The

Oncologist ®

The Etiology of Hepatocellular Carcinoma and Consequences

for Treatment

ARUN J. SANYAL,a SEUNG KEW YOON,b RICCARDO LENCIONIc

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a
Virginia Commonwealth University Medical Center, Richmond, Virginia, USA; bThe Catholic University of
Korea, Seoul, Korea; cPisa University School of Medicine, Pisa, Italy

Key Words. Hepatocellular carcinoma • Risk factors • Cirrhosis • Hepatitis B virus • Hepatitis C virus • Surveillance

Disclosures: Arun J. Sanyal: Consultant/advisory role: Takeda, Sanofi-Aventis, Salix, Ikaria, Astellas, Pfizer, Gilead, Vertex,
Exhalenz, Bayer-Onyx, Amylin, Norgine; Research funding/contracted research: Sanofi-Aventis, Salix, Gilead, Intercept, Roche;
Royalties: Uptodate; Seung Kew Yoon: None; Riccardo Lencioni: None.
The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from
commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer
reviewers.

ABSTRACT
Most patients with hepatocellular carcinoma (HCC) HCC, all of which have a direct impact on patient
have liver cirrhosis, which develops following long peri- characteristics and disease course, and although a
ods of chronic liver disease. Cirrhosis is characterized causative agent can often be identified, HCC remains
by a decrease in hepatocyte proliferation, indicating an an extremely complex condition associated with a
exhaustion of the regenerative capacity of the liver, and poor prognosis. Additionally, the geographic varia-
results in an increase in fibrous tissue and a destruction tion in etiology means that information from different
of liver cells, which may ultimately lead to the develop- countries is needed in order to optimize surveillance
ment of cancerous nodules. Half of all cases of HCC methods and develop effective chemoprevention
are associated with hepatitis B virus infection, with a strategies. Unfortunately, there are still many gaps in
further 25% associated with hepatitis C virus. Other our current understanding, and further research ef-
risk factors for developing HCC include alcoholic forts are needed to fully elucidate the diverse mecha-
liver disease, nonalcoholic steatohepatitis, intake of nisms involved in the pathogenesis of HCC and offer
aflatoxin-contaminated food, diabetes, and obesity. optimal prevention strategies for those at risk. The
There are multiple factors involved in the etiology of Oncologist 2010;15(suppl 4):14 –22

INTRODUCTION and cirrhosis, with major risk factors for developing cir-
Hepatocellular carcinoma (HCC) is the dominant form of rhosis including chronic infection with hepatitis B virus
primary liver cancer and is histologically and etiologi- (HBV), hepatitis C virus (HCV), alcoholic liver disease,
cally distinct from other forms of primary liver cancer and nonalcoholic steatohepatitis (NASH) [2, 3]. Addi-
[1]. Approximately 70%–90% of patients with HCC tional risk factors for developing HCC include intake of
have an established background of chronic liver disease aflatoxin-contaminated food, diabetes, obesity, certain
Correspondence: Arun J. Sanyal, M.D., F.A.C.P., Gastroenterology, Hepatology, Nutrition, Virginia Commonwealth University Medical
Center, Richmond, Virginia, USA. Telephone: 804-828-6314; Fax: 804-828-2992; e-mail: asanyal@mcvh-vcu.edu Received January
22, 2010; accepted for publication October 6, 2010. ©AlphaMed Press 1083-7159/2010/$30.00/0 doi: 10.1634/theoncologist.2010-S4-14

The Oncologist 2010;15(suppl 4):14 –22 www.TheOncologist.com

Sanyal, Yoon, Lencioni 15

hereditary conditions such as hemochromatosis, and

some metabolic disorders [2, 4, 5]. Table 1. Annual incidence rates of hepatocellular
carcinoma in patients with cirrhosis according to
HCC is unusual among human cancers in that the caus- underlying disease [40, 75]
ative agent is often clear. However, there are multiple etio- Annual
logic factors affecting HCC, all of which vary by Underlying disease incidence (%)
geographic location, have a direct impact on the character- Chronic hepatitis C 1–8
istics of these patients, and influence the disease course, Chronic hepatitis B 1–15
making HCC an extremely complex condition associated Alcoholic liver disease 1
with a poor prognosis [6]. Nonalcoholic steatohepatitis 2.6
HCC carcinogenesis is a complex process that can in- Hemochromatosis 2–6
volve various modifications to a number of molecular path- Primary biliary cirrhosis 2
ways as well as genetic alterations, and ultimately leads to
Autoimmune hepatitis ⬍0.2
malignant transformation and HCC disease progression [2,

