What is cancer?
The human body is composed of billions of cells that are continually ageing, dying and being replaced. Cell death, replacement, growth and development are normally tightly controlled. If this control breaks down, cells begin to grow and divide abnormally, clustering together to form a lump known as a tumour. These tumours are either benign or malignant. Cancer is the name given to a malignant tumour.
Benign liver tumours stay in the liver and do not spread to other organs or parts of the body. Usually they only grow for a limited amount of time and produce no symptoms.Most benign tumours are found by chance. Occasionally, they may need surgical removal if they are large, liable to bleed or cause any discomfort.
Malignant cancer tumours are cells growing without control, which go on to invade, erode or destroy normal, healthy tissue. Cancer is not a single disease. In fact, there are more than 200 different types of cancer, each with its own name, cause and treatment.
There are two broad categories of liver cancer: secondary and primary.
- Secondary liver cancer is a cancer that first develops elsewhere in the body and then spreads (metastasises) to the liver. It is sometimes called metastatic cancer.
- Primary liver cancers are cancers that start in the liver. The two main types are: Hepatoma, also called hepatocellular carcinoma (HCC) and Biliary tree cancer, which includes cholangiocarcinoma (bile duct cancer) and gallbladder cancer.
Causes of liver cancer
Secondary Liver Cancer
When a cancer forms in a part of the body, a few cancer cells may break off and find their way into the bloodstream. Because your liver filters your blood, any cancer cells in the bloodstream have a high chance of settling in the liver to form a cancer nodule (metastasis).
People who are most at risk of secondary liver cancer are those with cancers of the large bowel (colon), pancreas, stomach, lung or breast.
It is important to know where the cancer started as this will determine the type of cells which are causing the cancer and affect which treatment is best suited for you. Secondary cancer diagnosed in the liver may be a sign of cancer in other organs. If the original (primary) cancer is too small to be detected, it is called carcinoma of unknown primary.
Primary Liver Cancer
1. Hepatoma (hepatocellular carcinoma, or HCC)
The main cause of HCC is cirrhosis of the liver, where the liver has become scarred as a result of damage over a long period of time. Any disease that causes cirrhosis of the liver can lead to a hepatoma, but certain causes of cirrhosis have a particularly strong link with HCC.
- Viral infections hepatitis B and C
- Excessive alcohol consumption
- Haemochromatosis: a rare hereditary disease caused by an overload of iron in the body. High risk if not treated.
- Non-alcohol related fatty liver disease (NAFLD): specifically the advanced form non-alcohol related steatohepatitis (NASH) is thought to be the cause of many cases of cirrhosis previously labelled as of unknown cause (cryptogenic). It is increasingly being associated with HCC.
Other causes of cirrhosis less frequently associated with HCC.
- Primary biliary cholangitis/cirrhosis (PBC): nine out of ten people with PBC are women and have a relatively low risk of developing HCC. However, the risk is greater for men with PBC, who have a risk of developing HCC similar to those with alcohol related cirrhosis.
- Autoimmune hepatitis: people with this condition have only a very low risk of developing HCC, even when cirrhosis is present.
Having cirrhosis does not mean you will get primary liver cancer. Around three or four people out of a hundred with cirrhosis will go on to develop HCC each year.
As well as cirrhosis, other factors can also increase your risk of developing HCC.
- Infection with two or more viruses (coinfection) such as hepatitis B, hepatitis C or HIV leads to a greater risk than a single infection.
- Both obesity and type 2 diabetes are linked with a higher risk of developing HCC, the risk being greater if both are present. This is often associated with NASH as part of a group of conditions called ‘the metabolic syndrome.
- Heavy smoking, particularly in association with excessive alcohol consumption or infection with viral hepatitis is linked with HCC.
- Using anabolic steroids over a long period can lead to liver tumours. These are usually benign but can grow and rupture causing pain. These may in rare circumstances lead to HCC.
- Exposure over a long period to aflatoxin B, which may be present in mouldy rice, wheat, peanuts, corn and soybeans (particularly in areas of Asia and Africa) and the practice of chewing betel quid, also increase the risk of HCC.
If more than one of these apply to you, your risk of developing HCC will be greater.
