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CancerForum Volume 33 Number 2 July 2009
Forum
Cancer of the liver is the sixth most common type of cancer
worldwide, with 625,000 cases recorded in 2002. Globally,
liver cancer accounts for 5.6% of all cancers in humans -
with more cases diagnosed in males (where it accounts for
7.5% of all cancers) than females (3.5% of all cancers).1
The most common malignant primary liver cancer (PLC)
is hepatocellular carcinoma (HCC), which represents
75–90% of liver cancers worldwide. Less common types of
primary liver cancer include cholangiocarcinoma, tumours
of mesenchymal tissue, sarcomas and hepatoblastoma.2
Cancer of the liver and intrahepatic biliary ducts are
grouped together in the International Agency for Research
on Cancer publications and as specific statistics for the
rarer forms of cancer are not generally available, we
used the term ‘primary liver cancer’ (PLC) throughout
this report. Here we propose to define the magnitude of
primary liver cancer incidence and mortality globally and in
Australia, with particular focus in New South Wales.
International patterns of liver cancer
incidence and mortality
There are substantial variations in the distribution of
liver cancer incidence and mortality across geographical
locations, with PLC more common in regions of Africa
and Asia than in Western countries and more common
in middle and low income countries than in developed
nations. Approximately half of all primary liver cancers
occur in China.3
Epidemiology of primary liver cancer
Noore Alam1, Monica Robotin2 and Deborah Baker3
1. Monitoring, Evaluation and Research Unit, Cancer Institute NSW, Sydney, Australia.
2. Cancer Council NSW, Sydney, Australia; School of Public Health, University of Sydney, Sydney, Australia.
3. Monitoring, Evaluation and Research Unit, Cancer Institute NSW, Sydney, Australia.
Email: noore.alam@cancerinstitute.com.au
Abstract
Cancer of the liver is a significant cause of morbidity and mortality worldwide. Globally, 625,000 cases of liver cancer
were reported in 2002. The worldwide distribution of liver cancer is characterised by a great geographic variability,
with age-standardised incidence rates ranging from more than 30 cases per 100,000 population in eastern Asia and
parts of Africa, to fewer than five per 100,000 in the Americas and in Northern Europe. Much of this variability in the
distribution of the disease is related to the global distribution and the natural history of infection with hepatitis B and
C viruses. In Australia, both the incidence of and mortality from liver cancer have been progressively rising since the
mid-1980s. The age standardised incidence rates for liver cancer are highest in some overseas-born Australians,
especially among those born in hepatitis B and C endemic countries. The incidence of primary liver cancer in
Australia is projected to continue to rise over the next two decades, as a result of a large reservoir of asymptomatic
infections with chronic viral hepatitis, immigration from countries of high hepatitis B virus prevalence and the slow
disease progression from chronic hepatitis B virus infection to liver cancer. Public health strategies for targeted
interventions for the prevention, treatment and control of chronic viral hepatitis infection may effectively reduce the
burden of liver cancer globally, as well as in Australia.
Figure 1. Age standardiseda1 incidence of liver cancer in selected regions by sex, all ages, 2002 (per 100,000)
Source: GLOBOCAN 20027
a Standardised to world population.
Male
40 4030 3020 2010 100
Eastern Asia
Middle Africa
Eastern Africa
South-Eastern Asia
Western Africa
Southern Africa
Western Europe
Eastern Europe
Northern America
Western Asia
South America
Northern Africa
Australia/New Zealand
Northern Europe
Female
CancerForum Volume 33 Number 2 July 2009
Forum
Liver cancer incidence and mortality rates vary considerably
across different geographical areas, with much of this
variability related to the global distribution and natural
history of infection with hepatitis B virus (HBV) and hepatitis
C virus (HCV).4 The early age of infection with HBV in Asian
patients accounts for significant differences in the clinical
course of disease compared to Caucasians,5 placing them
at a higher risk of liver cancer than other populations who
acquire the infection in adolescence or adulthood.
