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Chapter 4
which can occur without any symptom of intestinal
amoebiasis.
52,53
Patients with an amoebic abscess
are usually more acutely ill than patients with a
pyogenic abscess, have high fever and abdominal
pain in the right upper quadrant. They are also
younger and are usually from high-prevalence areas
or recent travellers to such areas. Amoebic abscesses
are more often found in individuals with suppressed
cell-mediated immunity. Jaundice is an unusual
symptom and is found in patients with multiple
lesions or very large abscesses, and is associated
with adverse prognosis.
53
Both ultrasound and CT are sensitive in the
detection of amoebic liver abscesses. In many
patients, it is difficult to differentiate amoebic
abscesses from pyogenic abscesses, but epidemiologic
and clinical information in conjunction with
positive amoebic titres may suggest the diagnosis.
The lesion is typically oval or round and located
near the liver capsule. On contrast-enhanced CT,
amoebic abscesses usually appear as rounded welldefined lesions, with an enhancing wall 3–15 mm in
thickness, and a peripheral zone of oedema around
the abscess that is somewhat characteristic. The
central abscess cavity may contain multiple septa or
fluid-debris levels.
The diagnosis can be confirmed by demonstrating
E. histolytica trophozoites in aspirated pus, or more
frequently from the necrotic material obtained by
needle biopsy of the edge of the lesion. However, the
amoeba will be found in only a small percentage of
53
In contrast, serum antibodies to Entamoeba
cases.
species are present in >90% of cases.
52
Falsenegative serology tests may be obtained early in the
infection (first 7–10days), but repeated tests usually
will come back positive.
51
Management
Most amoebic liver abscesses can be treated with
metronidazole treatment alone.
therapeutic aspiration remains controversial. It is
reasonable to reserve aspiration for individuals in
whom the diagnosis is uncertain, when there is no
response to metronidazole, in individuals with large
left lobe abscesses (because of the risk of rupture
into the pericardium), and in severely ill patients.
Individuals with an amoebic liver abscess should
also be treated to eliminate intestinal colonisation
by E. histolytica.
51,52
51,52
The role of
52
Hydatid cysts
General
Echinococcosis or hydatid disease is a parasitic
illness caused by the tapeworm Echinococcus.
The liver is the most commonly infected organ.
Hepatic echinococcosis is (if not treated on time)
54
a life-threatening disease caused by Echinococcus
granulosus or Echinococcus multilocularis,
respectively causing a cystic and alveolar form.
Infection with E. granulosus is more common
whereas E. multilocularis infection is more serious.
55
54
E. granulosus has a worldwide distribution, with
the highest prevalence found in Mediterranean
countries, Russia, China, North and East Africa,
South America and Australia.
55
The parasite life
cycle involves dogs (or coyotes, dingoes and red
foxes) as definitive hosts and ungulates (sheep, pigs,
goats and horses) as intermediate hosts. Humans
can accidentally become ‘aberrant’ intermediate
hosts, after ingestion of Echinococcus eggs excreted
by infected carnivores. The eggs grow inside the
host organs (mainly the liver) and form a cyst
(hydatid cyst). Hydatid cysts are round in shape and
are usually filled with a clear fluid. The inner part of
the cyst features a germinating membrane while the
outer part features a laminated layer.
54
In time, the
parasite cysts expand and cause a granulomatous
inflammatory reaction which leads to the cyst
becoming walled off by fibrous tissue.
cysts may develop daughter cysts (cyst in a cyst) and
septations.
5,55
Peripheral calcifications are common
in both viable and non-viable cysts.
54,55
5
Maturing
E. multilocularis is endemic in the northern
hemisphere, including North America, Asia
and some European countries (mainly France,
Switzerland, Austria and Germany).
55
However, due
to migration of refugees, the disease is increasingly
found in non-endemic areas. The definitive hosts are
wild carnivores (such as the red fox) and domestic
cats and dogs, intermediate hosts are small rodents,
whereas humans are aberrant hosts who ingest
embryonated eggs.
alveolar structures with multiple vesicles of different
sizes within the liver.
spread locally or metastasise to the brain, bones or
lungs via the blood.
55
Echinococcal larvae form
54
Alveolar echinococcosis may
54
Clinical presentation
The majority of patients are asymptomatic, since
the cyst grows only slowly in the liver (1–5 mm
per year).
found incidentally. The most common presenting
symptoms are right upper quadrant discomfort
and loss of appetite.
cysts include cyst leakage or rupture resulting in
anaphylaxis, cholangitis due to obstruction of bile
ducts by daughter cysts or rupture of a cyst into a
biliary duct, or secondary infection of the cysts.
multilocularis is initially found in the liver (usually the
right lobe), but later in the infection it is possible to find
metastasis to lung, brain, bones and local extension
of the lesion (in the abdomen, retroperitoneum, or
diaphragm).
alveolar echinococcosis may present with liver failure.
54,55
Liver lesions are therefore often
54
Complications from hydatid
55
In late-stage disease, patients with
54,55
E.
72
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Benign liver lesions
Diagnosis
Ultrasound is a good tool for screening and follow-up.
