Biomarkers for the early diagnosis of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Although the prognosis of patients with HCC is generally poor, the5-year survival rate is 70% if patients are diagnosed at an early stage. However, early diagnosis of HCC is complicated by the coexistence of inflammation and cirrhosis. Thus, novel biomarkers for the early diagnosis of HCC are required. Currently, the diagnosis of HCC without pathological correlation is achieved by analyzing serum α.fetoprotein levels combined with imaging techniques. Advances in genomics and proteomics platforms and biomarker assay techniques over the last decade have resulted in the identification of numerous novel biomarkers and have improved the diagnosis of HCC. The most promising biomarkers,such as glypican-3, osteopontin, Golgi protein-73 and nucleic acids including microRNAs, are most likely to become clinically validated in the near future. These biomarkers are not only useful for early diagnosis of HCC, but also provide insight into the mechanisms driving oncogenesis. In addition, such molecular insight creates the basis for the development of potentially more effective treatment strategies. In this article,we provide an overview of the biomarkers that are currently used for the early diagnosis of HCC.     

肝细胞癌生物标志物的研究进展:对于临床诊断及预后的意义

肝细胞癌(HCC)是2020年癌症死亡的第三大原因,也是全球第六大常见癌症。大多数肝癌患者在就诊时已发展为晚期癌症,尽管HCC发病率很高,但对于晚期患者的治疗方案并不多,所以提高HCC患者的早期发现率非常必要。本文总结HCC中已发现的生物标志物,希望能够为肝癌的早期诊断和预后判断提供新的视角。     

Liquid biopsy in patients with hepatocellular carcinoma: Circulating tumor cells and cell-free nucleic acids

Hepatocellular carcinoma(HCC), with its high incidence and mortality rate, is one of the most common malignant tumors. Despite recent development of a diagnostic and treatment method, the prognosis of HCC remains poor. Therefore, to provide optimal treatment for each patient with HCC, more precise and effective biomarkers are urgently needed which could facilitate a more detailed individualized decision-making during HCC treatment, including the following; risk assessment, early cancer detection, prediction of treatment or prognostic outcome. In the blood of cancer patients, accumulating evidence about circulating tumor cells and cell-free nucleic acids has suggested their potent clinical utilities as novel biomarker. This concept, so-called "liquid biopsy" is widely known as an alternative approach to cancer tissue biopsy. This method might facilitate a more sensitive diagnosis and better decision-making by obtaining genetic and epigenetic aberrations that are closely associated with cancer initiation and progression. In this article, we review recent developments based on the available literature on both circulating tumor cells and cell-free nucleic acids in cancer patients, especially focusing on Hepatocellular carcinoma.     

Labordiagnostik bei primärem Leberzellkarzinom

For the successful treatment outcome of hepatocellular carcinoma (HCC) a diagnosis in the early stages is a prerequisite. Guidelines recommend surveillance programs in patients at risk using abdominal ultrasound and some medical associations recommend the use of laboratory biomarkers in addition. Due to the limitations in sensitivity and specificity the use of alpha fetoprotein (AFP) is discussed controversially. The available markers lectin-binding AFP (AFP-L3) and des-gamma-carboxy prothrombin (DCP) in combination with AFP can improve the recognition of tumors in the early stages. An increase in marker levels during surveillance indicates the development of HCC. Further markers are in the development and validation stages.     

Biomarkers for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) ranks high among the most common and fatal cancers in the world. HCC develops from chronic liver diseases, especially from hepatitis C virus-related and hepatitis B virus (HBV)-related liver diseases. In this sense, useful biomarkers for HCC detection for the patients at risk of HCC are quite important. Recently, new therapies for HCC have been developed, and the prognosis of the patients has improved. However, considering the recurrence rate of HCC after treatment is very high, biomarkers that detect recurrence at an early stage are also required. In addition, since new drugs such as multikinase inhibitors have been introduced to the clinical scene, surrogate biomarkers to predict the effectiveness of treatment will be required in the near future. So far, many biomarkers for HCC have been developed, and their clinical usefulness has been assessed. As a result, several biomarkers for HCC are widely used. However, investigations to discover more useful biomarkers that fit in clinical settings are under way. In this review article, biomarkers for HCC are overviewed to examine their clinical usefulness.     

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.     

