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dietary intake of salt (Piazuelo and Correa 2013). Some food might contain
carcinogens such as nitrates that are generally found in preservative-used food and
meat. These materials interact with the mucosal lining, irritate, and damage the
gastric tissue, forming lesions that can develop to cancer. Some types of NCGC
are commonly associated with chronic Helicobacter pylori infection, which usually
progresses to cause chronic gastric inflammation and GC. However, the diffuse type
of NCC has been associated genetically with E-cadherin gene silence mutation and
less likely to be associated with nutritional and other factors such as diet or smoking
(Anderson et al. 2010).
4.1.2 Grading of Gastric Cancer
Gastric cancer forms when malignant or cancerous cells arise in the stomach. From
outside the gastric wall has four defined layers: mucosa, submucosa, serosa, and
muscularis propria. The innermost and the most affected layer by gastric cancer is
the mucosa. It comes in direct contact with the food and gastric contents (Hosseini
and Dehghan 2014). Mucosa has three layers: epithelial layer, the innermost layer of
mucosa that absorbs food, secretes mucus, gastric acid, and digestive enzymes;
lamina propria, the middle layer of mucosa where the blood and lymph vessels
and mucosa-associated lymphoid tissue located; muscular mucosa, the outermost
layer of mucosa that contracts and mixes the food with gastric enzymes (Goldber g
and Raufman 2015). Submucosa, the next supporting layer of the mucosa. Then
muscularis propria, a thick muscular layer. Finally, serosa, the outer layer of the
stomach. Inside the epithelial layer, gastric pits have foveolar cells that secrete
mucus to protect the stomach from autodi gestion. Parietal cells located in the body
and fundus areas maintain the acidic pH by secreting hydrochloric acid (HCL). Chief
cells and G-cells, which secrete digestive enzymes such as pepsinogen and gastrin,
respectively (Curcic et al. 2014). Grading gastric cancer is a crucial step to evaluate
stomach cancer and develop an individualized treatment plan. It is based on a scale
of the depth of invasion, size, and growth (T), lymph nodes involvement (N), and
distant metastasis (M). This scale is described in detail in Table 4.1 (Sano et al. 2016;
Washington 2010).
4.1.3 Risk Factors
In the USA, gastric cancer was on the top in the leading causes of cancer deaths until
the late 1930s. Today, there is a global decline in the incidence of gastric cancer on
the list of the leading causes of death (Bray et al. 2018). Like most forms of cancer,
gastric cancer is considered a mul tifactorial disease that might originate due to
different causes. Risk factors for gastric cancer are genetic makeup and family
history of gastric cancer, age, smoking, alcohol consumption, and obesity (Eusebi
et al. 2014). Furthermore, Helicobacter pylori infection, nutritional factors, and
gender are specific risk factors that are commonly associated with intestinal subtype
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Table 4.1 Gastric cancer grading system
Grade Description
Grade 0
T0-N0-M0
Carcinoma in situ (tis), where cancer has not spread into the inner
layers, lymph nodes (N0), nor metastasized (M0)
Grade
I
(A)
T1-N0-M0 Cancer tissue reaches the upper layer of the mucosa (T1) but does not
reach the muscle layer with no lymph nodes involvement (N0) or
metastasis (M0)
Grade
I
(B)
T1-N1-M0
T2-N0-M0
Cancer tissues reach the upper layer of the mucosa (T1) and to a
maximum of two lymph nodes (N1) but no metastasis (M0).
or
Cancer tissues reach beneath the upper layer of cells into the muscularis
propria layer (T2), with no involvement in lymph nodes (N0) or distant
tissue (M0)
Grade
II
(A)
T1-N2-M0
T2-N1-M0
T3-N0-M0
Cancer tissues reach the upper layer of the mucosa (T1) but not the main
muscle layer, with three to six nearby lymph nodes involvement
(N2) but no distant tissue involvement (M0).
or
Cancer tissues reach beneath the top layer of cells (T2) with not more
than two nearby lymph nodes (N1) but no metastasis (M0).
or
Cancer tissues reach beneath the top layer into the subserosa (T3).
