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114 1 UPPER GASTROINTESTINAL CANCER
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6 Management of Diffuse Gastric Cancer
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Deborah Chia Hsin Chew1, Raja A.R. Ali
1
Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
2
School of Medical and Life Sciences, Sunway University, Selangor, Malaysia
3
UNSW Microbiome Research Centre, St. George and Sutherland Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health,
University of New South Wales, Sydney, New South Wales, Australia
4
GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
Introduction
Gastric cancer is among the top four leading causes of cancerrelated deaths worldwide. Gastric cancer is histologically
divided into intestinal and diffuse type (Lauren 1965). The
incidence of intestinal-type gastric cancer has decreased in the
last few decades, however the incidence of diffuse type gastric
cancer (DGC) continues to be unchanged (Henson et al. 2004;
van Der Kaaij et al. 2020). Gastric cancer can be further divided
into sporadic or inherited. Inherited gastric cancer is attributed
to high-risk mutations which have only been identified for the
diffuse histotype which is hereditary diffuse gastric cancer
(Chen et al. 2016; Petrelli et al. 2017). HDGC is a rare syndrome characterized by autosomal dominant inheritance with
high penetrance. The subtypes of gastric cancer have different
modes of dissemination patterns: intestinal gastric cancer generally disseminates hematogenously to the liver, while diffuse
gastric cancer spreads via the peritoneal surface (Garcia‐Pelaez
et al. 2021). This classification is of importance because it
determines the phenotypic nature as well as the prognosis. The
survival rate of DGC is poor, with an average of 18 months (van
Der Kaaij et al. 2020) owing to the late stage at diagnosis and
poor treatment response.
Hereditary diffuse gastric cancer (HDGC) is characterized
by mutations in the tumor suppressor CDH1 and, to a lesser
extent, pathogenic variants of CTNNA1 gene (Berx et al. 1998).
The CDH1 gene is situated on chromosome 16q221 and is
made up of 16 exons. It encodes the cell-to-cell adhesion protein E-cadherin (Luo et al. 2018) with germline variants distributed throughout the whole gene (Melo et al. 2017). CTNNA1
encodes for catenin alpha-1, which is a CDH-1 binding partner
(Benusiglio et al. 2019). The neoplastic process begins with the
downregulation of the second copy of the CDH1 gene or
somatic inactivation. Promoter hypermethylation is the most
frequent mechanism of biallelic CDH1 inactivation (Oliveira
et al. 2009). CDH1 genetic variants were discovered as the
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.
1,2,4
& Emad M. El-Omar
hallmark of DGC (Cho et al. 2017; Nemtsova et al. 2020; S. C.
Wang et al. 2020a). Clinically, the hallmark of HDGC is histologically proven multifocal growth accompanied by signet ring
cells in the gastric mucosa as well as lobular breast cancer.
Epidemiology
An estimated 50% of gastric adenocarcinoma are intestinal
gastric cancer, and 30% are diffuse gastric cancer, and 15–20%
are missed or indeterminate (Iyer et al. 2020). HDGC accounts
for 1–3% of all gastric cancer diagnoses (Fitzgerald et al. 2010).
The incidence of HDGC is estimated to be 5 in 100,000 persons
while the incidence of CDH1 mutation is estimated to be 1 in
100,000 (Majewski et al. 2013). The CDH1 mutation was first
reported by Yoshiura et al. in 1995 in several types of tumors
(Yoshiura et al. 1995). Subsequently in 1998, Guilford identified CDH1 genetic mutations in a large kindred from New
Zealand who had early onset diffuse gastric cancer (Guilford
et al. 1998). The incidence of CDH1 mutation in the Maori
population from New Zealand has been reported to be significantly higher. However, precise epidemiological data are still
lacking. Additionally, females who harbor a CDH1 germline
pathogenic mutation carry an elevated lifetime risk of 39–52%
for Lobular Breast Cancer (LBC) (Hansford et al. 2015). The
combined risk of gastric and breast cancer at 80 years of age is
approximately 90% (Blair et al. 2020). The median age of diagnosis of HDGC is 38 years (range 14–69 years) (Hansford et al.
2015). An estimated 40% of patients with HDGC have the
presence of CDH1 germline mutation (Hansford et al. 2015),
while the CTNNA1 gene mutation is much less common.
Pathophysiology
Diffuse gastric cancer demonstrates an absence of adhesion
molecules, and its hallmark histologically is a poorly differentiated, infiltrative, and poorly cohesive appearance (Iyer et al.
