Epidemiology of Gastric Cancer and Helicobacter Pylori: Jonathan Volk and Julie Parsonnet

Chapter 2
Epidemiology of Gastric Cancer

and Helicobacter pylori
Jonathan Volk and Julie Parsonnet
Introduction
In 1994, the International Agency for Research on Cancer (IARC) declared
Helicobacter pylori to be a type I carcinogen, or a definite cause of cancer in
humans (Humans 1994). This landmark decisionbased almost exclusively on
epidemiologic evidencewas immediately controversial. Some argued that H. pylori
could not be considered a cause of cancer but only a risk factor or cofactor
(although the difference between these two is largely semantic). Others maintained that
the absence of experimental evidence in animals was a critical flaw in the IARCs
arguments and left the possibility of residual confounding. Others straddled the
fence in anticipation of randomized clinical trials looking at whether H. pylori
eradication prevented cancer.
Now, almost 15 years after the IARCs declaration, there is broad consensus that
H. pylori causes gastric adenocarcinoma and lymphoma despite the failure of the
only completed randomized treatment trial to demonstrate adenocarcinoma prevention (Wong et al. 2004). Although the biology presented in this bookincluding
animal modelsprovides plausibility for this acausal association between H. pylori
and cancer (Pritchard and Przemeck 2004), it is the depth and breadth of epidemiologic evidence that remains the foundation for the scientific conviction. Herein, we
present these epidemiologic findings.
Gastric Cancer Epidemiology

Gastric cancers remain a leading cause of cancer morbidity and mortality worldwide, with adenocarcinomas arising from gastric glands accounting for 90% of incident cases (Aaltonen et al. 2000; Coleman et al. 1993). Other less-common epithelial
stomach cancers include squamous cell carcinoma, adenosquamous carcinoma,
small cell, and carcinoid tumors. Nonepithelial stomach cancers such as leiomyomas, stromal tumors, and malignant lymphomas can also be found in the stomach
(Aaltonen et al. 2000). For this chapter, we limit discussion to adenocarcinomas.
T.C. Wang et al. (eds.) The Biology of Gastric Cancers,

Springer Science + Business Media, LLC 2009
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J. Volk, J. Parsonnet
Classifications of Adenocarcinomas of the Stomach

Adenocarcinomasmalignant tumors of glandular epitheliumcan be classified
as proximal tumors, which originate in the stomach cardia and gastroesophageal
junction, or distal tumors, which originate in the fundus, body, or antrum of the
stomach (Brown and Devesa 2002). The location of the tumor is important, because
incidence, trends over time, risk factors, and mortality rates differ between distal
and proximal adenocarcinomas.
In 1965, gastric adenocarcinomas were further subdivided into two distinct
histologic subtypes, intestinal and diffuse (Lauren 1965), known as the Lauren
classification. Intestinal-type adenocarcinomas form recognizable glands whereas
diffuse adenocarcinomas consist of poorly cohesive cells that diffusely infiltrate the
gastric wall and form no recognizable glands (Aaltonen et al. 2000). The Lauren
classification has proven useful for observing the natural history and epidemiology
of gastric cancer. Even as early as 1965, Lauren observed a male predominance and
older age at diagnosis for patients with intestinal-type compared with diffuse-type
gastric cancer (Lauren 1965).
Importantly, preneoplastic lesions are only associated with the later development of
intestinal-type adenocarcinoma. In a model proposed by Correa (Correa 1992; Correa
et al. 1975), this multistep process for progression of normal gastric cells to adenocarcinomas starts with chronic gastritis. Chronic gastritis later develops into intestinal
metaplasia and dysplasia, with the partial or complete loss of cell differentiation
(Aaltonen et al. 2000; Correa 2002). Ultimately, these areas of dysplasia are thought to
progress to adenocarcinoma. However, because individual lesions are not followed over
time without intervention, it is impossible to prove that a specific preneoplastic lesion
has progressed to gastric adenocarcinoma. Others have suggested that intestinal
metaplasia does not progress to carcinoma but is instead an alternate endpoint from a
shared cause (Tatematsu et al. 2003). In contrast to intestinal-type adenocarcinoma,
there are no clearly defined precursors for diffuse-type adenocarcinoma.
Incidence of Gastric Cancer