However, it has not spread to lymph nodes (N0) nor metastasized (M0)
Grade
II
(B)
T1-N3a-
M0
T2-N2-M0
T3-N1-M0
T4a-N0-
M0
Cancer reaches the second layer, such as mucosa into the lamina propria
(T1), and has reached 7 to 15 nearby lymph nodes (N3a) with no
metastasis (M0).
or
Cancer reaches the muscularis propria (T2), and it has reached three to
six nearby lymph nodes (N2) with no metastasis (M0).
or
Cancer reaches the subserosa layer (T3) with one to two lymph nodes
(N1) involvement but no metastasis (M0)
or
Cancer reaches the stomach wall into the serosa (T4a) but no spread to
lymph nodes (N0) nor metastasis (M0)
Grade
III
(A)
T2-N3a-
M0
T3-N2-M0
T4a-N1-
M0
T4b-N0-
M0
Cancer reaches the outer muscular layers of the stomach wall (T2) with
spread to 7 to 15 lymph nodes (N3a) but no metastasis (M0).
or
Cancer penetrates all muscular layers into the connective tissue
or
Cancer penetrates all layers of the muscle into the connective tissue but
not into the peritoneal lining (T4a) with spread to one to two lymph
nodes (N1) but no metastasis (M0).
or
Cancer penetrates all layers of the muscle into the connective tissue and
has grown into nearby organs or structures (T4b) with no spread to
lymph nodes (N0) but no metastasis (M0)
Grade
III
(B)
T1/2-N3b-
M0
T3-N3a-
Cancer reaches the inner layer of the wall of the stomach or the outer
muscular layers of the stomach wall (T1/T2) and spread to 16 or more
lymph nodes (N3b), but no metastasis (M0).
(continued)
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gastric cancer (Eusebi et al. 2014). The overall improvement and the global shift
toward healthier practices, such as the rapid growth of the organic food industry,
consumption of preservative-free diet, and tobacco cessation believed to change the
trend and decrease the incidence of the disease (Zabaleta 2012). Also, the availability
of fresh vegetables and fruits, which believed to decrease the consumption of
preservatives, salted, and smoked foods (González and Agudo 2012).
Other researchers believed that Helicob acter pylori discovery and antibiotics
availability are major factors that reduce the rate of gastric cancer. Despite the global
decline in the incidence of intestinal and diffuse gastric cancer, gastric cancer is still
listed among one of the most aggressive types of cancer (Nagini 2012). Each of the
previously mentioned risk factors mediates an indi vidual impact on the disease
pathology depending on the disease subtype. Other protective factors to prevent
gastric cancer include a high intake of fruits, vegetables, fiber, and folate. Therefore,
regulation or dysregulation of gastric cancer etiology leads to a better or poor
prognosis (Resende et al. 2010 ). Figure 4.1 illustrates the risk factors for gastric
cancer.
4.1.3.1 Helicobacter Pylori Infection and Pathogenesis
Helicobacter pylori is a flagellated, spiral, and Gram-negative organism
(Wroblewski et al. 2010). It is classified as a fastidious organism that requires special
lab conditions to be grown; it is a microaerophilic bacterium, requires little oxygen
(O
2
) and more carbon dioxide (CO
2
). Also, it is an acidophilic bacterium as it
Table 4.1 (continued)
Grade Description
M0
T4b-N2-
M0
T4a-N3a-
M0
or
Cancer penetrates all stomach layers into the connective tissue but not
into the peritoneal lining or serosa (T3) with spread to 7 to 15 lymph
nodes (N3a) but no metastasis (M0).
or
Cancer reaches the main muscle layer into the connective tissue and
organs or structures (T4b) and spread to not more than seven lymph
nodes (N2), but no metastasis (M0).
or
Cancer penetrates all muscle layers into the connective tissue and grows
into the peritoneal lining or serosa (T4a) with spread to 7 to 15 lymph
nodes (N3a) but no metastasis (M0)
Grade
III
(C)
T3/T4a-
N3b-M0
T4b-N3a-
M0
Cancer penetrates all layers into the connective tissue and may have
grown into the peritoneal lining or serosa T3/T4a with spread to more
than 16 lymph nodes (N3b) but no metastasis (M0).
or
Cancer penetrates all layers into the connective tissue and nearby
organs (T4b) with spread to 7 or more lymph nodes (N3a) but no
metastasis (M0)
Grade IV The most advanced stage where cancer of any size has spread and
metastasized beyond the stomach into distant parts of the body
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Fig. 4.1 Risk factors for the progression of gastric carcinoma. Created with BioRender.com
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colonizes nearly 50% of the human’s stomachs’ mucosal layer (Yamaoka 2010).
