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256 3 HEPATOBILIARY AND PANCREAS CANCER
Incidence rate (per 100 person year)
Without cirrhosis
With cirrhosis
)
https://t.me/medicina_free
Overall
Age
Younger than
65
65 year and
older
Race
White
African
American
Hispanics
Diabetes
No
Yes
Alcohol use
No
Yes
Drug use
No
Yes
FIB-4
<1.45
1.45–3.25
>3.25
0.1 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4
Alcohol
Heavy alcohol intake, defined as ingestion of >50–70 g/day for
prolonged periods, is a well-established HCC risk factor. It is
unclear if risk of HCC is significantly altered in those with low
or moderate alcohol intake (Park etal. 2020). A meta-analysis
of prospective studies found there was no association between
HCC and lower levels of alcohol consumption (<3 drinks/day)
(Turati etal. 2014); however, a pooled analysis of prospective
studies showed this same level was associated with a significantly decreased risk of HCC even after excluding non-drinkers.
The latter study found no association between risk and lowerlevel consumption among persons with diabetes but found 35%
decreased risk among persons without diabetes (Petrick etal.
2018). Alcohol use could have a stronger association with HCC
risk among women than men. In a meta-analysis examining
heavy drinking (>4 drinks/day), alcohol was associated with a
1.6-fold increased risk of HCC among men but an almost
4-fold increase in risk among women. This could be due to differences in alcohol dehydrogenase activity or a stronger
association between alcohol and cirrhosis among women
(Frezza etal. 1990, 1992).
There is also evidence for a synergistic effect of heavy alcohol
ingestion with HCV or HBV. These factors presumably increase
HCC risk by collectively promoting cirrhosis. For example,
Donato etal. (2002) reported that among alcohol drinkers, HCC
risk increased linearly with a daily intake >60 g. However, the
concomitant presence of HCV infection led to an additional twofold increase in HCC risk over that observed with alcohol usage
alone (i.e., a positive synergistic effect).
1.82%
(95% CI, 1.66–2.0%
Figure 4 Annual incidence of HCC after
DAA-related SVR Stratified by cirrhosis.
Adapted from Kanwal F, Gastroenterology
2018.
Aflatoxin
Aflatoxins are mycotoxin produced by the Aspergillus fungus.
This fungus grows on foodstuffs like corn, maize, and peanuts
stored in warm, damp conditions. AFB1 occurs in many locations around the world, especially in countries with warm,
humid environments. Of the four principal aflatoxins, B1, B2,
G1, and G2, the most potent is aflatoxin B1 (AFB1) (Alberg
etal. 2014). Animal experiments showed that AFB
erful hepatocarcinogen, leading the International Agency for
Research on Cancer (IARC) to classify it as carcinogenic
(“Overall Evaluations of Carcinogenicity: An Updating of
IARC Monographs Volumes 1 to 42” 1987).
Once ingested, AFB
AFB
-exo-8,9-epoxide, that binds DNA and causes damage,
1
is metabolized to an active intermediate,
1
such as producing the characteristic serine 249 mutation in the
p53 tumor suppressor gene (Garner et al. 1972). This mutation
has been observed in 30–60% of HCC tumors in AFB
areas(Bressac etal. 1991; Turner etal. 2002).
Strong evidence that AFB
is an HCC risk factor. These
1
studies were possible due to the development of assays for
AFB
metabolites in urine and AFB1-albumin adducts in
1
serum as well as detection of the signature AFB
tion in tissues.
AFB1 is particularly carcinogenic when it co-occurs with
chronic HBV infection A meta-analysis estimated that AFB1
alone increased HCC risk by 6-fold, HBV alone by 11-fold, and
the two factors together by 54-fold (Liu etal. 2012). In most
areas where AFB
exposure is a problem, chronic HBV infec-
1
tion is highly prevalent. HBV vaccination in these areas should
is a pow-
1
-endemic
1
DNA muta-
1
14 EPIDEmIOLOgY AND RISk FACTORS OF HEPATOCELLuLAR CARCINOmA 257
Incidence rate per 1000 person-years
Diabetes
No
https://t.me/medicina_free
be the primary preventive tactic; however, chronically infected
persons will not benefit from vaccination. These individuals
could benefit from eliminating AFB
exposure. AFB1 contami-
1
nation of crops is difficult to combat because contamination
can occur both pre- and post-harvest (Udomkun etal. 2017).
