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13 EPIDEMIOLOGY, PATHOLOGY, DIAGNOSIS, PREVENTION, AND MANAGEMENT OF ANAL CANCER 245
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Key Take-Home Management Points
1 Assessment of anal cancer includes careful clinical assessment
under GA and obtaining tissue biopsy to be followed by local
(MRI) and systemic (CT and PET CT) staging.
50% of enlarged inguinal LN patients with anal cancer are
2
reactionary. PET CT or FNA can change the treatment field.
3 Chemoradiotherapy (5-FU + MMC + Radiotherapy) is the
current gold standard primary treatment for 80% of patients
with anal SCC.
The role of surgery in patients with anal cancer includes pre-
4
treatment defunctioning stoma formation, the management of
perianal fistulas, APER as primary or salvage treatment, and
local excision of small anal margin tumors.
5
The optimal interval to evaluate treatment response follow-
ing CRT completion is 26 weeks.
6 Persistent or recurrent disease usually occurs in the first 24
months from completion of CRT.
Anal melanoma is a rare tumor with a known poor prog-
7
nosis. The clinical and radiological assessment is similar anal
SCC.
8
Staging of anal melanoma, like other melanomas, is based
on disease spread into stage I (local disease), stage II (spread
into regional LN), and stage III (tumors with distant
metastasis).
Surgery provides survival benefits to patients with stage I
9
and stage II disease. There is no survival benefit from extensive
resection (APR) compared to local excision.
Areas for Further Research
• The role of screening and prevention of anal cancer in high-
risk groups.
• Personalized treatment for anal cancer. The role of HPV and
immunotherapy.
• The QoL in patients with anal cancer and the impact of dif-
ferent treatment options.
Trusted Websites for Further Reading
• Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up: https://www.esmo.org/guide
lines/guidelines-by-topic/gastrointestinal-cancers/anal-cancer
• NCCN (National Comprehensive Cancer Network) guidelines on anal cancer: https://www.nccn.org/professionals/phy
sician_gls/pdf/anal.pdf
• Surgical treatment of anorectal melanoma: a systematic review
and meta-analysis: https://academic.oup.com/bjsopen/article/
5/6/zrab107/6446962
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Section III Hepatobiliary and Pancreas
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Cancer
14 Epidemiology and Risk Factors of
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Hepatocellular Carcinoma
Hashem B. El-Serag, Maya Balakrishnan & Yamini Natarajan
Gastroenterology and Hepatology Section, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
Global Incidence of Hepatocellular
Carcinoma
Overview
Worldwide, primary liver cancer is the seventh most common
cancer and the fourth most common cause of cancer
mortality (Freddie Bray etal. 2018). Globally, over 840,000
people develop liver cancer each year, and 780,000 die of it.
More than 70% of deaths occur in men. (Mohammadian
etal. 2020). However, liver cancer burden is not evenly distributed throughout the world (Figure 1). Most cases of
hepatocellular carcinoma (HCC) occur in either Africa or
Asia. Mongolia has the single highest incidence rate, with an
age-standardized rate of 94.7/100,000 person-years (Petrick
and McGlynn 2019).
North and South America, Northern Europe, and Oceania
are low-rate areas for liver cancer (5.1–6.9/100,000) among
most populations. The rates in Latin America and the Caribbean
are nearly double (11.4/100,000). However, incidence rates are
increasing in areas previously thought to have low rates. Liver
cancer incidence rates are more than two-fold higher in males
than females in most regions of the world [US (male: 8/100,000,
female: 2.7/100,000), Europe (male: 10.1/100,000, female: 3.7
/100,000), Oceania (male: 17.1/100,000, female 5.9/100,000),
Africa (male: 12/100,000, female: 5.3/100,000), Latin America
and the Caribbean (male: 12/100,000, female: 5.3/100,000)]. In
Asia, the difference is attenuated (male: 6.1/100,000; female:
4.1/100,000) (Mohammadian etal. 2020).
HCC accounts for more than 75% of primary liver cancer
(Petrick etal. 2020). One noteworthy exception is the Khon
Kaen region of Thailand, which has one of the world’s highest
rates of liver cancer (age-standardized rate from 1993–1997
male: 88.0/100,000; female: 35.4/100,000). This disease burden
is due to endemic infestation with liver flukes, so the major
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.
type of liver cancer in this region is intrahepatic cholangiocarcinoma (Okuda etal. 2002).