Based on information from the United States National Cancer Institutes Surveillance
Epidemiology and End Results Program (SEER), which collected data from 17
sites between 20022004, 0.90% (1/111) of men and women born today in the
United States will be diagnosed with stomach cancer during their lifetime. SEER
data from 20002004 indicate current age-adjusted gastric cancer incidence rates
of 11.4 per 100,000 men and 5.6 per 100,000 women annually. The median age of
diagnosis is 71 years, and 70% of cases are diagnosed between ages 5584. As of
January 2004, 34,708 men and 25,592 women with gastric cancer were living in the
United States (Ries et al. 2007, based on November 2006 SEER data submission,
posted to the SEER Web site, 2007 #2571).
2 Epidemiology of Gastric Cancer and H. pylori
27
Geographical Distribution
Gastric cancer incidence rates vary significantly in different countries and
regions of the world. Japan has the highest rates of stomach cancer with 77.9
cases per 100,000 males and 33.3 per 100,000 females annually. Other countries in eastern Asia (including China and Korea), eastern Europe, and tropical
South America also have high gastric cancer incidence rates (Ferlay et al.
2004). In contrast, lower incidence rates of gastric cancer have been observed
in eastern and northern Africa, North America, and south and southeast Asia,
with average age-standardized incidence rates of 5.99.0 per 100,000 men and
2.65.3 per 100,000 women. Diagnostic and surveillance deficiencies may
account for some of the reported low rates in some of these countries. Although
incidence differs throughout the world, men consistently manifest incidence
higher than women (Parkin et al. 1999b).
Data from England and Wales demonstrate that country of birth is a stronger
predictor of stomach cancer risk than the country of current residence (Coggon
et al. 1990). Immigrants who migrate from regions at high risk for gastric cancer
to regions at lower risk have an intermediate risk level. A study of immigrants
from Japan to Hawaii found a lower age-adjusted rate of stomach cancer among
the immigrants compared with the remainder of the Japanese population still
living in Japan. An even lower rate was observed among second-generation
immigrants (Kolonel et al. 1981). A similar study of people from higher-risk
populations in England, Scotland, Ireland, Poland, the former Yugoslavia,
Greece, and Italy who moved to Australiaa low-risk population for gastric
cancerfound a risk reduction that increased with time spent in Australia
(McMichael et al. 1980).
Gastric cancer incidence rates also differ by ethnicity. In the United States
between 20002004, the highest annual incidence rates were observed among
Asian/Pacific Islanders (18.9 per 100,000 men and 10.8 per 100,000 women), followed by blacks (17.5 per 100,000 men and 9.1 per 100,000 women), Hispanics
(16.0 per 100,000 men and 9.6 per 100,000 women), American Indians and Alaska
Natives (16.3 per 100,000 men and 7.9 per 100,000 women), and whites (10.2 per
100,000 men and 4.7 per 100,000 women) (Ries et al. 2007). Interestingly, the
trends observed among ethnic groups are observed for both men and women.
Trends Over Time

The incidence of gastric cancer has decreased over time. In the United States from
1975 to 2004, there was a statistically significant decrease in gastric cancer
observed for both men and women (Ries et al. 2007). Outside of the United States,
the incidence of stomach cancer is also decreasing (Coleman et al. 1993; Parkin
et al. 1999b), even in higher-risk countries (Parsonnet 1995). In 1990, there were
only 6% more gastric cancer cases compared with 1985 despite an aging population
and an increase in total number of people in the world (Parkin et al. 1999a).
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Differences in Epidemiology of Various Tumor Types

