LIVER CANCER – Classification, Risk Factors, Stages, Clinical Manifestation, Diagnostic Evaluation and Management
Liver cancer (hepatocellular carcinoma) is a cancer arising from the liver. It is also known as primary liver cancer or hepatoma. The liver is made up of different cell types (bile ducts, blood vessels, and fat-storing cells). However, liver cells (hepatocytes) make up 80% of the liver tissue. Thus, the majority of primary liver cancers (over 90 to 95%) arises from liver cells and is called hepatocellular cancer or carcinoma.
There are a number of benign liver tumors. Hemangiomas are the most common benign tumor of the liver, and occur when a benign, blood-filled tumor forms within the liver. Other benign tumors include adenomas (benign tumors of the hepatocytes) and focal nodular hyperplasia (a localized growth of several types of liver cells). Although these tumors do not invade surrounding tissues or metastasize, it is often difficult to tell the difference between benign and malignant tumors on radiographic imaging.
In addition to being a common site of metastasis for cancers from other sites in the body, primary liver cancers can arise from within the liver itself. Cancer arising from the hepatocytes is known as hepatocellular carcinoma (HCC). It is the most common type of primary liver cancer and accounts for around 70% of all liver cancers. Cancers that arise from the bile ducts within the liver are known as cholangiocarcinomas and represent 10-20% of all liver cancers. These cancers can arise from the bile ducts within the liver (intrahepatic cholangiocarcinomas) or from in the bile ducts as they lead away from the liver (extrahepatic cholangiocarcinomas). Angiosarcoma and hemangiosarcoma (malignant blood-filled tumors) starts in the blood vessels of the liver and grows very rapidly. About 1% of adult primary liver cancers are angiosarcomas.
Other types of rare cancers can occur within the liver. These include:
- Hepatoblastoma: A rare malignant tumor, primarily developing in children. Most of these tumors form in the right lobe.
- Lymphoma of liver: A rare form of lymphoma that usually have diffuse infiltration to liver. It may also form a liver mass in rare occasions.
Most cases of liver cancer are actually cancers that started in another organ. This is called metastases. Because of its very high blood flow and many biological functions, the liver is one of the most common places for metastases to grow. Tumors that originally arise in the colon, pancreas, stomach, lung or breast can spread to the liver.
RISK FACTORS FOR LIVER CANCER
- Cirrhosis: In general, cirrhosis of any etiology is the major risk factor for hepatocellular carcinoma. About 80% of patients with newly diagnosed hepatocellular carcinoma have preexisting cirrhosis. Major causes of cirrhosis are attributed to alcohol, hepatitis C infection, and hepatitis B infection.
- Alcohol: Cirrhosis caused by chronic alcohol consumption is the most common association of liver cancer. Chronic alcohol use for more than 10 years increases risk of hepatocellular carcinoma 5-fold.
- Hepatitis B virus: Chronic HBV infection is the most common cause of hepatocellular carcinoma worldwide. Chronic infection in the setting of cirrhosis increases the risk of hepatocellular carcinoma 1000-fold. The mechanism by which the hepatitis B virus causes hepatocellular carcinoma is thought to be from a combination of chronic inflammation and integration of the viral genome into the host DNA.
- Hepatitis C virus: HCV is a global pandemic affecting 170 million persons. HCV infection results in a higher rate of chronic infection compared to HBV infection. The lifetime risk of hepatocellular carcinoma in patients with HCV is approximately 5%, appearing 30 years after infection. In hepatitis C virus patients, the risk factors for developing liver cancer include the presence of cirrhosis, older age, male gender, elevated baseline aloha-fetoprotein level (blood tumor marker), alcohol use, and co-infection with hepatitis B virus.
- Hemachromatosis: Patients with hemochromatosis, especially in the presence of cirrhosis are at an increased risk of developing hepatocellular carcinoma. Hepatocellular carcinoma accounts for about 30% of all iron-related deaths in hemochromatosis.
- Aflatoxin: Aflatoxin B1 is the most potent liver cancer-forming chemical known. It is a product of a mold called Aspergillus flavus, which is found in food that has been stored in a hot and humid environment. This mold is found in such foods as peanuts, rice, soybeans, corn, and wheat. It causes DNA damage and mutations of the p53 gene. Humans are exposed to aflatoxin through the ingestion of moldy foods found in susceptible grains.
