HEPATOCELLULAR CARCINOMA
1. DEFINITION
Primary hepatocellular carcinoma (HCC) is a malignant tumour of liver cells associated most frequently with chronic viral hepatitis or cirrhosis.
Less frequent causes include environmental toxins and hereditary haemochromatosis. Its ICD 10AM Code is C22.0. The prognosis is in general poor due to late diagnosis and the advanced state of liver disease usually found in these patients. Worldwide HCC results in between 250 000 and one million deaths annually with a wide geographic variation in the distribution of the disease consistent with its known causes. The development and dissemination of a vaccine for Hepatitis B should result in a fall in HCC in endemic areas.
2. NATURAL HISTORY
HCC develops as small nodules in the liver that are asymptomatic until late when there is invasion of surrounding structures. There is no convincing evidence that the aetiology of the tumour determines aggressiveness. The key factors influencing survival untreated are the severity of the underlying liver disease and tumour size. Untreated 50-90%
of Child-Pugh A cirrhosis will survive one year compared with only 20%
with Child-Pugh C. Survival with tumours smaller than 5cm is up to 100%
at one year and approximately 20% at three years without treatment (1).
3. EFFECTS OF INTERVENTION
Detection of earlier lesions by ultrasound or measurement of tumour markers has not been shown to improve long term survival. The only proven potentially curative treatment for HCC is surgical resection or liver transplantation but chemoembolisation can produce tumour necrosis and be effective for pain or bleeding. Hormonal therapy with Tamoxifen has shown no survival benefit in controlled trials.
4. ASSOCIATIONS
Cirrhosis is present in the vast majority of patients with HCC (2). Non cirrhotic HCC occurs occasionally in viral liver disease, particularly with HBV and occurs rarely in HCV infection and haemochromatosis. Familial clustering of HCC, though common, is due to vertical transmission of HBV and not genetic predisposition.
5. SECULAR CHANGES
The incidence of HCChas been rising in the last three decades and more recently in the west including the US, France and the UK (3). The proportion due to HBV is falling in these areas while that due to HCV is rising and 3-6% of patients with HCV cirrhosis develop HCC annually (4).
6. AGE
As HCC most frequently develops in the cirrhotic liver, most patients with HCC are older with a mean age at presentation of between 50 and 60 years.
7. GENDER
Males are far more likely to develop HBV related HCC than females
particularly in high incidence regions due to variations in hepatitis carrier
rates, exposure to environmental toxins and the effect of androgens. The
difference is less for HCV related tumours.
8. INCIDENCE AND GEOGRAPHIC FACTORS Globally the incidence of HCC varies markedly between high, intermediate and low incidence areas consistent with the distribution of the major risk factors, particularly Hepatitis B.
• High Rates (more than 20 per 10
5per year)
• Over 40% of all cases of HCC occur in the People’s Republic of China with an annual incidence of 137,000 cases. Other high incidence areas include sub-Saharan Africa, Hong Kong, Japan and Taiwan.
• Intermediate Rates (5-20 per 10
5per year)
• These occur in Singapore, Malays and Indians, Thailand, Indonesia, Jamaica, Haiti, New Zealand Maoris and Canadian Inuit.
• Low Rates (<5 per 10
5per year)
These areas are New Zealand, Australian, Canadian and UK whites, whites and blacks in America, Sweden, Denmark, Germany, Israel, India and Pakistan.
The differences in distribution of HCC are largely due to regional differences in exposure to hepatitis viruses and environmental toxins. The incidence in the United States has increased during the past two decades, partly due to the large pool of people with long standing chronic Hepatitis C from blood transfusions before the introduction of Hepatitis C testing and from IV drug use. The interval between acquisition of HCV and the development of cirrhosis and its complication is thought to be about 30 years (5).
9. GENETIC FACTORS
There is no evidence for a genetic predisposition to HCC.
