Hepatocellular carcinoma

Definition

Hepatocellular carcinoma, or liver cancer , is a form of cancer with a high mortality rate. Liver cancers can be classified into two types. They are either primary, when the cancer starts in the liver itself; or metastatic, when the cancer has spread to the liver from some other part of the body.

Description

Primary liver cancer

Primary liver cancer is a relatively rare disease in the United States, representing about 2% of all malignancies. It is, however, much more common in other parts of the world, representing from 10–50% of malignancies in Africa and parts of Asia. The American Cancer Society estimated that, in the United States in 2001, at least 16,200 new cases of liver cancer were diagnosed (10,700 in men and 5,500 in women), causing roughly 14,100 deaths.

In adults, most primary liver cancers belong to one of two types: hepatomas, or hepatocellular carcinomas, which start in the liver tissue itself; and cholangiomas, or cholangiocarcinomas, which are cancers that develop in the bile ducts inside the liver. About 75% of primary liver cancers are hepatomas. In the United States, about five persons in every 200,000 will develop a hepatoma; in Africa and Asia, over 40 persons in 200,000 will develop this form of cancer. Two rare types of primary liver cancer are mixed-cell tumors, or undifferentiated tumors.

There is one type of primary liver cancer that usually occurs in children younger than four years of age and between the ages of 12–15. This type of childhood liver cancer is called a hepatoblastoma. Unlike liver cancers in adults, hepatoblastomas have a good chance of being treated successfully. Approximately 70% of children with hepatoblastomas experience complete cures. If the tumor is detected early, the survival rate is over 90%.

Metastatic liver cancer

The second major category of liver cancer, meta-static liver cancer, is about 20 times as common in the United States as primary liver cancer. Because blood from all parts of the body must pass through the liver for filtration, cancer cells from other organs and tissues easily reach the liver, where they can lodge and grow into secondary tumors. Primary cancers in the colon, stomach, pancreas, rectum, esophagus, breast, lung, or skin are the most likely to spread (metastasize) to the liver. It is not unusual for the metastatic cancer in the liver to be the first noticeable sign of a cancer that started in another organ. After cirrhosis, metastatic liver cancer is the most common cause of fatal liver disease.

Genetic profile

Hepatocellular carcinoma has occasionally been reported to occur in familial clusters. It appears that first-degree relatives (siblings, children, or parents) of people with primary liver cancer are 2.4 times more likely to develop liver cancer themselves. This finding indicates a small overall genetic component, however, specific disease genes have not yet been identified. Certain genetic diseases are associated with a higher risk for liver cancers. These include Hemochromatosis , alpha-1 Antitrypsin deficiency, glycogen storage disease, tyrosinemia, Fanconi anemia , and Wilson disease .

Demographics

Hepatocellular carcinoma is the sixth most common cancer of men and eleventh most common cancer of women worldwide, affecting 250,000 to one million individuals annually. Liver cancer is becoming more common in the United States. It is 10 times more common in Africa and Asia where liver cancer is the most common type of cancer. Liver cancer affects men more often than women and, like most cancers, it is more common in older individuals.

Risk factors for primary liver cancer

The exact cause of primary liver cancer is still unknown. In adults, however, certain factors are known to place some individuals at higher risk of developing liver cancer. These factors include:

• Exposure to hepatitis B (HBV) or hepatitis C (HBC) viruses. In Africa and most of Asia, exposure to hepatitis B is an important factor; in Japan and some Western countries, exposure to hepatitis C is connected with a higher risk of developing liver cancer. In the United States, nearly 25% of patients with liver cancer show evidence of HBV infection. Hepatitis is commonly found among intravenous drug abusers.
• Exposure to substances in the environment that tend to cause cancer (carcinogens). These include a substance produced by a mold that grows on rice and peanuts (aflatoxin); thorium dioxide, which was used at one time as a contrast dye for x rays of the liver; and vinyl chloride, a now strictly regulated chemical used in manufacturing plastics.
• Cirrhosis. Hepatomas appear to be a frequent complication of cirrhosis of the liver. Between 30 and 70% of hepatoma patients also have cirrhosis. It is estimated that a patient with cirrhosis has 40 times the chance of developing a hepatoma than a person with a healthy liver.
• Use of oral estrogens for birth control. This association is based on studies of older, stronger birth control pills that are no longer prescribed. It is not clear if newer, lower dose birth control pills increase risk for liver cancer.
• Use of anabolic steroids (male hormones) for medical reasons or strength enhancement. Cortisone-like steroids do not appear to increase risk for liver cancer.
• Hereditary hemochromatosis. Hemochromatosis is a disorder characterized by abnormally high levels of iron storage in the body. It often develops into cirrhosis.
• Geographic location. Liver cancer is 10 times more common in Asia and Africa than in the United States.
• Male sex. The male/female ratio for hepatoma is 4:1.
• Age over 60 years.