2020). It has been demonstrated that mutations in adhesion
and motility protein in diffuse gastric cancer likely contribute
to its infiltrative and poorly cohesive histology (Iyer et al. 2020).
3
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E-cadherin is a type 1-cadherin that is present in the adherens
junctions of all epithelial tissues (Yu et al. 2019). It has an extracellular domain, a transmembrane domain, and an intracellular
domain. E-cadherin plays an important role in maintaining cell
polarity and homeostasis, and cell stability (Maître and
Heisenberg 2013). Soluble E-cadherin plays a role in regulating
many signaling pathways by both paracrine and autocrine signaling (Kourtidis et al. 2017), thereby modulating signaling
pathways such as cylin kinase inhibitor p27-mediated signaling, activation of mitogen-activated kinase (MAPK), rat sarcoma viral oncogene (Ras), phosphatidylinositol-3-kinase
(P13K)/AKT, ras-related C3 botulinum toxin substrate (Rac1)
signaling and HIPPO signaling and epithelial-mesenchymal
transition. Every domain of E-cadherin is susceptible to truncating and missense mutations, with truncation occurring
most commonly in EC2, EC3, EC5, and IC (Lo et al. 2019).
The loss of E-cadherin results in weakened adherence
junctions in epithelial tissues as well as reduced intercellular
stability, which is the first and most important step toward
tumorigenesis, metastasis, angiogenesis, and invasion (Goud
et al. 2020). E-cadherin is encoded by CDH1, and dysregulation
results in gastric epithelial cell dysfunction (Liu and Chu 2014).
CDH-1 mutation carriers have a predisposition toward chronic
gastritis, foveolar hyperplasia, cystic gland dilatation, and epithelial tufting and globoid changes (Rocha et al. 2018). The
most frequently encountered CDH1 mutations are truncating
of deleterious missense mutation, which happens in the cadherin domain (Iyer et al. 2020). CDH1 mutation carriers are
predisposed toward two types of precursor lesions: in situ signet-ring carcinoma and the second, which is signet-ring cells
with pagetoid growth patterns inside the glandular basal membrane below the non-neoplastic glandular epithelium and foveola (Cosma et al. 2022). While CDH1 mutations are inherited
in an autosomal dominant manner, the penetrance for gastric
cancer was shown to be 70% in males and 56% in females
(Katona et al. 2020). TP53 mutation was also discovered to be
important to the development of diffuse gastric cancer which is
likely to be mutated early in the disease (Iyer et al. 2020).
Diagnosis
Presentation
Diffuse gastric cancer is associated with a poor prognosis due
to its aggressive nature as well as late detection of the disease
with a poor five-year survival of 45% compared to intestinal
gastric cancer at 57.7% (Chen et al. 2016). Symptoms associated with diffuse gastric cancer are vague and can range from
asymptomatic to reflux symptoms. Additionally, diffuse gastric
cancer may be missed on endoscopy as tumor cells infiltrate in
an unpredictable pattern (Kumar et al. 2019; R. Wang et al.
2020a), hence the disease may not be endoscopically visible,
and random biopsies of the gastric mucosa may not pick up
cells which are too deep or scattered (Iyer et al. 2020). Diffuse
gastric cancer has a higher propensity to develop into peritoneal carcinomatosis, which may not be picked up on standard
imaging as well as the low standard uptake values (SUV) in
PET CT scans likely attributed to a decreased expression of glycolytic pathways compared to intestinal gastric cancer (R.
Wang et al. 2020a). In view of the increased propensity for peritoneal metastases in diffuse gastric cancer, diagnostic laparoscopy is a valuable diagnostic tool when clinical suspicion is
high in the setting of negative endoscopy (Rawicz‐Pruszyński
et al. 2019).
Surgical Approaches
Curative surgical management can be performed by total gastrectomy and Roux-en-Y esophagojejunostomy after a baseline
endoscopy (Iyer et al. 2020). In the setting of cT1aN0 disease
D1 dissection is frequently performed. In patients with cT1N+
and resectable T2–T4 tumors management differs between
East Asia and the West. In East Asia, gastrectomy plus D2 dissection is the standard of care. However, D2 dissection did not
demonstrate a survival benefit in the West. Therefore, D2 dissection is recommended but not mandatory and should be carried out in a high-volume center by a highly skilled surgeon
(Cuschieri et al. 1999; Hartgrink et al. 2004; Mihmanli et al.
