Hepatitis B core‐related antigen levels predict recurrence‐free survival in patients with HBV‐associated early‐stage hepatocellular carcinoma: results from a Dutch long‐term follow‐up study

Prognosis of hepatitis B (HBV)‐associated hepatocellular carcinoma (HCC) is poor due to high rates of HCC recurrence and progression of underlying liver disease. We studied whether serum hepatitis B core‐related antigen (HBcrAg) levels could predict HCC recurrence and outcome in HBV associated. Higher HBcrAg levels at HCC diagnosis were independently associated with reduced overall and recurrence‐free survival in patients with early, but not advanced, stage HCC.     

Hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis in Denmark: A nationwide cohort study

Cirrhosis in patients with chronic hepatitis C increases the risk of hepatocellular carcinoma (HCC ), and surveillance with ultrasound (US ) and alpha‐fetoprotein (AFP ) is recommended. This study aimed to estimate changes in the HCC incidence rate (IR ) over time, HCC stage and prognosis, and AFP and US performed in patients with hepatitis C and cirrhosis. Eligible patients were identified in the Danish Database for Hepatitis B and C, and data from national health registries and patient charts were obtained. Tumour stage was based on Barcelona‐Clinic Liver Cancer stage, TNM classification and size and number of lesions combined into stages 0‐3. We included 1075 patients with hepatitis C and cirrhosis, free of HCC and liver transplant at baseline. During 4988 person years (PY ), 115 HCC cases were diagnosed. The HCC incidence rate increased from 0.8/100 PY [CI 95% 0.4‐1.5] in 2002‐2003 to 2.9/100 PY [2.4‐3.4] in 2012‐2013. One‐year cumulative incidence of at least one AFP or US was 53% among all patients. The positive predictive value of an AFP  ≥ 20 ng mL^?1 was 17%. Twenty‐three (21%) patients were diagnosed with early‐stage HCC (stage 0/1) and 84 (79%) with late stage. Median survival after HCC for early‐stage HCC disease was 30.1 months and 7.4 months for advanced HCC (stage 2/3). The incidence rate of HCC increased over time among patients with hepatitis C and cirrhosis in Denmark. Application of AFP and US was suboptimal, and most patients were diagnosed with advanced HCC with a poor prognosis.     

Is the prognosis of young patients with hepatocellular carcinoma poorer than the prognosis of older patients? A comparative analysis of clinical characteristics, prognostic features, and survival outcome

Background  Hepatocellular carcinoma (HCC) is uncommon in young adults. This study examined the clinical characteristics and survival outcome of young HCC patients compared with those in older patients. Methods  Data were prospectively collected from 638 patients diagnosed with HCC over a 9-year period. Patients aged ≤40 years at diagnosis of HCC were defined as young HCC patients. Their clinical characteristics and survival was compared with those aged >40 years. Results  The prevalence of young HCC was 8.6% (55/638). Young HCC patients had a significantly higher rate of hepatitis B-related disease (HBsAg positivity: 85.5% vs. 59.7%, P = 0.003), better Child-Pugh status (Child-Pugh class A: 69.1% vs. 43.9%, P = 0.002), and lower rates of cirrhosis (12.7% vs. 34.3%, P = 0.001) compared with the older group. They had more advanced disease at diagnosis, with higher α-fetoprotein levels (>12 000 μg/l: 45.4% vs. 30.5%, P = 0.026), a higher incidence of portal vein involvement (63.6% vs. 40%, P = 0.003), and a more advanced TNM stage (TNM IV: 83.6% vs. 66.4%, P = 0.018). More young patients were eligible for surgical resection (18.2% vs. 8.2%, P = 0.014). The overall survival between the two groups was similar, but when the patients were stratified for stage of disease, the median survival of young patients with early disease was superior to that of older patients (51.2 vs. 11.6 months, P = 0.025). Conclusions  HCC in young adults occurs mainly in hepatitis B carriers and is often diagnosed at an advanced stage. Their survival outcome is not different from that of older patients because the advanced disease at presentation offsets the advantages of better liver function and a higher resection rate. However, there is a distinct survival advantage for young patients diagnosed with early disease. These results support the importance of extending HCC surveillance to young hepatitis B carriers.     