Changes in incidence rate described above do not apply to all types of gastric
cancer. Distal (fundus, body, and antrum), intestinal-type gastric cancer incidence
has declined, whereas the incidence of proximal (cardia and gastroesophageal
junction) adenocarcinomas has increased. This decrease in intestinal-type tumors
accounts for the overall declining trend in gastric cancer incidence (Correa and
Chen 1994; Howson et al. 1986).
In contrast to more distal tumors, the incidence of proximal tumors of the gastric
cardia has risen steadily from 1974 to 1994 among men, and to a lesser extent,
among women. The age-standardized incidence rates increased from 2.1 to 3.3 per
100,000 among whites and 1.0 to 1.9 per 100,000 among blacks (Devesa et al.
1998). These proximal tumors are more common in developed countries, especially
among whites and those of higher socioeconomic status. Obesity and gastroesophageal
reflux disease (GERD) both have important pathogenic roles for this gastric cancer
subtype (Crew and Neugut 2006).
Mortality and Case Fatality

Worldwide, an estimated 850,000 people died from gastric cancer in 2001 (522,000
men and 328,000 women), making gastric cancer the second leading cause of cancer
death after lung cancer (Parkin et al. 1999a). As of 1990, the 5-year mortality rate
for stomach cancer remained poor, only better than lung and pancreatic cancer in
most regions of the world (Parkin et al. 1999a). A notable exception to this dismal
prognosis is in Japan, where intensive screening efforts have resulted in the earlier
diagnosis of gastric cancer and a much higher 5-year survival rate (57%). In the
United States between 1992 and 1998, the overall 5-year survival for gastric cancer
for all disease stages was 22% (Jemal et al. 2003); localized disease had much
higher 5-year survival rates (59%) than metastatic disease (2%).
According to SEER data collected between 2000 and 2004, the median age of
death from gastric cancer was 74 years, with an age-adjusted death rate of 4.2 per
100,000 people (5.9 per 100,000 men and 3.0 per 100,000 women) (Ries et al.
2007). Age-adjusted mortality rates increase dramatically with age. The mortality
rate for individuals older than age 85 is 46.1 per 100,000 people, compared with
12.9 per 100,000 for people aged 6569 and 1.3 per 100,000 for those aged
4044. Notably, deaths from gastric cancer differed significantly among different
ethnic groups and paralleled the trends observed for gastric cancer incidence.
Rates were highest among black Americans (11.9 per 100,000 men and 5.8 per
100,000 women), followed by Asian/Pacific Islanders (10.5 per 100,000 men and
6.2 per 100,000 women), American Indian/Alaska native (9.6 per 100,000 men
and 5.5 per 100,000 women), Hispanic (9.1 per 100,000 men and 5.1 per 100,000
women), and white Americans (5.2 per 100,000 men and 2.6 per 100,000 women)
(Ries et al. 2007).
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Until the 1940s, gastric cancer was the most common cause of cancer death
among men (Howson et al. 1986). Decreases in stomach cancer mortality started as
early as 1926. Joint point analysis from the SEER database reveals statistically
significant decreases in gastric cancer mortality in the United States. Between 1990
and 2004, there was a 3% annual percentage change in gastric cancer mortality,
with a 3.5% decrease observed for men between the years 1991 and 2004 and a
2.6% decrease observed among women during the same time period (Ries et al.
2007). A statistically significant decrease in gastric cancer mortality rates was also
noted between 1975 and 1987 and a nonsignificant decrease between 1987 and
1990 (Ries et al. 2007). According to estimates from the National Center for Health
Statistics(American Cancer Society), an estimated 21,260 Americans (13,000 men
and 8,260 women) will be diagnosed with stomach cancer in 2007, with 11,210
deaths. This number represents a decrease from the 12,100 deaths seen in 2003.
The decrease in mortality rates seen in the last several decades likely reflects a
decreasing incidence of gastric cancer, because the case-fatality rates have changed
little. An exception to this, however, may be evident in regions where gastric cancer
screening has been undertaken. By identifying early cancers, surgical intervention
can be applied when it has the highest probability of benefit. Motivated by high
rates of gastric cancer incidence and mortality, Japan introduced a mass screening
program in the 1960s (Fukao et al. 1995). Double-contrast barium x-rays were
offered in all municipalities of Japan by 1975, and more recently, people have been
screened with endoscopy, serum pepsinogen concentrations, and anti-H. pylori
antibody tests. Using observational data, including cohort studies, case-control
studies, and ecologic analyses from different municipalities with varying levels of
screening participation, these screening efforts are thought to have caused a
decrease in stomach cancer mortality in Japan (Fukao et al. 1995; Miyamoto et al.
2007). No randomized trials of screening have been conducted and it is not clear
whether similar screening efforts would yield a benefit in populations with lower
rates of gastric cancer. Currently, neither the American Cancer Society (Smith et al.
2003) nor the National Cancer Institute (National Cancer Institute 2007) recommends
stomach cancer screening in the United States.
Risk Factors for Gastric Cancer, Excluding Helicobacter pylori