Warren and Marshall had first isolated Helicobacter pylori in 1981. However, the
global attention of understanding gastric cancer pathogenesis and subtypes has
suddenly shifted toward Helicobacter pylori in 1983, as it had been associated
with peptic ulcers (Marshall 2005). Mars hall et al. isolated this spiral curve, which
was later identified as Helicobacter pylori, from the stomach contents of gastric ulcer
patients. As a recognition of their great work and discoveries by Robin Warren, who
was a clinical pathologist, Western Australia, and was the first to observe the curved
bacteria under the microscope, and Barry Marshall, the person who consumed the
organism to develop gastritis, were awarded the Nobel Prize in 2005 (Moss 2013).
Since then, there were great efforts toward Helicobacter pylori eradication to
became the first-line focus for researchers, who shifted their efforts toward
Helicobacter pylori early diagnostic tools, treatment options, and prevention
(Thung et al. 2016).
In 1994, the International Agency for Research on Cancer reported that
Helicobacter pylori is classified among the group I carcinogen and a major risk
factor associated with gastric cancer development (Nishizawa and Suzuki 2015). It
was found that Helicobacter pylori infection predisposed the infected subject to both
forms of gastric cancer subtypes (Polk and Peek 2010). Helicobacter pylori infection
leads to gastritis, gastric atrophy, and a decrease in the stomach acidity as a defens e
mechanism in response to an increase in the concentration of serum gastrin. Thus,
hypergastrinemia, which leads to gastritis, is believed to promote stomach carcino-
genesis and has been linked to poor prognosis of gastric cancer and enhancement of
pathological behavior (Fossmark et al. 2015). Gastritis caused by the infection is
considered the strongest remarkable risk factor for gastric cancer. However, not all
cases of peptic ulcers as a result of Helicobacter pylori develop cancer after the
infection (Polk and Peek 2010). Developing the risk of gastric cancer can be
triggered by multiple factors; the presence of a specific strain of Helicobacter pylori
and its virulence factors, the infected host genotypes, and the specific host–microbe
interactions in terms of host inflammator y responses and subtypes of gastric cancer,
which have different epidemiological and pathophysiological features (Peek 2016).
Helicobacter pylori expresses several virulence factors that promote infection,
Debowski et al. reported that the ability of Helicobacter pylori to acquire resistance
and survive in the acidic environment that reaches pH as less as 1.0 is caused by
urease enzyme that converts urea (CH
4
N
2
O) into ammonia (NH
3
) and carbon
dioxide (CO
2
) (Debowski et al. 2017). Wroblewski et al. documented that urease
is required not only in disturbing the gastric pH but also in altering the tight junctions
between gastric epithelial cells; thus, urease activity considers a rate-limiting step in
the establishment of chronic infection (Wroblewski et al. 2009). Moreover,
cytotoxic-associated gene A (CagA), a common virulence protein that was well
studied in the literature which arose from cag island, is the most studied virulence
factor that is associa ted with Helicobacter pylori pathogenesis. It has been
documented that it has at least 20 known cellular binding partners (Backert et al.
2010). CagA gene encodes a protein with the type IV secret ion system, which
enables it to be exported and translocated from bacterial cells to form dimers in
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the epithelial cells (Mentis et al. 2019). Ohnishi et al. have reported that CagA-
positive Helicobacter pylori infection is associated with gastric cancer development
compared to the wildtype (Ohnishi et al. 2008).
