Zaporizhzhya State Medical University Chair of oncology

Anatoliy I. Shevchenko Alexandr M. Sidorenko Alexey P. Kolesnik

LIVER CANCER
(Lection for student of medical university)

Zaporizhzhya, 2008

Cancerous (malignant) tumours of the liver can be primary cancer cancer starting in the liver itself or secondary or metastatic cancer cancer which started in another part of the body and has spread to the liver. This data is about primary cancer of the liver.

The liver Primary liver cancer Causes of primary liver cancer Signs and symptoms How it is diagnosed Staging Treatment Follow-up Clinical trials Your feelings References

The liver The liver is the largest organ in the body, and the main heat-producing organ. It is surrounded by a fibrous capsule and is divided into sections called lobes. It is in the upper part of the abdomen on the right-hand side of the body and is surrounded and protected from injury by the lower ribs. The liver is an extremely important organ that has many functions. This includes producing proteins that circulate in the blood. Some of these help the blood to clot and prevent excessive bleeding, while others are essential for maintaining the balance of fluid in the body. The liver also destroys harmful substances such as alcohol and gets rid of waste products. It does this by breaking down substances not used by the body so that they can be passed out in the urine or stools (bowel motions).

Diagram showing the position of the liver The liver is also responsible for breaking down food containing carbohydrates (sugars) and fats, so that they can be used by the body for energy. It stores substances such as glucose and vitamins so that they can be used by the

body when needed. The liver also produces bile, a substance which breaks down the fats in food so that they can be absorbed from the bowel (intestine). The liver is connected to the first part of the small bowel (duodenum) by a tube called the bile duct. This duct takes the bile produced by the liver to the intestine. The liver has an amazing ability to repair itself. It can function normally even if only a small part of it is in working order. Primary liver cancer Primary liver cancer is quite rare in the UK and the rest of the Western world, but the number of people developing it is increasing. Approximately 2500 people in the UK are diagnosed with this type of cancer each year. In other parts of the world, such as tropical Africa and some parts of Asia, it is one of the most common cancers. It is twice as common in men as in women. There are two different types of primary liver cancer: Hepatoma or hepatocellular carcinoma (HCC) arises from the main cells of the liver (the hepatocytes). This type is usually confined to the liver, although occasionally it spreads to other organs. It is more common in men and occurs mostly in people with a liver disease called cirrhosis. There is also a rarer sub-type of hepatoma called fibrolamellar hepatoma, which may occur in younger people and is not related to previous liver disease. Cholangiocarcinoma or bile duct cancer is so called because it starts in the cells lining the bile ducts. Cholangiocarcinoma is more common in women. Some primary tumours in the liver are non-cancerous (benign) and do not spread to other parts of the body. They are usually small and may cause no symptoms. They are often discovered by chance during operations or investigations for other conditions. Unless they are causing symptoms they do not usually need to be removed. In the U.S. the highest frequency of liver cancer occurs in immigrants from Asian countries, where liver cancer is common. The frequency of liver cancer among Caucasians is the lowest, whereas among African-Americans and Hispanics, it is intermediate. The frequency of liver cancer is high among Asians because liver cancer is closely linked to chronic hepatitis B infection. This is especially so in individuals who have been infected with chronic hepatitis B for most of their lives. The initial presentation (symptoms) of liver cancer in patients in areas of high liver cancer frequency is quite different from that seen in low frequency areas. Patients from high frequency areas usually start developing liver cancer in their 40s, and the cancer is usually more aggressive. That is, the liver cancer presents with severe symptoms and is inoperable (too advanced for surgery) at the time of diagnosis. Also, in these areas, the frequency of liver cancer is three to four times higher in men than in women, and most of these patients are infected with chronic hepatitis B. In contrast, liver cancer in lower risk areas occurs in patients in their 50s and 60s and the predominance of men is less striking. Causes of primary liver cancer