In 2000, PLC was most prevalent in eastern Asia, middle
Africa and some countries of western Africa, with an
estimated age-adjusted incidence rate (AAIR) per 100,000
men approximately 10 times higher in eastern Asia,
compared to Australia and New Zealand.6 AAIRs in 2002
were highest in eastern Asia (36.9 per 100,000 males) and
in middle Africa (13.4 per 100,000 females) and lowest
in northern Europe (3.4 per 100,000 males and 1.7 per
100,000 females). Overall, Australia and New Zealand had
some of the lowest AAIRs of 1.3 per 100,000 population
(figure 1).
Significant PLC variations can exist among different
populations from the same countries, depending on
their ethnic origins. For example, during 1992-1996,
the overall AAIRs for liver cancer in the US were 3.1
per 100,000 people, but significant differences existed
along racial lines. The lowest rates were documented
in Caucasians (8.6 for males and 2.7 for females) and
the highest in Asian and Pacific islanders (20.9 in males
and 7.9 in females).8,9 In the US and the Netherlands,
primary liver cancer affected migrants from Asia and the
Pacific Islands disproportionately, compared to the locally-
born populations.9-11 Similarly in New Zealand, significant
discrepancies were noted between the rates of PLC in
Pacific Islanders, (in whom the annual incidence was
5.8 per 100,000 per year), the native Maori population
(2.8/100,000/year) and those of European descent
(0.6/100,000/year).12 Excess mortality rates are most
marked in the first generation migrants, compared to
subsequent generations.1,13
Compared with females, males have substantially higher
age-standardised incidence rates for PLC, with male to
female age adjusted incidence ratios worldwide ranging
from 1.3 to 3.6. In eastern Asia, primary liver cancer is the
most common cause of cancer-related death.7,14 Similar
to incidence, mortality rates are generally higher in less
developed countries, compared with more developed
countries.7,15,16
Primary liver cancer in Australia
Overall, Australia has comparable rates of incidence and
mortality from liver cancer to those recorded for similar
developed countries.15,17 Primary liver cancer is relatively
uncommon, ranking fifteenth in males and twentieth in
females, but its incidence has been progressively rising
over the last three decades. Age-standardised incidence
rates in males increased from 2.06 per 100,000 in 1983-
1985 to 3.97 during 1995-1997, and from 0.57 to 0.99
in females in the same time periods.18 In Australia, males
are 2.5 times more likely to be diagnosed and to die
of liver cancer than females. An Australian male’s risk
of developing liver cancer is one in 198 to age 75 and
one in 113 to age 85, which is comparable to the risk of
developing brain cancer (which is one in 164 by age 75
and one in 111 by age 85).19
During 1999–2003, the age-standardised incidence rates
of PLC in all states and territories in Australia ranged
from a high of 11.8 new cases per 100,000 for males in
the Northern Territory to a low of 1.4 cases per 100,000
females in Tasmania. It was estimated that, between 2002
and 2011, the rates will continue to increase by 27% in
females and 43% in males.20
During 2001–2005, the mortality rate for liver cancer
in males ranged from a high of 11.1 in the Northern
Territory to a low of 1.8 deaths per 100,000 in Western
Australian females. The Northern Territory statistics may
be attributable to higher incidence rates for HBV and HCV
infection.21
In 2006, in New South Wales (NSW), PLC ranked 13th in
males and 20th in females in terms of incidence, and 11th
in males and 13th in females in terms of cancer mortality.17
From 1972 to 2006 in NSW, age-standardised incidence
rates in males increased over 4-fold; from 2.0 new cases
per 100,000 to 8.4 per 100,000. In the same period, a
similar increase occurred for females, with rates increasing
from 0.5 new cases to 3.2 per 100,000 (figure 2).
