Surveillance for early diagnosis of hepatocellular carcinoma: How best to do it?

Surveillance for hepatocellular carcinoma(HCC)is considered a standard of care for patients with chronic liver disease who are at risk of developing this malignancy.Several studies have shown that surveillance can improve the prognosis of patients diagnosed with HCC through an increased likelihood of application of curative or effective treatments.Repetition of liver ultrasonography(US)every 6 mo is the recommended surveillance program to detect early HCCs,and a positive US has to entrain a well-defined recall policy based on contrast-enhanced,dynamic radiological imaging or biopsy for the diagnosis of HCC.Although HCC fulfills the accepted criteria regarding cost-effective cancer screening and surveillance,the implementation of surveillance in clinical practice is defective and this has a negative impact on the cost-effectiveness of the procedure.Education of both physicians and patients is of paramount importance in order to improve the surveillance application and its benefits in patients at risk of HCC.The promotion of specific educational programs for practitioners,clinicians and patients is instrumental in order to expand the correct use of surveillance in clinical practice and eventually improve HCC prognosis.     

Economic evaluation of a surveillance program of hepatocellular carcinoma (HCC) in India

Purpose Surveillance of patients of cirrhosis of liver is practiced for early detection of HCC. No data from any developing country on cost-effectiveness of such a program are available. Methods Economic evaluation of HCC surveillance was embedded in a prospective study undertaken to estimate the incidence of HCC in 194 cirrhotics. The protocol consisted of 6 monthly abdominal ultrasound (US) and serum alphafetoprotein (AFP) estimation, and yearly triple phase CT. Cost was estimated from the hospital and patient perspectives. Cost-effectiveness ratios for detecting a case of HCC were estimated. Modeling was done to estimate cost effectiveness with different combinations of diagnostic tests. Results Cost-effectiveness ratios of HCC surveillance program per HCC case detected were estimated as US$ 280 from the hospital perspective. From patient perspective, these were US$ 9,965 for outstation and US$ 2,808 for local patients. Cost-effectiveness ratio for direct medical cost per case of HCC detected by 6 monthly US and AFP, the EASL protocol, was estimated to be US$ 1,510 in the private sector. Conclusion The cost of HCC surveillance program is exorbitant for India (gross national income per capita US$ 620) and possibly other low/middle income countries.     

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.     

Diagnostic role of serum glypican-3 in differentiating hepatocellular carcinoma from non-malignant chronic liver disease and other liver cancers

Background and Aims:  The role of glypican-3 (GPC3), a novel serum marker, in differentiating hepatocellular carcinoma (HCC) from non-malignant chronic liver disease and other malignant space-occupying lesions in the liver is largely unknown. The aims of this study were to evaluate its diagnostic role and clinical correlations in patients with HCC.
Methods:  Six groups were studied which included 40 healthy subjects, 50 patients with chronic hepatitis (CH), 50 patients with liver cirrhosis (LC), 100 patients with HCC, 50 patients with intrahepatic cholangiocarcinoma (ICC) and 50 patients with metastatic carcinoma (MCA). Serum GPC3 levels were measured by using a sandwich enzyme-linked immunosorbent assay method.
Results:  Fifty-three percent of HCC patients had elevated serum GPC3 levels with values ranging 35.5–7826.6 ng/mL. The serum marker was undetectable in other groups except one patient (2%) with LC and another patient (2%) with MCA. In most cases of HCC, elevated GPC3 values did not correlate with α-fetoprotein (AFP) levels. Detectable GPC3 was significantly correlated with the presence of viral hepatitis markers but was not correlated with tumor size and stage of HCC. Serum GPC3 was superior to AFP in detecting small HCC (56.3% and 31.3%, respectively). A combination of serum GPC3 and AFP yielded an improved sensitivity for detecting small HCC to 75%.
Conclusion:  Serum GPC3 is highly specific for detecting HCC. The combined use of serum GPC3 and AFP provides a potentially promising tool to better differentiate HCC from benign liver disorders, as well as from other liver cancers.     

Optimal surveillance program for hepatocellular carcinoma - getting ready,but not yet

Hepatocellular carcinoma (HCC) secondary to chronic viral hepatitis is a major health problem in Asian-Pacific regions due to the endemics of chronic hepatitis B and C virus infection. HCC surveillance has been recommended to patients who are at risk to develop HCC. Unfortunately, a significant proportion of patients still died in long run due to tumor recurrence. The key components of an optimal surveillance program include an accurate tumor biomarker and optimal surveillance interval. Serum alpha-fetoprotein (AFP), despite of being the most widely used biomarker for HCC surveillance, it was criticized as neither sensitive nor specific. Other HCC biomarkers, including lectin-reactive AFP (AFP-L3), des-gamma carboxyprothrombin, are still under investigations. Recent study showed cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing to be accurate with both sensitivity and specificity close to 90% in detecting HCC in a case-control study. Concerning the optimal surveillance interval, we believe one size does not fit all patients. Accurate risk prediction to assist prognostication with well-validated HCC risk scores would be useful to decide the need for HCC surveillance. These key components of an optimal HCC surveillance program should be further validated at a surveillance setting.     

