Prevention of hepatocellular carcinoma: progress and challenges

Hepatocellular carcinoma (HCC) is a lethal cancer for both men and women and is caused by multiple risk factors. Most patients with HCC have an underlying liver disease caused by either chronic viral infection due to hepatitis B or hepatitis C virus or non-viral etiologic risk factors such as alcohol, fatty liver disease, dietary aflatoxin exposure, smoking and diabetes mellitus. While these risk factors are progressively and persistently damaging the liver, the majority of patients show very few symptoms of HCC. By the time symptoms appear the cancer is typically at a very advanced stage with limited options for treatment. In order to prevent death from HCC, it is therefore critically important to reduce the prevalence of the major risk factors, identify and treat those at high risk for development of HCC, and institute effective surveillance strategies for early diagnosis and treatment of HCC. This article reviews the recent progress and current challenges to the prevention of HCC.     

Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment

Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.     

Current impact of viral hepatitis on liver cancer development: The challenge remains

Chronic infections due to hepatitis B and hepatitis C viruses are responsible for most cases of hepatocellular carcinoma (HCC) worldwide, and this association is likely to remain during the next decade. Moreover, viral hepatitis-related HCC imposes an important burden on public health in terms of disability-adjusted life years. In order to reduce such a burden, some major challenges must be faced. Universal vaccination against hepatitis B virus, especially in the neonatal period, is probably the most relevant primary preventive measure against the development of HCC. Moreover, considering the large adult population already infected with hepatitis B and C viruses, it is also imperative to identify these individuals to ensure their access to treatment. Both hepatitis B and C currently have highly effective therapies, which are able to diminish the risk of development of liver cancer. Finally, it is essential for individuals at high-risk of HCC to be included in surveillance programs, so that tumors are detected at an early stage. Patients with hepatitis B or C and advanced liver fibrosis or cirrhosis benefit from being followed in a surveillance program. As hepatitis B virus is oncogenic and capable of leading to liver cancer even in individuals with early stages of liver fibrosis, other high-risk groups of patients with hepatitis B are also candidates for surveillance. Considerable effort is required concerning these strategies in order to decrease the incidence and the mortality of viral hepatitis-related HCC.     

Endoscopic ultrasound and fine needle aspiration for the diagnosis of hepatocellular carcinoma

Liver cancer is one of the most frequent solid cancers. The major risk factor associated with the development of hepatocellular carcinoma (HCC) is cirrhosis caused by hepatitis B, hepatitis C virus or chronic alcohol consumption. The overall prognosis of patients with HCC is very poor and this is mainly due to the advanced stages of cancer at presentation and also because of underlying cirrhosis. When HCC is diagnosed at early stages, prognosis is better with five-year disease free survival of around 50% with resection, or local ablative treatments such as radio-frequency ablation or percutaneous ethanol injection, and 70-80% with liver transplantation. Therefore, systematic screening of all the high-risk patients is the key to an early diagnosis of small HCC and the use of an appropriate treatment modality. The currently available tools for the screening, surveillance and diagnosis of HCC in the presence of cirrhosis remain sub-optimal. The advancements made in the past 10 years, however, have made HCC a potentially curable disease in a highly selected group of patients. This review will briefly discuss the current guidelines for surveillance and diagnosis of HCC in high-risk subjects and then review the potential role of endoscopic ultrasound and fine needle aspiration for the diagnosis of small HCC.     

Diagnostic and therapeutic management of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is an increasing health problem, representing the second cause of cancerrelated mortality worldwide. The major risk factorfor HCC is cirrhosis. In developing countries, viral hepatitis represent the major risk factor, whereas in developed countries, the epidemic of obesity, diabetes and nonalcoholic steatohepatitis contribute to the observed increase in HCC incidence. Cirrhotic patients are recommended to undergo HCC surveillance by abdominal ultrasounds at 6-mo intervals. The current diagnostic algorithms for HCC rely on typical radiological hallmarks in dynamic contrast-enhanced imaging, while the use of α-fetoprotein as an independent tool for HCC surveillance is not recommended by current guidelines due to its low sensitivity and specificity. Early diagnosis is crucial for curative treatments. Surgical resection, radiofrequency ablation and liver transplantation are considered the cornerstones of curative therapy, while for patients with more advanced HCC recommended options include sorafenib and trans-arterial chemoembolization. A multidisciplinary team, consisting of hepatologists, surgeons, radiologists, oncologists and pathologists, is fundamental for a correct management. In this paper, we review the diagnostic and therapeutic management of HCC, with a focus on the most recent evidences and recommendations from guidelines.     

