9.0 Hepatitis B related hepatocellular carcinoma

  • Hepatitis B Virus (HBV) is an oncogenic virus that is, globally, the most important aetiological factor in the development of hepatocellular carcinoma (HCC).
  • Treatment of chronic hepatitis B (CHB) decreases, but does not completely eliminate, risk of HCC, underscoring the need for ongoing HCC surveillance in at-risk individuals.
  • HCC surveillance by 6-monthly ultrasound scanning and alpha-fetoprotein level is recommended in patients with cirrhosis, and in patients with CHB who have additional risk factors.
  • Early diagnosis of HCC improves access to curative therapy and prognosis.
  • Curative therapies include liver transplantation and resection.
  • Additional therapies that prolong survival include transarterial chemoembolisation, radiofrequency ablation and sorafenib.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. Globally, over 80% of HCC is attributable to the combined effects of chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV), which confers a 20 to 100-fold increased risk of developing HCC relative to those without viral hepatitis infections (1, 2). There are large geographic variations in HCC incidence, with the highest prevalence being in eastern Asia and middle or western Africa, where the estimated age-adjusted incidence rates of HCC are about 10 times greater than in Australia and New Zealand (Figure 9.1) (3). In Australia, recent estimates suggest that over 200,000 Australians are living with chronic hepatitis B (CHB) (4), and primary liver cancer incidence rates have been rising faster than any other cancer (5, 6). This has propelled HCC from a rare cancer to among the top 10 causes of cancer death overall, and the seventh cause of cancer death in men (7). In New South Wales (NSW), nearly 90% of hepatitis B related HCC occurs in people born overseas, in particular from countries with high HBV prevalence (8). Standardised incidence rates of HCC are at least six times higher in men born in China, Hong Kong, Indonesia, Korea, Macau and Vietnam, and in women born in China and Vietnam, than in the Australian-born population. This trend mirrors those in the Netherlands and the United States of America (USA), where rising rates of HCC are reported in migrants from Asia and the Pacific Islands that are disproportionate in comparison to the locally born populations (9, 10). Aboriginal and Torres Strait Islander people are also disproportionately affected by CHB and related liver cancer: the prevalence of HBV in the Aboriginal and Torres Strait Islander population ranges from 3.6% to 26.0%, according to place of residence and age group (11) and, in some Aboriginal and Torres Strait Islander communities, rates of HCC are 5–10 times greater than in non-Indigenous Australians (12, 13). (see Chapter 1).

Figure 9.1 The global distribution of liver cancer (GLOBOCAN data)

Adapted from: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 01/07/2014.

HBV is an oncogenic virus that increases the risk of HCC occurrence directly (by viral mechanisms) and indirectly (by liver inflammation and cirrhosis). Thus, persistently high HBV DNA and alanine aminotransferase (ALT) are strong independent predictors of HBV-related HCC (22). The significance of HBV replication per se in HCC pathogenesis was demonstrated by the REVEAL study, a community-based natural history study of CHB in Taiwan, which found that HCC risk increased proportionally to serum HBV DNA viral load (Figure 9.2) (14). Chronic replication of HBV increases the risk of progression to cirrhosis and HCC (23). Cirrhosis increases HCC risk overall, and one third of people with cirrhosis develop HCC in their lifetime. Among people with cirrhosis, the annual incidence of HCC is 2–3% in western countries and 6–11% in Asian populations (18, 24). The incidence rates of HCC are two to three times higher in men than in women in all regions of the world (17). At each stage of chronic hepatitis, a positive family history (in first-degree relatives) increases HCC risk (21). Coexisting obesity, diabetes and non-alcoholic fatty liver disease (NAFLD) (19), together with alcohol and cigarette smoking (20), are additive risk factors for HCC development (see Table 9.1).

