Hepatic Carcinoma, Primary
Hepatocellular carcinoma (HCC) is a primary malignancy of the hepatocyte, generally leading to death within 6-20 months. Hepatocellular carcinoma frequently arises in the setting of cirrhosis, appearing 20-30 years following the initial insult to the liver. However, 25% of patients have no history or risk factors for the development of cirrhosis. The extent of hepatic dysfunction limits treatment options, and as many patients die of liver failure as from tumor progression.
Although it is currently one of the most common worldwide causes of cancer death, a major impact on the incidence of hepatocellular carcinoma should be achieved through current vaccination strategies for hepatitis B virus (HBV) infection, screening and treatment for hepatitis C virus (HCV) infections, and from the reduction of alcoholic liver disease. However, because the latency period from hepatic damage to hepatocellular carcinoma development is very long, it may be many years until the incidence of hepatocellular carcinoma decreases as a result of these interventions.
Tumors are multifocal within the liver 75% of the time. Late in the disease, metastases may develop in the lung, portal vein, periportal nodes, bone, or brain (see Media files 1 and 4).
Although hepatocellular carcinoma is uncommon, comprising only 2% of all malignancies, since the mid-1980s the incidence of hepatocellular carcinoma has been rising at an alarming rate.1, 2, 3 The age-adjusted incidence rates increased 2-fold between 1980 and 1998. Much of this increase is likely due to hepatitis C infection, a known risk factor for hepatocellular carcinoma.4 The American Cancer Society projects that 19,160 new cases of hepatocellular carcinoma and intrahepatic bile duct cancers were expected to be diagnosed in 2007 with 13,650 cases in men and 5,510 cases in women. An estimated 16,780 patients (11,280 men and 5,500 women) were expected to die of hepatocellular carcinoma and intrahepatic bile duct cancer in 2007.5
Hepatocellular carcinoma is the fifth most common cancer in men and the eighth most common cancer in women worldwide. An estimated 560,000 new cases are diagnosed annually. The incidence of hepatocellular carcinoma worldwide varies according to the prevalence of hepatitis B and C infections. Areas such as Asia and sub-Saharan Africa with high rates of infectious hepatitis have incidences as high as 120 cases per 100,000.6
Cure, usually through surgery, is possible in fewer than 5% of all patients.
Median survival from time of diagnosis is generally 6 months. Length of survival depends largely on the extent of cirrhosis in the liver; cirrhotic patients have shorter survival times and more limited therapeutic options; portal vein occlusion, which occurs commonly, portends an even shorter survival.
Complications from hepatocellular carcinoma are those of hepatic failure; death occurs from cachexia, variceal bleeding, or (rarely) tumor rupture and bleeding into the peritoneum.
Hepatocellular carcinoma is most commonly found among Asian persons, due to childhood infections with hepatitis B. However, due to the implementation of childhood hepatitis B vaccination programs in many Asian countries, a decrease in the incidence of hepatocellular carcinoma among Asians is expected.
Hepatocellular carcinoma occurs more commonly in men than in women.
In the United States, 74% of hepatocellular carcinoma cases occur in men.
In high-risk areas (China, sub-Saharan Africa, Japan), the difference in incidence between the sexes is more pronounced, with male-to-female ratios as high as 8:1.
Age at diagnosis varies widely according to geographic distribution.
In the United States and Europe, the median age at diagnosis is 65 years. Hepatocellular carcinoma is rarely diagnosed in persons younger than 40 years. However, between 1975 and 1998, the 45- to 49-year age group had the highest rate, a 3-fold increase in the incidence of hepatocellular carcinoma.
In Africa and Asia, age at diagnosis is substantially younger, occurring in the fourth and fifth decades of life, respectively. Diagnosis at a younger age is thought to reflect the natural history of hepatitis B and C related hepatocellular carcinoma.7
Patients generally present with symptoms of advancing cirrhosis.
