Liver Cancer

Definition

Liver cancer is a relatively rare form of cancer but has 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 and 4% of newly diagnosed cancers. Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world as of 2004. It is much more common outside the United States, representing 10% to 50% of malignancies in Africa and parts of Asia. Rates of HCC in men are at least two to three times higher than for women. In high-risk areas (East and Southeast Asia, sub-Saharan Africa), men are even more likely to have HCC than women.

According to the American Cancer Society, 18,920 people in the United States will be diagnosed with primary liver cancer in 2004, and 14,270 persons will die from the disease. The incidence of primary liver cancer has been rising in the United States and Canada since the mid-1990s, most likely as a result of the rising rate of hepatitis C infections.

TYPES OF PRIMARY LIVER CANCER. In adults, most primary liver cancers belong to one of two types: hepatomas, or hepatocellular carcinomas (HCC), which start in the liver tissue itself; and cholangiomas, or cholangiocarcinomas, which are cancers that develop in the bile ducts inside the liver. About 80% to 90% of primary liver cancers are hepatomas. In the United States, about five persons in every 200,000 will develop a hepatoma (70% to 75% of cases of primary liver cancers are HCC). In Africa and Asia, over 40 persons in 200,000 will develop this form of cancer (more than 90% of cases of primary liver are HCC). Two rare types of primary liver cancer are mixed-cell tumors and Kupffer cell sarcomas.

One type of primary liver cancer, called a hepatoblastoma, usually occurs in children younger than four years of age and between the ages of 12 and 15. 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, metastatic 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 metastasize (spread) 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.

Causes and symptoms

Risk factors

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:

• Male sex.
• Age over 60 years.
• Ethnicity. Asian Americans with cirrhosis have four times as great a chance of developing liver cancer as Caucasians with cirrhosis, and African Americans have twice the risk of Caucasians. In addition, Asians often develop liver cancer at much younger ages than either African Americans or Caucasians.
• 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 once used as a contrast dye for x rays of the liver; vinyl chloride, used in manufacturing plastics; and cigarette smoking.
• Use of oral estrogens for birth control.
• Hereditary hemochromatosis. This is a disorder characterized by abnormally high levels of iron storage in the body. It often develops into cirrhosis.
• 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.
• Exposure to hepatitis viruses: Hepatitis B (HBV), Hepatitis C (HCV), Hepatitis D (HDV), or Hepatitis G (HGV). It is estimated that 80% of worldwide HCC is associated with chronic HBV infection. 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. The 70% increase in HCC incidence in the United States is thought to be due to increasing rates of HBV and HCV infections due to increased sexual promiscuity and illicit drug needle sharing. The association between HDV and HGV and HCC is unclear at this time.

Symptoms of liver cancer

The early symptoms of primary, as well as metastatic, liver cancer are often vague and not unique to liver disorders. The long period between the beginning of the tumor's growth and the first signs of illness is the major reason why the disease has such a high mortality rate. At the time of diagnosis, patients are often fatigued, with fever, abdominal pain, and loss of appetite. They may look emaciated and generally ill. As the tumor enlarges, 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. A sample of the liver or tissue fluid is removed with a fine needle and is checked under a microscope for the presence of cancer cells. 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. First, the doctor makes a small cut in the patient's abdomen and inserts a small, lighted tube called a laparoscope to view the area. A small piece of liver tissue is removed and examined under a microscope for the presence of cancer cells.

Treatment

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. For many patients, treatment of liver cancer is primarily intended to relieve the pain caused by the cancer but cannot cure it.

Surgery

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 either cirrhosis, jaundice, or ascites, surgery is the best treatment option. Patients who can have their entire tumor removed have the best chance for survival. Unfortunately, only about 5% of patients with metastatic cancer (from primary tumors in the colon or rectum) fall into this group. 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).

A newer technique that is reported to be safe and effective is laparoscopic radiofrequency ablation (RFA). RFA is a technique in which the surgeon places a special needle electrode in the tumor under guidance from MRI or CT scanning. When the electrode has been properly placed, a radiofrequency current is passed through it, heating the tumor and killing the cancer cells. RFA can be used to treat tumors that are too small or too inaccessible for removal by conventional open surgery.

Chemotherapy

Some patients with metastatic cancer of the liver can have their lives prolonged for a few months by chemotherapy, although cure is not possible. 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. The pump allows much higher concentrations of the cancer drug to be carried to the tumor than is possible with chemotherapy carried through the bloodstream. The drug that is used for infusion pump therapy is usually floxuridine (FUDR), given for 14-day periods alternating with 14-day rests. Systemic chemotherapy can also be used to treat liver cancer. The medications usually used are 5-fluorouracil (Adrucil, Efudex) or methotrexate (MTX, Mexate). 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. Its use in liver cancer, however, is only to give short-term relief from some of the symptoms. Liver cancers are not sensitive to radiation, and radiation therapy will not prolong the patient's life.

Liver transplantation

Removal of the entire liver (total hepatectomy) and liver transplantation can be used to treat liver cancer. However, there is a high risk of tumor recurrence and metastases after transplantation. In addition, most patients have cancer that is too far advanced at the time of diagnosis to benefit from liver transplantation.

Other therapies

Other therapeutic approaches include:

• Hepatic artery embolization with chemotherapy (chemoembolization).
• Alcohol ablation via ultrasound-guided percutaneous injection.
• Ultrasound-guided cryoablation.
• Immunotherapy with monoclonal antibodies tagged with cytotoxic agents.
• Gene therapy with retroviral vectors containing genes expressing cytotoxic agents.

Alternative treatment

Many patients find that alternative and complementary therapies help to reduce the stress associated with illness, improve immune function, and boost spirits. While there is no clinical evidence that these therapies specifically combat disease, activities such as biofeedback, relaxation, therapeutic touch, massage therapy and guided imagery have no side effects and have been reported to enhance well-being.

