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Figure 2 Image demonstrating carcinogenesis in HCC and progressive adaptation of vasculature from normal anatomy with portal triad supply to
progressive angiogenesis and unpaired arterial supply. Abbreviations: HCC, hepatocellular carcinoma. Adapted from Yang and Poon (2008).
0.5% of these categorized as severe requiring blood transfusion (Rockey et al. 2009). Furthermore, there is a risk of tumor
seeding following needle biopsy which can lead to hematological spread of malignant cells and distant metastasis. The incidence of tumor seeding was originally reported at 0.9% per
year (Silva et al. 2008) although subsequent studies have
shown a lower risk of 0.14–0.76% (Chang et al. 2008;
Szpakowski et al. 2017). Tumor seeding potential is less of a
problem with advanced disease, however in isolated primary
tumors it may increase the risk of disease progression (Childs
et al. 2021). The ability to diagnose HCC without biopsy is
advantageous to patients on an individual basis; however
there is debate as to whether lack of access to histology has
actually delayed our understanding of the molecular pathogenesis of HCC compared to other cancers. In the last few
decades we have seen the emergence of cancer-specific, targeted therapies come to market, for example monoclonal
antibodies (mAb) such as Trastuzumab (Herceptin) in the
treatment of breast HER2 positive breast cancer (Wilson
et al. 2017) and the use of anti-androgen hormone therapies
in prostate cancer (Rice et al. 2019). It is the wide availability
of tissue histology from these cancers that has made it possible for these targeted treatments to be developed, arguably
this is something comparatively lacking in HCC research.
As with any imaging modality, the sensitivity of CT is also
dependent on the tumor size. Smaller lesions are invariably
more difficult to detect, a confident diagnosis of HCC has
been shown to not be feasible for sub centimeter (<1 cm) nodules (Bruix et al. 2011; Forner et al. 2008) which accounts for
why lesions < 1cm are re-evaluated in three months from
initial identification rather than being subject to further investigation. It is pertinent to consider that not all HCCs will have
the characteristic radiological features described previously.
Approximately 30% of HCCs will have an atypical appearance
(Bruix et al. 2011) and will require biopsy for further
evaluation, atypical appearance is more likely to be a feature in
smaller, well-differentiated HCCs (Kovac et al. 2021).
Magnetic Resonance Imaging (MRI)
Magnetic Resonance Imaging (MRI) is an excellent imaging
modality that produces highly detailed images of soft tissues
using a magnetic field and radio waves (Grover et al. 2015).
A clear advantage of MRI is that it does not use ionizing
radiation
to produce images, therefore it is relatively risk free for patients.
The lack of ionizing radiation is particularly advantageous in the
context of a chronic disease whereby repeated scans may be
required. MRI exploits the same vascular properties of HCC as
CT, it relies on the contrast-enhanced and subsequent washout
phase to diagnose HCC lesions. Several studies have showed
superiority of MRI over CT in terms of sensitivity in detecting
HCC (Noguchi et al. 2003; Semelka et al. 2001). A metanalysis of
11 studies showed superiority of contrast enhanced MRI
sensitivity over CT for HCC lesions > 2cm (89% and 79% respectively) and < 1cm (69% and 49% respectively) however, there was
no significant difference in specificity, positive likelihood ratio or
the diagnostic odds ratio (Roberts et al. 2018).
While MRI has fantastic diagnostic capability, it is one of the
most expensive imaging techniques used in modern clinical
practice. Cost-effectiveness is often expressed using Quality
Adjusted Life Years (QALYs) which measures the benefit of a
health intervention given to a patient over the course of their
lifetime at a certain cost. Different countries have different
ideas as to what constitutes as a cost-effective threshold, in the
UK the National Institute for Health and Care Excellence
(NICE) uses a threshold between £20, 000–£30, 000 per QALY
gained (McCabe et al. 2008); any intervention costing less than
these figures is deemed a cost-effective strategy. The cost of one
QALY gained by MRI HCC Surveillance has been reported to
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be as high as $100, 000 (Andersson et al. 2008). A systematic
review evaluating the cost of different methods of HCC surveillance using US data found the average cost of MRI per scan to
be $1400 (range $900–$1700) which compares to $640 for CT
and $185 for US alone (Andersson et al. 2008). It is clear that it
would not be a cost-effective strategy or indeed economically
feasible to use MRI as the primary tool for surveillance of HCC.
There are also other factors to consider with MRI for example,
patients may have certain devices such as pacemakers, cochlear
implants and neurostimulators that is, deep brain stimulator
electrodes which are not MRI compatible.