Hepatocellular carcinoma: an Asian perspective

Hepatocellular carcinoma (HCC) is one of the most frequently occurring malignancies in Asia. The incidence exceeds 30 cases/100,000/year in the east Asian region. Worldwide, it accounts for almost 1 million deaths/year. The high incidence in Asia is due to the high prevalence of chronic viral hepatitis, mainly chronic hepatitis B. With the introduction of universal vaccination for hepatitis B in some Asian countries in the mid 1980s, some of these countries are experiencing a decline in the incidence of HCC. This probably underscores the point that HCC caused by hepatitis B is a malignancy preventable by vaccine. Due to the relative paucity of symptoms in the early stages and the rapid doubling time of the tumor, most HCCs are discovered late in advanced stages at presentation. Most Asian countries have adopted a screening program for patients at risk. Earlier and smaller HCCs are detected through such programs but these programs have yet to demonstrate improved patient survival. Physicians managing patients with HCC are faced with two main challenges, the malignancy itself and the underlying liver disease. The extent of the tumor and the existing liver function limits the therapeutic choices available. Hepatic resection remains the treatment of choice. However, the majority of patients present with nonresectable tumors. Transarterial chemoembolization, percutaneous ethanol injection and radiofrequency ablation are the other treatment modalities. In patients with small tumors (<5 cm) and poor liver function, liver transplant offers a viable treatment alternative. In summary, the risk factor for HCC in Asia is predominantly chronic hepatitis B. Universal vaccination against hepatitis B is likely to reduce the incidence. The prognosis and outcome of treatment remains poor with a 5-year survival of 35% for patients treated surgically and less than 10% for nonresectable tumors. Current management is aimed at earlier detection and more effective treatment of early HCC. In future, the challenge will be managing HCC in the premalignant stage.     

Epidemiology and management of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major world health problem because of the high incidence and case fatality rate. In most patients, the diagnosis of HCC is made at an advanced stage, which limits the application of curative treatments. Most HCCs develop in patients with underlying chronic liver disease. Chronic viral hepatitis B and C are the major causes of liver cirrhosis and HCC. Recent improvements in treatment of viral hepatitis and in methods for surveillance and therapy for HCC have contributed to better survival of patients with HCC. This article reviews the epidemiology, cause, prevention, clinical manifestations, surveillance, diagnosis, and treatment approach for HCC.     

肝细胞癌高危人群标准的探讨

目的 从肝细胞癌患者中确立高危因素,探讨肝细胞癌高危人群的确立, 并由此推算高危人群普查及其定期自我检验的重要意义。方法 对1725例行肝细胞癌切除术的患者进行回顾性随访,将随访资料完整的1457例进行临床分期及其与肝内无瘤生存的相关分析,根据频数表划分肝细胞发病危人群段。结果 肝细胞癌患者年龄分布呈相对正态分布,取90％可信区间,高危人群年龄段为31－65岁。亚临床期肝细胞癌患者术后无瘤生存状况明显好于临床期者。结论 可将血清抗－HBc阳性或／及HBsAg阳性,尤其是乙型肝炎病史,年龄31－65岁者作为国内肝细胞癌的高危人群。加对此人群普查,增强其定期体检意识,可使大部份肝细胞癌患者得以在亚临床期早发现早治疗,在现有的医疗技术条件下将肝细胞癌的治疗提高到一个新水平。     

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.     

Alcohol and hepatocellular carcinoma: A review and a point of view

It is well recognized that one cause of chronic liver disease and hepatocellular carcinoma(HCC)is alcohol consumption.Research in Italy and the United States concludes that the most common cause of HCC(responsible for 32%to 45%of HCC)is alcohol.It has recently been shown that a significant relationship between alcohol intake,metabolic changes,and hepatitis virus infection does exist.Alcohol may be a factor in the development of HCC via direct(genotoxic)and indirect mechanisms(cirrhosis).There is only one way of diagnosing HCC,which is early identification through surveillance,when curative treatments become possible.After stopping alcohol intake the risk of liver cancer decreases by 6%to 7%a year,and an estimated time period of 23 years is also needed.Therefore,surveillance is also important in former drinkers and,in our opinion,independently from the presence of compensated cirrhosis.In cases of very early stage(VES)and early stage with portal hypertension,liver transplantation is the optimal option;and in cases of associated disease,percutaneous ethanol injections,radiofrequency and microwave ablation are the ideal treatments.Despite the possibility of detecting microvascular invasion with HR,several studies and some randomized controlled trials revealed that overall survival and DSF rates in patients with VES HCC are much the same after ablation and HR.Therefore,ablation can be regarded as a firstline choice for patients with VES HCC.It is important to emphasize that the choice of treatment should be weighed carefully in the context of a multidisciplinary cancer team.     

