Journal of Hepatology
Volume 39, Supplement 1 , Pages 59-63, 2003

Hepatitis B virus and hepatocellular carcinoma

BCLC Group, Liver Unit, Digestive Disease Institute, Hospital Clı́nic, IDIBAPS, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain

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1. Introduction 

The development of hepatocellular carcinoma (HCC) is a major global health problem [1], [2]. Its incidence has increased worldwide and nowadays it constitutes the 5th most frequent cancer representing around 5% of all cancers worldwide [2]. More than 500,000 new cases are diagnosed per year and it represents the third cause of cancer-related death and the first cause of death amongst cirrhotic patients [3], [4], [5]. HCC incidence has striking geographical differences [1]. In North America, Europe and Australia the age-adjusted incidence is less than 2/100,000 per year. This increases in the South European and Mediterranean countries and reaches the highest scores (>50/100,000) in Sub-Sahara Africa and South East Asia [1]. This geographic pattern overlaps with the distribution of risk factors and probably also reflects genetic characteristics inherited or acquired through oncogenic agents. While in some high risk areas the incidence has decreased as a result of a better health care of the population, the HCC incidence in several areas such as US and South Europe has increased. This may be due both to an increased disease awareness with a higher diagnostic capability, but also to the emergence of risk factors which up to now would have had a minor dissemination and thus, no impact. This is probably the case for hepatitis C virus (HCV)-related HCC that should represent the final step of the HCV epidemic that spread in some Western countries after the second world war, while in Asia it could have appeared decades before.

The most relevant oncogenic agent for HCC development is chronic hepatitis B virus (HBV) or HCV infection [1], [6]. Their prevalence is known to vary largely among the world population. Not unexpectedly, areas with high prevalence of viral infection have high HCC rates [1]. This association allowed the establishment of the relationship between HBV infection and HCC. Other risk factors such as alcoholism or hemochromatosis are also relevant, but have not yet reached the epidemiological and clinical importance of viral infection. In most cases, HCC development complicates an underlying chronic liver disease, but in all etiological categories the tumor may occur in the absence of cirrhosis or when minimal histologic changes have taken place.

The present chapter reviews the evidence that links HCC development with HBV infection, summarizes the mechanisms that may be involved in the HBV carcinogenic pathway and finally provides the guidelines to achieve early diagnosis and effective therapy.

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2. Epidemiological relationship between HBV infection and HCC 

Data linking HBV with HCC were raised soon after the discovery of the ‘Australia Antigen’ (corresponding to the hepatitis B surface antigen – HBsAg). Several epidemiological surveys demonstrate the geographic coincidence between HBV endemicity and HCC prevalence [7]. In South-East Asia the prevalence of HBV infection reaches 10–15% and the HCC rate ranges between 10 and 25/100,000 population [1], [8], [9]. In all areas the prevalence of serological markers of past or present HBV infection is higher in HCC patients than in those without this tumor. Figures may vary according to the background rate in the global population and may depend on the techniques employed to assess the existence of viral infection. HBV DNA might be found in the tumor and non-tumor liver tissue of HCC patients in whom serological markers may be negative or only positive for anti-HBc [10]. Accordingly, both in low and high incidence areas, the role of HBV in HCC development is very relevant. In addition to cross-sectional studies, cohort studies have established that chronic HBV infection carries an increased HCC risk and thus, of cancer related death [6], [8]. Again, big differences have been observed depending on the geographic area and the presence or absence of an underlying liver disease. In the seminal study by Beasley et al. including more than 22,000 Taiwanese men the risk in chronic HBV carriers was 100 times higher than in non-infected individuals [11]. A Japanese study performed also in males found a fifty-fold increased risk in HBV infected individuals [12]. Studies performed in Alaska [13], Europe [3], [14] and Canada [15] have established that the increased risk applies world-wide. However, while in Asian patients the tumor appears more frequently in an otherwise normal liver, in the Caucasian population HCCs mostly develop in patients with chronic liver disease, namely cirrhosis. Patients with HCC in a normal liver are usually younger and this may support the role of age at infection. The coexistence of additional oncogenic agents in those areas where the infection is acquired perinatally or during childhood may also be relevant. This might be the case for aflatoxin, a carcinogen that contaminates food stored in humid conditions [16]. It induces a unique missense mutation of codon 249 of the p53 gene [17]. While this is observed at early HCC stages in Asian patients, this genetic signature is rarely observed in Western tumors. The annual HCC incidence in chronic HBV carriers in Asia ranges between 0.4 and 0.6%. This figure is lower in Alaskan natives (0.26%/year) and even lower in Caucasian HBV carriers. The incidence in cirrhotics exceeds 2% in all areas. Male sex, advanced age (a potential surrogate for the disease duration) and increased alphafetoprotein (AFP) are associated with higher risk [6].

