Jack: Hi, everyone.
In this lecture, we'll be discussing the epidemiology
of gastric cancer, or stomach cancer.
Our goals for this lecture
are to review the anatomy and function of the stomach,
to describe the global burden of stomach cancer,
and identify high risk populations.
To describe the declining trends
in stomach cancer mortality,
and to discuss genetic factors
and the prevention and control of stomach cancer.
So to begin with,
and looking at the anatomy of the stomach,
we see that it's a hollow muscular organ
juxtaposed between the esophagus and the duodenum.
With a resting volume ranging
from 45 to 75 milliliters in the human adult.
The stomach is lined by a specialized epithelium
that secretes proteases,
which are enzymes that digest protein,
and hydrochloric acid.
The acidic nature of the stomach inhibits bacterial growth
and facilitates the correct acid environment
for activation of the enzymes
secreted by the gastric epithelium.
The stomach lining is folded into rugae
to allow expression and contraction.
The bolus, which is the masticator
chewed food that enters the stomach
comes in at the gastro esophageal sphincter
and is turned by muscular contractions of the stomach wall.
Chyme, or partially digested food passes from the stomach
through the pyloric sphincter
into the duodenum of the small intestine
where the extraction of nutrients begins.
When we look at the incidence rates
of stomach cancer globally
we see that gastro cancer remains one of the most common
forms of cancer worldwide.
In 2012, 951,594 cases were diagnosed
and 723,027 deaths occurred.
Gastric cancer was in about 9.9% of new cancers in 2012
and about 70% of the cases in deaths
occurred in low and middle income countries.
The incidents in mortality rates are highest
in China and Mongolia, Eastern Asia, the Indian regions
of South America, Eastern Europe, and Mali
and Zaire in Africa.
Gastric cancer used to be the leading cause of cancer deaths
in the world until the 1980s
when it was overtaken by lung cancer.
So, as previously discussed, when we're looking at
mortality rates of stomach cancer globally
we see high rates in South America,
in different parts of Asia
and in some African countries like Mali.
When we're looking at stomach cancer mortality rates
in the US, we see that they've declined significantly
since 1930 in both men and women,
and this mirrors is a declining cases globally.
In the US, death rates from stomach cancer have declined
by nearly 90% in men and women since 1930.
A similar pattern of declining mortality has emerged
in Japan, and Japan importantly is the nation
with the highest stomach cancer mortality in the world.
In 1950, when nearly a hundred deaths were occurring
per 100,000 in men.
Since then, mortality rates
from stomach cancer have declined by nearly 70%
in Japanese men and 90% in Japanese women.
In 2020 in the US, the age standardized incidence
of gastric cancer was 11.1 per 100,000 overall
but 15.8 per 100,000 men and 7 per 100,000 women.
The mortality was 7.7 per 100,000
or 11 per 100,000 men and 4.9 per 100,000 women.
So why has gastric carcinoma declined?
So we can call this an unplanned triumph
of epidemiology that's resulted
in changing balance of risk factors.
So the major reason for the decline
in stomach cancer in high income countries is the rapid
and widespread escalation of refrigeration since 1900.
The expansion of industrial refrigeration has meant
fresher produce for the consumer and in turn has resulted
in higher per capita intake of vitamins A, C, and E
which protect against gastric carcinogenesis.
Furthermore, the increase in refrigeration has reduced
the need for salting and pickling, two traditional means
of food preservation associated
with increased gastric cancer risk.
Improved food sanitation
through better techniques of processing, handling,
and refrigeration has reduced exposure
to the infectious microbe helicobacter pylori
particularly among children.
This bacterium is known to cause
chronic stomach inflammation and bacterial infiltrates
of the organism are commonly found associated
with gastric adenocarcinoma and its precursor lesions.
Studies combining methods of epidemiology
and microbiology clearly suggest
that helicobacter pylori should be considered
to be a major causal factor of gastric carcinoma.
So to give a little bit more background on H-pylori,
it's a gram negative microaerophilic bacterium found
in the stomach.
It was identified in 1982 when it was found present
in patients with chronic gastritis and gastric ulcers.
It's also been linked
to the development of duodenal ulcers and stomach cancer.
However, over 80% of the individuals infected
with the bacterium are asymptomatic
and it's been postulated that it may play an important role
in the natural stomach ecology.
