Epidemiology  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.hepatitis B and hepatitis C virus infection.  Incidence is highest in Asia and sub-Saharan Africa with as many as 120 cases per 100,000.1 Incidence is highest in Asia and sub-Saharan Africa with as many as 120 cases per 100,000.1  relatively uncommon in Europe and North America relatively uncommon in Europe and North America

…. HCC may be diagnosed more frequently over the next few years due to the hepatitis C epidemic.  3, 2 3, 2  HCC usually occurs years after the initial liver insult. HCC usually occurs years after the initial liver insult.  The average age of development of HCC is 66 years. The average age of development of HCC is 66 years.

Causes  liver cirrhosis - major risk factor in 90 to 95% of people who develop HCC  < Hepatitis B or hepatitis C infection. < Hepatitis B or hepatitis C infection.  350M have chronic hepatitis B. 350Mchronic hepatitis B.  Chronic hepatitis B infection is the most common cause of HCC worldwide. Chronic hepatitis B infection is the most common cause of HCC worldwide.  170 M have hepatitis C 170 M have hepatitis C  hepatitis C chronic infxn > B. hepatitis C chronic infxn > B.  Hepatitis C is the most common cause of HCC in Europe. Hepatitis C is the most common cause of HCC in Europe.  Hep B+C increases HCC risk further. Hep B+C increases HCC risk further.  Alcoholism. Alcoholism.  Genetic haemochromatosis. Genetic haemochromatosis.  Primary biliary cirrhosis. Primary biliary cirrhosis.  High aflatoxins in food. High aflatoxins in food.

Rare associations include:  1Androgenic steroids 1Androgenic steroids  Primary sclerosing cholangitis Primary sclerosing cholangitis  Alpha-1-antitrypsin deficiency Alpha-1-antitrypsin deficiency  Oral contraceptives Oral contraceptives  Porphyria cutanea tarda Porphyria cutanea tarda

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

SSymptoms  Pruritus Pruritus  Right upper quadrant pain Right upper quadrant pain

Signs  Jaundice Jaundice  Abdominal distension due to ascites Abdominal distension due to ascites  Jaundice Jaundice  Confusion and hepatic encephalopathy Confusion and hepatic encephalopathy  Bleeding oesophageal varices Bleeding oesophageal varices  Hepatomegaly Hepatomegaly  Cachexia Cachexia  Ascites Ascites  Spider naevi Spider naevi  Peripheral oedema Peripheral oedema  Periumbilical collateral veins Periumbilical collateral veins  Asterixis Asterixis

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

1Who should be screened for hepatocellular carcinoma?  cirrhosis < hepatitis B or C, or due to genetic haemochromatosis. cirrhosis < hepatitis B or C, or due to genetic haemochromatosis.  alcohol-related cirrhosis alcohol-related cirrhosis  cirrhosis <primary biliary cirrhosis (the risk of women developing HCC is low). cirrhosis primary biliary cirrhosis (the risk of women developing HCC is low).

Six-monthly screening with abdominal ultrasound and alpha-fetoprotein (AFP) was suggested.

Screening tests for hepatocellular carcinoma

The efficacy and cost- effectiveness of screening programmes for at-risk patients is unclear.  Note: lack of curative treatment options in all patients with cirrhosis. Note: lack of curative treatment options in all patients with cirrhosis.

1Possible screening tests include:  AFP AFP  N= ng/ml. N= ng/ml.  >400 ng/ml - >400 ng/ml -  CAVEATS on AFP CAVEATS on AFP  2/3of HCC <4 cm have AFP levels <200 ng/ml 2/3of HCC <4 cm have AFP levels <200 ng/ml  Up to 20% of HCC do not produce AFP. Up to 20% of HCC do not produce AFP.  F(+) High levels of AFP may be seen in regenerating nodules in viral cirrhosis F(+) High levels of AFP may be seen in regenerating nodules in viral cirrhosis

ImagingUltrasound scan (USS)  can detect large lesions ; can detect large lesions ;  less reliable for small lesions ; less reliable for small lesions ;  is user-dependent. is user-dependent.  USS +AFP measurements - better screening tool. USS +AFP measurements - better screening tool.

Diagnostic tests for hepatocellular carcinoma  A focal liver lesion in cirrhosis - highly likely HCC  If a >2 cm mass + Elev AFP  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.

Some sources state that seeding of tumour in the needle tract occurs in 1-3% of cases.

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

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

Staging  A number of staging systems have been developed. 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. 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.