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From Teufel A, Weinmann A, Centner C et al.
7–11]. Here, we review the main mechanisms thought to be Hepatocellular carcinoma in patients with autoimmune
involved in hepatocarcinogenesis and discuss how these hepatitis. World J Gastroenterol 2009;15:578 –582.
carcinogenic mechanisms differ according to the different Reproduced with permission from WJG Press.
etiologic risk factors.

ing telomere dysfunction and alterations in the micro- and

RISK FACTORS macroenvironment that stimulate cellular proliferation [2].
Telomerase plays an important role in maintaining telo-
Cirrhosis mere length and chromosomal stability in proliferating cells
The primary risk factor for developing HCC is cirrhosis, the such as hepatocytes [15]. Shortening of telomere limits pro-
major causes of which are HBV and HCV infection. Indeed, liferation in these cells and is therefore thought to reduce
there is evidence to show that 50% of all cases of HCC the regenerative capacity of organs during aging and
worldwide are associated with HBV infection, with a fur- chronic disease [16]. In hepatocytes of a cirrhotic liver,
ther 25% associated with HCV [12]. The annual incidence telomeres are significantly shorter than in noncirrhotic tis-
rates of HCC in patients with cirrhosis according to individ- sue, and this shortening has been shown to correlate with
ual underlying disease are shown in Table 1. Although fibrosis progression [16].
these incidence rates give an indication of the relative con- Telomere dysfunction has also been shown to increase
tributions of the underlying causes of cirrhosis to HCC pro- the number of early-stage hepatic neoplasms in mouse
gression, the development of cirrhosis and progression to models; however, this was accompanied by a decline in the
HCC is complex and may involve a combination of etiolo- occurrence of high-grade malignancies, suggesting that this
gies, for example, patients coinfected with both HCV and mechanism alone is insufficient to drive disease progres-
HBV [5]. sion to advanced HCC [17]. The effect of telomere dysfunc-
Cirrhosis develops following long periods of chronic tion appears to be dependent on other factors, such as cell
liver disease and is characterized by a decrease in hepato- type and p53 status, with a combination of telomere dys-
cyte proliferation, indicating an exhaustion of the regener- function and p53 mutation accelerating tumor onset [18].
ative capacity of the liver [13]. This is associated with an The decrease in hepatocyte proliferation that occurs
increase in fibrous tissue and a destruction of liver cells, during liver cirrhosis is thought to enhance cancer forma-
which provides the soil for development of cancerous nod- tion in cirrhotic livers. This was demonstrated in a rat
ules [14]. Because liver cirrhosis can have a significant im- model, in which the administration of various chemicals
pact on liver reserve and is often an integral part of the that inhibited hepatocyte proliferation also accelerated car-
morbidity and mortality associated with HCC, the presence cinogen-induced liver tumor formation [19]. Another char-
and severity of cirrhosis must be defined in all patients in acteristic of cirrhosis is the activation of stellate cells. This
order to assess prognosis and make treatment recommenda- leads to an increase in the production of cytokines, growth
tions. factors, and products of oxidative stress [20], many of
To date, many studies have investigated the possible which have been shown to affect hepatocyte proliferation
mechanisms involved in the development of HCC in pa- and so could play a role in tumor formation [2].
tients with cirrhosis, and a number of mechanisms thought The main oncogenic pathways involved in HCC are
to accelerate cancer formation have been identified, includ- phosphoinositol-3-kinase/Akt, myc, Wnt/␤-catenin, c-Met,

www.TheOncologist.com
16 Etiology of HCC and Treatment Consequences

attributable to HBV, with the majority of these in Africa,

55% Developmental pathways Asia, and the western Pacific region [25].
Prickle 1 HBV is a partially double-stranded DNA-containing vi-
26% 50%−60% 30%−40%
rus belonging to the Hepadnaviridae family. Infection with
Wnt/β-catenin Hedgehog c-Met
this virus is thought to cause HCC via both direct and indi-
rect pathways. First, HBV infection causes hepatocyte in-
Activation jury and chronic necroinflammation, with subsequent
Inactivation
Cell proliferation hepatocyte proliferation, fibrosis, and cirrhosis. The contin-
>90% Telomerase Stemness
Immortality
uous regeneration in cirrhosis leads to increased liver cell
turnover and accumulation of mutations in the host genome
that could result in genetic alterations, chromosomal rear-
myc PI3K/Akt rangements, activation of oncogenes, and inactivation of tu-
41% mor suppressor genes [26]. However, HBV can also cause