LI-RADS Classification
The Liver Imaging Reporting and Data System (LI-RADS)
has been developed to both standardize the interpretation
and reporting of liver lesions (Santillan et al. 2018) detected
on the different imaging modalities used in HCC surveillance. It is supported by the American College of Radiology
(ACR) and was created by a multinational, multidisciplinary
conglomerate of expert radiologists and specialists in liver
cancer imaging (Chernyak et al. 2018). Radiological features
of benign lesions such as simple cysts or haemangiomas will
be classified as LI-RAD one-half representing benign or probably benign. Radiological features highly suggestive of malignancy for example target diffusion restriction, peripheral
arterial enhancement or rim washout will be labeled in a
higher risk LI-RAD category (LI-RADS grading system summarized in Table 2) (Marrero et al. 2018). Growth is also used
as part of the major criterion in LI-RADS, any growth > 50%
in six months is highly suspicious for HCC however, the
lesion in question must be present on previous imaging
(Chernyak et al. 2018).
Naturally, the creation and utilization of LI-RADS preceded
the validation of evidence to support its use in clinical practice.
There is now emerging evidence that strongly favors its use, a
Table 2 Summary of LI-RADS classification for radiological description of
liver lesions.
Definitions in the LI-RADS classification system
LR-1 Benign
LR-2 Probably benign
LR-3 Intermediate probability of malignancy
LR-4 Probably HCC
LR-5 Definitely HCC
LR-M Probably or definitely malignancy but not HCC
LR-TIV Definitely tumor in vein
LR-NC Unable to categorize due to image degradation
Abbreviations: LR, liver reporting; LI-RADS, Liver Imaging Reporting and
Data System.
systematic review supports the “Major” criteria in LI-RADS
HCC reporting namely arterial-phase enhancement (APHE),
“washout” appearance and capsule appearance (Tang et al.
2018). It is consistently evaluated and updated in line with the
best available evidence. The integration of LI-RADS into the
AASLD guidance is based on the evidence that it significantly
improves the standardization of reporting and accuracy of risk
stratifying liver lesions (van der Pol et al. 2019). Although it is
a predominantly American system, LI-RADS has a worldwide
influence and guidance is used by clinicians globally to aid
understanding and reporting of HCC. EASL currently has
slightly different recommendations for the reporting of liver
lesions (Berzigotti et al. 2021), in the future it would be ideal to
see harmonization between different institutional guidance in
order to achieve consensus on best practice management of
liver disease among international experts. Figure 3 summarises
the HCC surveillance pathway based on the LI-RADS criteria.
Surveillance Harms
Although there are clear benefits to surveillance in patients at
high risk of HCC, it is important to consider the potential harms
of these strategies. In terms of harms to the patient, these can be
divided into physical and psychological harms (Heleno et al.
2013). With any test there is always a risk of a false-positive result
if radiology is inconclusive or indeed suggestive of HCC the
patient may go on to have an invasive investigation or interventional procedure. Prospective cohort studies have suggested that
approximately 5% of individuals enrolled in HCC surveillance
per year will go on to have unnecessary investigation and/or
intervention (Trinchet et al. 2015). For example, radiofrequency
ablation used in the management of small focal HCCs carries a
risk of bleeding, infection, and damage to internal structures
(Maeda et al. 2020). In relation to the harms of imaging specifically, repeated CT scans confer accumulative radiation exposure
which can increase the risk of cellular damage and associated cancer, a risk that many patients are not counselled on. Furthermore,
there is also an acute risk of contrast induced nephropathy which
can lead to renal failure; this is of particular relevance in patients
with cirrhosis (Safi et al. 2015) who may have associated hepatorenal syndrome in which their baseline kidney function is
already poor and at risk of further deterioration.
For patients who have advanced cirrhosis with poor
physiological reserve, surveillance is unlikely to infer any
benefit. The rationale is that this cohort of patients will not be
fit enough to survive invasive procedures or surgery thus, surveillance will not change the outcome for the patient (Taylor
et al. 2017). It is important that patients are counseled on the
purpose of surveillance and are aware of its limitations and the
possibility that it can lead to a number of unnecessary investigations and even treatments. The British Society of
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Figure 3 Summary of Hepatocellular Carcinoma (HCC) surveillance pathway in high-risk patients. Abbreviations: AFP, alpha-fetoprotein; CT, computed
tomography, HCC, hepatocellular carcinoma; LI-RADS, Liver Imaging Reporting and Data System; LR, liver reporting; US, ultrasound; MRI, magnetic
resonance imaging. Image adapted from Fitzmorris and Singal (2015); Moura Cunha et al. (2021).