A successful effort was the replacement of maize with rice as
the dietary staple in parts of China; these efforts are credited at
least partly for recent declines in liver cancer incidence and
mortality (Chen etal. 2013; Sun etal. 2013).
Non-alcoholic Fatty Liver Disease
(NAFLD)
NAFLD has become one of the most common causes of liver
disease globally (Cheemerla and Balakrishnan 2021). NAFLD
is the hepatic manifestation of metabolic syndrome, often coexisting with diabetes, hypertension, and obesity. Its prevalence
has doubled in the US to 30% of the population in the last 20
years, paralleling the obesity epidemic, NAFLD is now a leading
cause of cirrhosis and NASH is the second-leading cause of
liver transplantation related to HCC in the US (Liu etal. 2012).
NAFLD represents a broad spectrum of histologic severity;
so HCC incidence should be considered in the context of distinct histologic stages. Most NAFLD is of the nonalcoholic fatty
liver subtype (NAFL, simple steatosis), which is characterized
by hepatocyte fat accumulation without necroinflammation
and low risk of fibrosis progression. Up to 30% of NAFLD cases
are of the non-alcoholic steatohepatitis (NASH) category,
which is characterized by necroinflammation and is associated
with fibrosis progression.
The risk of HCC in NAFLD background ranges from 0 to
38% over a follow-up of 5–10 years. A large US Veterans
Affairs NAFLD cohort study reported an HCC incidence of
0.21 per 1000 person-years among patients with NAFLD,
which was significantly higher than controls without NAFLD
(Kanwal etal. 2018). The incidence of HCC is highest among
people with NAFLD-related cirrhosis, ranging from 2.4 to
12.8%(D. Q. Huang etal. 2021) (instead you could say 10–15
per 1000 person-years). However, this risk is substantially different depending on NAFLD subtype. A recent meta-analysis
of 16 studies reported an incidence rate of 0.03 per 1000 person-years in non-cirrhotic patients and 3.78 per 100 personyears in patients with NASH cirrhosis (Orci et al. 2021).
Individual studies have reported an HCC incidence ranging
from 0.08 to 0.62 per 1000 patient years among NAFLD populations excluding cirrhosis (Adams etal. 2005; Kawamura etal.
2012; Mittal etal. 2016; Sorensen etal. 1998; White etal. 2012).
It should be noted that while 20–30% of NAFLD-related HCCs
develop in the absence of cirrhosis, this still represents a rare
event (Udomkun etal. 2017).
Factors related to HCC risk associated with NAFLD include
clinical factors (cirrhosis, diabetes, obesity, hypertension),
demographic characteristics (age, race/ethnicity) (Figure 5),
and genetic susceptibility (e.g., genetic variability in PNPLA3).
In addition, diabetes or insulin resistance, obesity, older age,
and male gender conferred an increased risk (Younossi and
Henry 2021). It is unclear whether HCC risk in NAFLD is
mediated by the presence of metabolic traits, such as diabetes
and hypertension, or through the direct necroinflammatory
effects confers an increased risk compared with patients
No
Yes
Age (year)
<45
45–64
>65
Race
Black
White
Hispanic
Cirrhosis
Diagnosis, high FIB-4
Diagnosis, low FIB-4
High FIB-4
diagnosis, low FIB-4
Figure 5 HCC Incidence in Subgroups of Patients with NAFLD. (Source Kanwal etal. Gastroenterology 2018).
258 3 HEPATOBILIARY AND PANCREAS CANCER
Gastroenterol Hepatol. 2020
https://t.me/medicina_free
without these comorbidities. While weight loss can reduce
NAFLD severity, no studies have demonstrated that weight loss
is associated with a reduction in HCC risk.
HCC screening is recommended among patients with
NAFLD cirrhosis (Figure 6). This recommendation is based on
cost-effectiveness modeling that concluded a benefit based on
an annual HCC incidence in NAFLD cirrhosis ≥1.5% (Marrero
etal. 2018). There is no high-level evidence to support or refute
the value, method, or frequency of HCC surveillance among
the NAFLD population.