Strategy for improving survival and reducing recurrence of HCV-related hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the sixth most common cancer and the third leading cause of cancerrelated death in the world.With advances in imaging diagnostics,accompanied by better understanding of high-risk patients,HCC is now frequently detected at an early stage;however,the prognosis remains poor.The recurrence rate after treatment of HCC is higher than that associated with cancers of other organs.This may be because of the high incidence of intrahepatic distant recurrence and multicentric recurrence,especially with hepatitis C virus(HCV)-related hepatocellular carcinoma.The Barcelona Clinic Liver Cancer(BCLC)classification has recently emerged as the standard classification system for the clinical management of patients with HCC.According to the BCLC staging system,curative therapies(resection,transplantation,transcatheter arterial chemoembolization,percutaneous ethanol injection therapy,percutaneous microwave coagulation therapy and percutaneous radiofrequency ablation)can improve survival in HCC patients diagnosed at an early stage and offer a potential long-term cure.However,treatment strategies for recurrent disease are not mentioned in the BCLC classsification.The strategy for recurrence may differ according to the recurrence pattern,i.e.,intrahepatic distant recurrence vs multicentricrecurrence.In this article,we review recurrent HCC and the therapeutic strategies for reducing recurrent HCC,especially HCV-related HCC.     

Hepatocellular carcinoma in a male patient with early stage (stage I) primary biliary cirrhosis

The true incidence of hepatocellular carcinoma (HCC) in patients with primary biliary cirrhosis (PBC) remains undetermined due to limited epidemiological studies and some conflicting results. Some studies indicated that in PBC, male gender, cirrhosis, hepatitis C virus (HCV) superinfection, and history of blood transfusion are associated with the development of HCC, and the occurrence of HCC in the early stage of PBC is rare. We present herein a 75-year-old male patient with stage I PBC who developed oropharyngeal squamous cell carcinoma, followed by HCC and duodenal adenocarcinoma without hepatitis B or C virus infection. While it could be argued that the concurrence of HCC and stage I-PBC in our patient was coincidental, patients with early stage PBC should be strictly followed up as cirrhotic patients with PBC by monitoring the serum concentration of tumor markers for HCC and appropriate imaging methods.     

Safety of hepatectomy for elderly patients with hepatocellular carcinoma

The number of elderly patients with hepatocellular carcinoma (HCC) has been increasing. Characteristics of elderly HCC patients are a higher proportion of females, a lower rate of positive hepatitis B surface antigen, and a higher rate of positive hepatitis C antibodies. Careful patient selection is vital for performing hepatectomy safely in elderly HCC patients. Treatment strategy should be decided by not only considering tumor stage and hepatic functional reserve, but also physiological status, including comorbid disease. Various assessment tools have been applied to predict the risk of hepatectomy. The reported mortality and morbidity rates after hepatectomy in elderly HCC patients ranged from 0% to 42.9% and from 9% to 51%, respectively. Overall survival rate after hepatectomy in elderly HCC patients at 5 years ranged from 26% to 75.9%. Both short-term and long-term results after hepatectomy for strictly selected elderly HCC patients are almost the same as those for younger patients. However, considering physiological characteristics and the high prevalence of comorbid disease in elderly patients, it is important to assess patients more meticulously and to select them strictly if scheduled to undergo major hepatectomy.     

Detection of hepatocellular carcinoma during a clinical follow-up of chronic liver disease: observations in 31 patients.

In 31 patients with an initial diagnosis of cirrhosis or chronic hepatitis hepatocellular carcinoma (HCC) was detected after a clinical follow-up of 8 months to 14 years with an average of 59 months. They had had no scintigraphic and biochemical abnormalities suggestive of HCC at the beginning. The follow-up period before the detection of carcinoma was shorter in patients positive for hepatitis B surface antigen compared with those negative for hepatitis B surface antigen. Analyses of clinical data during the follow-up and liver scans made shortly before tumor detection suggested that in most of these patients HCC became discernible relatively early in the course of cirrhosis or long before cirrhosis reached an advanced stage. A sharp rise in serum alpha-fetoprotein level proved highly diagnostic in 11, it remained low throughout in 7, and tumor was already unresectable in the majority. Although continuous and regular check for alpha-fetoprotein is imperative in patients with chronic liver disease, particularly in those with hepatitis B surface antigenemia, additional diagnostic tools are necessary for the detection of small HCC in its resectable stage.     