Hepatocellular carcinoma in the caudate lobe: Early diagnosis and active treatment may result in long-term survival

Hepatocellular carcinoma (HCC) in the caudate lobe is rare and the prognosis of patients with HCC in the caudate lobe has been reported to be poor. Resection for HCC in the caudate lobe has carried a higher rate of surgical risk and early recurrence. The effect of transcatheter arterial embolization (TAE) in treating HCC in the caudate lobe remains unknown. With the wide application of modern diagnostic modalities, we can now detect HCC at an earlier stage for active treatment (surgery or TAE). The aim of the present study was to analyse the effect of different treatments for HCC in the caudate lobe. From 1985 to 1994, 15 patients with HCC in the caudate lobe were retrospectively studied. Another 264 consecutive patients with newly diagnosed HCC treated by TAE were selected as the control group. Two patients underwent surgical resection and survived well without recurrence after 43 and 136 months, respectively. Ten patients underwent TAE and their survival rate was similar to that of the 264 consecutively TAE-treated controls with HCC not in the caudate lobe (P=0.19). The 1, 3 and 5 year survival rates for TAE-treated patients in the caudate lobe were 67.7, 31.1 and 12.6%, respectively, while in controls these figures were 53.0, 18.4 and 9.1%, respectively. Two of the three patients receiving supportive treatment died within 1 month after diagnosis. Those patients having a smaller solitary tumour without intrahepatic metastasis tended to survive longer. In conclusion, HCC in the caudate lobe does not always indicate a poor prognosis so long as early detection and active treatment (surgery or TAE) are available. Transcatheter arterial embolization may act as an alternative treatment modality for patients with HCC in the caudate lobe.     

肝细胞癌诊断、疗效及预后相关标志物的研究进展

肝细胞癌(hepatocellular carcinoma, HCC)是常见的消化系统恶性肿瘤之一,其具有起病隐袭、早期症状不明显、进展迅速等特点,一经发现已发展至中晚期,给患者生命健康带来严重威胁。近年来,随着新型生物标志物的发现和检测技术的构建与应用,HCC的诊断、疗效及预后评估效果有了显著提升,大大提高了HCC患者生存质量。本文就近年来HCC的诊断、疗效及预后标志物的研究进展作一综述,重点分析HCC不同标志物的功能作用,为HCC标志物的临床应用提供重要依据。     

Toward the discovery of new biomarkers of hepatocellular carcinoma by proteomics.

Primary liver cancer is the fifth most frequent neoplasm and the third most common cause of cancer-related death, with more than 500,000 new cases diagnosed yearly. The outcome for hepatocellular carcinoma (HCC) patients still remains dismal, partly because of our limited knowledge of its molecular pathogenesis and the difficulty in detecting the disease at its early stages. Therefore, studies aimed at the definition of the mechanisms associated with HCC progression and the identification of new biomarkers leading to early diagnosis and more effective therapeutic interventions are urgently needed. Proteomics is a rapidly expanding discipline that is expected to change the way in which diseases will be diagnosed, treated, and monitored in the near future. In the last few years, HCC has been extensively investigated using different proteomic approaches on HCC cell lines, animal models, and human tumor tissues. In this review, state-of-the-art technology on proteomics is overviewed, and recent advances in liver cancer proteomics and their clinical projections are discussed.     

Factors affecting screening for hepatocellular carcinoma

Background and aim. Hepatocellular carcinoma (HCC) is a frequent cancer. Its prognosis is highly dependent on early diagnosis. Patients at risk for developing HCC should be enrolled in a surveillance programme. Nevertheless, many patients at risk are not regularly screened. We aimed at exploring the characteristics that affect enrolment in a surveillance programme.Material and methods. The characteristics of the patients included in the prospective Bern HCC cohort between August 2010 and August 2011 were analysed according to their participation in a surveillance programme.Results. Among the 82 patients included in the cohort during this period of time, 48 were in a surveillance program before the diagnosis of HCC. Thirty five percent of cirrhotic patients were not screened. Age, sex, level of education, Child-Pugh status and MELD score were similar between the patients who were screened and those who were not screened. Patients with a private insurance and patients treated by a liver specialist were more frequently enrolled in a surveillance program. Sixty seven percent of the screened patients were eligible for curative treatment whereas only 15% of the non-screened patients were.Conclusions. In conclusion the surveillance of patients at risk for developing HCC increases their chances to be diagnosed at an early stage to allow curative treatment. More than one third of cirrhotic patients were not regularly screened. Patients with chronic liver disease should be referred to identify those at risk and enrol them in a surveillance program.     