2016; Songun et al. 2010). If gastric cancer invades the duodenum then D2 dissection should be extended to encompass
the retro-pancreatic lymph nodes with this dissection being
termed D2+ (Mihmanli et al. 2016). There is no benefit of D3
dissection as it results in worse survival with associated higher
morbidity (Sasako et al. 2008).
Criteria for HDGC Genetic Testing
The International Gastric Cancer Linkage Consortium (IGCLC)
has defined the prerequisite in order to guide the clinician to
screen for CDH1/CTNNA1 mutation analysis (Blair et al. 2020).
The criteria state that genetic testing for CDH1 and CTNNA1
mutations should be performed in a family who has first or second degree relatives who have (1) two or more relatives with
gastric cancer regardless of age with at least one having diffuse
gastric cancer; (2) one or more relatives with diffuse gastric cancer diagnosed at any age and one or more cases of lobular breast
cancer before the age of 70; (3) two or more relatives with lobular breast cancer before the age of 50; meanwhile individual
criteria state that (4) diffuse gastric cancer in an individual
below the age of 50; (5) gastric in situ signet ring cells and/or
pagetoid spread of signet ring cells in an individual below the
age of 50; (6) diffuse type gastric cancer at age in an individual
with personal or first-degree family history of cleft lip or cleft
palate; (7) diffuse type gastric cancer and lobular breast cancer
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in an individual before the age of 70; (8) Bilateral lobular breast
cancer or lobular carcinoma in situ in an individual diagnosed
before the age of 70; (9) Diffuse type of gastric cancer in an
individual of Maori ethnicity diagnosed at any age. Genetic testing should be extended to those fulfilling the genetic testing criteria from the legal age of consent from ages 16 to 18 onwards
(Blair et al. 2020). Younger individuals may also be offered the
test if family history is suggestive (Blair et al. 2020).
Due to the increased risk of gastric cancer, prophylactic gastrectomy is advocated in individuals harboring the CDH1 mutation and with a history of diffuse gastric cancer in the family
(Treese et al. 2022). The recommended age for prophylactic
total gastrectomy is from 20 up to approximately 30 years old
(Blair et al. 2020). In patients who are above the age of 70 or
those with markedly elevated peri-operative morbidity, prophylactic gastrectomy carries a significantly elevated risk and hence
is not recommended. In individuals who decline surgery, annual
endoscopy in a center with an endoscopist well-versed in
HDGC is recommended (Blair et al. 2020). Helicobacter pylori
should be eradicated if found (Blair et al. 2020). If suspicious
lesions are found, especially in areas of pale mucosa or areas
with rigid wall motility on inflation and suction, they should be
biopsied (Treese et al. 2022). Five random biopsies from six
zones of the stomach in accordance with the Cambridge biopsy
protocol should be performed (Fitzgerald et al. 2010). Lifelong
follow-up post prophylactic total gastrectomy should be undertaken (Blair et al. 2020). Yearly screening for lobular breast cancer or bilateral mastectomy is recommended to reduce the risk
of lobular breast cancer (Blair et al. 2020).
The diagnosis of HDGC from endoscopic or surgical biopsy
should be made by an experienced pathologist and reported in
accordance with the World Health Organization (WHO) criteria
(Smyth et al. 2016). Once the diagnosis is confirmed, staging and
risk assessment should be performed which includes a contrastenhanced computed tomography scan of the thorax, and
abdomen ± pelvis. Patients should be managed in a multidisciplinary team. Total gastrectomy should be performed with intraoperative confirmation of esophageal squamous mucosa in the
proximal margin and duodenal mucosa in the distal margin with
D2 lymph node dissection (Blair et al. 2020). All patients should
receive lifelong follow-up and special attention should be given to
long-term complications of total gastrectomy symptoms, which
include nutritional, hormonal, neurocognitive, psychological,
and pharmacokinetic effects (van der Post et al. 2015).