The final demonstration of the role of HBV in the development of HCC comes from the preventive effect of vaccination. In Taiwan this has prompted a reduction of the prevalence of HBV infection in children from 15 to 1% and also a 60% reduction of HCC during childhood [18]. Considering that more than 70% of HCC in developing countries is attributable to HBV, the current challenge is to ensure the availability of the vaccine in all these countries. Other preventive measures should be addressed at public health campaigns to reduce food contamination by fungi, as well as to modulate the metabolism of aflatoxins once ingested, as has been proposed by the use of oltipraz. Dosage and schedule parameters for its administration have been described in a phase II study in Qidong, China [19], [20], where HCC is the leading cause of death and exposure to dietary aflatoxins is widespread. However, long-term outcome of randomized controlled trials (RCTs) are not yet available.

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3. Oncogenic mechanisms 

The oncogenic mechanisms of HBV are not fully understood [9], [21], [22]. HBV DNA may integrate into the genome of the hepatocytes [23] and this may cause several hits leading to transformation. However, HBV DNA integration is random and involves always different parts of the viral genome. The viral X gene may have an important role as it is a powerful transactivator for transcription of oncogenes such as c-myc and c-jun. Additional events that may be triggered by HBV DNA integration and X gene expression deregulation include DNA repair impairment, increased cytokine production and growth factors, inhibition of apoptosis and increased expression of angiogenic agents such as vascular endothelial growth factor and nitric oxide [9], [21]. This last agent may act as a potent mutagen [24] and can be induced both by HBV infection or the inflammation associated to chronic hepatitis.

Recent human studies suggest that HBV positive HCC are characterized by higher chromosomal instability leading to loss of heterozygosity as compared to tumors related to HCV [25]. However, there is no clear-cut HBV related genetic profile leading to HCC [26].

As mentioned above, in most cases HCCs appear in a cirrhotic liver after many years of inflammation, cellular necrosis and regeneration that define a microenvironment that is characterized by the release of several cytokines, growth factors and other mediators. This may affect the hepatocytes, promote oxidative stress and prompt the appearance of a critical genetic damage irrespective of the virus itself.

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4. Early detection and diagnostic confirmation 

Mortality from HCC may decrease due to effective implementation of preventive strategies and, less importantly, early detection and effective treatment. Prevention will be achieved by vaccination and by drugs that eradicate the virus prior to irreversible hepatic and/or genetic damage. In patients with chronic hepatitis B, interferon-α lamivudine, adefovir and other antiviral agents will reduce the incidence of cirrhosis, and also of HCC. If cirrhosis is established there is no agent that has been proven to diminish the HCC risk [6], [27], [28]. Therefore, in this setting the only option to decrease cancer related deaths will be early detection.

Early detection might be achieved by surveillance of the population at risk and its cost-effectiveness will depend on successful therapy. Thus, careful selection of patients for surveillance is mandatory. HCC meets most of the accepted criteria to establish surveillance [29]. It is a frequent event in the population at risk. This can be identified and the disease causes significant morbidity or mortality. The population should accept the surveillance strategy and this has to have a high detection and diagnostic accuracy. Abnormal results have to be clearly defined and the investigations necessary must be well established. Finally, effective therapy should be available.

There are no RCTs demonstrating a survival benefit of surveillance. The available evidence is derived from cohort studies showing that the proportion of patients diagnosed at an early stage, and thus amenable for effective treatment, is increased as compared to patients not included into surveillance [5], [6]. Cost-effectiveness has been assessed from cohort studies and multistage transition modelling [5], [30], [31]. An adequate relationship is achieved if surveillance is performed in patients with significant risk and if all treatments with positive impact are available and properly indicated to achieve the best possible outcome.

