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1 {1, 66}. This classification applies only to primary hepatocellular and cholangio-(intrahepatic bile duct) carcinomas of the liver.

2 A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.

3 For classification, the plane projecting between the bed of the gallbladder and the inferior vena cava divides the liver in two lobes.

Hepatocellular carcinoma

S. Hirohashi K.G. Ishak M. Kojiro I.R. Wanless N.D. Theise H. Tsukuma

H.E. Blum Y. Deugnier P. Laurent Puig H.P. Fischer M. Sakamoto

Definition

A malignant tumour derived from hepato-cytes. Most common aetiological factors are viral infections (HBV, HCV), dietary aflatoxin B1 ingestion and chronic alcohol abuse.

Epidemiology

Primary liver cancer (PLC) is a major public health problem worldwide. In 1990, the global number of new cases was estimated at 316,300 for males and 121,100 for females, accounting for 7.4% (males) and 3.2% (females) of all malignancies, excluding skin cancer {1469}. Hepatocellular carcinoma (HCC) is the most common histological type of PLC. Population-based cancer registries show that HCC as a percentage of histologically specified PLCs varies considerably {1471} but in over half of the registries, the fraction is above 70%. Regions with percentages less than 40% are exceptional, e.g., Khon Kaen (Thailand), where intrahepatic cholangiocarci-noma is predominant, due to endemic infection with liver flukes (Opisthorchis viverrini) {1470}. Owing to the limited availability of histological data, the following epidemiological survey is based on PLC but it can be assumed that it largely reflects HCC incidence and mortality.

Geographical distribution

The estimated PLC incidence in 1990 for 23 areas of the world is shown in Figure 8.01 {1469}. High-risk areas with an age-standardized incidence rate (ASIR, standardized to world population) of more than 20.1 per 100,000 for males are Sub-Saharan and South Africa, East Asia, and Melanesia. Low-risk areas with an ASR < 3.2 are North and South America, South-Central Asia, Northern Europe, Australia and New Zealand. Thus, developing countries carry the greatest disease burden, with more than 80% of accounted global cases. The geographical distribution of PLC is similar for males and females, although males have a considerably higher risk of developing PLC. Geographical variations in PLC risk are present even in relatively homogenous populations and environments {1471, 176}.

Geographical variations in HCC incidence and mortality can be ascribed to different levels of exposure to HCC risk factors: chronic infections with hepatitis B virus (HBV) and aflatoxin exposure in developing countries, and smoking and alcohol abuse in developed countries {1545, 1482, 1417}. In Japan, local differences in the age-standardized mortality rate (ASMR, standardized to

Fig. 8.03 Age-specific incidence rates of liver cancer in males for selected populations 1992. From: M. Parkin et al. {1471}.

world population) reflect the sero-preva-lence of anti-hepatitis C virus (anti-HCV) antibodies among blood donors {1973, 1893, 1471, 67}.

Time trends

In most countries, the incidence rates stayed largely constant or have decreased over the past two decades. However, they have increased in Japan and Italy, especially for males {982, 1522}. A changing prevalence of risk factors among populations as well as changes in diagnostic techniques and in classification of the disease and appreciably affected the disease incidence.

Hbv Infection RatesGeorge Engel Biopsychosoziales Modell
Fig. 8.04 Overview of outcome of HBV infection.

Age and sex distribution

Regional age-specific incidence rates differ significantly (Fig. 8.03). Qidong and Hong Kong (China) are high-risk populations for HBV-related HCC. Characteristics of their curves are a steep increase in the ages 20-34 years; in Qidong the curve levels off already at the age of 40. Osaka (Japan) is a high-risk area, but Varese (Italy) is a low to intermediate risk area; approximately 70% of HCC in these populations is related to chronic HCV infection {1417}. Their rates increase at older ages and show relatively high rates over age 55-59. The curve for whites in the USA (SEER data) is representative of both low-risk populations. Males are always more frequently affected than females but high male to female ratios of > 3 in the age-specific rates occur particularly in populations with a high incidence of HCC {1534, 402, 1906, 391, 452}.

Aetiology

Chronic infection with HBV, HCV or both is the most common cause of HCC worldwide {889}. Among Western populations, alcohol-induced liver injury is a leading cause of liver cirrhosis and constitutes the most important HCC risk {426}. In Southern China and sub-Saharan Africa, dietary ingestion of high levels of aflatoxin may present a special environmental hazard, particularly in individuals chronically infected with HBV Other exogenous factors have also been incriminated, including iron overload {1155}, long-term use of oral contraceptives {1158, 2034}, and high-dose anabolic steroids. The development of liver cirrhosis, particularly in association with inherited genetic diseases such as alpha-1-antitrypsin deficiency or haemo-chromatosis, place the individual at a greatly increased risk of HCC development.

HCC risk is increased if aetiological risk factors exist in combination, e.g., HCV infection and alcohol use {341} or HBV infection and exposure to aflatoxin {1864}.

