Adrian Di Bisceglie, M.D., F.A.C.S.a, and
Edward Tabor, M.D.b
|Primary liver cancer refers to any malignant tumor
arising in the liver itself, rather than originating elsewhere and
spreading--or metastasizing--to the liver. The most common forms of
primary liver cancer are hepatocellular carcinoma and
cholangiocarcinoma, which arise from the liver cells and the bile
ducts respectively. Other tumors may arise in the liver from cells
that are found throughout the body, such as angiosarcoma (from the
lining cells of blood vessels), and lymphoma (from white blood
cells) (Okuda, 1986).
Although hepatocellular carcinoma is one of the most common tumors worldwide, it remains relatively uncommon in the industrialized countries of the Western world. The highest world standardized incidence rates were noted for Khon Kaen, Thailand, and Quidong, China, with rates of 90 per 100,000. By contrast, United States rates were less than 5 per 100,000 (Parkin et al., 1992). There were about 16,000 cases of primary liver cancer in the United States in 1994.
Hepatocellular carcinoma is unusual in that the causative factor can often be identified in individual patients, whereas in other common forms of cancer (such as colon or breast cancer), only broad categories of risk can be identified. Hepatitis B virus, which is the most important factor in the occurrence of hepatocellular carcinoma worldwide, is endemic in those regions where hepatocellular carcinoma is most common (Szmuness, 1978). While some patients have been followed from detection of chronic hepatitis B infection to the development of hepatocellular carcinoma years or even decades later, not all patients with chronic hepatitis B develop tumors.. People from the Far East and Africa tend to acquire hepatitis B infection at birth or in early childhood, while in the United States it is usually contracted in adulthood . It is usually necessary for infection with hepatitis B to occur early in life in order for hepatocellular carcinoma to develop; it rarely develops in individuals who become infected in adulthood (Tabot, 1991). Males are at much greater risk (two- to seven-fold higher) for developing hepatocellular carcinoma than females. Finally, patients with cirrhosis of the liver resulting from hepatitis B are at much higher risk of developing hepatocellular carcinoma than those patients with less severe liver disease.
Other causative factors have been identified for hepatocellular carcinoma, the most common of which is cirrhosis of any cause. Cirrhosis refers to the consequences of chronic liver injury, i.e., extensive scarring of the liver in which the scar tissue surrounds "nodules" of regenerating liver tissue. The causes of cirrhosis include alcohol abuse, chronic hepatitis, prolonged obstruction to the outflow of bile from the liver, and some viral forms of autoimmune liver disease.
Recently, infection with the hepatitis C virus has been strongly linked with hepatocellular carcinoma. Hepatitis C is a very common form of hepatitis. Reports from Italy and Spain initially identified a large proportion of patients with hepatocellular carcinoma who tested positive in serum antibody to the hepatitis C virus (Colombo, 1989). Studies from Japan have shown that hepatocellular carcinoma often arises in patients with chronic liver disease attributed to hepatitis C (Lisker-Melman et al., 1989). Hepatocellular carcinoma has doubled in incidence in Japan during the past 25 years; all of the increase is attributable to hepatitis C virus-associated cases (Nishioka et al, 1991).
Exposure to some chemicals and toxins can lead to hepatocellular carcinoma. Perhaps the best known and extensively studied of these is aflatoxin, produced by a common mold that infests poorly stored peanuts and other foods. Dietary contamination with aflatoxin has been a particular problem in some underdeveloped countries in Africa and the Far East. Aflatoxin readily causes liver cancer in laboratory animals and, in man, may potentiate the cancer-causing effects of hepatitis B infection (Ross et al., 1992). However, the extent of its role as a cause of hepatocellular carcinoma in humans is not known.
Several reports of hepatocellular carcinoma occurring in users of oral contraceptives and anabolic steroids have linked the use of steroids to the development of this malignancy. Because of the relatively small numbers of patients involved, this link has been very difficult to confirm (Hsing et al., 1992).
Whether or not smoking increases the risk of hepatocellular carcinoma remains controversial. Some studies suggest that smoking may be a more important cause of hepatocellular carcinoma in the Western countries where hepatitis B is less common (Hsing et al., 1990).
Finally, the question of whether or not alcohol, by itself, causes hepatocellular carcinoma is undecided. While hepatocellular carcinoma often arises in the presence of alcoholic cirrhosis, it is not known whether the underlying cirrhosis or the alcohol itself predisposes to cancer. Alcohol use can increase the risk of hepatocellular carcinoma due to hepatitis B virus; a similar role in hepatitis C virus-associated hepatocellular carcinoma has not been observed (Shimizu et al., 1992; Ikeda et al, 1993).
Some forms of inherited metabolic diseases may predispose to hepatocellular carcinoma (Lisker-Melman et al., 1989). By far the most common of these is hemochromatosis, a disorder of iron metabolism which results in an excessive accumulation of iron in the body. This iron accumulation will eventually lead to cirrhosis if it is not treated and the cirrhosis again provides the right environment for the development of hepatocellular carcinoma. Other, rarer, metabolic diseases that are sometimes linked to hepatocellular carcinoma include tyrosinemia, glycogen storage disease, and alpha-1-antitrypsin deficiency.