0
2
4
6
8
10
1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006
Year of diagnosis
Rate per 100,000
Male Female Source: NSW Central Cancer Registry
Figure 2. Trends in liver cancer: age–standardised incidence rate per 100,000 population by sex, all ages, NSW 1972-2006
CancerForum Volume 33 Number 2 July 2009
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Age standardised incidence rates for liver cancer in
Australia are highest in some overseas-born populations,
with this discrepancy unlikely to be caused by increased
liver cancer screening, or increased alcohol consumption
in specific groups, but most likely due to chronic infection
with hepatitis B or C.18
Although people born in China and Vietnam represent
only about 5% of the Australian population, half of all
cases of chronic hepatitis B (CHB) infection in Australia
occur in these populations.22 The significant numbers of
undiagnosed CHB infections in these populations, coupled
with the natural history of CHB infection in populations
where the infection is acquired early in life,5,23 contribute to
the increasing prevalence of PLC in Australia.18
Another population group at increased risk of PLC in
Australia are Indigenous people, in whom PLC incidence
rates are 5-10 times greater than in non-Indigenous
Australians.24 Indigenous Australians represented only
2.4% of the Australian population in the 2001 census, but
accounted for 16% of estimated CHB infections.25 One
study found that among Aboriginal people diagnosed with
PLC in Australia, more than 60% were HBsAg positive,24
suggesting that CHB infection is the major cause of HCC
in this population.26
During 1991–2000, the Indigenous populations in the
Northern Territory had substantially higher death rates
from liver and gallbladder cancer, compared with the total
Australian population (RR 5.7, 95% CI: 4.2–7.6).27 Similarly,
from 2000 to 2004 in NSW, liver cancer represented 2.1%
of all cancers in Aboriginal males, as compared to 1.3% in
non-Aboriginal Australian males.28
In NSW, PLC incidence rates have been rising faster
than any other cancer, with an average annual increase
recorded between 1997 and 2006 of 5.3% for males
and 8.8% for females, surpassing cancers of the
prostate, thyroid, skin (melanoma) and oesophagus.17,29
Approximately half of all PLCs occurred in overseas-born
people in NSW, with males born in Vietnam, Hong Kong,
Macau, Korea, Indonesia and China, and females born in
Vietnam and China, 6-12 times more likely to develop PLC
than Australian-born individuals.30
PLC exhibits a striking pattern of geographic clustering in
NSW, with the highest rates occurring in South Western
Sydney where, in 2005, the incidence of PLC (7.7 per
100,000, 95% CI: 7.0-8.4) far exceeded the NSW state
average (5.2 per 100,000, 95% CI: 5.0-5.5).15 A hospital-
based case series of patients presenting to the two
teaching hospitals in this region found a 36% increase
of incidence of HCC from 1993 to 2003.31 Almost half
(46%) of these patients were Asian-born, with 42%
having evidence of CHB infection and 75% presenting at
a symptomatic stage, explaining a poor median survival
of 5.1 months.31
In NSW, the median age at diagnosis for liver cancer in
2005 was 64 years for males and 76.5 years for females.
In 2005, 46.4% of all new cases of liver cancer in NSW
were localised, 9.1% had regional spread, approximately
30% were disseminated; in 15% of cases the degree of
spread was unknown. In 2006, liver cancer accounted
for 3% of all male cancer deaths and 1.9% of all female
cancer deaths in NSW. The trend of mortality rates mirror
the trend of incidence mainly due to poor survival.17
Projected trends in liver cancer incidence
and mortality
Future projections of liver cancer incidence suggest
a continuing upward trend in developed countries for
some decades to come, as a result of past infection
with hepatitis B and C viruses,1 while recent declines in
PLC have been attributed to the effects of hepatitis B
vaccination programs.1,32
The high level of migration to Australia from countries of
high hepatitis B prevalence has been associated with
increasing prevalence of CHB infection.29,33 As national
vaccination programs in Vietnam and China have only
commenced during the last decade, it is unlikely that any
substantial reductions in the burden of chronic hepatitis
B and liver cancer among people born in these countries
will occur over the next two decades.29 If the current
trend in population migration to Australia from the CHB
prevalent countries continues, the incidence of PLC will
continue to rise, with one study suggesting that among
Australians born in China, the number of CHB-related
HCC cases will double over the period 2005-2025,34
unless pharmacological treatments of hepatitis B infection
can reverse this trend.
