Quite often, it is assumed that liver cancer is synonymous with hepatocellular carcinoma (HCC). This is, however, not entirely true. We should be reminded that other malignant lesions could arise from the liver. These include hepatoblastoma that affects mainly the children, metastatic liver disease and more rarely, angiosarcoma, which is classically associated with prior exposure to vinyl chloride or thorotrast, and primary lymphoma of the liver. It is nonetheless true that HCC is indeed the commonest primary liver cancer in Singapore.

Mortality rates
Over the years, HCC remains as one of the top ten cancers that cause death in both males and females in Singapore. This does not only reflect the high frequency of HCC in our community but our current inability to provide good lifesaving treatment for HCC by the time many patients were diagnosed with the condition. This is particularly apparent if we look at the females with HCC. While the incidence of HCC is not among the top ten cancers afflicting the females, it is one of the top ten causes of cancer death in females. This is because curative and good palliative treatment that renders good survival is available for some of the other commoner cancers that affect females.

The difficulty in treating HCC is multi-fold:
(1)	in the background of liver cirrhosis, where HCC develops in most instances, there is a tendency of multricentricity (i.e. having more than one tumour occurring concurrently at different sites of the liver) which frequently precludes curative resection, as well as the propensity of recurrent HCC after initial successful curative resection;
(2)	advanced stage of disease at presentation due to the lack of early warning symptoms for HCC
(3)	the lack of good and effective palliative treatment for advanced HCC.

Identifying ‘at-risk’ population
It is precisely because of the silent nature of HCC that screening for early, resectable tumour in at risk population is recommended. Hence, it is important that we are able to identify the ‘at-risk’ population. Thank goodness, the majority, if not almost all, of the HCC tend to occur in specific population with known predisposing factors for HCC.

They include patients with chronic viral hepatitis B and C, patients with alcoholic liver disease and liver cirrhosis of other causes. There is, however, individual difference in HCC risk profiles among liver diseases of different aetiologies. For example, HCC may occur in young, non-cirrhotic hepatitis B patients, whereas the presence of cirrhosis is the single most important risk factor for development of HCC in patients with chronic hepatitis C.

Similarly, while both are hereditary disorders causing metal deposition in the liver, patients with haemochromatosis, which is associated with iron deposition, are more prone to develop HCC than patients with Wilson’s disease, which is associated with copper deposition. In addition, certain drugs and toxins, such as aflatoxins, anabolic steroids, etc, predispose the individuals to development of HCC.

Screening tools
The generally accepted screening tools for HCC include blood testing for alpha-fetoprotein level and ultrasonography of the liver. Screening tests are best offered to high-risk population. These tests can be done in 3 – 6 monthly and 6 - 12 monthly intervals, respectively, depending on the state of the patient’s liver disease and hence the individual’s risk of HCC. Upon discovery of any suspicious findings, further confirmatory tests, such as CT scan, MRI or hepatic angiography, can then be carried out.

Sometimes, the interpretation of an elevated alpha-fetoprotein level may be confounded by the concomitant presence of necroinflammation of the liver, such as in the case of chronic viral hepatitis B or C. Identification of L3, a variant form of alpha-fetoprotein, that is more specific for HCC, will decrease the false positive pick up rate during screening of HCC. This has recently been made available in the laboratory in SGH.

Tumour resectability
Upon diagnosis of HCC, the best available treatment option, whenever possible, is surgical resection. This, however, is limited by the extent of the tumour, as well as the patient’s hepatic function. Other than for very small tumour, when certain treatment option, such as alcohol injection 1, has proven to provide the same survival rate as surgical resection. Surgical option is considered to be the only curative option for HCC. The main limiting factors include multricentricity, portal vein thrombosis and metastatic liver disease.

In situations where the liver function is compromised by underlying liver cirrhosis, curative resection may be contraindicated for an otherwise operable tumour as the extent of resection demanded by the size or the location of the tumour may risk development of clinical decompensation of hepatic disease post-operatively. Sometimes, extensive resection may be necessary in order to get good tumour-free margin for tumours that, albeit small, are located close to a vessel. In such circumstances, liver transplantation and various palliative treatment options may be considered.

Other treatment options
To avoid recurrence of HCC in the liver allograft, liver transplantation for HCC should only be carried out in patients with limited tumour load within the liver when the contraindication for surgical resection is that of compromised liver function. 2 For the rest of the unfortunate patients, we’ll need to consider palliative treatment options, which may be in the form of regional or systemic treatment.

The former is for tumours that are limited to the liver only that include conventional transarterial chemoembolisation (TACE) and other newer treatment modalities such as radiofrequency ablation (RFA), targeted delivery of radioactive beads, etc; whereas chemotherapy will be the more appropriate therapeutic option for patients with metastatic disease. Unfortunately, each has their limitations and none has provided good, long-term survival. In the case of systemic chemotherapy, the cost of treatment and the associated side effects, which do not necessarily commensurate to its benefits, are significant limiting factors.

Hence, treating HCC should be individualised, taking into consideration the patient’s existing liver function, age and associated medical conditions. Various authors in this issue have discussed these topics in more detail.

Prevention
In conclusion, life-long surveillance is required for patients who are at risk of developing, and those who have already developed HCC. Routine screening using s. alpha-fetoprotein testing and ultrasonography is necessary to pick up these early, silent tumours that may be considered for curative surgical resection.

Prevention of HCC should be targeted at primary prevention of viral hepatitis and avoidance of excessive alcohol ingestion. Thus the importance of universal hepatitis B vaccination programme and public education on high-risk lifestyles is apparent. The benefit of hepatitis B vaccination at birth has been well demonstrated in Taiwan where there is a significant decrease in incidence of HCC in children in the recent years after implementation of universal hepatitis B vaccination policy for more than 10 years. 3 For patients who, unfortunately, already have chronic viral hepatitis B or C, regular follow-up and prompt treatment to prevent cirrhosis are the best secondary preventive measures.

By Dr Chow Wan Cheng
Head/Sr. Consultant
Dept of Gastroenterology,
Singapore General Hospital

Reference:

1	Kotoh K et al. The effect of percutaneous ethanol injection therapy on small solitary hepatocellular carcinoma is comparable to that of hepatectomy. Am J Gastroentrol 1994; 89:194–8.
2	Mazzaferro V et al. Liver transplantation for treatment of small hepatocellular carcinoma in patients with cirrhosis. N Engl J Med 1996; 334:693-9.
3	Lee CL et al. Trends in the incidence of hepatocellular carcinoma in boys and girls in Taiwan after large-scale hepatitis B vaccination. Cancer Epidemiology, Biomarkers & Prevention 2003; 12:57-9.