Encouraging trends in liver cancer incidence have been seen
in some high-rate areas (Valery etal. 2018). Between 1978 and
2012, incidence decreased in multiple Asian countries and
southern Europe like Spain and Italy. The rates may have plateaued in the US but have increased in countries with historically low rates, including Oceania (Figure 2) (McGlynn etal.
2021) (Valery etal. 2018).
Decreasing rates in Asia are likely due to hepatitis B virus
(HBV) vaccination programs. In Taiwan, a national newborn
vaccination began in 1984. HCC incidence declined 80% and
mortality declined 92% in children born after the vaccination
program began (C.-L. Lin and Kao 2020). China, Singapore,
and Spain implemented similar programs, resulting in
decreased incidence of HCC among children. (McGlynn
etal. 2015). It is too early to expect an impact on HCC incidence on adults, therefore the impact on HCC incidence
among people less than 18 are reported. Other public health
measures could have contributed to declines in HCC incidence in high-risk areas of China. A Chinese government
program started in the late 1980s to shift the staple diet of the
Jiangsu Province from corn to rice has limited hepatocarcinogen aflatoxin B
2013; Sun et al. 2013). Similarly, another Chinese public
health campaign initiated in the early 1970s to encourage
drinking of well water rather than pond or ditch water could
have decreased consumption of microcystins, cyanobacteriaproduced compounds shown to be hepatocarcinogenic in
experimental animals (Yu n.d.).
In contrast, registries in several low-rate areas reported
increases in HCC incidence between 1978–1982 and 1993–
1997. These registries include the US, UK, and Australia. The
increased incidence in low-rate areas may be related to an
increased prevalence of hepatitis C virus (HCV) infection in
these areas. However, reasons for the decreased incidence in
high-rate areas and the increased incidence in low-rate areas
are not yet clear, emphasizing the important of conducting case
studies in these areas.
(AFB1) exposure in this area (Chen etal.
1
251
252 3 HEPATOBILIARY AND PANCREAS CANCER
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Figure 1 Regional variations in incidence rates of HCC categorized by age-adjusted incidence rates for 2018. Data source: GLOBOCAN 2018. Graph
production: IARC (http://gco.iarc.fr/today), World Health Organization.
Race/Ethnicity
HCC incidence rates vary widely among different populations
living in the same region. For example, ethnic Indian, Chinese,
and Malay populations in Singapore had age-adjusted rates ranging from 21.21/100,000 among Chinese males to 7.86/100,000
among Indian males between 1993 and 1997. Conversely, rates
within an ethnic group can vary by geographic location.
Populations of ethnic Chinese patients in China have higher
incidence than those outside China (McGlynn et al. 2015).
Evaluation of the California Cancer Registry showed foreign-born Chinese, Korean, and Vietnamese patients had higher
incidence of HCC than US-born patients of the same ethnic
groups. In the US between 2006 and 2010, Asian and Pacific
Islanders had an incidence rate of 9.8–11.7/100,000 (McGlynn
et al. 2021; Sangaramoorthy et al. 2020). The reasons for this
interethnic variability likely include differences in the prevalence
and acquisition time of major risk factors for liver disease and
HCC. In the US, Hispanic and Black patients have almost twofold higher HCC incidence versus white patients (9.8/100,000
and 8.1/100,000 vs 4.6/100,000, respectively). Despite some differences related to genetic risk factors, these differences are more
likely to be driven by socioeconomic determinants than biologic,
including genetics, processes (McGlynn etal. 2021).
Gender
In almost all populations, males have higher liver cancer rates
than females, with male:female ratios averaging between 2:1 and
4:1. The highest ratios are seen in Europe [France (male:female
ratio = 5:0), Malta (male:female ratio = 4:8)] (Petrick and
McGlynn 2019). However, several countries in Africa and central
and South America have a nearly equal male:female ratio [Uganda
(male:female ratio = 1.1), Costa Rica (male:female ratio = 1.6),
and Ecuador (male:female ratio = 1.0)]. In addition, rates of HCC
in men in the US younger than 50 have declined (X. Zhang etal.
2020). While estrogen could have a protective effect for HCC,
men over 70 years have a three-fold higher rate of HCC compared
with post-menopausal women (X. Zhang etal. 2020).
