1Hepatocellular carcinoma epidemiology
Introduction
The epidemiology of liver cancer is made complex by the difficulty to separate the large number of secondary tumours from primary liver cancers [1]. In most populations, the major histological type of primary liver neoplasm is hepatocellular carcinoma (HCC), other forms including adult cholangiocarcinoma originating from the intrahepatic biliary ducts, angiosarcoma from the intrahepatic blood vessels, and childhood hepatoblastoma ∗[2], [3], [4].
Primary liver cancer (namely HCC) is one of the most frequent malignancies in the world: it ranks as the fifth most common cause of cancer in men and the seventh one in women, with an estimated number of new cases of 520,000 and 230,000 respectively for men and women in 2008 [5]. Age-standardized rates (world population) are particularly high in eastern and south-eastern Asia (over 20/100,000 men and over 10/100,000 women) and middle and western Africa (15–20/100,000 men and about 8–19/100,000 women); in most high-income countries, including the Americas, Australia, and western and northern Europe, rates are below 7.5/100,000 men and below 2.5/100,000 women, while intermediate rates (around 10/100,000 men and 3/100,000 women) are observed in Southern Europe. Rates are 2–3 folds higher in men than women, the difference being generally larger in high-incidence than in low-incidence areas. Liver cancer incidence has substantially increased in North America and Northern Europe, while it has been decreasing in some high-risk countries from Asia [6], [7], [8]. Although almost half liver cancers worldwide are from China, there are scanty incidence data on liver cancer from this country; aflatoxin is its second cause after persistent infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) in China, and its control is responsible for some likely recent falls in rates [9].
Five-year survival from liver cancer was about 15% in the USA in 2002–2008 [8], about 12% in Europe in 2000–2007 [10], and even lower (about 5% in 2002) in low-income countries [11]. Given its poor prognosis, the estimated number of deaths from liver cancer is not appreciably different from that of new cases (about 500,000 in men and 220,000 in women in 2008) and liver cancer represents the third most frequent cause of cancer death worldwide (the second one in low-income countries) [5].
Although liver cancer is a rapidly evolving and fatal disease for which treatment is still unsatisfactory, there is sufficient knowledge for effective primary prevention ∗[2], [3], [4]. Indeed, causal factors have been identified for three major histological types of primary liver cancer, i.e., HCC, cholangiocarcinoma, and angiosarcoma. Persistent infections by HBV or HCV – which account for over three-quarters of all liver cancer cases in the world – result in chronic liver damage, which can play an important role in liver cancer development. In the minority of liver cancers in which viral infection is not involved, exposures that also damage the liver, as heavy alcohol consumption, or may be directly genotoxic, as tobacco smoke or aflatoxin, are of relevant importance.
In the present review, we provide some descriptive information on the geographic patterns and time trends in mortality from primary liver cancer (namely HCC) in major European countries, the European Union (EU) as a whole, and, for comparison purpose, in the USA, Japan, and Australia. Moreover, we give an overview of major environmental risk factors for this neoplasm, including established ones, as HBV and HCV infections, heavy alcohol drinking, tobacco smoking, aflatoxin, as well as selected dietary factors, overweight/obesity, diabetes, and use of oral contraceptives (OC) ∗[2], [3], [4], [12]. Familial and genetic factors are also considered.
Section snippets
Mortality from hepatocellular carcinoma
Over the last few decades, mortality from HCC has been considerably variable across Europe [13], [14]. Mortality from primary liver cancer (namely HCC) in the EU overall, after an increase in the early 1990's, started to decline since 1994, with a decline by 1.9% per year in men and by 3.4% in women [15]. Between 2002 and 2007, overall EU mortality rates (age-standardized on the world population) from HCC decreased from 3.9 to 3.6/100,000 men and from 0.93 to 0.77/100,000 women. Male mortality
Hepatitis infections
Chronic infections with HBV and HCV are the major recognized risk factors for HCC worldwide ∗[2], [3], [4], [20], HBV being most common in eastern Asia and HCV in Mediterranean countries [16].
Several epidemiological studies conducted over the last few decades in more than 25 countries provided definite evidence for a causal role of chronic HBV infection in HCC [20]. Most studies estimated excess risks of HCC between 10 and 30 for serologic Hepatitis B surface antigen (HBsAg) positivity, the
Obesity and diabetes
Epidemiologic data suggested that overweight/obesity is associated with an increased risk of HCC, as of other cancers [119]. A meta-analysis of 11 cohort studies reported a RR for liver cancer of 1.17 (95% CI 1.02–1.34) for overweight and of 1.89 (95% CI 1.51–2.36) for obese versus normo-weight subjects [120].
The effect of obesity on liver cancer risk may be mediated, at least in part, through the strong relationship of overweight with diabetes mellitus [121]. Several epidemiological studies,
Familial and genetic susceptibility for hepatocellular carcinoma
Familial aggregation of liver cancer has been reported. Transmission of HBV and HCV within family and shared unfavourable lifestyle habits and environmental factors, such as heavy alcohol drinking, tobacco smoking and obesity, may explain part of such clustering. Indeed, familial clustering of HCC has been frequently observed in eastern Asia, particularly in China [131], [132], where the prevalence of chronic HBV infection is high. However, family history was associated with the risk of HCC
Summary
During the last 30 years, epidemiologic research has revealed the causes of most HCC cases. Chronic infection with HBV and HCV dominates the etiology of the disease in low and middle income countries. Aflatoxin exposure also contributes to HCC development in Africa and eastern Asia (Table 1). In high-income countries, however, these factors are less prevalent, and heavy alcohol drinking and tobacco smoking have a more relevant role. Diet may also affect the development of liver cancer, but the
Role of the funding
The study sponsors had no role in the collection, analysis, and interpretation of data and in the writing of the manuscript.
