Liver cancer tumours can either be metastatic (90%) or primary (10%). In this article we will focus on hepatocellular carcinoma (HCC) – the main primary liver tumour, and end with a brief discussion of secondary liver cancers.
Hepatocellular carcinoma is the sixth most common cancer worldwide and the third leading cause of cancer death.
The incidence rates vary significantly across the globe. In China there are 401 cases per 100,000 people, whilst in the UK there are just 13 cases per 100,000 people – the majority of which occur in those over the age of 70 years, and 64% of cases occurring in males.
HCC arises as a result of a chronic inflammatory process affecting the liver. The aetiology of the inflammation varies, yet worldwide it is most commonly due to viral hepatitis.
Other common causes for HCC are chronic alcoholism, hereditary haemochromatosis, primary biliary cirrhosis (PBC), and aflatoxin (a toxic fungal metabolite that can be found on cereals and nuts).
Hepatocellular carcinoma commonly occurs in the setting of cirrhosis and therefore its main risk factors are those which cause cirrhosis:
- Viral hepatitis
- A recent meta-analysis found that smoking is associated with a 51% increased risk of HCC
- High alcohol intake
- Advanced age (>70yrs)
- Aflatoxin exposure
- Family history of liver disease
Hepatitis B and C are both carcinogenic. In developing countries, viral hepatitis accounts for around 90% of HCC cases. HCC is found more commonly among Asian persons, secondary to childhood infections with hepatitis B – however this is declining due to current vaccination programmes. In the UK, only 16% of cases are thought to arise secondary to hepatitis.
While the combined oral contraceptive pill is known to increase the risk of hepatic adenomas, data remains inconclusive regarding its relationship with malignant disease.
The main presenting symptoms of hepatocellular carcinoma are that of liver cirrhosis. This may include vague, non-specific symptoms, such as fatigue, fever, weight loss and lethargy.
A dull ache in the right upper abdomen is uncommon, yet when present is characteristic of hepatocellular carcinoma, and should raise suspicion in patients with cirrhosis. Advanced disease may present with features of liver failure – e.g. ascites, jaundice, and signs of portal venous hypertension.
On examination, an irregular, enlarged, craggy and tender liver is highly suggestive of liver malignancy.
In a patient presenting with liver failure or non-specific liver signs, other differential diagnoses include:
- Infectious hepatitis (presence of specific serology)
- Cardiac failure (smooth hepatomegaly)
- Benign hepatocellular adenoma
- Other causes of liver cirrhosis (described above).
A patient with suspected liver cancer should have initial liver function tests (ALP, ALT, AST, bilirubin), which may be deranged. Other routine bloods should be taken, which may show low platelets and prolonged clotting associated with liver failure.
An alpha fetoprotein (AFP) level should be measured, as it is raised in 70% of cases. It is also used to monitor treatment response and recurrence.
Note: If AST:ALT ratio >2, likely alcoholic liver disease; if AST:ALT around 1, likely viral hepatitis.
Ultrasound is the initial imaging modality of choice. If a mass of >2cm is found with a raised AFP, this is virtually diagnostic. This may then be followed by a staging CT scan for further evaluation.
Patients with rising AFP and suggestive US nodules can also undergo MRI liver scanning for further assessment*. If the diagnosis is still in doubt, a biopsy or percutaneous fine-needle aspiration may be performed to confirm, yet is last-resort due to difficulties commonly in this setting of active ascites and/or deranged clotting, and the risks associated with biopsy and tumour-seeding.
*MRI scanning and contrast CT angiography may demonstrate a mass with arterial hypervascularisation – a characteristic feature of HCC.
The Barcelona Clinic Liver Cancer staging system (BCLC) is the most accepted staging system for HCC. It takes into account the tumour stage, liver function, physical status and cancer related symptoms to provide guidance on what treatment is most suitable.
The Child-Pugh score is a predictor of mortality from cirrhosis. Those with a high Child-Pugh score are less likely to respond to curative treatments.
In the UK, treatment for hepatocellular carcinoma is organised through a multidisciplinary team – including oncologists, radiologists, hepato-biliary surgeons, and specialist nurses.
Surgical resection and transplantation are the only curative options, but are limited by tumour size and liver function.
- Surgical resection – the treatment of choice in patients without cirrhosis and with a good baseline health status. Five-year recurrence of HCC post-resection occurs in 50-60% of cases.
- Transplantation – can be considered in patients that fulfil the Milan Criteria:
- One lesion is smaller than 5cm or three lesions are smaller than 3cm
- There are no extrahepatic manifestations
- There is no vascular infiltration
Liver transplantation is a significant operation; therefore patient’s pre-existing co-morbidities will need to be considered. A Model for End Stage Liver Disease (MELD) score can be used to predict the likelihood of a patient tolerating their transplant.
Image-guided ablation is indicated for patients with early HCC (BCLC 0 or A). Ultrasound probes (or microwave probes) are placed in the tumour mass to induce necrosis.
Alcohol ablation is another technique, involving the injection of alcohol into the tumour, acting to destroy the malignant tissue. It is most effective on small tumours in those with well-functioning livers, also being the treatment of choice in those with small inoperable cancers.
Transarterial Chemoembolisation (TACE)
TACE is reserved for patients with BCLC stage B (a large multinodular tumour), whereby high concentrations of chemotherapy drugs are injected directly into the hepatic artery, and an embolising agent (e.g. cellulose) is then added to induce ischaemia.
Radiological techniques are used to selectively inject and embolise the branches of the hepatic artery supplying the tumour, which preserves the majority of the liver.
Note: Other non-surgical therapies include systemic chemotherapy, anti-angiogenesis agents and Tyrosine kinase inhibitors – these are beyond the scope of this article. Sorafenib is a tyrosine kinase inhibitor and is the only drug that has been currently demonstrated to extend survival in individuals with advanced HCC.
The prognosis of hepatocellular carcinoma depends on the extend of the underlying cirrhosis – as this plays a large role in determining how aggressively the cancer can be treated.
Median survival time from diagnosis is around 6 months.
Secondary Liver Malignancy
Metastatic liver cancer is the most common underlying cause of death in patients with cancer.
The most common cancers that metastasise to the liver are those from bowel (via the portal circulation), breast, pancreas, stomach, and lung.
Clinical features and investigations are similar to that of HCC. Hepatomegaly and ascites are present in roughly half of patients, alongside non-specific cancer symptoms; patients may be jaundiced or have upper abdominal pain.
Bloods may show derangement of LFTs, with ALP almost invariably raised (a sign of biliary obstruction), and ultrasound scanning is often the initial imaging modality of choice. A CT scan may be used secondarily to stage metastases, allowing imaging of the rest of the body and also the opportunity to investigate the source of the metastasis.
Biopsy is not advised if the tumour is operable, as the needle tract may lead to seeding of tumour.
For the majority of patients with metastatic liver disease, the primary tumour has metastasised to other sites, which makes surgery a more difficult and less useful option. Oncological and palliative services are often closely involved in the decision making process.
Surgery may be indicated in patients with metastases confined to the liver who have their primary tumour under control. Alternative treatment methods include transarterial chemoembolisation and selective internal radiotherapy.
Note: A 2014 systematic review found no particular surgical method to be the most effective of resecting metastatic colorectal tumours.