With ultrasound imaging, hydatid sand (scolices in
the cyst fluid from ruptured vesiculae which form a
white sediment), floating membranes, daughter cysts
and vesicles inside the cyst can be identified. CT can
identify cyst wall or septal calcifications, internal
cystic structures and assess for complications
Fig. 4.7). MRI is superior for demonstrating cyst
(
wall defects, biliary communication and neural
involvement. Serological diagnosis is useful to
confirm a radiological diagnosis and may also
be an important tool for follow-up after surgical
or pharmacological treatment. However, not all
patients with cystic echinococcosis have a detectable
immune response as this is dependent on the degree
of echinoccal antigen secretion.
55
Management
The treatment options for cystic echinococcosis
include surgery, percutaneous treatments and
medical treatment with a benzimidazole (such
as albendazole or mebendazole), and should
be undertaken in a centre with expertise in this
54,55
disease.
depends on multiple variables such as diseasespecific characteristics (cyst number, size, site and
presence of cystobiliary communication) and
clinical condition of the patient.
Surgery is currently reserved for complicated
cysts (biliary fistula), multiseptated cysts, cysts with
daughter cysts and large superficial cysts with a high
risk of perforation.
hydatid cysts offers the best chance to completely
cure the disease.
reduce the risk of anaphylaxis and secondary cystic
echinococcosis.
The most appropriate treatment option
54
If feasible, surgical removal of
55
A benzimidazole is often given to
Another treatment option is the PAIR method;
an acronym which stands for Puncture, Aspiration,
Injection, Re-aspiration. With this strategy, the
cyst is punctured under ultrasound guidance, the
cyst fluid is aspirated, a protoscolicidal agent (e.g.
hypertonic saline or ethanol) is injected and the
fluid re-aspirated. In selected patients, a success
rate of up to 97% has been reported, but this
method is less suitable for cysts that have daughter
54
Furthermore, PAIR should not be used if
cysts.
a cystobiliary communication is present, due to
the risk of developing sclerosing cholangitis. To
minimise the risk of secondary echinococcosis,
concurrent treatment with a benzimidazole is
recommended. This is usually given 4 hours before
the puncture and continued for a month.
55
An
alternative percutaneous method is placement of a
broad tube to remove the solid components of the
cysts as well as the daughter cysts.
54
Medical treatment without surgery or PAIR
may be used for patients with small cysts (<
5 cm)
without daughter cysts or septations. Otherwise,
this treatment should be restricted to patients
that cannot undergo surgical or percutaneous
treatment.
54,55
It is reported that complete cure (i.e.
cyst disappearance) only occurs in approximately
a third of patients treated with a benzimidazole
55
alone.
E. multilocularis cysts are treated with surgery or
pharmacotherapy. Surgery is the first choice option
in all operable patients.
54,55
Liver transplantation
may be an option in patients with advanced liver
failure. Albendazole treatment should be given for a
prolonged period after surgery (at least 2years) and
patients should be monitored for recurrent disease.
For patients not suitable for surgery, the optimal
duration of therapy is not clear and a benzimidazole
could even be necessary for life.
55
Figure4.7 • CT of a patient with Echinococcus
granulosus showing a non-calcified hydatid cyst with
daughter cysts.
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Other liver lesions
Mesenchymal hamartoma is an uncommon benign
liver lesion that mainly occurs in young children
2 years of age), although cases in adults have
(<
been reported. These lesions consist of a mixture
of epithelial and mesenchymal structures. If the
lesions enlarge, surgical resection is recommended.
Transformation to undifferentiated (embryological)
sarcoma has rarely been described.
Focal steatosis and fatty sparing (also referred to as
focal fatty change of the liver) are a frequent findings
on liver imaging and can mimic solid lesions. Regional
variations in the degree of fat accumulation in the
liver can be related to vascular anomalies, metabolic
disorders, use of certain drugs or coexistence of
hepatic masses. If the diagnosis is made (with or
without biopsy), no further treatment is necessary.
73
Chapter 4
Inflammatory hepatic pseudotumours are rare
hepatic lesions that can mimic malignant lesions.
They can occur at all ages. The aetiology is unclear,
but an underlying infectious cause has been suggested.
Patients can present without any symptoms or
with fever, weight loss or upper abdominal pain. A
biopsy can be necessary to differentiate the lesion
from other tumours. On histological examination
myofibroblasts, polyclonal plasma cells and fibrous
tissue can be found. The course of the disease is
unpredictable. Spontaneous regression has been
reported, although recurrence after regression has
also been described.
56
Treatment with antibiotics or
steroids should be considered.
Key points
• Benign liver lesions are common and often asymptomatic.
• Asymptomatic lesions can usually be managed conservatively.
• Haemangiomata are the commonest benign liver lesion, and can be >10 cm in diameter (giant
haemangioma). They are more common in females.
• Haemangiomata are managed conservatively, although for lesions with recurrent pain and very large
lesions, resection might be considered.
• Focal nodular hyperplasia (FNH) is the second commonest benign liver tumour, and if the diagnosis
is certain neither a resection, nor follow-up of asymptomatic patients is necessary.
• Hepatocellular adenomas are rare hepatic tumours, mainly found in women of child-bearing age and
are associated with the use of oral contraceptives.
