Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. The global burden of cancer in 2012 was an all-time high of 14 million cases and is predicted to grow to 22 million over the next two decades. Liver cancers have the seventh highest age-adjusted incidence rate in the world, with 0.8 million cases diagnosed for the year 2012. Its most common etiological factor in the world is hepatitis B virus (HBV) infection. The development of cirrhosis is associated with high risk for developing HCC with most common risk factors including alcohol, viral hepatitis such as hepatitis C virus (HCV), and nonalcoholic fatty liver disease (NAFLD). Due to the wide prevalence of HCC, it carries a significant economic burden on society at large, especially in the East Asian countries where HBV infection is endemic. This is the third most common cause of cancer-related death in the world and seventh most common cause in the United States (US).[3,4] Surveillance programs have also been implemented to screen for HCC in high-risk individuals, which is more cost-effective than the treatment of HCC.
The initial approach in the management of HCC is to determine if either surgical resection or liver transplantation is feasible. Since the majority of HCC cases develop in cirrhotic patients, surgical interventions can become challenging and the treatment has been directed toward liver transplantation. Certainly, prevention of the tumor seems to be a preferred strategy to tackle the shortage of donor organs. Hence, understanding the epidemiology, etiology, and pathogenesis of this economically burdening cancer is of prime significance for hepatologists and oncologists.
HCC is more common among males with a male:female ratio of 2.4 in its worldwide distribution. The most common age at presentation is usually between 30 and 50 years. HCC is predominant in Asian countries including China, Mongolia, Southeast Asia, and Sub-Saharan Western and Eastern Africa. The prevalence of HCC in developed countries of the world is lower, except Japan, Italy, and France.
In the US surveillance, epidemiology, and end results (SEER) database program, HCC accounts for 65% of all cases of liver cancers.[7,8] The incidence rate of HCC has increased from 1.4/100,000 cases/year between 1976–1980 to 6.2/100,000 cases reported in 2011. There are almost two times higher incidence of HCC among dark-skinned males compared to light-skinned males; a similar trend is seen among females with two times higher incidence rate among dark-skinned when compared to light-skinned. The 5-year survival trend has improved by >60% from 1975 to 2005.[9,10]
HCC has a multitude of etiological risk factors, with some that have shown to have a strong association with development of HCC. Hepatotropic viruses such as HBV, HCV, and hepatitis D virus (HDV) have a strong association with development of HCC; thus, the worldwide distribution of HCC mirrors the distributions of such viral infections. Various other associated risk factors are summarized in Table 1. Around 80%–90% of HCC cases occur in the setting of underlying cirrhosis. In addition, there is an incremental effect of presence of more than one risk factor responsible for HCC as the presence of HBV/HCV and HBV/HDV coinfections increases risk of HCC by two to six folds. Similarly, alcohol abuse further increases this risk.[15,16] Below, discussion will be focused on the most common risk factors for HCC.