The reasons for higher rates of liver cancer in males could
relate to gender-specific differences in exposure to risk factors.
Men are more likely to be infected with HBV and HCV and
tend to consume more alcohol and smoke cigarettes than
women. The declining rates of HCC in men parallel declining
rates of HCV. Higher androgenic hormone levels and increased
body mass index (BMI) could also adversely affect male risk.
Age
Many factors contribute to variations in global age distribution
of patients with HCC, including gender, region, and etiology of
liver disease (El-Serag and Rudolph 2007). For developed
countries considered low risk, the highest rates of HCC were in
men between 75–80 years of age and in women 80–85 years of
age. In high-risk regions, HCC cases were highest in those
50–59 years old (Sharma 2020). In some high-risk regions, such
as Haimen, China, rates among men are bimodal, with peaks at
ages 50 and 80 years (F. Bray etal. 2017). These variable agespecific patterns are likely related to differences in the dominant hepatitis virus in the population, the age at viral infection,
14 EPIDEmIOLOgY AND RISk FACTORS OF HEPATOCELLuLAR CARCINOmA 253
Africa
Age-Ajusted Rate per 100,000 person-years
Spain
Switzerland
m
Eastern Asia South-Eastern Asia South-We stern Asia Centra l/Eastern Europe North-Western Europe
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100
0.1
10
100
2000
2005
100
2010
100
100
2000
2005
2010
100
0.1
10
1
1995
1990
1985
1980
India
Israel
Kuwait
10
1
1995
1990
1985
1980
Phillipines
Thailand
100
10
1
0.1 0.1
2010
1980
2005
2000
100
100
10
1
1995
1990
1985
1980
Uganda
2000
2005
2010
100
1
1995
1990
1985
1980
China
Japan
Korea
1990
1985
Czech Republic
Slovakia
1995
2000
2005
100
2010
100
10
1
1980
1985
1990
OceaniaSouth AmericaNorth AmericaWestern EuropeSouthern EuropeNorth-Eastern Europe
1995
Denmark
Iceland
Ireland
Norway
United kingdo
2000
2005
2010
Age-Ajusted Rate per 10 0,000 person-years
0.1
2000
2005
10
11
0.1
2010
1980
1995
1990
1985
Croatia
Italy
Malta
Slovenia
10
1995
1990
1985
1980
Estonia
Latvia
Lithuania
2000
2005
10
1
0.1
2010
1980
1990
1985
Austria
France
Germany
The Netherlands
1995
2000
2005
10
1
0.1
2010
1980
1985
1995
1990
Canada
Costa Rica
Puerto Rico
United States
2000
2005
0.1
2010
1980
1985
1995
1990
Brazil
Colombia
Ecuador
2000
2005
1010
11
0.1
2010
1980
1990
1985
1995
Australia
New Zealand
2000
2005
2010
Figure 2 Trends in hepatocellular carcinoma incidence rates by country, 1978–1982 through 2008–2012. Rates are per 100,000 person-years and
age-adjusted to the world standard population. Adapted from McGlynn etal. (2021).
254 3 HEPATOBILIARY AND PANCREAS CANCER
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and other risk factors. Notably, while most HCV carriers
become infected as adults, most HBV carriers are infected at a
very young age.
Distribution of HCC Risk Factors
Major risk factors for HCC vary by region. In most high-risk
areas, the dominant risk factor is chronic HBV infection. In
Asia, HBV is largely acquired by maternal transmission,
whereas sibling-to-sibling transmission at young ages is more
common in Africa. Consumption of AFB
is another major HCC risk factor in most high-rate areas.
Unlike most of Asia, the dominant hepatitis virus in Japan is
HCV, which began to circulate shortly after World War II
(Yoshizawa 2002). Consequently, HCC rates increased sharply
in the mid-1970s peaked around 2010 and started declining
after that.
In low-rate HCC areas, the dominant risk factors for HCC
include cirrhosis due to HCV and, to a lesser extent alcoholic
and non-alcoholic fatty liver disease, as well as a general
improvement in survival among cirrhosis patients. HCV began
to infect large numbers of young adults in North America and
South and Central Europe in the 1960s and 1970s due to injection drug use (Armstrong etal. 2000). The virus then moved
into national blood supplies and circulated until a screening
test was developed in 1990, after which rates of new infection
dropped dramatically. Currently, it has been estimated that
HCV-related HCC in low-rate countries peaked around 2020
(El-Serag and Kanwal 2014; Petrick etal. 2016).