In the Western world, most people who develop hepatoma usually also have a condition called cirrhosis of the liver. This is a fine scarring throughout the liver which is due to a variety of causes including infection and heavy alcohol drinking over a long period of time. However, only a small proportion of people who have cirrhosis of the liver develop primary liver cancer. Infection with either the hepatitis B or hepatitis C virus can lead to liver cancer and can also be the cause of cirrhosis, which increases the risk of developing hepatoma. People who have a rare condition called haemochromatosis, which causes excess deposits of iron in the body, have a higher chance of developing hepatoma. In Africa and Asia a poison called aflatoxin, found in mouldy peanuts and grain, is a major cause of hepatoma. Bile duct cancers (cholangiocarcinomas) are less common than hepatomas. The cause of most bile duct cancers is unknown, but they are slightly more likely to occur in people with conditions which cause inflammation of the bowel, such as ulcerative colitis. In Africa and Asia, infection with a parasite known as the liver fluke is thought to cause many cholangiocarcinomas. In the Western world, cancer of the liver usually occurs in middle-aged and elderly people, although rarely it can also affect children and young adults. In Africa and Asia it often occurs in young adults. Hepatitis B infection The role of hepatitis B virus (HBV) infection in causing liver cancer is well established. Several lines of evidence point to this strong association. As noted earlier, the frequency of liver cancer relates to (correlates with) the frequency of chronic hepatitis B virus infection. In addition, the patients with hepatitis B virus who are at greatest risk for liver cancer are men with hepatitis B virus cirrhosis (scarring of the liver) and a family history of liver cancer. Perhaps the most convincing evidence, however, comes from a prospective (looking forward in time) study done in the 1970's in Taiwan involving male government employees over the age of 40. In this study, the investigators found that the risk of developing liver cancer was 200 times higher among employees who had chronic hepatitis B virus as compared to employees without chronic hepatitis B virus! Studies in animals also have provided evidence that hepatitis B virus can cause liver cancer. For example, we have learned that liver cancer develops in other mammals that are naturally infected with hepatitis B virus-related viruses. Finally, by infecting transgenic mice with certain parts of the hepatitis B virus, scientists caused liver cancer to develop in mice that do not usually develop liver cancer. (Transgenic mice are mice that have been injected with new or foreign genetic material.) How does chronic hepatitis B virus cause liver cancer? In patients with both chronic hepatitis B virus and liver cancer, the genetic material of hepatitis B virus is frequently found to be part of the genetic material of the cancer cells. It is thought, therefore, that specific regions of the hepatitis B virus genome (genetic

code) enter the genetic material of the liver cells. This hepatitis B virus genetic material may then disrupt the normal genetic material in the liver cells, thereby causing the liver cells to become cancerous. The vast majority of liver cancer that is associated with chronic hepatitis B virus occurs in individuals who have been infected most of their lives. In areas where hepatitis B virus is not always present (endemic) in the community (for example, the U.S.), liver cancer is relatively uncommon. The reason for this is that most of the people with chronic hepatitis B virus in these areas acquired the infection as adults. However, liver cancer can develop in individuals who acquired chronic hepatitis B virus in adulthood if there are other risk factors, such as chronic alcohol use or co-infection with chronic hepatitis C virus infection. Hepatitis C infection Hepatitis C virus (HCV) infection is also associated with the development of liver cancer. In fact, in Japan, hepatitis C virus is present in up to 75% of cases of liver cancer. As with hepatitis B virus, the majority of hepatitis C virus patients with liver cancer have associated cirrhosis (liver scarring). In several retrospectiveprospective studies (looking backward and forward in time) of the natural history of hepatitis C, the average time to develop liver cancer after exposure to hepatitis C virus was about 28 years. The liver cancer occurred about eight to 10 years after the development of cirrhosis in these patients with hepatitis C. Several prospective European studies report that the annual incidence (occurrence over time) of liver cancer in cirrhotic hepatitis C virus patients ranges from 1.4 to 2.5% per year. In hepatitis C virus patients, the risk factors for developing liver cancer include the presence of cirrhosis, older age, male gender, elevated baseline alphafetoprotein level (a blood tumor marker), alcohol use, and co-infection with hepatitis B virus. Some earlier studies suggested that hepatitis C virus genotype 1b (a common genotype in the U.S.) may be a risk factor, but more recent studies do not support this finding. The way in which hepatitis C virus causes liver cancer is not well understood. Unlike hepatitis B virus, the genetic material of hepatitis C virus is not inserted directly into the genetic material of the liver cells. It is known, however, that cirrhosis from any cause is a risk factor for the development of liver cancer. It has been argued, therefore, that hepatitis C virus, which causes cirrhosis of the liver, is an indirect cause of liver cancer. On the other hand, there are some chronic hepatitis C virus infected individuals who have liver cancer without cirrhosis. So, it has been suggested that the core (central) protein of hepatitis C virus is the culprit in the development of liver cancer. The core protein itself (a part of the hepatitis C virus) is thought to impede the natural process of cell death or interfere with the function of a normal tumor suppressor (inhibitor) gene (the p53 gene). The result of these actions is that

the liver cells go on living and reproducing without the normal restraints, which is what
happens in cancer.