New advances in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the leading cause of deaths in cirrhotic patients and the third cause of cancer related deaths.Most HCC are associated withwell known underlying risk factors,in fact,HCC arise in cirrhotic patients in up to 90%of cases,mainly due to chronic viral hepatitis and alcohol abuse.The worldwide prevention strategies are conducted to avoid the infection of new subjects and to minimize the risk of liver disease progression in infected patients.HCC is a condition which lends itself to surveillance as at-risk individuals can readily be identified.The American and European guidelines recommended implementation of surveillance programs with ultrasound every six months in patient atrisk for developing HCC.The diagnosis of HCC can be based on non-invasive criteria(only in cirrhotic patient)or pathology.Accurately staging patients is essential to oncology practice.The ideal tumour staging system in HCC needs to account for both tumour characteristics and liver function.Treatment allocation is based on several factors:Liver function,size and number of tumours,macrovascular invasion or extrahepatic spread.The recommendations in terms of selection for different treatment strategies must be based on evidence-based data.Resection,liver transplant and interventional radiology treatment are mainstays of HCC therapy and achieve the best outcomes in well-selected candidates.Chemoembolization is the most widely used treatment for unresectable HCC or progression after curative treatment.Finally,in patients with advanced HCC with preserved liver function,sorafenib is the only approved systemic drug that has demonstrated a survival benefit and is the standard of care in this group of patients.     

A 6-month versus a 12-month surveillance for hepatocellular carcinoma in 559 hemophiliacs infected with the hepatitis C virus

Hepatocellular carcinoma (HCC) is an increasingly frequent cause of mortality in hemophiliacs with chronic viral hepatitis. Early diagnosis of the tumor at an initial stage is known to improve the outcome of HCC treatment. Because all HCC cases detected in a previous study based upon annual ultrasound (US) surveillance of hemophiliacs with elevated alanine aminotransferase levels were multinodular, this study was designed to evaluate if a more intense surveillance with US and alphafetoprotein (AFP) serum levels of all the patients infected with the hepatitis C virus (HCV) improved the identification of single nodule tumors. A multicenter cohort of 559 HCV-infected hemophiliacs was divided into 2 arms, one followed up at 6-month intervals and one at 12-month intervals depending on the choice and available facilities of each treatment center. During a 6-year surveillance period, HCC was diagnosed in 5 (2.4%) of 210 patients in the 6-month group and in 3 (0.9%) of 349 patients in the 12-month group. The overall incidence rate of HCC was 239 per 100 000 per year (397 per 100 000 per year in the 6-month group and 143 per 100 000 per year in the 12-month group; differences not statistically significant). By multivariate analysis, HCC risk was increased 12.9-fold with alcohol intake more than 80 g/d and 15.2-fold with AFP levels higher than 11 ng/mL. Liver-related death occurred in 8 cases (1.4%), including 3 with HCC. Still alive and tumor free after 24 to 34 months from diagnosis are 3 patients with multinodular tumors treated with repeat chemoembolization followed by orthotopic liver transplantation. In conclusion, 6-month surveillance with US did not increase the chances of detection of single nodule tumors, but it is reasonable to assume that successful treatment of multinodular tumors based upon debulking with chemoembolization and liver transplantation was facilitated by this approach.     