Gastroenterology (BSG) published up to date best practice
guidance for HCC surveillance in 2021 and recommends that
patients who have liver cirrhosis classified with Child-Pugh C
or Child-Pugh B7 Cirrhosis with uncontrolled ascites are not
suitable for surveillance as they will not tolerate anticancer
treatments, they can however be considered for liver
transplantation(Kanwal and Amit G. Singal 2019).
space acting as purely vascular marker (Motz et al. 2021).
A metanalysis evaluated use of CEUS for diagnosis of HCC, the
pooled sensitivity of which was 92%, specificity 87%, diagnostic odds ratio (OR) 104 and a positive likelihood ratio of
0.09 (Wu et al. 2018).
Despite its advantages, CEUS has not been recommended
in surveillance of HCC by EASL & AASLD. In part, this is due
to its limited ability to distinguish between HCC and intrahe-
Future Directions of Imaging in HCC
Surveillance
In recent years, contrast enhanced ultrasound (CEUS) is a
significant advancement from conventional US. CEUS produces real time images of focal liver lesions with the ability to
assess the enhancement/washout pattern observed with contrast (Lyshchik et al. 2018) as used in other imaging modalities
previously described. A key difference is the methodology of
contrast administration, CEUS uses microbubble based contrast agents which are injected intravenously (Bartolotta et al.
2019). They consist of flexible phospholipid shells which contain soluble gas bubbles which remain within the intravascular
patic cholangiocarcinoma (ICC) (Vilana et al. 2010), which is
another cirrhosis-associated malignancy that occurs in 1–5%
of individuals with cirrhosis per year (Blechacz 2017). It also
subject to the same limitations as conventional US such as
operator dependence and patient factors (Kim et al. 2017).
Additionally, it is only able to visualize one area of the liver at
a time during contrast administration, this compares to CT/
MRI which is able to analyze contrast uptake in the whole
liver at any one time. In 2017, LI-RADS criteria was developed for use specifically in CEUS (Chernyak et al. 2018), similar in concept to the LI-RADS criteria used in CT/MRI, and
has which has improved the standardization of reporting (Lee
et al. 2021).
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There have been no randomized controlled trials (RCTs)
looking at HCC surveillance and non-surveillance in patient
with cirrhosis(Julie K. Heimbach et al. 2018), largely because
surveillance is widely accepted to be beneficial and it would be
unethical to deprive patients from access to this for randomization purposes. Unfortunately, the hierarchy of evidence for surveillance is therefore limited and relies heavily on systematic
reviews and metanalysis of observational cohort studies. Of the
evidence available, one of the largest systematic reviews of 47
studies (which included a total of 15,158 patients) conducted in
China demonstrated that surveillance more than doubled the
chance of early tumor detection and of being offered curative
treatment options (Singal et al. 2014). Surveillance was also significantly associated with improved pooled three-year survival
rate of 50.8% compared to 27.9% for patients who presented
symptomatically or diagnosed incidentally. Observational
studies are subject to lead time bias and often studies to not
take this into consideration when reporting statistical significance; this is something that must be considered when evaluating the evidence base.
Despite the widely accepted benefits, the uptake of HCC surveillance is notoriously poor with less than one in five patients
estimated to be receiving surveillance globally (Singal et al.
2017). Of the 18,186 patients with HBV in the large RCT by
Zhang et al., only 60% of subjects persistently adhered to sixmonthly surveillance intervals (Zhang et al. 2004). Patients
with viral-related liver cirrhosis have been shown to have the
highest rate of compliance to surveillance compared to patients
with alcohol or NASH related cirrhosis (Harris et al. 2019;
Henrion et al. 2000). There are a multitude of reasons that compliance and adherence to surveillance is poor, and these can
broadly be divided into healthcare and patient-related factors.
First and foremost, there is a disparity in access to surveillance
between different countries and populations. In many settings,
cirrhosis and liver disease may be managed in a primary care
setting rather than under specialist hepatology care. Evidence
suggests that patients are less likely to be referred for regular
surveillance screening the in primary care setting than if they
are cared for in secondary care (Davila et al. 2010). Qualitative
survey data from primary care providers suggests that reasons
for this disparity include a lack of awareness of up to date surveillance guidance, difficulty communicating with patients
about surveillance, in addition to the breadth and volume of
primary care workload making HCC surveillance less of priority compared to other health conditions(Guss et al. 2018).