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30%−60% 38%
HCC in the absence of cirrhosis [2]. HBV is able to inte-
PTEN
grate its DNA into host cells and so may act as a mutagenic
Oncogenic pathways
agent, causing secondary chromosomal rearrangement and
increasing genomic instability [8]. In addition, the regula-
Figure 1. Main oncogenic pathways associated with hepato-
carcinogenesis [2]. tory protein HBx is thought to transactivate genes involved
Abbreviations: PI3K, phosphoinositol-3-kinase; PTEN, in cell proliferation control, resulting in stimulation of the
phosphatase and tensin homologue deleted on chromosome protein kinase C and nuclear factor kappa B pathways, as
ten. well as deregulation of cell cycle control and interference
Reprinted from El-Serag HB, Rudolph KL. Hepatocellular
carcinoma: Epidemiology and molecular carcinogenesis. Gas- with cellular DNA repair and apoptosis [27].
troenterology 2007;132:2557–2576. ©2007, with permission
from Elsevier. HCV Infection
HCV infection causes chronic inflammation, cell death,
and hedgehog (Fig. 1) [2, 10, 11]. The latter three are de- proliferation, and cirrhosis of the liver [26]. Thus, HCV-
velopmental pathways, which suggests that some HCCs related HCC is found almost exclusively in patients with
may arise from liver stem cells. The growth-inhibitory en- cirrhosis [26]. The risk for developing HCC is ⬃17-fold
vironment of a cirrhotic liver may activate and transform higher in HCV-infected patients [28], although this risk
liver stem cells, and there is some evidence to suggest that a varies depending on the degree of liver fibrosis at the time
stem-cell gene-expression signature exists in a subset of hu- of HCV infection. Approximately 195,000 cases of liver
man HCCs [21]. In liver cirrhosis, activation of Akt signal- cancer (31.1% of cases globally) are attributable to HCV,
ing is thought to promote tumor formation by suppressing with northern and middle Africa being the areas of highest
transforming growth factor (TGF)-␤–induced apoptosis prevalence [25].
[2]. Activation of this pathway has also been linked to ac- HCV belongs to the Hepacivirus genus of the Flaviviri-
tivation of ␤-catenin signaling, so further driving the hepa- dae family [8]. Unlike HBV, HCV is an RNA-containing
tocarcinogenic process. virus and so is unable to integrate into the host genome.
Finally, a number of molecular alterations that affect HCV therefore causes HCC by various indirect mecha-
DNA damage checkpoints have been described, which may nisms. For example, HCV core protein is thought to enter
promote tumor formation in the cirrhotic liver. These in- the host cell, where it localizes in the outer mitochondrial
clude loss of function of the p53 tumor suppressor gene membrane as well as the endoplasmic reticulum and pro-
[22], inactivation of the p27 cell cycle regulator [23], loss of motes oxidative stress. This results in activation of key sig-
heterozygosity of the insulin-like growth factor 2 receptor naling pathways such as the p38 mitogen-activated protein
locus [24], and loss of protein expression of the p16 cell cy- kinase and nuclear factor kappa B pathways, leading to up-
cle inhibitor [23]. regulation of genes involved in cytokine production and
subsequent inflammation, alterations in apoptotic path-
HBV Infection ways, and tumor formation [7]. The nonstructural proteins
HBV infection causes acute and chronic liver disease, and of HCV, NS3, and NS5A are also thought to act as key me-
has been shown to increase the risk for developing liver diators to induce oxidative stress and inflammation [7].
cancer 100-fold in chronic carriers [8]. Approximately Interestingly, HCV infection has also been found to
340,000 cases of liver cancer (54.4% of cases globally) are induce insulin resistance (IR), which in turn has been
Sanyal, Yoon, Lencioni 17

