Epidemiology of hepatocellular carcinoma in Japan

Primary liver cancer, 95% of which is hepatocellular carcinoma (HCC), has ranked third in men and fifth in women as a cause of death from malignant neoplasm in Japan. Although the number of deaths and death rates from HCC increased until 2002 in Japan, annual deaths (34 089) and the death rate (27.0/100 000) from liver cancer decreased in 2003. Hepatitis C virus (HCV)-related HCC represents 75% of all HCC in Japan. The incidence of HCC without hepatitis B surface antigen (HBsAg) or anti-HCV accounted for 7–12% of HCC in Japan andhalf of non-B non-C-HCC was of unknown origin. Geographically, HCC is more frequent in western than eastern Japan, and the death rates from HCC in each prefecture correlate with the prevalence of anti-HCV, but not with HBsAg prevalence. Interferon therapy for chronic hepatitis C has reduced the risk factors for development of HCC, especially among patients with sustained response.     

Radiological diagnosis of hepatocellular carcinoma

Treatment of hepatocellular carcinomas (HCC) is often complicated by the fact that early HCCs are mostly asymptomatic and the carcinoma is often discovered at an advanced stage. The aim of diagnostic imaging is to detect HCC at an early stage, when curative options are available. In recent years, there have been many efforts to improve early detection of small HCC. The purpose of this article is to describe the pertinent findings of HCCs in non‐invasive, diagnostic imaging, including ultrasound, computed tomography, as well as modern magnetic resonance imaging techniques. Special emphasis is given to the frequently addressed difficulties of differentiation of precancerous lesions and small HCCs. A non‐invasive diagnostic approach is considered with a review of the literature.     

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.     

International consensus on histologic diagnosis of early hepatocellular neoplasia

1. The precursor lesions for the development of hepatocellular carcinoma are believed to be high-grade dysplastic nodules. These lesions have atypical and proliferative features that distinguish them from normal or cirrhotic liver but are not sufficient for the diagnosis of carcinoma.
2. Individual HGDN are often heterogeneous and complete sampling may reveal regions of carcinoma within these otherwise benign lesions.
3. Invasion of stroma is considered a definitive feature of HCC. However, this feature is not always present in early HCC and is seldom found in needle biopsies.
4. Accurate diagnosis of dysplastic nodules and well-differentiated HCC requires skill and experience. However, accurate diagnosis with needle biopsies may be impossible if the highest grade of atypia is not sampled. Fine needle aspiration is not appropriate for small lesions that are expected to be early hepatic neoplasia. This technique should be reserved for suspected moderate- or poorly differentiated HCC.     

Hepatocellular carcinoma screening practices and impact on survival among hepatitis B-infected Asian Americans

Asians Americans have a high burden of hepatitis B virus (HBV) associated hepatocellular carcinoma (HCC). HCC screening practices in this population are unknown. We aimed to investigate predictors and patterns of HCC screening and its impact on survival in HBV-infected Asian Americans. Clinical data were obtained from a retrospective cohort of 1870 HBsAg-positive Asians in San Francisco's safety net clinics. In 824 patients at-risk for HCC, screening (≥1 imaging and/or AFP per year) decreased from 67% to 47% to 24% from the 1st to 2nd to 10th year after HBV diagnosis, respectively. AFP, imaging, and imaging plus AFP were used in 37%, 14%, and 49% during the first year after diagnosis, and imaging plus AFP increased to 64% by the 10th year. Among 1431 patients followed in 2007, age 40-64 years, female gender, cirrhosis, hepatologist evaluation, HBV diagnosis after 2003, and testing for HBeAg were associated with HCC screening. Of the 51 patients with HCC, more cirrhotics received screening and were diagnosed with early stage disease. Median survival following HCC diagnosis was higher in screened patients (1624 days vs. 111 days, P = 0.02). MELD score at HCC diagnosis (HR 1.2, 95% CI 1.1-1.3) and receipt of curative therapy (HR 0.3, 95% CI 0.08-0.94) were associated with survival. Screening rates in at-risk Asian Americans, particularly among noncirrhotics, were suboptimal and decreased over time. Among patients with HCC, receipt of prior screening improved survival, and this survival benefit was related to better liver function at HCC diagnosis and receipt of curative therapy.     

