Hepatocellular Carcinoma: Epidemiology, Screening and Prevention

Morris Sherman

Epidemiology

Hepatocellular carcinoma (HCC) is the fifth most common solid tumor in the world, accounting for >500,000 deaths each year (1). Most HCC occurs as a complication of underlying chronic liver disease. Therefore, the epidemiology of HCC is largely the epidemiology of the underlying liver diseases. Furthermore, the epidemiology of HCC is changing as the epidemiology of the underlying liver diseases also changes. For example, the incidence of HCC in children in Taiwan and other places has been dramatically reduced by the introduction of neonatal hepatitis B vaccination (2). In contrast, HCC related to chronic hepatitis C is increasing in incidence, related to epidemics of hepatitis C that occurred many years ago.

China has the highest incidence of HCC in the world (∼100/100,000 population) (1,3). The major risk factor in China is chronic hepatitis B infection. Similarly, in Africa, where the HCC incidence is also very high, the major risk factor is also chronic hepatitis B. In contrast, hepatitis C accounts for about 63% of the attributable risk in Europe (3). In the United States, hepatitis C is the major contributor, but the attributable risk due to alcohol is also high at about 45% (3).

North America and Western Europe are generally considered to be low incidence regions (incidence 2.6–9.8/100,000 population) (3), but the incidence of HCC is rising in these regions. Studies from cancer registries have shown a rising trend in HCC incidence and death in the United States, France, Japan, the United Kingdom, and Italy (3,4,5,6,7). In the United States, HCC incidence has increased from 1.4/100,000/year to 2.4/100,000/year between 1976 and 1995. The increased incidence is present among all races and is mainly due to an increase in the incidence of HCC related to hepatitis C, with much smaller increases in the incidence of HCC associated with alcohol and hepatitis B (8).

The incidence of HCC increases with age, but the age distribution varies in different local regions of the world. The pattern suggests that with urbanization, the median age of onset is shifted to older age groups. In less well-developed countries, it is not rare to find HCC in persons younger than 45 years. However, the incidence of HCC in developed countries only really starts to increase in persons older than 45 years, and it continues to increase until a person reaches his or her 70s (3). These differences may reflect a difference in the age of exposure to hepatitis viruses, exposure occurring at younger ages in high incidence countries. The incidence of HCC is higher in men than in women. The incidence ratio varies in different parts of the world but ranges from 1.3 to 3.6 (3). There are, as yet, no satisfactory explanations for this phenomenon. Studies in migrant populations have clearly shown that first-generation immigrants carry with them the high incidence of HCC that is present in their native countries. However, in the second and subsequent generations, the incidence decreases (9). This is likely a reflection of improved sanitation, improved health care, and improved health in general, resulting in a lower prevalence of underlying viral hepatitis. In North America, HCC incidence may be particularly high in specific ethnic groups. First-generation immigrants from Hong Kong, China, and Taiwan bring with them the high prevalence of chronic hepatitis B and are at risk for HCC. Immigrants from Egypt, Somalia, Vietnam, and Pakistan have a high prevalence of hepatitis C. Thus, trends in immigration will also affect HCC incidence.

Hepatitis B

That chronic hepatitis B infection is a risk factor for HCC has been known for some years. The first prospective cohort study to show this was that of Beasley et al. (10,11), who, in a now classic prospective cohort study, showed that the relative risk of HCC in a carrier versus noninfected was about 100. In that study, the annual incidence of HCC in hepatitis B carriers was 0.5%. The annual incidence increased with age, so that at age 70 the incidence was 1%. The incidence in patients with known cirrhosis was 2.5% per year. A second prospective study by Sakuma et al. (12) found the incidence of HCC in male Japanese railway workers who were hepatitis B carriers was 0.4%/year. Both populations were male and Asian, with the hepatitis B infection likely acquired at birth or in early childhood. There are no equivalent studies in Asian women, but the incidence of HCC in Asian women is about one-fourth to one-eighth of that in men. Uncontrolled prospective cohort studies in North America, where the epidemiology of hepatitis B is often different (i.e., hepatitis may be acquired later in life), have found a wide incidence of HCC in hepatitis B carriers, ranging from 0% to 0.46% (13,14,15). In Europe, HCC in hepatitis B carriers occurs mainly in patients with established cirrhosis (16,17). Caucasian noncirrhotic chronic carriers who are anti–HBe positive with long-term inactive viral replication have little risk of developing HCC (18,19,20). This may not be true for Asian noncirrhotic hepatitis B carriers, who remain at risk for HCC regardless of replication status (21,22,23,24). Similarly, the risk of HCC persists in long-term HBV carriers from Asia who lose HBsAg (25). In Caucasian hepatitis B carriers who lose surface antigen, the risk of HCC seems to decline dramatically (26).