Alcohol Cirrhosis caused by chronic alcohol consumption is the most common association of liver cancer in the developed world. Actually, we now understand that many of these cases are also infected with chronic hepatitis C virus. The usual setting is an individual with alcoholic cirrhosis who has stopped drinking for ten years, and then develops liver cancer. It is somewhat unusual for an actively drinking alcoholic to develop liver cancer. What happens is that when the drinking is stopped, the liver cells try to heal by regenerating (reproducing). It is during this active regeneration that a cancer-producing genetic change (mutation) can occur, which explains the occurrence of liver cancer after the drinking has been stopped. Patients who are actively drinking are more likely to die from non-cancer related complications of alcoholic liver disease (for example, liver failure). Indeed, patients with alcoholic cirrhosis who die of liver cancer are about 10 years older than patients who die of non-cancer causes. Finally, as noted above, alcohol adds to the risk of developing liver cancer in patients with chronic hepatitis C virus or hepatitis B virus infections. Aflatoxin B1 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. Aflatoxin B1 has been implicated in the development of liver cancer in Southern China and Sub-Saharan Africa. It is thought to cause cancer by producing changes (mutations) in the p53 gene. These mutations work by interfering with the gene's important tumor suppressing (inhibiting) functions. Drugs, medications, and chemicals There are no medications that cause liver cancer, but female hormones (estrogens) and protein-building (anabolic) steroids are associated with the development of hepatic adenomas. These are benign liver tumors that may have the potential to become malignant (cancerous). Thus, in some individuals, hepatic adenoma can evolve into cancer. Certain chemicals are associated with other types of cancers found in the liver. For example, thorotrast, a previously used contrast agent for imaging, caused a cancer of the blood vessels in the liver called hepatic angiosarcoma. Also, vinyl chloride, a compound used in the plastics industry, can cause hepatic angiosarcomas that appear many years after the exposure.

Hemochromatosis Liver cancer will develop in up to 30% of patients with hereditary hemochromatosis. Patients at the greatest risk are those who develop cirrhosis with their hemochromatosis. Unfortunately, once cirrhosis is established, effective removal of excess iron (the treatment for hemochromatosis) will not reduce the risk of developing liver cancer. Cirrhosis Individuals with most types of cirrhosis of the liver are at an increased risk of developing liver cancer. In addition to the conditions described above (hepatitis B, hepatitis C, alcohol, and hemochromatosis), alpha 1 anti-trypsin deficiency, a hereditary condition that can cause emphysema and cirrhosis, may lead to liver cancer. Liver cancer is also strongly associated with hereditary tyrosinemia, a childhood biochemical abnormality that results in early cirrhosis. Certain causes of cirrhosis are less frequently associated with liver cancer than are other causes. For example, liver cancer is rarely seen with the cirrhosis in Wilson's disease (abnormal copper metabolism) or primary sclerosing cholangitis (chronic scarring and narrowing of the bile ducts). It used to be thought that liver cancer is rarely found in primary biliary cirrhosis (PBC) as well. Recent studies, however, show that the frequency of liver cancer in PBC is comparable to that in other forms of cirrhosis. Signs and symptoms In the early stages of primary liver cancer there are often no symptoms. People sometimes notice a vague discomfort in the upper abdomen that may become painful. This is due to enlargement of the liver. Pain can sometimes also be felt in the right shoulder. This is known as referred pain and is due to an enlarged liver stimulating the nerves beneath the diaphragm (the sheet of muscle under the lungs) which are connected to nerves in the right shoulder. Loss of appetite, weight loss, feeling sick (nausea), and weakness and tiredness (lethargy) are common symptoms. Some people may also develop a high temperature and feel shivery. Jaundice If the bile duct becomes blocked, bile produced by the liver will flow back into the bloodstream, causing jaundice. This will cause the skin and whites of the eyes to go yellow and may make the skin very itchy. The itching may sometimes be relieved by antihistamine tablets or other drugs, which your doctor can prescribe. Sometimes the jaundice itself can be relieved. This is done by inserting a narrow tube called a stent into the bile duct to keep it open and to allow the bile to flow normally into the small intestine. Other signs of jaundice are dark-coloured urine and pale stools (bowel motions).

