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Figure 2 Adenocarcinoma of ductus choledochus, H&E
Ax0,2, Bx3,1.
the microscopic precursor lesion whereas the cell of origin
for small duct type iCCA is still debated. The distinction between large duct and small duct type iCCA may be challenging especially in tumors with mixed histology, in poorly
differentiated tumors or in small biopsies. This requires
additional immunohistochemical stainings and/or genetic
tests proving the biliary origin of the tumor and differentiating between subtypes of iCCA. There are several common
markers in biliary tree originated cancers including CK7,
CK19, EMA (MUC1) but neither of them is entirely specific
and should be always interpreted with histology. For establishing the diagnosis of small duct type iCCA the panel of
N-cadherin, CD56 CRP and tubulin-beta3 (TUBB3) markers
can be performed while S100P expression is supposed to be
more specific for large duct type iCCA.
The genetic milieu of intrahepatic carcinoma may be subclassified into inflammation subtype with morphological
cholangiolar differentiation and activation of inflammatory
pathways that is, IL10 and IL6 overexpression and STAT3
activation and proliferation subtype with moderate/poor
histological differentiation, chromosomal instability, and
activation of oncogenes like RAS, MAPK, c-MET, BRAF and
KRAS (Graham etal. 2014). It is in up to 40% cases of iCCAs
that the main driver mutation can be determined (Braconi
etal. 2019). Analyzing the molecular profile of iCCAs there
are also significant differences between the subtypes. In
large duct type iCCA the gene mutations are similar to more
distal and pancreatic lesions with KRAS, SMAD4, MDM2,
ERBB2, and TP53 mutations or amplifications. The small
duct type iCCA hosts different and more specific list of
molecular changes including IDH1/IDH2, ARID1A BAP1,
and BRAF mutations and FGFR2 fusion which seems to be
reserved to this subtype only (Akita etal. 2017; Saha etal.
2014). This warrants the rapidly evolving area of precisely
directed antitumor treatment. The FGFR2 gene fusion is
present in 10–20% of CCA and FGFR2 alterations can be
detected by NGS, FISH or immunohistochemical methods
(Maruki etal. 2021) for the selection of patients who might
respond to FGFR competitive inhibitor. Similarly, frequent
IDH1/2 mutated iCCAs may respond to specific inhibitor
therapy and the status of the tumor can be determined by
NGS. (Abou-Alfa etal. 2020).
It is to be underlined that histologic diagnosis of iCCA might
be difficult in terms of differentiation with other adenocarcinomas metastasizing to the liver. As mentioned earlier, there is
no specific immunohistochemical marker for iCCA and the
metastatic tumors of certain origin may also produce rich
fibrotic stroma and be neuroinvasive. The wide panel of IHC
for exclusion should be then performed as proposed for cancer
of unknown primary (CUP) (Fizazi etal. 2015). The thorough
morphomolecular analysis methods though have shifted substantial number of cases from CUP to iCCA based on the
specific genetic driver change.
The microscopic diagnosis of pCCAs and dCCAs is especially challenging due to shortage of material. Histologically
these tumors are composed of blunt, often well differentiated
cancer glands with sometimes minimal atypia and abundant
cytoplasm. Cancer cells are embedded in rich fibrotic stroma
and the type of growth may be mass forming or locally narrowing the bile ducts (Figure 2). The acquisition of histological
material is sometimes impossible so the diagnoses must rely on
cytology acquired during ERCP or EUS procedures.
Conventional cytology is highly specific (97%) but has the sensitivity of only 43%. The specimens are often inadequate since
CCAs are desmoplastic and paucicellular. The diagnostic
performance may be improved by using additional methods on
cytology material to prove neoplastic nature of the cells. FISH
analyses to confirm the chromosomal instability (aneusomy or
polysomy), NGS panels for driver mutations detection or miRNAs detection also in bile fluid (Rizvi etal. 2017).