Bile acids as drivers and biomarkers of hepatocellular carcinoma

The prevalence of hepatocellular carcinoma (HCC) is rapidly increasing, driven not least in part by the escalating prevalence of non-alcoholic fatty liver disease. Bile acid (BA) profiles are altered in patients with HCC and there is a developing body of evidence from in vitro human cellular models as well as rodent data suggesting that BA are able to modulate fundamental processes that impact on cellular phenotype predisposing to the development of HCC including senescence, proliferation and epithelial-mesenchymal transition. Changes in BA profiles associated with HCC have the potential to be exploited clinically. Whilst excellent diagnostic and imaging tools are available, their use to screen populations with advanced liver disease at risk of HCC is limited by high cost and low availability. The mainstay for HCC screening among subjects with cirrhosis remains frequent interval ultrasound scanning. Importantly, currently available serum biomarkers add little to diagnostic accuracy. Here, we review the current literature on the use of BA measurements as predictors of HCC incidence in addition to their use as a potential screening method for the early detection of HCC. Whilst these approaches do show early promise, there are limitations including the relatively small cohort sizes, the lack of a standardized approach to BA measurement, and the use of inappropriate control comparator samples.     

Hepatocellular carcinoma tumour markers: Current role and expectations

Tumour markers could be helpful along the continuum of care for patients with hepatocellular carcinoma; however, there is insufficient data for routine use of most current biomarkers in clinical practice. Therefore, the backbone of early detection, diagnosis and treatment response for hepatocellular carcinoma remains imaging-based. Alpha fetoprotein is the best studied of all biomarkers and may be of benefit for early detection when used in combination with ultrasound. Several other biomarkers, including AFP-L3, DCP, osteopontin, and GP73, are also being evaluated for early detection of hepatocellular carcinoma in phase III biomarker studies. Serum and tissue-based biomarkers and genomics may aid in HCC diagnosis, prognosis, and treatment selection; however, further studies are needed to better characterize their accuracy and potential role in clinical practice.     

Diagnostics and treatment of hepatocellular carcinoma. Recommendations of the Portal Hypertension Working Group of the Czech Hepatology Society and the J.E. Purkinje Czech Medical Society

Hepatocellular carcionma (HCC) is almost exclusively associated with liver cirrhosis as a significant HCC risk marker in advanced countries. Applicable therapy depends on early diagnosis, and risk patients should be screened for the presence of HCC on a regular basis. Liver ultrasound and determination of alpha-fetoprotein serum levels (AFP) are the screening methods used. Spiral CT is the most often used method for HCC staging. Non-invasive methods may under certain circumstances replace aimed biopsy. There are 3 basic curative therapies for the early stage of HCC: liver transplantation, surgical resection and different methods of local destruction of tumour (i.e., ethanolisation, thermoablation, etc.). Patients at medium stage of HCC may profit from chemoembolisation. Current available systemic chemotherapy is ineffective. Patients with advanced HCC are treated symptomatically. Patient survival prognosis after the application of one of the above treatment methods may be similar with that for HCC free cirrhosis patients, however, prognosis for advanced HCC patients is bad, with survival period from one to nine months.     

Current biomarkers for hepatocellular carcinoma: Surveillance,diagnosis and prediction of prognosis

Biomarkers for surveillance, diagnosis and prediction of prognosis in patients with hepatocellular carcinoma(HCC) are currently not ready for introduction into clinical practice because of limited sensitivity and specificity. Especially for the early detection of small HCC novel biomarkers are needed to improve the current effectiveness of screening performed byultrasound. The use of high-throughput technologies in hepatocellular research allows to identify molecules involved in the complex pathways in hepatocarcinogenesis. Several invasive and non-invasive biomarkers have been identified already and have been evaluated in different clinical settings. Gene signatures with prognostic potential have been identified by gene expression profiling from tumor tissue. However, a single "all-in-one" biomarker that fits all-surveillance, diagnosis, prediction of prognosis-has not been found so far. The future of biomarkers most probably lies in a combination of non-invasive biomarkers, imaging and clinical parameters in a surveillance setting. Molecular profiling of tumorous and non-tumorous liver tissue may allow a prediction of prognosis for the individual patient and hopefully clear the way for individual treatment approaches. This article gives an overview on current developments in biomarker research in HCC with a focus on currently available and novel biomarkers, in particular on micro RNA.     

Evaluation of the surveillance program for hepatocellular carcinoma

We examined the compliance with, and efficacy of, the clinical guideline for the diagnosis of hepatocellular carcinoma (HCC). We classified 74 patients with HCC into 3 categories;23 surveillance cases, 18 non-surveillance cases, and 33 incidental cases. Patients from affiliated hospitals included more non-surveillance and incidental cases than in university hospital-treated cases. HCC was diagnosed at an earlier stage in the surveillance group than the incidental group, and the surveillance group had a better outcome than the incidental group. There was no significant difference in HCC stage or outcome between surveillance and non-surveillance groups. The guidelines appeared to be useful for early diagnosis of HCC except for the fact that some in the surveillance group were diagnosed at an advanced stage and around 30% of the incidental group had some risk factors of HCC. Those conducting surveillance must improve their skills for early diagnosis of HCC and both doctors and patients must increase compliance with the guidelines.     