Hepatocellular Carcinoma in Young Adults: The Clinical Characteristics, Prognosis, and Findings of a Patient Survival Analysis

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. However, HCC is rare in young Japanese patients and the clinical features of young patients with HCC have not yet been fully studied. This study was designed to determine the clinical characteristics and prognosis of patients with HCC who are younger than aged 40 years. A retrospective analysis was performed for patients newly diagnosed with HCC and observed from January 1990 to December 2003 at our hospitals. Patients younger than aged 40 years at the diagnosis of HCC were defined as the young group and were reviewed. There were 20 patients (16 males) with HCC who were younger than aged 40 years. The mean age at diagnosis was 33.6 (range, 20–39) years. Fifteen of 20 patients were positive for hepatitis B surface antigen (HBsAg) and 2 patients were positive for hepatitis C virus antibody. According to the Child-Pugh grading, the liver function was relatively good in all patients. Because most of the patients did not receive periodic follow-up, this disease often was discovered at an advanced stage, usually after the appearance of some symptoms. Although intensive treatment was performed for such young patients, the survival was nevertheless poor. Most patients died from this cancer within 1 year. However, one patient who received periodic follow-up and also was in relatively good physical condition had a better prognosis, and he survived for 88 months. Young patients with HCC tended to have a poor prognosis because of advanced stage of HCC, despite a well-preserved liver function and aggressive treatment. Screening for HCC and an early diagnosis is needed for such patients to demonstrate an improved prognosis, especially for HBsAg-positive patients.     

Annexin A2 as a biomarker for hepatocellular carcinoma in Egyptian patients

AIM To investigate the clinical utility of serum annexin A2(ANXA2) as a diagnostic marker for early hepatocellular carcinoma(HCC).METHODS This study was performed in HCC Clinic of Ain Shams University Hospitals, Cairo, Egypt and included: Group 1: Fifty patients with early stage HCC(Barcelona Clinic Liver Cancer stage A); Group 2: Twenty five patients with chronic liver disease; and Control Group: Fifteen healthy, age-and sex-matched subjects who were seronegative for viral hepatitis markers. The followinglaboratory investigations were done: Viral hepatitis markers [hepatitis B surface antigen and hepatitis C virus(HCV) antibodies], HCV RNA in HCV antibody-positive patients, serum alpha fetoprotein(AFP), and serum ANXA2 levels.RESULTS In this study, 88% of HCC patients(n = 44) were HCVpositive, while HBV infection represented only 8% of all HCC patients(n = 4); and two patients were negative for both viral markers. A highly significant difference was found between patients with HCC and chronic liver disease as well as controls with regard to serum ANXA2 levels(130, IQR 15-240; 15, IQR 15-17; and 17, IQR 15-30 ng/m L, respectively). The area under the curve of ANXA2 was 0.865; the cut-off value was established to be 18 ng/mL with a diagnostic sensitivity of 74% and a specificity of 88%, while the sensitivity and specificity of AFP at the cut-off value of 200 ng/dL were 20% and 100%, respectively.CONCLUSION Serum ANXA2 may serve as a biomarker for the early detection of HCC.     

同种异体原位肝移植14例次治疗经验

目的：总结终末期肝病患者同种异体肝移植手术的临床经验,介绍肝移植供体获取和受体手术的方法和术后处理方案。方法：对13例患者行14次手术(再次肝移植1例),其中乙肝肝硬化并肝癌7例,终末期乙肝肝硬化1例,丙肝肝硬化并“意外癌”1例,重症肝炎肝衰4例(1例为肝移植术后10个月,因乙肝复发,重型肝炎行二次肝移植术)。手术行改良背驮式5例,经典非转流术式9例次,其中1例行减体积肝移植(左肝外叶切除)。结果：手术移植物成活率100％,无原发性移植肝无功能和功能延迟恢复发生。手术成功率：良性终末期肝病和肝癌100％(9／9),重症肝炎为60％(3／5),总成功率为85．7％(12／14)。远期存活8例,存活1年以上5例。结论肝移植是治疗由各种急、慢性肝病导致的终末期肝功能衰竭和肝癌的有效方法。良性终末期肝病和早期肝癌的手术效果良好,明显优于重症肝炎和晚期肝癌。选择适当的手术时机,合理的手术方式,良好的供体质量,术中麻醉管理和术后早期ICU的围手术期管理,术后免疫抑制剂的应用,术后并发症处理是保证手术成功的重要条件。乙肝和肝癌等移植后易复发疾病的控制,对于提高肝移植术后患者的长期存活率非常重要。     