15 Pathology, Molecular Pathology, and genoMics of hePatobiliary and Pancreatic cancer 267
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Ductal Adenocarcinoma of Pancreas
Morphologically ductal adenocarcinoma is characterized by
the formation of well or moderately differentiated glandular
structures with luminar or intracellular mucin infiltrating
pancreatic parenchyma and evoking strong desmoplastic reaction and production of rich fibrotic stroma (Figure 3). The
amount of stroma, number of cancer associated fibroblasts,
myofibroblasts, vessels, and inflammatory cells (lymphocytes
and macrophages) may quite often be higher than neoplastic
epithelial component. In well-differentiated adenocarcinomas
the glands may be angular, branching, ruptured with multilayered epithelium and cribriform pattern while in moderately
differentiated cases the tumor is more heterogenous and the
well-differentiated component is intermixed with cribriform,
papillary, micropapillary, and gyriform forming patterns as
well as with the foci of more pleomorphic cells which takes
place usually at the margin of the tumor. The cancer cells are
cuboidal or columnar with round or ovoid nuclei. The nucleoli
are inconspicuous, and the mitotic figures are rare. The cytoplasm is eosinophilic, foamy, or clear. Well-differentiated ductal
adenocarcinoma is sometimes extremely difficult to distinguish from nonneoplastic ducts and the tumor specific histological features are of value in making microscopic diagnosis.
Perineural invasion is quite specific for ductal adenocarcinoma
as is lymphatic and vascular invasion (Figure 4). The neoplastic
epithelium may completely replace the endothelium of the vein
which resemble and may be mistaken for pancreatic intraepithelial neoplasia (PanIN). For highly suggestive of neoplastic
nature should be treated the presence of isolated (naked ducts)
glands in fatty tissue or in proximity of muscular arteries and
unaccompanied vessels within or at the periphery of the lesion.
Sometimes the neoplastic glands invade nonneoplastic acini or
are intermingled with the remnants of islets or single islets cells
(cancerization of the acini). The poorly differentiated ductal
adenocarcinoma contains abundant sheets of solid or trabecular and cribriform neoplastic cells as well as individual cancer
cells immersed in more loosely structured stroma (Shlitter etal.
Figure 3 Ductal adenocarcinoma of the pancreas – classical type,
H&E x1,3.
Figure 4 Adenocarcinoma of the pancreas – neuroinvasion, H&E x10.
2017). The production of the mucus is decreased, the cells are
evidently pleomorphic with numerous mitoses and focal
squamous or spindle cell metaplasia.
The common immunohistochemical markers of ductal adenocarcinoma include CK7, CK8/18, CK19, CEA, Ca 19–9,
EMA (MUC1), and MUC5AC but neither of them is sufficiently specific and sensitive for unequivocal confirmation
and/or differentiation of ductal adenocarcinoma from other
mucin producing adenocarcinomas particularly from bile
ducts and the stomach. Ductal adenocarcinoma is usually negative for vimentin (expect for undifferentiated carcinoma),
neuroendocrine markers (chromogranin A and synaptophysin) and acinar markers (BCL10, trypsin). The loss of nuclear
expression of SMAD4(DPC4) and p16(CDKN2A) or the loss/
gain of p53 expression can be observed in 55%, 75%, and
75–80% of cases respectively (Shiltter et al. 2017), which
include the most prevalent mutations in ductal adenocarcinoma along with KRAS mutation. In addition, the ongoing
studies on PDAC have divided this tumor molecularly into
classical and basal-like types oncogenic pathways both with
activated or normal stroma. Within the subtypes (squamous,
ADEX, pancreatic progenitor, and immunogenic) there are
lesions with different histology, prognosis, and potential
therapeutic approach) (Bailey etal. 2016; Collisson etal. 2019).
There are several morphological patterns and histological
subtypes of ductal adenocarcinoma that can be distinguished
microscopically, differ immunohistochemically and molecularly, have different prognosis, and may require different therapeutical approach.
Morphological patterns:
1
Large duct pattern – neoplastic duct measure >0.5mm and are
very well differentiated and blunt and have to be differentiated
form intraductal papillary mucionous neoplasm (IPMN)
(Kosmahl etal. 2005).
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Ductal adenocarcinoma with foamy gland pattern – neoplastic glands with foamy or vacuolated cytoplasm with basally
located nuclei of gastric like foveolar epithelium type, very well
differentiated, requires differentiation form non neoplastic epithelium (Dursun etal. 2010).
2 Histological subtypes:
Adenosquamous carcinoma – ductal carcinoma with
squamous differentiation recognized when the squamous component exceeds 30% of the tumor (Borazanci etal. 2015). The
squamous part of the tumor should display squamous epithelium markers (p63, p40) and these tumors almost universally
harbor KRAS mutations in codon 12 (367), TP53,
p16(CDKN2A) and SMAD4 mutations. They belong to the
basal-like genomic subtype of ductal adenocarcinoma and warrants worse prognosis (Bailey etal. 2016) (Figure 5).
Colloid carcinoma – consist of neoplastic epithelium
suspended in extracellular mucin pools. This lesion arises from
intestinal type IPMN and the cells express intestinal markers
(CDX2 and MUC2). Colloid carcinoma is supposed to have
better prognosis than common type PDAC.