Not all geographical areas will have access to specialist hepatologists or gastroenterologists however, in countries whereby
these services are available, it is important to refer cirrhotic
patients to improve continuity and consistent surveillance
(Goldberg et al. 2016). Naturally, underdiagnosis of liver disease also results in lower rates of surveillance, of all etiologies
NASH-related cirrhosis most frequently goes undiagnosed
which poses a significant problem with the growing number of
patients with metabolic disease globally (Zhai et al. 2021).
Evidence suggests that HCC disproportionately affects individuals from low socio-economic backgrounds and those from
ethnic minority backgrounds. A retrospective cohort study of
904 patients with cirrhosis found that only 13% of all patients
received annual surveillance and only 2% biannual surveillance
with the lowest rates in African-American individuals and
uninsured patients in the US (Singal et al. 2015), other studies
have shown a similar pattern with the poorest uptake rates
among African-American patients (Artinyan et al. 2010; Davila
et al. 2010). Clinical factors shown to be positive predictors of
surveillance adherence include presentation to hospital with
decompensation of liver disease and if patients have a co-morbidity
associated with metabolic disease (Goldberg et al. 2016).
Patient attitudes and beliefs also have an impact on HCC surveillance, misconceptions include the belief that abstaining
from alcohol and eating a healthy diet limits the need for surveillance, as well as being asymptomatic or having a normal
physical examination (Farvardin et al. 2017). Other practical
barriers include distance from surveillance centers, lack of
transportation, and difficulty with scheduling appointments.
Furthermore, patients affected by alcoholism and drug
dependence are less likely to be able to engage with healthcare
services and consequently have poorer rates of surveillance
(Farvardin et al. 2017).
It is essential that healthcare professionals continue to educate patients on the importance of surveillance and practice a
patient-centered approach to healthcare. By involving patients
at every step of the decision-making process, they are more
likely to feel empowered and take ownership of their health.
Ultimately, the aim is to raise awareness, support patients with
adherence to surveillance in order to diagnose HCC early and
ultimately improve patient outcomes.
Biomarkers
Biomarkers are measurable biological substances which can be
used as correlates for disease. In HCC, they serve an important
role in early diagnosis, prognosis, and treatment selection. In
particular, early detection of curable HCC through surveillance
of high-risk liver cirrhosis patients is essential to improve
patient survival. Several serum biomarkers have been studied.
However, few HCC biomarkers fulfill the standardized biomarker validation criteria (Pepe et al. 2001), due to a lack of
large prospective longitudinal studies. Serum protein biomarkers are the most well studied, with alpha-fetoprotein
(AFP) the only to undergo stage five validation (Tayob et al.
2019). Other serum protein biomarkers including AFP-L3 and
des-gamma-carboxy prothrombin (DCP) have demonstrated
promise but lacked sufficient validation for widespread clinical
use. The advancement in high-throughput sequencing has led
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to the development of promising genomic markers, including
MicroRNAs (miRNA) (Zhang et al. 2017) and cell-free DNA
(cfDNA) (Jiao et al. 2018). This chapter will explore the main
biomarkers in early diagnosis, prognosis and treatment of
HCC.
Alpha-Fetoprotein (AFP)
Normal Physiology and Pathophysiology
AFP is the most widely used biomarker for HCC surveillance
and prognosis. AFP is a 70kD glycoprotein, with structural
similarity to serum albumin (Deutsch 1991), with the AFP
gene located on chromosome 4 (Lazarevich 2000). It was first
identified in fetal serum in 1956 (Bergstrand and Czar 1956)
and is produced by the yolk sac during the first trimester of
pregnancy, and subsequently the fetal liver after yolk sac regression. It serves as the key serum protein for transportation of
ligands in the fetal bloodstream (Mizejewski 2001). After birth,
AFP levels regress and remain low during normal healthy lifespan, with serum albumin becoming the main serum protein.
Elevated levels of AFP were first identified in patients with
HCC in 1964 (Tatarinov 1964), and are seen in 60% of cases
(Trevisani et al. 2001). Elevated levels are also seen in acute and
chronic viral hepatitis (Abdoul et al. 2008; Kew et al. 1973),
gonadal (Talerman et al. 1980) and gastric (Lu et al. 2021)
tumors and pregnancy (Mizejewski 2003). The mechanism for
overexpression of the AFP gene in HCC is not fully understood, but appears to be due to epigenetic silencing of suppressors at the gene promoting region (Shen et al. 2008). Though
AFP correlates with specific molecular subclasses of HCC
(Hoshida et al. 2009), its role carcinogenesis and proliferation is
not well established. In clinical practice, the main utility of AFP
is as a biomarker in surveillance, prognosis, and disease monitoring of HCC.