Serum markers of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world with increasing incidence worldwide. Most of patients with HCC are diagnosed at a late stage. Therefore, the prognosis of HCC patients is generally very poor with a 5-year survival rate of less than 5%. Screening strategies including alpha-fetoprotein (AFP) and ultrasound every 6 months in patients with liver cirrhosis, the major risk factor for HCC development, have been recommended to detect HCC at earlier stages amenable to effective treatment strategies. AFP, however, is a marker with poor sensitivity and specificity and the ultrasound is highly dependent on the operator's experience. Apart from AFP, lens culinaris agglutinin-reactive AFP and des-gamma carboxyprothrombin and several other biomarkers (e.g., glypican-3, human hepatocyte growth factor, and insulin-like growth factor) have been proposed as markers for HCC detection. In addition, with recently employed techniques, such as gene-expressing microarrays and proteomics, it is to be expected that new HCC-specific markers will become available in the near future. For all such proposed markers, however, the clinical usefulness has to be carefully evaluated and validated.     

Risk prediction of hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy

Hepatocellular carcinoma(HCC)is a grave primary liver cancer that has a limited therapeutic option because it is generally diagnosed later in an advanced stage due to its aggressive biologic behavior.The early detection of HCC has a great impact on the treatment efficacy and survival of patients at high risk for cancer.Potential host,environmental,and virus-related risk factors have been introduced.Hepatitis B virus(HBV)is a major cause of end-stage liver diseases such as liver cirrhosis or HCC in endemic areas,and its serologic or virologic status is considered an important risk factor.HCC risk prediction derived from the identification of major risk factors is necessary for providing adequate screening/surveillance strategies to high-risk individuals.Several risk prediction models for HBV-related HCC have been presented recently with simple,efficient,and readily available to use parameters applicable to average-or unknown-risk populations as well as high-risk individuals.Predictive scoring systems of risk estimation to assess HCC development can provide the way to an evidence-based clinical approach for cost-and effort-effective outcomes,capable of inducing a personalized surveillance program according to risk stratification.In this review,the concepts and perspectives of the risk prediction of HCC are discussed through the analysis of several risk prediction models of HBV-related HCC.     

肝细胞癌诊治中的若干问题

随着肝细胞癌（HCC）肿瘤标志物和CT／MRI诊断的应用、手术切除及局部消融等治疗方法的进步,使HCC的5年生存率达到了63．4％。但是由于我国HCC早期诊断水平的不均衡,可进行手术切除的病例仅仅有20％～30％。对于高危人群定期开展血清肿瘤标志物和肝脏超声检查;提高三期动态增强CT和Gd—DTPA增强MRI等影像学诊断水平,同时积极开展多学科会诊,制定个性化治疗方案和减少术后肝功能衰竭发生等若干问题,是提高我国HCC早期诊断水平,提高治疗效果,延长生存期的有效手段。     

Does surveillance for hepatocellular carcinoma in HCV cirrhotic patients improve treatment outcome mainly due to better clinical status at diagnosis?

BACKGROUND/AIMS: Cirrhotic patients with hepatitis C virus infection are a group at higher risk for hepatocellular carcinoma. Conventional screening programs detect only few early hepatocellular carcinomas that are eligible for radical treatment. Our aim was to compare characteristics of patients, modality of treatment, and outcome in anti-HCV positive cirrhotics with hepatocellular carcinoma diagnosed during follow-up, or incidentally. METHODOLOGY: Sixty-one hepatocellular carcinomas were consecutively diagnosed in cirrhotic anti-HCV patients from 1993-1998 among which 34 during biannual ultrasonographic-biochemical follow-up and the others incidentally. Child-Pugh's score, alpha-fetoprotein levels, uni- or multifocality of the tumor, and treatment and survival of the patients were then analyzed on the basis of modality of diagnosis. RESULTS: Surgical treatment was feasible only in a minority of patients. Radical and palliative treatment was more frequent among patients with HCC diagnosed during follow-up. Child-Pugh's score was lower in these patients, moreover their survival rate was better. Analysis of survival of patients treated with the same procedure and grouped by modality of diagnosis did not demonstrate any differences. Regression analysis showed that patients with a lower Child-Pugh's score, one nodule, with a tumor diagnosed during follow-up and who were treated had a better survival rate. CONCLUSIONS: In our population surveillance did not detect a higher percentage of curable HCC. Nevertheless the results of palliative treatment and of curative treatment overlapped. Overall better outcome was observed in patients with preserved liver function whatever the treatment. Surveillance allowed us to diagnose HCC in patients with these characteristics thus leading to an improved survival rate.