Hepatocellular Carcinoma

oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

In most cases, hepatocellular carcinoma develops in patients with chronic liver disease (70-90% of all patients).[1] Hepatocellular carcinoma accounts for 90% of all liver cancers.[2] Tumours are multifocal in the liver in 75% of cases at diagnosis.[2]

The incidence of primary liver cancer is increasing in several developed countries and the increase will likely continue for some decades. This is due to infection with hepatitis B and hepatitis C viruses, which peaked in the 1950s to 1980s. In some developing countries, the incidence of primary liver cancer has decreased, possibly as a result of the introduction of hepatitis B vaccine. The geographic variability in incidence of primary liver cancer is largely due to the distribution and the natural history of the hepatitis B and C viruses.[3]

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

  • Worldwide, its prevalence follows that of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection.[3][4]
  • Incidence is highest in Asia and sub-Saharan Africa with as many as 120 cases per 100,000.[4] It is relatively uncommon in Europe and North America.
  • The age-standardised incidence rate for liver cancer in the UK in 2008 was 4.3 per 100,000 population.[5]
  • HCC usually occurs 20-30 years after the initial liver insult.[4]
  • The average age of development of HCC in the UK is 66 years.
  • HCC is four to eight times more common in men.[2]
  • HCC is the second most common hepatic malignancy in children (behind hepatoblastomas):[6] it usually occurs in children with pre-existing liver disease (hepatic fibrosis and cirrhosis), eg secondary to metabolic liver disease, viral hepatitis, chemotherapy or total parenteral nutrition.

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Causes

Patients with cirrhosis have the highest risk of developing HCC.[1] 90-95% of people who develop HCC have underlying cirrhosis but non-cirrhotic HCC does occur. Cirrhosis may be due to:

It usually presents with symptoms of advancing cirrhosis and liver failure.

Symptoms

Signs

Metastases can develop in the lung, portal vein, periportal nodes, bone or brain.[4]

  • Patients at high risk for HCC should be offered entry into surveillance programmes. These patients include all cirrhotic HBV carriers, non-cirrhotic patients with high HBV DNA concentration, and patients with HCV-related or alcoholic cirrhosis.
  • Surveillance should be performed using ultrasonography at 6- to 12-monthly intervals, associated or not with alpha-fetoprotein (AFP) determination, in order to detect early HCC amenable to curative surgical treatment.

Screening tests for HCC

  • The efficacy and cost-effectiveness of screening programmes for at-risk patients is unclear.
  • Although HCC may be discovered at an earlier stage, there is a lack of curative treatment options in all patients with cirrhosis. Therefore, for some, earlier tumour detection may not lead to improvements in survival.[4]

Possible screening tests include:

  • AFP:
    • The normal range for AFP is 10-20 ng/mL. The diagnostic sensitivity of AFP for detecting HCC is around 60%.[1]
    • A level of >400 ng/mL may be regarded as diagnostic for HCC by some.
    • But note: two thirds of HCC <4 cm have AFP levels <200 ng/mL and up to 20% of HCC do not produce AFP.
    • High levels of AFP may be seen in regenerating nodules in viral cirrhosis, so false positives may occur.
  • Imaging:
    • The preferred imaging method for surveillance is ultrasound, which has a sensitivity of 60-80% and specificity of over 90%.[1]

Combining both USS and AFP measurements seems to be better as a screening tool.

  • A focal liver lesion in someone with cirrhosis is highly likely to be HCC.
  • 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. CT of the liver can look for local spread and CT of the thorax can look for metastases.
  • 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.[10] However, controversy exists over these figures.[4]

Other investigations:

  • AFP is elevated in 75% of cases.[4] A level of >400 ng/mL may be regarded as diagnostic by some.
  • LFTs may be consistent with cirrhosis.
  • Check for clotting abnormalities.
  • Albumin may be low.
  • CXR may show a raised right hemidiaphragm or lung metastases.

See also separate article Liver tumours.

A number of staging systems have been developed. Those that incorporate the state of liver function and the patient's clinical state (eg 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) enables an estimation of survival. A score between 0-2 for each of the four features listed below. The cumulative score ranging from 0-6 is the CLIP score:[4]
    • 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 separate related Cirrhosis article.)
      • 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.
    • AFP:
      • 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; with a score of 2, 13 months; with a score of 3, 8 months; and scores of 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.[1] The BCLC classification has been validated in different settings and establishes treatment recommendations for all stages of HCC.

The mainstay of treatment is resection and chemotherapy but many tumours are unresectable at presentation.

For more details see separate articles Cirrhosis and Liver failure.

Liver transplantation

  • Only about 5% of people with HCC are suitable for transplantation.[4]
  • Because of limited donors, the 'Milan criteria' help to select transplantation candidates carefully.[8] Liver transplantation is most beneficial for individuals who are not good candidates for resection, especially those within Milan criteria (solitary tumour ≤5 cm and up to three nodules ≤3 cm).[1]
  • For patients being considered for liver transplantation, a Model for End-stage Liver Disease (MELD) score is mandatory.[2]

Tumour resection

  • Resection is the treatment of choice for hepatocellular carcinoma in individuals without cirrhosis.[1]
  • 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 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.