Obesity
In adults, greater adiposity has been shown to slightly increases
risk of liver cancer (Lauby-Secretan etal. 2016). BMI may not
accurately capture important elements of obesity, thus studies
have examined waist and hip circumference as measures of
excess abdominal and gluteofemoral adiposity, respectively. US
and European cohort studies found a two-fold increase in HCC
risk among those with high waist circumference, and this
difference remained when accounting for BMI and hip circumference (Campbell etal. 2016; Florio et al. 2020; Schlesinger
et al. 2013). One study indicated that among people with
normal or low weight, abdominal size but not gluteofemoral
size was associated with increased HCC risk (Florio etal. 2020).
There may be a stronger effect of adiposity that develops at
earlier ages. A study out of Denmark found a one-unit increase
in BMI z-score at 7 or 13 years of age was associated with a
20–30% increased risk of liver cancer (Berentzen etal. 2014).
US and Swedish studies found that obesity in late adolescence
and early adulthood was associated with two- to three-fold
increase in HCC risk compared to BMI 18–25 (Hagström etal.
2018; B. Yang etal. 2017).
Diabetes Mellitus
Increasing evidence suggests that metabolic syndrome, a
collection of conditions including insulin resistance, abdominal obesity, atherogenic dyslipidemia, and hypertension,
increases risk of HCC. A 2014 meta-analysis estimated that
metabolic syndrome was associated with an 81% increased
risk (Ohkuma et al. 2018). Treating one of the metabolic
syndrome conditions, dyslipidemia, with statins, however,
may ameliorate risk by 37–42% (Franciosi etal. 2013; Singh
etal. 2013).
Type 2 diabetes may confer HCC risk via development of
NASH/cirrhosis or indirectly via increased levels of insulin and
insulin-like growth factors, which are potentially cancer-promoting factors. Case-control studies from the US, Greece, Italy,
Taiwan, and Japan have reported mixed findings regarding the
association between diabetes, primarily type 2, and HCC
(Davila 2005; La Vecchia etal. 1997). However, it is important
to remember that cross-sectional and case-control studies are
limited by potential reverse causation: approximately 10–20%
NAFLD
Established NAFLD cirrhosis?
No
Suspects advanced brosis or occult cirrhosis as evidenced
by 2 concordant tests out of the following:
1) Point of care tests
2) Specialized tests
3) Non-invasive imaging
Ye s
Consider HCC screening with Ultrasound +/–
AFP and documentation of visualization score
Inadequate visualisation
Consider CT or MRI for HCC surveillance
Figure 6 Screening for HCC in NAFLD. Huang, D et al. 2021 / Springer Nature.
Ye s
No
Adequate visualization
Huang D, El-Serag HB, Loomba R. Nat Rev
HCC screening
HCC
Screening not rountinely
required
Continue screening with
Ultrasound +/– AFP
14 EPIDEmIOLOgY AND RISk FACTORS OF HEPATOCELLuLAR CARCINOmA 259
HCC rate (%)
Years of follow up
14
0.25
https://t.me/medicina_free
0.20
Diabetes
0.15
0.10
0.05
0.00
0
Figure 7 The cumulative incidence of HCC among US veteran patients hospitalized between 1985 and 1990. The study followed 173,463 patients with
diabetes and 650,620 without diabetes. No patient had acute or chronic liver disease recorded before, during, or within one year of their index
hospitalization.
of patients with cirrhosis have overt diabetes and a larger
percentage have impaired glucose tolerance. Thus, diabetes
could be a result of cirrhosis.
Cohort studies, which are better suited to discern temporal
2
46
smokers (Alberg et al. 2014) compared to lifetime nonsmokers. More recent data found that HCC risk returned to
the non-smoker baseline 30 years after tobacco cessation
(Petrick etal. 2018).
No diabetes
8
10 12
P < 0.0001
relationships between exposure and disease, have been conducted that compared HCC incidence in cohorts of diabetic
patients with either the expected incidence based on HCC rates
in the underlying population or with the observed HCC incidence of a defined cohort without diabetes. Studies among
diverse populations have reported that diabetes is associated
with a 2 to 3-fold increased risk of HCC (Figure 7) (El-Serag
etal. 2004), with a significantly greater relative risk among men
than women (Hui Zhang etal. 2013). Longer duration of diabetes
may be also associated with an incremental increase in risk of
HCC; however, the relationship between diabetes severity or glycemic control and HCC risk is unclear (Lauby-Secretan et al.