10. CAUSES OF HCC
It is unclear whether cirrhosis per se is biologically important in the
tumorigenic pathway, or if tumour development and fibrogenesis take place
concurrently. The causes of cirrhosis include the Hepatitis B carrier state,
environmental toxins, chronic Hepatitis C virus (HCV) infection, hereditary
haemochromatosis and cirrhosis from almost any cause. The risk of HCC
development in cirrhosis due to auto immune hepatitis, primary sclerosing
cholangitis in either sex and alcoholic and primary biliary cirrhosis in
women is generally low. Non cirrhotic HCCs do occur in viral hepatitis but
the absolute risk is low.
10.1 HBV
HBV infection with cirrhosis carries a high risk of development of HCC of the order of 1.5% annually. Infection early in life and development of the HBV carrier state are strongly associated with HCC. HBV can be involved in the pathogenesis of HCC even in those who are HBsAg negative as these patients may still have evidence of infection using molecular techniques (6).
The risk of HCC is also higher in patients who are HBeAg positive compared to those who are HBsAg positive but HBeAg negative (324 v 39/10
5person years). Cirrhosis increases the risk of HCC as may other hepatotrophic stimuli, such as alcohol and cigarettes that act synergistically in the pathogenesis of HCC.
10.2 HCV
HCV cirrhosis and HCV carriers have a higher risk of HCC of about 3- 5% p.a. Genotype 1b may be a bigger risk factor than genotype 2 and 3 having been associated with more severe liver disease, however duration of infection appears to be more important that genotype.
10.3 HCV and Alcohol
Alcohol acts synergistically with HCV to increase the risk of HCC.
Moreover the prevalence of anti-HCV has shown to be higher in patients with alcoholic cirrhosis and HCC (76%) than in patients with alcoholic cirrhosis alone (38.7%) (7).
10.4 HBV and HCV
The combination of HCV and HBV infection appears to augment the risk of developing HCC (8).
10.5 Cigarette Smoking
Its role in the development of HCC is controversial.
10.6 Haemochromatosis
HCC is virtually limited to those patients with hereditary
haemochromatosis who develop cirrhosis. The risk is high and about 7-9%
p.a. The increased risk (1-3% p.a.) seen in less severe diseases may be due to the amount of mobilizable iron and delay in initial treatment.
10.7 Other causes of cirrhosis
The risk of HCC among patients with cirrhosis from PBC, Wilson’s disease and auto immune causes seems to be slightly increased but difficult to quantify.
10.8 Aflatoxin and Betel Nut
Aflatoxin, a mycotoxin that commonly contaminates corn, soybeans and peanuts and microcystin blue-green algal toxin that contaminates drinking water have both been associated with an increased risk of HCC. Betel nut chewers, frequent in Asia, may also have an increased risk of cirrhosis and HCC.
10.9 Alcohol
The relationship between alcohol and HCC is unclear and may be related to the development of cirrhosis rather than alcohol being a direct carcinogen.
It is estimated HCCs develop at about 1-4% p.a., similar to the rate in HCV and HBV cirrhosis.
10.10 The Oral Contraceptive Pill
The risk of HCC from prolonged use of the OCP is small if it exists at all.
References
1. Barbara L, Benzi G, Galani S. Natural history of small untreated hepatocellular carcinoma in cirrhosis; a multivariate analysis of prognostic factors of tumour growth rate and patient survival. Hepatology 16,132-7 (1992).
2. Giarelli L, Melato M, Zanconati F et al. Primary liver cancer in non-cirrhotic liver.
Epidemiological study based on autopsies performed in Trieste, Italy and Kurume, Japan.
J .Gastroenterol .Hepatol. 6,278-82 (1991).
3. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N.Engl. J. Med. 340,745-50 (1999).
4. Okuda K, Takayasu K. Primary malignant tumours of the liver : in Okuda K (ed) Hepatobiliary diseases. (Blackwell Science, Oxford, 2001).
5. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma : A population-based study.
Gastroenterology 127,1372-80 (2004).
6. Liang TJ, Jeffers LJ, Reddy R et al. Viral pathogenesis of hepatocellular carcinoma in the United States. Hepatology 18,1326 (1993).
7. Bruix J, Barrera JM, Calvet X et al. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 2(8670), 1004-6 (1989)
8. Colombo M, Kuo G, Choo QL, Donato MF, Del Ninno E, Tommasini MA, Dioguardi N, Houghton M. Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet 2 (8670):1006-6 (1989).