Several other healing therapies are sometimes used as supplemental or replacement cancer treatments, such as antineoplastons, cancell, cartilage (bovine and shark), laetrile, and mistletoe. Many of these therapies have not been the subject of safety and efficacy trials by the National Cancer Institute (NCI). The NCI has conducted trials on cancell, laetrile, and other alternative therapies and found no anticancer activity. These treatments have varying effectiveness and safety considerations. Patients using any alternative remedy should first consult their doctor in order to prevent harmful side effects or interactions with traditional cancer 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 six months of diagnosis, usually from liver failure; fewer than 5% are cured of the disease. 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.

As of 2004, African American and Hispanic patients have much lower 5-year survival rates than Caucasian patients. It is not yet known, however, whether cultural differences as well as biological factors may be partly responsible for the variation in survival rates.

Prevention

There are no useful strategies at present for preventing metastatic cancers of the liver. Primary liver cancers, however, are 75% to 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. Most important, however, is avoidance of alcohol and drug abuse. Alcohol abuse is responsible for 60% to 75% of cases of cirrhosis, which is a major risk factor for eventual development of primary liver cancer. Hepatitis is a widespread disease among persons who abuse intravenous drugs.

KEY TERMS

Aflatoxin— A substance produced by molds that grow on rice and peanuts. Exposure to aflatoxin is thought to explain the high rates of primary liver cancer in Africa and parts of Asia.

Alpha-fetoprotein— A protein in blood serum that is found in abnormally high concentrations in most patients with primary liver cancer.

Cirrhosis— A chronic degenerative disease of the liver, in which normal cells are replaced by fibrous tissue. Cirrhosis is a major risk factor for the later development of liver cancer.

Cryoablation— A technique for removing cancerous tissue by killing it with extreme cold.

Hepatitis— A viral disease characterized by inflammation of the liver cells (hepatocytes). People infected with hepatitis B or hepatitis C virus are at an increased risk for developing liver cancer.

Metastatic cancer— A cancer that has spread to an organ or tissue from a primary cancer located elsewhere in the body.

Radiofrequency ablation— A technique for removing a tumor by heating it with a radiofrequency current passed through a needle electrode.

Resources

BOOKS

Beers, Mark H., MD, and Robert Berkow, MD., editors. "Primary Liver Cancer." In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

PERIODICALS

Berber, E., A. Senagore, F. Remzi, et al. "Laparoscopic Radiofrequency Ablation of Liver Tumors Combined with Colorectal Procedures." Surgical Laparoscopy, Endoscopy and Percutaneous Techniques 14 (August 2004): 186-190.

Cahill, B. A., and D. Braccia. "Current Treatment for Hepatocellular Carcinoma." Clinical Journal of Oncology Nursing 8 (August 2004): 393-399.

Decadt, B., and A. K. Siriwardena. "Radiofrequency Ablation of Liver Tumours: Systematic Review." Lancet Oncology 5 (September 2004): 550-560.

Harrison, L. E., T. Reichman, B. Koneru, et al. "Racial Discrepancies in the Outcome of Patients with Hepatocellular Carcinoma." Archives of Surgery 139 (September 2004): 992-996.

Nguyen, M. H., A. S. Whittemore, R. T. Garcia, et al. "Role of Ethnicity in Risk for Hepatocellular Carcinoma in Patients with Chronic Hepatitis C and Cirrhosis." Clinical Gastroenterology and Hepatology 2 (September 2004): 820-824.

Stuart, Keith E., MD. "Hepatic Carcinoma, Primary." eMedicine July 20, 2004. 〈http://www.emedicine.com/med/topic2664.htm〉.

ORGANIZATIONS

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

American Institute for Cancer Research (AICR). 1759 R St. NW, Washington, DC 20009. (800) 843-8114. 〈http://www.aicr.org〉.

American Liver Foundation.1425 Pompton Ave., Cedar Grove, NJ 07009. (800) 223-0179. 〈http://www.liverfoundation.org〉.

Cancer Care, Inc. 275 Seventh Ave., New York, NY 10001.(800) 813-HOPE. 〈http://www.cancercare.org〉.

Cancer Hope Network. Suite A., Two North Rd., Chester, NJ 07930. (877) HOPENET. 〈http://www.cancerhopenetwork.org〉.

Hospicelink. Hospice Education Institute, 190 Westbrook Rd., Essex, CT, 06426-1510. (800) 331-1620. 〈http://www.hospiceworld.com〉.

National Cancer Institute (National Institutes of Health). 9000 Rockville Pike, Bethesda, MD 20892. (800) 422-6237. 〈http://www.nci.nih.gov〉.

Wellness Community. Suite 412, 35 E. Seventh St., Cincinnati, OH 45202. (888) 793-9355. 〈http://www.wellness-community.org〉.

OTHER

American Cancer Society (ACS). Cancer Facts & Figures 2004. 〈http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf〉.

Liver cancer

Definition

Liver cancer is a relatively rare form of cancer in the United States but has 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

Many types of tumors, benign and malignant, can form in the liver. The types of malignant tumors that can start in the liver include hepatocellular carcinoma, the most common type of liver cancer in adults, and rarer types of liver cancers such as cholangiocarcinoma, angiosarcoma, hemangiosarcoma, and hepatoblastoma, which is a rare childhood cancer.

Metastatic liver cancer

The second major category of liver cancer, metastatic liver cancer, is about 20 times more common in the United States than 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 metastasize (spread) 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.