Surveillance in Liver Cirrhosis
AFP’s role as a biomarker for HCC surveillance in patients with
liver cirrhosis has been subject to debate. Using a cut-off value
of 20 ng/mL, serum AFP achieved a maximal sensitivity of 60%
for HCC, compared to higher cut-off values (Trevisani et al.
2001). AFP showed a high specificity of 90.6% at this level. In a
population with a 5% prevalence of HCC, this equated to a
positive predictive value (PPV) of only 25%, with a negative
predictive value (NPV) of 90%, demonstrating the value of
AFP in excluding HCC, but limitation in detecting HCC.
Furthermore, AFP missed over half of early and small HCCs,
with non-elevated levels seen in 52% of HCCs less than 3cm
and 53.5% of early HCCs (Farinati et al. 2006). Due to its poor
sensitivity, AFP used on its own appears to have a limited role
in surveillance. However, AFP shows higher utility when used
as an adjunct to ultrasound surveillance. A meta-analysis of 32
studies demonstrated ultrasound alone had a lower sensitivity
than ultrasound plus AFP in detecting early (Relative risk 0.88;
95% Confidence Interval, 0.83–0.93) and all (Relative risk 0.81;
95% Confidence Interval, 0.71–0.93) (Tzartzeva et al. 2018).
The authors did note a decrease in specificity with the addition
of AFP to ultrasound (92%, 95%CI 85%–96% vs. 84%, 95%CI
77%–89%).
Due to the limited evidence and clear clinical benefit seen
from these studies, both the European Association for the
Study of the Liver (EASL) and the American Association for
the Study of Liver Diseases (AASLD) remain equivocal on the
role of AFP in surveillance, and do not actively endorse its use
in six monthly HCC surveillance of liver cirrhosis patients
(Galle et al. 2018; Julie K Heimbach et al. 2018).
Prognosis of Hepatocellular Carcinoma
AFP has a significant role in prognostication in HCC. Elevated
levels of AFP are associated with poor prognosis (Ikai et al.
2004; Tangkijvanich et al. 2000). Serum AFP is predictive of
clinical response to various HCC treatment modalities. In liver
transplant, it has a high utility in predicting cancer recurrence
and post-transplant survival (Ikai et al. 2004; Zheng et al. 2008).
In a large study of 12,118 patients, five-year post-transplant
survival reduced from 61.5% to 41.5% for serum AFP values
greater than 200 ng/mL compared to less than 20 ng/mL (Ikai
et al. 2004). Multiple studies have shown values greater than
400 ng/mL is associated with significantly higher recurrence
rates (Kwon et al. 2007; Toso et al. 2015; Zheng et al. 2008).
Furthermore, reduction in AFP levels prior to liver transplant
improves post-transplant survival (Merani et al. 2011; Ravaioli
et al. 2008). As AFP demonstrates a clear predictive role in
transplant outcomes, several transplant criteria models have
incorporated its use. The AFP-French (Duvoux et al. 2012),
Hangzhou criteria (Zheng et al. 2008) and Seoul criteria (Hong
et al. 2016) all use serum AFP in the selection criteria for transplantation. However currently the EASL and AASLD society
guidelines do not incorporate it’s use in transplantation selection (Galle et al. 2018; Heimbach et al. 2018). AFP also predicts
prognosis in non-transplant therapy. Elevated AFP is associated with increased recurrence and reduced survival in patients
undergoing radiofrequency ablation (N’Kontchou et al. 2009),
transcatheter arterial chemo-embolization (Takayasu et al.
2012), and systemic chemotherapy (Ando et al. 2020; Hong
et al. 2021). Changes in AFP post-systemic therapy can demonstrate favorable outcomes (Kodama et al. 2019; Nakazawa et al.
2013) and early data suggests a reduction in serum levels correlates to immunotherapy response (Kuzuya et al. 2022; Sun et al.
2021). The REACH study demonstrated serum AFP levels can
inform treatment decisions. Second-line use of ramucirumab
showed significant survival benefit in patients with serum AFP
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greater than 400 ng/mL but was ineffective in patients with
levels below this (Zhu et al. 2015). Subsequently a dedicated
phase III trial of patients with AFP greater than 400 ng/mL
demonstrated ramucirumab significantly improved overall
survival and disease control rate (Zhu et al. 2019). This was the
first study to implement HCC treatment based on biomarker
levels.
