Keywords

1 Incidence and Mortality

The World Health Organization (WHO) estimates that, worldwide, approximately 900,000 individuals develop each year hepatocellular carcinoma (HCC), the most common form of liver cancer [1]. Overall, 69.8% of all HCC cases occur in males, with a male-to-female ratio of 2.66. Accordingly, HCC is the fifth most frequent incident cancer type in men, the ninth in women, and the sixth in the two sexes combined (Table 1.1). From a geographical perspective, the incidence of HCC shows very wide variations. According to the Global Cancer Observatory (GCO), part of the International Agency for Research on Cancer (IARC), 72.5% of all new cases of HCC occur in Asia, where standardized incidence rates peak to 11.6 cases per 100,000 inhabitants/year. In Africa, HCC is the fourth most common incident cancer, with an 8.8 standardized yearly incidence rate of new cases per 100,000 individuals (Table 1.1). In Oceania, Northern America, and Europe, HCC is less common than in Asia or Africa, with the lowest incidence rate being documented in Europe (5.2 new cases per 100,000 individuals per year) where HCC ranks thirteenth overall among incident cancer types.

Table 1.1 Hepatocellular carcinoma incidence, mortality, and prevalence in 2020
Full size table

With regard to mortality, HCC is, worldwide, the third most common oncological cause of death: more than 830,000 persons die because of HCC every year. Most of these deaths (69.6%) occur among males, with a peak in mortality rates of 12.9 deaths per 100,000 people per year: HCC is the second cause of oncological deaths in males and the sixth among females (Table 1.1). Deaths caused by HCC are particularly frequent in Asia, where HCC is the second cause of cancer death. HCC mortality is also very frequent in Africa, with a mortality rate of 8.5 deaths per year per 100,000 individuals (HCC is the third cause of oncological deaths in the continent), whereas it is less common in Oceania, Northern America, and Europe, where HCC ranks seventeenth among oncological death causes, with a mortality rate (8.5 deaths per year per 100,000 individuals) 2.4 times lower than that registered in Asia (Table 1.1).

2 Prevalence

Prevalence is a statistical parameter that indicates the number of people living, in a specific geographic area and period, after a cancer diagnosis dating back one or more years. The prevalence of cancer patients is strictly related to the frequency (i.e., incidence) and the prognosis (i.e., survival) of the disease, and, to a lesser extent, to various factors like population aging, time trends in cancer incidence and survival [2]. In general, about 5% of the population is living after a diagnosis of all cancer types combined. The number of prevalent cases has increased at an annual mean rate of approximately 3%, an increase largely attributable to long-term survivorship of patients with cancers like, among others, breast, prostate and colon-rectum carcinomas [2,3,4]. Worldwide, it is estimated that 995,000 people are living after a diagnosis of HCC, i.e., 12.8 cases per 100,000 individuals. Most of these prevalent cases are males (69.8%) and from Asia (73.6%) while the proportion ranges from 6.1/100,000 in Latin America and the Caribbean to 15.8/100,000 in Asia (Table 1.1).

Long-term prevalence has been used as a surrogate for cancer cure, denoting disease-free survivors with mortality patterns resembling those of a population group without cancer of the same sex and age. Patients living after a cancer diagnosis include individuals under treatment, relapse-free ones at excess risk of recurrence or death, and patients who have the same death rate as the corresponding general population—they also represent the so-called “cured cancer patients” [5]. For European cancer patients diagnosed in 2000, the cure fraction widely varies according to cancer type and sex. Among men, the cure fraction ranges from 94% of those with testicular cancer to 4% of men with pancreatic carcinoma while, among women, it ranges from 87% for thyroid cancer to 5% for pancreatic cancer. Prevalent cancer patients with HCC show the second lowest cure fraction, i.e., 5% among men and 7% among women [6].

3 Survival of Patients Diagnosed with Hepatocellular Carcinoma

Overall, HCC is the second most lethal tumor after pancreatic cancer. In the United States, data from population-based cancer registries collected by the Surveillance, Epidemiology and End Results (SEER) Program estimated a 20.3% 5-year relative survival for people diagnosed with HCC. Relative survival is an estimate of the percentage of patients who would be expected to survive the effects of their cancer after excluding the risk of dying from other causes [7]. No difference emerged in survival rates at each time interval between men and women.