Demographics

Primary liver cancer, while still a relatively rare disease in the United States, is increasing in incidence possibly due to the increase in the incidence of hepatitis C in the United States. Hepatocellular carcinoma (HCC) is the most common of the hepatobiliary cancers. It is much more common outside the United States, representing 10% to 50% of malignancies in Africa and parts of Asia. Rates of HCC in men are at least two to three times higher than for women. In high-risk areas (East and Southeast Asia, sub-Saharan Africa), men are even more likely to have HCC than women. Worldwide, the mean age at time of diagnosis is between 50 and 60 years. According to the American Cancer Society, 19,160 people in the United States were diagnosed with primary liver cancer in 2007, and 16,780 persons will die from the disease. The incidence of primary liver cancer has been rising in the United States and Canada since the mid-1990s, most likely as a result of the rising rate of hepatitis C infections.

Causes and symptoms

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

• Male sex.
• Age over 60 years.
• Exposure to substances in the environment that tend to cause cancer (carcinogens). An example is aflatoxin, a substance produced by a mold that grows on rice, wheat, soybeans, corn and peanuts. These foods are tested for aflatoxin contamination in the United States and Europe. Other substances include thorium dioxide, which was once used as a contrast dye for x rays of the liver; vinyl chloride, used in manufacturing plastics; and cigarette smoking.
• Birth control. Use of oral estrogens for birth control may slightly increase the risk of developing liver cancer.
• Hereditary hemochromatosis. A disorder characterized by abnormally high levels of iron storage in the body. It often develops into cirrhosis.
• 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.
• Exposure to hepatitis viruses, especially hepatitis B (HBV) and hepatitis C (HCV). It is estimated that 80% of worldwide HCC is associated with chronic HBV infection. In Africa and most of Asia, exposure to hepatitis B is an important factor; in the United States, chronic infection with hepatitis C is correlated with a higher risk of developing primary liver cancer. The hepatitis B and hepatitis C viruses are spread from person to person through unprotected sexual activity, by sharing dirty needles (drug use), during childbirth, and through blood transfusions. In the United States, blood products are tested for hepatitis so there is a rare chance the virus will be transmitted during a blood transfusion in the United States. The period between time of exposure to hepatitis B or C and the development of hepatocellular cancer is thought to be between 30 and 50 years. Individuals infected with the hepatitis A virus are not at increased risk of developing primary liver cancer.
• Obesity. May increase the risk for primary liver cancer.
• Diabetes. Especially in combination with heavy alcohol consumption and a diagnosis of viral hepatitis.

Symptoms of liver cancer

The early symptoms of primary, as well as metastatic, liver cancer are often vague and not unique to liver disorders. The long period between the beginning of the tumor's growth and the first signs of illness is the major reason why the disease has a high mortality rate. At the time of diagnosis, patients are often fatigued, feverish, have abdominal pain , and loss of appetite (anorexia). They often report the sensation of being very full despite having eaten only a small meal. They may look emaciated and generally ill. As the tumor enlarges, 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 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. 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 (CT) scan. Imaging studies 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. A sample of the liver or tissue fluid is removed with a fine needle and is checked under a microscope for the presence of cancer cells. 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 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 perform a laparoscopy to help in the diagnosis of liver cancer. First, the doctor makes a small cut in the patient's abdomen and inserts a small, lighted tube called a laparoscope to view the area. A small piece of liver tissue is removed and examined under a microscope for the presence of cancer cells.

Clinical staging

There are several staging systems for liver cancer. One major system, the American Joint Committee on Cancer (AJCC) Tumor Node Metastasis (TNM) system stages liver cancer using Roman numerals I through IV. In this type of staging system, typically the lower the number the more favorable the prognosis. A higher number usually indicates a more advanced cancer.

• Stage I: Cancer cells are in one area of the liver and may be treated by surgical removal of that area.
• Stage II: The tumor is in multiple areas in the liver and may or may not be treatable with surgical removal of the infected areas.
• Stage III: Cancer cells have infected the liver and surrounding tissues/organs. Surgical removal is usually not possible at this advanced stage. Other forms of treatment are used.
• Stage IV: Cancer cells have spread throughout the liver and the entire body. Surgical treatment often provides no benefit and other forms of treatment are used instead.

Treatment

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. For many patients, treatment of liver cancer is primarily intended to relieve the pain caused by the cancer but cannot cure it.

Surgery

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. Unfortunately, only about 5% of patients with metastatic cancer (from primary tumors in the colon or rectum) fall into this group. If the entire visible tumor can be removed, about 25% of patients are cured. The operation performed is called a partial hepatectomy, or partial removal of the liver. The surgeon removes either an entire lobe of the liver (a lobectomy) or cuts out the area around the tumor (a wedge resection).

A newer technique that is reported to be safe and effective is laparoscopic radiofrequency ablation (RFA). RFA is a technique in which the surgeon places a special needle electrode in the tumor under guidance from MRI or CT scanning. When the electrode is properly placed, a radiofrequency current is passed through it, heating the tumor and killing the cancer cells. RFA can be used to treat tumors that are too small or too inaccessible for removal by conventional open surgery. This technique does not cure the cancer, but it may allow the patient to live longer than without the treatment.

Chemotherapy

Some patients with metastatic cancer of the liver can have their lives prolonged for a few months by chemotherapy , although cure is not possible. If the tumor cannot be removed by surgery, a tube (catheter) is placed in the main artery of the liver and an implantable infusion pump is installed. The pump allows much higher concentrations of the cancer drug to be carried to the tumor than is possible with systemic chemotherapy in which drugs are carried through the bloodstream. Systemic chemotherapy does not 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. Its use in liver cancer is only to give short-term relief from some of the symptoms. Liver cancers are not sensitive to radiation, and radiation therapy will not prolong the patient's life.

