Hepatocellular carcinoma is the most common primary liver malignancy.
Epidemiology
Hepatocellular carcinoma is highly variable in geographic distribution due to hepatitis infection, exposure to aflatoxin, and lifestyle factors. The highest risk areas are sub-Saharan Africa, eastern Asia and the Pacific islands.
Hepatocellular carcinoma is most common in men in all regions. The median age of diagnosis varies considerably from early adulthood in China to later life in the USA and Europe.
The incidence in Australia is about 3.1 per 100,000 people per year.
Aetiology
Liver cirrhosis is the single most important preceding factor for development of hepatocellular carcinoma, and is present in most patients with the disease.
Endemic infection with hepatitis B virus is the most commonly associated cause, conveying a 100-fold increase in risk. There is Exposure to aflatoxin in this population is also common and perhaps syngergistic with HBV. In Australia, hepatitis C infection and alcoholic liver cirrhosis are more important.
Less common factors include haemochromatosis and use of anabolic steroids.
Hepatitis
Hepatitis B is strongly indicated in the development of hepatocellular carcinoma. Rates of the cancer have fallen with the introduction of the hepatitis B vaccine. The HBV genome is often incorporated into the DNA of hepatocellular carcinomas.
In contrast, Hepatitis C appears to lead to hepatocellular carcinoma through the induction of cirrhosis in infected patients rather than incorporation into hepatocyte DNA.
Lifestyle
Alcohol is the most important risk factor in Australia which has low rates of both HBV and HCV. It is also synergistic with the effects of HBV and HCV. Alcohol leads to hepatocellular carcinoma by causing cirrhosis.
Environmental
Aflatoxin is a product of Aspergillus and may be found in grains in tropical countries. It is a potent carcinogen, particularly in combination with hepatitis B virus infection. When activated, it is able to cause a particular mutation in TP53 which is often seen in patients from countries where aflatoxin is encountered.
Natural History
Cirrhosis is the 'pre-invasive' histology. Pre-invasive lesions arise from cirrhosis. Poorly differentiated tumours are thought to arise from well differentiated tumours.
Tumours tend to spread locally into the portal vein (70%) and to distant sites within the liver. Bile duct invasion is notably rare. Haematogenous spread occurs to the lungs.
Clinical Presentation
Symptoms
Patients present with weight loss, fatigue, and abdominal pain, often due to the cirrhosis rather than the malignancy which may be found incidentally.
Signs
Ascites and hepatomegaly are the most common presenting signs. Jaundice, splenomegaly or fever may also be present.
Bloods
Alpha-feto-protein is frequently elevated in hepatocellular carcinomas and is diagnostic in combination with the typical triple-phase CT appearance.
Normal liver function tests are frequently deranged, but may be due to cirrhosis rather than the malignancy.
Imaging
CT
Non-contrast CT is insufficient for evaluation of hepatocellular carcinoma due to minimal difference in enhancement between the tumour and the liver parenchyma. Triple phase contrast CT is recommended:
- In the arterial phase, the tumour takes up contrast more rapidly than the liver parenchyma
- In the venous and delayed phases, the tumour has significantly less contrast uptake than the liver parenchyma
This pattern is diagnostic of hepatocellular carcinoma when combined with an elevated AFP.
Ultrasound
MRI
MRI with contrast also provides good delineation of hepatocellular carcinoma but images may be compromised by slow acquisition time and breathing artefact.
PET
Hepatocellular carcinomas are often PET avid and this technique is appropriate, but not government funded, for staging investigations.
Tissue Diagnosis
For a suspected hepatocellular carcinoma with the classical CT appearance and elevated AFP, formal tissue biopsy prior to surgery is not recommended as it may lead to tumour spillage. Other cases require biopsy before proceeding, and regardless the risk of tumour spillage is low.
Tumour/Normal Tissue Features
Macroscopic
The appearance macroscopically is most dependent on the health of the underlying liver. In normal liver, the tumour is frequently large without a capsule; tumours arising in the cirrhotic liver often have a capsule and septations. There may be intrahepatic metastases of the tumour.
Microscopic
Malignant hepatocytes surrounded by a sinusoidal stroma is the classical appearance. The sinusoids are the classical feature of hepatocellular carcinoma. The architecture is usually trabecular in well differentiated tumours, but may also show glandular, acinar or other architecture. Poorly differentiated tumours show increased cellular anaplasia and minimal sinusoidal spaces.
Immunohistochemistry
The hepatocyte protein
Genetics
TP53, as described above, is often the target of a point mutation in patients with exposure to aflatoxin. The HBV X gene (from HBV infection) may be incorporated into the DNA; the protein product of this gene binds to the p53 protein and inhibits its function. Activation of oncogenes is rare.
Staging / Classification
Staging is via TNM.
T Stage
T1: Solitary tumour with no vascular invasion
T2: Solitary tumour with vascular invasion or multiple tumours (largest < 5 cm)
T3: Multiple tumours > 5 cm or invasion of major branch of portal/hepatic vein
T4: Invasion of adjacent structures or penetration of visceral peritoneum
N Stage
N1: Regional nodal disease (porta hepatis, hepatic ligament, hepatoduodenal ligament, inferior vena cava, hepatic artery or those along the portal vein)
M Stage
M1: Distant metastatic disease
Final Stage
| Stage | T | N | M |
|---|---|---|---|
| I | T1 | N0 | M0 |
| II | T2 | N0 | M0 |
| IIIA | T3 | N0 | M0 |
| IIIB | T4 | N0 | M0 |
| IIIC | Tany | N1 | M0 |
| IV | Tany | Nany | M1 |
