Primary hepatocellular carcinoma in intertropical Africa: relationship between age and hepatitis B virus etiology

Clinical observations of patients with primary hepatocellular carcinoma (PHC) at Le Dantec Hospital, Dakar, Senegal, were studied to determine a correlation with hepatitis B virus (HBV) infection. Of the 103 patients with PHC, 80 had an active HBV infection (HBsAg and/or anti-HBc); 23 showed signs of previous HBV infection (anti-HBs and anti-HBc). The two groups were similar in the detection of alpha-fetoprotein (approximately 60%) and in the major clinical findings: hepatomegaly, 76.25% and 86.96%, respectively; and ascites, 57.50% and 47.83%, respectively. Jaundice, however, was three times more frequent (P < 0.01) in the group of patients with signs of active HBV replication. Distribution of HBV markers as a function of age at onset of PHC revealed that the presence of HBsAg was primarily confined to the sera of the younger patients (< 50 yr old). When compared with leprosy patients and blood donors, the younger PHC patients differed in the frequency of detection of HBsAg and anti-HBs. The older people (> 50 yr old) in the three groups (PHC patients, leprosy patients, and blood donors) had identical HBV markers.     

Skull metastasis from hepatocellular carcinoma with chronic hepatitis B

A 56-year-old male visited our hospital for evaluation of an occipital mass. Contrast computed tomography showed hypervascular enhancement with osteolytic change in the skull and a huge enhanced mass in the liver. Magnetic resonance imaging showed bone metastasis in the thoracic vertebrae. Assays for hepatitis B surface antigen and hepatitis B core antibody were positive and his liver condition was Child-Pugh grade A. Our diagnosis was hepatocellular carcinoma (HCC) with skull and vertebrae metastases on chronic hepatitis B. He was treated with radiation therapy for bone metastases and transcatheter arterial chemoembolization for HCC. But he developed acute respiratory failure because of aspiration pneumonia, congestion and oedema with haemorrhage of the lungs and died. Dissection showed HCC with multiple bone metastases. The liver tumor was categorized as well-differentiated HCC, Edmondson classification I, trabecular type and pseudoglandular type. In the liver mild infiltration of lymphocytes was seen in Glisson's capsules which were significantly enlarged with well preserved limiting plates. Piecemeal necrosis was not obvious. No fibrosis was noted. An 8 cm × 7 cm × 3 cm metastatic lesion had formed in the left occipitotemporal part of the cranial bone. The lesion was osteolytic and showed invasion into the dura mater. Neither the subdural cavity nor the brain showed involvement from the metastatic tumor. However, skull metastasis from HCC is very rare and it affects the patient's prognosis and the quality of life. Therefore, it is very important to make an early diagnosis and carry out proper management of skull metastasis from HCC.     

Prevention of hepatitis B virus-related hepatocellular carcinoma

Hepatocellular carcinoma (HCC), especially hepatitis B virus (HBV)-related, remains a major cause of cancer-related mortality worldwide. Unless there is early d...     

Brain metastasis from hepatocellular carcinoma associated with hepatitis B virus

Four cases of brain metastasis from hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV) are reported in an area not endemic for HBV infection. Two cases are unusual, since cerebral metastases were the only secondary localization. In these cases, no other sites of metastasization were detected either before or immediately following neurosurgical treatment. In all cases the expression of pRB, p53 and p16 tumor suppressor protein was studied with immunohistochemistry, both, in the primary and metastatic lesions. The pRB expression was as follows: in two cases, lack and moderate expression were observed both, in the primary and in the metastases; in the other two, pRB was not detected. In all cases p53 expression was negative both, in the primary and the metastases. P16 expression was moderately expressed in three cases, both in the primary and the metastases. In one case it was absent. Hepatocarcinogenesis is a multistep process, in which several oncogenes and oncosuppressor genes are involved. In four unusual cases of spread to the brain, we evidenced that tumor suppressor protein expression of p16, p53, and particularly pRB (its aberrated expression is usually associated with metastasis) were altered. We also suggest that HBV and its X protein (HBX) might play an important role in such aggressive behavior of the neoplasia.     