2. Biliary tree cancer
In most people, there is no clear reason why they develop cholangiocarcinoma or gallbladder cancer. However, people who have the following problems are more likely to develop cholangiocarcinoma:
- a liver problem called primary sclerosing cholangitis (PSC). The risk is increased by smoking.
- chronic inflammation of the bile ducts due to multiple stones within the liver
- parasitic infections (liver fluke) common in SE Asia
- cirrhosis of any cause but particularly due to viral hepatitis B and C.
3. Fibrolamellar carcinoma
A rare variation of HCC usually found in people between 20 to 40 years old without cirrhosis being present. It is usually well contained and can be removed with surgery.
What are the symptoms?
Often there are no symptoms in the early stages of liver cancer because the liver can function very well when only a portion of it is working. If you do notice any symptoms, they are usually vague and similar to symptoms for other liver conditions. They may include:
- fatigue (tiredness) and weakness
- a general feeling of poor health
- loss of appetite
- feeling sick (nausea) and vomiting
- loss of weight
- pain or discomfort over the liver area (place your right hand over the lower right hand side of your ribs and it will just about cover the area of your liver)
- itchy skin
- fine blood vessels visible on the skin in a radial pattern resembling the legs of a spider (known as spider naevi)
- enlarged and tender liver (you may feel tender below your right ribs)
- dark urine/grey pale stools (faeces)
- loss of sex drive (libido).
Some symptoms may be a sign of a more serious problem. If you have any of these you should seek medical advice at once:
- skin and eyes turning yellow (jaundice) – often the first and sometimes the only sign of liver disease
- swelling of the abdomen, which can be due to the growing cancer itself or a build up of fluid within the abdomen (ascites)
- fever with high temperatures and shivers
- vomiting blood
- dark black tarry stools (faeces).
Your diagnosis will usually depend on whether you have secondary or primary liver cancer.
If you have secondary liver cancer it is quite possible that your liver cancer will be discovered when the primary cancer is diagnosed. For example, people with bowel cancer will also have tests to look for any spread to the liver. In this case your secondary liver cancer will usually be diagnosed by a specialist cancer doctor (oncologist) or a surgeon.
Primary liver cancer, including biliary tree cancer, is usually diagnosed in the following way:
- your GP will take your medical history – finding out about your symptoms – and perform a detailed clinical examination
- your GP will then take some blood samples and may arrange an abdominal ultrasound
- if blood tests and ultrasound indicate a tumour may be present, you will be sent to see a specialist doctor (surgeon or gastroenterologist/ hepatologist) who may take more blood tests and arrange for you to have special imaging of your liver to examine it more closely (see below)
- you may be sent for a biopsy (see below) if the imaging is not conclusive.
Tests and investigations for liver cancer
A blood test provides information on the general health of your liver. In addition, if HCC is suspected, a protein found in blood called alpha-fetoprotein (AFP) will also be measured. In around five to seven out of ten people with HCC, AFP levels will rise as the disease progresses. AFP levels usually come down if a treatment is working, so it is a useful tool to measure how effective treatment is. However, around one in five HCC tumours do not produce an elevated AFP, even when large.
In biliary tree cancer, blood tests for the tumour markers CA 19-9 and CEA may also be used. However, these do not give a certain diagnosis as other conditions may also cause these markers to be raised.
Ultrasound, the same technology used to confirm that all is well in pregnancy, sends sound waves into the body. The echoes are picked up and used to build a picture of the condition of the liver, bile ducts and gallbladder. Ultrasound is painless. If the ultrasound highlights any areas of tissue which could be a tumour you should be referred to a specialist liver unit for a CT or MRI scan. You should be seen by a specialist within two weeks.
CT scan (computed tomography)
A CT machine takes X-ray pictures of the body from different angles that are then fed into a computer.The computer processes the pictures as a series of cross sections (or ‘slices’) giving a 3-dimensional image of the inside of your body enabling doctors to get an insight into the liver and other organs. This will show how far the tumour has spread and if it is present in other organs.
MRI (magnetic resonance imaging)
MRI uses radiofrequency waves and a strong magnetic field, not X-rays, to create a clear and detailed picture of internal organs and tissues and may be used where more detailed examination is required. When investigating possible bile duct cancer a particular form of MRI may be used called MRCP (magnetic resonance cholangiopancreatography).