In NSW, if the historical trends in the incidence of liver
cancer continue, the age–standardised incidence rates
for liver cancer are expected to increase by 11.3-16.4%
for males and 24.8% for females over the next five years
(2007–2011), with the trends in mortality expected to
follow incidence patterns.15
Risk factors for primary liver cancer
Chronic infection with HBV and HCV, aflatoxin ingestion and
excessive alcohol consumption contribute to significant
inter-country variations of HCC incidence around the
world. Although other factors, such as genetic/family
history, diet and tobacco smoking, have been implicated
in disease development, their contribution to disease
causation remains uncertain.2,16
Overall, it is estimated that 75-80% of cases of PLC
are attributable to chronic HBV or HCV infections, with
HBV responsible for 50-55% cases overall and HCV
for approximately 25-30%.1 People with chronic HBV
or HCV infection are at 20 to 200-fold greater risk of
developing HCC than those uninfected.35-37 According to
a World Health Organisation report published in 2004, an
estimated two billion people worldwide were infected with
HBV (with approximately 350 million chronically infected)
and 170 million people were infected with HCV. Some
500,000 – 1.2 million deaths each year are caused by
HBV infection, with 320,000 deaths due to liver cancer.38
CancerForum Volume 33 Number 2 July 2009
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As almost a third of all people with HBV infection in the
world live in China, its burden of HBV related disease is
considerable, with 300,000 deaths annually from HBV
related conditions, including 180,000 deaths from HCC.39
The strong positive correlation between the incidence
of HCC and the prevalence of HBV surface antigen
in a population, termed “geographic parallelism”, was
first described in 1969,40 explaining, for example, the
high rates of PLC in Taiwan, where 80% of cases are
associated with chronic HBV infection.41
In Africa and Asia the largest attributable fractions for
PLC (approximately 60%) relate to CHB infection, with
HCV infection accounting for another 20%. In Europe
and the United States the figures are reversed, with 60%
attributable to HCV infection, 22% to HBV and 45%
due to alcohol ingestion (allowing for the joint effects of
several risk factors in some cases).1 A synergistic effect
of co-infection with HBV and HCV on HCC development
has been documented.42,43
Approximately 30% of chronic viral hepatitis cases are
complicated by cirrhosis, with the annual incidence of
liver cancer in people with cirrhosis ranging from 2-3%
in Western countries to 6-11% in Asian populations.44
Approximately 80% of PLCs develop in cirrhotic livers,14
but liver cancer can also develop in livers with minimal
histological changes. This phenomenon is more common
in southern Africa (where approximately 40% of liver cancer
cases have minimal liver damage) than in Asia, America
and Europe (where more than 90% are associated with
liver cirrhosis).45
Ample evidence exists that chronic alcohol consumption
is a cause of liver cirrhosis, which predisposes to liver
cancer, but the exact mechanism that explains this
process remains unclear. A systematic review of 133
studies found that alcoholics with HCV infection are at
increased risk of developing liver diseases, compared with
non-alcoholics, with or without HCV infection.46 Alcoholics
with HCV also have more rapid and frequent occurrence
of cirrhosis, compared with non-alcoholics.47-49 While liver
cancer was not considered a tobacco-related cancer in
a recent review by the International Agency for Research
on Cancer,50 some studies found an association between
smoking and liver cirrhosis,51-53 particularly among drinkers
(relative risk (RR=9.3, 95% CI:1.1–78.8), compared to
non-drinkers (RR=1.85, 95% CI: 0.98-3.51).53
Being diabetic also increases the risk of liver cancer, with
a large cohort study finding standardised incidence ratios
of 4.1 (95% CI: 3.8–4.5) in diabetics compared to non-
diabetics.54 Retrospective studies also found a positive
association between type-2 diabetes mellitus and the risk
of HCC.55-57
Several studies have found an association between
increased body fat and primary liver cancer.58,59 A cohort
study of over 350,000 Swedish men found that obesity
significantly increased the risk of liver cancer for men (RR
3.6, 95% CI: 2.6–5.0).60
Conclusion
The incidence of primary liver cancer in Australia is likely
to continue to rise over the next two decades, as a result
of a large reservoir of asymptomatic chronic viral hepatitis,
immigration from countries of high HBV prevalence and
the slow disease progression from chronic HBV infection
to liver cancer.18,22,61 Without targeted interventions for
the prevention, treatment and control of chronic viral
hepatitis, 25% of these people are likely to die from the
consequences of liver disease, which include liver cancer,
as well as end-stage liver disease.61 While the impact of
hepatitis B vaccination is likely to provide significant long-
term dividends for disease prevention, vaccination will
not have a significant impact for those already infected
and asymptomatic. Increasing the accuracy and reliability
of predictors of malignant transformation in individual
patients with established risk factors is needed to improve
disease outcomes,62 coupled with public health strategies
addressing the significant burden of disease related to
liver cancer in at risk populations.
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