Diagnosis and Treatment of hepatocellular carcinoma ( HCC )

Risk factors:

HCC is unusual among human cancers in that the etiological agent responsible is usually readily identifiable. The prevalence of HCC worldwide parallels that of viral hepatitis. Alcohol, genetic haemochromatosis and rarely primary biliary cirrhosis are associated.
The risk of HCC development is much greater in men for the majority of aetiologies.
Cirrhosis is present in the vast majority of patients with HCC in the UK and europe: estimates varies between 90 % and 95 %. It is unclear if cirrhosis per se is biologically important in the tumorigenic pathway, or if tumour development and fibrogenesis take place concurrently but with fibrosis taking a shorter time period.
Non-cirrhotic HCC occur in the young patients ( fibrolamellar variant ) and in the elderly ( apparent de novo HCC )

Natural History of HCC:

• The estimated doubling time is one to 19 months with a median of 6 months.
• 50 - 90 % of patients with Child Pugh A cirrhosis will survive a year untreated with only 20 % of Child Pugh C patients.
• Smaller HCC at presentation have realtively long tumor doubling time and overall survival with tumour size less than 5 cm was 81 -100 % at one year and 17 - 21% at three year with no therapy.

Screening:

As per British Gastroenterology guidelines, surveillance for hepatocellular carcinoma should be considered in the following high risk groups:

1. Male and Female with established cirrhosis due to hepatitis B virus, particularly those with ongoing viral replication.
2. Male and Female with established cirrhosis due to HCV.
3. Male and Female with established cirrhosis due to genetic haemochromatosis.
4. Male with alcohol related cirrhosis who are abstinent from alcohol or likely to comply with treatment
5. Male with cirrhosis due to primary biliary cirrhosis.

The risk of HCC development in cirrhosis due to autoimmune hepatitis, primary sclerosing cholangitis in both sexes, and alcoholic and primary biliary cirrhosis in women is generally low.

If the surveillance is offered, it should be six monthly abdominal ultrasound assessments in combination with serum alpha feto protein estimation.

AFP, a normal serum protein synthesised by fetal liver cells and yolk sac cells, is the most widely used screening test for HCC. The normal range for AFP is 10 - 20 ng/ml and a level > 400 ng/ml is usually regarded as diagnostic. Two thirds of HCC less than 4 cm however has AFP levels less than 200 ng/ml and up to 20 % of HCC do not produce AFP, even when very large. A rising AFT over time, even if the levels does not reach 400 ng/ml is virtually diagnostic of HCC.

Diagnosis of HCC:

When a patient presents with a liver mass, irrespective of screening, there is a requirement to make a diagnosis and to stage the disease.

If the patient known to have pre-existing cirrhosis:

A mass greater than 2 cm has 95 % chance of being HCC.
- If the AFP is raised, this confirms the diagnosis and further investigation is only required to establish the most appropriate therapy.
- If the AFP is normal, further imaging ( CT/MRI or lipoidol angiography with follow up CT) will usually allow a confident diagnosis to be made.
- In a very few cases where there is real diagnosis in doubt, biopsy may be indicated.

A mass less than 2 cm on ultrasound, probably 75 % of such nodules turn out to be HCC. Again radiological diagnosis CT/MRI and AFP may establish a definitive diagnosis. If not either a repeat examination to show enlargement of the lesion, percutaneous fine needle aspiration, or biopsy may be indicated.

The risk of seedling of tumor in the needle tract occurs in 1 - 3 %. Biopsy of potentially operable lesions should be avoided where possible.

Treatment of HCC:

Surgical Methods:
The only proven potentially curative therapy for HCC remains surgical, either hepatic resection or liver transplatation, and patients with single small HCC ( less than 5 cm ) or up to three lesions less than 3 cm should be referred for assessments of these treatment modalities.

• Liver transplantation should be considered in any patient with cirrhosis.
• Hepatic resection should be considered as primary therapy in any patient with HCC and a non-cirrhotic liver.
• Hepatic resection can be carried out in highly selective patients with hepatic cirrhosis and well preserved hepatic function ( Child-Pugh A) who are unsuitable for liver transplantation.
• Patients with replicating HBV had a worse outlook due to HBV recurrence and were previously not considered candidates for transplantation. Effective antiviral therapy is now available and patients with small HCC, as defined above should be assessed for transplantation.

Non-surgical methods:

Non-surgical methods should only be used where surgical therapy is not possible.

• Percutaneous Ethanol injection ( PEI ) has been shown to produce necrosis of small HCC. It is best suited to peripheral lesions, less than 3 cm in diameter.
• Chemoembolisation
• Systemic chemotherapy with standard agents has a poor response rate.
• Hormonal therapy with tamoxifen has shown no survival beneift.