closely linked to the development of fibrosis and type 2 Coinfection with HIV
diabetes in these patients [29]. Although the mechanisms HIV infection shortens the survival of patients with HCV-
involved in the development of IR are not fully under- related cirrhosis [36]. In addition, hepatocarcinogenesis
stood, the immune response against HCV infection is could be a more rapid and aggressive process in HIV/HCV
thought to be involved and research suggests that the pro- coinfected patients [37].
cess may be multifactorial. Preclinical data from trans-
genic mice have demonstrated greater IR and higher Autoimmune Hepatitis
levels of the proinflammatory cytokine tumor necrosis Autoimmune hepatitis (AIH) is a condition of unknown eti-
factor (TNF)-␣ in the presence of HCV core protein [30]. ology that is characterized by a progressive destruction of
In humans, HCV infection is associated with signifi- the liver parenchyma, often leading to fibrosis and liver cir-
cantly higher levels of HOMA-IR (homeostasis model rhosis. Studies have shown that HCC occurs rarely in pa-
assessment of IR), TNF-␣, and interleukin 6 compared tients with AIH (⬍1%) and is almost exclusively restricted
with healthy controls [31]. These proinflammatory cyto- to patients with AIH and long-standing liver cirrhosis [38 –

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kines are both known to induce IR [32], and there is ev- 40].
idence to suggest that Kupffer cells [7] stimulated by This surprisingly low incidence of HCC in patients with
oxidative stress [33] and exposure to the HCV core pro- AIH suggests that there may be some pathologic mecha-
tein [34] are a likely source. Although the mechanism has nism preventing cancer progression. One hypothesis has
yet to be fully elucidated, one hypothesis concerning highlighted the common use of immunosuppressants in
TNF-␣–related IR proposes an inhibition of insulin re- these patients. Because these agents suppress cytokines
such as interleukin 1␤ and TNF-␣, which are known to play
ceptor substrates [30]. Taken together, these data suggest
an important role in tumor growth and proliferation, it has
that the process by which HCV infection can contribute
been suggested that downregulation of these cytokines
to IR is complex and involves multiple mechanisms. Fur-
might contribute to a protective mechanism from the devel-
ther evidence is needed to fully understand the relation-
opment of HCC [40]. If confirmed, this could affect future
ship among HCV infection, immune response, IR, and
therapeutic options afforded to patients with HCC. How-
HCC.
ever, further characterization is needed before any defini-
Finally, alcohol is an important cofactor in patients with
tive conclusions can be drawn.
HCV infection, with HCV reported in 4.6%–55.5% of al-
coholics [35]. Patients with both HCV infection and alcohol
Nonalcoholic Fatty Liver Disease and NASH
abuse have been shown to develop more severe fibrosis and
Nonalcoholic fatty liver disease (NAFLD) is the most com-
have higher rates of cirrhosis and HCC than nondrinkers
mon liver disorder in western countries, with ⬃20% of in-
[35]. The risk for developing HCC has also been shown to dividuals affected [41]. It occurs in the absence of alcohol
increase as levels of alcohol intake rise [28]. The mecha- use, although the hepatic histology appears consistent with
nisms by which alcohol worsens HCV-related liver disease alcoholic hepatitis [42], with changes in histology includ-
are not clear, although several possibilities have been pro- ing hepatic steatosis, inflammation, hepatocyte injury as
posed, including: greater HCV replication in the presence exemplified by cytologic ballooning and Mallory’s hyaline,
of alcohol; alcohol-associated changes in the hypervariable and fibrosis [43]. Thus, NAFLD comprises a spectrum of
region of the viral genome, leading to more aggressive conditions ranging from fat alone to fat plus inflammation,
HCV-related liver disease and resistance to interferon ther- fat plus ballooning degeneration, and NASH, the latter be-
apy; and inhibition of hepatic expression of Bcl-2 by alco- ing the most serious form of NAFLD [42, 44].
hol, resulting in increased apoptosis and more severe liver Epidemiologic studies show that NAFLD is closely
injury [35]. However, the dominant mechanism for syner- linked with the metabolic syndrome, particularly type 2 di-
gism between alcohol and HCV infection appears to be in- abetes mellitus and obesity [45], with NAFLD occurring al-
creased oxidative stress. As mentioned above, HCV core most universally among diabetic patients who are morbidly
protein localizes at the mitochondrial membrane and pro- obese [46]. Moreover, NASH in association with multiple
motes oxidative stress. Ethanol potentiates this mitochon- components of the metabolic syndrome is thought to in-
drial injury by further increasing reactive oxygen species crease the risk for developing chronic liver disease, cirrho-
(ROS) production and enhancing hepatic glutathione oxi- sis, and HCC [45]. Additionally, a recent study has shown
dation. Moreover, alcohol and HCV core protein act syner- that NAFLD is a principal risk factor in the development of
gistically in causing lipid perioxidation and increasing HCC, irrespective of age [47].
hepatic TGF-␤ and TNF-␣ expression [35]. Although the pathophysiologic mechanisms driving