Furthermore, the vacuolating cytotoxin (VacA) gene is another virulence factor of
Helicobacter pylori that promotes cellular impairment by vacuole formation and
cytochrome C release (Qadri et al. 2014). Decreasing cellular activation, inhibiting
cellular proliferation, and reducing signaling pathways result in mitochon drial
damage and induction of apoptosis (Ishaq an d Nunn 2015). Outer-inflammatory
proteins (OipA) and other virulence factors have also been associated with gastric
cancer pathogenesis and progression of gastric cancer; the interaction of these
virulence factors is believed to induce a synergistic effect toward cancer develop-
ment (Sokolova and Naumann 20 17). In 2014, a study investigated genetic
deviations presented in gastric epithelium with Helicobacter pylori infection from
patients with and without gastric tumors. Yamaoka had presented some evidence
that Helicobacter pylori disease patterns presented differently based on geographic
distribution. Helicobacter pylori and its virulence factors vary according to geo-
graphical distribution. Thus, East Asian populations were found to report a high
incidence of gastric carcinoma and a high prevalence of Helicobacter pylori infec-
tion compared to South Asian and other African nation populations (Yamaoka
2010).
Peek and Blaser have proposed the mechanisms by which Helicobacter pylori
induces gastritis inside the gastric mucosa; thus, increasing the risk for an intestinal
form of gastric cancer (Peek and Blaser 2002). The colonization of gastric epithelial
cells with Helicobacter pylori initiates this process by inducing a potent inflamma-
tory response and a signal transduction cascade of events that involves host–cell
protein interaction (Nešić et al. 2010). Phosphorylated CagA is involved signifi-
cantly by increasing the expression level of proinflammatory cytokines, which
recruit neutrophils and macrophages to the gastric lining to initiate an inflammatory
response leading to an increase in the risk of developing severe gastritis, gastric
atrophy, and peptic ulcer (Fazeli et al. 2016). Continuous inflammation generated by
the prolonged immune activation leads to mucosal damage and chronic gastritis that
cause DNA damage as a result of reactive oxygen species (ROS), that is released by
activated immune cells (Na and Woo 2014). Over time, as a result of repetitive injury
and repair, gastric epithelium undergoes transdifferentiation (morphological and
molecular) changes to become epithelial-mesenchymal transition (EMT) cells
(Marck and Bracke 2013). These cells resemble the intestinal epithelium in a process
called metaplasia, foci of dysplasia develop in the area to invade the lamina propria
forming an invasive carcinoma that leads to loss of parietal, chief, and glandular cells
atrophy (Carcas 2014). The hallmark of transdifferentiation is defined by the pres-
ence of intracellular Cag-A that downregulates E-cadherin and upregulates
N-cadherin, which is a mesenchymal marker (Corso et al. 2011). Thus,
transdifferentiation changes such as altering the cellular adhesion, increasing cellular
detachment and motility while losing cellular polarity will be observed (Huang et al.
2015). Acquired motility of poorly attached epithelial cells enhances the spread and
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invasion of the carcinogenic cells to nearby tissues and distant locations
(Diepenbruck and Christofori 2016).
Furthermore, Helicobacter pylori causes genetic instability in the progression of
gastric cancer via the aberrant promoter methylation (Maleki and Röcken 2017).
Metaplastic cells are prone to accumulate mutations in some genes that are involved
in cell cycle and division, which results in DNA damage (Li et al. 2015). Somatic
mutations were accumulated in multiple genes inside infected gastric tissues with
Helicobacter pylori. Therefore, increased cytidine activity inside gastric inflamed
tissues upregulates the formation of somatic mutations and promotes gastric cancer
formation in subjects with Helicobacter pylori infection (Shimizu et al. 2014).