The epidemiology of hepatitis B is changing as a result of the introduction of mass vaccination against hepatitis B. It has already been shown that the incidence of childhood HCC has been dramatically reduced following the introduction of hepatitis B vaccination (2). It is likely that as the vaccinated cohort ages the incidence of HCC in older age groups will also decrease. However, there are still many millions of individuals persistently infected with hepatitis B, who remain at risk for the development of HCC.

Hepatitis C

The risk of HCC in hepatitis C infection is largely associated with the presence of cirrhosis (27,28,29,30). In these patients, the incidence of HCC is between 2% and 8% per year. Noncirrhotic hepatitis C–infected individuals have a much lower risk of developing HCC (30). Most of the data is from clinic-based studies. However, a prospective population-based study of 12,008 men of (31) found a 20-fold increased risk of HCC compared to anti–hepatitis C virus (HCV)-negative subjects. The presence or absence of cirrhosis was not evaluated.

The epidemiology of hepatitis C is different in North America and elsewhere. In Japan, Italy, Eastern Europe, and elsewhere, an epidemic of hepatitis C infection occurred between the end of the Second World War and about 1975 to 1980. This was related to medical procedures, injections, vaccinations, transfusions, and hospitalizations, as well as the use of improperly sterilized equipment. Those infected during that era are now at least in their 50s and are entering the period of highest risk for HCC. In contrast, in the United States and Northern Europe, the epidemic of HCV infection occurred in the 1960s and 1970s related to injection drug use. Thus, the peak onset of HCC in these populations is still to come. It is predicted that the incidence of HCC will increase by about 80% over the next 20 years in the United States (32) but will more than triple elsewhere (33,34).

Cirrhosis Due to Causes Other Than Viral Hepatitis

The incidence of HCC in cirrhosis caused by diseases other than viral hepatitis is, with some exceptions, not accurately known. Most of the studies of the incidence of HCC in alcoholic cirrhosis date from before the identification of the HCV. Given that hepatitis C is relatively frequent in alcoholics, most of the reported incidence rates in these earlier studies are likely to be overestimates. Thus, it is not possible to provide precise estimates of HCC incidence in this group. Nonetheless, alcoholic cirrhosis is a well-recognized risk factor for HCC. In one study, alcoholic liver disease accounted for 32% of all HCCs (35). In an Austrian cohort with HCC, alcoholic liver disease was the risk factor in 35% of subjects (36). In the United States, the approximate hospitalization rate for HCC related to alcoholic cirrhosis is 8–9/100,000/year compared to about 7/100,000/year for hepatitis C (37). This study did not determine the incidence of HCC in alcoholic liver disease, but it does confirm that alcoholic cirrhosis is a significant risk factor for HCC, probably sufficient to warrant surveillance for HCC.

With the recognition of nonalcoholic liver disease (mainly steatohepatitis) as a cause of cirrhosis has come the suspicion that this too is a risk factor for HCC. No study to date has followed a sufficiently large group of patients for long enough to describe an incidence rate for HCC. In one cohort study of patients with HCC (38), diabetes was found in 20% as the only risk factor for HCC. The likely link is insulin resistance causing steatohepatitis, in turn causing cirrhosis. Whether these patients were cirrhotic was not noted. Nonalcoholic fatty liver disease has also been described in cohorts of patients with HCC (39,40).