Summary
Diffuse gastric cancer encompasses approximately 30% of gastric
cancer diagnoses and carries a high mortality due to its late presentation and chemoresistance. Endoscopists must be familiar
with its pathophysiology and diffuse presentation, which may
result in it not being visualized endoscopically. Given its
propensity for peritoneal disease, if the clinical suspicion remains
high, there is a role for diagnostic laparoscopy. The most commonly encountered mutation in diffuse gastric cancer is CDH1
which is part of the hereditary syndrome. The clinician should
be familiar with the IGCLC diagnostic criteria of HDGC and
offer genetic testing for CDH1 and CTNNA1 where the criteria
are met. Consideration of prophylactic total gastrectomy or
yearly surveillance endoscopy in those who decline surgery with
biopsies performed according to the Cambridge protocol should
be performed. Lifelong follow-up is needed post-total gastrectomy to monitor for its complications. Screening for lobular
breast cancer with yearly imaging or prophylactic bilateral mastectomy is also recommended to reduce the risk of breast
cancer.
Key Take Home Messages
1 Forms of diffuse gastric cancer can be tested by CD1 and
CTNNA1 assays.
2
Lifelong screening for gastric and breast cancer is often
required.
Areas for Further Research
1 Forms of cancer prevention without invasive surgery
2 Better understanding of the penetrance of the disease
Trusted Websites for Further Research
https://rarediseases.info.nih.gov/diseases/10334/diffuse-gastric-
cancer
https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/
rare-digestive-system-tumors/hereditary-diffuse-gastric-cancer
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7 Intestinal-type Gastric Cancer
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Ka Shing Cheung
1
Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
2
Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
3
Hong Kong Sanatorium Hospital, Hong Kong, China
1,2
, Annie On On Chan
Introduction
For over 100 years, gastric cancer has remained one of the most
important malignant diseases with significant geographical,
ethnic, and socioeconomic differences in distribution.
Currently, gastric cancer is the fifth most common cancer with
over one million incident cases worldwide in 2020, accounting
for 5.6% of new cancers (Sung et al. 2021). It ranked the fourth
for cancer-related mortality with an estimated 769,000 deaths,
accounting for 7.7% of all cancer deaths. The incidence has
great regional variability, being the highest in East Asia (in
particular China, Japan, and Korea) where around half of the
new cases are diagnosed, followed by Latin America and
Eastern Europe. With the rapid decline in the global incidence
of gastric cancer, the discovery of Helicobacter pylori (H. pylori),
and the advancement in molecular biology, the view toward
gastric cancer has been changing. This chapter focuses on the
intestinal type of gastric cancer, the staging system, treatment,
prognosis and follow-up.
Intestinal Gastric Cancer
Gastric cancer is a heterogeneous disease entity with different
proposed types of classification according to histology (Lauren
and World Health Organization [WHO]) and, more recently,
molecular characteristics. The Lauren classification has been
traditionally used, in which gastric cancer is classified into
intestinal, diffuse and mixed types, according to glandular
formation (Lauren 1965). Intestinal and diffuse types are different with regard to epidemiology, etiology, pathogenesis, and
behavior. For molecular characteristics, there are two
classifications according to the Cancer Genome Atlas (TCGA)
research group (2014) and Asian Cancer Research Group
(ACRG) (Cristescu et al. 2015).
Intestinal gastric cancer is more common in male and older
age groups and is likely linked to environmental factors.
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.
1,3
& Benjamin Chun Yu Wong
A recent decline in the incidence of the intestinal type in the
past few decades worldwide that parallels the overall decline in
cursor lesions and environmental factors are summarized in
the following section.
Precursor Lesions and Environmental
Factors
Helicobacter Pylori and the Correa’s Cascade
Studies of gastric cancer among migrants have shown that emigrants from high-incidence countries to low-incidence locations often experience a decreased risk of developing gastric
carcinoma. This reduction in the risk was seen in subsequent
generations and to a lesser degree in the first generation
(Haenszel 1982). Such findings strongly suggest that environmental factors play an important role in the etiology of gastric
cancer and that exposure to risk factors occurs early in life.
The intestinal-type gastric cancer typically arises through the
Correa’s cascade, progressing from chronic gastritis to chronic
atrophic gastritis, intestinal metaplasia, dysplasia, and eventually to adenocarcinomas (Correa 1982; Correa á 1983; Correa
1988; Correa et al. 1975). Recently, intestinal metaplasia has
been recognized as a surrogate biomarker of the genetic instability that promotes the progression of gastric stem cells to cancer stem cells. The most common etiological agent triggering
the Correa’s cascade is H. pylori infection. This association has
been demonstrated in large epidemiology studies (Kikuchi
et al. 1995; Parsonnet et al. 1991a, 1991b; Wong et al. 1999).
The WHO’s International Agency for Research on Cancer classified H. pylori as a Group 1 or definite carcinogen (IARC
WGotEoCRtH, Cancer IAfRo, Organization WH 1994).