Medullary carcinoma – is characterized by the syncytial growth
of epithelial cells with occasional glandular formations which are
intermixed and surrounded by dense lymphocytic infiltrate
(tumor infiltrating lymphocytes – TILs).(Wilentz etal. 2000). The
tumor has usually pushing border type periphery with no distinct
invasive nature (1816). On molecular ground medullary carcinoma is often microsatellite instable and the patients may potentially benefit form immunotherapy (Le etal. 2015).
Invasive micropapillary carcinoma – in which >50% of the
tumor is formed by the nests of cells suspended in small lacunae
and the orientation of the epithelial cells is inversed, the neutrophilic infiltrate in epithelial cells is also the feature of this
subtype (WHO 2019). This is an aggressive subtype of the
PDAC with worse prognosis.
Undifferentiated carcinoma – when the tumor cells proliferative without forming any recognizable glandular structures,
the cells are discohesive and the stroma is sparse (Strobel etal.
2011). The tumor cells express at least focally cytokeratin which
proves their epithelial nature and vimentin (which is not a feature of PDAC) (Paal etal. 2001) but the presence of intercellular adhesion marker E-cadherin is typically negative. This
subtype is highly aggressive.
Undifferentiated carcinoma with osteoclast-like giant cells –
the special subtype of PDAC where atypical and poorly differentiated epithelial component is accompanied by a mononuclear
histocytic component and nonneoplastic osteoclast-like multinucleated giant cells (Muraki etal. 2016).
The other extremely rare histological subtypes of PDAC
include: hepatoid carcinoma, signet-ring cell (poorly cohesive
cell) carcinoma, choriocarcinoma, clear cell carcinoma, oncocytic carcinoma (WHO 2019).
Acinic Cells Carcinoma of the Pancreas
Histologically these tumors are formed by proliferation of
monotonous neoplastic acinar cells accompanied by scant
fibrous stroma and the foci of necrosis. Nuclei are uniform with
single nucleolus and the cytoplasm is abundant, granular, and
contain PASD positive granules. The architectural patterns
include acinar, glandular, trabecular, and solid proliferations
and the squamoid features are absent (La Rosa etal. 2012). In
well-differentiated cases acinic cell carcinoma resembles
normal nonneoplastic acini and the absence of pancreatic duct
and the islets is then the helpful diagnostic element.
Immunohistochemically acinic cell carcinoma expresses
trypsin, chymotrypsin and BCL10 which performed together is
sensitive enough for the diagnosis. Acinic cell carcinoma has to
be differentiated form neuroendocrine tumors and pancreatoblastoma, particularly in the face of fact that acinic cell carcinoma is the most common type of pancreatic carcinoma in
children (La Rosa etal. 2015).
Acinic cell carcinoma differs molecularly form PDAC and
usually lack the most common mutations of KRAS, SMAD4
and CDKN2A found in PDAC. The tumor shows chromosomal
instability with high TMB and low levels of methylation. No
genetic alteration may be considered typical of acinic cell carcinoma and the genetic mutations described in acinic cell carcinoma include: MYC, APC, and CTNNB1 and TP53 (Klimstra
etal. 2016).
Figure 5 Adenosquamous carcinoma of the pancreas H&E x10.
Genomics of Hepatic and Pancreatic Cancer
Hepatic cancer is probably best studied. The commonest cause
world-wide is due to viral infection and a recent large series of
whole genome structural variant analysis STVs has been conducted. The oncogenic changes are found in both coding and
15 Pathology, Molecular Pathology, and genoMics of hePatobiliary and Pancreatic cancer 269
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non-coding regions of the genome. In particular, a significant
association with replication timing and identified known
(CDKN2A, CCND1, APC, and TERT) and new (ASH1L,
NCOR1, and MACROD2) cancer-related genes that were
recurrently affected by STVs, leading to altered expression.
These comprehensive and complex changes indicate the difficulty of identifying and therapeutically abrogating potential
driver mutations (Fujimoto A 2016).
In pancreatic carcinoma over 30 recurrently mutated
genes were identified. However, in signaling/functional in
silico analyses these could be aggregated into 10 pathways:
KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signaling,
G1/S transition, SWI-SNF, chromatin modification, DNA
repair and RNA processing. Furthermore, expression analysis defined four subtypes: (1) squamous; (2) pancreatic
progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological and molecular pathological characteristics
(Bailey P 2016).