• The risk of bleeding and malignant transformation increases with hepatocellular adenomas >5 cm in
diameter; the risk of malignancy is higher in men.
• Hepatic cysts are common and if asymptomatic need no further treatment.
• Cystadenomas are rare benign cystic tumours of the liver that should be considered for resection.
• Cystadenomas are more frequently found in women, and if found in men carry a higher risk of a
malignancy.
• Hepatic liver abscesses should be treated with antibiotics and/or percutaneous drainage.
• Amoebic liver abscesses should be treated initially with metronidazole.
• Hepatic echinococcosis is a parasitic illness, in which humans are an accidental intermediate host.
Although the disease is mainly found in endemic areas, it is increasingly found in non-endemic areas
due to migration of refugees and should be managed in centres with expertise in the disease.
Full references available at http://expertconsult.
inkling.com
Key references
7. MarreroJA, AhnJ, Rajender ReddyK, etal. ACG
clinical guideline: the diagnosis and management of
focal liver lesions. Am J Gastroenterol 2014;109:
1328–47; quiz 48. PMID: 25135008.
In this guideline of the American College of
Gastroenterology the authors provide an evidencebased approach to the diagnosis and management of
a focal liver lesion. Clinicians should consider not only
malignant liver lesions, but also benign solid and cystic
liver lesions such as haemangioma, focal nodular
hyperplasia, hepatocellular adenoma and hepatic
cysts.
15. Thomeer MG, Broker M, Verheij J, et al.
Hepatocellular adenoma: when and how to
treat? Update of current evidence. Therap
Adv Gastroenterol 2016;9:898–912. PMID:
27803743.
Review that discusses the decision-making processes
and associated risk analyses for hepatocellular adenoma
based on lesion size and subtype. Hepatocellular
adenomas >
oral contraceptives, lesions with a β-catenin mutation,
or lesions in male patients, associated with steroid use,
glycogen storage disease, or underlying viral hepatitis
should be considered for an intervention.
16. BlancJF, FrulioN, ChicheL, etal. Hepatocellular
adenoma management: call for shared guidelines
and multidisciplinary approach. Clin Res Hepatol
Gastroenterol 2015;39:180–7. PMID: 25434466.
Describes the molecular subtypes of hepatocellular
adenomas and their potential relevance for
management. β-catenin-mutated hepatocellular
adenomas are associated with a higher risk of
malignancy, but also other mutations in the heterogenic
group of hepatocellular adenomas are discussed.
5 cm present for 6 months after stopping
74
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Benign liver lesions
17. StootJH, CoelenRJ, De JongMC, etal. Malignant
transformation of hepatocellular adenomas into
hepatocellular carcinomas: a systematic review
including more than 1600 adenoma cases. HPB
(Oxford) 2010;12:509–22. PMID: 20887318.
A systematic review of hepatocellular adenomas
focusing on malignant transformation. The
authors conclude that malignant transformation of
hepatocellular adenomas is rare (4.2%) and is mainly
observed in lesions >
5 cm.
26. Lantinga MA, Gevers TJ, Drenth JP. Evaluation
of hepatic cystic lesions. World J Gastroenterol
2013;19:3543–54. PMID: 23801855.
This review article describes the literature and an
algorithm to guide clinicians in characterising hepatic
cystic lesions. The diagnosis of simple liver cysts is
based on typical ultrasound characteristics, whereas
serodiagnostic tests and microbubble contrastenhanced ultrasound are invaluable in differentiating
complicated cysts, echinococcosis and cystadenoma/
cystadenocarcinoma when ultrasound, CT and MRI
show ambiguous findings.
28. WijnandsTF, GortjesAP, GeversTJ, etal. Efficacy
and safety of aspiration sclerotherapy of simple
hepatic cysts: a systematic review. AJR Am J
Roentgenol 2017;208:201–7. PMID: 27824501.
A systematic review, in which the efficacy and safety
of aspiration sclerotherapy is studied. In the majority
of studies a reduction in volume of the cyst and a
decrease or disappearance of symptoms was found.
37. Arnaoutakis DJ, Kim Y, Pulitano C, et al.
Management of biliary cystic tumors: a multiinstitutional analysis of a rare liver tumor. Ann Surg
2015;261:361–7. PMID: 24509187.
Describes a retrospective study of 248 patients with
a biliary cystic tumour. Among patients undergoing
surgery for biliary cystic tumours, associated
malignancy was found in 10% of patients and no
preoperative findings reliably predicted underlying
biliary cystadenocarcinoma.
41. HoekstraLT, BiezeM, ErdoganD, etal. Management
of giant liver hemangiomas: an update. Expert
Rev Gastroenterol Hepatol 2013;7:263–8. PMID:
23445235.
A literature review on giant haemangiomata, defined
5 cm. In patients with a giant liver haemangioma,
as >
observation is justified in the absence of symptoms,
whereas surgical resection could be considered
in selected patients with abdominal (mechanical)
complaints or complications, or when diagnosis
remains inconclusive.
49. Cai YL, Xiong XZ, Lu J, et al. Percutaneous
needle aspiration versus catheter drainage in the
management of liver abscess: a systematic review
and meta-analysis. HPB (Oxford) 2015;17:195–201.
PMID: 25209740.