Hepatic angiography is an X-ray study of the blood vessels that supply the liver and may be needed if the diagnosis is still doubtful after a CT and MRI scan. It may also be used as part of some treatment techniques such a chemoembolisation (see treatment section for further information). The procedure uses a catheter (a thin, flexible tube) that is placed into a blood vessel through a small cut in the groin. A dye is then injected through the catheter which ‘lights up’ the blood vessels in the tumour.
A hepatic angiogram is usually done under local anaesthetic and you are also likely to be given sedation. Because of this, you may be asked to stay in hospital overnight (the minimum stay is six hours).
Endoscopic retrograde cholangiopancreatography (ERCP)
This technique is used if you have suspected biliary tree cancer, to examine your bile ducts in more detail. It uses a small camera on the end of a flexible tube (endoscope). The camera is gently passed down your throat guided by an X-ray scanner to the bile ducts. A liquid will be injected to make yourbile ducts show up more clearly. A small needle may also be passed down through the endoscope to take a tissue sample for examination (biopsy).
A laparoscopy may be performed to assess damage to your liver and bile ducts and also to look for tumours in the abdominal cavity. In this procedure a tiny camera with a light on the end of a flexible fibre optic tube is inserted into your side through a small cut in your skin (‘keyhole’) to take pictures of your liver. If needed, a biopsy of your liver can be taken at the same time. A laparoscopy is performed under a general anaesthetic.
Usually diagnosis can be made using imaging techniques but occasionally a biopsy may be required. During a liver biopsy, a tiny piece of the liver is taken for study. This usually involves a fine hollow needle being passed through the skin into the liver and a small sample of tissue being withdrawn. In some circumstances it can be done using an endoscope (see above). The test is usually done under local anaesthetic and may mean an overnight stay in hospital, although some people may be allowed home later the same day.
When all the tests have been completed your consultant will review your test results with a medical team which may include specialists in surgery, liver disease (hepatologist), digestive diseases (gastroenterologist) and cancer (oncologist).
As well as diagnosing the presence of cancer, the tests will also provide information on how advanced the cancer is (size, number of tumours, location). This is referred to as ‘staging’ the cancer and is often measured using the TNM classification:
- Tumour (T) – the extent of the primary tumour
- Node (N) – whether the tumour has spread to your lymph nodes
- Metastases (M) – whether the tumour has spread to other organs.
The health of your liver will also be classified, using a scoring system called Child-Pugh (class A, B, C) which takes into consideration blood test results, the presence of fluid in the abdomen (ascites) and brain function (encephalopathy). A Child-Pugh class A, indicates the liver is working well, whereas class C indicates severe liver damage.
This information will help your medical team to decide on the most appropriate treatment options to discuss with you.
If you have been diagnosed with cirrhosis (particularly related to hepatitis B, C alcohol or haemochromatosis you should receive regular ultrasound scans and blood tests (every 6 to 12 months) to monitor your liver. Early detection of any tumours will give the best opportunities for successful treatment. Surveillance may not be offered if you have alcohol related cirrhosis and continue to drink, as the continued damage from alcohol would reduce the chances of any successful treatment.
In addition, should you develop cancer in another part of your body, especially if the primary cancer is in your stomach, oesophagus, pancreas, colon or bowel, screening for early symptoms of secondary liver cancer will give you a chance of finding this at an early stage when more treatment options are available.
Primary and secondary cancer will require different approaches to treatment. The following treatments are used for primary liver cancer. Some of these may also be offered if your liver cancer is secondary, depending on the source of the primary cancer.
A number of treatment options are available. The aim of some treatments (surgery or liver transplant) is to get rid of the cancer to achieve a cure. If this is not possible then treatment will aim to shrink the size of the cancer to relieve symptoms, delay progression or to make surgery possible. Treatments may be used on their own or in combination.
Unfortunately a cure is only possible in a minority of people because liver cancer produces few symptoms and many people are not diagnosed until it is well advanced.
The treatment you receive will depend on a number of factors, including:
- the exact position of the cancer in the liver – sometimes there are several areas
- the stage of the cancer (size and extent of the tumour, whether it has spread to other organs)
- your general health, in particular the general state of your liver function (many people with primary liver cancer have a damaged liver due to cirrhosis).