Prevention of hepatocellular carcinoma in the Asia–Pacific region: Consensus statements

Among approximately 650 000 people who die from hepatocellular carcinoma (HCC) each year, at least two‐thirds live in Asia. Efforts to improve early diagnosis and treatment have not yet impacted mortality. An Asia–Pacific Working Party convened in Hong Kong in June 2008 to consider ways to prevent HCC in this region. Separate reviews have summarized epidemiology of HCC, preventive approaches related to hepatitis B virus (HBV), hepatitis C virus (HCV) and non‐viral liver diseases, and the role of surveillance to detect HCC at a curative stage. We now present Consensus Statements from these deliberations and reviews. As chronic hepatitis B is the most common cause of HCC in Asia, effective hepatitis B vaccination programs are the most important strategy to reduce HCC incidence. Prevention of HCV by screening blood donors, universal precautions against blood contamination in health‐care settings and reducing HCV transmission from injection drug use are also vital. There is strong evidence that effective antiviral therapy to control HBV infection or eradicate HCV substantially reduces (but does not abolish) HCC risk. With hemochromatosis, family screening, early diagnosis and correcting iron overload to prevent liver fibrosis prevents HCC. There is currently insufficient evidence to give firm recommendations on alcohol, obesity/metabolic risk factors and other liver diseases. HCC surveillance for high‐risk groups is recommended in individual cases but cost‐effectiveness is not as high as infant hepatitis B vaccination and screening blood for HCV. Widespread application of HCC surveillance in Asia–Pacific countries depends on economic factors and health‐care priorities.     

Application of surveillance programs for hepatocellular carcinoma in the Asia–Pacific Region

Hepatocellular carcinoma (HCC) is a potential target for cancer surveillance (or screening) as it occurs in well-defined, at-risk populations and curative therapy is possible only for small tumors. Surveillance has been recommended by regional liver societies and is practiced widely, but its benefits are not clearly established. Hepatic ultrasonography with or without alpha fetoprotein (AFP) performed every 6 months is the preferred program. Surveillance of HCC has been well shown to detect small tumors for curative treatment, which may be translated to improved patient survival. However, most studies are limited by lead-time bias, length bias for early diagnosis of small HCC, different tumor growth rates and poor compliance with surveillance. Cost-effectiveness of surveillance programs depends on the rate of small HCC detected 'accidentally' (routine imaging) in a comparator group, annual incidence of HCC with various etiologies, patient age and the availability of liver transplantation. The incremental cost-effectiveness for 6-monthly AFP and ultrasound has been estimated from approximately $US26 000–74 000/quality adjusted life years (QALY). All cirrhotic patients are therefore recommended for HCC surveillance unless the disease is too advanced for any curative treatment. As chronic hepatitis B can develop into HCC without going through liver cirrhosis, high-risk non-cirrhotic chronic hepatitis B patients are also recommended for HCC surveillance. In conclusion, HCC surveillance could be effective at reducing disease-specific mortality with acceptable cost-effectiveness among selected patient groups, provided it is a well-organized program.     

Hepatocellular carcinoma in patients with autoimmune hepatitis

AIM： To evaluate and confirm the low incidence of hepatocellular carcinoma （HCC） in patients with autoimmune hepatitis （AIH）. At present only very few cases of HCC in patients with AIH and definite exclusion of chronic viral hepatitis have been published, suggesting that HCC due to AIH is rare. METHODS： In order to further investigate the incidence of HCC in patients with AIH, we reviewed our large cohort of 278 patients with AIH. RESULTS： Eighty-nine patients （32%） were diagnosed with liver cirrhosis, a preneoplastic condition for HCC. We studied a total of 431 patient years of cirrhosis in these patients, an average 4.8 years per patient. During this period none of the patients of our own study cohort developed HCC. However, three patients with HCC due to AIH associated liver cirrhosis were referred to our department for further treatment of HCC. In all three patients chronic viral hepatitis was excluded. CONCLUSION： We conclude that HCC may under rare circumstances develop due to chronic AIH dependent liver cirrhosis. Compared to other causes of liver cirrhosis such as chronic viral hepatitis, alcohol, or hemochromatosis, the incidence of HCC is significantly lower. Pathophysiological differences between AIH and chronic viral hepatitis responsible for differences in the incidence of HCC are yet to be further characterized and may lead to new therapeutic concepts in prevention and treatment of liver cancer.     