Serum Protein Biomarkers
In addition to AFP, other serum protein biomarkers for HCC
have been studied. The lens culinaris agglutinin-reactive glycosylated isoform of AFP, AFP-L3, has been used as a biomarker
for early detection of HCC. AFP-L3 shows a higher specificity
for HCC tissue compared to AFP and percentage fraction of
AFP-L3 can be used to distinguish tumor diagnosis from
underlying liver disease (Kumada et al. 2011). However, despite
a high specificity, it has a low sensitivity, and AFP has shown a
superior diagnostic performance than AFP-L3 fraction in
detecting early HCC in cirrhosis (Kim et al. 2019; Marrero et al.
2009). Furthermore performance of the AFP-L3 assay is technically limited, with imprecise measurements seen at low (<10
ng/mL) and high (>400 ng/mL) AFP levels (Yamamoto et al.
2010). Addition of ALP-L3 to AFP has been showed to improve
diagnostic performance for early stage HCC (Choi et al. 2019),
but robust prospective validation still remains lacking. Desgamma-carboxy prothrombin (DCP), (also known as prothrombin induced by vitamin K absence II (PIVKA-II)), is an
aberrant protein caused by defect in vitamin K uptake in hepatocytes undergoing malignant transformation (Durazo et al.
2008). Elevated DCP levels are also seen with vitamin K deficiency, and coumarin anticoagulants (Deyashiki et al. 1989).
DCP has high specificity (81–98%) but poor sensitivity (34–
62%) for detection of early-stage HCC (Tsai et al. 1990). Similar
to AFP-L3, there is a lack of high-quality prospective evidence
to advocate its use as a biomarker on its own. However,
combination of these serum biomarkers has been used in predictive clinical models. The GALAD score combines gender
and age with the three protein biomarkers AFP, AFP-L3 and
DCP to predict early HCC (Johnson et al. 2014). This integrated
scoring system has shown a high sensitivity and specificity in
detecting early stage HCC less than 3 cm in size (Berhane et al.
2016). Furthermore, it has shown utility in early detection of
HCC in non-alcoholic steatohepatitis (NASH) (Best et al. 2020)
cohorts, and combination with ultrasound (GALADUS) shows
superior diagnostic accuracy compared to ultrasound alone
(Yang et al. 2019). Future prospective multi-center studies will
validate these promising findings in HCC surveillance. Other
serum protein biomarkers including osteopontin (Sun et al.
2018), midkine (Vongsuvanh et al. 2016) and Dikkopf-1 (Jang
et al. 2016) have all been studied in early detection of HCC, but
lack longitudinal validation for routine use in clinical practice.
Genomic Biomarkers
HCC carcinogenesis is characterized by genetic DNA mutations, with epigenetic modification. Mutations seen in HCC
cells can also be detected in serum and/or urine samples of
patients, raising the potential for biomarker use. Genetic mutation of the TERT promoter is present in up to 60% of HCC
cases (Nault et al. 2013) and is present in up to 47% of serum of
patients with HCC (Jiao et al. 2018). Aberrant expression of
miRNAs also plays a key role in carcinogenesis and have been
studied as potential biomarkers for HCC. miRNA-21 and
miRNA-199a are elevated in HCC patients (Zhang et al. 2017)
and may have utility in early detection of HCC, though larger
longitudinal validation is needed.
Prevention
Liver cirrhosis remains the greatest risk factor for HCC, present
in up to 90% of cases (Forner et al. 2012). Primary prevention
of HCC is achieved through treatment of chronic liver diseases,
and prevention of progression of fibrosis. Chronic viral
hepatitis remains the greatest risk factor for HCC worldwide
(Akinyemiju et al. 2017). In the west, increasing rates of nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver
disease (ArLD) represent growing risk factors for HCC. Genetic
and autoimmune causes of chronic liver disease represent a
smaller, but preventable group of HCC risk factors. This section will outline the main treatment strategies to prevent HCC
for these different etiologies of liver disease.
Chronic Viral Hepatitis
Chronic viral Hepatitis B (HBV) and C (HCV) represent the
largest risk factors for HCC worldwide (Akinyemiju et al.
2017). Vaccination represents the main tool for primary prevention against HBV and reduces HCC incidence. Vertical
transmission through pregnancy and childbirth represents the
significant risk factor for development of chronic HBV, with a
risk of over 90% in children infected under the age of one
year(Stevens et al. 1975). Childhood vaccine has been essential
in reducing chronic HBV infections (Liang et al. 2009; Ott et al.