Ascites Sometimes fluid builds up in the abdomen and causes swelling known as ascites. There may be several possible reasons for this: if cancer cells have spread to the lining of the abdomen, they can irritate it and cause fluid to build up if the liver itself is affected by cancer cells, this causes an increase in pressure in the veins that lead into the liver. Fluid from the abdomen cannot then pass quickly enough through the liver, so it starts to collect in the abdomen if the liver is damaged, it may produce less blood protein. This may upset the bodys fluid balance, which causes fluid to build up in the body tissues, including the abdomen Cancer cells blocking the lymphatic system. The lymphatic system is a network of fine channels which runs throughout the body. One of its functions is to drain off excess fluid, which is eventually passed out of the body in the urine. If some of these channels are blocked, the system cannot drain efficiently and fluid may build up. If ascites does develop, a tube can be put through the wall of the abdomen to drain the fluid away. The initial symptoms (the clinical presentations) of liver cancer are variable. In countries where liver cancer is very common, the cancer generally is discovered at a very advanced stage of disease for several reasons. For one thing, areas where there is a high frequency of liver cancer are generally developing countries where access to healthcare is limited. For another, screening examinations for patients at risk for developing liver cancer are not available in these areas. In addition, patients from these regions actually have more aggressive liver cancer disease. In other words, the tumor usually reaches an advanced stage and causes symptoms more rapidly. In contrast, patients in areas of low liver cancer frequency tend to have liver cancer tumors that progress more slowly and, therefore, remain without symptoms longer. Abdominal pain is the most common symptom of liver cancer and usually signifies a very large tumor or widespread involvement of the liver. Additionally, unexplained weight loss or unexplained fevers are warning signs of liver cancer in patients with cirrhosis. These symptoms are less common in individuals with liver cancer in the U.S. because these patients are usually diagnosed at an earlier stage. However, whenever the overall health of a patient with cirrhosis deteriorates, every effort should be made to look for liver cancer. A very common initial presentation of liver cancer in a patient with compensated cirrhosis (no complications of liver disease) is the sudden onset of a complication. For example, the sudden appearance of ascites (abdominal fluid and swelling), jaundice (yellow color of the skin), or muscle wasting without causative (precipitating) factors (for example, alcohol consumption) suggests the possibility of liver cancer. What's more, the cancer can invade and block the portal vein (a large vein that brings blood to the liver from the intestine and spleen). When this happens, the blood will travel paths of less resistance, such as through esophageal veins. This causes increased pressure in these veins, which results in dilated (widened) veins called esophageal varices. The patient then is at risk for

hemorrhage from the rupture of the varices into the gastrointestinal tract. Rarely, the cancer itself can rupture and bleed into the abdominal cavity, resulting in bloody ascites. On physical examination, an enlarged, sometimes tender, liver is the most common finding. Liver cancers are very vascular (containing many blood vessels) tumors. Thus, increased amounts of blood feed into the hepatic artery (artery to the liver) and cause turbulent blood flow in the artery. The turbulence results in a distinct sound in the liver (hepatic bruit) that can be heard with a stethoscope in about one quarter to one half of patients with liver cancer. Any sign of advanced liver disease (for example, ascites, jaundice, or muscle wasting) means a poor prognosis. Rarely, a patient with liver cancer can become suddenly jaundiced when the tumor erodes into the bile duct. The jaundice occurs in this situation because both sloughing of the tumor into the duct and bleeding that clots in the duct can block the duct. In advanced liver cancer, the tumor can spread locally to neighboring tissues or, through the blood vessels, to elsewhere in the body (distant metastasis). Locally, liver cancer can invade the veins that drain the liver (hepatic veins). The tumor can then block these veins, which results in congestion of the liver. The congestion occurs because the blocked veins cannot drain the blood out of the liver. (Normally, the blood in the hepatic veins leaving the liver flows through the inferior vena cava, which is the largest vein that drains into the heart.) In African patients, the tumor frequently blocks the inferior vena cava. Blockage of either the hepatic veins or the inferior vena cava results in a very swollen liver and massive formation of ascites. In some patients, as previously mentioned, the tumor can invade the portal vein and lead to the rupture of esophageal varices. Regarding the distant metastases, liver cancer frequently spreads to the lungs, presumably by way of the blood stream. Usually, patients do not have symptoms from the lung metastases, which are diagnosed by radiologic (x-ray) studies. Rarely, in very advanced cases, liver cancer can spread to the bone or brain. How it is diagnosed Liver ultrasound scan This test uses sound waves to make up a picture of the liver. It is done in the hospital scanning department. Patient will be asked not to eat, and to drink clear fluids only (nothing fizzy or milky) for 46 hours before the scan. Once patient are lying comfortably on your back, a gel is spread onto your abdomen. A small device like a microphone is then rubbed over the area. The sound waves are converted into a picture using a computer. The test is completely painless and takes about 1520 minutes. CT (computerised tomography) scan This is a series of x-rays that builds up a three-dimensional picture of the inside of the body. The scan is painless and takes about 30 minutes. It may be used to find where a tumour started and can also show whether a tumour has spread.