Surgery is the only treatment which offers a chance of a cure, but may not always be possible. Whether you will be suitable for surgery will depend on a number of different factors, including:
- the size of the cancer and if it is contained in one part of the liver and no major blood vessels are involved
- if the cancer has spread beyond the liver
- whether the rest of your liver would be able to cope after an operation
- other health conditions which could hinder the operation or your recovery.
The most frequent form of liver surgery is known as resection, where the part of the liver affected by the cancer is cut away and removed. The liver will then re-grow this section.
Resection surgery is only suitable for those who have very good liver function (Child Pugh class A). If you have a hepatoma (HCC) caused by damage to the liver through cirrhosis, then resection is usually not possible. This is because your liver may be too damaged to recover after the operation. A liver transplant may be considered, but only a few people are suitable for this.
Liver surgery is a major operation and there are some risks such as infection, bleeding or bile leakage. There is a risk that the cancer may come back as it is not always possible to determine if cancer cells have spread into the blood stream. In around half (50%) of people who have had resection surgery, liver cancer does not recur within five years.
A liver transplant may be considered if you have:
- a single tumour less than 5cms in diameter or
- up to five tumours, but all less than 3cms in diameter or
- a single tumour greater than 5cms but less than 7cms if there has been no tumour progression for six months.
Both CT and MRI scans are required to determine the number and size of the tumours, and measurements will be taken from whichever records the largest.
If you meet the criteria your consultant may recommend that you are put on the transplant waiting list. You will need to be assessed by a transplant team to check that you are well enough to go through this major operation. Unfortunately, there is a shortage of donor livers. It may be some time before a suitable liver becomes available and you may need other treatments to slow the growth of the tumour in the meantime. Liver transplantation is not recommended for those with cholangiocarcinoma as the cancer often returns very quickly18.
There are a number of treatments aimed at reducing the growth of the cancer if surgery is not an option. In some circumstances these may be effective at halting the cancer for several years.
These use a needle to deliver substances directly into cancer cells to kill them, and work best in small tumours which cannot be operated on. Two techniques commonly in use are radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI).
Radiofrequency ablation is a way of destroying a cancer tumour using heat. It is done by passing a needle into the tumour. When the needle is inside the tumour a high frequency current heats up and destroys the cancer. You may experience some tiredness or nausea following treatment.
Radiofrequency ablation is not suitable for all tumours, particularly if they are close to the gallbladder and biliary duct. Of the people whose small tumours are completely destroyed by this technique, around one in four (25%) live for at least five years.
Ethanol is a type of pure alcohol that can be injected into liver cancers to kill the cancer cells by dehydrating them. The ethanol is injected through the skin into the tumour using a very thin needle. You may need more than five sessions of injections to destroy the cancer and this may require a general anaesthetic.
Ethanol injections are often suitable if your tumours are few, well defined and easy to reach. For those people with small tumours and good liver function, five year survival rates are around one in two (50%).
Cryotherapy or cryosurgery
This technique uses a metal probe to deliver liquid nitrogen, which is extremely cold, into the tumour to destroy the cells by freezing them. It has been used for tumours up to 4cms where surgery is not suitable or to treat cancer which has recurred after resection surgery, there are uncertainties about how well it works and its use has declined22. NICE (National Institute of Clinical Excellence) has recommended that it should only be used with special arrangement.
Embolisation is a technique used to cut off the blood supply to the cancer killing the cells. It works best for people who have good liver function.
Transarterial embolisation (TAE) and transarterial chemoembolisation (TACE)
Transarterial embolisation involves giving an injection into the main artery of the liver of a substance containing tiny gel-like beads or pieces of a gelatin sponge. This creates a seal that blocks the supply of blood to the tumour to stop it growing.
Chemoembolisation is a type of chemotherapy (see below) that directly targets a tumour. This reduces the side effects of using anti-cancer (chemotherapy) drugs directly in the patient’s bloodstream. In chemoembolisation a drug (such as doxorubicin) is mixed with an oily dye (lipiodol) and injected before the embolising substance. The drug is sealed in to make it attack only the tumour, and for a longer time. This therapy is given under local anaesthetic and requires a stay of up to two days in hospital. New methods aimed at improving delivery of the drug in this way are emerging. Your medical advisor can provide more information about these treatments.