Secondary prevention of hepatocellular carcinoma

Two decades have gone by since the earlier trials of alpha-fetoprotein (AFP) screening for hepatocellular carcinoma (HCC) were conducted in Africa and China. It is accepted that early detection, diagnosis and treatment of HCC remains an important target to be achieved before a breakthrough appears on the primary prevention of HCC. In the present study, screening investigations were performed in a high risk population of HCC, defined as persons who had hepatitis, blood transfusions, a family history of HCC, and were hepatitis B virus carriers. Ultrasonography combined with AFP serosurvey was accepted as an effective screening procedure to detect small HCC. Early diagnosis of HCC was not difficult if tumour markers and medical imaging were combined. Early resection has been proven to prolong survival of patients with small HCC. Repeated intralesional ethanol injection is an alternative treatment to surgery, while transcatheter arterial embolization is a less effective alternative. Re-resection of subclinical recurrence after curative resection has proven of merit in prolonging survival even further. Resection of small HCC remains an important approach in getting long-term HCC survival and to improving 5-year survival rates. It is more effective than treatment of large HCC. Studies on the secondary prevention of HCC have stimulated research into tumour markers, the natural history and cellular origin of HCC and oncogenes. However, the issue of ‘cost-effectiveness’ remains to be evaluated.     

Diagnosis and treatment of hepatocellular carcinoma

The diagnosis and treatment of hepatocellular carcinoma (HCC) have witnessed major changes over the past decade. Until the early 1990s, HCC was a relatively rare malignancy, typically diagnosed at an advanced stage in a symptomatic patient, and there were no known effective palliative or therapeutic options. However, the rising incidence of HCC in several regions around the world coupled with emerging evidence for efficacy of screening in high-risk patients, liver transplantation as a curative option in select patients, ability to make definitive diagnosis using high-resolution imaging of the liver, less dependency on obtaining tissue diagnosis, and proven efficacy of transarterial chemoembolization and sorafenib as palliative therapy have improved the outlook for HCC patients. In this article, we present a summary of the most recent information on screening, diagnosis, staging, and different treatment modalities of HCC, as well as our recommended management approach.     

Outcome of small liver nodules detected by computed tomographic angiography in patients with hepatocellular carcinoma

Purpose

Hepatic lesions identified by computed tomography (CT) during arterial portography (CTAP) or CT hepatic arteriography (CTHA) in hepatocellular carcinoma (HCC) patients are sometimes too small to be diagnosed as HCC. We undertook this cohort study to assess whether these small lesions are actually HCC, and to clarify the effectiveness of these imaging examinations in a clinical setting.

Methods

We assessed the characteristics of 74 tiny lesions detected by CTAP and/or CTHA, but not by CT in 67 patients.

Results

Seven out of 10 nodules were histologically confirmed as HCC and 18 out of 64 lesions increased in size and showed typical findings of HCC during the follow-up period. Multivariate analysis revealed that the size of the main tumor (>30 mm in diameter) was associated with the presence of tiny additional HCC lesions (P = 0.002).

Conclusions

These findings indicate that CTAP and CTHA are recommended for determining the stage of HCC, especially when the HCC nodule is larger than 30 mm in diameter.     

The 2008 Okuda lecture: Management of hepatocellular carcinoma: From surveillance to molecular targeted therapy