Patients with genetic hemochromatosis (GH) who have established cirrhosis have an increased risk of HCC (41,42,43) of about 20-fold. The standardized incidence ratio of HCC in cirrhotic GH is 92.9 (95% confidence interval, 25–238). For cirrhosis due to alpha 1-antitrypsin deficiency (44,45) or autoimmune hepatitis, there are insufficient data from cohort studies to accurately assess HCC incidence. However, there does seem to be an increased HCC risk. The incidence of HCC in stage 4 primary biliary cirrhosis is about the same as in cirrhosis due to hepatitis C (46).

Screening for Hepatocellular Carcinoma

HCC develops silently. There is no opportunity for early detection by self-examination as with breast or skin cancer, nor does it call attention to itself by bleeding into a hollow organ, as bladder or bowel cancer might. Therefore, in the absence of screening and early detection programs, HCC presents late in the course of the disease with the onset of symptoms due to liver failure (massive replacement of liver by tumor), obstructive jaundice due to bile duct infiltration, or constitutional symptoms. At this late stage of disease, curative therapy can seldom be applied and has a low chance of success. Palliative therapy may also not be possible because of advanced hepatic failure. Furthermore, progression of disease is usually rapid with a prognosis of only a few weeks to months. Therefore, there has long been an interest in early detection of HCC, although formalization of methods of early detection and definition of the diagnostic features of early HCC have only been recently achieved.

The objective of cancer screening is to reduce the mortality from that specific cancer. Several studies have shown that screening does detect earlier disease (stage migration) (47). There are several surrogate markers of successful screening, including stage migration. Clearly, it is important to find cancers at an earlier stage, but stage migration does not necessarily correlate with a reduction in disease-specific mortality. Similarly, changes in 5-year survival may reflect changes in underlying cancer incidence rather than changes in mortality (50). Uncontrolled studies, all subject to lead-time bias, have also suggested that survival is improved after screening (48,49,50).

There have been two randomized controlled trials of HCC screening. Both were conducted in China. The first failed because although screening found early cancers, too many patients did not get the proposed treatment (51). The second study, a large population-based study followed patients for 5 years (52). This study used cluster randomization to allocate patients with chronic hepatitis B to a screening or no screening arm. Screening was with ultrasonography and alpha-fetoprotein (AFP) testing at 6-month intervals. The study found a 37% reduction in HCC-related mortality despite a compliance rate that was less than optimal. There are limitations to generalizing this study to HCC related to other liver diseases. In the study, the main therapy that was offered was resection. However, in hepatitis B, as discussed later in this chapter, HCC develops in noncirrhotic as well as cirrhotic livers, although at lower frequency. The presence of cirrhosis in diseases other than hepatitis B limits the possibility for resection. Therefore, in all other causes of HCC, fewer patients will be able to have resections. The possibility of using local ablation and liver transplantation as therapy also makes it harder to generalize these results, and although one would expect the availability of these
additional forms of therapy to improve the results, the presence of cirrhosis itself will limit survival.

In addition, there have been several decision analytic models of screening for HCC (53,54). In summary, all suggest that there is benefit to HCC screening under standard baseline conditions, but the increase in life expectancy is only just above the 3-month limit considered to be acceptable. Screening for HCC may also be appropriate because the cure rate for symptomatic cancers is very low (0%–10% 5-year survival) (55,56,57,58,59). However, 5-year diseasefree survival of >50% has been reported for liver transplantation (60,61,62,63). The more advanced the disease, the less likely that liver transplant will eradicate it.

There are cogent reasons to undertake screening in all patients at sufficiently high risk:

Cure is more likely with treatment of early stage disease, especially with liver transplantation.
Advances in the ability to treat HCC are unlikely to come from treating late stage disease; therefore, it is important to find early stage disease. Ideally, patients with HCC found on screening should be entered into clinical trials of newer forms of therapy.
A randomized controlled trial of screening versus no screening in hepatitis C and other causes of cirrhosis will likely never be undertaken because of the difficulties such a trial would involve. Thus, patient management decisions will have to be made in the absence of high-quality evidence.
Minimally invasive therapies, such as radiofrequency ablation, can completely ablate small lesions with an appreciable frequency, which might approach 95% in very small lesions (64).