2016). Several meta-analyses reported that treatment of type 2
diabetes with metformin decreases risk by as much as 50%,
whereas use of insulin and sulfonylureas increases risk (Franciosi
Coffee
Coffee has been consistently associated with decreased risk of
liver cancer (Ma et al. 2019). A 2017 meta-analysis of both
cohort and case-control studies reported that an extra two cups
of coffee per day compared to no coffee was associated with a
35% reduced risk (Kennedy etal. 2017). Coffee has also been
associated with lower liver enzyme levels, slower progression of
fibrosis, and lower risk of diabetes. The mechanisms underlying a possible protective effect of coffee, however, are not
clear. Experimental evidence suggests there may be beneficial
effects of caffeine as well as many other coffee components
(e.g., diterpenes) in reducing inflammation, fibrosis, insulin
resistance and oncogenesis (H. I. Yang etal. 2011).
etal. 2013; Singh etal. 2013; Hui; Zhang etal. 2013). However,
these studies could be confounded by diabetes severity. Patients
with well controlled diabetes on metformin monotherapy could
be a phenotypically different subset of patients with diabetes
compared with patients who need insulin, thus the correlation of
medication with disease severity might lead to an overestimation
of risk reduction by metformin (Gordon etal. 2014).
Genetic Epidemiology of HCC
Epidemiologic research has demonstrated that most adultonset HCC cases are sporadic (i.e., have no similarly affected
first-degree relative) and many have at least one established
acquired (non-genetic) risk factor like habitual alcohol abuse
or chronic infection with HBV or HCV. However, most people
Tobacco
The relationship between cigarette smoking and HCC has
been examined in more than 50 studies in both low- and
high-rate areas. In almost all countries, there were findings
of both positive associations and lack of association. A 2014
US Surgeon General’s report of 113 studies found a 70%
increased risk of HCC in current smokers and 40% in former
with these non-genetic risk factors for HCC never develop cirrhosis or HCC, and a sizable minority of HCC cases develop
among individuals without any known risk factors. Few HCC
cases are associated with familial disorders with mendelian
inheritance like hereditary hemochromatosis, alpha-1-antitrypsin deficiency, or porphyria. Polymorphisms, originally
examined in candidate-locus studies, have also been related to
HCC risk. A 2011 meta-analysis found that polymorphisms in
260 3 HEPATOBILIARY AND PANCREAS CANCER
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UGT1A7, MnSOD and IL-1B were significantly associated
with risk (Lee etal. 2018).
Genome-wide association studies (GWAS) conducted in
Asian populations where HBV or HCV were factors reported
increased risks in association with a number of loci, most
commonly ones located in the HLA region (HLA-DP,
HLA-DQ, HLA-DR, MICA) (Baecker etal. 2018; Jiang etal.
2013; Kumar etal. 2011; Lee et al. 2018; S. Li et al. 2012; Y.,
2018; Y. Y. Lin etal. 2017; Maucort-Boulch etal. 2018; Miki
et al. 2011; Qu et al. 2016; Hongxing Zhang et al. 2010).
Another reported association maps to chromosome 1p36.22, a
region that may harbor a tumor suppressor gene for HCC
(Hongxing Zhang etal. 2010). The KIF1B gene in this region
has been reported to be associated with apoptosis, and its
association with HCC was replicated in subsequent studies
from other Asian populations. Associations with STAT4,
GRIK1, EFCAB11, and EFCAB11 have also been found (Y. Y.
Lin etal. 2017; Miki etal. 2011; Hongxing Zhang etal. 2010).
GWASs in Chinese and Japanese populations identified SNPs
at chromosomes 1p36.22 (KIF1B), (B. Yang etal. 2017) 2q32.22q32.3 (STAT4) (Campbell et al. 2016), 6p21.3 (HLA-DQ)
(Campbell etal. 2016), 6p21.32 (HLA-DQAQ/DRB1) (Florio
etal. 2020), 6p21.33 (MICA) (Schlesinger etal. 2013), 7q21.13
(CDK14) (Stepanova et al. 2013), (52) 21q21.3 (GRIK1)
(Florio etal. 2020), and 22q11.2 (DEPDC5) (Wattacheril and
Chalasani 2012) as associated with HCC progression in
patients with HBV or HCV infection.