Liver cirrhosis

The major clinical HCC risk factor is liver cirrhosis, largely independent of its aetiology (Fig. 8.04). Approximately 70-90% of HCCs develop in patients with macronodular cirrhosis which is characterised by the presence of large nodules of varying size (up to several centimeters in diameter), containing portal fields and efferent veins, separated by broad, irregularly shaped connective tissue septae and scars. Macronodular and mixed macro-micro-nodular cirrhosis are typically caused by or associated with viral hepatitis, metabolic disorders, and toxic liver injury. Micronodular cirrhosis is characterised by uniform nodules of approximately 3 mm that lack the typical liver architecture and do not contain a central vein. They are typically observed as a consequence of alcoholic liver disease, haemochromatosis, and biliary cirrhosis.

Hepatitis B virus (HBV)

HBV is a small DNA virus belonging to the group of hepatotropic DNA viruses known as hepadnaviruses. HBV consists of an outer envelope, composed mainly of hepatitis B surface antigen (HBsAg), and an internal core (nucleocapsid), which contains hepatitis B core antigen (HBcAg), a DNA polymerase/reverse transcriptase, and the viral genome. The genome consists of a partly double-stranded circular DNA molecule of about 3200 base pairs with known sequence and genetic organisation. In recent years, HBV variants with mutations in viral genes and in some regulatory genetic elements have been detected in patients with HBV infection; these mutations can have biological consequences. Epidemiological studies have convincingly shown that HCC development is closely associated with chronic HBV infection. The incidence of HCC in chron ically HBV-infected individuals is approximately 100 times higher than in the uninfected population, and the lifetime HCC risk of males infected at birth approaches 50%. In the absence of a common molecular mechanism for HBV-induced hepatocarcinogenesis, definitive proof for a direct oncogenic role of HBV is still lacking. Nevertheless, at least three lines of evidence support a direct oncogenic role for HBV in the development of HCC: (1) integration of HBV DNA into the chromosomal DNA of HCCs, (2) the role of the HBV X gene in the pathogenesis of HBV-associated HCCs, in particular its binding to and inactivation of p53, and (3) HCC development in animal models of chronic hepadnavirus infection. In addition, the declining HCC incidence following HBV vaccination clearly supports the aetiological contribution {275). Chronic hepatitis D virus (HDV) infection does not increase the risk of HCC development over that of HBV infection alone, but the latency period between HDV infection and HCC development is 30-40

Fig. 8.05 Interactions between aflatoxin B, (AFB,) and HBV infection in liver cancer.

Fig. 8.05 Interactions between aflatoxin B, (AFB,) and HBV infection in liver cancer.

Fig. 8.06 Hepatocellular carcinoma. A Nodular type. B Massive type. C Diffuse type. D Multifocal type.

years, compared with 30-60 years for HBV infection alone.

Hepatitis C virus (HCV)

HCV has a single-stranded RNA genome of positive polarity, around 10 kb in length, that codes for a single polyprotein consisting of 3010-3033 amino acids. Post-translational processing in the 5'-3' direction yields the structural protein C (RNA-binding nucleocapsid protein) and the E1 and E2 envelope proteins, and the non-structural proteins NS1-NS5, including RNA-dependent RNA polymerase {321}. As soon as the HCV genome was cloned, it became evident that viruses isolated from various geographic regions have marked genetic heterogeneity. Sequence comparison shows at least 6 different HCV genotypes. Although mutations have been identified in all regions of the HCV genome, the genes for the envelope proteins E1 and E2 appear to be particularly variable. A mutation rate of 1 or 2 nucleotides per 1000 bases per infection-year appears to be characteristic of chronic HCV infection. This mutation rate is about 10 times higher than that of HBV. Some HCV genotypes may be more frequently associated with HCC development than others {321}. Anti-HCV antibodies are found in 15-80% of HCC patients, depending on the patient population studied. HCV appears to be a major cause of HCC in Japan, Italy, and Spain, but it seems to play a less important role in South Africa and Taiwan {321}. HCV-associated HCCs typically develop after 20-30 years of infection and are generally preceded by liver cirrhosis. Thus far, there is no evidence to suggest that HCV integrates into the cellular genome or has another direct role in the molecular pathogenesis of HCC. Rather, HCC develops via HCV-induced chronic liver injury, progressing to fibrosis and cirrhosis.

Alcohol

Among Western populations, alcohol-induced liver injury is the leading cause of chronic liver disease and liver cirrhosis and constitutes the most important HCC risk factor {426}. Regular daily consumption of > 50g ethanol in females or > 80g in males is generally considered sufficient to induce liver cirrhosis, although individual susceptibility can vary considerably. Patients who abuse alcohol and have coexisting liver disease from other causes (such as chronic HCV infection) have the highest risk for HCC development {341, 1432, 1508, 2106}.

Aflatoxin B1 (AFB)

AFB1 is a potent liver carcinogen in several animal species as well as in humans {2128}. It is produced by the moulds Aspergillus parasiticus and Aspergillus flavus which under hot and humid conditions in tropical countries typically contaminate grain, particularly ground nuts

(peanuts). Dietary ingestion of high levels of aflatoxins presents a significant environmental hazard, particularly in the context of coexisting chronic HBV infection {1864, 1265} which leads to a more than 50-fold increase in the risk of developing HCC (Fig. 8.05). AFB1 is metabolized by cytochrome P450 enzymes to its reactive form, AFB1-5,9-oxide, which covalently binds to cellular macromolecules. Reaction with DNA at the N7 position of guanine preferentially causes a G:C > T:A muta-

Fig. 8.07 Hepatocellular carcinoma, trabecular.

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