H. pylori infects around 50% of the population worldwide, with
significant geographical variation ranging from 19% to 88%
(Hooi et al. 2017). Around 1–2% of H. pylori infected subjects
will develop gastric cancer (Uemura et al. 2001). H. pylori is a
Gram-negative rod bacterium that localizes beneath the
mucous layer of the mucosa from stomach, metaplastic
1
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esophagus, duodenum, and even Meckel’s diverticulum. The
Helicobacter genus also includes mustelae, muridarum, and
nemestrinae, which are urease-positive but appear to be limited
to stomachs of other mammals (Blaser 1992). The ability of the
bacterium to survive in the acidic environment of the stomach
relies on the presence of a high molecular weight urease. This
enzyme catalyzes the transformation of urea to ammonium and
bicarbonate, which alkalinizes the environment and protects
the bacteria from gastric acid. The organism’s production of
proteases, lipases, phospholipases, and cytotoxins, combined
with its ability to attach to epithelial cells via adherence proteins, contributes to its pathogenicity (Fennerty 1994).
Elder pointed out that 10% of patients with chronic atrophic
gastritis would eventually develop gastric cancer within a period
of 15 years (Elder 1995). In atrophic gastritis, there is progressive atrophy of the glandular epithelium with loss of parietal and
chief cells. The loss of the normal exocrine glands of the gastric
mucosa causes hypochlorhydria and a resultant increase in
gastric pH. An abnormally high pH in the stomach allows
microbial colonization, some of which possess nitrate reductase,
allowing nitrosation that is genotoxic. In addition, there is a loss
of endocrine cells which normally secrete epidermal and transforming growth factors, which aid the stomach in regenerating
damaged tissue (Elder 1995). Finally, populations with a high
prevalence of atrophic gastritis also have a high prevalence of
gastric cancer, and vice versa (Genta 1998).
Metaplasia is a potentially reversible change from a fully differentiated cell type to another cell type, a process in adaptation
to environmental stimuli. In the stomach, intestinal-type metaplasia is the most common form. This occurs as a result of
Helicobacter pylori infection, or bile reflux (Sobala et al. 1993),
or can be induced experimentally by irradiation (Watanabe
1978). Extensive gastric intestinal metaplasia refers to intestinal
metaplasia involving both the antrum and corpus or corpus
alone; while limited gastric intestinal metaplasia refers to
involvement of only antrum or incisura (Gawron et al. 2020).
Histologically, intestinal metaplasia can be classified as
complete and incomplete based on the epithelial cells types
(small intestine or colon) and types I to III intestinal metaplasia
according to mucin types produced by the goblet cells (sialomucins and sulfomucins) (Correa et al. 2010). Intestinal metaplasia is more frequent in countries with a higher incidence of
gastric carcinoma (Correa et al. 1970), and has been shown to
precede gastric carcinoma (Sasajima et al. 1979). Within the
gastric cancer risk index, the presence of intestinal metaplasia
was the only criterion associated with the development of
intestinal type gastric cancer in Japan (Shimoyama et al. 2000).
Atrophy and intestinal metaplasia occur significantly more
often in the antrum of carcinoma patients. The incidence rate
of progression from intestinal metaplasia to dysplasia and
gastric cancer is 97.6 cases and 12.4 cases per 10,000 person–
years, respectively (Gawron et al. 2020). Risk factors for
progression include family history of gastric cancer, extensive
intestinal metaplasia and incomplete intestinal metaplasia
(Gawron et al. 2020). Two validated histologic staging systems
based on the degree and extent of gastric atrophy and/or
intestinal metaplasia, namely Operative Link for Gastritis
Assessment (OLGA) (Rugge et al. 2007) and Operative Link on
Gastric Intestinal Metaplasia Assessment (OLGIM) (Capelle
et al. 2010) have been proposed for stratifying risk of gastric
cancer. Those with OLGA or OLGIM stages III-IV are considered to be at high risk.
Most patients diagnosed with high grade dysplasia of the
gastric mucosa will either already have developed or soon
develop gastric cancer. In gastrectomy specimens for gastric
cancer, 20–40% of patients had associated dysplasia, and progression of dysplasia to gastric cancer has been estimated at
21%, 33%, and 57% of cases of mild, moderate, and severe dysplasia, respectively (Rugge et al. 1994). In a population-based
cohort study, the risk of gastric cancer increased progressively
with the presence of atrophic gastritis, intestinal metaplasia and
dysplasia as compared with normal gastric mucosa by a hazard
ratio (HR) of 4.5, 6.2, and 10.9, respectively (Song et al. 2015).