Ablative therapy

Image-guided tumour ablation is now a standard treatment option for patients with early-stage HCC.[1]

  • 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. 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.
  • Radiofrequency ablation - high-frequency ultrasound probes are placed into the tumour mass. This is a relatively new technique that produces tumour necrosis. It may be more effective than ethanol injection for larger tumours. More studies are needed. This procedure is approved by the National Institute for Health and Clinical Excellence (NICE).[11] Radiofrequency ablation is considered as a possible first-line treatment for patients with a single small HCC tumour up to 3 cm.[12]
  • 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.[13]
  • Acetic acid, laser or cold ablation may also be used.[4]

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.[8]
  • It seems to be effective in reducing tumour size as well as treating pain or bleeding.
  • Careful patient selection is crucial prior to transarterial chemoembolisation, as the procedure may be associated with an increased risk of liver failure.[12]
  • Median survival is >2 years and there is work to improve this by using better embolic agents and increasing the local exposure to chemotherapy.[14]

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.[15] One meta-analysis concluded that sorafenib should be the first-line treatment in patients with advanced and inoperable HCC but that the role of sorafenib in the management of early-stage HCC remains to be determined.[12] However, NICE does not recommend sorafenib for the treatment of advanced HCC in patients for whom surgical or locoregional therapies have failed or are not suitable.[16]

Other treatments

  • Retinoids and adaptive immunotherapy (using primed peripheral lymphocytes) have been used to help prevent tumour recurrence after ablation or resection. 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.[4] This is not widely available at present.
  • Image-guided transcatheter treatments are based on selective intravascular delivery of drugs into the arterial vessels supplying the tumour. These treatments are considered for patients with large cancers or multifocal disease that is not amenable to curative treatments. Chemotherapy drugs, embolic particles or radioactive materials can be injected and induce tumour necrosis.[1]
  • This depends on the extent of underlying cirrhosis, as this can limit the treatment options.
  • Median survival from time of diagnosis is about six months.[4]
  • Liver failure can occur with death due to cachexia, variceal bleeding and, occasionally, tumour rupture with intraperitoneal bleeding.[4]
  • Surgical resection, liver transplantation and ablation by radiofrequency or ethanol injection are now conventional therapies for early-stage disease. With these treatments, survival at five years is between 50% and 70%.[8]
  • High AFP concentration is associated with a poor prognosis.[1]
  • The hepatitis B vaccine will, it is hoped, reduce the incidence of HCC.[3]
  • A sensible approach to alcohol consumption would also be beneficial.
  • Patients with cirrhosis are at highest risk of developing this malignant disease, and ultrasonography every six months is recommended. Surveillance with ultrasonography allows diagnosis at early stages when the tumour might be curable by resection, liver transplantation, or ablation, and five-year survival higher than 50% can be achieved.[1]

Further reading & references

  1. Forner A, Llovet JM, Bruix J; Hepatocellular carcinoma. Lancet. 2012 Mar 31;379(9822):1245-55. Epub 2012 Feb 20.
  2. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2010)
  3. Bosch FX, Ribes J, Diaz M, et al; Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004 Nov;127(5 Suppl 1):S5-S16.
  4. Stuart KE et al, Primary Hepatic Carcinoma, Medscape, May 2012
  5. Liver cancer statistics - UK, Cancer Research UK
  6. Gow KW et al, Pediatric Liver Tumors, Medscape, Mar 2012
  7. Calle EE, Rodriguez C, Walker-Thurmond K, et al; Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003 Apr 24;348(17):1625-38.
  8. Bruix J, Llovet JM; Major achievements in hepatocellular carcinoma. Lancet. 2009 Feb 21;373(9664):614-6.
  9. Chuang SC, La Vecchia C, Boffetta P; Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV Cancer Lett. 2009 Dec 1;286(1):9-14. Epub 2008 Dec 16.
  10. Silva MA, Hegab B, Hyde C, et al; Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut. 2008 Nov;57(11):1592-6. Epub 2008 Jul 31.
  11. Radiofrequency ablation of hepatocellular carcinoma, NICE (2003)
  12. Salhab M, Canelo R; An overview of evidence-based management of hepatocellular carcinoma: a J Cancer Res Ther. 2011 Oct-Dec;7(4):463-75.
  13. Microwave ablation of hepatocellular carcinoma, NICE Interventional Procedure Guideline (2007)
  14. Bruix J, Sala M, Llovet JM; Chemoembolization for hepatocellular carcinoma. Gastroenterology. 2004 Nov;127(5 Suppl 1):S179-88.
  15. Llovet JM, Ricci S, Mazzaferro V, et al; Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90.
  16. Hepatocellular carcinoma (advanced and metastatic) - sorafenib (first line), NICE Technology Appraisal (May 2010)

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Michelle Wright
Current Version:
Peer Reviewer:
Dr John Cox
Last Checked:
13/06/2012
Document ID:
2253 (v23)
© EMIS