Risk factors for gastric cancer that have undergone extensive investigation include
genetic susceptibility, use of cigarettes, poor nutrition, alcohol abuse, obesity,
gastroesophageal reflux, pernicious anemia, radiation exposure, and partial gastrectomies. When examining the relationships among these risk factors and the subsequent development of gastric cancer, it is important to control for H. pylori, an
important confounding variable that is discussed in detail in its own section.
Unfortunately, many studies of gastric cancer risk factors do not adequately control
for H. pylori and other potential confounders. For example, although higher stomach
cancer rates are seen among individuals with low socioeconomic status (Neugut et al.
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1996), this depressed socioeconomic status is confounded by increased usage of

tobacco, decreased intake of fruits and vegetables, poorer sanitary conditions that
may and probable increased H. pylori transmission.
Genetic Factors
Although most familial gastric cancers results from concordant H. pylori infection
within families (Lugli et al. 2007), there are some families with extraordinarily
high rates of diffuse-type gastric cancer occurring at unusually young ages.
Genetic susceptibility has proved to have a role in these families. The most wellstudied familial genetic defect is a germline mutation in a cell-adhesion protein,
E-cadherin. First observed in a kindred group of Maori ethnicity (Guilford et al.
1998), germline mutations of e-cadherin have been identified in familial cancers in
Europe (Gayther et al. 1998; Guilford et al. 1999), Japan (Shinmura et al. 1999;
Yabuta et al. 2002), the United States (Oliveira et al. 2002), and Korea (Yoon et al.
1999). An individual who possesses one of the germline e-cadherin gene mutations
listed in the International Gastric Cancer Linkage Consortium has a cumulative risk
of gastric cancer before 80 years of age of 67% [95% confidence interval (CI),
33%99%] for men and 83% (95% CI, 58%99%) for women (Pharoah et al.
2001). Fortunately, e-cadherin mutations are rare and are thought to account for
less than 3% of gastric tumors (Stone et al. 1999).
Other genetic factors besides e-cadherin have been linked to malignancy.
Gastric tumors are sometimes observed in hereditary cancer syndromes such as
hereditary nonpolyposis colorectal cancer, Li-Fraumeni syndrome, familial adenomatous polyposis, and Peutz-Jeghers syndrome (Caldas et al. 1999). Since the first
report in 1953, numerous studies have demonstrated that individuals with blood
type A (El Hajj et al. 2007) have higher rates of intestinal-type gastric cancer,
chronic atrophic gastritis, intestinal metaplasia, and dysplasia (El Hajj et al. 2007;
Kneller et al. 1992) It is postulated that H. pylori expressing the BabA adhesin are
better able to adhere to the gastric epithelium on individuals expressing blood type
A antigens (Gerhard et al. 1999; Ilver et al. 1998), enhancing the persistence of
H. pylori infection and subsequent gastric cancer development.
Environmental Factors
Familial clusters of cancer do not always indicate inherited genes, because
smoking, environmental exposures, alcohol, and especially H. pylori also aggregate
in families. Cigarette smoking increases the risk of proximal and distal stomach
cancers independent of H. pylori infection. Although smoking and H. pylori often
go hand-in-hand, an IARC working group on Tobacco Smoke and Involuntary
Smoking concluded that smoking tobacco independently increased gastric cancer
risk (IARC 2004) and that confounding by H. pylori could be reasonably ruled
out. They also noted a dose-response relationship with tobacco exposure and