Recent large GWAS have identified SNPs influencing the
development and severity of NAFLD (Palmer et al. 2013).
The strongest and most consistent associations are with
rs738409 C>G SNP (I148M) of Patatin-like phospholipase
domain-containing 3 (PNPLA3), and the variant risk allele
was more prevalent in Hispanics than Europeans or African
Americans (Ahmed et al. 2015). The rs738409 SNP in the
PNPLA3 gene was initially reported to be related to NAFLD
(Romeo etal. 2008). A meta-analysis of studies of this polymorphism and risk of HCC found a significant association
between this SNP and HCC among white populations (odds
ratio = 1.75) but no evidence of an association among Asian
populations (Z. Huang etal. 2019). Other variants with possible HCC associations include the rs58542926 C>T SNP
(E167K) in transmembrane 6 superfamily 2 (TM6SF2) and
the rs641738 C>T SNP of membrane-bound O-acy ltransferase
domain-containing 7 (MBOAT7). A meta-analysis associated
rs2228603 in Neurocan (NCAN) and rs4240624 in Protein
Phosphatase 1 Regulatory Subunit 3B (PPP1R3B) with
increased hep148Iatic steatosis in African Americans; the
former had a reverse, protective effect in Hispanics (Vernon
etal. 2011). A few studies have also demonstrated potential
utility of a polygenic risk score derived from these NAFLDrelated SNPs for predicting HCC in cured HCV (Degasperi
etal. 2020; Wong etal. 2014) and NAFLD patients (Bianco
etal. 2021; Kanwal etal. 2018).
Key Take Home Messages
• There has been a shift in the main HCC risk factors from
strong but relatively infrequent agents (e.g., HBV and HCV) to
weak but very common conditions (e.g., obesity, diabetes, metabolic syndrome).
• There has been a decline in the incidence of HBV and HCV
(i.e., vaccination, screening of blood products), prevalence of HCV
(i.e., effective novel HCC therapies), and carcinogenic potential of
HCV (i.e., treatment related sustained virological response) and
HBV (i.e., treatment related adequate viral suppression).
• HBV remains an important etiological especially in Asia and
Africa.
• Novel highly effective therapies for HCV is expected to lead
to further decline in rates of HCC in low HCC incidence countries like the US. However, despite HCV treatment, HCC risk
remains elevated in those who already developed cirrhosis and
hence HCC screening may still be needed in this group.
• Obesity, diabetes, and metabolic syndrome traits are associated with 1.5–2.0-fold increase in HCC that while mostly
affects those with cirrhosis is increasingly recognized in
patients without cirrhosis or advanced fibrosis.
• Host genetic variants (e.g., PNPLA3) and environmental
risk factors (e.g., alcohol, aflatoxins, tobacco) are important
HCC risk enhancers.
Knowledge Gaps
• The major shift of HCC risk factors toward common conditions (e.g., NAFLD, obesity, diabetes) creates major clinical and
public health dilemmas, and requires examination and
identification of demographic, clinical, genetic, and biochemical
markers of HCC that allows better risk stratification and
relatively targeted prevention and screening strategies.
• The increasing number of people with treated HCV and
HBV need to be examined to determine the residual risk of
HCC and the determinants of this risk.
• The considerable disparities in HCC incidence among racial
and ethnic groups, and the possible role of socioeconomic
determinants of health needs to examined.
• The potential clinical role of host genetics (e.g., polygenic
risk scores) as predictors of the incidence and prognosis of
HCC needs to be examined.
Trusted Websites for Further Reading
• https://www.mayoclinic.org/diseases-conditions/
hepatocellular-carcinoma/cdc-20354552
• https://www.mdanderson.org/cancerwise/giving-othershope-after-hepatocellular-carcinoma.h00-158986656.html
14 EPIDEmIOLOgY AND RISk FACTORS OF HEPATOCELLuLAR CARCINOmA 261
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15 Pathology, Molecular Pathology, and
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Genomics of Hepatobiliary and
Pancreatic Cancer
Andrzej Mróz
Department of Pathology, Center of Postgraduate Medical Education, Warsaw, Poland
Department of Pathology, Maria Skłodowska-Curie Memorial Cancer Hospital and Institute, Warsaw, Poland
Hepatic Cancer
Hepatocellular carcinoma (HCC) is a primary malignant
tumor of the liver consisting of epithelial cells displaying
hepatocellular differentiation. On histological grounds the
proliferating cells usually form trabeculae or macrotrabeculae
as well as pseudoglands and solid nests with obliteration of
normal hepatic architecture including portal tracts and reticulin framework loss, arterialization, and capillarization.