Table 9.1 Risk factors for hepatitis B related hepatocellular carcinoma
Risk factorReference
Active HBV DNA replication or viral load Chen et al (2006) (14)
HBV genotype C Yang et al (2002) (15)
HBeAg negative core promoter mutation Yang et al (2002) (15)
Cirrhosis Schiff et al (2006) (16)
Male sex Bosch (1999) (17)
Asian, African, Aboriginal and Torres Strait Islander or Australian ethnicity Fattovich (2003),
Parker (2014) (12, 18)
Coexisting NAFLD and diabetes El-Serag (2001) (19)
Smoking, alcohol, obesity Marrero (2005) (20)
Positive family history, first-degree relative Loomba (2013) (21)
HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; NAFLD, non-alcoholic fatty liver disease


Figure 9.2 Viral load as a predictor of hepatocellular carcinoma risk (25)

The most effective and practical means to control HBV infection and its long-term sequelae (cirrhosis and HCC) is to reduce or eliminate viral transmission by primary prevention. Secondary prevention aims to reduce progression to end-stage liver disease and HCC, by optimising medical management. This approach is intuitive, and is based on the close correlation between HBV replication and the risk of disease progression and liver cancer. Data suggest that effective suppression of viral replication may reduce risk of HCC (26-28).

The aim of HCC surveillance is to detect tumours at an early stage, when curative treatment can be offered. However, the benefits of a surveillance strategy have to be balanced against the cumulative risk of developing the disease, and against the costs, sensitivity and specificity of the screening tests. The effect of lead-time bias (i.e. the period by which screening advances diagnosis of the disease) on survival leads to uncertainty about the cost-effectiveness of screening protocols and the effect that antiviral treatment may have on screening for HCC prevention (24, 29). Nevertheless, current clinical practice guidelines recommend HCC screening by ultrasound scanning as being of benefit in all patients with cirrhosis (30). Liver ultrasound is considered the HCC screening test of choice because it can detect tumours as small as 1–2 cm in diameter (sensitivity 94%); however, it is operator dependent and does not reliably discriminate between HCC and other liver pathology (e.g. haemangiomas or cirrhotic nodules). In HBV patients with complete viral suppression on antiviral therapy, in particular, the addition of serum alpha-fetoprotein (AFP) measurement increases detection of HCC, and elevation of AFP may precede the detection of HCC by ultrasound by 6 months (31). However, serum AFP may be significantly elevated in patients undergoing an HBV flare, and may not be a useful marker of HCC in that situation. Serum AFP alone is inadequate for HCC surveillance because AFP is secreted by only about 50% of small HCC lesions, and levels may remain normal even in the setting of advanced disease. HCC screening using both ultrasound and AFP is recommended by the Asian Pacific Association for the Study of the Liver (32) and the Gastroenterological Society of Australia (33).

Surveillance has been shown to decrease HCC-related mortality in Chinese patients with CHB, regardless of the presence of cirrhosis (34). This randomised controlled trial (RCT) enrolled over 18,000 people with CHB, and reported a 37% reduction of mortality in people screened for HCC compared to those receiving usual medical care (34).

Target groups for HCC surveillance
  • those with cirrhosis
  • those without cirrhosis but with any of the following additional risk factors:
    – Asian men over 40 years
    – Asian women over 50 years
    – Africans over 20 years
    – Aboriginal and Torres Strait Islander people over 50 years
    – those with a family history of HCC.

The benefit of HCC surveillance in pre-cirrhotic CHB patients is controversial, and population-based HCC screening of high-risk groups is currently not systematically practised in Australia. However, guidelines from the American Association for the Study of Liver Disease (AASLD) highlight some important sub-populations that may benefit from surveillance in the absence of cirrhosis. These include HBV-infected Asian-born males over the age of 40, Asian-born females over the age of 50, African-born people over the age of 20 and those with a family history of primary liver cancer (35). Given that the individual annual risk of HCC in HBV-infected Aboriginal and Torres Strait Islander people over 50 years of age is estimated to be 0.34–0.86%, this population should be also be included in HCC surveillance (12).

A negative screening result cannot reliably exclude the presence of a HCC; hence, enrolment in a regular surveillance programme is required (36). Generally a 6-month interval is recommended between screenings, which takes into consideration the estimated doubling time of HCCs smaller than 5 cm in diameter (37).

Unequivocal diagnosis of HCC is required if there is an abnormal screening test. Diagnosis of HCC can be made non-invasively through imaging, on the basis of its radiological hallmark, enhancement with contrast in the arterial phase and washout in the portal or delayed phase. Diagnostic imaging modalities include four-phase computed tomography (CT) scanning and magnetic resonance imaging (MRI) (30). Diagnosis can be confirmed by one radiological technique in nodules over 2 cm; however, two techniques (CT, and MRI or contrast-enhanced ultrasound) are recommended in lesions 1–2 cm. Typical imaging findings in one modality with serum AFP greater than or equal to 100 ng/mL is also diagnostic.