Preneoplastic markers of hepatitis B virus-associated hepatocellular carcinoma

Hepatitis B virus (HBV) carriers are at high risk for the development of hepatocellular carcinoma (HCC), but there are no reliable markers that will identify such high-risk carriers. The objective of this work is to identify serologic markers that may indicate the early presence of HCC. Since HBV-encoded X antigen (HBxAg) likely contributes to HCC by up- or down-regulation of host gene expression, X positive and negative HepG2 cells were made and subjected to cDNA subtraction. When specific ELISAs were constructed measuring differentially expressed antigens and corresponding antibodies, antibodies to several differentially expressed genes were detected. In cross-sectional and longitudinal studies, antibodies were predominantly present in patients with HBV-associated cirrhosis and HCC, but not in most carriers with hepatic inflammation alone or without active liver disease. Antibodies were also present in patients with hepatitis C virus (HCV)-related HCC, but rarely detected in sera from uninfected individuals, those with tumors other than HCC, or those with drug-induced hepatitis. Statistical analysis showed that HCC patients with four or more antibodies detectable before the appearance of HCC had decreased survival, suggesting that these markers may reflect stepwise hepatocarcinogenesis. Hence, these antibodies may serve as preneoplastic markers for HCC in HBV carriers with chronic liver disease, and may be identified by a simple blood test.     

乙肝相关肝细胞癌的分子机制研究新进展

肝细胞癌是最常见的恶性肿瘤之一,同时也是排列全球第三位的肿瘤相关致死原因。其发病率在我国仅次于肺癌,居第二位。乙肝病毒是一类DNA病毒,它主要感染肝细胞并引起一系列持续且较急性的肝脏病变。尽管有大量流行病学研究证明慢性乙型肝炎在肝癌的发生发展过程中发挥了重要的作用,但是其潜在的病毒导向致瘤的分子作用机制尚存在巨大的争议。本文系统总结相关文献,讨论乙肝病毒在原发性肝癌的致瘤过程中的相关分子机制。     

Does hepatitis B virus cause hepatocellular carcinoma?

Evaluation of the hypothesis of an association between hepatitis and hepatocellular carcinoma (HCC), first suspected on pathologic grounds, was made easier by the discovery of hepatitis B surface antigen. Population correlation and analytical epidemiologic studies established that there is a strong and specific association between hepatitis B virus (HBV) and HCC. The association is restricted to chronically active forms of HBV infection and is universally present, equally strong in the USA and Europe as in Africa and Asia. The causal nature of the association between HBV and HCC appears indisputable, even though the pathogenesis of HBV-related HCC has not been established. There is no evidence to support any of the non-causal interpretations, i.e., that a third factor causes both persistence of HBV and HCC, or that HCC increases susceptibility to the HBV carrier state. Since about 200 million people are hepatitis B surface antigen carriers, HBV would appear to be second only to cigarette smoking as the most important known human carcinogen. However, a substantial proportion of HCC cases throughout the world show no evidence of active HBV infection; for those cases other causal agents must be invoked. Aflatoxin may be an important etiologic factor in Africa and Asia, whereas in Europe and the USA cigarette smoking and alcohol drinking are serious and numerically important suspects for hepatocellular carcinogenicity. Several other factors, including natural and synthetic chemical carcinogens, infectious agents and steroid hormones are also suspected, but the supporting evidence is weak and the numerical importance of the factors probably limited.     

Epigenetic mechanisms in hepatitis B virus-associated hepatocellular carcinoma

Chronic infection of the liver by the hepatitis B virus (HBV) is associated with increased risk for developing hepatocellular carcinoma (HCC). A multitude of st...     

Integration of hepatitis B virus DNA in hepatocellular carcinoma

Integration of hepatitis B virus (HBV) DNA into genomic DNA was investigated in 34 livers bearing hepatocellular carcinoma (HCC) by Southern blot hybridization using 32P-labeled, cloned and purified HBV DNA as a probe. Rehybridization of nitrocellulose paper with a probe containing only the cloning vector was performed after dehybridization to avoid possible false-positive results. Integrated HBV DNA was detected in all 9 hepatitis B surface antigen (HBsAg)-seropositive cases and 3 out of 25 (12%) HBsAg seronegative cases. The hybridization patterns of viral DNA were the same among several cancer nodules in two HCC cases with multiple liver tumors, indicating unicentric hepatocarcinogenesis in these two cases. These results, obtained with avoidance of false-positive results, showed that only a minority of HBsAg-seronegative HCC cases in Japan had demonstrable HBV DNA in the tumors studied by the Southern blot hybridization technique.     