For those with advanced hepatoma but good liver function, and where other treatments are not suitable, sorafenib (a drug used to treat kidney cancer) has been shown to slow tumour growth, relieving symptoms and giving people some extra months.
NICE has issued guidance that sorafenib should not be prescribed on the NHS as it is not considered to be cost effective. However, if your cancer specialist believes you would benefit from a treatment not routinely available through the NHS they can apply to the local Primary Care Trust for exceptional funding. There are also proposals for other initiatives through which the Department of Health will cover the costs of cancer drugs, such as a Cancer Drugs Fund. Talk to your cancer specialist to see if any of these would be options for you.
You may also be able to receive sorafenib as part of a clinical trial in combination with other therapies (see below).
Non-surgical treatments for Biliary Cancer
In order to relieve symptoms of bile duct cancer your consultant may suggest inserting a stent. Biliary stenting is used to treat obstructions that occur in the bile ducts in order to allow bile to drain away and relieve symptoms. When there is a narrowing (stricture) in the bile duct the doctor can insert a small, thin wire-mesh or plastic tube, called a stent, to open up the duct to keep it from collapsing. The stent can be inserted using endoscopic retrograde cholangiopancreatography (ERCP) and can remain in place permanently to help to drain away bile into the duodenum.
Radiotherapy may be used to treat bile duct cancer, either externally (using a machine to target the cancer with radioactive beams) or internally (using a wire inside your bile duct).
Photodynamic therapy (PDT)
PDT is a relatively new technique that aims to destroy cancer cells while minimising damage to normal tissue. Patients are given a ‘photosensitising’ drug intravenously that makes cells more sensitive to light. A low power red light, usually from a laser, is then directed onto the treatment area at the time of biliary stenting, up to two days after the photosensitising drug has been given. This activates the drug to attack the nearby cancerous tissue and thus improve the drainage of bile from the liver. NICE has not recommended PDT as standard treatment on the NHS, however it may be available as part of a clinical trial.
Chemotherapy is a treatment which uses drugs to kill cancer cells, or to stop them from multiplying. It aims to shrink the tumour down and slow the development of the disease. Drugs are given by injection or tablet form. Chemotherapy will not cure your cancer, but it may control the cancer or even reduce its size. This can help to reduce symptoms and may also extend your life. In a very small number of cases chemotherapy may shrink a cancer sufficiently to make it possible to operate on it.
Not everyone will be able to have chemotherapy. Chemotherapy is not often used for HCC as this type of cancer does not respond well, but it is standard treatment for biliary tree cancer. However, if you have biliary cancer you may not be able to have chemotherapy if you have any signs of jaundice (yellow skin or eyes). This is because your liver may not be able to cope with the toxicity of the chemotherapy drugs. Other treatments, such as the use of a stent, may be needed to treat the jaundice before chemotherapy can begin.
Radioembolisation/ Selective Internal Radiation Therapy (SIRT)
Like chemoembolisation, this technique uses tiny beads to block the supply of blood to the cancer. The beads contain a radioactive substance called yttrrium-90, which helps to kill the cells using radiation. A course of chemotherapy may also be given at the same time. This may be an option if you have good liver function but resection is not suitable. Research is being undertaken to further evaluate the safety and effectiveness of the technique. You may be able to take part in the research as part of a clinical trial. The technique is available through the NHS with the condition that uncertainties, benefits and risks are fully discussed with patients before they consent, and outcomes of treatment are monitored.
This is a procedure, similar to radiofrequency ablation, which uses heat from microwave energy to destroy cancer cells. It can be used to treat primary liver cancer. Like other ablative therapies, it is not aimed at curing your cancer. NICE has approved this procedure for use in the NHS under the condition that patients fully understand what is involved and the results of treatment are recorded to provide more information on how well the procedure works.
Biological therapies and tumour characterisation
An area of active research is focussing on identifying elements in the process of tumour development which can be targeted with new drugs, used alone or in combination. Alongside this, work is ongoing to identify differences in the genetic make up of HCC tumours so that these can be grouped into types (characterised). Certain types of HCC tumours respond better to certain drugs. By characterising tumours in this way it should be possible to individualise a person’s treatment to maximise the effect on the tumour and minimise side effects.