Key Take Home Messages
• The diagnosis of hepatocellular, cholangio-cellular and
pancreatic carcinomas is based on histology and/or cytology.
• This diagnosis has to be made in the context of clinical data
and with the results of immunohistochemical and molecular
studies.
• It is to be underlined that there are no specific markers
pathognomonic for cancers arising in these areas.
• The morphomolecular subtypes selection is vital for recruiting patients amenable to personalized anticancer treatment.
• The prognosis of hepatocellular cancer and ductal adenocarcinoma of the pancreas, aside from staging, can be fine-tuned
by detailed pathology and molecular pathology
sub-classification.
Areas for Further Research
• Methods of harvesting tissue material for cancer diagnosis
specially in pCCAs and dCCAs
• Identification of more specific immunohistochemical
markers for hepatic, biliary tracts and pancreatic cancers diagnosis and differentiation
• Further studies on molecular subtypes to fully cover the
whole morphological spectrum of the lesions
• Individualization of treatment in patients with hepatic, biliary tracts, and pancreatic cancers based on detailed morphomolecular diagnosis
• The genomics of those most likely to develop hepatocellular
cancer.
Trusted Websites for Further Reading
• College of American pathologists https://www.cap.org/
member-resources/pathology-case-challenge/liver-4
• Pubmed https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC2020752
• WHO https://www.who.int/health-topics/cancer#tab=tab_1
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16 Screening, Surveillance, and Prevention
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of Hepatocellular Carcinoma
Lauren J. McEneaney, Mathew Vithayathil & Shahid Khan
St. Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK
Introduction
Hepatobiliary cancer refers to any malignancy affecting the
liver, bile ducts, or gall bladder. HCC is the most common form
of primary liver cancer and poses a significant global health
issue. According to the World Health Organisation (WHO), at
present it is the fifth-most commonly diagnosed cancer and
fourth-leading cause of cancer-related mortality worldwide
(Bray et al. 2018). These cancers are associated with a high
mortality, as patients are often asymptomatic until late in the
disease pathogenesis whereby curative treatments are no longer
an option. In this chapter we will be focusing specifically on the
screening, surveillance, and prevention of Hepatocellular
Carcinoma (HCC).
Risk Factors
The majority of HCC cases will occur in individuals with
established risk factors for chronic liver disease, these factors
include but are not exclusive to non-alcoholic fatty liver disease (NAFLD), heavy alcohol consumption, chronic viral
hepatitis (specifically hepatitis B and C viruses), haemachromatosis and rarer causes such as inborn errors of metabolism
or specific autoimmune diseases(Akinyemiju et al. 2017;
El-Serag and Rudolph 2007) (see Table 1 for summary). The
risk factors for development of HCC are also risk factors for
liver cirrhosis, which is estimated to be present in 90% of
patients diagnosed with HCC in the Western World (Llovet
et al. 2021). For this reason, it is not cost-effective or indeed
necessary for a national screening program to take place in the
general population. However, current expert society guidance
recommends regular surveillance for patients with established
risk factors for HCC (Foerster and Galle 2019) and those with
underlying liver cirrhosis.
Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach,
Second Edition. Edited by Janusz A. Z. Jankowski.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
Liver Cirrhosis and Relationship to HCC
Cirrhosis is defined as chronic liver disease characterized by
diffuse fibrous changes and progressive disruption to normal
liver architecture which results in portal hypertension, synthetic
dysfunction, and ultimately liver failure (Ginés et al. 1987). It is
a complex cascade of molecular, cellular, and structural changes
which accumulate over time and predispose to the malignant
transformation of hepatocytes. Liver cirrhosis is associated
with a chronic inflammatory state, this is a result of the release
of endogenous damage-associated molecular patterns
(DAMPs) when the extracellular matrix of hepatocytes is
broken down following repeated exposure to insults (Kono and
Rock 2008). Cirrhosis is also strongly associated with multiorgan failure and can lead to coexisting kidney failure, coagulopathy, brain dysfunction, as well as circulatory collapse,
immunosuppression, and disruption of the intestinal microbiome (Arroyo et al. 2016). There are a number of classification
systems used to grade the severity of liver cirrhosis, for example
the Child-Pugh Classification System and the Model for EndStage Liver Disease (MELD) score. Universally, Child-Pugh
Classification is the most commonly used to define the severity
of liver dysfunction and associated prognosis, it uses a number
of variables including values of bilirubin, prothrombin time,
and albumin, in addition to the presence of encephalopathy
and ascites (Angermayr et al. 2003; Cooper et al. 1997). ChildPugh C carries the worst prognosis with a less than <50% one
year survival rate, this is statistically worse than many cancers
(D’Amico et al. 2006).