H. pylori is associated with adenocarcinoma of non-cardia
regions of the stomach, including both intestinal and diffuse
types. H. pylori infection has been estimated to increase the risk
of gastric cancer by around three fold (Cavaleiro-Pinto et al.
2011). It is estimated that H. pylori infection attributes to 89%
of non-cardia gastric cancer cases and 78% of all gastric cancer
cases (Plummer et al. 2015). On the other hand, adenocarcinoma of the cardia (accounting for 10–15% of gastric cancer) is
more related to GERD, obesity and smoking (Yusefi et al. 2018).
More recent evidence suggests that cardia cancer may still arise
from H-pylori-induced atrophic gastric mucosa if two-thirds of
the tumor extends into the stomach (Malfertheiner et al. 2017).
Three sources of evidence support the association of H. pylori
infection and gastric cancer: epidemiologic studies comparing
gastric cancer and H. pylori infection prevalence rates,
cross-sectional studies evaluating H. pylori infection in cancer
patients, and prospective studies associating H. pylori with
gastric cancer (Eurogast Study Group 1993; Forman 1991;
Nomura et al. 1991; Parsonnet et al. 1991a, 1991b; Talley et al.
1991; Parsonnet 1993). Epidemiologically, the incidences of
both H. pylori infection and gastric cancer follow similar geo-
graphic and temporal trends (Parsonnet 1993). Cross-sectional
studies investigating H. pylori infection in gastric cancer
patients have revealed that H. pylori is more likely to infect
populations of gastric cancer patients than normal populations,
with rates of infection ranging from 50% to 100% in patients
with gastric adenocarcinoma (Parsonnet et al. 1991a; Parsonnet,
1993). Paradoxically, histologic association of the bacteria with
tumor can be difficult to determine because H. pylori has an
affinity for normal gastric mucosa but not metaplastic, dysplastic, or malignant tissue (Hazell et al. 1987). Prospective
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studies of H. pylori and cancer reveal that H. pylori infection
increases the risk of developing gastric cancer in later life,
although most people infected with H. pylori do not develop
gastric carcinoma (Forman et al. 1991; Nomura et al. 1991;
Parsonnet et al. 1991a). However, a paradox in H. pylori infec-
tion is that divergent clinical outcomes occur: patients may
develop duodenal ulcer or gastric cancer, while the majority of
them develop no significant clinical symptoms. Bacterial virulence factors have failed to explain why the ulcer or the gastric
cancer phenotype develops. This has highlighted the need to
explore host genetic factors as determinants of clinical outcome
of the infection, including gastric cancer.
It is noteworthy that although H. pylori is the most important
cause of gastric cancer, H. pylori eradication only reduces
gastric cancer risk by 46% from a meta-analysis of seven
randomized controlled trials (RCTs), six of which were conducted in East Asian countries (Ford et al. 2020). This is related
the presence of baseline pre-cancerous lesions undermining
the efficacy of H. pylori eradication in reducing gastric cancer
risk (Chen et al. 2016; Wong et al. 2004). While H. pylori eradication reverses chronic gastritis and atrophic gastritis, it may
not regress intestinal metaplasia lesions (Pimanov et al. 2008;
Rokkas et al. 2007; Watari et al. 2008), which was once considered a “point of no return” in the Correa’s cascade (Wong et al.
2004). However, a recent prospective study with a follow-up
duration of up to 10 years did not detect difference in the prevalence of intestinal metaplasia between H. pylori-eradicated
and H. pylori-negative groups in the antrum and corpus, after
the follow-up periods of ≥ 5 and ≥ 3 years, respectively (Hwang
et al. 2018). The probability of intestinal metaplasia reversal
decreases with increasing Operative Link on Gastric Intestinal
Metaplasia Assessment (OLGIM) stages (Lee et al. 2021).
Another study that observed 2,258 patients for up to 15 years
showed that H. pylori eradication reduced gastric cancer risk
even in those with intestinal metaplasia and dysplasia (Li et al.
2014). Moreover, H. pylori eradication reduces subsequent
gastric cancer risk by 51% in patients who underwent endoscopic resection for gastric neoplasia (Ford et al. 2020).