2012), and has reduced HCC incidence in over 80% of cases
(Chang et al. 1997, 2016; Chiang et al. 2013). The World Health
Organization (WHO) advocates vaccination for Hepatitis B in
all new-borns, with the aim of reducing childhood prevalence
of HBV to 0.1% by 2030 (World Health Organization (WHO)
2016), though implementation varies between countries globally (Muhoza et al. 2021). In those with chronic HBV, high viral
load is a risk factor for HCC, in addition to presence of underlying liver fibrosis (Chen et al. 2006). Anti-viral treatment is
associated with a reduced incidence of HCC (Singal et al. 2013;
Wang et al. 2017) and there is a low threshold to start treatment
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with antiviral therapy agents including tenofovir and entecavir
for patients with evidence of high HBV viral load, liver inflammation, or previous family history of HCC (Galle et al. 2018).
For HCV there is no clinically available vaccine. However,
reduction risk factors for blood-borne viral transmission
should be implemented. This includes viral screening of all
donor blood products (Roth et al. 2002) and implementation of
safe needle-exchange programs for intravenous drug users
(Kåberg et al. 2020). Treatment of chronic HCV has been revolutionized by direct acting agents (DAAs). Protease inhibitors
have been shown to achieve a sustained virological response
(SVR) of up to 90% for the majority of HCV genotypes (FaladeNwulia et al. 2017; Pawlotsky 2014). There is limited data to
suggested DAA associated SVR is associated with reduce incidence of HCC (Ioannou et al. 2018), though post-treatment
cancer surveillance is required in patients with underlying cirrhosis (Roche et al. 2018).
Non-Alcoholic Fatty Liver Disease
(NAFLD)
The rising rates of obesity worldwide has been associated with
increased rates of NAFLD (Fan et al. 2017; Younossi et al. 2016)
and NAFLD-related HCC (Dyson et al. 2014; Wong et al. 2014).
Non-alcoholic steatohepatitis (NASH) can cause HCC in the
absence of cirrhosis in 15–63% of cases (Kanwal et al. 2018;
Pais et al. 2017; Pinyopornpanish et al. 2021; Piscaglia et al.
2016). Lifestyle and medical treatment of underlying NASH
and NAFLD is therefore important for HCC prevention.
Healthy lifestyle factors, including normal body mass index
and a Mediterranean diet, are associated with a lower risk of
HCC (Luu et al. 2021). Furthermore, increased physical activity
(Baumeister et al. 2019) and weight reduction have shown suggestive negative associations with HCC (Kwak et al. 2020).
Several population studies have demonstrated medical therapy
with metformin is associated with a reduction in HCC (Singh
et al. 2013; Zhang et al. 2012), though prospective randomized
controlled trials are lacking. Similarly, statins have also been
associated with a lower risk of HCC (Facciorusso et al. 2020;
Islam et al. 2020), with prospective randomized clinical trials
ongoing (Lange et al. 2021). Newer NASH targeted therapies,
including vitamin E (Abdel-Maboud et al. 2020) and obeticholic acid (Ratziu et al. 2019) may represent potential mechanisms for reducing future risk of HCC.
Alcohol-related Liver Disease (ArLD)
and Other Chronic Liver Diseases
ArLD remains a significant preventable risk factor for HCC
(Donato et al. 2002). Due to limited medical therapy, preventative therapy relies on reduction in high-risk intake of alcohol
and requires psychological and sociological strategies at small
and large community levels. Public health strategies including
alcohol taxation and increased pricing policies can reduce the
burden of ArLD, but vary greatly different countries (VenturaCots et al. 2019). Medical therapies for autoimmune liver diseases such as autoimmune hepatitis (Choi and Choi et al. 2019;
Vaz et al. 2020) and primary biliary cirrhosis (Kuiper et al.
2010; Trivedi et al. 2016) are important for reducing inflammation, progression to cirrhosis, and HCC. Similarly, management
of genetic conditions including hereditary haemochromatosis
and Wilson’s disease can reduce risk of progression of cirrhosis
and HCC (Elmberg et al. 2003; Reyes 2008). Venesection, iron
chelation and genetic screening of relatives are all effective
treatment strategies in haemochromatosis (Niederau et al.
1996).
Aspirin
The chemopreventative role of aspirin has been studied in
multiple cancers. Through cyclooxygenase-1 (COX-1) and -2
(COX-2) inhibition, aspirin exhibits antiplatelet and
anti-inflammatory effects, mediating cancer prevention.
A recent meta-analysis of all observational studies on aspirin
for the prevention of digestive tract cancers estimated the
pooled relative risk (RR) of cancer for regular aspirin use
versus non-use using random effects models (Bosetti et al.