-contaminated foods
1
HCC in the United States
Age-adjusted HCC incidence rates increased more than two-fold
between 1985 and 2002 (El-Serag etal. 2004). However, the rate
of increase slowed between 2009–2013 (Kim and El-Serag 2019).
Recent changes in management of risk factors, including novel
agents for treating and managing HBV and HCV infection have
contributed to this reduced rate increase. However, regions in the
US, such as Texas, have rising incidence (9.7/100000) that primarily affects the Hispanic population (Kim and El-Serag 2019).
In recent years as incidence rates increased, the age distribution
of HCC patients has skewed relatively younger, with the greatest
proportional increases between the ages of 45 and 60. Between
1999 and 2016, HCC-related deaths increased from 5,112 to
11,073 (Kim and El-Serag 2019).
Risk Factors of Hepatocellular
Carcinoma
HCC largely occurs within an established background of
chronic liver disease and cirrhosis (approximately 70–90% of
all detected HCC cases). Major causes of cirrhosis in patients
with HCC include HBV, HCV, alcoholic liver disease, and nonalcoholic steatohepatitis.
Hepatitis B Virus
Globally, HBV is the most frequent underlying cause of HCC
with an estimated 240–350 million persons with chronic infection worldwide (McGlynn et al. 2015). HBV DNA is found in
the host genome of infected and malignant hepatic cells. Thus,
HBV could initiate malignant transformation through a direct
carcinogenic mechanism by increasing the likelihood of viral
DNA insertion in or near proto-oncogenes or tumor suppressor
genes. Chronic HBV carriers have a 10–25% lifetime risk of
HCC. Between 70% and 90%, of HBV-related HCC develops in
a background of cirrhosis (Kulik and El-Serag 2019). The annual
HCC incidence is 0.42% in chronic HBV carriers in the US and
0.6% and 3.7% in HBV carriers without and with cirrhosis in
east Asia, respectively (El-Serag 2012; McGlynn etal. 2021).
The increased HCC risk associated with HBV infection particularly applies to areas where HBV is endemic. In these areas,
HBV is usually transmitted from mother to newborn (vertical
transmission) with up to 90% of infected persons experiencing
chronic infection (El-Serag 2012). This pattern is different in
areas with low HCC incidence rates where HBV is acquired in
adulthood through sexual and parenteral routes (horizontal
transmission) with >90% of acute infections resolving
spontaneously.
Several other factors have been reported to increase HCC
risk among HBV carriers. These include male gender, older
age, longer duration of infection, Asian or African race, cirrhosis, family history of HCC, exposure to AFB
tobacco use, or coinfection with HCV, HIV or hepatitis delta
virus. HCC risk is also increased in patients with higher levels
of HBV replication, as indicated by presence of hepatitis B e
antigen and high HBV DNA levels. It has been suggested in
Asian studies that genotype C is associated with more severe
liver disease than genotype B (McGlynn etal. 2015). Some risk
factors have been incorporated into scoring systems or surveillance recommendations, such as CAMD score (Figure 3), and
the one devised by the American Association for the Study of
Liver Diseases based on cirrhosis, family history of HCC, age,
and Asian or African American race/ethnicity.
HBV vaccination programs are the key HCC prevention
strategy. In Taiwan, HCC incidence declined 80% and
mortality declined 92% in cohorts born after the vaccination
program began (El-Serag and Kanwal 2014). Many other
countries that implemented programs in the 1980s, such as
China, Singapore, and Spain are seeing reductions similar to
those of Taiwan in the prevalence of HBV in vaccinated
cohorts (Gordon etal. 2014).