Mutations can occur in both sides of cell cycle regulatory pathways: tumor suppres-
sor genes which downregulate the cell cycle by coding for proteins that stop the cell
division and promote apoptosis or proto-oncogenes which upregulate cell division
and normally code for accelerator proteins that promote the cell cycle (Machlowska
et al. 2018). Tumor suppressor genes such as p16 are downregulated by the
Helicobacter pylori, which induce promoter hypermethylation in gastric cancer
(Liu et al. 2019). Because of such mutations, metaplastic cells start dividing uncon-
trollably, and more mutations are passed with each division to become malignant
cells with special ability to invade nearby cells or metastasis and spread to distant
sites (Cai et al. 2019). Even though the presence of the same etiological agent,
Helicobacter pylori, predisposes some people to gastric cancer, it is likely to protect
them from other forms of cancer (Carcas 2014). Polyzos et al. showed some
evidence that Helicobacter pylori decreases the risk of developing esophageal cancer
by reducing the incidence of GERD, metaplasia of the distal part of the esophagus
(Polyzos et al. 2018). Therefore, regardless of the great decline in the rate of
Helicobacter pylori infection due to the availability of antibiotics and increase in
the awareness toward clean food consumption, Helicobacter pylori infection is
considered a promoter in chronic gastric cancer cases (Akhavan-Niaki and Samadani
2014).
4.1.3.2 Other Risk Factors
Gastric cancer global distribution varies fundamentally around the world. These
variations across geographical regions are justified by a plentiful factors that are
associated with gastric cancer incidence, patients’ survival, and mortality rate
(Resende et al. 2011). In the 2018 status report, the global incidence and mortality,
for both sexes combined, of gastric cancer were reported to cause more than 1 million
new cases and nearly 800,000 deaths. Among males, gastric cancer was the fourth on
the list of the most common cancer and the leading cause of cancer death (Bray et al.
2018). According to the same report, the eastern Asian population was shown on the
top of the list. Almost 32% of the world’s cases are diagnosed in Asia; nearly half of
that percentage is diagnosed in China, followed by Eastern Europe in the second and
South America in the third place (Ferlay et al. 2010a). Despite the global migration,
the first generation of Asian diaspora, who migrate from countries with higher
incidence rates, maintain the high risk of developing the disease from their country
of origin. However, the incidence rate declines in the following generations, the
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second and third, due to the environmental factors and lifestyle influences (Anderson
et al. 2010).
Despite the degree of variability among mostly affected populations within a
similar geographic region, other demographic factors such as ethnicity, socioeco-
nomic status, and lifestyles might influence the gastric cancer distribution
rate. J. Ferlay et al. reported in the USA socioeconomic differences between classes
play a role in gastric cancer distribution; it was found that gastric cancer cases
reported more at lower-income citizens among the African American population.
Also, ethnic predisposition can be supported by an increasing percentage of gastric
cancer reported cases among Hispanics and Native Americans compared to Cauca-
sian Americans (Ferlay et al. 2013). For a long time, cigarette smoking, salty food,
and food preservatives have been connected with an incre ased risk of developing
CGC (Piazuelo and Correa 2013). However, less developed countries carry a greater
gastric cancer burden than developed countries, as NCGC is more likely to affect
persons of lower socioeconomic classes (Blot and Tarone 2015). Moreover, Western
and European populations experience less burden of Helicobacter pylori compared
to the Asian population who reported having the majority of the world’s gastric
cancer cases (Ferlay et al. 2010b). Also, the risk of Helicobacter pylori infection has
been associated with lower socioeconomic status, poverty, overcrowding, and
unsanitary conditions (De Sablet et al. 2011) (Fig. 4.2).
Moreover, it is also reported that environmental and nutritional factors can justify
some differences in the development of gastric cancer. For example, Tan et al.
presented that the prevalence of Helicobacter pylori infection reported being high
in many African countries. Today, the rate of gastric cancer in the same countries is
very low. He justified discrepanci es in his results to be caused by the coinfection
with intestinal helminths rather than the differences in ethnicity and genetic makeup
of the individuals living in these countries (Tan et al. 2012). He hypothesized that
coinfection with intestinal helminths changes the T-helper cell response from an
inflammatory (Th 1-type) to a non-inflammatory (Th2-type) immune response. How-
ever, in 2000, Fox et al. responded to that hypothesis and suggested with some
evidence that coca chewing, which was associated with a reduction in gastritis,
might be responsible for providing some protection (Fox and Wang 2000).