Liver transplantation

Removal of the entire liver (total hepatectomy) and liver transplantation can be used to treat liver cancer. Transplantation may be recommended if cirrhosis is present or if there is a very large tumor. Liver transplantation may be an option for a very small number of patients with early-onset liver cancers. There is a high risk of tumor recurrence and metastases after transplantation. In addition, most patients have cancer that is too advanced at the time of diagnosis to benefit from liver transplantation.

Other therapies

Other therapeutic approaches include:

• Hepatic artery embolization with chemotherapy (chemoembolization). Chemotherapy drugs are injected into the liver and the artery supplying blood to the tumor is blocked in order to kill cancer cells.
• Alcohol ablation via ultrasound-guided percutaneous injection. Injection of ethanol directly into affected areas of the liver using radiologic imaging for guidance.
• Ultrasound-guided cryoablation. Use of liquid nitrogen to freeze and kill tumor cells.

Clinical trials

As of 2008, there are over 100 clinical trials in progress related to adult primary liver cancer.

Alternative and complementary therapies

Many patients use alternative and complementary therapies to help reduce stress associated with illness, improve immune function, and boost spirits. While there is no clinical evidence that these therapies specifically combat disease, such activities as biofeedback , relaxation , therapeutic touch, massage therapy and guided imagery have no side effects and have been reported to enhance well-being.

Several other healing therapies are sometimes used as supplemental or replacement cancer treatments, such as antineoplastons, cancell, cartilage (bovine and shark), laetrile, and mistletoe. The safety and efficacy of many of these have not undergone trials by the National Cancer Institute (NCI). The NCI has conducted trials on cancell, laetrile, and some other alternative therapies and found no anticancer activity. These treatments have varying effectiveness and safety considerations. (Laetrile, for example, has caused deaths and is not available in the United States.) Patients using any alternative remedy should first consult their treatment team in order to prevent harmful side effects or interactions with traditional cancer treatment.

KEY TERMS

Aflatoxin —A substance produced by molds that grow on rice and peanuts. Exposure to aflatoxin is thought to explain the high rates of primary liver cancer in Africa and parts of Asia.

Alpha-fetoprotein —A protein in blood serum that is found in abnormally high concentrations in most patients with primary liver cancer.

Cryoablation —A technique for removing cancerous tissue by killing it with extreme cold.

Hepatitis —A viral disease characterized by inflammation of the liver cells (hepatocytes). People infected with hepatitis B or hepatitis C virus are at an increased risk for developing liver cancer.

Metastatic cancer —A cancer that has spread to an organ or tissue from a primary cancer located elsewhere in the body.

Radiofrequency ablation —A technique for removing a tumor by heating it with a radiofrequency current passed through a needle electrode.

Prognosis

Prognosis is dependent upon the extent of the cancer at the time of diagnosis. For example, patients diagnosed with localized hepatocellular cancer who are able to be treated with surgery had a median survival that approached three years in 2007. Patients diagnosed with advanced liver cancer the median survival time is approximately two to four months.

QUESTIONS TO ASK YOUR DOCTOR

• What type of liver cancer do I have?
• What is the stage of the disease?
• What are the treatment choices? Which do you recommend? Why?
• What are the risks and possible side effects of each treatment?
• What are the success rates for the treatment choices?
• What new treatments are being studied in clinical trials?
• How long will treatment last?
• Will I have to stay in the hospital?
• Will treatment affect my normal activities? If so, for how long?
• What is the treatment likely to cost?

The overall five-year survival rate for primary liver cancer is less than 10%.

Prevention

There are no known useful strategies for preventing metastatic cancers of the liver. However, primary liver cancers are 75% to 80% preventable. Current strategies focus on widespread vaccination for hepatitis B, early treatment of hereditary hemochromatosis (a metabolic disorder), 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. Most important is avoidance of alcohol and drug abuse. Alcohol abuse is responsible for 60% to 75% of cases of cirrhosis, which is a major risk factor for development of primary liver cancer. Hepatitis is a widespread disease among persons who abuse intravenous drugs.

Caregiver concerns

Side effects of treatment, nutrition , emotional well-being, and other issues are all parts of coping with cancer. There are many possible side effects of cancer treatment including:

• constipation
• constipation
• delirium
• fatigue
• fever, chills, sweats
• nausea and vomiting
• mouth sores, dry mouth, bleeding gums
• pruritus (itching)
• sexual dysfunction
• sleep disorders

Anxiety, depression , feelings of loss, post-traumatic stress disorder, sexual dysfunction , and substance abuse are all possible emotional side-effects. Patients should seek out a support network to help them through treatment. Loss of appetite before, during, and after a treatment can also be of concern. Other complications of coping with cancer treatment include fever and pain.

Resources

BOOKS

Beers, Mark H., MD, and Robert Berkow, MD, editors. “Primary Liver Cancer.

” Section 4, Chapter 47. In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2002.

PERIODICALS

Berber, E., A. Senagore, F. Remzi, et al. “Laparoscopic Radiofrequency Ablation of Liver Tumors Combined with Colorectal Procedures.” Surgical Laparoscopy, Endoscopy and Percutaneous Techniques 14 (August 2004): 186–90.

Cahill, B. A., and D. Braccia. “Current Treatment for Hepatocellular Carcinoma.” Clinical Journal of Oncology Nursing 8 (August 2004): 393–9.

Decadt, B., and A. K. Siriwardena. “Radiofrequency Ablation of Liver Tumours: Systematic Review.” Lancet Oncology 5 (September 2004): 550–60.

Harrison, L. E., T. Reichman, B. Koneru, et al. “Racial Discrepancies in the Outcome of Patients with Hepatocellular Carcinoma.” Archives of Surgery 139 (September 2004): 992–96.

Nguyen, M. H., A. S. Whittemore, R. T. Garcia, et al. “Role of Ethnicity in Risk for Hepatocellular Carcinoma in Patients with Chronic Hepatitis C and Cirrhosis.” Clinical Gastroenterology and Hepatology 2 (September 2004): 820–24.