Although the broad outlines of the risk groups that might benefit from screening are well known, it is clear that not all patients need screening. For example, in male hepatitis B carriers, the risk of HCC only starts to rise significantly in persons older than 40 years (10,11). This is not to say that there is no HCC at younger ages. However, from a cost-efficacy point of view, it might be difficult to justify screening in a population with a low incidence of HCC.

Definition of the At-Risk Population

The decision to enter a patient into an HCC screening program depends on the physician’s perception of the patient’s risk of developing HCC. Patients at high risk are offered screening, whereas those at low risk (usually interpreted as risk equivalent to the general population risk) are not. However, risk is hard to quantitate, and most physicians equate risk with HCC incidence. There are no experimental data to indicate what level of risk or what incidence of HCC should trigger surveillance. HCC incidence in the general population is low. In contrast, in various populations with liver disease, the incidence may be as high as 8% annually. The incidence at which screening becomes worthwhile probably varies with different liver diseases. Decision analysis has been used to determine incidence rates at which screening might be effective. As a general rule in decision analysis, an intervention is considered effective if it provides an increase in longevity of about 100 days (i.e., about 3 months). If this can be achieved at a cost of less than about $50,000/year of life gained, the intervention is considered cost effective (65,66). There are now several published decision analysis/cost-efficacy models for HCC surveillance. The models differ in the nature of the theoretical population being analyzed and in the intervention being applied. Nonetheless, these models have several results in common. They all find that surveillance is cost effective, although in some cases only marginally so, and most find that the efficacy of surveillance is highly dependent on the incidence of HCC. For example, Sarasin et al. (53) studied a theoretical cohort of patients with child’s A cirrhosis and found that if the incidence of HCC was 1.5%/year, surveillance resulted in an increase in longevity of about 3 months. However, if the incidence of HCC was 6%, the increase in survival was about 9 months. This study did not include transplantation as a treatment option. Arguedas et al. (54), using a similar analysis that did include liver transplantation in a population of hepatitis C cirrhotics with normal liver function, found that surveillance with either computed tomography (CT) scanning alone or CT scanning plus ultrasound (US) became cost effective when the incidence of HCC was >1.4%. However, this study has to be interpreted cautiously because the performance characteristics of CT scanning were derived from diagnostic studies, not surveillance studies. Lin et al. (67) found that surveillance with AFP and US was cost effective regardless of HCC incidence. Thus, for patients with cirrhosis of varying etiologies, surveillance should be offered when the risk of HCC is ≥1.5%/year. Table 29.1 describes the groups of patients in which these limits are exceeded.

HCC in patients with chronic hepatitis B may develop in a noncirrhotic liver, particularly in Asian and African patients. The previous cost-efficacy analyses, which were restricted to cirrhotic populations, cannot be applied to noncirrhotic hepatitis B carriers. These patients, particularly in Asia and Africa, are also at risk for HCC. A cost-efficacy analysis of surveillance of hepatitis B carriers using US and AFP levels suggested that surveillance became cost effective once the incidence of HCC exceeded 0.2%/year (J. Collier and M. Sherman, unpublished observations, 2000). The subgroups of hepatitis B carriers in which the incidence of HCC exceeds 0.2%/year are listed in Table 29.1. These groups are discussed in more detail later in this chapter.

Screening, as used here, refers to the repeated application of diagnostic tests to asymptomatic subjects who have a defined risk of developing HCC but in whom there is no reason to believe that HCC is present. Patients who have some reason to suspect that HCC is present, such as an abnormal screening test result, are no longer candidates for screening. Instead,
they undergo enhanced follow-up. This is the process of confirming or refuting that an abnormal screening test result is due to HCC. Enhanced follow-up is more frequent than screening and involves a wider range of diagnostic tests. Part of enhanced follow-up is a strategy to deal with equivocal diagnostic test results, and it requires an understanding of the diagnostic features of early HCC.

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