A systematic review and meta-analysis on the treatment
of liver abscesses. Percutaneous catheter drainage is
more effective than percutaneous needle aspiration
because it facilitates a higher success rate and reduces
the time required to achieve clinical relief.
52. Stanley SL, Jr, Amoebiasis. Lancet 2003;361:1025–
34. PMID: 12660071.
Describes epidemiology, diagnosis and treatment of
amoebiasis. Amoebic liver abscesses grow inexorably
and, at one time, were almost always fatal, but now
even large abscesses can be cured by one dose of
antibiotic.
54. Mihmanli M, Idiz UO, Kaya C, et al. Current
status of diagnosis and treatment of hepatic
echinococcosis. World J Hepatol 2016;8:1169–81.
PMID: 27729953.
Reviews the diagnosis and treatment of E. granulosus
and E. multilocularis infections. The available
treatment options for E. granulosus infection include
open surgery, percutaneous interventions and
pharmacotherapy, whereas E. multilocularis is treated
with aggressive surgery as the first-choice treatment,
while pharmacotherapy is used as an adjunct to
surgery.
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75
5
5
Primary malignant tumours of the liver
Chetana Lim
Olivier Farges
With the exception of hepatocellular carcinoma
(HCC), which is one of the most common
malignancies, primary tumours of the liver are
relatively rare in adults. HCC arises from hepatocytes
and cirrhosis is its main aetiological factor. This tumour
remains a subject of considerable interest due to its
rising incidence and the development of innovative
treatments. Intrahepatic cholangiocarcinoma (ICCA)
arises from the peripheral intrahepatic biliary
radicles, and other rare primary tumours arise
from mesodermal cells and include angiosarcoma,
epithelioid haemangioendothelioma and sarcoma.
Hepatocellular carcinoma
HCC accounts for 90% of all primary liver
malignancy and its incidence continues to increase. It
is the sixth most common neoplasm, accounting for
more than 5% of all cancers, and is the second most
common cause of cancer-related deaths worldwide.
The International Agency for Research on Cancer
has estimated in 2012 through its GLOBOCAN
series that primary liver cancer caused more than
745 000 deaths worldwide (9.1% of the total).
HCC usually occurs in male patients, and cirrhosis
precedes its development in most cases. Due to
better medical management of cirrhosis, survival of
cirrhotic patients has steadily increased in the last
two decades resulting in a greater risk of developing
HCC. Cohort studies have reported that in patients
with HCC, the death rate due to cancer is 50–60%
while hepatic failure and gastrointestinal bleeding
are responsible for approximately 30% and 10% of
the deaths, respectively. HCC may now be identified
1
at an early stage, particularly through the screening
of high-risk patients.
Control of HCC nodules may be achieved successfully
by surgical resection and by percutaneous treatment
but their precise role will depend on the morphological
features of the tumour and the functional status of
the non-tumourous liver. Unfortunately tumour
recurrence is common due to the persistence of the
underlying cirrhosis, which represents a preneoplastic
condition. Liver transplantation may seem a logical
alternative treatment but has its own limitations,
including tumour recurrence, limited availability of
grafts and cost. The most exciting areas of progress
are the control of hepatitis B virus (HBV) or
hepatitis C virus (HCV), prevention of carcinogenesis
in patients with chronic liver disease, early radiological
screening and the development of medical therapies.
In the setting of liver surgery, better liver function
assessment and understanding of the segmental liver
anatomy with more accurate imaging evaluation are
the most important factors that have led to a decrease
in postoperative mortality rates. Active follow-up
and treatment of recurrence have also contributed to
increase the 5-year survival to as much as 70%.
2
Incidence of HCC
The world age-adjusted incidence of HCC in men
is 14.9 per 100 000. Geographical variation related
to the prevalence of hepatitis B (HBV) and hepatitis
C virus infections are the two main risk factors
worldwide, and account for more than three-quarters
of all cases (Table5.1). The incidence may be as high
76
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Primary malignant tumours of the liver
Table5.1 • Age and prevalence of HBV and HCV among patients with HCC in different geographical areas
Area Age (years) HBV (%) HCV (%) Combined (%)
Africa 47 47 18 65
USA 63 16 48 64
South America 55 43 21 64
Western Europe 65 18 44 62
Eastern Europe 60 51 15 66
South-Western Asia 52 42 27 69
Japan 65 15 75 91
China, Korea 52 70 18 88
World 53 25 78
as 99 per 100 000 in Mongolian men. Other high-rate
areas include Eastern and South-Eastern Asia (>20
cases per 100 000). By contrast, Northern Europe
and South Central Asia are areas with low incidences
5 cases per 100 000); in these areas, HCV is the
(<
main risk factor, together with alcohol abuse, nonalcoholic fatty liver disease and obesity. Southern
Europe and North America have intermediate rates.
The rising incidence of HCC was first documented
in the USA, where this doubled between the late 1970s
and early 1990s, reaching 3 cases per 100 000. The
epidemic of HCV infection probably accounted for
a large part of this increase. Alternative explanations
include ageing of the population, increased detection,
improved survival of cirrhotic patients and the
epidemic of obesity and type II diabetes.
