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Jordi Bruix, Josep M. Llovet, BCLC Group. Liver Unit. IMD, University of Barcelona, Spain
The incidence of hepatocellular carcinoma has increased worldwide and nowadays it constitutes the 5th most frequent cancer representing around 5% of all cancers worldwide. There are marked geographic differences in risk factors and incidence, but in all areas chronic HBV infection constitutes a major oncogenic agent. The annual incidence in HBV carrier’s ranges between 0.2% and 0.6%, but it reaches 2% when hepatic cirrhosis is established. The oncogenic mechanism leading to liver cancer involves different pathways that are not fully elucidated.
Prevention through universal vaccination has effectively decreased the incidence of liver cancer and new therapeutic agents may delay or avoid the establishment of cirrhosis. This implies a high probability of cancer development during follow up and consequently, the only chance for long term survival after HCC diagnosis is to achieve early detection through regular surveillance by ultrasound and AFP determination. This will allow the indication of effective therapy such as surgical resection, liver transplantation or percutaneous ablation.
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 (3-5). 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-Saharan 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 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 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 viral infection with the HBV or the HCV (1; 6). Their prevalence is known to vary largely among the world population. Not unexpectedly, those areas with higher prevalence of viral infection present the highest HCC rates (1). This association allowed the establishment of the relationship between HBV infection and HCC. Other risk factors such as alcoholism or iron deposition are also relevant, but have not yet reached the epidemiological and health care 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, summarises the mechanisms that may participate in the HBV carcinogenic pathway and finally provides the guidelines to achieve early diagnosis and effective therapy.
Epidemiological relationship between HBV 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 expose the geographic coincidence between areas with high HBV endemicity and high HCC prevalence (7). In South-East Asia the prevalence of HBV infection in the population reaches 10-15% and the HCC rate ranges between 10 to 25/100.000 habitants (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 the neoplasm. 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 tumoral and non-tumoral liver tissue of HCC patients in whom serological markers may even be negative or solely present antibodies against the HBV core (10). Accordingly, both in low and high incidence areas, the role of HBV in HCC development are very relevant. In addition to transversal investigations, cohort studies have established that chronic HBV infection implies an increased HCC risk and thus, of cancer related death (6; 8). Again, sharp 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 males performed in Taiwan 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 the appearance of HCC is mostly restricted to 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 during childhood may also be relevant. This might be the case of aflatoxin, a carcinogen that contaminates food stored in humid conditions (16). It induces a unique hotspot missense mutation of the 249 codon of p53 gene (17). While this is observed at early HCC stages in Asian cases, this genetic signature is seldom observed in Western tumors. The annual incidence in Asian chronic HBV carriers ranges between 0.4% and 0.6%. The 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 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 significant reduction of the prevalence of HBV carriage 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 spoilage 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, but long term outcome of RCTs are awaited.
The oncogenic mechanism of HBV exerts is not fully understood (9; 21; 22). HBV DNA may integrate into the genome of the hepatocytes (23) and this may produce several hits leading to transformation. However, DNA integration is 100% present and it constitutes a random phenomenon affecting any DNA site. The X gene of the HBV may have an important role as it is a powerful transactivator for transcription factors such as c-myc and c-jun. Additional events that may be triggered by HBV integration and X 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 factors and nitric oxide (9; 21). This last agent may act as a potent mutagen (24) and be released both because of the HBV cell entry and as a result of the inflammation associated to chronic hepatic infection.
Recent human studies have suggested that HBV positive HCC would be characterised by higher chromosomic instability leading to loss of heterozigosty as compared to tumors related to hepatitis C virus (25). However, there is no clear- cut HBV related genetic profile leading to HCC (26).
As commented, in most cases the tumor appears in a cirrhotic liver, this has suffered years of inflammation, cellular necrosis and regeneration that define a microenvironment affected 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.
Early Detection and Diagnostic Confirmation
Mortality attributable to HCC may decrease because of the effective implementation of preventive strategies and less importantly, from the achievement of early detection and application of effective treatments. The first approach will be obtained by vaccination and by the availability of pharmacological agents that may eradicate the virus prior to the establishment of irreversible hepatic and/or genetic damage. In patients with chronic hepatitis B, lamivudine, adefovir and other antiviral agents will decrease the proportion of patients developing cirrhosis, and this should reduce the long term incidence of HCC. If cirrhosis is established there is no agent that has been proven to diminish the risk of HCC during follow-up (6; 27; 28). Accordingly, in this setting the sole option to decrease cancer related deaths will come from early detection.
Early detection might be achieved by surveillance of the population at risk and its adequate cost-effectiveness will come from the success of 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 induces a 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 to perform upon their registry well established. Finally, effective therapy should be available.
There are no RCTs confirming the survival benefits 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 that in 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 outcomes possible.
According to the incidence of HCC during follow-up in patients with HBV cirrhosis, it is worth to enrol them in surveillance irrespective of their racial origin. If cirrhosis is not established the evidence is controversial. The 0.4%-0.6% yearly risk of Asian HBV carriers justifies their surveillance, but the very low figures in Caucasians predict a low number of HCC tumors to be detected and a reduced cost-effectiveness (6).