The association of hepatocellular carcinoma in childhood with hepatitis B virus infection

Eleven cases of hepatocellular carcinoma (HCC) in childhood were investigated by immunohistochemistry for association with hepatitis B virus (HBV) infection. Seven of 11 cases (64%) demonstrated positivity for hepatitis B surface antigen (HBsAG), whereas all 11 were negative for hepatitis B core antigen (HBcAG). Cirrhosis was absent in all cases, and other causes for HCC in childhood were not found. All children with HBV-associated HCC died within 6 months of diagnosis. The median survival time of these children was 2 months. Only one child with HCC of trabecular subtype without HBV association is still living after 18 months. However, this child has metastases and a local recurrence. Three other children with HCC of fibrolamellar subtype are free of disease after 2, 5, and 6 years, respectively. The high number of cases of HBV-associated HCC shows the important role of HBV infection as an etiologic factor for the development of childhood HCC in middle Europe.     

乙型肝炎病毒感染与原发性肝癌相关的危险度分析

目的:分析原发性肝癌(PHC)患者血清中乙型肝炎病毒(HBV)标志情况,探讨HBV感染与PHC危险性的关系。方法:收集在中国医科大学附属第一医院介入科住院的PHC患者224例作为病例组,同时期在此科住院的其他非肝病患者280例作为对照组,记录其血清HBV标志,与既往乙型肝炎和肝硬化等情况进行病例对照研究。结果:PHC组HBV总感染率为68.22%(146/214),以HBsAg阳性(65.42%,140/214)和抗-HBe阳性(30.84%,66/214)为主,对照组总感染率为7.63%(20/262),其中以HBsAg(3.44%,9/262)和抗-HBe(7.63%,20/262)为主。病例组感染率明显高于对照组(χ2=200.1,P<0.000 1),优势比OR=27.4(95%CI为16.0~46.9)。结论:HBV慢性感染是PHC的一个危险因素,在HBV慢性感染者中进行PHC筛查,对早期诊断PHC提高其临床疗效有重要意义。     

Association of hepatitis B virus infection with hepatocellular carcinoma in American patients

Thirty-four patients from the Philadelphia area with hepatocellular carcinoma (HCC) were matched with colon cancer patients, lung cancer patients and blood donors according to age and sex. Sera from the four groups were tested to determine the prevalence of hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc). Five of the HCC patients (14.7%) and none of the controls were positive for HBsAg. At least one of the three serologic markers of hepatitis B virus (HBV) infection was found in 51.5% of the HCC patients, 5.3% of the colon cancer patients, 11.1% of the lung cancer patients, and 10.7% of the blood donors. Twelve of the seventeen seropositive HCC patients (70.6%) were positive for anti-HBc alone, while all of the seropositive lung cancer patients and donors were positive for anti-HBs alone. Sera positive for any HBV marker were also tested for e antigen (HBeAg) and its antibody (anti-HBe). Four of the HCC patients (23.5% of the seropositives) had anti-HBe, while none of the sera tested had HBeAg. A history of alcoholism did not appear to influence HBV seropositivity in the HCC patients. This study supports the hypothesis that HBV infection is closely associated with HCC even in areas where both conditions are uncommon. The wide disparity between seropositivity for HBsAg and anti-HBc in the HCC patients is an unusual feature, for which an age effect may be the best explanation.     

Prevention of hepatocellular carcinoma in patients with chronic hepatitis B virus infection

Chronic hepatitis B (CHB) accounts for approximately 50% of the underlying etiologies for the development of hepatocellular carcinoma (HCC) worldwide. We reviewed the primary, secondary, and tertiary measures for the prevention of HCC in CHB patients. First, the most effective method is preventing the acquisition of CHB through global vaccination of infants. However, in patients already chronically infected, antiviral treatment using interferon or nucleoside analogs can prevent disease progression to cirrhosis or HCC. Studies have found viral replications indicated by a HBV DNA level to be a strong predictor for cirrhosis and HCC, irrespective of other viral and biochemical factors. Additionally, periodic surveillance using ultrasonography and serum α-fetoprotein every 3-6 months for earlier detection of HCC is also important so that curative treatments can be used. Once HCC occurs, hepatic resection is the mainstay of curative treatments. To prevent tumor recurrence after resection, adjuvant interferon treatments have been tried with promising results based on the assumption that they not only suppress viral activity but also have tumoricidal, antiangiogenetic, and antiproliferative effects. Using nucleoside analogs also has its rationale for preventing de novo tumor development in remnant liver, considering that viral replications are a strong risk factor for HCC. Optimal preventive plans should be further investigated in future studies.     