Hepatocellular carcinoma (HCC) is responsible for approximately 600 000–700 000 deaths worldwide. It is highly prevalent in the Asia‐Pacific region and Africa, and is increasing in Western countries. Alpha fetoprotein (AFP) alone is insufficient for HCC screening. A combination with other tumor markers, such as PIVKA‐II and AFP‐L3, and periodical ultrasound surveillance is necessary. Sensitivity of AFP in depicting HCC is highest, followed by PIVKA‐II and AFP‐L3, but the order of the specificity is inverse, AFP‐L3, PIVKA‐II, and AFP. Sonazoid‐enhanced ultrasound (US) is extremely useful to characterize hepatic tumors equal to or more than multidetector row computed tomography (MDCT). Sonazoid‐enhanced US with defect re‐perfusion imaging is a breakthrough technique in the treatment of HCC. Defect re‐perfusion imaging will markedly change the therapeutic strategy for liver cancer. Gd‐EOB‐DTPA‐magnetic resonance imaging is a newly developed imaging technique in the detection and diagnosis of HCC. It is the most sensitive tool in the differentiation of early HCC from dysplastic nodules. Regarding the treatment strategy, there has been no established systemic chemotherapy for advanced HCC, except for Sorafenib. Empirically, intrahepatic arterial infusion chemotherapy using implanted reservoir port is known to be effective in response rate and overall survival for advanced HCC with vascular invasion. Sorafenib in combination with transcatheter arterial chemoembolization or adjuvant use after ablation or resection will significantly prolong the life expectancy if ongoing clinical trials provide positive results. In conclusion, it is expected that readers will gain deeper insight into the latest progress and updated diagnosis and treatment of HCC described in this review.     

Advancement in HCC imaging: diagnosis, staging and treatment efficacy assessments

Diagnostic confirmation and assessment of disease extent are crucial for proper management of patients with hepatocellular carcinoma (HCC). Imaging studies play a crucial role in the diagnosis and staging of HCC. The imaging techniques commonly used for the diagnosis of HCC include ultrasound, computed tomography, and magnetic resonance imaging. Currently, improvements in imaging technology make a noninvasive and reliable diagnostic assessment of hepatocellular nodules possible in the cirrhotic liver. Biopsy is infrequently required prior to treatment, and the diagnosis of HCC is strongly dependent on hemodynamic features (arterial hypervascularity and washout in the venous phase) on dynamic imaging. Accurate staging of HCC is important in determining prognosis and in deciding optimal treatment for each patient. In addition, although there is a strong demand for an accurate diagnostic tool to detect smaller tumors, until now, the major challenge for radiologists in imaging cirrhosis is the characterization of small hepatocellular nodules in the cirrhotic liver. Further improvement of imaging technologies including functional imaging such as elastography, perfusion imaging and diffusion imaging, and development of new contrast media will undoubtedly improve the detection and characterization of small tumors. In this article, we present a summary of the most recent information on the diagnosis and staging of HCC.     

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.     

Detection and characterization of small hepatocellular carcinoma

Abstract   Early detection and characterization of small hepatocellular carcinoma (HCC) by imaging is possible with high confidence, and is important for the improvement of the prognosis of the patient with liver cirrhosis. In this lecture, screening of HCC and its characterization by imaging, with special reference to imaging features of human multi step hepato carcinogenesis will be discussed.     

Early diagnosis of primary liver cancer: imaging versus genetics

Early diagnosis of hepatocellular carcinoma (HCC) in nodules smaller than 2 cm detected by screening ultrasounds becomes essential given that, at that stage, no vascular invasion is usually detected and treatment is associated with a high rate of long-term survival. Improvements in imaging techniques in the last few years have allowed a conclusive diagnosis of HCC in these small nodules without invasive procedures. However, a conclusive diagnosis of HCC by imaging is not always possible and, in more than half of cases, biopsy is needed. On the other hand, histological confirmation of HCC in such tiny nodules is very complex, and in most cases impossible because of the limited sample obtained. In addition, serum tumor markers currently available show low accuracy and are useless for early diagnosis. Progress in the knowledge of molecular mechanisms associated with malignant transformation will allow the use of new techniques that will facilitate diagnosis for HCC in very early stages.     

Resecting hepatocellular carcinoma in cirrhotic liver

Abstract   Resecting hepatocellular carcinoma (HCC) in a cirrhotic patient is potentially dangerous and recurrence of HCC after operation is high. Our current strategy consists of careful preoperative assessment of liver functions by indocyanine green clearance test, intraoperative techniques to reduce blood loss, and postoperative surveillance and prompt treatment of recurrences. The 5-year overall survival rate of HCC patients after resection is 34.3%, which is comparable with that in patients with normal liver (37.3%) or chronic hepatitis (45.3%).     