It has been estimated that HCV began to infect
large numbers of young adults in North America and
South and Central Europe in the 1960s and 1970s
as a result of intravenous drug use. The virus moved
into national blood supplies and circulated until a
screening test was developed in 1990, after which
time rates of new infection decreased dramatically.
In Canada, Australia, Japan and various European
countries, where HCV infection spread earlier than
in the USA, a similar trend was observed, but in some
countries the incidence of HCC is now decreasing.
Due to recent advances with the advent of the new
direct-acting antivirals, current HCV infection cure
rates may reach 90% and this major progress may
be associated with several beneficial consequences.
3
Firstly, the incidence of HCV-related HCC will
decrease as a result of the eradication of HCV
infection and secondly, the evolution of HCVinfected patients progressing to cirrhosis and the
need for transplantation will also decrease.
4
Risk factors for HCC
The main risk factor for HCC is liver cirrhosis. Once
present, male gender, age (as a marker of the duration
of exposure to a given aetiological agent), stage of
cirrhosis and diabetes are additional independent
risk factors.
Cirrhosis vs no underlying liver disease
Up to 80–90% of HCC arise in patients with
underlying liver disease. The risk of tumour
development varies with the type of cirrhosis;
the highest risk is reported for chronic viral
hepatitis, whereas lower risks are associated with
other forms of cirrhosis such as primary biliary
cirrhosis.
HCC developing in the absence of cirrhosis is
found in 10–20% of patients. The term ‘absence
of cirrhosis’ appears more appropriate than
‘normal liver’ as these patients frequently have
some degree of mild fibrosis, necro-inflammation,
steatosis or liver cell dysplasia. HCC in the
absence of cirrhosis may be related to some of the
same aetiologies as those responsible for HCC in
cirrhotic livers such as HBV infection or alcohol
abuse. Alternatively, HCC may occur as a result of
conditions that infrequently lead to cirrhosis such
-antitrypsin deficiency, haemochromatosis, or
as α
1
in the setting of specific aetiologies that do not
result in cirrhosis such as hormonal exposure or
glycogenosis.
HBV infection
Chronic HBV infection is the most frequent risk
factor for HCC worldwide, and accounts for more
than 50% of all cases. It is estimated that 40 million
people are currently affected by HBV, particularly in
less industrialised countries; HBV infection should,
however, begin to decline as a result of increased
utilisation of HBV immunisation.
There is evidence that HBV-DNA sequences
integrate into the genome of malignant hepatocytes
and can be detected in the liver tissue of patients
with HCC despite the absence of classical HBV
serological markers. HBV-specific protein may
also interact with liver genes. HBV is therefore a
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77
Chapter 5
direct risk factor for HCC and can occur in patients
without cirrhosis.
The risk of HBV-associated HCC increases
with the severity of the underlying hepatitis, age
at infection and duration of infection, as well as
level of viral replication. An Asian patient with
HBV-related cirrhosis has a 17% cumulative risk
of developing HCC over a 5-year period. In the
West, this cumulative risk is 10%. This may be
explained by the earlier acquisition of HBV in
Asia through vertical transmission (rather than
horizontal transmission in the West, through sexual
or parenteral routes), longer duration of disease,
or additional exposure to environmental factors.
Ongoing HBV replication or hepatitis Be antigen
(HBeAg) infection accelerates the progression to
cirrhosis and also to HCC. A study conducted
in Taiwanese men reported that the risk of HCC
increased 10-fold when HBsAg was present and
60-fold when HBeAg was present. Similarly,
HBV-DNA levels greater than 10
4
or 106 copies/
mL are associated with a 2.3 and 6.1 hazard risk
respectively, compared to patients with lower
levels of replication.
5
Additional cofactors that
increase the risk of HCC are male gender (3–6
times higher risk), age >
40 years, concurrent HCV
infection (twofold increased risk), HDV co-infection
(threefold), heavy alcohol consumption (twoto threefold) and, in endemic regions, aflatoxin
ingestion.
HCV infection
The expansion of HCV infection probably accounts
for a significant proportion of the increased
incidence of HCC observed over the past 10years.
In Western countries, up to 70% of HCC patients
have anti-HCV antibodies in their serum and the
mean time for developing HCC following HCV
infection is approximately 30years.
In HCV-positive patients with initially compensated
viral cirrhosis, HCC is both the most frequent and
first complication. The annual incidence of HCC is
0–2% in patients with chronic hepatitis and 1–4%
in those with compensated cirrhosis, although rates
as high as 7% have been reported in Japan. In
patients with cirrhosis, additional independent risk
factors increasing the risk of HCC are age >
(two- to fourfold), male gender (two- to threefold),
diabetes (twofold), alcohol intake greater than 60–
80 g/day (two- to fourfold) and HBV co-infection
(two- to sixfold). Obesity is also a likely cofactor. In
contrast, the viral genotype or viral concentration
has no impact on the risk of HCC.
The mechanism of HCV-related HCC is still
not very clear. The great majority of patients with
HCV-related HCC have cirrhosis, suggesting that
it is the presence of cirrhosis that is crucial for the
development of this tumour.