Rapid progression of hepatocellular carcinoma in a patient with autoimmune hepatitis

We describe a case of a 69-year-old woman who developed rapidly progressive hepatocellular carcinoma (HCC) associated with autoimmune hepatitis (AIH) after a 7-year follow-up. Markers for viral hepatitis were negative. Serum tumor markers including alpha-fetoprotein and prothrombin induced by vitamin K absence II rose suddenly, and a large tumor was detected in spite of regular surveillance for HCC. Surgical treatment was performed. The resected liver specimen revealed well to moderately differentiated HCC. Ki67 staining showed rapid proliferation of the HCC. Although the incidence of HCC in patients with AIH has been unclarified, the possible complication by HCC must not be overlooked.     

Characteristics and prognosis of patients in Japan with viral marker-negative hepatocellular carcinoma

Background and Aim: The characteristics and prognosis of patients with hepatitis virus marker‐negative hepatocellular carcinoma (HCC) is not fully elucidated in Japan. We investigated the characteristics and prognosis of HCC patients in whom no markers for hepatitis virus infection were detected, in comparison with those of HCC patients with hepatitis virus infection. Methods: Viral markers for hepatitis B and C virus (HBV and HCV) infection were measured in 1152 patients in whom initial HCC was diagnosed between 1991 and 2004. Patient characteristics, characteristics of HCC and survival were compared between patients in whom no marker was positive (viral marker‐negative HCC) and those in whom chronic HBV or HCV infection was confirmed by viral markers (viral HCC). Results: Overall, 119 patients (10.3%) were shown to have viral marker‐negative HCC. Hepatocellular carcinoma was detected under surveillance in a significantly smaller percentage of patients with viral marker‐negative HCC than of patients with viral HCC (P < 0.0001). The tumor was significantly larger (P < 0.0001) and vascular invasion was significantly more prevalent (P = 0.0003) in patients with viral marker‐negative HCC than in those with viral HCC. The survival rate of patients with viral marker‐negative HCC was significantly lower than that of patients with viral HCC (P = 0.0378). Conclusion: The patients with HCC in whom hepatitis viral infection had not been confirmed tended not to be under surveillance, resulting in the detection of HCC at more advanced stage and with a poorer prognosis. Efforts to identify patients without hepatitis virus infection who should be under surveillance for HCC will be necessary in the future.     

Role of antiviral treatment for HCC prevention

Chemoprevention of hepatocellular carcinoma (HCC) is listed as a yet highly debated long-term benefit of a successful treatment of patients with chronic viral hepatitis. In the hepatitis B virus (HBV) arena, the retrospective scrutiny of both interferon and nucleos(t)ide analogues (NUC) studies failed to provide robust evidence for HCC chemoprevention, due to a number of confoundings in the studies that were originally designed to assess the antiviral activity of interferon therapy. However, the reanalysis of outcomes following patients stratification for risk factors of HCC, provided a clue to find an association between NUC therapy and a reduced risk of liver cancer in non cirrhotic patients, only. In the hepatitis C scenario, a meta analysis of 30 observational studies of patients treated with interferon demonstrated a more than 70% reduction of HCC risk occurring independently of severity of underlying liver fibrosis which was less pronounced in aged patients and those with more advanced liver fibrosis. While the reasons for the residual risk of HCC in virological responders remain largely unexplained, international societies recommend surveillance for HCC of both HBV and HCV responders to antiviral therapy.     