www.TheOncologist.com
18 Etiology of HCC and Treatment Consequences

Table 2. Common causes of liver cirrhosis that could

result in the development of hepatocellular carcinoma
[52]
Most common causes of Less common causes
cirrhosis of cirrhosis
Alcohol (60%–70%) Autoimmune chronic
hepatitis
Biliary obstruction (5%–10%) Drugs and toxins
Primary/secondary biliary Genetic metabolic
cirrhosis diseases
Chronic hepatitis B or C virus Infection
(10%)
Hemochromatosis Vascular abnormalities

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Nonalcoholic fatty liver disease Veno-occlusive disease
(10%) Idiopathic
From Heidelbaugh JJ, Bruderly M. Cirrhosis and chronic
Figure 2. Insulin resistance and the development of non- liver failure: Part I. Diagnosis and evaluation. Am Fam
alcoholic steatohepatitis [46]. Physician 2006;74:756 –762. Reproduced with permission
Abbreviations: Apo B, apolipoprotein B; FFA, free fatty from the American Academy of Family Physicians.
acids; MTP, microsomal triglyceride transfer protein; PPAR␥,
peroxisome proliferator-activated receptor gamma; SREBP-
1c, sterol regulatory element binding protein-1c; TG, triglyc- Other Risk Factors
erides; VLDL, very low-density lipoprotein.
From Adams LA, Angulo P, Lindor KD. Nonalcoholic HCC in noncirrhotic livers is rare and mostly occurs as a
fatty liver disease. CMAJ 2005;172:899 –905. Reproduced result of HBV infection, as described earlier [2]. However,
with permission from Professor Keith Lindor. HCC in noncirrhotic livers can also occur as a result of con-
tamination of foodstuffs with aflatoxin B1 [50]. Aflatoxin
B1 is a mycotoxin produced by the Aspergillus fungus that
NAFLD and the associated progressive hepatocellular grows readily on food when stored in warm, damp condi-
damage are not fully understood, a number of processes tions [2]. When ingested, it is metabolized into the active
have been described. A well-established driver of AFB1-exo-8,9-epoxide, which binds to DNA to cause dam-
NAFLD is IR (Fig. 2). IR is a complex process that likely age, including the production of mutations of the p53 tumor
involves both insulin secretion and action, and is closely suppressor gene. Indeed, this mutation has been reported in
associated with obesity [46]. IR causes increased periph- 50% of HCC tumors in southern Africa, where aflatoxin B1
eral lipolysis and increases circulating fatty acids that are is a known risk factor for developing HCC [51].
taken up by the liver. At the same time, there is an in- Another risk factor for developing HCC is alcoholic
crease in de novo liponeogenesis in the hepatocytes and a liver disease. Heavy alcohol intake (⬎50 –70 g/day) is the
reduction in the hepatic secretion of very-low-density li- most common cause of liver cirrhosis [52], and is a well-
poproteins, resulting in hepatic triglyceride accumula- established risk factor for HCC, although it is unclear
tion or fatty liver. whether HCC risk is also affected by light to moderate al-
Increased intrahepatic fatty acid levels are also cohol intake [2]. As mentioned, heavy alcohol intake is
thought to provide a source of oxidative stress, which thought to act synergistically with HCV to promote liver
may play an important role in the development from ste- cirrhosis [28]. Similar results were seen for HBV, with a
atosis to steatohepatitis associated with progression to twofold higher odds ratio for each hepatitis virus infection
cirrhosis [48]. ROS produced by the mitochondria oxi- for drinkers of ⬎60 g/day [28].
dize fat deposits to release lipid peroxidation products, Finally, a number of other risk factors for developing
which together with ROS impair the respiratory chain via HCC exist, including primary biliary cirrhosis, silent
oxidative damage to the mitochondrial genome [49]. chronic liver disease, and hereditary hemochromatosis
ROS and lipid peroxidation products also increase the [52]. Other less common causes of hepatic cirrhosis that
production of various cytokines, including TNF- ␣ , could contribute to the development of HCC are shown in
TGF-␤, and Fas ligand. Proinflammatory cytokines also Table 2 and include genetic metabolic diseases, certain in-
activate hepatic stellate cells, which produce a collagen fections, and vascular and venous abnormalities. Impli-
matrix and drive the development of fibrosis [9]. cated genetic disorders of the metabolism include ␣-1
Sanyal, Yoon, Lencioni 19