MRI (magnetic resonance imaging) scan This type of scan uses magnetism (not x-rays) to form a series of cross-sectional pictures of the inside of the body. During the scan patient will be asked to lie very still on the couch inside a metal cylinder. The test can take up to an hour and is completely painless, although the machine is quite noisy. If you dont like enclosed spaces patient may find the machine claustrophobic. Liver biopsy The only way to be sure of the diagnosis is to take some cells or a small piece of tissue from the affected area to look at under a microscope. This is called a biopsy. A fine needle is passed into the tumour through the skin after the area has been numbed using a local anaesthetic injection. CT or ultrasound may be used at the same time, to make sure that the biopsy is taken from the right place. After a liver biopsy you will need to stay in hospital for a couple of hours and possibly overnight. This is because there is a risk of bleeding afterwards. There is a small risk that the cancer can spread along the pathway of the biopsy needle. Laparoscopy This is a small operation that allows to look at the liver and other internal organs in the area. It is done under a general anaesthetic and will mean a short stay in hospital. While patient are under anaesthetic the doctor will make a small cut (incision) in the front of abdomen and insert a thin tube containing a light and a camera (laparoscope). The doctor is able to look at the liver and can take a small sample of tissue (biopsy) for examination under a microscope. During the operation, carbon dioxide gas is passed into the abdominal cavity and this can cause uncomfortable wind and/or shoulder pains for several days. The pain is often eased by walking about or taking sips of peppermint water. After the laparoscopy you will have one or two stitches in your abdomen. Hepatic angiogram This tests allows to see how the tumour is affecting the main blood vessels around the liver. A fine tube is inserted into an artery in patient groin and a dye is injected through the tube. The dye circulates in the arteries to make them show up on x-ray. An angiogram is carried out in a room within the x-ray department. Sometimes an MRI scan can be used to show up the blood vessels of the liver and then an angiogram will not be necessary. Staging The 'stage' of a cancer is a term used to describe its size and whether it has spread beyond its original site. Knowing the particular type and the stage of the cancer helps the doctors to decide on the most appropriate treatment. Cancer can spread in the body, either in the bloodstream or through the lymphatic system. The lymphatic system is part of the bodys defence against infection and disease. The system is made up of a network of lymph glands (also known as lymph nodes) that are linked by fine ducts containing lymph fluid.

Stage 1 The cancer is no bigger than 2cm in size and has not begun to spread. Stage 2 The cancer is affecting blood vessels in the liver, or there is more than one tumour in the liver. Stage 3A The cancer is bigger than 5cm in size or has spread to the blood vessels near the liver. Stage 3B The cancer has spread to nearby organs, such as the bowel or the stomach, but has not spread to the lymph nodes. Stage 3C The cancer can be of any size and has spread to nearby lymph nodes. Stage 4 The cancer has spread to parts of the body further away from the liver, such as the lungs. Treatment
Important factors for planunf treatment:

whether the cancer is a primary or secondary liver cancer age general health the type and size of the cancer whether it has spread beyond liver whether liver is affected by any other disease, such as cirrhosis.