Significance of viral status on prognosis of hepatitis B‐related hepatocellular carcinoma after curative resection in East Asia

Tumor recurrence remains one major obstacle for further improving the prognosis of hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) patients after curative liver resection. It has been widely reported that tumor size, positive surgical margin, macroscopic vascular invasion, tumor–node–metastasis stage and Edmondson's grade were significantly related to HCC recurrence. However, the association between HCC recurrence and important viral factors, including the HBV DNA levels, status of hepatitis B surface antigen and hepatitis B e‐antigen, levels of cccDNA and hepatitis B core‐related antigen, viral genotypes and specific viral sequence mutations remained controversial. Meanwhile, studies on the effect of postoperative adjuvant antiviral therapy on HCC recurrence have been relatively limited and have yielded conflicting results. Identification of certain viral risk factors for HCC recurrence and stratification of patient risk are very important to perform future surveillance programs. As a HBV hyperendemic region, the majority of HBV‐related HCC patients develop in East Asia. In this article, we thus systematically reviewed the risk of important viral factors involved in recurrent carcinogenesis and the role of adjuvant antiviral therapy in preventing tumor recurrence in this area.     

Hepatocellular carcinoma prevention： A worldwide emergence between the opulence of developed countries and the economic constraints of developing nations

INTRODUCTION Hepatocellular carcinoma (HCC) is the fifth most common neoplasm, the major cause of death in patients with liver cirrhosis, and the third most common cause of cancer- related death in the world[1,2]. Every year, 560 000 people in the world d…     

De novo Hepatocellular Carcinoma after Liver Transplantation

Liver transplantation is the definitive therapy for patients with advanced liver disease and its complications. Patients who are transplanted with a diagnosis of hepatocellular carcinoma (HCC) are at risk of recurrent cancer, and these patients are monitored on a regular basis for recurrence. In contrast, de novo HCC following liver transplantation is a very rare complication, and recipients without HCC at the time of transplantation are not screened. We describe the clinical features of de novo HCC over a decade after achieving a sustained viral response with treatment of hepatitis C and two decades after liver transplantation. Our case highlights the necessity of screening for HCC in the post-transplant patient with advanced liver disease even after viral clearance.     

Hepatocellular carcinoma in Sydney South West: late symptomatic presentation and poor outcome for most

Background: Hepatocellular cancer (HCC) is a serious complication of cirrhosis and chronic hepatitis B infection. The aim of the study was to determine the characteristics of patients with HCC presenting within the South West Sydney area, including an analysis of the rates and benefits of hepatocellular surveillance. Methods: Data from patients with HCC presenting to Liverpool and Bankstown Hospitals from July 1993 to June 2003 were analysed retrospectively, predominantly from hospital records. Results: Of the 151 HCC patients, 41% were Asian born. Most of the patients required an interpreter. Chronic viral hepatitis infection was present in 91 patients, of whom only 7% had previously received antiviral therapy. Alcohol alone was considered responsible in 31 patients. Cirrhosis could be documented in 58% of patients. Most of the patients (75%) presented symptomatically. The median survival was 5.1 months. When HCC was detected by surveillance, the tumours were slightly but not significantly more likely to be operable and the patients tended to be offered some form of active treatment more frequently. Multivariate analysis identified detection by surveillance, lower Child–Pugh score, smaller tumour size and eligibility for some form of treatment to be associated with a more favourable outcome. Conclusion: We observed low rates of surveillance for HCC, low recognition of cirrhosis before development of HCC and low rates of prior treatment of viral hepatitis. The poor outcome of HCC in the small group who had some sort of community surveillance is also a concern requiring further investigation.     

Hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy

Patients with chronic hepatitis B are at increased risk of hepatocellular carcinoma(HCC),while the inhibition of viral replication can represent a reasonable target for HCC prevention.Interferon-αtherapy results in decreased HCC risk,which is more evident in patients with high baseline HCC risk.The majority of chronic hepatitis B patients are treated with a nucleos(t)ide analogue(NA)for several reasons including the nonsustained response after interferon-α.The effect of the first licensed and low genetic barrier NA,lamivudine,on HCC incidence,has been repeatedly evaluated.Lamivudine,compared to no treatment,reduces the HCC incidence,which may increase again in cases with lamivudine resistance.Emerging data with the currently first-line NAs,entecavir and tenofovir,suggest that they also reduce the HCC incidence.The treatment benefit in reduction of the HCC incidence is always greater in patients with high baseline HCC risk,particularly cirrhotics,and without virological remission under entecavir/tenofovir.However,the HCC risk is not eliminated even in the vast majority of patients who remain in virological remission under entecavir/tenofovir.Therefore,patients at increased baseline HCC risk should continue to undergo HCC surveillance even if they have achieved complete long-term inhibition of viral replication and improvements in liver histology.     