Signs and symptoms

The early symptoms of primary, as well as meta-static, liver cancer are often vague and not unique to liver disorders. The long lag time between the beginning of the tumor's growth and signs of illness is the major reason why the disease has such a high mortality rate. At the time of diagnosis, patients are often tired, with fever, abdominal pain, and loss of appetite. They may look emaciated and generally ill. As the tumor grows bigger, it stretches the membrane surrounding the liver (the capsule), causing pain in the upper abdomen on the right side. The pain may extend into the back and shoulder. Some patients develop a collection of fluid, known as ascites, in the abdominal cavity. Others may show signs of bleeding into the digestive tract. In addition, the tumor may block the ducts of the liver or the gall bladder, leading to jaundice. In patients with jaundice, the whites of the eyes and the skin may turn yellow, and the urine becomes dark-colored.

Diagnosis

Physical examination

If the doctor suspects a diagnosis of liver cancer, he or she will check the patient's history for risk factors and pay close attention to the condition of the patient's abdomen during the physical examination. Masses or lumps in the liver and ascites can often be felt while the patient is lying flat on the examination table. The liver is usually swollen and hard in patients with liver cancer; it may be sore when the doctor presses on it. In some cases, the patient's spleen is also enlarged. The doctor may be able to hear an abnormal sound (bruit) or rubbing noise (friction rub) if he or she uses a stethoscope to listen to the blood vessels that lie near the liver. The noises are caused by the pressure of the tumor on the blood vessels.

Laboratory tests

Blood tests may be used to test liver function or to evaluate risk factors in the patient's history. Between 50% and 75% of primary liver cancer patients have abnormally high blood serum levels of a particular protein (alpha-fetoprotein or AFP). The AFP test, however, cannot be used by itself to confirm a diagnosis of liver cancer, because cirrhosis or chronic hepatitis can also produce high alpha-fetoprotein levels. Tests for alkaline phosphatase, bilirubin, lactic dehydrogenase, and other chemicals indicate that the liver is not functioning normally. About 75% of patients with liver cancer show evidence of hepatitis infection. Again, however, abnormal liver function test results are not specific for liver cancer.

Imaging studies

Imaging studies are useful in locating specific areas of abnormal tissue in the liver. Liver tumors as small as an inch across can now be detected by ultrasound or computed tomography scan (CT scan). Imaging studies, however, cannot tell the difference between a hepatoma and other abnormal masses or lumps of tissue (nodules) in the liver. A sample of liver tissue for biopsy is needed

to make the definitive diagnosis of a primary liver cancer. CT or ultrasound can be used to guide the doctor in selecting the best location for obtaining the biopsy sample. Chest x rays may be used to see whether the liver tumor is primary or has metastasized from a primary tumor in the lungs.

Liver biopsy

Liver biopsy is considered to provide the definite diagnosis of liver cancer. In about 70% of cases, the biopsy is positive for cancer. In most cases, there is little risk to the patient from the biopsy procedure. In about 0.4% of cases, however, the patient develops a fatal hemorrhage from the biopsy because some tumors are supplied with a large number of blood vessels and bleed very easily.

Laparoscopy

The doctor may also perform a laparoscopy to help in the diagnosis of liver cancer. A laparoscope is a small tube-shaped instrument with a light at one end. The doctor makes a small cut in the patient's abdomen and inserts the laparoscope. A small piece of liver tissue is removed and examined under a microscope for the presence of cancer cells.

Treatment and management

Treatment of liver cancer is based on several factors, including the type of cancer (primary or metastatic); stage (early or advanced); the location of other primary cancers or metastases in the patient's body; the patient's age; and other coexisting diseases, including cirrhosis. Treatment options include surgery, radiation, and chemotherapy. At times, two or all three of these may be used together. For many patients, treatment of liver cancer is primarily intended to relieve the pain caused by the cancer but cannot cure it.

Surgery

The goal of surgery is to remove the entire tumor, curing liver cancer. However, few liver cancers in adults can be cured by surgery because they are usually too advanced by the time they are discovered. If the cancer is contained within one lobe of the liver, and if the patient does not have cirrhosis, jaundice, or ascites, surgery is the best treatment option. Patients who can have their entire tumor removed have the best chance for survival.

If the entire visible tumor can be removed, about 25% of patients will be cured. The operation that is performed is called a partial hepatectomy, or partial removal of the liver. The surgeon will remove either an entire lobe of the liver (a lobectomy) or cut out the area around the tumor (a wedge resection).

Doctors may also offer tumor embolization or ablation. Embolization involves killing a tumor by blocking its blood supply. Ablation is a method of destroying a tumor without removing it. One method of ablation, cryosurgery, involves freezing the tumor, thereby destroying it. In another method of ablation, ethanol ablation, doctors kill the tumor by injecting alcohol into it. A new method of ablation using high-energy radio waves is under development.