Based on H&E staining, histological grading is performed by
comparison of the cancer cells (nuclear atypia and cytoplasm)
to nonneoplastic hepatocytes and divide hepatocellular carcinoma into three degrees of differentiation: well differentiated,
moderately differentiated, and poorly differentiated (Burt
etal. 2018; Han etal. 2013). As in many cases there might be
more than one grade and it is always the worst which predicts
the prognosis (Han etal. 2013). For establishing hepatocellular origin and differentiating liver tumors from premalignant and nonneoplastic changes, several immunohistochemical
markers can be utilized as well as diagnostic molecular
pathology methods. The most widely used hepatocellular
markers are Arginase-1, HepPar 1, HSP70, glutamine synthetase (GS), Glypican 3, polyclonal CEA, CD10 and AFP however none of these markers is sensitive enough to base the
diagnosis on and has to be considered in conjunction with
histological picture since the expression differs between
tumor grade and subtype. In reference to molecular profile
the most common gene mutations in HCC include TERT promoter, TP53, CTNNB1, AXIN1, ARID1A, ARID1B, ARID2,
FGF19 amplification, DNA methylation and amplification
(Schulze etal. 2015; Nault etal. 2014;).
According to WHO 2019 classification the special subtype
can be determined in 35% of HCCs and is related to histoclinical picture, molecular profile, prognosis, and therapeutical
approach (WHO 2019). These special subtypes include:
The subtypes with the worse prognosis:
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.
• Macrotrabecular massive pattern (MTM) HCC with the
incidence of 5% developing in patients with HBV infection.
Histologically it is characterized by the presence of thick cord
(up to 10 cells) of neoplastic cells and vascular invasion.
Molecularly TP53 mutations and FGF19 amplifications are
common as is activation of angiogenesis (high ANGPT2 mRNA
levels) (Calderaro etal. 2017).
• Neutrophil rich HCC with low incidence (1%) and neutrophil rich inflammatory infiltrate within neoplastic cells and
focal sarcomatoid appearance. The patients have elevated numbers of WBC and increased concentration of CRP and IL6 in
the serum while the tumor produces G-CSF which can be displayed immunohistochemically (Torbenson 2017).
• Scirrhous HCC in 4% of cases in which >50% of area is occupied by intratumoral fibrosis, the activation of EMT and TGFβ
signaling pathways and TSC1/TSC2 mutations are present
(Seok etal. 2012; WHO 2019).
The subtypes with the similar prognosis (to not the “speci-
fied type” of HCC)
• Steatohepatic HCC with the incidence of 5–20% in patients
with metabolic syndrome or alcohol abuse. Histologically is
characterized by the presence of inflammatory cells in the context of steatosis (steatohepatitis) in >50% of the tumor. The
activation of the Il-6/JAK/STAT pathway is often present with
lower frequency of TERT, CTNNB1 and TP53 mutations
(Calderaro etal. 2017).
• Fibrolamellar HCC comprises 1% of the cases and occur in
younger patients in noncirrhotic liver. Microscopically large
eosinophilic cells with prominent nucleoli are seen mixed with
dense, lamellar fibrosis. The molecular hallmark of lamellar
HCC is DNAJB1-PRKACA gene fusion with subsequent protein kinase A activation. This fusion can be detected in FISH
assay (Graham and Torbenson 2017).
• Chromophobe HCC with the 3% incidence rate and partly
clear (chromophobe) cytoplasm and blunt nuclei in histology.
Alternative lengthening of telomere is a key molecular feature
of this subtype (Torbensosn 2017).
The subtypes with better prognosis:
264
15 Pathology, Molecular Pathology, and genoMics of hePatobiliary and Pancreatic cancer 265
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• Lymphocyte-rich HCC with low (<1%) incidence rate and
rich lymphocyte (CD8+) infiltrate outnumbering the tumor
cells and forming lymphocyte-rich HCC (with well or moderately differentiated cancer cells) or lymphoepithelioma-like
HCC (with poorly differentiated cancer cells). No specific
molecular changes responsible for its development are found
up to date and EBV infection seems to be not related to this
subtype (Torbensosn 2017; Wada etal. 1998).