More than 50% of the world's population harbor H-pylori
in the upper gastrointestinal tract
and infection is more prevalent
in low and middle income countries
and incidences decreasing in high income countries.
To colonize the stomach, H-pylori must survive the acidic pH
of the lumen and uses flagella to burrow
into the mucus to reach its habitat
or its niche close to the stomach's epithelial cell layer.
Many bacteria can be found deep in the mucus
which is continuously secreted
by mucus secreting cells and removed
on the luminal side.
To avoid being carried into the lumen
H-pylori senses the pH gradient within the mucus layer
by chemotaxis and swims away from the acidic contents
of the lumen towards the more neutral pH environment
of the epithelial cell surface.
H-pylori also produces large amounts
of the enzyme urease, which breaks down urea
which is normally secreted into the stomach.
It breaks it down to carbon dioxide and ammonia.
Ammonia is converted to ammonium
which neutralizes gastric acid.
This neutralization of gastric acid allows
for the survival of H-pylori in the acidic stomach.
The ammonia produced is toxic to the gastric epithelium
and causes damage and neoplastic transformation.
We see that key stomach cancer risk factors are again
cigarette smoking and other forms of tobacco addiction.
A recent comprehensive review in meta-analysis
of the available data found a twofold increase
in the risk of stomach cancer among male chronic smokers.
There's also consistent evidence that tobacco addiction
in combination with chronic alcohol consumption
synergistically heightens the risk by fivefold.
More than 90% of gastric cancers are adenocarcinomas
which are divisible pathologically
and anatomically into two subtypes.
The first is poorly differentiated or diffuse
adenocarcinomas arising near the cardia,
just distal to the gastro esophageal junction.
There's also well differentiated or intestinal
adenocarcinomas that arise elsewhere
in the corpus of the stomach or non-cardia adenocarcinomas.
Well differentiated or intestinal
non-cardia adenocarcinomas of the stomach
develop primarily as a consequence
of environmental factors like chronic H-pylorus infection
particularly due to Cag-A positive strains
resulting in chronic severe atrophic gastritis
that progresses to invasive cancer.
Synergism of H-pylorus infection
with other environmental factors
including high salt diets, nutritional deficits,
and chronic tobacco and alcohol exposure can increase risk.
The non-cardia intestinal subtype
of gastric cancer predominates
in high risk regions of the world
and rates of this subtype have declined dramatically
in many developed nations
primarily due to refrigeration
replacing salt preservation efficient meat,
better access to fresh fruits and vegetables,
improved sanitation, reduces in tobacco and alcohol use,
and effective antibiotic therapy for H-pylorus infection.
In contrast to the decline
in non-cardia intestinal gastric cancer,
the rates of diffuse gastric adenocarcinomas arising
near the cardia are increasing
in many high income countries
particularly among Caucasian males.
The increasing incidence of the diffuse type
of a adenocarcinomas arising near the cardia of the stomach
is related to obesity and other conditions that predispose
to gastro esophageal reflex disease,
or GERD and Barrett's esophagus.
It's been hypothesized that ablation of colonization
of the stomach by H-pylorus has accentuated the development
of these conditions in some developed populations.
There's also key genetic factors that can predispose
for stomach cancer, so case control and cohort analyses
of gastro cancer patients have shown that the risk
of gastric cancer in first degree relatives
of index cases is increased two to three fold
and familial clusters of hereditary diffuse
gastric carcinoma have been discovered.
Such families manifest key germline mutations
in the CDH1 gene that encodes E-Cadherin
an important calcium dependent cell adhesion molecule.
Excess cases of gastric cancer have also been observed
in families with the adenomatous polyposis coli gene
that predisposes to familial adenomatous polyposis, or FAP.
And in families with hereditary non-polyposis
colorectal cancer or lynch syndrome
which is due to mutated mismatched DNA repair genes.
Blood group A has been reported to be more prevalent
among gastric cancer cases than among controls
and appears to be associated
with the development of the diffuse type of disease.
Finally, patients with pernicious anemia are also
at increased risk for the development of gastric cancer.
Pernicious anemia is due to the lack
of intrinsic factor and failure to observe vitamin B12.
Finally, to briefly discuss the prevention of stomach cancer
we see that stomach cancer is caused
by interactions between carcinogens
and inflammatory factors derived from various sources.
Salt restriction are less than six grams per day.
The avoidance of processed meat, absence from tobacco
and limitation of alcohol intake are all important
for prevention and control of stomach cancer.