Much of the progress in the developing field of hepatocellular carcinoma (HCC) depends on general progress: in public health initiatives based on improved knowledge in epidemiology, in many non-cancer-related areas such as antiviral therapeutics and treatment of chronic liver diseases leading to cancer prevention, in diagnostic modalities making early tumour detection possible, in accurate staging which guides better treatment selection, and in non-surgical and surgical treatments leading to improved safety and improved prognosis.
In the current issue, Leong & Leong outline the marked geographical variation of HCC worldwide, and emphasize the magnitude of the problem, which is becoming increasingly important in the western world, with increasing rates of hepatitis C (HCV) infection. Research into the aetiological factors of HCC leads to the conclusion that as with other carcinomas, HCC develops by a multi-step mechanism which involves complex interactions between multiple factors. Environmental factors which have been found to be closely related to HCC are chronic hepatitis B (HBV) infection, HCV infection, chemical carcinogens and plant toxins. Although chronic alcohol abuse often complicates HCC, alcohol is not a cirrhosis-causing agent and has not been shown to have a carcinogenic effect in the liver. However, alcohol may play a role as a co-carcinogen with other agents. Smoking also induces the cytochrome P450 system, thus having a synergistic effect with alcohol and chronic HBV infection, and is a significant risk factor for HCC in some countries. Some genetic diseases and inborn errors of metabolism are known to be associated with HCC. HCC displays numerous genetic abnormalities, mutations and epigenetic alterations. Because HCC exhibits a high degree of genetic heterogeneity, it is likely that multiple molecular pathways are involved in the production of subsets of hepatocellular tumours. The concept of premalignant lesions of the liver and cellular alterations preceding fully developed HCC has been controversial. It is interesting to note from this article the diagnostic criteria used by histopathologists for early HCC. It is also very educational for a clinician to understand the meanings of the terms used by the histopathologists such as dysplastic nodule (and its synonyms), nodular regenerative hyperplasia, and large and small liver cell dysplasia.
The high incidence of HCC and its poor prognosis are the two reasons that are especially relevant in considering the need to prevent this tumour. Primary prevention lends itself particularly well to viral, chemical and physical causes of HCC. Primary prevention could best be accomplished by immunization against HBV. Unfortunately, despite considerable research over a number of years, there appears to be little likelihood of a vaccine against HCV becoming available in the near future. Other forms of primary prevention against HBV and HCV include safe injection practices, screening of donated blood for the presence of hepatitis viruses, the rational use of viral inactivation steps in the manufacture of blood products, passive immunization and antiviral agents. Aflatoxin B1 is the most potent human hepatocarcinogen and it is produced by the fungi Aspergillus flavus and A. parasiticus. Attempts at primary prevention in this area need to focus on minimizing contamination by these fungi during the growth of crops and improper storage.
Dietary iron overload in Black Africans in urban parts of sub-Saharan Africa has virtually disappeared as a result of a change in their drinking habits from homebrewed sorghum-based beverages with a high iron content to commercially available iron-free varieties of alcohol. However, the pattern of alcohol consumption in rural areas remains largely unchanged and a large-scale intervention programme has yet to be attempted. Attempts have also been made in China to urge the rural population to drink running water or deep well-water to prevent the population from using ditch, pond or river water contaminated by blue-green algae that produce microcystins. Minor risk factors are oral contraceptive steroids and smoking. Secondary prevention entails the use of natural or synthetic chemicals to block, retard, or reverse the carcinogenic process. Preliminary evidence indicates that chemoprevention might be possible with the use of chlorophyllin, oltipraz and polyprenoeic acid. A decrease in the risk of HCC correlates with an increased consumption of leafy, green vegetables. Other chemoprevention possibilities include the use of glycosinolates and isothiocyanates from broccoli sprouts. The ‘de-ironing’ of patients with hereditary haemochromatosis by repeated venesection would be expected to have a secondary preventive effect against HCC formation both by reversing the accumulation of iron and by preventing the development of cirrhosis. Attempts have also been made in tertiary prevention of HCC to prevent the progression of chronic hepatitis or cirrhosis to HCC by treating the preneoplastic virally induced necroinflammation. Interferon-alpha has been used for both HCV- and HBV-induced diseases, and glycyrrhizin has been tried in chronic HCV infection. These agents may be regarded as being immunopreventive by functioning as biological response modifiers. An excellent article by Kew on the prevention of HCC appears in this issue of HPB.