2020). In this study, regular aspirin use was associated with a
reduced risk of colorectal cancer (RR 0.73, 95% CI 0.69–0.78,
45 studies), squamous-cell esophageal cancer (RR 0.67, 95%
CI 0.57–0.79, 13 studies), adenocarcinoma of the esophagus
and gastric cardia (RR 0.61, 95% CI 0.49 – 0.77, 10 studies),
stomach cancer (RR 0.64, 95% CI 0.51–0.82, 14 studies), hepato-biliary tract cancer (RR 0.62, 95% CI 0.440–0.86, five
studies), and pancreatic cancer (RR 0.78, 95% CI 0.68–0.89,
15 studies).While the strongest evidence for cancer prevention is seen in colorectal cancer (Burn et al. 2020; Ishikawa
et al. 2021), there is growing evidence for aspirin’s role in prevention of HCC in both general and high-risk populations.
Long-term data from the Nurses’ Health Study (Simon et al.
2018) and the National Cohort Study of Korean Adults
(Hwang et al. 2018) demonstrate aspirin reduced HCC risk
in patients with and without underlying liver disease. Aspirin
use in patients with HBV is associated with a reduction in
HCC incidence of 29–56% in Korean and Taiwanese populations (Lee et al. 2017, 2019). Similar risk reduction with lowdose aspirin use was seen in patients with chronic HCV (Lee
et al. 2020; Liao et al. 2020; Simon et al. 2020) and alcohol
associated liver disease (Shin et al. 2020). Aspirin use can
reduce the progression to fibrosis in NAFLD (Simon et al.
2019) and has been associated with up to a 50% reduction in
HCC in prospective population studies (Simon et al. 2018).
The biological plausibility of aspirin reducing the risk of hepatobiliary cancer, in parallel to the published epidemiological
16 SCREENING, SURVEILLANCE, AND PREVENTION OF HEPATOCELLULAR CARCINOMA 283
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data, has been extensively reviewed and includes its ability
to: inhibit COX-2 in dysplastic tissue (which promotes
inflammation and cell proliferation), inhibit activation of
nuclear factor kB, prevent platelet aggregation (which may
slow metastatic spread), modulate Wnt signaling via both
COX-dependent and COX-independent pathways, upregulate tumor suppressor genes and stabilize DNA mismatchrepair proteins (Shen and Shen 2021). Though observational
studies show promising outcomes, there is a need for high-
can be used in routine clinical practice. Given the increased
bleeding risk in patients with chronic liver disease, robust
clinical trial data is needed to evaluate the full safety and efficacy profile of aspirin in this cohort.
Key Take Home Messages
• Imaging surveillance of high-risk patients with chronic liver
disease and chronic hepatitis B reduces hepatocellular carcinoma related mortality.
• Arterial enhancement followed by washout during the portal
venous and delayed acquisition phase on computer topography
and magnetic resonance imaging allow for radiological diagnosis of hepatocellular carcinoma without the need for tissue
biopsy.
• Primary prevention of chronic hepatitis B through childhood
vaccination and antiviral therapy for chronic hepatitis B
reduces hepatocellular carcinoma and mortality.
• Alpha-fetoprotein has utility in predicting disease recurrence and survival post liver transplant and is incorporated in
transplant selection criteria.
• Surveillance of hepatocellular carcinoma is less than 20%, with
better access to secondary care essential for improving rates.
Knowledge Gaps
• The utility of serum biomarkers in hepatocellular carcinoma
surveillance remains unclear. Further high quality randomized
prospective evaluation of biomarkers in combination with
imaging for surveillance is needed.
• The optimal imaging modality for surveillance remains
unclear, with computer topography, magnetic resonance
imaging, ultrasound, and contrast-enhanced ultrasound demonstrating varied clinical and economic advantages. Longer
term head-to-head randomized clinical trials are needed to
determine the optimal surveillance strategies.
• Primary and secondary prevention strategies and therapeutics are needed to tackle the rising incidence of non-alcoholic
fatty liver disease and limit the impact on rates of hepatocellular carcinoma.
• Alpha-fetoprotein demonstrates promise for guiding nontransplant therapeutic selection, but further studies are needed
for its utility in precision medicine.
• “Is chemoprevention possible with aspirin or other
medications?”
Trusted Websites for Further Reading
https://www.mdanderson.org/research/departments-labs-
institutes/spores/hepatocellular-carcinoma-spore/investiga
tors-and-staff.html
https://mayoclinic.pure.elsevier.com/en/publications/preven
tion-of-hepatocellular-carcinoma-progress-and-chal lenges
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