In the natural history of chronic HBV infection, spontaneous
or treatment-induced development of antibodies against
, alcohol or
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14 EPIDEmIOLOgY AND RISk FACTORS OF HEPATOCELLuLAR CARCINOmA 255
The simple formula of the CAMD score The CAMD score stratifies the risks of HCC during continuous
Follow-up (months)
36
https://t.me/medicina_free
antiviral therapy in patients with chronic hepatitis B
Variable Risk score
Cirrhosis
No cirrhosis
Cirrhosis with age <40 yr
Age
Age <40 yr
Age 40–49 yr
Age 50–59 yr
Age 60 yr or older
Gender
Female sex
Male sex
Diabetes mellitus
Not diabetic
Diabetic
Figure 3 Cirrhosis, Age, Male, Diabetes (CAMD) model for predicting the risk of developing future hepatocellular carcinoma among patients with
chronic HBV who are receiving oral antiviral treatment.
0
10
6Cirrhosis with age ≥40 yr
0
5
8
10
0
2
0
1
20
15
10
5
Cumulative incidance (%)
0
Low risk, <8 points
Intermediate risk, 8–13 points
High risk, >13 points
Log-rank ρ<0.001
0
12
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hepatitis B surface antigen and hepatitis B e antigen or consistently lower level of viral load measured by HBV DNA leads
to improved clinical outcomes. Randomized controlled trials
have shown that antiviral treatment of HBV infection can
achieve sustained reductions in HBV-DNA levels and
improve liver function and histology (World Health
Organization 2015). A meta-analysis found that HBV
treatment with the nucleoside analogs, significantly lowers
HCC incidence by 3.6% (6.4%vs 2.8%) (Papatheodoridis
etal. 2010). Entecavir or tenofovir, both nucleoside reverse
transcriptase inhibitors, are the current first line treatments
are also associated a significant reduction in HCC risk. The
5-year cumulative incidence of HCC in enectavir or tenfovir
was 0.5–6.9% in patients without cirrhosis, 4.5–21.6% in
compensated cirrhosis, and 36.3–46.5% in decompensated
cirrhosis (Tseng etal. 2020).
Using sensitive amplification assays, many studies have demonstrated that HBV DNA persists as an “occult HBV infection”
for decades among persons with serological recovery from
acute infection (i.e., hepatitis B surface antigen negative).
Occult HBV is associated with antibodies to hepatitis B core
and/or surface proteins (El-Serag 2012). However, in a
significant proportion of individuals, neither antibody can be
detected. A systematic review of 16 studies found a small
association with HCC in four longitudinal studies but this was
overestimated due to an erratum in one of the included studies.
The remaining studies found no association; however, they
were limited by small numbers of cases. Currently, there is no
conclusive evidence that occult HBV infection increases HCC
risk (El-Serag 2012; X. Huang and Hollinger 2014).
Hepatitis C Virus
Chronic HCV infection is a major risk factor for HCC
development. HCV is an RNA virus that does not integrate into
the host’s genome and is, thus, unlikely to be the primary initiator of tumorigenesis. Rather, as approximately 90% of HCV
associated HCC cases are preceded by cirrhosis, HCV likely promotes tumorigenesis through repetitive damage, regeneration,
and fibrosis (Davis etal. 2010). Chronic HCV is associated with
a 15–20-fold increase in HCC (Donato etal. 2002). Once HCVrelated cirrhosis is established, HCC develops at an annual rate of
1–4%. The proportion of HCV infection markers in HCC cases
are found in 44–66% of HCC cases in Italy (Fasani etal. 1999;
Stroffolini etal. 1999), 27–58% of cases in France, 60–75% of
cases in Spain, and 80–90% of cases in Japan (Yoshizawa 2002).
Factors that increase the risk of HCC include male sex, older
age, Hispanic ethnicity, heavy alcohol intake, tobacco smoking,
diabetes, obesity, and coinfection with HIV or HBV. Viral
factors such as HCV genotype 3, duration of infection, and
presence of viremia are also associated with increased risk
(McGlynn etal. 2021; Morgan etal. 2013; Petrick etal. 2016).
The advent of direct acting antiviral agents has led to widespread treatment of HCV infection. Sustained virologic
response (SVR) has been shown to decrease the risk of HCC by
50–80% (Ioannou etal. 2017) but not to baseline especially in
patients with advanced fibrosis or cirrhosis. Patients with SVR
have an HCC incidence of 0.24 per 100 person years in patients
without cirrhosis and 1.97 per 100 person years in patients with
cirrhosis. These incidence rates are at, or below, the threshold
for cost-effective HCC surveillance (Figure 4) (Ioannou etal.
2017; Kanwal etal. 2018).
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