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.     

Liver cancer in Korea

Hepatocellular carcinoma (HCC) is a highly malignant cancer and third major cause of death in Korean. It is more prevalent among men in the sixth to seventh decades. HCC is particularly prevalent in Korea where the age-standardized incidence rate is 45.0/100 000 population in males and 12.0/100 000 population in females. The death rate from HCC is 20.0/100 000 population. Approximately 65–75% of HCC patients were positive for hepatitis B surface antigen (HBsAg), where 10–20% of patients were anti-hepatitis C virus (HCV) positive. The high incidence rate of HCC in Korea is thought to be related to the high carrier rate of hepatitis B virus (HBV) in the general population. For primary prevention, a nationwide HBV vaccination program has been conducted since the late1980s in Korea. Although advances have been made in the various methods of management of HCC, there has been little overall survival improvement during the past 20 years. Only few patients are candidates for potentially curative forms of treatment. Therefore, the early detection of HCC is a key issue. When compared with clinical outcomes of HCC based on recent 10-year institutional data, our screening and surveillance programs might enable early detection and increased applicability of curative treatments.     

Clinical usefulness of des-γ-carboxy prothrombin assay in early diagnosis of hepatocellular carcinoma

Des--carboxy prothrombin (DCP) was evaluated as a serological marker for hepatocellular carcinoma (HCC), particularly in patients with early HCC. In 1192 patients with various diseases, plasma DCP levels were measured by a newly developed enzyme immunoassay method using an anti-DCP monoclonal antibody. Of the 254 patients with HCC, 143 (56%) had abnormal DCP levels of greater than 0.1 AU/ml. In contrast, elevated DCP levels were rarely observed in patients with chronic hepatitis, liver cirrhosis, metastatic liver cancer, and other malignant tumors. Because no correlation was observed between DCP and -fetoprotein (AFP), the combined measurement of these two complementary markers appears to be useful in the diagnosis of HCC. Since normal levels were observed in 29 of 30 patients (97%) with small liver tumors measuring 2 cm or less in diameter, the diagnostic application of the DCP assay to small liver tumors is limited. However, in patients with tumors larger than 2 cm, the plasma DCP assay may even be more useful than AFP. Among 46 patients with liver cirrhosis or chronic hepatitis who subsequently developed HCC, significantly increased DCP and AFP levels were observed in nine patients (20%) and 14 patients (30%), respectively, when a tumor was detected. When the results of both assays were combined, 19 patients (41%) had elevated levels of one or both markers. Although the plasma DCP assay alone is not sensitive enough to detect early small liver cancers, it could be applied as a complementary tumor marker together with AFP. The use of both these markers together with imaging modalities in the regular follow-up of patients with chronic liver disease who are at high risk for HCC might be of great benefit.This work was supported in part by a grant from the Japanese Society of Hepatology.     

Diagnosis of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is responsible for a large proportion of cancer deaths worldwide. HCC is frequently diagnosed after the development of clinical deterioration at which time survival is measured in months. Long-term survival requires detection of small tumors, often present in asymptomatic individuals, which may be more amenable to invasive therapeutic options. Surveillance of high-risk individuals for HCC is commonly performed using the serum marker alpha-fetoprotein (AFP) often in combination with ultrasonography. Various other serologic markers are currently being tested to help improve surveillance accuracy. Diagnosis of HCC often requires more sophisticated imaging modalities such as CT scan and MRI, which have multiphasic contrast enhancement capabilities. Serum AFP used alone can be helpful if levels are markedly elevated, which occurs in fewer than half of cases at time of diagnosis. Confirmation by liver biopsy can be performed under circumstances when the diagnosis of HCC remains unclear.     