18F-FDG PET/CT双时相显像在肝癌诊断中的应用价值探讨

目的 本研究的目的是探讨¹⁸F-FDG PET/CT双时相显像在不同类型肝细胞癌（HCC）诊断中的不同表现,以提高该方法诊断的灵敏度和特异度。方法 对经病理学检查确诊的小肝癌、结节型肝癌和巨块型肝癌各40例进行回顾性评价。使用德国Siemens Biograph Turepoint 40 PET/CT 成像仪和¹⁸氟-脱氧葡萄糖（¹⁸F-FDG）对所有病例进行PET/CT显像检查,依托半定量评估基础,计算最大标准摄入值（SUVmax）。结果 在40例小肝癌患者中,21例（52.5%）、在40例结节型肝癌中,24例（60.0%）和40例巨块型肝癌中,37例（92.5%）病灶延迟相SUVmax较早期相升高（F=16.714,P=0.000）;小肝癌患者早期相和延迟相SUVmax分别为3.99±1.40和4.17±1.99（t=-1.406,P=0.168）,结节型肝癌患者早期相和延迟相SUVmax分别为5.04±1.87和5.23±2.25（t=-1.364,P=0.180）,巨块型肝癌患者早期相和延迟相SUVmax分别为6.98±2.57和8.10±3.11（t=-4.119,P=0.000）,后者差异有统计学意义;三种类型肝癌之间早期相SUVmax值存在差异（F=22.765,P=0.000）,延迟相SUVmax值也存在差异（F=26.435,P=0.000）。结论 在HCC,随肿瘤直径的增大,双时相显像诊断的可能性增大。     

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 small hepatocellular carcinoma

In the last years the incidence of hepatocellular carcinoma (HCC) is rising in cirrhotic patients worldwide. Due the importance of early and definite diagnosis of HCC, any nodular lesion detected in patients with chronic liver disease should be considered as suspicious for HCC. The screening and surveillance programs in patients with liver diseases have increased the number of small HCC detected at an early stage, when the therapeutic options available are able to provide benefit. The introduction of new imaging techniques has improved the accuracy of characterizing these nodules. According to the EASL recommendations, contrast-enhanced computed tomography (CT), contrast enhanced ultrasound (US) and magnetic resonance (MR) with different MR-contrast agents are currently used to characterize liver lesions. Imaging guided biopsy is recommended for small nodules or in lesions without typical features (arterial hypervascularization) in at least two imaging techniques. Frequently the differential diagnosis of small nodules is complicated by discordant vascularity and recent studies have also demonstrated the presence of small hypovascular HCC at perfusional US and helical CT. At present, different treatment options can be offered to patients with diagnosis of small HCC at an early stage; percutaneous techniques, surgical resection and liver transplantation can provide benefit in properly selected patients. This review describes some critical points regarding the detection, diagnosis and therapeutic management of small nodules of HCC in cirrhotic patients.     

Metastasis of hepatocellular carcinoma to spleen and small intestine

Metastasis of cancer to the spleen or small intestine is rare. We encountered a case of hepatocellular carcinoma (HCC) with splenic and jejunal metastases. A 60-year-old man was referred to us in February 2005 with a diagnosis of splenic tumor. Since 2001, he had been treated repeatedly for HCC with liver cirrhosis due to hepatitis C virus infection; partial liver resection, transcatheter arterial chemo-embolization, and radiofrequency ablation therapy had been performed. In October 2004, he had undergone partial pulmonary resection due to metastasis of HCC to the lung. The splenic tumor, which was detected by computed tomography, seemed to be a metastasis of HCC. Splenectomy was performed for the splenic tumor, and a jejunal tumor was discovered and also resected. Both the splenic and jejunal tumors were diagnosed pathologically as metastases from the HCC. After repeated treatment for HCC, metastases can appear in various organs; thus, careful observation is necessary during follow-up.     

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.