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cancer risk, with decreased risk observed with increased duration of tobacco
cessation. A large study by Chao et al. that followed 467,788 men and 588,053
women for 14 years concluded that 28% of gastric cancers in men and 14% in women
could be attributed to smoking (Chao et al. 2002); unfortunately, H. pylori was not
directly evaluated as a confounder in this study.
In 1997, the World Cancer Research Fund (WCRF) and the American Institute
for Cancer Research (AICR) conducted a thorough review exploring the relationship between food and nutrition and cancer risk (World Cancer Research Fund
and American Institute for Cancer Research 1997). Using data from case-control
and cohort studies, the panel concluded that diets high in fruits and vegetables
conferred a protective benefit for stomach cancer. In the European Prospective
Investigation into Cancer and Nutrition cohort (EPIC), a large study of 521,457
men and women aged 3570 years, increased intake of total meat, red meat, and
processed meat was associated with distal gastric cancers, although not with
proximal cancers. The relationship between diet and distal cancers was particularly significant striking among individuals also infected with H. pylori (Gonzalez
et al. 2006). This study also demonstrated an inverse relationship between gastric
cancer risk and high levels of plasma vitamin C, particularly among individuals
with high intakes of red meat and other processed meats.
Salt was found to be a risk factor for gastric tumors by the WCRF/AICR panel
(World Cancer Research Fund and American Institute for Cancer Research 1997).
One proposed mechanism for this deleterious effect is that salt results in mucosal
damage in the stomach, and consequently, an inflammatory regenerative response
with increased DNA synthesis and cell proliferation (Bergin et al. 2003). This
increased cell proliferation in turn increases the risk for tumorigenesis. The use of
refrigeration has been found to decrease stomach cancer risk, likely the result of
less salt being used in refrigerated food, as well as the decreased risk of food
contamination with carcinogenic compounds.
Proximal gastric cancers have a different pathogenesis and different risk factors
than from tumors of the distal stomach. For example, although alcohol does not affect
overall gastric cancer rates, heavy drinking may increase rates of proximal tumors
(Terry et al. 2002). A significant association between body mass index and proximal
tumorsbut not distal tumorshas been observed (Chow et al. 1999; Ji et al. 1997;
Terry et al. 2002). Although GERD is a clear risk factor for the development
of adenocarcinoma of the esophagus (Farrow et al. 2000), the evidence in support of
GERD as a risk factor for gastric tumors is mixed. Some studies have concluded that
reflux is only weakly associated with proximal adenocarcinomas of the gastric cardia
(Mayne and Navarro 2002). Other studies demonstrated increased proximal stomach
cancers with increased GERD symptom severity (Lagergren et al. 1999). However,
other studies have found no relationship between GERD and proximal gastric cancers
(Farrow et al. 2000).
Other risk factors for gastric cancer are rarely encountered. Pernicious anemia,
which may result in severe atrophic gastritis and intrinsic factor deficiency,
increases risk for both gastric cancer and carcinoid tumors (Hsing et al. 1993; Kokkola
et al. 1998). Exposure to radiation also increases gastric cancer risk. After the bombing
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of Hiroshima and Nagasaki, a greater than expected number of gastric tumors