The Host: Blood Group, Genetic
Polymorphisms, Germline Mutation
The role of genetic factors was first suggested by the study of
blood groups and determinants of chronic gastritis (Langman
1988). Individuals of blood group A have been known for
decades to show approximately 20% higher rates of gastric cancer than those of group O, B, or AB. They also show a similar
increase of pernicious anemia. Some data suggest that group A
may be particularly associated with the diffuse type of gastric
cancer (Langman 1988). A genetic etiology has been reported
for chronic atrophic gastritis (Bonney et al. 1986). The genetic
segregation analysis showed Mendelian transmission of a
recessive autosomal gene with penetrance dependent on age
and the status of chronic atrophic gastritis in the mother. Of
individuals with affected mothers 48% were affected as compared to only 7% of those who mother did not have chronic
atrophic gastritis. A familial tendency to stomach cancer has
long been suspected and repeatedly confirmed (Langman 1988;
Palli et al. 1994; Zhao et al. 1994).
The human interleukin-1 beta (IL-1B) gene is the most
important candidate gene in the host that could affect the
clinical outcome of H. pylori infection, because it is upregulated
by infection, is profoundly proinflammatory, and is the most
powerful acid inhibitor known. Polymorphisms in the IL-1B
gene (carriers of IL-1B-511*T) and in the IL-1 receptor antagonist gene (IL-1RN*2/*2) were found to be associated with an
increased risk of gastric cancer (El-Omar et al. 2000).
Figueiredo, Machado, Pharoah, Seruca, Sousa, Carvalho,
Capelinha, Quint, Caldas, and van Doorn (Figueiredo et al.
2002) had further suggested I L-1B-511*T carriers (IL-1B511*T/*T or IL-1B-511*T/*C) homozygous for the short allele
of IL-1RN (IL-1RN*2/*2) in the presence of vacAs1-, vacAm1-,
and cagA-positive strains of H. pylori had an increased gastric
carcinoma risk. The presence of several cytokine polymorphisms also leads to a multiplied risk of cancer.
The IFNGR1 gene encodes chain 1 of the interferon-gamma
(IFN-gamma) receptor. Sequencing of IFNGR1 revealed
-56C→T, H318P, and L450P variants, which were found to be
associated with high H. pylori antibody concentrations. The
variants were more prevalent in Africans than in whites. These
findings indicate that IFN-gamma signaling plays an essential
role in human H. pylori infection, and they might in part
explain the observations of high prevalences and relatively low
pathogenicity of H. pylori in Africa (Thye et al. 2003).
Genetic polymorphisms of methylenetetrahydrofolate
reductase (MTHFR) have also been associated with gastric
cancer, but mainly in East Asians (Zintzaras 2006).
A germline mutation in the cadherin 1 (CDH1) gene, which
encodes the cell adhesion protein E-cadherin, was identified in
a New Zealand family with gastric cancer (Guilford et al. 1998)
and in several UK families in 1999 (Richards et al. 1999).
Thereafter, in two kindreds with familial gastric cancer and
germline E-cadherin mutation, promoter CpG hypermethylation was found to be the second “genetic hit” in abrogating
E-cadherin expression (Grady et al. 2000). Other triggering
mechanisms for inactivation of the second allele of E-cadherin
include mutation and loss of heterozygosity. These results show
that CHD1 gene is an important putative tumor suppressor
gene involved in gastric carcinogenesis, which has a penetrance
rate of more than 60% (Oliveira et al. 2015). It is one of the
causes for hereditary diffuse-type gastric cancer accounting for
1–2% of gastric cancer (Oliveira et al. 2015).
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Interplay between Environmental Factors,
the Organism and the Host
Tsugane et al. have found that in a Japanese population, higher
salt intake correlates with higher prevalence of H. pylori infection (Tsugane et al. 1994). It was postulated that gastric mucosal
damage caused by high salt intake facilitated H. pylori infection. The resultant hypochlorhydria and bacterial overgrowth,
with the subsequent conversion of nitrites to the mutagenic
N-nitrosamines, were postulated to be the instigating events
that led to metaplasia, dysplasia, and cancer. Gastric juice of H.