While the majority of patients who develop HCC will have
underlying liver cirrhosis, it is worth noting that HCC can
develop in the absence of underlying cirrhosis in various circumstances. For example, the Hepatitis B Virus is a double
stranded DNA virus that directly alters hepatocyte DNA
(Iannacone and Guidotti 2022) by integrating into the host
genome. The process of integration can lead to genetic mutations which can result in either oncogene activation and/or
deactivation of tumor suppressor genes (Yuen et al. 2018).
Disruption to these genes can lead to malignant transformation
271
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Table 1 A summary of the major risk factors for the development of
Hepatocellular Carcinoma.
Infectious Chronic Hepatitis B (HBV) infection
Chronic Hepatitis C (HCV) infection
HIV
Liver Flukes
Toxins Alcohol
Aflatoxins
Drug-induced liver injury (DILI)
Autoimmune Autoimmune hepatitis (AI)
Primary biliary sclerosis
Primary sclerosing cholangitis
Metabolic syndrome
Inborn errors of metabolism
Congenital
Table adapted from Chidambaranathan-Reghupaty et al. (2021).
Non-alcoholic fatty liver disease
(NAFLD)
Diabetes, hyperlipidemia, obesity
Hereditary haemochromatosis
Wilson’s disease
Alpha-1-antitrypsin deficiency
Biliary atresia
Congenital hepatic fibrosis
of cells in the absence of cirrhosis and it is for this reason that
HCC surveillance is recommended for patients with chronic
Hepatitis B Virus, even those with normal liver architecture
(Anugwom et al. 2021).
Pathogenesis of Hepatocellular Carcinoma
(HCC)
HCC is, by nature, a highly heterogeneous malignancy with
molecular patterns that vary patient to patient. It is this variation that makes HCC difficult to target with systemic therapies;
there is a distinct lack of a common molecular target.
Notwithstanding, the use of next-generation genomic
sequencing has identified a number of key mutations which are
central to HCC tumorigenesis. Approximately ~140 genes have
been identified to promote malignant transformation of cells in
any cancer, with a typical tumor containing between 2–8 of
these “driver” mutations which confer a selective growth
advantage, while the remaining mutations are neutral passengers that are neither favorable or unfavorable to carcinogenesis
(Vogelstein et al. 2013). Genetic risk factors and events involved
in HCC carcinogenesis can broadly arise in three ways: inherited genetic variants, acquired somatic mutations, and
integration of viral DNA into the host genome (Caruso et al.
2021) (Figure 1).
Susceptibility to HCC is multifactorial, involving both ge-
netic and environmental factors. There are a number inherited single-nucleotide polymorphisms (SNPs) which affect
the predisposition to risk factors associated and severity of
liver disease. SNPs refer to DNA sequence modification
caused by variation in a single nucleotide; many SNPs occur
within a non-coding stretch of DNA material, they can
modify gene-product expression and associated function if
they occur within coding DNA (Nahon and Zucman-Rossi
2012). SNPs generally account for ~90% of allelic variation
within the human population (Andreassen et al. 2002); this
contributes to how individuals are differently affected by
disease.
A number of genetic polymorphisms have been shown to
increase the incidence and severity of NAFLD. The PNPLA3
gene is expressed in liver and adipose tissue, it is thought to
play a role in lipolysis and triglyceride hydrolysis (Hassan et al.
2013). Certain alleles of PNPLA3 have been shown promote triglyceride accumulation within hepatocytes and subsequently
increase the risk of NAFLD, particularly in patients with high
chronic alcohol intake (Romeo et al. 2008). Interestingly, the
toxicity of the carcinogen Aflatoxin B1 has been shown to be
potentiated by HBV infection, particularly in individuals who
carry a null polymorphism in GSTT1 (Wang et al. 2010).
Functionally, GST encodes Glutathione-S-transferases which
are involved in the detoxification of substances through the
process of conjugation. A small number of individuals are able
to constitutionally clear themselves of HCV infection without
any treatment. A number of pivotal GWAS studies linked a
particular SNP located in the Interleukin-28B (IL-28B) gene to
a much higher probability of natural clearance of HCV by the
host (Rauch et al. 2010; Thomas et al. 2009). The ability to clear
HCV reduces the chance of chronic inflammation and cirrhosis, which in turn reduces the likelihood of going on to
develop HCC.