Based on the incidence of HCC in patients with HBV cirrhosis, surveillance is indicated irrespective of the racial background. In non-cirrhotics the evidence is controversial. The 0.4–0.6% yearly risk of Asian HBV carriers justifies their surveillance. The very low risk in Caucasians, however, results in a low number of detected HCCs and a reduced cost-effectiveness [6].

It is important to stress that only those individuals who could be treated should enter the program while those who are not candidates for curative therapy should be excluded. Therefore, the ideal target population are patients with normal liver function or with Child-Pugh A cirrhosis. Child-Pugh C cirrhotics should be evaluated for liver transplantation in the absence of an HCC. If this option is not feasible, there will be no benefit from surveillance. Child-Pugh B cirrhotics are a controversial group. Without liver transplantation it is very unlikely that any therapy will offer a significant survival benefit and hence, they should probably not become a target group for surveillance.

4.1. Surveillance for HCC 

The growth of small HCC from undetectable to 2 cm takes about 4–12 months [6]. Aiming to detect tumors smaller than 3 cm in diameter, a 6-month interval has been set for surveillance. Patients with increased risk do not require shorter intervals, because increased risk does not mean faster growth. The surveillance tools are AFP and ultrasonography (US). AFP is not a very good screening test. Its sensitivity is 39–64%, its specificity 76–91% and its positive predictive value 9–32% [6], [15], [32], [33]. AFP as the only tool for surveillance has not been properly investigated and this has maintained it in most surveillance strategies. US is a more effective tool. As a screening test in HBsAg carriers, it has a sensitivity of 71% and a specificity of 93%, with a reduced positive predictive value of 14% [15]. US should be conducted by an experienced operator. If US or AFP are abnormal, the patients should be referred to a comprehensive cancer unit offering the most updated human and technical resources [6].

4.2. Recall procedures and diagnostic confirmation 

This is an area of clinical research. There are no prospective studies assessing the efficacy of different strategies. In the recent EASL Monothematic Conference on HCC a panel of experts proposed a set of guidelines depicted in Fig. 1 [6]. The US discovery of a hypo- or hyperechoic nodule during follow-up should raise a HCC suspicion, depending on size. Pathological studies have shown that 50% of nodules <1 cm are not malignant [34] and the available diagnostic techniques do not allow proper classification. Therefore, US control of the nodules every 3 months is recommended until disappearance or progressive growth to >1 cm. Even a true HCC may remain stable for more than 1 year and thus, absence of growth during the follow-up period does not exclude malignancy. For lesions >1 cm HCCs are more likely and diagnostic confirmation is required. A positive fine needle biopsy (tissue sample for cytology and histology) was felt mandatory for nodules <2 cm because the imaging techniques are not sufficiently accurate. By contrast, in cirrhotic patients, the incidental finding of a hepatic nodule >2 cm showing arterial hypervascularization in at least two imaging techniques (US, CT, angiography and magnetic resonance imaging) may suffice to establish the diagnosis (Table 1) [34]. In fact, with these characteristics, a negative biopsy will not rule out an HCC and thus, this result will not change the clinical diagnosis. AFP >400 ng/ml may also establish the diagnosis, if coinciding with a highly suspicious hepatic nodule in a cirrhotic liver [6], [33]. However, transient AFP increases might be observed coinciding with inflammatory flares [35] and thus, care should be taken to properly characterize the hepatic nodules through imaging techniques. In any case, the request for a diagnostic biopsy should take into account the impact of the result on the clinical decision making and the balance between the potential risks of biopsy and the risk of invasive treatments (i.e. transplantation) to be applied thereafter.

Table 1. Diagnostic criteria for HCC [6]
● Cyto-histological criteria
● Non-invasive criteria (cirrhotic patients)
1. Radiological criteria: two coincidental imaging techniquesa
– Focal lesion >2 cm with arterial hypervascularization
2. Combined criteria: one imaging technique associated to AFP
– Focal lesion >2 cm with arterial hypervascularization
– AFP levels >400 ng/ml

a Four techniques considered: US, Spiral CT, MRI and angiography.