Survival substantially depends on cancer stage at diagnosis, which determines treatment options and has a strong influence on the length of survival. In general, a cancer is deemed localized when it is found only in the part of the body where it started (also called stage 1 cancer). If a cancer has spread to a different part of the body, the stage is deemed regional or distant. The earlier HCC is discovered, the better is the chance of a person surviving five years after being diagnosed. Table 1.2 shows the distribution of liver cancer cases according to stage of disease at diagnosis, and the corresponding relative survival probability. In the United States, 45% of HCC are diagnosed at local stage, 26% at regional stage, and 18% at distant stage; the corresponding percentages of 5-year relative survival range from 35.3% to 2.7%.

Table 1.2 Distribution of hepatocellular carcinoma cases by stage and corresponding 5-year relative survival in the United States, 2011–2017
Full size table

At a population level, in Europe the survival probability of cancer patients has been evaluated by EUROCARE—a large cooperative study of population-based cancer survival. Overall, the results from EUROCARE indicates that cancer survival is improving over time although differences among countries persist. EUROCARE data from 107 cancer registries for more than 10 million cancer patients diagnosed up to 2007, and followed up to 2008, have shown that 5-year relative survival generally increased steadily over time for all European regions. However, improvements in survival for liver cancer and other rapidly fatal cancers (e.g., esophagus, pancreas, and pleura) were limited. For liver cancer, 5-year survival was approximately 12% [8].

Similarly, population-based survival probabilities for patients with liver cancer have been documented for England by the Cancer Research UK [9] for the period 2013–2017. As shown in Table 1.3, 38.1% of patients survived one year after diagnosis—a percentage drastically reduced to 12.7% after 5 years. It is worth stressing the substantial survival advantage of women as compared to men (13.7% vs. 10.7% at 5-year survival).

Table 1.3 One- and five-year relative survival for liver cancer in England, 2013–2017
Full size table

In Italy, the relative 5-year survival of Italian patients with liver cancer appears to be higher than the European average, i.e., 20%, without significant differences between men (20–21%) and women (19–22%), or among geographic areas. Interestingly, HCC patients who survive one year after diagnosis show a 33% probability of surviving an additional five years [10].

4 Main Risk Factors for Hepatocellular Carcinoma

The types and distribution of risk factors largely reflect the wide geographic variations documented in incidence and mortality rates across countries, and the higher frequency of HCC in men as compared to women.

Most HCC cases occur in individuals with a pre-existing liver disease, in particular liver cirrhosis or fatty liver disease. Worldwide, infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) are the most frequent causes of HCC [11]. With regard to HBV infection, it should be stressed that in high endemic areas—i.e., in Asia or in some sub-Saharan African countries—about 8% of individuals are chronically infected, and approximately 80% of HCC cases are recorded in people who are HBsAg-positive [12]. In contrast, HCV infection is the predominant risk factor for HCC in the USA, North America, Europe, and Japan [9], especially in HCV-infected patients with advanced fibrosis. Maucort-Boulch et al. [13] used data on the prevalence of HBV and HCV infection among 119,000 people with HCC from 50 countries worldwide to extrapolate data to countries without prevalence data. Globally, they estimated that 56% of the 770,000 cases of HCC that were recorded worldwide in 2012 were attributable to HBV and 20% to HCV. HBV is thought to be the cause of two out of three cases of HCC in less developed countries, and of one in four cases in more developed countries [13]. Antiviral therapies are effective in reducing the incidence of HCC, but do not eradicate the risk. Among patients with HCV infection who have a sustained virologic response to interferon-based treatment regimens, the risk of HCC is reduced from 6.2% to 1.5%, as compared with patients who do not have a response [14]. Promising results are progressively emerging from the use of direct-acting antivirals to treat and cure HCV infections, which are associated not only with a reduced mortality but also with a decreased risk of HCC development [15].

Alcoholic cirrhosis is the second most important risk factor for HCC in Europe and North America, the USA included. Alcoholic liver disease negatively impacts on liver metabolism and the risk of HCC increases with duration and quantity of alcohol consumption, starting from very low doses (<10 g/day). A statistically significant increased risk of 4% (from 2% to 6%) for every 10 g/day of alcoholic beverages has been estimated by the World Cancer Research Fund [16]. It is worthy of note that the alcohol-related risk of developing HCC substantially increases in association with several conditions, including HBV or HCV infection, older age, and obesity [17]. Smoking and coinfection with the human immunodeficiency virus can also contribute to the development of HCC.

5 Conclusion

Epidemiological data on HCC are an important tool to set priorities for liver cancer prevention. High-coverage of HBV vaccination will be transformational in HBV-endemic countries, but the prevention of HCV transmission and the treatment of chronic carriers of both viruses require actions toward new scalable solutions. In western countries, the reduction of alcohol consumption remains an essential step for HCC prevention.