ORGANIZATIONS

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

American Institute for Cancer Research (AICR). 1759 R St. NW, Washington, DC 20009. (800) 843-8114. http://www.aicr.org.

American Liver Foundation. 908 Pompton Ave., Cedar Grove, NJ 07009. (800) 223-0179.

Cancer Care, Inc. 275 Seventh Ave., New York, NY 10001. (800) 813-HOPE. http://www.cancercare.org.

Cancer Hope Network. Two North Rd., Suite A., Chester, NJ 07930. (877) HOPENET. http://www.cancerhope-network.org.

Hospicelink. Hospice Education Institute. 190 Westbrook Rd., Essex, CT, 06426-1510. (800) 331-1620. http://www.hospiceworld.com.

National Cancer Institute (National Institutes of Health). 9000 Rockville Pike, Bethesda, MD 20892. (800) 422-6237. http://www.nci.nih.gov.

The Wellness Community. 35 E. Seventh St., Suite 412, Cincinnati, OH 45202. (888) 793-9355. http://www.wellness-community.org.

OTHER

Adult Primary Liver Cancer Treatment (PDQ). National Cancer Institute (NCI). March 3, 2008 [cited March 22, 2008]. http://www.cancer.gov/cancertopics/pdq/treatment/adult-primary-liver/HealthProfessional

Overview: Liver Cancer. American Cancer Society (ACS).

May 14, 2007 [cited March 22, 2008]. http://www.cancer.org/docroot/CRI/CRI_2_1x.asp?rnav=criov&dt=25

Practice Guidelines in Oncology—v.2.2008 Hepatobiliary Cancers. National Comprehensive Cancer Network (NCCN). http://www.nccn.org.

Stuart, Keith E., MD. “Hepatic Carcinoma, Primary.” eMedicine June 5, 2006 [cited March 22, 2008]. http://www.emedicine.com/med/topic2664.htm

Rebecca J. Frey Ph.D.

Laura Ruth Ph.D.

Melinda Oberleitner R.N., D.N.S.

Liver cancer

Definition

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 and demographics

Primary liver cancer

Primary liver cancer is a relatively rare disease in the United States, representing about 2% of all malignancies and 4% of newly diagnosed cancers. Hepatocellular carcinoma (HCC) is one of the top eight most common cancers in the world. It is, however, much more common outside the United States, representing 10% to 50% of malignancies in Africa and parts of Asia. Rates of HCC in men are at least two to three times higher than for women. In high-risk areas (East and Southeast Asia, sub-Saharan Africa), men are even more likely to have HCC than women.

TYPES OF PRIMARY LIVER CANCER.

In adults, most primary liver cancers belong to one of two types: hepatomas, or hepatocellular carcinomas (HCC), which start in the liver tissue itself; and cholangiomas, or cholangiocarcinomas, which are cancers that develop in the bile ducts inside the liver. About 80% to 90% of primary liver cancers are hepatomas. In the United States, about five persons in every 200, 000 will develop a hepatoma (70% to 75% of cases of primary liver cancers are HCC). In Africa and Asia, over 40 persons in 200, 000 will develop this form of cancer (more than 90% of cases of primary liver are HCC). Two rare types of primary liver cancer are mixed-cell tumors and Kupffer cell sarcomas .

One type of primary liver cancer, called a hepatoblastoma, usually occurs in children younger than four years of age and between the ages of 12 and 15. 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, metastatic liver cancer, is about 20 times more common in the United States than 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 metastasize (spread) 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.

Causes and symptoms

Risk factors

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:

• Male sex.
• Age over 60 years.
• 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 once used as a contrast dye for x rays of the liver; vinyl chloride, used in manufacturing plastics; and cigarette smoking.
• Use of oral estrogens for birth control.
• Hereditary hemochromatosis. This is a disorder characterized by abnormally high levels of iron storage in the body. It often develops into cirrhosis.
• 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.
• Exposure to hepatitis viruses: Hepatitis B (HBV), Hepatitis C (HCV), Hepatitis D (HDV), or Hepatitis G (HGV). It is estimated that 80% of worldwide HCC is associated with chronic HBV infection. 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. The increase in HCC incidence in the United States is thought to be due to increasing rates of HBV and HCV infections due to increased sexual promiscuity and illicit drug needle sharing. The association between HDV and HGV and HCC is unclear at this time.

Symptoms of liver cancer

The early symptoms of primary, as well as metastatic, liver cancer are often vague and not unique to liver disorders. The long period between the beginning of the tumor's growth and the first signs of illness is the major reason why the disease has a high mortality rate. At the time of diagnosis, patients are often fatigued, with fever , abdominal pain, and loss of appetite (anorexia ). They may look emaciated and generally ill. As the tumor enlarges, 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. A sample of the liver or tissue fluid is removed with a fine needle and is checked under a microscope for the presence of cancer cells. 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. First, the doctor makes a small cut in the patient's abdomen and inserts a small, lighted tube called a laparoscope to view the area. A small piece of liver tissue is removed and examined under a microscope for the presence of cancer cells.

Clinical staging

Currently, the pathogenesis of HCC is not well understood. It is not clear how the different risk factors for HCC affect each other. In addition, the environmental factors vary from region to region.

Treatment

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. For many patients, treatment of liver cancer is primarily intended to relieve the pain caused by the cancer but cannot cure it.

Surgery

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 either cirrhosis, jaundice, or ascites, surgery is the best treatment option. Patients who can have their entire tumor removed have the best chance for survival. Unfortunately, only about 5% of patients with metastatic cancer (from primary tumors in the colon or rectum) fall into this group. 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).