Histological diagnosis by guided liver biopsy is not often required, but is recommended for nodules occurring in non-cirrhotic livers and nodules with inconclusive or atypical imaging appearances in cirrhotic livers.

Historically, HCC has been diagnosed in advanced disease stages, when prognosis is uniformly poor; with earlier detection, outcomes have been improving. Predictors of HCC prognosis include tumour-related factors (size, number, vascular invasion and metastases), AFP level, age, severity of liver disease (Child-Pugh classification) and the degree of existing functional reserve. The Barcelona Clinic Liver Cancer (BCLC) staging system incorporates these factors, and is now widely adopted to determine prognosis and allocate therapies (Figure 9.3) (30, 38).

Very early HCC is defined as a single HCC of less than 2 cm with good performance status; however, less than 10% of all patients are diagnosed at this very early stage. They are amenable to curative treatments; these include orthotopic liver transplantation (OLT) and liver resection, which are associated with 5-year survival rates of over 80% and over 70%, respectively.

Early HCC is defined as a single tumour over 2 cm, or three nodules of less than 3 cm, performance status 0, and Child-Pugh class A or B. OLT is considered in cases where there is a single tumour less than or equal to 5 cm, or up to three nodules less than or equal to 3 cm (Milan Criteria). OLT remains the only curative option for those with resectable tumours and decompensated cirrhosis, because it removes not only the tumour, but also the underlying liver disease. However, the lack of available livers for transplantation means that many of those on the waiting list may ultimately be denied transplantation, because of tumour advancement during the waiting period.

The local ablation of HCC is an acceptable alternative to resection for small liver cancers (<3 cm) in Child-Pugh class A patients. Tumour ablation is also first-line treatment for unresectable, small HCCs with up to three nodules in Child-Pugh class A or B cirrhosis. Image-guided percutaneous ablation of tumours is generally performed with radiofrequency ablation (RFA) or microwave ablation, using extreme temperature to destroy tumour cells. Other ablation techniques that may be used include instillation of chemicals such as ethanol or acetic acid (39, 40), or the use of laser or cryotherapy. Choice of ablative therapies is determined by tumour position in relation to vascular structures, size and number, as well as the resources and expertise available.

Transcatheter arterial embolisation (TAE) and transcatheter arterial chemoembolisation (TACE) may be indicated in non-surgical patients who are free of vascular invasion or extrahepatic tumour extension. These techniques aim to obstruct the blood supply to intermediate- sized tumours; they use an embolising agent (e.g. gelfoam, starch microspheres or metallic coils) that, in the case of TACE, is combined with a chemotherapeutic agent (e.g. doxorubicin or cisplatinum).

Systemic therapies for HCC are recommended for the treatment of advanced stage patients who are not suitable for loco-regional therapies and who have good liver function. Cytotoxic therapies are not routinely recommended, but the multi-tyrosine kinase inhibitor sorafenib is increasingly being used, based on a demonstrated survival benefit in advanced HCC in phase III clinical trials. In the SHARP trial, sorafenib increased median survival to 10.7 months, compared to 7.9 months with placebo (41). This treatment is indicated for advanced HCC with well-preserved liver function, or for tumours that are progressing despite loco-regional therapies. 

Patients with advanced HCC and very poor performance status have a poor prognosis, with a median survival of only 3–4 months. They should be offered the best supportive palliative care to alleviate symptoms.

Figure 9.3 Barcelona Clinic Liver Cancer staging system

Hepatitis B related HCC is an important global disease. Primary prevention of HBV infection remains the most effective long-term intervention; however, for those diagnosed with CHB, early detection and treatment of HCC has led to improved outcomes. HCC surveillance may increase the proportion being diagnosed at a curable stage. Although screening for HCC remains a topic for debate, earlier detection of these tumours has been associated with good results in the short and intermediate term. Disease recurrence and the treatment of advanced cancer remain a challenge. It is likely that the treatment of CHB infection will continue to make a significant impact on end-stage disease, and reduce the probability of developing liver cancer, but these benefits will take a long time to become apparent.

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Dr David Sheridan, Storr Liver Unit, Westmead Millennium Institute, University of Sydney, and Plymouth University Peninsula School of Medicine & Dentistry, United Kingdom

& Dr Monica Robotin, Cancer Council NSW and the School of Public Health, University of Sydney, Camperdown, NSW