Utility of alpha-fetoprotein (AFP) in the screening of patients with virus-related chronic liver disease: does different viral etiology influence AFP levels in HCC? A study in 350 western patients

BACKGROUND/AIMS: Dosage of serum AFP (alpha-fetoprotein) is widely used for HCC screening in patients with chronic liver disease. Virus-related chronic liver disease is the main cause of cirrhosis and HCC in Western and Far Eastern countries, but the relationship between viral etiology and AFP levels in HCC is still unclear. The aim of this study was to verify, in Western patients with post-viral chronic liver disease, the usefulness of AFP dosage for the detection of HCC, and the influence of viral etiology on AFP levels in HCC. METHODOLOGY: The study population included 350 patients with post viral chronic liver disease that underwent liver biopsy, serum AFP determination and ultrasound liver evaluation. Seven patients had normal liver histology, 197 had chronic hepatitis, 72 had cirrhosis, and 74 had cirrhosis and HCC. ROC (receiver operating characteristic) analysis was used to assess the best diagnostic AFP threshold value for HCC detection. Logistic regression analysis was performed to individuate independent predictors of HCC diagnosis. RESULTS: No difference was observed in AFP levels between HCV- and HBV-positive patients, neither in the whole population nor in the HCC patients only. ROC area under curve for AFP was 0.801 (95% CI: 0.721-0.867). The analysis individuated a best accurate AFP threshold value for HCC diagnosis of 50 ng/mL. HCC was detected with specificity > or = 95% only for AFP > 100 ng/mL. The sensitivity however was poor (25%). Male sex, age > 60, and AFP were independent predictors of HCC diagnosis. CONCLUSIONS: Serum AFP levels in HCC patients are not influenced by virus B or C hepatitis pattern. AFP dosage should not be used for HCC diagnosis in non-cirrhotic patients. Male patients with cirrhosis should be regarded with a more "aggressive" screening program compared to females.     

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.     

Hepatocellular carcinoma surveillance:An evidence-based approach

Hepatocellular carcinoma(HCC) makes up 75%-85% of all primary liver cancers and is the fourth most common cause of cancer related death worldwide. Chronic liver disease is the most significant risk factor for HCC with 80%-90% of new cases occurring in the background of cirrhosis. Studies have shown that early diagnosis of HCC through surveillance programs improve prognosis and availability of curative therapies. All patients with cirrhosis and high-risk hepatitis B patients are at risk for HCC and should undergo surveillance. The recommended surveillance modality is abdominal ultrasound(US) given that it is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with non-alcoholic fatty liver disease(NAFLD). With the current obesity epidemic and rise in the prevalence of NAFLD, abdominal computed tomography or magnetic resonance imaging may be indicated as the primary screening modality in these patients. The addition of alpha-fetoprotein to a surveillance regimen is thought to improve the sensitivity of HCC detection.Further investigation of serum biomarkers is needed. Semiannual screening is the suggested surveillance interval. Surveillance for HCC is underutilized and low adherence disproportionately affects certain demographics such as nonCaucasian race and low socioeconomic status.     

Sensitivity and specificity of des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinomas varies according to tumor size

OBJECTIVES: Serum levels of des-gamma-carboxy prothrombin (DCP) and alpha-fetoprotein (AFP) are known to be useful tumor markers for the diagnosis of hepatocellular carcinoma (HCC). The aim of this study was to examine the diagnostic efficacy of DCP and AFP in differentiating HCC from chronic liver diseases. METHODS: We examined 1,377 HCC patients and 355 patients with chronic hepatitis or cirrhosis (non-HCC) who visited our institute and affiliated hospitals between June 1997 and September 2003. RESULTS: The median values of DCP and AFP were 60 mAU/mL and 34 ng/mL in HCC patients, respectively, and 18 mAU/mL and 3 ng/mL in non-HCC patients, respectively. The areas under the receiver operating characteristic (ROC) curves of DCP and AFP were 0.812 and 0.887, respectively (p < 0.0001). The area under the DCP ROC curve was significantly smaller than that of AFP in tumors less than 3 cm in diameter (p < 0.0001). However, the ROC area of DCP was significantly larger than that of AFP in tumors greater than 5 cm in diameter (p < 0.0001). CONCLUSIONS: The utility of DCP for the diagnosis of HCC was lower than that of AFP for small tumors, but higher than that of AFP for large tumors.     

Antiviral therapy and primary and secondary prevention of hepatocellular carcinoma

Viral hepatitis due to chronic hepatitis B and C virus (HBV/HCV) infects more than 500 000 000 individuals worldwide. These chronic viral diseases are highly linked to the development of hepatocellular carcinoma (HCC), the fifth most common cause of cancer death worldwide. HCC is much more common in Asia and Africa than in the USA and Europe, although HCC is one of the few cancers with a rising incidence in the USA. There are 530 000 cases of HCC worldwide of which 82% are related to viral hepatitis. 316 000 cases of HCC are HBV-associated, 118 000 are HCV-associated. The most effective way to prevent HCC is to prevent viral infection through immunization. Currently there are effective vaccinesagainst hepatitis B and A, but not against HCV, the virus that accounts for most HCC in the USA. The published work supporting the use of antiviral therapy in preventing liver cancer is limited. Data supporting the use of antiviral therapy in preventing recurrence of HCC after initial anticancer approaches is even less available. Nevertheless, the weight of evidence suggests that treatment of HBV/HCV-related fibrosis will reduce the risk of developing HCC.     