55 years
Because anti-HCV vaccination is not available,
prevention of HCV infection and of progression of
chronic HCV infection to cirrhosis through antiviral
treatment is the only means to reduce the incidence
of HCV-related HCC. Sustained virological response
in HCV-infected patients is associated with a
significantly decreased risk of developing HCC.6 New
direct-acting antivirals have raised several promising
perspectives that will likely decrease both the
incidence of HCV-related HCC and the requirement
for transplantation.
Human immunodeficiency virus
(HIV) infection
The incidence of HCC is expected to rise in HIVpositive persons predominantly because of the
higher prevalence of associated well-known risk
factors: not only co-infection with HCV and HBV,
but also alcohol abuse, non-alcoholic steatohepatitis
(NASH) and diabetes. HIV-positive patients who
are co-infected with HBV or HCV may have more
rapidly progressive liver disease, and when they
become cirrhotic they are also at increased risk
of HCC. The Mortavic study indicated that HCC
caused 25% of all liver-related deaths among HIV
patients.
7
Cirrhosis and HCC occur 15–20 years earlier in
HIV-HCV co-infected patients than in patients
infected by HCV alone. The course of the disease
is also considered more aggressive.
8
Screening for
HCC should, however, be the same as in HIVnegative patients.
Other viral infections
Infection with the hepatitis delta virus (HDV) is
found in patients who are also infected with HBV.
Hepatitis A virus (HAV) and hepatitis E virus (HEV)
infection cause neither chronic hepatitis nor HCC.
Alcohol
Heavy (>50–70 g/day) and prolonged alcohol
ingestion is a classical risk factor for cirrhosis and
therefore HCC. Data available from cohort studies
of European or US patients with alcohol-related
cirrhosis suggest an annual incidence of HCC of
1.7% (as compared with 2.2% and 3.7% in patients
from the same geographical area with HBV- or HCVassociated cirrhosis). Alcohol is also a very frequent
additional risk factor in patients with HBV or HCV
cirrhosis, as well as in those with chronic liver disease
associated with the metabolic syndrome.
Non-alcoholic fatty liver disease (NAFLD)
NAFLD has been recognised as being one of the
most common causes of liver disease in the USA
(and other Western countries). Histological changes
78
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Primary malignant tumours of the liver
in the liver range from simple steatosis to more
severe forms of NASH, including cirrhosis. It is
closely associated with type II diabetes, central
obesity and dyslipidaemia as part of the metabolic
syndrome, the prevalence of which has increased as
an epidemic. Sixty percent of patients older than
50 years with diabetes and obesity are likely to
have NASH with advanced liver fibrosis.
medical conditions such as obesity and diabetes
increase the risk of HCC.
Obesity and diabetes increase the risk of HCC.
10,11
9
Chronic
An association between NAFLD and HCC was
first identified in 2002 by several studies focusing
on HCC patients with chronic liver disease in the
absence of HBV/HCV infection or alcohol abuse. In
this population, there was a much higher prevalence
of obesity, diabetes, hypertriglyceridaemia and
pathological features of NAFLD. At the same time,
evidence was accumulating linking common features
of the metabolic syndrome/NASH with HCC. In
particular, obesity increases mortality from liver
cancer, far more than for any other cancer. Similarly,
diabetes was found to increase the risk of HCC with
and without acute or chronic liver disease.
The incidence of HCC among patients with NAFLD
increases with male gender, increasing age, sinusoidal
iron deposition and severity of underlying liver
disease. In surgical series, overt cirrhosis is present
in only one-third of patients, while the others have
less severe liver damage.
12
In addition, there is also
evidence that NAFLD may act synergistically with
other risk factors such as chronic HCV or alcoholic
consumption to potentiate the development of HCC.
As obesity and the metabolic syndrome are
growing epidemics worldwide, the incidence of
HCC will undoubtedly increase in the future. Nearly
25% of patients with metabolic syndrome develop
cirrhosis. After cirrhosis develops, 4–27% of patients
develop HCC.
metabolic syndrome-related HCC is approximately
6–10%.
as an indication for liver transplantation increased
nearly fourfold from 2002 to 2012.
13
In surgical series, the prevalence of
14,15
Compared to HCV, NASH-related HCC
16
(13.3-fold) and alcohol abuse (2.3-fold) may act
synergistically with iron overload to increase the
risk of HCC among patients with cirrhosis caused by
HH. In a recent meta-analysis including nine studies
of 1102 patients with HCC, mainly from European
populations, it has been reported that C282Y
mutation was associated with an increased risk of
HCC (4-fold) in alcoholic liver cirrhosis patients,
but not for the viral liver cirrhosis population.
17
Interestingly, pathological conditions other than
HH that are associated with iron overload, such
as homozygous β-thalassaemia or the so-called
African overload syndrome, are also associated
with an increased risk of HCC. Similarly, there is
also evidence of a link between iron deposits within
the liver and HCC in patients with and without
cirrhosis.
Cirrhosis of other aetiologies
Primary biliary cirrhosis (PBC) has been considered
as a low risk factor for HCC, not only because of
its rare incidence but also because it predominantly
affects women (with a sex ratio of 9:1). A recent
meta-analysis of 12 studies reported that PBC is
significantly associated with an increased risk of HCC
(18.8-fold) compared to the general population.