Chemotherapy

Some patients with metastatic cancer of the liver can have their lives prolonged for a few months by chemotherapy , although cure is not possible. 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. The pump allows much higher concentrations of the cancer drug to be carried to the tumor than is possible with chemotherapy carried through the bloodstream. The drug that is used for infusion pump therapy is usually floxuridine (FUDR), given for 14-day periods alternating with 14-day rests. Systemic chemotherapy can also be used to treat liver cancer. The medications usually used are 5-fluorouracil (Adrucil, Efudex) or methotrexate (MTX, Mexate). 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. Its use inliver cancer, however, is only to give short-term relief from some of the symptoms. Liver cancers are not sensitive to radiation, and radiation therapy will not prolong the patient's life.

Liver transplantation

Removal of the entire liver (total hepatectomy) and liver transplantation can be used to treat liver cancer. However, there is a high risk of tumor recurrence and metastases after transplantation.

Other Therapies

Other therapeutic approaches include:

• Hepatic artery embolization with chemotherapy (chemoembolization).
• Alcohol ablation via ultrasound-guided percutaneous injection.
• Ultrasound-guided cryoablation.
• Immunotherapy with monoclonal antibodies tagged with cytotoxic agents.
• Gene therapy with retroviral vectors containing genes expressing cytotoxic agents.

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.

Alternative and complementary therapies

Many patients find that alternative and complementary therapies help to reduce the stress associated with illness, improve immune function, and boost spirits. While there is no clinical evidence that these therapies specifically combat disease, activities such as biofeedback, relaxation, therapeutic touch, massage therapy and guided imagery have no side effects and have been reported to enhance well-being.

Several other healing therapies are sometimes used as supplemental or replacement cancer treatments, such as antineoplastons, cancell, cartilage (bovine and shark), laetrile, and mistletoe. Many of these therapies have not been the subject of safety and efficacy trials by the National Cancer Institute (NCI). The NCI has conducted trials on cancell, laetrile, and some other alternative therapies and found no anticancer activity. These treatments have varying effectiveness and safety considerations. (Laetrile, for example, has caused deaths and is not available in the U.S.) Patients using any alternative remedy should first consult their doctor in order to prevent harmful side effects or interactions with traditional cancer treatment.

Coping with cancer treatment

Side effects of treatment, nutrition, emotional well-being, and other issues are all parts of coping with cancer. There are many possible side effects for a cancer treatment that include:

• constipation
• delirium
• fatigue
• fever, chills, sweats
• nausea and vomiting
• mouth sores, dry mouth, bleeding gums
• pruritus (itching)
• affected sexuality
• sleep disorders

Anxiety, depression , feelings of loss, post-traumatic stress disorder, affected sexuality, and substance abuse are all possible emotional side-effects. Patients should seek out a support network to help them through treatment. Loss of appetite before, during, and after a treatment can also be of concern. Other complications of coping with cancer treatment include fever and pain.

Clinical trials

There are many clinical trials in place studying new types of radiation therapy and chemotherapy, new drugs and drug combinations, biological therapies, ways of combining various types of treatment for liver cancer, side effect reduction, and quality of life. Information on clinical trials can be acquired from the National Cancer Institute at <http://www.nci.nih.gov> or (800) 4-CANCER.

Prevention

There are no useful strategies at present for preventing metastatic cancers of the liver. Primary liver cancers, however, are 75% to 80% preventable. Current strategies focus on widespread vaccination for hepatitis B, early treatment of hereditary hemochromatosis (a metabolic disorder), 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. Most important, however, is avoidance of alcohol and drug abuse. Alcohol abuse is responsible for 60% to 75% of cases of cirrhosis, which is a major risk factor for eventual development of primary liver cancer. Hepatitis is a widespread disease among persons who abuse intravenous drugs.

See Also CT-guided biopsy; Hepatic arterial infusion; Immunologic therapy; Alcohol consumption

Resources

BOOKS

Berkow, Robert, et al., eds. "Hepatic and Biliary Disorders:Neoplasms of the Liver." In The Merck Manual of Diag nosis and Therapy. Rahway, NJ: Merck Research Laboratories, 1997.

Dollinger, Malin. Everyone's Guide to Cancer Therapy. Kansas City: Somerville House Books Limited, 1994.

Friedman, Lawrence S. "Liver, Biliary Tract, & Pancreas." InCurrent Medical Diagnosis & Treatment 1998. Stamford, CT: Appleton & Lange, 1997.

Isselbacher, K.J., and J.L. Dienstag. "Tumors of the Liver and Biliary Tract." In Harrison's Principles of Internal Medi cine. Fauci, Anthony S., et al., eds. New York:McGraw-Hill, 1998.

Loeb, Stanley, et al., eds. "Liver Cancer." In Professional Guide to Diseases. Springhouse, PA: Springhouse Corporation, 1991.

Rudolph, Rebecca E., and Kris V. Kowdley. "Cirrhosis of the Liver." In Current Diagnosis 9. Conn, Rex B., et al., eds. Philadelphia: W. B. Saunders Company, 1997.

Way, Lawrence W. "Liver." In Current Surgical Diagnosis & Treatment. Stamford, CT: Appleton & Lange, 1994.

PERIODICALS

El-Serag, H.B. "Epidemiology of Hepatocellular Carcinoma"Clinics in Liver Disease (February 2001): 87-107.

Macdonald, G.A. "Pathogenesis of Hepatocellular Carcinoma"Clinical Liver Disease (February 2001): 69-85.

Yu, M.C., et al. "Epidemiology of Hepatocellular Carcinoma"Canadian Journal of Gastroenterology (September 2000):703-9.

ORGANIZATIONS

American Cancer Society. 1599 Clifton Rd. NE, Atlanta, GA30329. (800) 227-2345. <http://www.cancer.org>.