Cost-effectiveness of liver cancer screening

Screening for primary liver cancer means surveillance for hepatocellular carcinoma (HCC), which is one of the most common cancers worldwide. Detection of HCC for curative treatment is increased by surveillance, but target population, optimal periodicity and cost-effectiveness aspects are still debated issues. The aim of surveillance is to obtain a reduction in HCC-related mortality and this is usually achieved through an early diagnosis that increases both applicability and cost-effectiveness of curative treatments. The aim of the present review is to analyse economic aspects of HCC surveillance. Articles that assessed cost-effectiveness of surveillance for HCC, published between 1996 and February 2013, were reviewed in order to verify the cost-effectiveness of surveillance, its optimal periodicity, the target population and the role of alternative surveillance strategies. International guidelines are currently based on the results of such cost-effectiveness analyses, highlighting the importance of the release of cost-effectiveness-guided guidelines for HCC management.     

Very high alpha-fetoprotein in a young man due to concomitant presentation of hepatocellular carcinoma and Sertoli cell testis tumor

Studies reported that there is a close relationship between hepatocellular carcinoma (HCC) and testis carcinoma. Both tumors can be presented as synchronal tumors, or as testicular metastases of HCC or as hepatic metastases of testicular tumor. HCC is one of the most common malignancies worldwide and the incidence of HCC increases with age. The relationship between hepatitis B incidence and HCC rates is also well recognized. Alpha fetoprotein (AFP) is produced by 70% of HCC. Though a level of AFP >400 ng/mL is diagnostic for HCC, in the presence of active hepatitis B infection, the cut-off level should be considered to be at least 1 000-4 000 ng/mL. Like HCC, germ cell tumors of the testis also release AFP; but it is shown that some of Sertoli cell tumors of testis can also release AFP. Herein we have reported about the first case of HCC in the literature which is presented concomitantly with Sertoli-Leydig tumor of testis, leading to extremely high level of AFP in a 21-year-old man.     

Diagnostic accuracy of tumor markers for hepatocellular carcinoma: a systematic review

Background and aims The role of alphafetoprotein (AFP) in the diagnosis and surveillance of hepatocellular carcinoma (HCC) is getting smaller owing to the advances in imaging modalities. The aims of this study were to assess the diagnostic accuracy of tumor markers in small HCC and to find the optimal cutoff value of each tumor marker for efficient surveillance. Methods Studies in all languages were identified by searching MEDLINE from 1982 to 2002. Studies were included when they showed sensitivity and specificity for HCCs 5 cm or smaller and recruited only patients with chronic hepatitis or liver cirrhosis as control. We assessed diagnostic odds ratios (DORs) for the evaluation of diagnostic accuracy of tumor markers and positive likelihood ratios (LRs+) to find the optimal cutoff value. DORs and LRs+ were combined according to the random effect model. The summary receiver operating characteristics (ROC) curve was also assessed. Results Seventeen articles on three tumor markers—AFP, des-gamma-carboxyprothrombin (DCP), and Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3)—were enrolled after full-text evaluation. AFP was inferior to DCP and AFP-L3 in both DOR (4.50 vs. 8.16 and 10.50) and area under the ROC curve (0.647 vs. 0.688 and 0.695). Optimal cutoff values that provide the best LR+ were 200 ng/ml for AFP, 40 mAU/ml for DCP, and 15% for AFP-L3. Conclusions Diagnostic accuracy of AFP in small HCC was substantially limited. Surveillance including other tumor markers with optimal cutoff value should be conducted to confirm the efficacy of the policy. This study was supported by the Ministry of Health, Labour and Welfare in Japan (H14-Iryo-032).     

Managing hepatitis B to prevent liver cancer: recent advances

Chronic hepatitis B (CHB) infection is a major cause of human mortality worldwide. The majority of people with CHB are infected early in life, and 20–40% of men and 15% of women with chronic infection will develop hepatocellular carcinoma (HCC). Antiviral therapy is recommended for patients with CHB who have cirrhosis or active disease with the aims of reducing disease progression to cirrhosis, liver failure and liver cancer, thereby preventing death. Evidence that treatment with interferon or with early nucleos(t)ide analogue therapy reduces HCC has been somewhat conflicting, however evidence is emerging to support a significant role in HCC prevention of the more effective antivirals, entecavir and tenofovir. Older patients, those with cirrhosis, and those undergoing curative treatments for HCC derive the greatest medium-term benefit in terms of HCC reduction, but HCC can still occur and long-term surveillance is recommended.