National Survey of Hepatocellular Carcinoma in Heavy Drinkers in Japan

Background: The major cause of hepatocellular carcinoma (HCC) in the general Japanese population is an infection related to hepatotropic viruses, especially hepatitis virus C (HCV). Even in heavy drinkers, the major cause of HCC is HCV infection. However, HCC without viral infection has been reported in heavy drinkers. Alcohol has been also reported to be associated with an increased risk of cancer. In this study, we investigated aspects of HCC pathogenesis in heavy drinkers in Japan.
Methods: Questionnaires were sent to 1350 hospitals authorized by the Japanese Society of Gastroenterology. The questionnaires asked about the number of inpatients with the different types of alcoholic liver diseases, admitted to each hospital between 1998 and 2001.
Results: The percentage of heavy drinkers among all admitted patients with liver diseases or liver cirrhosis was approximately 15%. Of the patients with alcoholic liver cirrhosis, the cirrhosis was derived from alcohol alone in 61% and from alcohol plus a virus in 39% of patients. Furthermore, the percentage of patients with alcoholic liver cirrhosis caused by alcohol alone and who did not have HCC was 80%. However, the percentage of HCC patients who tested negative for viral hepatitis serum markers was 27% of the total number of heavy drinkers admitted for HCC. A study mainly on liver cirrhosis performed in the early 1990s demonstrated that the alcohol-alone group accounted for 44% of admitted patients with alcoholic liver cirrhosis and 18% of heavy drinkers admitted for HCC.
Conclusions: Because the consumption of alcohol is increasing in Japan, the frequency and number of cases of alcoholic liver cirrhosis are increasing. Viral hepatitis infection, however, still plays an important role in hepatocarcinogenesis in heavy drinkers. Radiographical examination is recommended even in patients with alcoholic liver cirrhosis who test negative for serum markers of viral hepatitis.     

National Survey of Hepatocellular Carcinoma in Heavy Drinkers in Japan

Background: The major cause of hepatocellular carcinoma (HCC) in the general Japanese population is an infection related to hepatotropic viruses, especially hepatitis virus C (HCV). Even in heavy drinkers, the major cause of HCC is HCV infection. However, HCC without viral infection has been reported in heavy drinkers. Alcohol has been also reported to be associated with an increased risk of cancer. In this study, we investigated aspects of HCC pathogenesis in heavy drinkers in Japan. Methods: Questionnaires were sent to 1350 hospitals authorized by the Japanese Society of Gastroenterology. The questionnaires asked about the number of inpatients with the different types of alcoholic liver diseases, admitted to each hospital between 1998 and 2001. Results: The percentage of heavy drinkers among all admitted patients with liver diseases or liver cirrhosis was approximately 15%. Of the patients with alcoholic liver cirrhosis, the cirrhosis was derived from alcohol alone in 61% and from alcohol plus a virus in 39% of patients. Furthermore, the percentage of patients with alcoholic liver cirrhosis caused by alcohol alone and who did not have HCC was 80%. However, the percentage of HCC patients who tested negative for viral hepatitis serum markers was 27% of the total number of heavy drinkers admitted for HCC. A study mainly on liver cirrhosis performed in the early 1990s demonstrated that the alcohol‐alone group accounted for 44% of admitted patients with alcoholic liver cirrhosis and 18% of heavy drinkers admitted for HCC. Conclusions: Because the consumption of alcohol is increasing in Japan, the frequency and number of cases of alcoholic liver cirrhosis are increasing. Viral hepatitis infection, however, still plays an important role in hepatocarcinogenesis in heavy drinkers. Radiographical examination is recommended even in patients with alcoholic liver cirrhosis who test negative for serum markers of viral hepatitis.