Surgery Surgery is the most effective treatment for primary liver cancer, but this is not always possible due to the size or position of the tumour. It is also not possible to operate if the cancer has spread beyond the liver. If the liver is severely damaged by cirrhosis it may not be safe to have surgery. Liver resection If only certain areas of the liver are affected by the cancer and the rest of the liver is healthy, it may be possible to have an operation to remove the affected part: this is called a liver resection. Lobectomy If the operation removes a whole lobe of the liver, it is called a lobectomy. The liver has an amazing ability to repair itself. Even if up to three-quarters of the liver is removed it will start to re-grow very quickly, and may be back to normal size within a few weeks. Liver transplant Removing the whole liver and replacing it with a liver from another person is another possible form of treatment for primary liver cancer, but can only be done in a very few cases when the tumour is small (less than 5cm) or there are less than three tumours, all smaller than 3cm in size. Tumour ablation. This type of treatment is used for tumours less than 5cm (2 inches) in diameter. Liquids such as alcohol (ethanol) or acetic acid are injected through the skin and into the tumour. The liquids destroy the cancer cells. This procedure is usually done in the scanning department so that ultrasound can be

used to guide the needle directly into the tumour. If the tumour grows again, the treatment can be repeated. Laser or radiofrequency (thermal) ablation. This treatment uses a laser or electrical generator to destroy the cancer cells. Under local anaesthetic, a fine needle is inserted into the centre of the tumour. Powerful laser light or radio waves are then passed through the needle and into the tumour; these heat the cancer cells and destroy them. Chemotherapy Chemotherapy is the use of anti-cancer (cytotoxic) drugs to destroy cancer cells. It is sometimes used to treat primary liver cancers that cannot be removed. Chemotherapy drugs are usually given by injection into a vein (intravenously) or by injecting the drug directly into the hepatic artery (the blood vessel that takes blood to the liver). Chemotherapy is often given as a session of treatment, usually lasting a few days. This is followed by a rest period of a few weeks to allow patients to recover from any side effects of the treatment. The number of sessions patient have will depend on the type of liver cancer patient have and how well it is responding to the drugs. Chemotherapy can sometimes cause unpleasant side effects, but it can also make patient feel better by relieving the symptoms of the cancer. Any side effects that occur are usually temporary and can often be well controlled with medicine. The main side effects are a reduced resistance to infection, feeling sick, a sore mouth, and hair loss. Radiotherapy Radiotherapy is the use of high-energy x-rays to destroy cancer cells, while doing as little harm as possible to normal cells. It is not usually used to treat hepatomas, but it may be used to treat cholangiocarcinoma. Other treatments The following treatments are still being evaluated as part of research trials. Cryosurgery or cryotherapy In cryotherapy treatment a device called a cryoprobe is inserted into the centre of the tumour during an operation. Liquid nitrogen is then passed through the probe. This freezes the surrounding area and destroys the cancer cells. Chemoembolisation This treatment involves mixing chemotherapy drugs with an oily substance called lipiodol. Under local anaesthetic the mixture is then injected into the liver through a tube inserted into the hepatic artery (the main blood vessel carrying blood to the liver). It is thought that adding lipiodol to the chemotherapy drugs helps them to remain in the liver for longer, and makes the treatment more effective. This treatment can be repeated several times. It is carried out in the x-ray department and you would usually need to stay in hospital for 24 48 hours.

Follow-up After treatment has been completed, doctor will ask patients to return for regular check-ups and x-rays or scans. These are good opportunities to discuss with doctor any worries or problems patient may have. However, if patient notice any new symptoms or are anxious about anything else in the meantime, patients must contact with doctor or the ward sister for advice. References This section has been compiled using information from a number of reliable sources, including: 1. Oxford Textbook of Oncology (2nd edition). Souhami et al. Oxford University Press, 2002. 2. Gastrointestinal Oncology: Principles and Practice. Kelsen et al. Lippincott Williams and Wilkins, 2002. 3. The Textbook of Uncommon Cancers (2nd edition). Raghavan et al. Wiley, 1999. 4. Radiofrequency Ablation of Hepatocellular Carcinoma. NICE July 2003. 5. West J et al. Trends in the Incidence of Primary Liver and Biliary Tract Cancers in England and Wales 1971-2001. Br