possibility. Furthermore,
approximately 25% of resected patients will have
an R1 or R2 resection. Survival following an R2
resection is usually comparable to, and occasionally
worse than that of non-resected patients. Median
survival following an R1 resection is typically
12months and 3-year survival is nil.
According to the series published over the past
decade, the 1-, 3- and 5-year survival rates following
resection of ICCA are 67%, 38% and 27%,
respectively. There are few data on survival beyond
5years. Variables that influence postoperative survival
most are the presence of lymph node invasion and an
R1 resection.
86
Intraductal-growth-type ICCAs are
rare but have a better long-term prognosis. Infiltratingtype ICCAs have a worse prognosis than the massforming type due to spread along Glisson’s capsule
and high incidence of lymph node involvement.
There is little evidence that these figures have improved
over the past 10 years. However, recent studies have
suggested that systemic chemotherapy may be effective
in unresectable patients, which opens the possibility
of combining surgery with either adjuvant and/or
neoadjuvant chemotherapy.
87
One recent multicentre
study reported that well-selected cirrhotic patients wit h
b
Figure5.7 • CT of a patient with an intrahepatic/peripheral
cholangiocarcinoma. Note the presence of typical satellite
nodules at the periphery of the tumour (a), the absence of
vascular uptake (b) and the retraction of the capsula (c).
‘very early ICCAs’ (single tumours ≤20 mm) may
become good candidates for liver transplantation
with acceptable survival outcomes.
Surgical resection remains the only curative
treatment for ICCA.
Improvement in outcome will be dependent
on multimodal treatment, including surgery and
chemotherapy.
88
Epithelioid
haemangioendothelioma
(EHE)
EHEs are neoplasms of vascular origin that arise
predominantly from soft tissues, bones and visceral
organs, in particular the lung and the liver. Hepatic
EHE develops from the endothelial cells lining the
sinusoids and progresses along the sinusoids and
vascular pedicles. It is extremely rare (no more than
200 cases have been reported) with an incidence of
less than 1 per million population. It does not arise on
a background of liver disease and there is no identified
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99
Chapter 5
causative factor. Mean age at presentation is 42years
with a female to male ratio of 3:2.
89
Half present with
right upper quadrant pain, a quarter incidentally and
the remainder with severe symptoms such as ascites,
jaundice, weakness and weight loss. Liver failure as a
result of massive infiltration has been described.
These tumours are usually discovered at an
advanced stage; almost 90% are multifocal and
then usually involve both lobes. Approximately
one-third of patients have extrahepatic spread to
regional lymph nodes, peritoneum, lung and spleen.
Although the diagnosis is obvious when appropriate
immunohistochemical staining is performed on
tumour samples, it is frequently misdiagnosed on
other investigations. Laboratory parameters are
non-specific and tumour markers are normal. On
imaging studies, the lesions are frequently confused
with cholangiocarcinoma, metastatic carcinoma,
sclerosing angioma or inflammatory pseudotumours.
They are usually hypoechoic or heterogeneous on
US, hypodense on CT with peripheral and/or central
marginal enhancement on the arterial phase becoming
isodense during the later phase and may display
a halo or target pattern of enhancement. On MRI,
they are hypointense on T1-weighted images, and
heterogeneously hyperintense on T2-weighted images
with similar contrast enhancement as that seen on CT.
Multiplicity of lesions (especially if coalescent), their
subcapsular location with liver capsule retraction
and the presence of calcification (10–30%) or central
necrotic and haemorrhagic areas should raise the
suspicion of the diagnosis, especially in young patients.
Histology shows a tumour composed of epithelioid
and dendritic cells in variable proportions with a
propensity for invasion of hepatic and portal veins,
an overall ill-defined growth pattern and infiltrative
margins. These features are difficult to identify or
differentiate from other tumours on a percutaneous
biopsy sample but immunostaining for factor VIIIrelated antigens is highly specific, demonstrating
endothelial differentiation. Most tumours also stain
positive for CD34 and CD31 endothelial markers.
Epithelial markers including cytokeratins are negative.
The natural history of this tumour is highly variable.
Although exceptional, prolonged survival of more
than 10years has been reported without treatment,
and both partial and complete spontaneous tumour
regression has even been described. On the other
hand, some patients die within 2weeks of diagnosis
and 20% are dead within 1 year. Overall, only
20–40% survive more than 5years. Because of the
rarity of this tumour and its highly variable course,
there is no widely accepted therapeutic strategy.
Partial hepatectomy is rarely feasible due to the
invariable multifocal involvement of the liver.
Palliative resection is not advocated as some have
raised concerns that liver regeneration could promote
a flare-up of residual tumours. Reports of favourable
outcome with an estimated 5-year survival of 75%
probably represent a highly selected subgroup.