Conflict of interest
None.
Acknowledgements
This work was partially supported by the Italian Foundation for cancer Research (FIRC) and the Italian Association for Cancer Research (AIRC, Grant number 13203). The authors thank Mrs Ivana Garimoldi for editorial assistance.
References (155)
- et al.
Cancer survival in Europe 1999–2007 by country and age: results of EUROCARE–5-a population-based study
Lancet Oncol
(2014) - et al.
Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection
Cancer Lett
(2009) - et al.
Trends in mortality from primary liver cancer in Europe
Eur J Cancer
(2000) - et al.
A comparison of trends in mortality from primary liver cancer and intrahepatic cholangiocarcinoma in Europe
Ann Oncol
(2013) - et al.
Epidemiology and prevention of hepatocellular carcinoma
Cancer Lett
(2009) - et al.
Incidence of primary liver cancer in Italy between 1988 and 2002: an age-period-cohort analysis
Eur J Cancer
(2008) - et al.
Primary liver cancer: worldwide incidence and trends
Gastroenterology
(2004) - et al.
Socio-economic status and the risk of liver cancer mortality: a prospective study in Korean men
Public Health
(2008) - et al.
Alcohol and liver cancer: a systematic review and meta-analysis of prospective studies
Ann Oncol
(2014) - et al.
Light alcohol drinking and cancer: a meta-analysis
Ann Oncol
(2013)
Cigarette smoking and site-specific cancer mortality: testing uncertain associations using extended follow-up of the original Whitehall study
Ann Oncol
Human aflatoxicosis in developing countries: a review of toxicology, exposure, potential health consequences, and interventions
Am J Clin Nutr
Population attributable risk of aflatoxin-related liver cancer: systematic review and meta-analysis
Eur J Cancer
Attributable risks for hepatocellular carcinoma in northern Italy
Eur J Cancer
Consumption of fish and meats and risk of hepatocellular carcinoma: the European Prospective Investigation into Cancer and Nutrition (EPIC)
Ann Oncol
Consumption of n-3 fatty acids and fish reduces risk of hepatocellular carcinoma
Gastroenterology
Fish consumption and cancer risk
Am J Clin Nutr
Mediterranean diet and hepatocellular carcinoma
J Hepatol
Is concordance with World Cancer Research Fund/American Institute for Cancer Research guidelines for cancer prevention related to subsequent risk of cancer? Results from the EPIC study
Am J Clin Nutr
Dietary glycemic load and hepatocellular carcinoma with or without chronic hepatitis infection
Ann Oncol
Glycemic load in relation to hepatocellular carcinoma among patients with chronic hepatitis infection
Ann Oncol
Glycemic index, glycemic load, dietary carbohydrate, and dietary fiber intake and risk of liver and biliary tract cancers in Western Europeans
Ann Oncol
Glycemic index, glycemic load and cancer risk
Ann Oncol
The accuracy of liver cancer as the underlying cause of death on death certificates
Public Health Rep
Liver cancer
Cancer of the liver and biliary tract
Cancer of the liver and biliary tract
Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008
Int J Cancer
Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005
J Clin Oncol
International trends in liver cancer incidence rates
Cancer Epidemiol Biomarkers Prev
Cancer statistics, 2013
CA Cancer J Clin
Attributable causes of liver cancer mortality and incidence in China
Asian Pac J Cancer Prev
Global cancer statistics, 2002
CA Cancer J Clin
Trends in mortality from hepatocellular carcinoma in Europe, 1980–2004
Hepatology
The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update
Ann Intern Med
Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis
Diabetes Metab Res Rev
IARC monographs on the evaluation of carcinogenic risks to humans
Prospective study of hepatitis B and C viral infections, cigarette smoking, alcohol consumption, and other factors associated with hepatocellular carcinoma risk in Japan
Am J Epidemiol
Eight-year follow-up of the 90,000-person Haimen city cohort: I. Hepatocellular carcinoma mortality, risk factors, and gender differences
Cancer Epidemiol Biomarkers Prev
Hepatitis B e antigen and the risk of hepatocellular carcinoma
N Engl J Med
Hepatitis viruses, alcohol, and tobacco in the etiology of hepatocellular carcinoma in Italy
Cancer Epidemiol Biomarkers Prev
Patterns of familial transmission of HBV and the risk of developing liver cancer: a case-control study in the Philippines
Int J Cancer
Birth order, as a proxy for age at infection, in the etiology of hepatocellular carcinoma
Epidemiology
The global health burden of infection-associated cancers in the year 2002
Int J Cancer
Case-control study on hepatitis C virus (HCV) as a risk factor for hepatocellular carcinoma: the role of HCV genotypes and the synergism with hepatitis B virus and alcohol. Brescia HCC Study
Int J Cancer
Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women
Am J Epidemiol
A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma
Int J Cancer
Liver cirrhosis and the risk of primary liver cancer
Eur J Cancer Prev
Therapy of hepatitis C–back to the future
N Engl J Med
A meta-analysis of alcohol drinking and cancer risk
Br J Cancer
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