- Rare Associations: These include primary biliary cirrhosis, androgenic steroids, primary sclerosing cholangitis, 1-antitrypsin deficiency, Thorotrast radioactive contrast, vinyl chloride, arsenic exposure, oral contraceptives, and porphyria cutanea tarda. Obesity and diabetes have been implicated as risk factors for hepatocellular carcinoma, most likely through the development of nonalcoholic steatohepatitis (NASH).
STAGING OF LIVER CANCER
Stage 1: This is the earliest stage of HCC. The tumor has not spread to the blood vessels, lymph nodes, or other parts of the body (T1, N0, M0).
Stage II: The tumor involves nearby blood vessels, but it has not spread to the regional lymph nodes or other parts of the body (T2, N0, M0).
Stage IIIA: The cancer has not spread beyond the liver, but the area of the cancer is larger than stage I or II, (T3a, N0, M0).
Stage IIIB: The cancer involves a major vein around the liver, but it has not spread to nearby lymph nodes or other parts of the body (T3b, N0, M0).
Stage IIIC: Any tumor that has spread to the organs near the liver (except the gall bladder), or if the tumor is present with perforation of the visceral peritoneum. There is no spread to nearby lymph nodes or other parts of the body. (T4, N0, M0).
Stage IVA: Any tumor that has spread to the regional lymph nodes but not to other parts of the body (any T, N1, M0).
Stage IVB: Any tumor that has spread to other parts of the body (any T, any N, M1).
Liver cancer is sometimes called a “silent disease” because in an early stage it often does not cause symptoms. But as the cancer grows, symptoms may include:
- Pain in the right upper abdomen; the pain may extend to the back and shoulder
- Swollen right upper abdomen (bloating)
- Abdominal lump
- Enlarged liver
- Unexplained weight loss
- Loss of appetite and feelings of fullness
- Weakness or feeling very tired or Fatigue
- Yellow skin and eyes, and dark urine from jaundice
- Nausea and Vomiting
- Fluid retention (ascites)
- Liver damage
- Metabolic disturbances
- Hepatic encephalopathy
The diagnostic tests used in the diagnosis of Liver cancer include
- Physical examination: If a person has symptoms of HCC, the doctor will feel the abdomen to check the liver, spleen, and other nearby organs for lumps, swelling, or other changes. The doctor will also look for an abnormal buildup of fluid in the abdomen and for signs of jaundice.
- Blood tests: At the same time as the physical examination, the doctor will most likely do a blood test to look for a substance called alpha-fetoprotein (AFP). AFP is found in elevated levels in the blood of about 50% to 70% of people who have adult primary liver cancer. The doctor will also test the patient’s blood to see if he or she has hepatitis B or C.
- Ultrasound: An ultrasound uses sound waves to create a picture of the internal organs. The sound waves bounce off the liver, other organs, and tumors. Each creates a different appearance on a computer monitor.
- Computed tomography: CT scan creates a 3-dimensional picture of the inside of the body with an x-ray machine. A computer then combines these images into a detailed, cross-sectional view that shows any abnormalities or tumors. Sometimes, a contrast medium is injected into a patient’s vein to provide better detail.
- Magnetic resonance imaging: An MRI uses magnetic fields, not x-rays, to produce detailed images of the body. A contrast medium may be injected into a patient’s vein to create a clearer picture.
- Angiogram: An angiogram is an x-ray picture of the blood vessels. A dye is injected into the bloodstream, so the blood vessels of the liver show up on an x-ray.
- Laparoscopy: A Laparoscopy uses a thin, lighted tube to look at the liver and other internal organs. The tube is inserted through a small incision in the abdomen.
- Biopsy: A biopsy is the removal of a small amount of tissue for examination under a microscope. The biopsy can be taken during a laparoscopy, by fine needle aspiration, or by core biopsy.
- Surgery: Liver cancer surgery can consist of either partial hepatectomy or removal of the whole liver followed by liver transplantation. When a portion of the liver is removes, the surgery is called a hepatectomy. A hepatectomy can be done only if the cancer is limited to one part of the liver, and the liver is otherwise functioning well. Sometimes, a liver transplantation can be done. This procedure is possible only when the cancer is confined to the live, a suitable donor is found, and very specific criteria are fulfilled. After a transplant, the patient will be watched closely for signs that the body might be rejecting the new liver, or that the tumor has recurred. The patient must take medication to prevent the rejection. Liver transplantation is a particularly effective treatment for people with small tumors.
