Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer.

• Worldwide, its prevalence follows that of hepatitis B and hepatitis C virus infection.^1,2
• Incidence is highest in Asia and sub-Saharan Africa with as many as 120 cases per 100,000.¹ It is relatively uncommon in Europe and North America.
• In the UK there are about 1,500 deaths per year from HCC.³ It is thought that HCC may be diagnosed more frequently in the UK over the next few years due to the hepatitis C epidemic.^3,2
• HCC usually occurs 20-30 years after the initial liver insult.¹
• The average age of development of HCC in the UK is 66 years.³

Causes

Underlying liver cirrhosis is the major risk factor. 90 to 95% of people who develop HCC have underlying cirrhosis but non-cirrhotic HCC does occur.³ Cirrhosis may be due to:

• Hepatitis B or hepatitis C infection.
  • 350 million people worldwide are thought to have chronic hepatitis B.¹
  • Chronic hepatitis B infection is the most common cause of HCC worldwide.
  • 170 million people worldwide are thought to be infected with hepatitis C.¹
  • The rate of chronic infection is higher for hepatitis C than B.
  • An estimated 200,000 people are chronically infected with hepatitis C in England.⁴
  • Hepatitis C is the most common cause of HCC in Europe.¹
  • There is a 3-5% per year risk of developing HCC if someone has either hepatitis B or C infection.³
  • Co-infection with both hepatitis B and C increases the risk of HCC further.
• Alcoholism.
• Genetic haemochromatosis.
• Primary biliary cirrhosis.

HCC may also be associated with a high concentration of aflatoxins in food. In sub-Saharan Africa and in Asia such high levels can occur due to fungal contamination of foodstuffs including peanuts and grains.¹

The metabolic syndrome related to obesity and diabetes is an important risk factor.^5,6

Rare associations include:¹

• Androgenic steroids
• Primary sclerosing cholangitis
• Alpha-1-antitrypsin deficiency
• Oral contraceptives
• Porphyria cutanea tarda

For most of the underlying aetiologies, it is more likely that men rather than women will develop HCC.³

This is usually with symptoms of advancing cirrhosis and liver failure.

Symptoms

• Pruritus
• Splenomegaly
• Bleeding oesophageal varices
• Cachexia
• Jaundice
• Confusion and hepatic encephalopathy
• Abdominal distension due to ascites
• Right upper quadrant pain

Signs

• Jaundice
• Hepatomegaly
• Ascites
• Spider naevi
• Peripheral oedema
• Periumbilical collateral veins
• Asterixis

Metastases can develop in the lung, portal vein, periportal nodes, bone or brain.¹

A paper commissioned by the British Society of Gastroenterologists in 2003 suggested that the following groups be screened for HCC:

• Men and women with established cirrhosis due to hepatitis B or C infection, or due to genetic haemochromatosis.
• Men with alcohol-related cirrhosis who are abstinent from alcohol or likely to comply with treatment (the risk of women developing HCC is low).
• Men with cirrhosis due to primary biliary cirrhosis (the risk of women developing HCC is low).

Six-monthly screening with abdominal ultrasound and alpha-fetoprotein (AFP) was suggested. It was also stressed that patients should be aware of the implications of early diagnosis and the lack of proven survival benefit.

• A focal liver lesion in someone with cirrhosis is highly likely to be HCC.³
• If a >2 cm mass is detected on USS and AFP is also raised, this is diagnostic. Further investigation is only needed to determine the best treatment.³ CT of the liver can look for local spread and CT of the thorax can look for metastases.³
• MRI scanning with contrast or angiography with lipiodol injection with follow-up CT may also be used in assessment.
• If diagnosis is still in doubt, percutaneous fine needle aspiration or biopsy may be needed. Some sources state that seeding of tumour in the needle tract occurs in 1-3% of cases.^3,7 However, controversy exists over these figures.¹

Other investigations:

• Alpha-fetoprotein is elevated in 75% of cases.¹ A level of >400 ng/ml may be regarded as diagnostic by some.³
• Liver function tests may be consistent with cirrhosis.
• Check for clotting abnormalities.
• Albumin may be low.
• Chest X-ray may show a raised right hemidiaphragm or lung metastases.

• Cirrhosis
• Cholangio-carcinoma
• Primary lymphoma of the liver
• Metastatic carcinoma (30 times as common in Europe as HCC)

A number of staging systems have been developed. Those that incorporate that state of liver function and the patient's clinical state (e.g. presence of ascites, portal vein involvement, etc.) as well as the tumour morphology, may be most useful. The Cancer of the Liver Italian Program (CLIP) scoring system is one of these. From this, an estimated survival can be determined.

Score between 0-2 for each of the 4 features listed below. The cumulative score ranging from 0-6 is the CLIP score.¹

• Child-Pugh stage - the Child-Pugh-Turcotte (CPT) classification system - is a widely-used and validated way to estimate prognosis in those with cirrhosis: (Further details can be found in the related article Cirrhosis)
  • Stage A = 0
  • Stage B = 1
  • Stage C = 2
• Tumour morphology:
  • Uninodular and extension less than 50% = 0
  • Multinodular and extension less than 50% = 1
  • Massive and extension greater than 50% = 2
• Alpha-fetoprotein:
  • Less than 400 = 0
  • Greater than 400 = 1
• Portal vein thrombosis:
  • Absent = 0
  • Present = 1

Estimated survival based on CLIP score:

• Patients with a CLIP score of 0 have an estimated survival of 31 months; those with score of 1, about 27 months; score of 2, 13 months; score of 3, 8 months; and scores 4-6, approximately 2 months.