There are no robust data to define the recall policy for patients who present an increased AFP value. In the absence of a coincidental nodule on US a triple phase CT scan may be needed to rule out an HCC. If negative, a persistently increased AFP classifies the patient as a high risk individual for HCC development [6].

Applying this surveillance strategy 40–80% of the detected HCC are solitary, but only half of them are suitable for curative treatment after careful evaluation [5], [6].

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5. Treatment of HCC 

Patients diagnosed with early stage HCC benefit from radical options (surgery, percutaneous ablation) that provide a high rate of complete responses according to oncologic criteria [6], [36], [37]. An untreated control arm to test the impact of these options is not ethical and the survival benefits from treatment have been derived from cohort studies. By contrast, the absence of effective therapies for advanced HCC has allowed the conduction of several RCTs comparing some of the available alternatives versus no treatment [6], [36].

5.1. Treatment of early HCC 

There are no studies comparing the available curative treatment options – resection, liver transplantation and percutaneous ablation – against no treatment or amongst themselves. Thus, there are no data to establish the first-line treatment in patients with HCC in compensated cirrhosis. Each group, center and country should establish the preferred schedule taking into account the results of cohort studies and the available resources [6], [36]. However, in patients with early HCC in decompensated liver disease, the outcome after transplantation is clearly superior to other alternatives.

Surgical resection is considered for single asymptomatic HCC in patients with preserved liver function. The Child-Pugh classification is not adequate to select surgical candidates, since even Child-Pugh A may include relevant functional impairment and minor ascites. Indocyanine green retention rate or the selection of patients with normal bilirubin and no portal hypertension identify the candidates that will achieve a 70% 5-year survival [36], [38]. Vascular invasion, satellites and poor differentiation are associated with an increased risk of recurrence of up to more than 70% within 5 years and no effective prevention of recurrence [36], [37], [38].

The optimal candidates for transplantation are patients with early HCC (single lesion <5 cm or up to three lesions <3 cm) with a 70% 5-year survival and a recurrence rate below 15% [36], [37]. Transplantation is not available worldwide and there is a severe shortage of donors. Antitumoral treatments upon listing may benefit some patients, but there are no RCTs to prove their efficacy. One of the major risks after transplantation is the re-infection of the graft. Hyperimmune globulin and new antiviral agents discussed elsewhere in this issue markedly reduce this risk and allow optimal graft and patient survival.

Percutaneous ethanol injection (PEI) under US guidance achieves a complete response in 70–80% of solitary tumors <3 cm. Child-Pugh A cirrhotics may achieve a 50% 5-year survival. By contrast, survival benefits of PEI in Child-Pugh B class patients are controversial. PEI is inexpensive and carries almost no treatment related mortality. Hence, it constitutes the standard technique against which new options have to be compared [36], [37], [38].

5.2. Treatment of intermediate/advanced HCC 

The survival benefits of palliative options are highly controversial due to the low number of RCTs. Chemoembolization has been extensively evaluated [36], [37] and recent Western [39] and Eastern [40] investigations have provided positive findings that support a beneficial effect. Tamoxifen administration has no efficacy [36] and other options such as systemic chemotherapy, octreotide, internal radiation, proton beam radiation, antiandrogens and immunotherapy have been assessed in single investigations including a limited number of patients and/or lacking an untreated control arm. Unfortunately, some of them lack any antitumoral effect and/or are associated to relevant toxicity [36], [37].

In summary, HCC is a major complication of chronic HBV infection representing one of the most frequent causes of death. Universal vaccination will eventually eradicate this infection and thus, diminish the incidence of liver cancer. Effective antiviral therapy may prevent cirrhosis and ultimately cancer. However, if cirrhosis is already established, the only chance for long-term HCC cure will come from early detection and effective treatment.

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Acknowledgements 

Dr. Llovet is a recipient of a contract from Programa “Ramon y Cajal” (Ministerio de Ciencia y Tecnologı́a).

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PII: S0168-8278(03)00140-5

doi:10.1016/S0168-8278(03)00140-5

Journal of Hepatology
Volume 39, Supplement 1 , Pages 59-63, 2003

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