Increasing abdominal girth (portal vein occlusion by thrombus with rapid development of ascites)
Right upper quadrant pain (uncommon)
Alcoholic stigmata (Dupuytren contracture, spider angiomata)
Periumbilical collateral veins
Enlarged hemorrhoidal veins
Cirrhosis: In general, cirrhosis of any etiology is the major risk factor for hepatocellular carcinoma.8, 9 About 80% of patients with newly diagnosed hepatocellular carcinoma have preexisting cirrhosis. Major causes of cirrhosis in the United States are attributed to alcohol, hepatitis C infection, and hepatitis B infection.4
In the United States, about 30% of hepatocellular carcinoma cases are thought to be related to excessive alcohol use. Chronic alcohol use (>80 g/d or >6-7 drinks per day) for more than 10 years increases risk of hepatocellular carcinoma 5-fold.
Approximately 50% of US patients have histories of alcohol abuse. As many as 50% of alcoholics may have subclinical hepatocellular carcinoma at autopsy.
The risk of hepatocellular carcinoma is greater once the patient stops drinking alcohol, because heavy drinkers do not survive long enough to develop cancer.
The risk of hepatocellular carcinoma in patients with decompensated alcoholic cirrhosis is approximately 1% per year.
Hepatitis B virus
Global incidence of chronic HBV infection is estimated to be 350 million persons; chronic HBV infection is the most common cause of hepatocellular carcinoma worldwide. In the United States, about 20% of hepatocellular carcinoma cases are thought to be related to chronic hepatitis B infection.
Chronic infection in the setting of cirrhosis increases the risk of hepatocellular carcinoma 1000-fold.
The mechanism by which the hepatitis B virus causes hepatocellular carcinoma is thought to be from a combination of chronic inflammation and integration of the viral genome into the host DNA.
In a Taiwanese study, hepatitis B vaccination in newborns and children has already shown a 75% decrease in the incidence of hepatocellular carcinoma in children.10 Thus far, 135 countries have added hepatitis B vaccination to their routine vaccination programs. It is anticipated that with implementation of worldwide vaccination, the incidence of hepatitis B-related hepatocellular carcinoma is going to decrease.
See related CME at Understanding Resistance in Hepatitis B–Clinical Implications and Strategies in the Management of Chronic Hepatitis B.
Hepatitis C virus
HCV is a global pandemic affecting 170 million persons. HCV infection results in a higher rate of chronic infection compared to HBV infection (approximately 80% of infected subjects).
It has become the most common cause of hepatocellular carcinoma in Japan and Europe, and it is also responsible for the recent increased incidence in the United States.1 About 2.7 million Americans have chronic HCV infection. In the United States, about 30% of hepatocellular carcinoma cases are thought to be related to HCV infection. Some 5-30% of individuals with HCV infection develop chronic liver disease. In this group, about 30% progress to cirrhosis, and in these, about 1-2% per year develop hepatocellular carcinoma.
The lifetime risk of hepatocellular carcinoma in patients with HCV is approximately 5%, appearing 30 years after infection.
Co-infection with HBV further increases the risk; many patients are co-infected with both viruses. Alcohol use in the setting of chronic HCV doubles the risk of hepatocellular carcinoma compared with HCV infection alone.
Recent studies suggest that antiviral treatment of chronic HCV infections may reduce the risk of hepatocellular carcinoma significantly.
See related CME at Diabetes May Increase Risk for Hepatocellular Carcinoma in Patients With Hepatitis C.
Hemochromatosis: Patients with hemochromatosis, especially in the presence of cirrhosis, are at an increased risk of developing hepatocellular carcinoma. Hepatocellular carcinoma accounts for about 30% of all iron-related deaths in hemochromatosis.
Aflatoxin: This hepatic carcinogen is a byproduct of fungal contamination of foodstuffs in sub-Saharan Africa and East and Southeast Asia. It causes DNA damage and mutations of the p53 gene. Humans are exposed to aflatoxin through the ingestion of moldy foods found in susceptible grains. Dietary levels in endemic areas correlate directly with incidence of hepatocellular carcinoma.
Rare associations: These include primary biliary cirrhosis, androgenic steroids, primary sclerosing cholangitis, 1-antitrypsin deficiency, Thorotrast radioactive contrast, oral contraceptives, and porphyria cutanea tarda. Obesity and diabetes have been implicated as risk factors for hepatocellular carcinoma, most likely through the development of nonalcoholic steatohepatitis (NASH).11, 2, 12, 13 In the analysis of a large managed care database, the incidence of hepatocellular carcinoma linked to nonalcoholic fatty liver disease rose by 10 times from 0.03-0.46 per 100,000 between the years 1997 and 2005.14