Primary hepatic malignant lymphoma: its occurrence in a patient with chronic active hepatitis, cirrhosis, and hepatocellular carcinoma associated with hepatitis B viral infection

A patient with hepatitis B induced chronic active hepatitis and cirrhosis had hepatocellular carcinoma and poorly differentiated lymphocytic malignant lymphoma localized in the liver. Whereas a close relationship between hepatitis B viral infection, chronic active hepatitis, macronodular cirrhosis, and hepatocellular carcinoma is now recognized, no such association has been reported with primary hepatic malignant lymphoma, which is a distinctly rare entity. In a large autopsy population that we reviewed systemic malignant lymphoma rarely occurred in association with cirrhosis. Such an association has been noted in other studies, however. We speculate half if an association exists between malignant lymphoma and cirrhosis it might have an immunologic basis such as seen in certain autoimmune diseases.     

Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy.

BACKGROUND: Cancer patients who are hepatitis B virus (HBV) carriers and undergoing chemotherapy (CT) may be complicated by HBV reactivation. Over 80% of hepatocellular carcinoma (HCC) patients are HBV carriers; however, the incidence of HBV reactivation during CT has not been well-reported. A prospective study was conducted to determine the incidence of HBV reactivation, the associated morbidity and mortality, and possible risk factors. PATIENTS AND METHODS: 102 HBsAg-positive patients with inoperable HCC underwent systemic CT. Patients received either combination cisplatin, interferon, doxorubicin and fluorouracil (PIAF) or single-agent doxorubicin. They were followed up during and for 8 weeks after CT. RESULTS: In 102 patients, 59 (58%) developed hepatitis amongst whom 37 (36%) were attributable to HBV reactivation. Twelve (30%) died of HBV reactivation. CT was interrupted in 32 patients (86%) with reactivation and 54 (83%) without reactivation (P>0.05). The median survivals were 6.00 and 5.62 months, respectively (P=0.694). Elevated baseline alanine aminotransferase (ALT) was found to be a risk factor. CONCLUSION: HBV reactivation is a common cause of liver damage during CT in HBsAg-positive HCC patients. The only identifiable associated risk factor was elevated pre-treatment ALT. Further studies into the role of antiviral and novel anticancer therapies are required to improve the prognosis of these patients.     

Recent advances in hepatitis B viruses and hepatocellular carcinoma

The data reviewed at this meeting reinforce the notion that HBV may contribute to the development of liver cancer through a variety of mechanisms, including activation of oncogenes (c-myc and N-myc) by insertional mutagenesis, expression of viral proteins (X and pre-S2/S) that function as trans-activators and possibly oncoproteins, and introduction of chromosomal defects through enzymatically mediated integration into the host genome. Not all of these mechanisms appear to be active in every tumor, however. Thus, future work will be aimed at characterizing each mechanism in more detail and determining its relative importance in the carcinogenic process.     

Interactive effects of chemical carcinogens and hepatitis B virus in the pathogenesis of hepatocellular carcinoma

Liver cancer is one of the most prevalent forms of cancer in the world. Hepatitis B virus (HBV) is considered to be a major aetiological factor. Evidence from epidemiological studies has also indicated that environmental contaminants such as mycotoxins may, either in combination with HBV or independently, be important aetiological factors in the pathogenesis of primary hepatocellular carcinoma (PHC). Laboratory data also suggest an interplay between viral and chemical factors in the multifactorial aetiology of PHC. Aflatoxin B1, the chemical carcinogen most frequently implicated in the aetiology of hepatocellular carcinoma is a procarcinogen that must be activated by mixed-function oxidases to an electrophilic metabolite before it can exert its carcinogenic effects. Interindividual differences (greater than 10-fold) in the metabolic activation of aflatoxin B1 are observed. These differences may play a part in an individual's oncogenic susceptibility to aflatoxin B1. Chemical carcinogens and integrated HBV may activate cellular oncogenes, eg N-ras, and inactivate tumour suppressor genes. Recently developed methods that allow monitoring of aflatoxin B1 and HBV exposures and also genetic damage caused by these agents in individuals should help in biochemical and molecular epidemiological studies concerning the aetiology of hepatocellular carcinoma. We identify areas of uncertainties and of future experimentation and propose a hypothesis of liver carcinogenesis.     

Clinicopathologic comparison of hepatitis B virus-related and hepatitis C virus-related hepatocellular carcinoma

137 cases of hepatocellular carcinoma associated with cirrhosis that had undergone resection between 1991-95 have been analyzed. One hundred and three had hepatitis C (positive for anti HCV alone) and 34 hepatitis B (positive for HBsAg alone). The hepatitis C cases were older and were associated with more severe cirrhosis. The tumors from hepatitis B cases were on average larger and histologically less-differentiated, and were more likely to occur in the background of macronodular cirrhosis than hepatitis C cases.