Relation between hepatocarcinoma and hepatitis C virus infection

The incidence of hepatocarcinoma (HCC) has increased in industralized countries. Its relation with hepatitis C virus (HCV) has already been established. The mechanisms by which HCV promotes HCC development are poorly understood. The continuous necrotic and inflammatory effect with subsequent liberation of various cytoquines and modifications in hepatocyte genome have been proposed. Chronic infection with HCV leads to chronic liver disease and cirrhosis which is described as the main precursory lesion to HCC. The assessment methods for patients with chronic liver diseases allow those patients with high risk for HCC to be identified and the process to identify this tumor at an early stage to be initiated.     

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.     

Natural history of hepatitis B

The natural course of hepatitis B virus (HBV) chronic infection is variable, ranging from an inactive HBsAg carrier state to a more or less progressive chronic hepatitis, potentially evolving to cirrhosis and hepatocellular carcinoma (HCC). Chronic hepatitis may present as typical HBeAg-positive chronic hepatitis B or HBeAg-negative chronic hepatitis B. HBeAg-positive chronic hepatitis is due to wild type HBV; it represents the early phase of chronic HBV infection. HBeAg-negative chronic hepatitis is due to a naturally occurring HBV variant with mutations in the precore or/and basic core promoter regions of the genome; it represents a late phase of chronic HBV infection. The latter form of the disease has been recognized as increasing in many countries within the last decade and it represents the majority of cases in many countries. HBeAg-negative chronic hepatitis B is generally associated with a more severe liver disease with a very low rate of spontaneous disease remission and a low sustained response rate to antiviral therapy. Longitudinal studies of patients with chronic hepatitis B indicate that, after diagnosis, the 5-year cumulative incidence of developing cirrhosis ranges from 8-20%. Morbidity and mortality in chronic hepatitis B are linked to evolution to cirrhosis or HCC. The 5-year cumulative incidence of hepatic decompensation is approximately 20%. The 5-year probability of survival is approximately 80-86% in patients with compensated cirrhosis. Patients with decompensated cirrhosis have a poor prognosis (14-35% probability of survival at 5 years). HBV-related end-stage liver disease or HCC are responsible for at least 500,000 deaths per year.     

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma

Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC.     

Factors affecting prognosis of small hepatocellular carcinoma in Taiwanese patients following hepatic resection

BACKGROUND:

Small hepatocellular carcinoma (HCC) affects millions of individuals worldwide. Surveillance of high-risk patients increases the early detection of small HCC.

OBJECTIVE:

To identify prognostic factors affecting the overall survival (OS) and recurrence-free survival (RFS) of patients with small HCC.

METHODS:

The present prospective study enrolled 140 Taiwanese patients with stage I or stage II small HCC. Clinical parameters of interest included operation type, tumour size, tumour histology, Child-Pugh class, presence of hepatitis B surface antigen and liver cirrhosis, hepatitis C status, alpha-fetoprotein, total bilirubin and serum albumin levels, and administration of antiviral and salvage therapies.

RESULTS:

Tumour size correlated significantly with poorer OS in patients with stage I small HCC (P=0.014); however, patients with stage II small HCC experienced a significantly poorer RFS (P=0.033). OS rates did not differ significantly between patients with stage I and stage II small HCC. Tumour margins, tumour histology and cirrhosis did not significantly affect OS or RFS (P>0.05).

DISCUSSION:

Increasing tumour size has generally been associated with poorer prognoses in cases of HCC. The present study verified the relationship between small HCC tumour size and OS; however, a reduction in OS with increasing tumour size was demonstrated for patients with stage I – but not for stage II – small HCC.

CONCLUSION:

Patients with stage II small HCC may benefit from aggressive surveillance for tumour recurrence and appropriate salvage treatment. Further studies are needed for additional stratification of stage I patients to identify those at increased risk of death.