antitrypsin deficiency; various amino acid, bile acid, carbo- influences the decision to implement surveillance, irrespec-
hydrate, and lipid disorders; urea cycle defects; porphyria; tive of the etiology of the liver disease. However, guidelines
and Wilson’s disease. Infectious agents such as brucellosis, also support surveillance for HCC in specific groups of in-
syphilis, echinococcosis, and schistosomiases are known to dividuals with HBV, even without cirrhosis (e.g., those
cause cirrhosis, as are vascular abnormalities such as right- with a family history of HCC) [59, 63, 64]. There is some
sided heart failure, pericarditis, hereditary hemorrhagic tel- suggestion that NAFLD/NASH may predispose to HCC in
angiectasia, and veno-occlusive diseases, for example, the absence of cirrhosis [65, 66], although more data are
Budd-Chiari syndrome [52, 53]. needed on this.

SURVEILLANCE IMPACT OF ETIOLOGY ON TREATMENT

Given the established links between liver cirrhosis and the The complex etiology of HCC affects the possible treat-
development of HCC, there is a strong rationale for surveil- ment options offered to patients. For example, patients with
lance of patients with cirrhosis, and guidelines support ob- compromised liver function as a result of cirrhosis are inel-

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servation of this group, regardless of etiology. The value of igible for surgical resection because of the risk for postop-
surveillance has already been demonstrated in Japan, where erative decompensation [54]. The coexistence of cirrhosis
80% of HCC cases are detected at an asymptomatic stage as and associated liver dysfunction may also limit the nonsur-
a result of screening patients with known cirrhosis. In con- gical treatment options available and is likely to be a large
trast, in the U.K., up to 40% of cases present with HCC as contributory factor to the poor prognosis of many HCC pa-
the first indication of underlying liver disease [54]. Further- tients. The presence of comorbidities such as cardiac con-
more, studies in China and Italy have shown that survival is ditions or neurodegenerative disorders in patients with
improved by surveillance for HCC [55, 56]. hemochromatosis, or diabetes, obesity, or cardiac condi-
Earlier diagnosis of HCC significantly affects treatment tions in patients with NASH, may influence treatment op-
choices [54, 57– 60] and treatment recommendations for tions for HCC, and the use of concomitant medications
patients with earlier-stage HCC are described in detail else- should also be carefully considered.
where in this issue [61]. The benefits of earlier diagnosis Patients with HBV or HCV require antiviral therapy to
through surveillance were highlighted in a retrospective control viral replication and improve cirrhosis-related out-
chart review of patients with HCV and HCC treated in the comes. For patients with HBV infection, antiviral therapy
South Texas Veteran Healthcare System. That study may also block the hepatocarcinogenic properties of viral
showed that all screened patients were diagnosed with ear- proteins such as HBx [5, 67]. Indeed, prospective and ret-
lier-stage disease and were 10 times more likely to have re- rospective studies of large numbers of patients with chronic
ceived potentially curative treatment than unscreened HBV infection and advanced liver disease, including cir-
patients [62]. rhosis, have shown that treatment with the nucleotide ana-
The serum marker ␣-fetoprotein (AFP) has been used as log lamivudine delays disease progression and also reduces
a diagnostic test for HCC; however, it has limited sensitiv- the incidence of HCC [67, 68]. Because chemotherapy can
ity/specificity as a surveillance test when used alone. Ultra- reactivate the virus in HBV carriers, prophylactic lamivu-
sound is a widely used method of detecting HCC, although dine therapy during and 6 months after treatment is recom-
it has been suggested that the reliability of this method is mended in patients scheduled to receive chemotherapy
influenced by the expertise of the operator as well as the [67].
provision of dedicated equipment [54]. However, as ex- Prevention of HCC is also an important goal, and op-
pected, the levels of sensitivity and specificity are also de- portunities exist for the further development of preventative
pendent on the size of the tumor, with ultrasound able to measures (Fig. 3) [69]. The success of intervention was first
detect 80%–95% of tumors 3–5 cm in diameter and 60%– demonstrated by the nationwide Taiwanese vaccination
80% of tumors ⬍1 cm in diameter [54]. Combining ultra- program against HBV, which was implemented in the
sound and AFP appears to improve detection rates, but also 1980s and successfully reduced both the number of HBV
increases costs and the rate of false positives. The American carriers and the incidence of HCC in children, with recent
Association for the Study of Liver Diseases guidelines rec- evidence confirming that the benefit is maintained into
ommend that surveillance for HCC be performed using ul- early adulthood [70 –73]. Subsequently, studies conducted
trasonography at 6- to 12-month intervals and that AFP in patients with HCV, with and without cirrhosis, have
alone should not be used for screening unless ultrasound is shown that treatment with interferon therapy is associated
not available [59]. with a lower risk for developing HCC [74]. However, the
Currently, the presence of cirrhosis is the key factor that potential role of interferon in future treatment strategies to