American Institute for Cancer Research (AICR). 1759 R St.NW, Washington, DC 20009. (800) 843-8114. <http://www.aicr.org>.

American Liver Foundation. 908 Pompton Ave., Cedar Grove, NJ 07009. (800) 223-0179.

Cancer Care, Inc. 275 Seventh Ave., New York, NY10001.(800) 813-HOPE. <http://www.cancercare.org>.

Cancer Hope Network. Suite A., Two North Rd., Chester, NJ 07930.(877) HOPENET. <http://www.cancerhopenetwork.org>.

Hospicelink. Hospice Education Institute, 190 Westbrook Rd., Essex, CT, 06426-1510. (800) 331-1620. <http://www.hospiceworld.com>.

National Cancer Institute (National Institutes of Health). 9000Rockville Pike, Bethesda, MD 20892. (800) 422-6237.<http://www.nci.nih.gov>.

The Wellness Community. Suite 412, 35 E. Seventh St., Cincinnati, OH 45202. (888) 793-9355. <http://www.wellness-community.org>.

Rebecca J. Frey, Ph.D

Laura Ruth, Ph.D.

QUESTIONS TO ASK THE DOCTOR

• What type of liver cancer do I have?
• What is the stage of the disease?
• What are the treatment choices? Which do you recommend? Why?
• What are the risks and possible side effects of each treatment?
• What are the chances that the treatment will be successful?
• What new treatments are being studied in clinical trials?
• How long will treatment last?
• Will I have to stay in the hospital?
• Will treatment affect my normal activities? If so, for how long?
• What is the treatment likely to cost?

KEY TERMS

Aflatoxin

—A substance produced by molds that grow on rice and peanuts. Exposure to aflatoxin is thought to explain the high rates of primary liver cancer in Africa and parts of Asia.

Alpha-fetoprotein

—A protein in blood serum that is found in abnormally high concentrations in most patients with primary liver cancer.

Cirrhosis

—A chronic degenerative disease of the liver, in which normal cells are replaced by fibrous tissue. Cirrhosis is a major risk factor for the later development of liver cancer.

Hepatitis

—A viral disease characterized by inflammation of the liver cells (hepatocytes). People infected with hepatitis B or hepatitis C virus are at an increased risk for developing liver cancer.

Metastatic cancer

—A cancer that has spread to an organ or tissue from a primary cancer located elsewhere in the body.

Liver Cancer

Definition

Liver cancer is a form of cancer with a high mortality rate. Liver cancers are classified into two types. They are either primary, when the cancer starts in the liver itself; or metastatic, when the cancer has metastasized (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 much more common in other parts of the world, representing from 10-50% of malignancies in Africa and parts of Asia. According to the American Cancer Society, in the United States during 1998, more than 14,000 new cases of primary liver cancer were diagnosed, and approximately 13,000 deaths were attributable to it.

TYPES OF PRIMARY LIVER CANCER. In adults, most primary liver cancers belong to one of two types: hepatomas, also known as hepatocellular carcinomas, which start in the liver tissue itself; and cholangiocarcinomas, which are cancers that develop in the bile ducts inside the liver. About 90% of primary liver cancers are hepatomas. In the United States, about one person in every 40,000 will develop a hepatoma; in Africa and Asia, over 8 persons in 40,000 will develop this form of cancer. Two rare types of primary liver cancer are mixed-cell tumors and Kupffer cell sarcomas.

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. When the tumor is detected early, the survival rate is over 90%.

Metastatic liver cancer

The second major category of liver cancer, metastatic 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 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. Second only to cirrhosis, metastatic liver cancer is the most common cause of fatal liver disease.

Causes and symptoms

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:

• Gender. The male/female ratio for hepatoma is 4:1.
• Age over 60 years.
• Environmental exposure to carcinogens (cancer causing substances). Examples of environmental carcinogens are aflatoxin, substance produced by a mold that grows on rice and peanuts; thorium dioxide, used at one time as a contrast dye for x rays of the liver; and vinyl chloride, used in manufacturing plastics.
• Use of oral estrogens for contraception (birth control).
• Hereditary hemochromatosis. Hemochromatosis is a disorder characterized by abnormally high levels of iron storage in the body. It often progresses to cirrhosis.
• Cirrhosis. Hepatomas appear to be a frequent complication of cirrhosis of the liver. Between 30-70% 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. Cirrhosis usually results from alcohol abuse or chronic viral hepatitis.
• 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 associated with a higher risk of developing liver cancer. In the United States, nearly 25% of patients with liver cancer have evidence of HBV infection. Hepatitis B and C are commonly found among intravenous drug abusers.

Symptoms of liver cancer

The early symptoms of primary, as well as metastatic, liver cancer are often vague and not specific to liver disorders. The long delay between the beginning of the tumor's growth and signs of illness is the major reason 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 ascites (a collection of fluid) in the abdominal cavity. Others may have gastrointestinal bleeding. 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

When a diagnosis of primary liver cancer is suspected, the physician will scrutinize the patient's history for risk factors and pay close attention to the condition of the 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 physician presses on it. In some cases, the patient's spleen is also enlarged. The physician may be able to hear a bruit (an abnormal sound) or friction rub when a stethoscope is used to listen to the blood vessels that lie near the liver. These abnormal sounds are caused by the pressure of the tumor on the blood vessels.

Laboratory tests

Blood tests, performed by a laboratory technologist or technician, may be used to evaluate liver function or to confirm risk factors, such as hepatitis B or C infection. About 75% of patients with liver cancer show evidence of hepatitis infection. Between 50-75% of primary liver cancer patients have abnormally high blood serum levels of alpha-fetoprotein (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. Though useful, abnormal liver function test results can not alone establish the diagnosis of liver cancer.