Child-Pugh stage - the Child-Pugh- Turcotte (CPT) classification system -  widely-used and validated way to estimate prognosis in those with cirrhosis widely-used and validated way to estimate prognosis in those with cirrhosis  Stage A = 0 Stage A = 0  Stage B = 1 Stage B = 1  Stage C = 2 Stage C = 2

Tumour morphology:  Uninodular and extension less than 50% = 0 Uninodular and extension less than 50% = 0  Multinodular and extension less than 50% = 1 Multinodular and extension less than 50% = 1  Massive and extension greater than 50% = 2 Massive and extension greater than 50% = 2

Alpha-fetoprotein:  Less than 400 = 0 Less than 400 = 0  Greater than 400 = 1 Greater than 400 = 1  Portal vein thrombosis: Portal vein thrombosis:  Absent = 0 Absent = 0  Present = 1 Present = 1

Estimated survival based on CLIP score:  Patients with a CLIP score of 0 have an estimated survival of 31 months; Patients with a CLIP score of 0 have an estimated survival of 31 months;  those with score of 1, about 27 months those with score of 1, about 27 months  score of 2, 13 months; score of 2, 13 months;  score of 3, 8 months; and score of 3, 8 months; and  scores 4-6, approximately 2 months. 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. is another tool that is used by many for management.

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

Treatment options for HCC: depend on:  1The size, number and location of tumours. 1The size, number and location of tumours.  The presence or absence of cirrhosis. The presence or absence of cirrhosis.  The operative risk based on extent of cirrhosis and co-morbid diseases. The operative risk based on extent of cirrhosis and co-morbid diseases.  The patient's overall performance status. The patient's overall performance status.  The patency of the portal vein The patency of the portal vein .Whether there is metastatic disease..Whether there is metastatic disease.

Liver transplantation  Only about 5% of people with HCC are suitable for transplantation. Only about 5% of people with HCC are suitable for transplantation.  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. 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.

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. 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.  Very good liver function needed if for resection. Decompensation possible after surgery. Very good liver function needed if for resection. Decompensation possible after surgery.  Liver left behind after resection still has malignant potential and recurrence rates are 50-60% after five years. Liver left behind after resection still has malignant potential and recurrence rates are 50-60% after five years.

Ablative therapy - Alcohol (ethanol) injection -  this is done percutaneously and has been carried out on small tumours in those with good underlying liver function. this is done percutaneously and has been carried out on small tumours in those with good underlying liver function.  Limited ablation success and high recurrence rates for Larger lesions Limited ablation success and high recurrence ratesLarger lesions

Treatment - 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 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. high frequency ultrasound probes are placed into the tumour mass.  relatively new technique that produces tumour necrosis. relatively new technique that produces tumour necrosis.  It may be more effective than ethanol injection for larger tumours. It may be more effective than ethanol injection for larger tumours.  This procedure is approved by NICE.

Microwave ablation -  this is approved by NICE. this is approved by NICE.  It destroys tumour cells by heat and results in localised areas of necrosis and tissue destruction. 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 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. Acetic acid, laser or cold ablation may also be used.

Chemoembolisation  delivery of high concentrations of chemotherapy drugs directly to the tumour via the hepatic artery using embolising agents such as cellulose. delivery of high concentrations of chemotherapy drugs directly to the tumour via the hepatic artery using embolising agents such as cellulose.  used in those with preserved liver function with large or multifocal tumours without vascular invasion or extrahepatic spread, and who have no symptoms. used in those with preserved liver function with large or multifocal tumours without vascular invasion or extrahepatic spread, and who have no symptoms.  effective in reducing tumour size as well as treating pain or bleeding. effective in reducing tumour size as well as treating pain or bleeding.  Median survival is >2 years Median survival is >2 years

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

Other treatments  Retinoids and adaptive immunotherapy (using primed peripheral lymphocytes) Retinoids and adaptive immunotherapy (using primed peripheral lymphocytes)  CyberKnife® stereotactic radiosurgery is a new technology. 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. 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. 1 This is not widely available at present.

Interferon treatment in chronic hepatitis  Treatment of chronic hepatitis C can clear the virus in more than half of people treated. Treatment of chronic hepatitis C can clear the virus in more than half of people treated.

NICE recommends a combination therapy of pegylated interferon and ribavirin for the treatment of chronic hepatitis C.

Prognosis - depends on the extent of underlying cirrhosis  Median survival ~ about 6 months.  Liver failure can occur with death  < cachexia, variceal bleeding and, occasionally, tumour rupture with intraperitoneal bleeding.

Surgical resection, liver transplantation and ablation by radiofrequency or ethanol injection are now conventional therapies for early stage disease.

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