www.TheOncologist.com
20 Etiology of HCC and Treatment Consequences

NAFLD, also appears to further drive the hepatocarcino-

genic process.
A broad range of mechanisms involved in the pathogen-
esis of HCC have been identified, including telomere dys-
function, activation of oncogenic pathways, abrogation of
DNA damage checkpoints, activation of proinflammatory
pathways, and induction of the oxidative stress response.
However, the exact role of each of these pathways is
thought to vary according to the etiologic agent, and signif-
icant gaps remain in the data available. Further research ef-
forts are therefore needed to fully elucidate the diverse
mechanisms involved in the pathogenesis of HCC as well as
Figure 3. Strategies for primary and secondary liver cancer the possible interactions between different etiologic agents.
prevention in healthy subjects and in those with chronic hepa-

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titis infection [69].
The geographic variation in etiology means that further in-
Abbreviations: HBV, hepatitis B virus; HCC, hepatocellu- formation from different countries around the world is also
lar carcinoma. needed if we are to improve our global understanding in this
From Chang MH. Cancer prevention by vaccination area and develop effective surveillance programs and che-
against hepatitis B. Recent Results Cancer Res 2009;181:85–
moprevention strategies. Indeed, a better understanding of
94. Reproduced with permission. ©2009, Springer-Verlag
Berlin Heidelberg. the etiology of HCC may offer us the best chance of achiev-
ing earlier diagnosis and intervention, which would ulti-
prevent HCC in HCV-infected patients remains controver- mately improve the outlook for those at risk for developing
sial. HCC.

CONCLUSIONS ACKNOWLEDGMENTS
These findings show that the etiology of HCC is extremely The authors take full responsibility for the scope, direction,
complex, with many confounding factors affecting disease and content of the manuscript and have approved the sub-
course and patient prognosis. For example, most patients mitted manuscript. They would like to thank Karen Bray-
with HCC have cirrhosis, which develops following long shaw, Ph.D., at Complete HealthVizion for her assistance in
periods of chronic liver disease and results in increased fi- the preparation and revision of the draft manuscript, based
brous tissue and a destruction of liver cells, and may ulti- on detailed discussion and feedback from all the authors.
mately promote tumor development. Both HBV and HCV Editorial assistance was supported by a grant from Bayer
infection increase the likelihood of developing liver cancer, HealthCare Pharmaceuticals.
with an incidence of 54.4% and 31.1% of liver cancer cases
globally, respectively. Additional risk factors for develop- AUTHOR CONTRIBUTIONS
ing HCC include NAFLD/NASH, alcoholic liver disease, Conception/Design: Arun J. Sanyal, Seung Kew Yoon, Riccardo Lencioni
Data analysis and interpretation: Arun J. Sanyal, Seung Kew Yoon, Riccardo
intake of aflatoxin-contaminated food, diabetes, and obe- Lencioni
sity. The presence of multiple components, such as alcohol Manuscript writing: Arun J. Sanyal, Seung Kew Yoon, Riccardo Lencioni
Final approval of manuscript: Arun J. Sanyal, Seung Kew Yoon, Riccardo
abuse in patients with HCV or obesity in patients with Lencioni

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