In recent years the focus of much research on HCC has revolved around diagnostic strategies to identify early HCC, which is potentially amenable to curative therapy. HCC classically arises and grows in a silent fashion, making its diagnosis challenging prior to the development of late stage disease. Although surveillance of individuals at risk for HCC is an attractive strategy for early diagnosis, whether screening is cost-effective is still a matter of controversy. The cost of surveillance for HCC varies according to the region, population incidence and screening tools used. The clinical presentations of patients with HCC relate to the extent of the tumour, the hepatic reserve at the time of diagnosis and whether the tumours present with complications (such as tumour rupture), metastases or paraneoplastic phenomena. Bialecki & Di Bisceglie have provided an excellent review on the role of tumour markers, ultrasound, computed tomography, magnetic resonance imaging, angiography and positron emission tomography in diagnosing and staging HCC. Furthermore, the value and the potential risks of liver biopsy are discussed in this article on the diagnosis of HCC.
Cancer staging should serve to select the appropriate primary and adjuvant therapy, to estimate the prognosis, to assist in the evaluation of the results of treatments, and to exchange information without ambiguity. In HCC, apart from treatment efficacy, patient survival is related to tumour stage, degree of liver function impairment of the underlying cirrhotic liver and the general health status of the patient. The article by Pons et al. on the staging systems for HCC discusses in detail the staging systems that are currently in use in different parts of the world. Some of these staging systems use tumour stage and its variables only (ER classification) while some use tumour stage (and its variables) and liver function (Okuda stage, CLIP classifications, TNM staging), whereas others use tumour stage (and its variables), liver function and health status of the patients (French classification, BCLC staging and CUPI index). The value and the limitations of each of these staging systems are reviewed, making this article very interesting to read.
Surgery, including liver transplantation (LT), remains the most efficient treatment for patients with HCC. Unfortunately only about 15–30% of patients are eligible for surgical treatment at the time of clinical presentation because of the extent of the tumour and associated cirrhosis. HCC which develops in a non-cirrhotic liver has a much better long-term result than in cirrhosis. These favourable results are observed in both fibrolamellar and non-fibrolamellar HCC variants, suggesting that the absence of underlying liver disease is a major factor in short- and long-term prognosis. In the article by Belghiti & Kianmanesh on surgical treatment of HCC, details are given on the indications for hepatectomy, preoperative evaluation of liver functional reserve, extent of resection, and factors that lead to improvements in results of surgical resection, including the use of intermittent inflow occlusion and anterior approach. The approach to recurrence following resection of HCC and the results of liver resection are also reviewed. This article also covers LT for the treatment of HCC, including tumour management while awaiting LT and the increasing use of living donor LT. Living donor LT opens the potential for the expansion of the Milan criteria, which are now commonly used.
Recent developments suggest that apart from surgery, other therapeutic modalities such as radio-frequency ablation (RFA) and percutaneous ethanol injection (PEI) are also potentially ‘curative’. Johnson in his excellent article reviews the non-surgical treatment of HCC. He classifies the non-surgical treatment into locoregional (which includes intra-arterial or percutaneous local ablative approaches) or systemic therapy. These different types of treatment can be combined in the treatment of HCC. Intra-arterial therapy reviewed by the author includes transcatheter oily chemoembolization or internal radiation with intra-arterial radioisotopes. Local ablative therapies reviewed include PEI, RFA, cryotherapy and laser ablation. Systemic therapies reviewed include systemic chemotherapy, and hormonal and biotherapy. Loco-regional therapies are capable of delivering complete local control of HCC in a percentage of patients, the percentage decreasing as the tumour size increases. Unfortunately recurrence after local control might be a rule. To date, systemic therapy has not convincingly been demonstrated to be effective in the treatment of HCC.
This special issue on hepatocellular carcinoma contains articles from experts from different parts of the world. The topics and the authors have been carefully chosen and the articles have been extremely well written. I am sure that these articles will be referred to by future authors for many years to come.