However, there were several confounding factors
in this meta-analysis, such as advanced histological
stage of PBC, history of blood transfusion, smoking
or drinking habit, which might be associated with
increased probability for HCC development in PBC
patients or directly associated with PBC development.
In contrast, HCC development in patients with
secondary biliary cirrhosis is exceptionally rare, if it
even exists.
Autoimmune hepatitis has a low risk of HCC
development. Potential reasons are the female
predominance and the delayed development of
cirrhosis through corticosteroid therapy. HCV
infection needs to be ruled out as it may induce
autoantibodies. Recent data reported that cirrhosis
at presentation is an important prognostic risk factor
for HCC. In a prospective multicentre cohort study
evaluating 193 Japanese patients with autoimmune
hepatitis, seven (3.6%) developed HCC during the
8-year period, all of whom had underlying cirrhosis.
18
19
Hereditary haemochromatosis
Hereditary haemochromatosis (HH) is an autosomal
recessive disorder associated with homozygosity for
the C282Y mutation in the haemochromatosis gene
and is characterised by excessive gastrointestinal
absorption of iron. HH is a long-known risk factor
for HCC, and the risk is increasing in patients with
cirrhosis. Other risk factors include male gender
and diabetes. Several additional risk factors such as
HBV infection (4.9-fold), age greater than 55years
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Aflatoxin
Aflatoxin B1 has also long been associated with
the development of HCC, because areas with a
large consumption of this toxin coincide with areas
of high incidence of HCC (Asia and sub-Saharan
Africa). Aflatoxin is ingested in food as a result of
contamination of imperfectly stored staple crops
by Aspergillus flavus. It is thought to induce HCC
through mutation of the tumour suppressor gene
p53. Although some studies suggest that it is an
79
Chapter 5
independent risk factor, others suggest that it could be
a co-carcinogen only in patients with HBV infection.
HCC in this setting frequently develops in a noncirrhotic liver.
Metabolic liver diseases and HCC
An increased risk of HCC is recognised in some
other forms of metabolic liver diseases such as α
-
1
antitrypsin deficiency, porphyria cutanea tarda,
tyrosinaemia and hypercitrullinaemia. Patients with
glycogenosis type IV, hereditary fructose intolerance
and Wilson disease may also develop HCC, but with
a lower risk. There is evidence that iron and copper
overload in haemochromatosis and Wilson disease
generate, respectively, oxygen/nitrogen species and
unsaturated aldehydes that cause mutations in the
p53 tumour suppressor gene.
Adenoma, contraceptives and androgens
As with adenoma in other locations, hepatocellular
adenomas (HCAs) have a risk of malignant
transformation and hepatocyte dysplasia is the
intermediate step between HCAs and HCC. A recent
systematic review estimated the risk to be 4.2%.
This risk and the treatment strategy to prevent it
may, however, be refined.
HCAs are most classical in women of childbearing age and are associated with the prolonged
use of oral contraceptives and oestrogen treatments.
Discontinuation of oral contraceptives does not
completely avoid the risk of transformation.
Malignancy within HCAs <
4 cm in this context
is exceptional. There is also recent evidence that
HCAs may develop in men, frequently in a context
of metabolic syndrome. The risk of malignant
transformation in men is 50% (10 times higher
than in women) and malignancy can occur in HCAs
as small as 1 cm.21 Therefore, whereas resection
of HCAs >
irrespective of size should be resected (or ablated)
in men.
4 cm is warranted in women, all HCAs
22
The number of HCAs does not appear to increase
the risk of malignant transformation and in
particular, patients with adenomatosis are not at
increased risk.
21,23,24
Malignant transformation of HCAs has also been
linked to the genotype and phenotype of HCAs. It is
more prevalent in telangiectatic or atypical HCAs than
in steatotic HCAs. Most importantly, the presence
of a β-catenin mutation (observed in approximately
10–15% of HCAs) confers a particularly high risk of
malignancy.
23
Malignant transformation of HCAs may also
occur within known specific aetiologic contexts,
such as with type I glycogenosis, use of anabolic
steroids or androgen treatments and Fanconi disease.
Recreational anabolic steroid use is also known to
20
potentially result in the development of adenoma, and
malignant transformation to HCC has been reported.
Pathology of HCC and of nodular
lesions in chronic liver disease
Preneoplastic lesions are morphologically
characterised by the appearance of dysplastic
lesions in the form of microscopic dysplastic foci
and macroscopic dysplastic nodules (DNs).
Dysplastic foci are microscopic lesions composed
of dysplastic hepatocytes <
chronic liver disease, particularly in cirrhosis. DNs
are divided into low and high grade depending on the
degree of cytological or architectural atypia. DNs are
defined as a nodular region <
dysplasia but without definite histological criteria
of malignancy. Low-grade DNs are approximately
1 cm in diameter, slightly yellowish and have a very
low probability of becoming malignant. High-grade
DNs are less common with slightly larger nodules
(up to 2 cm) and characterised by increased cell
density with an irregular thin-trabecular pattern
and occasionally unpaired arteries. These are often
difficult to differentiate from highly differentiated
HCC. They may contain distinct foci of welldifferentiated HCC and are therefore considered
as precancerous lesions and become malignant in a
third of cases. It must, however, be appreciated that
lesions <
2 cm may also represent HCC.