Somatic mutations are acquired during a lifetime; certain
mutations can result in aberrant disruption of downstream
molecular pathways and play a key role in HCC carcinogenesis. Telomerase is activated in over 80% of HCCs, this occurs
through various different mechanisms including TERT promoter mutations, viral DNA insertions or chromosome translocation (Guichard et al. 2012). The most frequent site of HBV
DNA insertion and mutagenesis involves the TERT promoter
region, the subsequent over expression of telomerase results in
maintenance of telomere length. These lengthened telomeres
protect hepatocytes from cellular senescence and promote
ongoing replication (Nault et al. 2019). Other dysregulated
pathways include the beta-catenin/Wnt pathway which promotes HCC stem cell features and prevents apoptosis of malignant cells, this occurs in approximately 50% of HCCs
(Guichard et al. 2012).
Receptor-Tyrosine Kinase (RTK) pathways have also been
implicated in the development of HCC as with many other
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Figure 1 Diagram demonstrating three distinct genetic mechanisms involved in HCC Carcinogenesis. Abbreviations: HBV, hepatitis B virus; HCC,
hepatocellular carcinoma; HCV, hepatitis C virus; mTOR, mammalian target of rapamycin; RTK, receptor-tyrosine kinase.
cancers. RTKs are a subfamily of different receptors including
vascular endothelial growth factor (VEGF), hepatocyte
growth factor receptor (HGFR), tie 2 and RET (Regad 2015;
Robinson et al. 2000); binding of a ligand to its specific RTK
causes phosphorylation of target proteins involved in downstream signaling pathways (Gotink and Verheul 2010).
Mutations affecting RTK function, genetic amplification,
translocation, or the autocrine activation of RTKs can lead to
downstream aberration of oncogenic pathways which lead to
tumorigenesis, local invasion, and angiogenesis (Sudhesh
Dev et al. 2021). HCC is a highly angiogenic cancer and relies
heavily on the formation of new blood vessels in order to sustain growth (Andrew X Zhu et al. 2011). The net excess secretion of pro-angiogenic cytokines in HCC, such as VGEF,
results in the proliferation and migration of endothelial cells
avoiding alcohol, keeping a healthy BMI, and not partaking in
practices that carry a risk of contracting the Hepatitis B or C
virus, they could effectively reduce their risk of developing this
type of cancer. However, this ignores the complexity of the
factors at play which contribute to humans making choices that
can have negative impact on their health. Lifestyle risk factors
are not unique to HCC, the risk of most cancers increases with
exposure to carcinogens such as smoking in lung cancer and
the Human Papillomavirus (HPV) in cervical cancer (Psyrri
and DiMaio 2008). In a utopian reality we would be able to
empower patients to only make choices that benefit their health
and eliminate exposure to risk factors. This, of course, is an
impossible task and while prevention is better than cure, surveillance is a necessary strategy that aims to reduce the mor-
bidity and mortality associated with HCC.
which form cord precursors to blood vessels (Dvorak 2002).
Arterialization of HCC, compared to the vascularization of
surrounding non-malignant liver parenchyma, can be
exploited for diagnosis and treatment; this will be discussed
in more detail later in the chapter.
Environmental risk factors for HCC are largely avoidable, if
the population were able to maintain a healthy lifestyle by
Surveillance
Surveillance is the systematic and ongoing process used to
monitor a disease condition in patients deemed to be at higher
risk (Pelletier et al. 2005). This differs from screening which is
the active search for disease amongst a seemingly healthy
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population (Oleske 2009). In relation to HCC, surveillance is
the more appropriate terminology to use as the process takes
place in patients who high risk for HCC development due to
the presence of established risk factors.
The ideal surveillance program for any type of cancer should
be minimally invasive, highly sensitive, specific, inexpensive,
and easy to implement in a clinical setting (Fitzmorris and
Singal 2015) with the aim of identifying cancer early to give the
best possible chance of cure. In relation to HCC, early detection
makes it more likely that the cancer will be amenable to potentially curative treatments such as radiofrequency or microwave
ablation, surgical resection, or liver transplantation (Kanwal
and Amit G Singal 2019). Surveillance methods and strategies
for HCC have long been a subject of debate, in this section of
the chapter we will give an overview and discuss the evidence
base for current practice and future directions.
International guidance has been published to give clinicians
around the world access to the best evidence-based practice so
that they can provide the best possible care for their patients.