It is important to stress that only those individuals who would be treated if diagnosed with an HCC should enter the program while those who are not suitable for curative therapy should be excluded. Accordingly, the ideal target population are those patients with normal liver function or with Child-Pugh’s A cirrhosis. Child-Pugh’s C cirrhotics should be evaluated for liver transplantation even in the absence of an HCC. If this option is not feasible, there will be no benefit from surveillance. Child-Pugh’s B cirrhotics constitute a controversial population. In the absence of liver transplantation it is very unlikely that any therapy will offer significant survival benefits and hence, they should probably not become a target group for surveillance.
Surveillance for HCC
The growth rate of small HCC indicates that the time from an undetectable lesion to 2 cm is 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 a smaller interval, as 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% to 64%, its specificity 76% to 91% and its positive predictive value 9% to 32% (6; 15; 32; 33). The use of minor AFP as a tool for surveillance has not been as 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 a trained operator. Upon detecting a warning sign by US or AFP, the patients should be referred to a comprehensive cancer Unit offering the most updated human and technical resources (6).
Recall procedures and diagnostic confirmation
This is an area of clinical research where prospective studies assessing the efficacy of different strategies are lacking. In the recent EASL Monothematic Conference on HCC a panel of experts proposed a set of guidelines depicted in Figure 1 (6). The US discovery of a hypo or hyper echoic nodule during follow-up should raise the HCC suspicion, but a different attitude was proposed according to size. Pathological studies have shown that half of minute nodules < 1 cm do not correspond to an HCC (34) and the available diagnostic techniques do not bear enough accuracy to achieve proper classification. Thus, US controls of the nodule every 3 months were recommended. These have to be maintained until disappearance or progressive growth to > 1cm. Even a true HCC may remain stable for more than one year and thus, absence of growth during the follow-up period does not discard malignancy. Upon exceeding 1 cm, the HCC likelihood is higher and diagnostic confirmation is required. A positive fine needle biopsy (tissue sample for cytology and histology) was felt mandatory for nodules smaller than 2 cm as the imaging techniques do not have enough diagnostic accuracy. By contrast, in cirrhotic patients, the coincidental finding of a hepatic nodule > 2 cm showing arterial hypervascularization in at least two imaging techniques (out of US, CT, angiography and magnetic resonance imaging) may suffice to establish the diagnosis (6). In fact, with these characteristics, a negative biopsy will never rule out an HCC and thus, this result will not change the clinical diagnosis. Increased AFP above 400 ng/mL may also set 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 characterise 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.
There are no robust data to define the recall policy for patients who present an increased AFP value. In the absence of coincidental nodule detection by US a triple phase CT scan may rule out an HCC missed by US. 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 radical treatment after a careful evaluation (5; 6).
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 should not be considered 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).
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). Contrarily, in patients with early HCC in decompensated liver disease, the outcome offered by transplantation is clearly higher than with other alternatives.
- Surgical resection is considered for single asymptomatic HCC in patients with preserved liver function. The Child-Pugh’s classification is not adequate to select surgical candidates, since even Child-Pugh’s A may include relevant functional impairment and minor ascites. Indocianine green retention rate or the selection of patients with normal bilirubin and no portal hypertension identify the candidates that will achieve a 70% survival at 5 years (36; 38). Vascular invasion, satellites and poor differentiation degree are associated with increased recurrence risk that affects more than 70% of the patients at five years, there being no effective intervention to diminish recurrence (36-38).
- The optimal candidates for transplantation are patients with early HCC (single < 5 cm or up to 3 nodules < 3 cm). They achieve a 70% 5-year survival with a recurrence rate below 15% (36; 37). Transplantation is not available worldwide and there is a severe shortage of donors. Antitumoral treatment upon enlisting may benefit some patients, but there is no RCT to proof 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 Conference markedly reduce this risk and allow optimal graft and patient survival.
- Percutaneous ethanol injection (PEI) under US guidance obtains complete response in 70-80% of solitary tumors < 3 cm. Child-Pugh’s A cirrhotic may achieve a 50% 5-year survival. By contrast, survival benefits of PEI in Child-Pugh’s B class patients are controversial. PEI has a reduced cost and has almost no treatment related mortality. Hence, it constitutes the standard technique against which new options have to be compared (36-38).
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 Eastern (39) and Western (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, the data depicted above indicate that HBV is a major complication during the evolution of chronic HBV infection representing one of the most frequent causes of death. Universal vaccination will eradicate this infective agent and thus, diminish the development of liver cancer. Effective antiviral therapy may prevent the evolution towards cirrhosis and ultimately to cancer. However, if cirrhosis is already established, the only chance for long term HCC cure will come from early detection allowing effective treatment to be indicated.
Table 1.- Diagnostic criteria for HCC (6).
Reproduced from J. Hepatol 2001;35:421-430.
Figure 1. Surveillance and recall strategy (6)
Reproduced from J Hepatol 2001;35:421-430.
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