Canadian Trends in Liver Cancer: a Brief Clinical and Epidemiologic Overview

and is projected to increase into the future 6. An examination of age-specific incidence rates in men shows the highest incidence occurring among those 70–79 years of age, although statistically significant rate increases have occurred in all age groups examined (that is, 40+ years) since 1980 (Figure 2). The death rate has followed a similar upward trajectory, reflecting the poor prognosis with this cancer and the late-stage at which it is commonly detected 7. The 5-year relative survival in all stages of the disease is currently only 18% in Canada 8. The major risk factor for primary liver cancer is infection with viral hepatitis. Chronic infection with hepatitis B virus (hbv) accounts for approximately 23% of hcc cases in developed countries, but the percentage is much higher in the developing world, including Southeast Asia and sub-Saharan Africa 9. ABSTRACT Although primary liver cancer is rare, its incidence rate has been rising quickly in Canada, more than tripling since the early 1980s. This cancer is more common in men than women, and the age-specific incidence rates in men have been increasing significantly in all age groups from 40 years of age onward. The death rate has followed a similar upward trajec-tory, in part because of the low 5-year survival rate of 18% in both sexes. Infection with the hepatitis B or C virus continues to be the most common risk factor, but other factors may also play a role. Risk reduction strategies, such as viral hepatitis screening, have been recommended in other countries and warrant consideration in Canada as part of a coordinated strategy of disease prevention and control.


INTRODUCTION
Primary liver cancer originates in the bile ducts, blood vessels, or connective tissue of the liver.Worldwide, this cancer is the fifth most common among men and the seventh most common among women 1 .Primary liver cancer remains relatively uncommon in Canada, accounting for an estimated 1% of all new cancer diagnoses and deaths in 2012, but it is a rising cause of cancer-related deaths and liver transplants.We used data from the Canadian Cancer Registry to examine the incidence and mortality trends for primary liver cancer between 1980 and 2007.
Our review shows that incidence and mortality rates have increased substantially in Canada since the early 1980s (Figure 1), particularly for hepatocellular carcinoma (hcc), which is the predominant histologic type 4 , comprising about 70% of new cases.The incidence rate is higher in men than in women, and in men, it tripled to 6.8 from 2.2 per 100,000 between Patients with chronic hbv have a risk of developing liver cancer that is 20-100 times higher than that for uninfected individuals 10 .Chronic inflammation and repeated cellular regeneration is thought to be the mechanism by which such cases develop, typically after 25-30 years of hbv infection 11 .Most hbv infections in the developing world are transmitted from mother to child at birth, but worldwide, the virus is also commonly transmitted between sexual partners or through household contact or other activities (for example, needle-sharing) that result in exposure to contaminated blood or body fluids 11 .
Chronic infection with hepatitis C virus (hcv), believed to be associated with exposure to contaminated blood, a more pertinent risk factor for nonhbv-related liver cancers in developed countries 12 , especially in populations such as injection drug users and blood transfusion recipients (before hcv screening of blood was implemented in Canada in the early 1990s).Some cases of hcv infection are also attributable to immigration from high-prevalence countries such as Egypt, Italy, and Japan 12 .
In the United States and some northern European countries, more than half of hcc cases are found to be both hbv-and hcv-negative 13 , implying that other risk factors may play a role.Those factors include alcoholrelated cirrhosis of the liver 14,15 , fatty liver disease associated with obesity 16,17 , diabetes 18 , smoking 19 , and oral contraceptives 20 .Less-common risk factors include hereditary hemachromatosis, α1-antitrypsin deficiency, primary biliary cirrhosis, autoimmune hepatitis, Wilson disease, and nonalcoholic steatohepatitis 20 .

PRESENTATION AND DIAGNOSIS
The asymptomatic nature of liver cancer means that patients often present with late-stage or advanced malignancy 7 .Symptoms at presentation can include abdominal pain, abdominal mass, and on occasion, paraneoplastic syndromes, including hypercalcemia, watery diarrhea, hypoglycemia, and erythrocytosis 21 .Routine ultrasonographic screening of patients with chronic viral hepatitis or cirrhosis may identify asymptomatic early-stage disease that is amenable to treatment and, conceivably, improve survival 21 .Further details can be found in the recently published Canadian recommendations for the clinical management of hcc 22 .

RISK REDUCTION
In 2008, the U.S. Centers for Disease Control and Prevention (cdc) published updated guidelines for broadening hbv screening to all individuals in the United States who have lived or were born in world regions with intermediate or high hbv prevalence 23 .Recommendations by the U.S. Institute of Medicine were also recently expanded to include communitybased programs for hbv screening, testing, and vaccination services for immigrants 24 .The cdc also recently released draft guidelines proposing a onetime hcv test for people in the United States born between 1945 and 1965, many of whom are unaware that they are infected with the virus 25 .
Similar national strategies have not been implemented in Canada, but other options have been recommended, including catch-up hbv immunization for adolescents, screening for hbv in adults and children immigrating from at-risk regions, and prompt screening and treatment of household contacts of liver cancer patients 26,27 .Those efforts could be complemented with efforts to reduce stigma and to raise awareness in at-risk populations about chronic hbv and hcv infection.Such efforts could include developing a national education and awareness campaign targeting the general public and at-risk communities, creating a national advocacy plan to educate policymakers about the importance of viral hepatitis infections, and ensuring that health care professionals are educated about whom to vaccinate for hbv and to screen for both hbv and hcv 28 .Primary health care providers can play an additional important role by providing culturally relevant education about the risk factors for liver cancer to their patients as part of the range of disease prevention and control activities outlined in Table i.

IMPLICATIONS
Liver cancer trends in Canada are partly a result of greater immigration from areas of the world in which liver cancer and hbv are endemic 29,30 .Census data indicate an ongoing rise in immigration from Asia, with immigrants from other regions of the world making up a smaller percentage of all new arrivals to Canada 31,32 .There is also some evidence of declining  • Be vigilant about liver cancer and hepatitis C virus (hcv) infection in high-risk populations such as injection drug users, recipients of blood transfusions before 1990, and recent immigrants from high-prevalence countries.
• Testing for hcv should be undertaken in patients who show abnormal aminotransferase or who are past or active injection drug users, blood transfusion recipients before 1990, or immigrants from countries of high hcv prevalence.
• Counselling against binge drinking and prompt treatment of chronic hbv and hcv infections can help to reduce the burden of liver cirrhosis.
• Consult the latest Canadian hbv and hcv clinical management guidelines at http://www.hepatology.ca/cm/.
• Consult the latest Canadian clinical management and treatment guidelines for hepatocellular carcinoma at http://www.currentoncology.com/index.php/oncology/article/view/952.

table i
What can primary health care providers do about liver cancer?•Bevigilant about liver cancer and hepatitis B virus (hbv) infection in recent immigrants (especially Asian men) and in household contacts of individuals who are at high risk of hbv infection.Concomitant risk factors to consider are older age, persistence of viral replication, and co-infection with hiv, or the presence of other liver diseases.