The Barcelona Clinic Liver Cancer (BCLC) staging and treatment approach is another tool that is used by many for management. The algorithm for this can be found in the Lancet reference below.⁶

• Before treatment of the primary tumour, any complications of cirrhosis or liver failure must be treated.
• These include ascites, encephalopathy or spontaneous bacterial peritonitis and oesophageal varices.

For more details see separate articles: Cirrhosis (click here) and Liver Failure.
Treatment options for HCC depend on:¹

• The size, number and location of tumours.
• The presence or absence of cirrhosis.
• The operative risk based on extent of cirrhosis and co-morbid diseases.
• The patient's overall performance status.
• The patency of the portal vein.
• Whether there is metastatic disease.

Liver transplantation

• Only about 5% of people with HCC are suitable for transplantation.¹
• Because of limited donors, the 'Milan criteria' help to select transplantation candidates carefully:⁶
  • Single lesions of ≤5 cm diameter, or up to three lesions of ≤3 cm with no vascular invasion seen on imaging, have an almost zero recurrence rate after liver transplantation.³

Tumour resection

• In the short-term, resection produces similar results as transplantation but, at three years, there is a higher chance of tumour-free survival after transplantation.³
• Very good liver function is needed if resection is to be considered. This is because decompensation can occur after surgery.
• Also, the liver that is left behind after resection still has malignant potential and recurrence rates are 50-60% after five years.³

Ablative therapy

• Alcohol (ethanol) injection - this is done percutaneously and has been carried out on small tumours in those with good underlying liver function. Larger lesions have been treated but with limited ablation success and high recurrence rates.³ Treatment is difficult in the posterior segments of the liver and needle tract tumour seeding is a risk, as well as bile duct injury. This may be the best treatment for those with small, inoperable HCCs.³
• Radiofrequency ablation - high frequency ultrasound probes are placed into the tumour mass. This is a relatively new technique that produces tumour necrosis.³ It may be more effective than ethanol injection for larger tumours. More studies are needed.³ This procedure is approved by NICE.⁸
• Microwave ablation - this is approved by NICE. It destroys tumour cells by heat and results in localised areas of necrosis and tissue destruction. Needle electrodes are inserted into the liver, either percutaneously or at laparoscopy or laparotomy, and are attached to a microwave generator.⁹
• Acetic acid, laser or cold ablation may also be used.¹

Chemoembolisation

• This is the delivery of high concentrations of chemotherapy drugs directly to the tumour via the hepatic artery using embolising agents such as cellulose.
• It tends to be used in those with preserved liver function with large or multifocal tumours without vascular invasion or extrahepatic spread, and who have no symptoms.⁶
• It seems to be effective in reducing tumour size as well as treating pain or bleeding.³
• Median survival is >2 years and there is work to improve this by using better embolic agents and increasing the local exposure to chemotherapy.¹⁰

Systemic chemotherapy

• This may be used in advanced disease but HCC is relatively chemotherapy-resistant.
• Therapies with molecular targeted therapies, such as sorafenib, are also being investigated and are so far very promising.¹¹
• Sorafenib is currently being assessed by NICE.

Other treatments

• Retinoids and adaptive immunotherapy (using primed peripheral lymphocytes) have been used to help prevent tumour recurrence after ablation or resection.³ More research is needed to determine their benefits.
• CyberKnife® stereotactic radiosurgery is a new technology. It combines robotics and image guidance so that highly focused, concentrated beams of radiation can be delivered to the tumour.¹ This is not widely available at present.

• Treatment of chronic hepatitis C can clear the virus in more than half of people treated.⁴
• NICE recommends a combination therapy of pegylated interferon and ribavirin for the treatment of chronic hepatitis C.^12,13
• Further information about the treatment of hepatitis C can be found in the related article hepatitis C.
• A recent review concluded that future research is needed to provide evidence-based recommendations about optimal antiviral therapy in adults with chronic hepatitis B infection.¹⁴

• This depends on the extent of underlying cirrhosis as this can limit the treatment options.
• Median survival from time of diagnosis is about 6 months.¹
• Liver failure can occur with death due to cachexia, variceal bleeding and, occasionally, tumour rupture with intraperitoneal bleeding.¹
• Surgical resection, liver transplantation and ablation by radiofrequency or ethanol injection are now conventional therapies for early stage disease. With these treatments, survival at 5 years is between 50% and 70%.⁶

Prevention is the best approach.

• The hepatitis B vaccine will, it is hoped, reduce the incidence of HCC.²
• There is so far no vaccine against hepatitis C but treatments including interferon alpha may have a beneficial effect.¹⁵
• A sensible approach to alcohol consumption would also be beneficial.