- Radiofrequency Ablation: RFA uses high frequency radio-waves to destroy tumor by local heating. The electrodes are inserted into the liver tumor under ultrasound image guidance using percutaneous, laparoscopic or open surgical approach. The local heat that is generated melts the tissue (coagulative necrosis) that is adjacent to the probe. The probe is left in place for about 10 to 15 minutes. It is suitable for small tumors less than 3 cm.
- Percutaneous Ethanol Injection: Ethanol injections are performed by injecting ethanol (alcohol) directly into tumors using small needles. The high concentration of ethanol used in these injections can result in killing of the tumor.
- Cryosurgery: Cryosurgery is the destruction of abnormal tissue using sub-zero temperatures. The tumor is not removed and the destroyed cancer is left to be reabsorbed by the body. Cryosurgery involves the placement of a stainless steel probe into the center of the tumor. Liquid nitrogen or argon is used to cool probes that are inserted directly into the tumor during an operative procedure. The probes freeze the cancer cells, killing them. This technique has the advantage of treating very little normal tissue, thereby reducing the risk of side effects from the treatment
- Chemotherapy: Use of chemotherapy in liver cancer has been difficult because liver cancers have been found to be relatively resistant to chemotherapy, and because most patients with liver cancer have defects in their overall liver function. Chemotherapy is often processed within the liver, and a decrease in liver function can make the delivery of chemotherapy more difficult
- Hepatic Arterial Infusion: Hepatic arterial infusion uses an anticancer drug injected into a catheter that has been placed in the major artery supplying blood to the liver (hepatic artery). This treatment is a type of chemotherapy, but it does not have as many side effects.
- Transcatheter Arterial Chemoembolization: TACE is usually performed for unresectable tumors or as a temporary treatment while waiting for liver transplant. TACE is done by injecting an antineoplastic drug (cisplatin) mixed with a radioopaque contrast (Lipiodol) and an embolic agent (Gelfoam) into the right or left hepatic artery via the groin artery. The blood flow through the artery is blocked and the blood supply to the tumor is disrupted. TACE is not suitable for big tumors, presence of portal vein thrombus, tumors with portal-systemic shunt and patients with poor liver function
- Radiation Therapy: Another potential method of treating liver cancer is radiation therapy. The radiation comes in the form of high energy x-rays that are delivered to the patient only in the areas at highest risk for cancer. The high energy of x-rays in radiation therapy results in damage to the DNA of cells. Because cancer cells are not as good as normal, healthy cell at repairing DNA damage, radiation results in relatively more damage to the cancer cells than to normal cells. Some centers are now using brachytherapy for HCC, which is a radiation treatment using implant. Internal radiation therapy for HCC involves placing radioactive beads into the artery that supplies the tumor with blood in a manner similar to chemoembolization.
- Immunotherapy Therapy: Biologic therapy is designed to boost the body’s natural defenses to fight the cancer. It uses materials either made by the body or in a laboratory to bolster, target, or restore immune system function
- Targeted Therapy: Targeted therapy is a treatment that targets faulty genes or proteins that contribute to cancer growth and development. Anti-angiogenic drugs are a type of targeted therapy that block the formation of new blood vessels that are needed for a tumor to grow and spread. This is one of the ways sorafenib (Nexavar), a drug that is being studied for HCC, is thought to work. Sorafenib is administered orally.
Most cases of HCC can be avoided by preventing viral hepatitis and cirrhosis. A vaccine can protect healthy people from contracting hepatitis B. There is no vaccine against hepatitis C, which is most often associated with current or previous intravenous drug abuse. Cirrhosis can be avoided by not abusing alcohol and preventing viral hepatitis. Most industrialized countries have regulations to protect people from cancer-causing chemicals. There is increasing evidence that certain medications can control chronic hepatitis B or C infection, and thereby reduce the inflammation they cause in the liver. This may reduce the risk of cancer development, particularly if the medications are taken before cirrhosis develops. It is recommended that information about such treatment come from a hepatologist, which is a doctor who specializes in diseases of the liver.
If you know you have cirrhosis or other risk factors, it is important to discuss with your doctor whether you should be regularly screened for liver cancer. Early detection, before any symptoms have developed, may increase the likelihood of successful treatment.