Imaging studies

Imaging studies are used to locate specific areas of abnormal tissue in the liver. Liver tumors as small as an inch across can 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 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 may be used to guide the physician 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. Imaging studies, including chest x rays, are usually performed by a radiology technician.

Liver biopsy

Liver biopsy provides the definite diagnosis of liver cancer. A sample of the liver or tissue fluid is removed with a fine needle and is examined by a pathologist, under a microscope, for the presence of cancer cells. 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 physician also may perform a laparoscopy to assist in the diagnosis of liver cancer. A laparoscope is a small tube-shaped instrument with a light at one end that is inserted into the patient's abdomen. A small piece of liver tissue is removed and sent for biopsy (microscopic examination for the presence of cancer cells).

Treatment

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; the patient's age; and other coexisting diseases, including cirrhosis. For many patients, treatment of liver cancer is primarily intended to relieve the pain caused by the cancer; it aims to relieve symptoms but not to cure the disease.

Surgery

Few liver cancers in adults can be cured surgically 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, then surgery is the best treatment option. Patients who can have their entire tumors removed have the best chances for survival. Unfortunately, only about 5% of patients with metastatic cancer (from primary tumors in the colon or rectum) fall into this group. If the entire visible tumor can be removed, about 25% of patients will be cured. The surgical procedure 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).

Chemotherapy

Some patients with metastatic cancer of the liver may have their lives prolonged for a few months by chemotherapy, although cure is not possible. If the tumor cannot be removed by surgery, then a catheter may be placed in the main artery (hepatic artery) of the liver and an implantable infusion pump can be installed. The pump allows much higher concentrations of the anticancer drug to be carried to the tumor than is possible with chemotherapy carried through the bloodstream. The drug used for infusion pump therapy is usually floxuridine (FUDR), given for 14-day periods alternating with 14-day rests.

Systemic chemotherapy, given through a peripheral vein, can also be used to treat liver cancer. The drugs usually used are 5-fluorouracil (Adrucil, Efudex) or methotrexate (MTX, Mexate). Systemic chemotherapy does not, however, significantly increase survival time.

Radiation therapy

Radiation therapy may be used to relieve some symptoms of the disease. In general, radiation therapy will not prolong survival. Radioimmunotherapy is an experimental form of radiation therapy used to treat some types of liver cancer. A radioactive isotope is given intravenously and concentrates in the liver, where it radiates the tumor internally.

Liver transplantation

Since 1998, removal of the entire liver (total hepatectomy) and liver transplantation have very rarely been used to treat 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 viable treatment modality.

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.

Health care team roles

Like other cancer patients, patients with liver cancer are usually cared for by a multidisciplinary team of health professionals. The patient's family physician or primary care physician collaborates with other physician specialists, such as surgeons and oncologists. Radiologic technicians perform x ray, CT and MRI scans and nurses and laboratory technicians may obtain samples of blood, urine and other laboratory tests. Nurses also perform patient and family education.

Before and after any surgical procedures, including biopsies, nurses explain the procedures and help to prepare patients and families. Patients may also benefit from counseling from social workers, other mental health professionals or pastoral counselors.

Prevention

Presently, there are no useful strategies 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 alphafetoprotein testing and ultrasound examinations.

Lifestyle factors that may be modified in order to prevent liver cancer include avoidance of exposure to environmental carcinogens, toxic chemicals, and foods harboring molds that produce aflatoxin. Most important, however, is avoidance of alcohol and drug abuse. Alcohol abuse is responsible for 60-75% of cases of cirrhosis, which is a major risk factor for eventual development of primary liver cancer. Hepatitis is a widespread disease among persons who abuse intravenous drugs.

KEY TERMS

Aflatoxin— A substance produced by molds that grow on rice and peanuts. Exposure to aflatoxin is thought to explain the high rates of primary liver cancer in Africa and parts of Asia.

Alpha-fetoprotein— A protein in blood serum that is found in abnormally high concentrations in most patients with primary liver cancer.

Cirrhosis— A chronic degenerative disease of the liver, in which normal cells are replaced by fibrous tissue. Cirrhosis is a major risk factor for the later development of liver cancer.

Hepatitis— A viral disease characterized by inflammation of the liver cells (hepatocytes). People infected with hepatitis B or hepatitis C virus are at an increased risk for developing liver cancer.

Resources

BOOKS

Friedman, Lawrence S. "Liver, Biliary Tract, & Pancreas." In Current Medical Diagnosis & Treatment 1998, edited by Lawrence M. Tierney, Jr., et al. Stamford, CT: Appleton & Lange, 1997.

Murphy, Gerald P. et al. American Cancer Society Textbook of Clinical Oncology Second Edition Atlanta, GA: The American Cancer Society, Inc. 1995.

Rudolph, Rebecca E., and Kris V. Kowdley. "Cirrhosis of the Liver." In Current Diagnosis 9, edited by Rex B. Conn, et al. Philadelphia: W. B. Saunders Company, 1997.

Way, Lawrence W. "Liver." In Current Surgical Diagnosis & Treatment, edited by Lawrence W. Way. Stamford, CT: Appleton & Lange, 1994.

ORGANIZATIONS

American Cancer Society. 1599 Clifton Road, N.E., Atlanta, GA 30329. (800)227-2345.

American Liver Foundation. 1425 Pompton Avenue, Cedar Grove, NJ 07009. (800)465-4837.

Cancer Research Institute. 681 Fifth Avenue, New York, NY 10022. (800)992-2623.

National Cancer Institute (National Institutes of Health). 9000 Rockville Pike, Bethesda, MD 20892. (800) 422-6237.

hepatoblastoma (hep-ă-toh-blas-toh-mă) n. a malignant tumour of the liver occurring in children, made up of embryonic liver cells.