Primary Hepatic Carcinoma
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 of cirrhosis or risk factors for it. 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 in 75% of cases. Late in the disease, metastases may develop in the lung, portal vein, periportal nodes, bone, or brain (see images below).
In general, cirrhosis of any etiology is the major risk factor for hepatocellular carcinoma. [1, 2] 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. 
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.
The global incidence of chronic hepatitis B virus (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.  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 will decrease.
Hepatitis C virus (HCV) infection is a global pandemic affecting 170 million persons. HCV infection results in a higher rate of chronic infection compared with HBV infection (approximately 80% of infected subjects).
HCV infection 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.  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.
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.
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.
Obesity and diabetes have been implicated as risk factors for hepatocellular carcinoma, most likely through the development of nonalcoholic steatohepatitis (NASH). [6, 7, 8, 9] 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. 
These include the following:
The incidence of HCC has more than tripled since 1980; from 2005 to 2014, the rate increased by about 3% per year. For 2018, the American Cancer Society estimates that 42,220 new cases of hepatocellular carcinoma and intrahepatic bile duct cancers will be diagnosed and 30,200 deaths will occur. 
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. 
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 is about 3 times more common in men than in women in the United States.  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. 
Overall prognosis for survival is poor, with a 5-year relative survival rate of 18%. In patients diagnosed with a localized stage of disease, the 5-year survival is 31%.  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.
The influence of diabetes, obesity, and glycemic control continues to be evaluated in studies of the etiology and outcomes of HCC. For example, in a study of patients who had undergone curative resection for solitary HCV-related HCC, the tumor-free survival rate at 3 years was more than twice as high in patients in patients who had a normal hemoglobin A1c than in those whose hemoglobin A1c was 6.5% or higher (66% versus 27%). 
Complications from HCC are those of hepatic failure; death occurs from cachexia, variceal bleeding, or (rarely) tumor rupture and bleeding into the peritoneum. Signs and symptoms of hepatic failure may signify tumor recurrence and/or progression.
Various studies have reported extrahepatic metastasis in up to 30–50% of cases of HCC, with lungs the commonest site, followed by lymph nodes and bones. Unusual extrahepatic metastatic sites include the following  :
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Keith E Stuart, MD Chairman, Department of Hematology and Oncology, Lahey Hospital and Medical Center
Disclosure: Nothing to disclose.
Zsofia K Stadler, MD Fellow, Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard University
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
N Joseph Espat, MD, MS, FACS Harold J Wanebo Professor of Surgery, Assistant Dean of Clinical Affairs, Boston University School of Medicine; Chairman, Department of Surgery, Director, Adele R Decof Cancer Center, Roger Williams Medical Center
N Joseph Espat, MD, MS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Parenteral and Enteral Nutrition, American Society of Clinical Oncology, Americas Hepato-Pancreato-Biliary Association, Association for Academic Surgery, Central Surgical Association, Chicago Medical Society, International Hepato-Pancreato-Biliary Association, Pancreas Club, Sigma Xi, Society for Leukocyte Biology, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Society of Surgical Oncology, Society of University Surgeons, Southeastern Surgical Congress, Southern Medical Association, Surgical Infection Society
Disclosure: Nothing to disclose.
Antoni Ribas, MD Assistant Professor of Medicine, Division of Hematology-Oncology, University of California at Los Angeles Medical Center
Disclosure: Nothing to disclose.
Primary Hepatic Carcinoma
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