HCCs can be subdivided according to their gross
morphology, degree of differentiation, vascularity,
presence of a surrounding capsule and presence of
vascular invasion. All of these criteria have practical
implications.
On gross morphology, HCCs can be solitary or
multinodular, consisting of either a collection of
discrete lesions in different segments developing
synchronously (multicentric HCC) or as one dominant
mass and a number of ‘daughter’ nodules (intrahepatic
metastases) located in the adjacent segments. Diffuse
HCCs are relatively rare at presentation and consist
of poorly defined, widely infiltrative masses that
present particular diagnostic challenges on imaging.
A third type is the infiltrating HCC, which typically is
less differentiated with ill-defined margins.
Microscopically, HCCs exhibit variable degrees
of differentiation that are usually stratified into
four different histological grades, known as
Edmondson grades 1–4, which correspond to welldifferentiated, moderately differentiated, poorly
differentiated and undifferentiated types. The degree
of differentiation typically decreases as the tumour
increases in diameter. Very well-differentiated HCC
can resemble normal hepatocytes and the trabecular
structure may reproduce a near normal lobar
1 mm in size, and occur in
2 cm in diameter with
80
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Primary malignant tumours of the liver
architecture so that histological diagnosis by biopsy
or following resection may be difficult. A number of
immunomarkers have been described to selectively
identify the malignant nature of these HCCs,
not only in resected specimens but also in liver
biopsies: Glypican 3 (GPC3), Heat Shock Protein
70 (HSP70) and Glutamine Synthetase (GS). Positive
staining for any two markers can detect early and
well-differentiated HCC in 50–73% of cases, with
100% specificity when the analysis is performed on
resected specimens.
25
Our understanding of the molecular pathogenesis
of HCC has significantly advanced with the
identification of the major driver genes mutated
in HCC over the last decade. TERT promoter
mutations are the most frequent mutation (60%)
observed in HCC development and progression.
26
The subsequent increase in telomerase expression is
a determinant of malignant transformation. The use
of these molecular markers, obtained from biopsy
or resection specimens, may be useful to determine
prognosis, select treatment and assess response to
chemotherapy.
Vascularisation is a key parameter in differentiating
HCC from regenerating nodules. Progression from
macroregenerative nodule to low-grade DN, highgrade DN and frank HCC is characterised by loss
of visualisation of portal tracts and development of
new non-triadal arterial vessels which become the
dominant blood supply in overt HCC lesions. This
arterial neoangiogenesis is the landmark of HCC
diagnosis and the rationale for chemoembolisation
and anti-angiogenic treatment.
Tumour nodules may be surrounded by a distinct
fibrous capsule. This capsule, present in 80% of
resected HCCs, has a variable thickness, which
may not be complete, and is frequently infiltrated
by tumour cells. Capsular microscopic invasion
by tumour cells is present in almost one-third of
tumours <
2 cm in diameter, as compared with two-
thirds of those with a larger diameter.
HCC has a great tendency to spread locally and to
invade blood vessels. The rate of portal invasion is
higher in the expansive type, in poorly differentiated
HCC and in large tumours. Characteristically,
microscopic vascular invasion involves 20% of
tumours <
2 cm in diameter, 30–60% of cases
in nodules 2–5 cm and up to 60–90% in nodules
>5 cm in size. The presence of portal invasion is
the most important predictive factor associated
with recurrence. The tumour thrombus has its
own arterial supply, mainly from the site of the
original venous invasion. Once HCC invades the
portal vein, tumour thrombi grow rapidly in both
directions, and in particular towards the main
portal vein. As a consequence, tumour fragments
spread throughout the liver as the thrombus crosses
segmental branches. Once the tumour thrombus
has extended into the main portal vein, there is a
high risk of complete thrombosis and increased
portal hypertension. This accounts for the frequent
presentation with fatal rupture of oesophageal
varices, or liver decompensation including ascites
Fig.5.1), jaundice and encephalopathy. Invasion of
(
hepatic veins is possible, although less frequent. The
thrombus eventually extends into the suprahepatic
vena cava or the right atrium and is associated with
a high risk of lung metastases. Rarely, HCC may
invade the biliary tract and give rise to jaundice or
haemobilia. Mechanisms of HCC-induced biliary
obstruction include:
• intraductal tumour extension;
• obstruction by a fragment of necrotic tumour
debris;
• haemorrhage of the tumour resulting in
haemobilia;
• metastatic lymph node compression of major
bile ducts in the porta hepatis.
The rate of invasion of the portal vein, hepatic
vein and bile duct at the time of diagnosis is
15%, 5% and 3%, respectively. However, it is
estimated that during the natural history of HCC,
approximately 1 in 3 patients will develop portal
vein thrombosis.
When present, metastases are most frequently
found in the lung. Other locations, in decreasing
order of frequency, are: adrenal glands, bones, lymph
nodes, meninges, pancreas, brain and kidney. Large
tumour size, bilobar disease and poor differentiation
are risk factors for metastatic disease.
Figure5.1 • CT scan of a patient with a tumour
thrombus originating from an HCC located in the right
liver. The thrombus extends in the main portal vein.
Ascites is present.
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81