There are three main international bodies who have produced
robust guidance on HCC surveillance, these are the European
Association for the Study of the Liver (EASL), American
Associated for the Study of Liver Diseases (AASLD) and the
Asian Pacific Association for Study of the Liver (APASL)
(Foerster and Galle 2019). We have discussed how HCC has a
much higher incidence in individuals with liver cirrhosis compared to that of the general population, it therefore is logical
that HCC surveillance is focused on this patient cohort. The
annual incidence of HCC in patients with cirrhosis ranges from
1–6% (Trinchet et al. 2015) although this does vary with different underlying etiologies. For patients with viral or autoimmune related cirrhosis the adjusted relative risk of developing
HCC is 2–3 fold compared to alcoholic liver cirrhosis (West
et al. 2017), although the exact reason for this disparity is not
fully understood. The AASLD has produced guidance on this
subject, it states that surveillance should be offered to patients
when their relative risk of HCC exceeds 1.5% per annum based
on cost-effectiveness data (Bruix et al. 2011), interestingly by
these standards surveillance in alcohol related cirrhosis is only
just considered cost-effective.
It is important to consider that certain risk factors for HCC are
more or less prevalent in different populations and this will inevitably have an impact on surveillance programs. Even within the
West there is a big variation in the predominance in these etiological risk factors, for example in North America the HCV epidemic
has been the most common cause of hepatocarcinogenesis
whereas in Central and Eastern Europe, alcohol consumption is
the major player (Singal et al. 2020). Contrastingly, in many countries in South East Asia (with the exception of Japan) HBV associated HCC is far more common in the population compared to
other lifestyle related risk factors (Terrault et al. 2018). This is in
part due to barriers accessing testing and vaccination as well as a
lack of education as to the mode of viral transmission which is
predominantly through sexual contact, injecting drug use, and
also vertical transmission (Wait et al. 2016). Both the East and
West follow the same general consensus on methods of HCC surveillance set out by the international societies; however, they do
adopt different approaches with regards to how these methods are
implemented. For example, in the West the uptake of surveillance
is lower and relies on individual compliance and choice rather
than a nationwide approach. A systematic review of US studies
found that only 20% of eligible individuals underwent HCC surveillance (Singal et al. 2012). Contrastingly, in South East Asian
countries such as Japan, national surveillance programs exist in
part due to endemic nature of HBV/HCV within the population.
As a result, the majority of HCC cases are detected at an early
stage and with an average 45% five-year survival rate (Kudo
2012), which is clearly superior to the average international statistic of 20% five-year survival rate for HCC (Siegel
et al. 2018).
An Introduction to Radiology in the
Surveillance of Hepatocellular
Carcinoma
Radiology currently forms the basis of HCC surveillance.
Current GOLD standard methods recommended in all
guidelines include the use of Ultrasonography (US),
Computed Tomography (CT) and Magnetic Resonance
Imaging (MRI) in the surveillance and diagnosis of HCC
(Foerster and Galle 2019).
Ultrasound (US)
Ultrasound (US), or Ultrasonography, is an imaging modality
that uses high-frequency sounds waves to produce real time
images of structures within the body. It is a very safe, non-invasive and an inexpensive technique which makes it favorable in
the screening and diagnosis of HCC (Harris et al. 2019). These
factors are the reason that US currently forms the backbone of
HCC surveillance; current guidance recommends that patient
with cirrhosis undergo six-monthly check-ups for HCC with
ultrasonography screening (Barbara et al. 1992). Globally, the
consensus of the six-monthly time frame interval is based on
evidence that survival rates are better compared to annual
screening but without inferior outcomes compared to threemonthly testing (Trinchet et al. 2011). There has been a single
randomized controlled trial (RCT) which has evaluated the
outcomes of surveillance vs. no surveillance in 18,816 patients
with Hepatitis B infection in China. The trial looked specifically at the use of liver US and serum alpha-fetoprotein (AFP)
measurements as the means of surveillance and showed a 37%
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reduction in HCC related mortality at five-year follow up in the
surveillance group (Zhang et al. 2004).
The classical US appearance of a small focal HCC is a
hypoechoic nodule when compared to surrounding liver
architecture. Larger lesions are more likely to be heterogeneous
in appearance as a consequence of inflammation, fatty infiltration, necrosis, and calcification (Venkatesh et al. 2014).
Ultrasound is not used to definitively diagnose HCC but rather
to identify suspicious lesions which will go on to be evaluated
further with contrast CT, MRI, or USS. The majority of lesions
< 1cm are difficult to diagnose and often do not represent HCC
so in this instance cross-sectional imaging is not recommended, rather follow up with repeat ultrasonography in three
months (Marrero et al. 2018). By contrast, guidance suggests
that lesions measuring >1cm in diameter should be further
evaluated with CT or MRI the role of which will be discussed
later in this chapter.