4.2 Pathogenesis of Gastric Cancer
As previously mentioned, intestinal and diffuse are the two main subtypes of gastric
cancer (Ferlay et al. 2010b). The intestinal subtype of adenocarcinoma manifest s at a
later age, presents as a well-differentiated large irregular ulcer located on the antrum
part of the stomach, and progresses fast in a relatively well-defined series of steps.
This subtype of gastric cancer (Shah et al. 2011). This subtype of gastric cancer is
generally developed due to a premalignant change in terms of atrophic gastritis,
which develops on a chronic inflammation background induced by Helicobacter
pylori infection (Piazuelo and Correa 2013). Also, Peek and Blaser have proposed
the mechanisms by which gastritis is induced by Helicobacter pylori inside the
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Fig. 4.2 Role of Helicobacter pylori in the progression of gastric cancer. Created with BioRender.com
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gastric mucosa and increasing the risk for intestinal-type of GC (Peek and Blaser
2002). It has been proposed that gastritis during Helicobacter pylori infection
generates a special altered environment where inflammatory cytokines, chemokines,
and growth factors activate signaling transduction cascade inflammatory events,
which may lead to chronic gastritis (Machado et al. 2010). Infection induced
inflammatory response enhances lymphocytes, neutrophils, and macrophages
recruitment. Also, persistent inflammation is commonly associated with genetic
variations and DNA damage that upregulate the status of chronic gastritis, which
is believed to predispose the host to develop gastric tumorigenesis (Malfertheiner
2011). Gastric cancer presents with genetic instability in terms of permanent DNA
damage and impairment of DNA repair mechanisms. Helicobacter pylori infection is
believed to generate mitochondrial-DNA mutations, increase the rate of DNA
damage, and decrease DNA repair (Ding et al. 2010). Spontaneous mutations at
the epithelial cells are induced by DNA methylation, oxidative damage, chromo-
somal or microsatellite instability, which downregulate major DNA repair pathways
(Sayed et al. 2020).
Alternatively, the diffuse subtype of adenocarcinoma affects both genders equally
but is considered more common in younger generations. The mechanism of cancer
cell formation of the diffuse subtype of gastric cancer has been clearly explained and
well-documented (Assumpção et al. 2020). It arises from normal gastric mucosa and
characterizes by non-adherent cell formation; adhesion proteins were downregulated
to enhance the form ation of cancer lesions and spread to adjacent cells. It can
manifest at any part of the stomach, and it is mostly related to genetic mutations in
the CDH1 genes that code for a membrane adhesion molecule called E-cadherin
(Fitzgerald et al. 2010). This protein is responsible for the tight junction between
epithelial cells and signals transduction to regulate the cell cycle. This disturbance in
the function of E-cadherin to maintain cellular junction results in uncontrolled cell
division and loss of cellular communication (Jafferbhoy et al. 2013). Metastases of
cancer cells from one part to another in the stomach structure, which progresses the
disease rapidly and worsens the condition (Tomita et al. 2011). Also, its desmoplasia
will be associated with inflammation and generated as a result of the chronic
inflammation, but with the absence of atrophic gastritis that usually characterizes
the intestinal subtype; therefore, this subtype of gastric cancer has a poor prognosis
(Bass et al. 2014). However, the diffuse type has more pronounced desmoplasia,
adhesion, and dense fibrosis with thick and rigid stomach wall caused by the
detachment of cancer cells to invade connective tissue at the submucosa causing
gastric linitis plastica (GLP) (Hanahan and Weinberg 2011). Unlike the intestinal
subtype, this type is rarely associated with Helicobacter pylori (Yakirevich and
Resnick 2013). Thus, diffuse gastric cancer has been associated with Helicobacter
pylori infection by some researchers, but many others rejected its responsibility in
developing gastric cancer. Bornaschein and his colleagues have reported that
Helicobacter pylori infection increases the individual risk of developing gastric
cancer compared to noninfective subjects that might result from the inflammation
(Bornschein et al. 2010). The presence of an acid-resistant bacteria that invades the
gastric lining with a reduction of stomach acidity as a result of anti-acid medication
contributes to the development of diffuse gastric cancer (Khatri et al. 2020).
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