• Clear cell HCC occurring in 3–7% of patients where the
clear cell change (due to glycogen accumulation) is found in
more than 80% cells of the tumor. No molecular basis has
been established in this subtypes but the tumors are usually
less advanced with better differentiation and no lymphovascular invasion which warrants better prognosis (Li et al.
2011).
This histological subtypes with their clinical characteristics
and gene mutations make the proposal to molecular tumor
classification which may be adopted to clinical practice in the
future (Calderaro etal. 2017).
In 4–28% of HCC the expression of CK19 is positive. It is a
marker of cholangiocytes and liver progenitor cells and signifies the worse prognosis in HCC patients. Clinically these
patients have higher levels of AFP, cancer is often related to
HBV infection and is more advanced with lymph node metastases. On pathological level the type of growth is infiltrative
with abundant fibrotic stroma and frequent vascular invasion
(Rhee 2020). Furthermore, in these cases the TGFβ and EMT
pathways are activated and the tumors are resistant to TACE
and RFA therapies. (Rhee 2020).
WHO (2019) classification settles the concept of combined
hepatocellular and cholangiocellular carcinoma (cHCC-CCA)
as a tumor with unequivocal differentiation toward hepatic and
cholangiocytic cells within the same tumor. The diagnosis is
based only on H&E histological picture and IHC is used as
adjunct methods with HepPar1, ARG1, Gly3, pCEA, CD10,
AFP in favor of HCC and CK7, CK19, and EpCAM in favor of
CCA (Siarra 2020). Based on international consensus proposed
by Burt E and al (Burt et al. 2018) stem cell/progenitor and
intermediate cell subtypes as well as cholangiolocelluar carcinoma (CLC) with HCC (WHO 2010) have been removed and
placed under cHCC-CCA umbrella (usually representing part
or foci of histological pattern) whereas the CLC without HCC
has been incorporated into the CCA group as a subtype (Moeini
etal. 2017). The term intermediate cell carcinoma is preserved
for the rare cases where the nearly entire tumor is composed of
monotonous cells with scant cytoplasm with the morphology
in between hepatocytes and cholangiocytes embedded in rich
fibrous stroma.
Cholangiocarcinomas
Cholangiocarcinomas are the epithelial tumors arising anywhere along biliary tree and are anatomically divided into
intrahepatic cholangiocarcinomas (iCCAs) which arise
proximal to the second order bile ducts, perihilar cholangiocarcinomas (pCCAs) which arise between second order biliary
ducts and cystic duct and distal extrahepatic cholangiocarcinoma (dCCAs) which arise between cystic duct and the
ampulla of Vater (Labib etal. 2019; Rizvi et al. 2017). These
tumors are also classified based on their macroscopic appearance (mass-forming, periductal, or intraductal) or the cell of
origin (cholangicytes, peribilliary glands, hepatic progenitor
cells, or hepatocytes (Labib etal. 2019). Most of cholangiocarcinomas are adenocarcinomas consisting of variably sized and
shaped glands built of variably atypical columnar or cuboidal
neoplastic cells with conspicuous pale cytoplasm surrounded
typically by rather rich fibrotic stroma. There are significant
differences between types of cholangiocarcinoma in terms of
histology, immunophenotype, and molecular characteristics.
iCCA consists of two main types: large duct and small duct
iCCA. The former arises in large intrahepatic bile ducts close
to the liver hilum and the latter develops peripherally within
liver parenchyma. Morphologically large duct type iCCA
resembles distal cholangiocarcinomas (pCCAs and dCCAs)
and is characterized by large ducts lined by columnar epithelium producing mucus. These glands are embedded in rich
fibrous stroma (Figure 1). The presence of neural and lymphovascular invasion is typical as is the presence of lymph
nodes metastases. The small duct type iCCA is formed by
small tubules with variably sized lumens lined by small
cuboidal cells with less pronounced production of mucus
and ductular and cord-like components with slit-like lumina.
The cancer replaces liver parenchyma and the rich fibrous
stroma is also the feature. For large duct type iCCA it is
believed to be biliary intraepithelial neoplasia (BillN) to be
Figure 1 Cholangiocarcinoma large duct type, H&E x6,3.
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