occurred to those exposed in childhood (Kai et al. 1997).
Partial gastrectomy is a long-recognized predisposing factor for cancer. Although
peptic ulcer disease and its surgical treatment have become increasingly rare in the
modern era of acid inhibition, H. pylori eradication, and aggressive endoscopy
(Higham et al. 2002; Targownik and Nabalamba 2006), some patients still undergo
partial gastrectomy for gastrointestinal bleeding. A review of 58 studies showed
that individuals who had partial gastrectomies and survived more than 15 years
after surgery had a two- to fourfold increase in stomach cancer risk (Stalnikowicz
and Benbassat 1990). A metaanalysis also done in 1990 (Tersmette et al. 1990)
concluded that this increased cancer risk was limited to a subset of patients who had
partial gastrectomies for gastric ulcers (relative risk = 2.12; 95% CI, 1.732.59) as
compared with duodenal ulcers (relative risk = 0.84; 95% CI, 0.661.05). In support of this finding, individuals with a history of duodenal ulcer seem to be at lower
risk for gastric malignancy than those without (Hansson et al. 1996).
The impact of proton pump inhibitors and histamine-2 antagonists in gastric carcinogenesis is unclear. In animals, these medications have been linked to gastric carcinoid tumors (Gillen and McColl 2001). Although there have been no longitudinal
studies exploring whether proton pump inhibitors and histamine antagonists increase
gastric cancer risk in humans, a postmarketing surveillance report of cimetidine indicated no increase in gastric cancer incidence with its use (Colin-Jones et al. 1992).
Despite this, some researchers suggest eradicating H. pylori before the initiation of
these medications because hypochlorhydria promotes extension of H. pylori throughout the stomach and development of atrophic gastritis (Kuipers et al. 1996).
Epstein-Barr VirusRelated Tumors
Fewer than 1% of gastric cancers are lymphoepithelioma-like carcinomas (LELCs)
epithelial tumors with extensive lymphoid infiltration into the stroma. These tumors
are histopathologically similar to nasopharyngeal carcinomas and contain monoclonally integrated Epstein-Barr virus (EBV) (Herrmann and Niedobitek 2003; Wu et al.
2000). LELC gastric tumors have distinctive oncogene expression, such as p53 overexpression and underexpression of c-erb2 and E-cadherin that likely have causal roles
for this gastric cancer subtype (Wu et al. 2000). EBV-associated tumors occur more
frequently in males and in younger patients. They are also more often located in the
gastric body or cardia rather than in the antrum (Takada 2000). EBV may also have a
role in non-LELC gastric tumors, although the evidence remains inconclusive.
Helicobacter pylori Epidemiology

Spiral-shaped bacteria were first observed in the stomachs of humans well over a
century ago (Weisse 1996). Although early research linked these spiral-shaped
bacteria to gastric inflammation and other upper gastrointestinal disorders (Doenges
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1938; Kreinitz 1906), later studies would deem these bacteria contaminants (Palmer
1954) and the field stagnated.
The subsequent history of H. pyloris discovery and the ultimate Nobel prize
to Marshall and Warren is now widely known. Together, Marshall and Warren
showed that unidentified curved bacilli in gastric biopsies were associated
with active, chronic gastritis and with ulcers (Marshall and Warren 1984;
Marshall et al. 1985b). In the face of the worlds skepticism, Marshall ultimately
swallowed an inoculum of H. pylori to prove its pathogenicity (Marshall et al.
1985a). Although they were barraged with criticism, Marshall and Warren persisted in their insistence that the organism caused gastritis and ulcer disease and
finally a cascade of data from investigators around the world proved their theory
correct.
Research reveals that humans have been infected with H. pylori for at least
58,000 years, before human migration from Africa (Linz et al., Nature, 2007).
The investigators, using a large data set of H. pylori strains, found a decrease in
bacterial genetic diversity with increasing distance from east Africa. In fact, human
migration in modern times can be predicted from phylogenetic bacterial models
(Falush et al. 2003; Kersulyte et al. 2000).
Prevalence and Incidence by Region

Approximately half of the worlds population is infected with H. pylori,
although prevalence rates differ tremendously in different regions of the world.
Prevalence of H. pylori infection increases with age, and is higher in developing than in developed countries (Brown 2000). An exception to this increasing
H. pylori prevalence with age is the lower prevalence often seen in the very
elderly (Taylor et al. 1995). It is likely that advancing gastric atrophy and intestinal metaplasia with age sometimes causes loss of infection with advancing
age in the elderly (Ohata et al. 2004).
In developing countries, infection can be so common as to be almost universal
in adults, although there are some notable exceptions. For example, Indonesia and
Papua New Guinea have reported disproportionately low prevalences of H. pylori
in some regions (Mitchell et al. 1988; Tokudome et al. 2005). The pattern of higher
prevalence in developing countries is also seen among children, with prevalence
rates estimated as low as 1.2% in a sample of 24 year-old children from the
Netherlands to as high as 7080% in some developing countries (Magalhaes
Queiroz and Luzza 2006; Mourad-Baars et al. 2007).
H. pylori incidence is more difficult to determine than prevalence because the
initial infection invariably goes unnoticed and undiagnosed. Based on changes in
prevalence with age, the incidence of H. pylori has been estimated to be 1% per
year among white Americans and as high as 3% per year among African Americans
(Graham et al. 1991; Parsonnet 1995). The incidence of H. pylori in developing
countries is much higher, with yearly incidence rates as high as 3%10% (Parsonnet
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1995). Incidence of infection is highest in early childhood; the majority of infections