Doctors are always trying to find better ways of treating people. Your specialist may talk to you about the possibility of taking part in a clinical trial. This may involve treatment with new drugs or new ways of using drugs.
You do not have to take part in clinical trials and your care will not be affected if you do not. If you do take part, you may receive extra monitoring which may be beneficial to your treatment. The doctor involved in the research will give you specific information about any clinical trials.
You can find more information on trials which are currently running at www.controlled-trials.com
Looking after yourself
If you are finding it difficult to eat, there are plenty of dietary supplements available on prescription. Some are powders you sprinkle on your food and some are drinks that are complete meals in themselves. Sipping a supplement between meals throughout the day can really boost your calorie intake. Ask your doctor or dietician for help.
Alcohol and smoking
Alcohol is processed by your liver, and as a result, it can be dangerous for anyone with liver problems. Check with your doctor whether it is safe for you to drink any alcohol, and if so, how much. Smoking is dangerous to everyone’s health. People with liver disease are more vulnerable to infection and to poor health overall, so smoking or exposure to passive smoking is not advisable.
Ascites is a build up of fluid in the lower tummy area (abdomen). There are several possible reasons for ascites including:
- cancer cells in the lining of the abdomen cause fluid to leak out into the abdomen
- pressure develops in veins around the liver because the liver is not working properly; this causes fluid to leak out into the abdomen.
Symptoms of ascites such as a large, uncomfortable abdomen, can be relieved by taking water tablets (diuretics) or by inserting a temporary tube into the abdomen to drain the fluid. Unfortunately, despite both of these treatments ascites may come back again.
Pain may develop in the abdomen and sometimes in the back. If pain affects you, there are a range of painkillers you can try. You will probably be started on some simple painkillers such as paracetamol or co-dydramol; some people do not need anything stronger than these.
However, if these are not effective then you may be offered a morphine based painkiller such as morphine sulphate tablets (MST). Do not worry about becoming addicted to morphine. Morphine taken to relieve pain works in a different way than morphine taken for ‘recreation’.
Morphine-like drugs can also be given as a patch, similar to nicotine patches. This way of delivering painkillers may be used for patients who are not able to take tablets.
Complementary and alternative medicines
Many complementary and alternative medicines are available that are suggested to ease the symptoms of liver disease. Most of these are processed by the liver, so can be toxic to people with liver problems. Some can damage the liver and make you more severely ill. At present, healthcare professionals are not clear on the role and place of some therapies in managing liver disease. More research needs to be done on the use of such therapies.
Many products are not licensed as a medicine and there is therefore no regulation of the product, which means you cannot be sure how much of the active ingredient you are getting or how pure it is. It is wise to be cautious about the claims made for herbal remedies, particularly those advertised on the internet, as they can offer false hope. It is a good idea to discuss the use of these remedies with your doctor.
NICE Guidance on the use of Sorafenib
The British Liver Trust is pleased that its submission to the National Institute for Health and Care Excellence (NICE) regarding sorafenib (Nexavar) on behalf of patients has been listened to and that NICE have now approved the drug for use in England.
Sorafenib is for patients with a type of liver cancer called hepatocellular carcinoma (HCC). It works by stopping the proteins on the surface of cells to inhibit the growth of tumors and can help improve the quality of life and alleviate some of the symptoms for some patients.
Read the NICE guidance documents here
Please visit the support section of our website for information on Support groups in your area or visit our Useful Links section for other organisations who may be able to offer information and support. Other organisations which may be able to offer informationon cancer are:
Cancer Research UK
Helpline: 0808 800 4040
Macmillan Cancer Support
Helpline: 0808 808 0000
Marie Curie Cancer Care
Helpline: 0800 090 2309
Download: Liver Cancer LCZ/04/18.pdf
Reviewed by: Professor Graeme Alexander Consultant Physician in Hepatology, Professor Paolo Muiesan, Consultant Hapatobiliary and Transplant Surgeon, Gillian Al-Kadhimi, Liver Cancer Nurse Specialist, Ray Fagan, Lay Reviewer.
The Trust has been donated the use of this video discussing the physiology of Liver Cancer – it is aimed at medical students but after asking for feedback, some patients have also said they find it useful. It can be quite technical, so please discuss any content that you are unsure about with your medical team.