pylori-positive individuals had a lower concentration of vitamin
C than H. pylori-negative individuals, but the concentration
returned to normal when H. pylori was eradicated (Schorah
et al. 1991). Therefore, vitamin C could play an important role
in preventing the damage caused by H. pylori through its antioxidant effect (Schorah et al. 1991). In addition, through their
anti-nitrosation and antioxidant effects, beta-carotene and
ascorbic acid are believed to halt this progression to cancer and
thus act as protective factors (Parsonnet 1993). However, this
dogma has been supplanted by the hypothesis that H. pylori
infection in early life leads to the formation of chronic atrophic
gastritis, and the resultant transformation to metaplasia, dysplasia, and, ultimately, malignancy. The most convincing hypothesis is that chronic inflammation, with the resultant
inflammation-related mutagenesis, may lead to genetic mutations culminating in malignant transformation. In addition,
the resulting cellular proliferation may increase the likelihood
of mitotic error and invoke a role for genotoxicity. This model
also acknowledges the role of dietary factors in gastric carcinogenesis. While dietary mutagens may increase the risk of mutation, dietary antioxidants may act as protective factors. Because
some DNA damage can be self-corrected, H. pylori-related
mutations may only rarely lead to malignant transformation.
Thus, longer duration of infection, especially infection acquired
during childhood and continuing until old age, increases the
risk of significant DNA damage with subsequent malignant
transformation (Parsonnet 1993). In addition, both H. pylori
genotype and host genetic polymorphisms play a role in determining the clinical consequences of H. pylori infection and
hence the risk of developing gastric cancer. It has been suggested that combined bacterial/host genotyping may provide
an important tool in defining disease risk and targeting H.
pylori eradication to high-risk individuals.
Despite the proposal of dietary, environmental factors and the
identification of H. pylori, the rapid global decline in gastric cancer is still not fully explained. An interesting hypothesis is that the
introduction of refrigeration marks a pivotal point for the decline
(Coggon et al. 1989; La Vecchia et al. 1990; Park et al. 2011).
Refrigerators improved the storage of food, thereby reducing salting for preserving food and preventing bacterial and fungal contamination of food. Refrigeration also enables fresh food and
vegetables to be more readily available, which may be a valuable
source of antioxidants important for cancer prevention.
Diet
Large epidemiology studies demonstrating the association
between diet and gastric cancer were mainly based on the
amount of food imported and produced rather than actual
food consumption (Howson et al. 1986). This takes no
account of the losses during storage, distribution, and consumption of food, nor any ethnic dietary differences.
Nonetheless, the information provides important insights
into environmental causes of gastric cancer. The association
between N-nitroso compounds and gastric cancer has been
summarized by Bartsch, O’Neill, and Schulte-Hermann
(Bartsch et al. 1987). The risk of gastric cancer induced by
N-nitroso compounds has been demonstrated in animal
experiments (Bulay et al. 1979; Druckrey 1975; Magee 1976).
An increase in gastric nitrite was observed in patients with
intestinal metaplasia, dysplasia, and gastric cancer (Jones
et al. 1978; Stewart 1967; Ruddell et al. 1978). The use of
nitrate-based fertilizers (Fraser et al. 1980; Jones et al. 1978;
Schlag et al. 1980) and consumption of pickled foods that
contain nitrosated products (Haenszel et al. 1972; Sato 1959)
have been shown to positively correlate with gastric cancer.
Diets low in vegetables, fruits, milk, and vitamin A, and high
in fried food, processed meat, and fish and alcohol have
been associated with an increased risk of gastric carcinoma
in several cohort studies (Graham et al. 1990). Diets low in
citrus fruit show the strongest association with gastric carcinoma. The protection afforded by vegetables and fruits is
most likely related to their vitamin C content, which is
thought to reduce the formation of carcinogenic N-nitroso
compounds inside the stomach. Cooked vegetables, however, do not show the same protective effect as uncooked
vegetables (Buiatti et al. 1989). High salt intake has been
shown to damage stomach mucosa and increase the susceptibility to carcinogenesis in rodents (Hanawa et al. 1980;
Takahashi et al. 1984; Tatematsu et al. 1975). The positive
correlation between nitrate intake, salt excretion and gastric
cancer has recently been shown in the INTERSALT study
involving 24 countries from 39 populations (Joossens et al.
1996). A meta-analysis of 42 studies showed that smoking
increased gastric cancer risk by approximately 50%, irrespective of cancer subsite (Ladeiras-Lopes et al. 2008). The
risk declined significantly after 10 years of smoking cessation from a large prospective European cohort (González
et al. 2003). On the other hand, an association between
alcohol consumption and gastric cancer risk has not been
consistently demonstrated (Barstad et al. 2005; Tramacere
et al. 2012; Wang et al. 2018).
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