Chemotherapy

Chemotherapy involves using very strong drugs, taken by mouth or intravenously, to suppress or kill tumor cells. Chemotherapy also damages normal cells, leading to side effects such as hair loss, vomiting, mouth sores, loss of appetite, and fatigue.

Some patients with incurable metastatic cancer of the liver can have their lives prolonged for a few months by chemotherapy. If the tumor cannot be removed by surgery, a tube (catheter) can be placed in the main artery of the liver and an implantable infusion pump can be installed (hepatic artery infusion). The pump allows much higher concentrations of cancer drugs to be carried directly to the tumor.

Hepatocellular carcinoma is resistant to most drugs. Specific drugs such as doxorubicin and cisplatin have been proven effective against this type of cancer. Systemic chemotherapy can also be used to treat liver cancer. Systemic chemotherapy does not, however, significantly lengthen the patient's survival time.

Radiation therapy

Radiation therapy is the use of high-energy rays or x rays to kill cancer cells or to shrink tumors. In liver cancer, however, radiation is only able to give brief relief from some of the symptoms, including pain. Liver cancers are not sensitive to levels of radiation considered safe for surrounding tissues. Radiation therapy has not been shown to prolong the life of a patient with liver cancer.

Liver transplantation

Removal of the entire liver (total hepatectomy) and liver transplantation are used very rarely in treating liver cancer. This is because very few patients are eligible for this procedure, either because the cancer has spread beyond the liver or because there are no suitable donors. Further research in the field of transplant immunology may make liver transplantation a possible treatment method for more patients in the future.

Future treatments

Gene therapy may be a future treatment for liver cancer. Scientists are still investigating the possible use of gene therapy as a treatment for cancer. There is controversy surrounding experimentation with gene therapy on humans. As such, it may be years before science is able to create a clinically available gene therapy treatment.

Prognosis

Liver cancer has a very poor prognosis because it is often not diagnosed until it has metastasized. Fewer than 10% of patients survive three years after the initial diagnosis; the overall five-year survival rate for patients with hepatomas is around 4%. Most patients with primary liver cancer die within several months of diagnosis. Patients with liver cancers that metastasized from cancers in the colon live slightly longer than those whose cancers spread from cancers in the stomach or pancreas.

Prevention

There are no useful strategies at present for preventing metastatic cancers of the liver. Primary liver cancers, however, are 75–80% preventable. Current strategies focus on widespread vaccination for hepatitis B; early treatment of hereditary hemochromatosis; and screening of high-risk patients with alpha-fetoprotein testing and ultrasound examinations.

Lifestyle factors that can be modified in order to prevent liver cancer include avoidance of exposure to toxic chemicals and foods harboring molds that produce aflatoxin. In the United States laws protect workers from exposure to toxic chemicals. Changing grain storage methods in other countries may reduce aflatoxin exposure. Avoidance of alcohol and drug abuse is also very important. Alcohol abuse is responsible for 60–75% of cases of cirrhosis, which is a major risk factor for eventual development of primary liver cancer.

A vaccination for hepatitis B is now available. Widespread immunization prevents infection, reducing a person's risk for liver cancer. Other protective measures against hepatitis include using protection during sex and not sharing needles. Scientists have found that interferon injections may lower the risk for someone with hepatitis C or cirrhosis to develop liver cancer.

Resources

BOOKS

Blumberg, Baruch S. Hepatitis B and the Prevention of Cancer of the Liver. River Edge, NJ: World Scientific Publishing Company, Inc., 2000.

Elmore, Lynne W., and Curtis C. Harris. "Hepatocellular Carcinoma." The Genetic Basis of Human Cancer. Ed. Bert Vogelstein and Kenneth Kinzler, 681–89. New York: McGraw-Hill, 1998.

Shannon, Joyce Brennfleck. Liver Disorders Source Book: Basic Consumer Health Information about the Liver, and How It Works. Detroit: Omnigraphics Inc., 2000.

PERIODICALS

Greenlee, Robert T., et al. "Cancer Statistics, 2001." CA: A Cancer Journal for Clinicians. 51 (January/February 2001): 15–36.

Hussain, S. A., et al. "Hepatocellular carcinoma." Annals of Oncology 12 (February 2001): 161–72.

Ogunbiyi, J. "Hepatocellular carcinoma in the developing world." Seminars in Oncology 28 (April 2001): 179–87.

ORGANIZATIONS

American Cancer Society. 1599 Clifton Rd. NE, Atlanta, GA 30329. (800) 227-2345. <http://www.cancer.org>.

American Liver Foundation. 75 Maiden Lane, Suite 603, New York, NY 10038. (800) 465-4837 or (888) 443-7222. <http://www.liverfoundation.org>.

National Cancer Institute. Office of Communications, 31 Center Dr. MSC 2580, Bldg. 1 Room 10A16, Bethesda, MD 20892-2580. (800) 422-6237. <http://www.nci.nih.gov>.

Rebecca J. Frey, PhD

Judy C. Hawkins, MS