The place of liver transplantation has recently been
clarified by a multi-institutional analysis.
90
In 59
patients reported to the European Liver Transplant
Registry, impressive 5- and 10-year survival rates
of 83% and 74%, respectively, were reported.
Invasion of lymph nodes and presence of restricted
extrahepatic involvement had limited impact on
survival and should therefore not be considered as
contraindications to transplantation.
91
The current
shortage of liver grafts and the prolonged waiting
time may dictate that liver transplantation is
indicated only in highly selected patients. Experience
with locoregional or systemic chemotherapy is small
and of limited value, especially as first-line therapy.
Neoadjuvant combination therapies using antiVEGF antibodies, however, deserve investigation.
Angiosarcoma
Angiosarcomas of the liver are rare tumours with a
dismal prognosis. A recent European survey estimated
its incidence as being 0.1 per million/year, being less
than 1% of primary liver tumours. The 1-, 3- and 5-year
survival rates were 20%, 8% and 5%, respectively.
Despite its rarity, it has received attention because of its
frequent association with environmental carcinogens.
There is clear association with prior exposure to
thorium dioxide (Thorotrast), arsenicals and vinyl
chloride. Association with androgenic anabolic
steroids, oestrogens, oral contraceptives, phenelzine
and cupric acid has also been reported. Overall, up to
50% of angiosarcomas are associated with previous
exposure to a chemical carcinogenic agent.
These environmental risk factors may account for
the male predominance (gender ratio of 3:1) and age
at the time of diagnosis (50–70years). Patients usually
experience non-specific symptoms such as abdominal
pain, weakness, fatigue, anorexia and weight loss,
but an acute abdomen related to tumour rupture is a
classical presentation. Biological abnormalities may
include haemolytic anaemia and thrombocytopenia,
which are related to microangiopathic haemolysis
and intravascular coagulation respectively.
Morphologically, angiosarcoma may present as a
large solitary mass or as multinodular lesions. On
CT, they are usually hypodense and remain so after
contrast injection except for occasional focal areas
of central or peripheral ring-shaped enhancement
Fig.5.8). On delayed imaging, the lesion continues
(
to enhance compared with that of the early-phase
images. On MRI, the lesions tend to be hyperintense
on T2-weighted images and heterogeneous on T1weighted images, with focal hyperintensity on a
background of hypointensity. Enhancement on
the arterial and portal phases is heterogeneous.
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Primary malignant tumours of the liver
Figure5.8 • CT of a patient with an angiosarcoma located in the right liver. Note that the lesion is spontaneously
hypodense and remains so after contrast injection except for occasional focal areas of central or peripheral ring-shaped
enhancement.
Although the progressive enhancement could mimic
that of angioma, angiosarcomas clearly differ in that
they are usually multiple and more heterogeneous,
Other sarcomas, including leiomyosarcoma, tend
to have a better prognosis and should be resected
if feasible.
92
and enhancement is of lower intensity compared to
the aorta, whereas it is the same for angioma.
The tumour develops from endothelial cells lining
Primary hepatic lymphoma
the hepatic sinusoids, and grows along these and the
blood vessels. Disruption of hepatic plates may result
in the development of cavities filled with tumour
debris or haematoma, which favours the invasion
of hepatic and portal veins. These tumours have illdefined borders and typically involve the entire liver.
Angiosarcomas are rapidly growing and median
survival is 6months. Most patients have metastases
at presentation, most notably in the lung and
spleen. The latter may be involved in up to half of
patients. Death may also result from liver failure or
intraperitoneal bleeding due to tumour rupture.
It is considered reasonable to attempt resection when
possible and to administer chemotherapy, although it is
still poorly effective. Radiation therapy may have some
value in this particular tumour. Transplantation has not
been associated with survival beyond 3 years due to
tumour recurrence, and is therefore not indicated.
Although malignant lymphoma frequently involves
the liver, primary hepatic lymphomas are rare.
Gross examination reveals a single large tumour
mass, multiple masses or diffuse infiltration in
approximately a third of cases each. Most primary
hepatic lymphomas are classified as diffuse largecell lymphomas of B-cell lineage. Some cases of
primary hepatic lymphomas have been reported
in association with AIDS or with chronic liver
disease. On imaging, they appear as hypodense
lesions (
Fig. 5.9), not always homogeneous. Rim
enhancement and calcifications may be present.
They are hypointense on T1-MRI and slightly
enhanced on T2 sequences. The primary treatment
is chemotherapy. However, some solitary lesions
are resected without a preoperative diagnosis and
chemotherapy is then administered postoperatively.
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101