An important factor to consider when evaluating the use of
ultrasound is that the sensitivity is often operator dependent.
The ability to accurately scan and detect a possible HCC lesion
will depend heavily on the experience and skill set of the
individual performing the scan, this can vary dramatically. For
example, a large scale meta-analysis looked at studies evaluating the sensitivity of US in detection of any-stage HCC found
a huge variation in sensitivity from 28% to 100% (Tzartzeva
et al. 2018). Not only does the sensitivity vary between operators, the sensitivity for HCC detection also depends on the
stage of the cancer at point of detection. The same meta-analysis
showed that the pooled sensitivity was 84% however significantly lower for early-stage HCC detection at only 47%. This
poses an issue in that detection of early HCC, the very aim of
surveillance, is much less sensitive compared to more advanced
HCC which are less likely to be cured. Interestingly, the sensitivity of US is also lower in patients with advanced cirrhosis.
This phenomena is thought to be due to the increased nodularity and coarse texture of the liver which distorts the ultrasound
images (Andreana et al. 2009); this is clearly a significant pitfall
given that the majority of patients under surveillance will have
cirrhosis. In practice, patient factors will also have an impact on
the ability of US to detect HCC. For example, patients with
NAFLD as the causative etiology for their cirrhosis are more
likely to be overweight or obese. Large body habitus limits the
quality of US images and increases the likelihood of a false negative result (Esfeh et al. 2020), this means that patients may go
on to have more invasive scans which carry a risk of ionizing
radiation such as CT.
To improve its sensitivity, US can be used in conjunction
with serum alpha-fetoprotein (AFP) measurements when
monitoring for HCC development. AFP is the only validated
and widely accepted biomarker for surveillance (Tayob et al.
2019) but remains controversial; this will be discussed in more
detail later in this chapter.
Computed Tomography (CT)
The GOLD Standard imaging technique for the diagnosis of
HCC is a CT liver triple-phase with delayed contrast sequences,
this exploits the unique vascular properties of HCC which
make it distinct from other types of malignancy. CT as standard practice is endorsed by all of the international societies for
the study of liver disease and whilst US is the mainstay of surveillance, CT is superior in the diagnosis of HCC as images
confer a higher sensitivity and specificity.
Hepatocarcinogenesis occurs stepwise fashion of progressive cellular de-differentiation of cirrhotic nodules to dysplastic nodules. Over time dysplastic cells replace the
surrounding cirrhotic tissue, as these cells are cloned and
replicated they will eventually produce nodules with a malignant phenotype (Choi et al. 2014). The described process
does not occur in isolation; often carcinogenesis is occurring
simultaneously in multiple areas of the liver parenchyma as
patient has been diagnosed with one HCC, their risk of
further lesions rises exponentially (Kim et al. 2020). In
normal anatomy, the liver is unique in that it receives dual
blood supply from the hepatic artery and the hepatic portal
vein. These vessels are also paired with a bile duct to form a
structure referred to as the portal triad. As a HCC develops it
recruits arteriolar blood supply through secretion of angiogenic growth factors, such as vascular endothelial growth
factor (VGEF) (Andrew X. Zhu et al. 2011). As a consequence,
a HCC will receive the majority of its blood supply via arterial
collaterals and gradually loses its venous supply (illustrated
in Figure 2) (Morse et al. 2019); it is this phenomena that is
exploited for the diagnosis of HCC using contrast-enhanced
triple phase CT.
Contrast is injected and images are taken during the arterial
phase, this results in high uptake of contrast in the HCC
lesion due to its high arterial vascularity; a process called
enhancement. Following this, images are then taken during
the portal venous phase and the delayed acquisition phase at
3–5 minutes post contrast injection (Shah et al. 2014). During
these phases, there is a characteristic “washout” pattern,
regarded as the radiological hallmark of HCC. This washout
pattern has an overall sensitivity of 89% and specificity of 96%
for pooled any stage HCC (van der Pol et al. 2019) making it
an excellent imaging modality for diagnosis without the need
for histological confirmation with biopsy which is a stark
difference to most other cancers which require biopsy for
GOLD standard diagnosis. The ability to diagnose cancer
without biopsy is a clear advantage, particularly in patients
with liver disease who often have a coagulopathy as a result of
synthetic liver dysfunction and for which bleeding would be a
significant risk with any invasive procedure. Bleeding following liver biopsy occurs in approximately 3–4% of cases, with
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