in high prevalence areas occur before age 5 (Granstrom et al. 1997; Malaty et al.
2002; Rothenbacher et al. 2002; Rowland et al. 2006). In studies of children
younger than 2 years, there have been reports of children who initially test positive
for H. pylori but on repeat breath test are seronegative negative (Goodman et al.
2005; Klein et al. 1994; Rothenbacher et al. 2002; Thomas et al. 1999). It has not
yet been determined whether the conversion reversion from H. pylori seropositive
positive to seronegative negative in children reflects transient infections or, rather,
false positives in a population with low seroprevalence infection prevalence
(Nurgalieva et al. 2006; Perry and Parsonnet 2005; Rosenstock et al. 2000). For
adults in developed countries throughout the world, the incidence is low, estimated
at 0.5% of susceptible adults becoming infected yearly.
In recent years, there has been a decrease in H. pylori prevalence worldwide that
has coincided with improved hygiene and socioeconomic status. For example, a study
of healthy adults from southern China showed a significant decrease in H. pylori
seroprevalence (62.5% to 49.3%) from 1993 to 2003 (Chen et al. 2007). Because H.
pylori infection typically remains in the stomach for life, a decrease in incidence over
time is eventually manifest by disproportionately higher rates of H. pylori in the elderly than in the young (a birth cohort effect). This birth cohort effect has been documented in Europe and the United States, with a 10% decrease in incidence per decade
(Banatvala et al. 1993; Parsonnet et al. 1992; Roosendaal et al. 1997).
Risk Factors for Infection

Lower socioeconomic status, often measured indirectly using level of education,
household crowding, sharing of beds, plumbing, and water sanitation, has been
consistently identified as a risk factor for H. pylori infection (Brown 2000). A large
study of 3,194 people from 17 countries showed an inverse relationship between
education and H. pylori seroprevalence in 11 of 17 populations studied; the remaining 6 populations also showed this relationship, but without reaching clinical significance (Eurogast Study 1993). Similarly, a study of children from northeastern
Brazil found that children from lower socioeconomic status had much higher
H. pylori seroprevalence rates (55%) compared with the wealthier children (16.4%)
(Parente et al. 2006). Socioeconomic status in childhood, rather than later in life, is
most important in determining H. pylori infection (Torres et al. 1998; Ueda et al.
2003). This finding is substantiated by studies of immigrants. Adult immigrants
from countries with high prevalence of H. pylori infection have prevalence that
parallels their country of origin (Perez-Perez et al. 2005; Tsai et al. 2005). Children
of immigrants have a prevalence closer to that of the new country, especially after
controlling for such variables as household crowding and parents level of education
(ORourke et al. 2003; Tsai et al. 2005).
Large differences in H. pylori seroprevalence also exist among ethnic groups
even within the same country or region. These differences are likely the result, at
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least in part, of socioeconomic differences. In the United States, non-Hispanic

whites have lower H. pylori infection rates than African Americans and Hispanic
populations (Graham et al. 1991; Hopkins et al. 1990). In a large cross-sectional
study of adult Americans from 1988 to 1991, the overall H. pylori seroprevalence
was 33%, with the highest rates seen in Mexican Americans (62%) followed by
African Americans (53%) and non-Hispanic whites (26%) (Everhart et al. 2000).
Similar differences between ethnic groups have been observed outside of the
Americas. In a study done in New Zealand, indigenous Maori have significantly
higher rates of infection (39%70%) than white New Zealanders (15%) (Morris
et al. 1986). Similarly, Aborigines from western Australia have 23 times higher
rates of H. pylori infection than nonindigenous Australians (Windsor et al. 2005).
Other studies have also found ethnic differences in Belgium (Blecker et al. 1993)
and Malaysia (Goh and Parasakthi 2001).
Higher H. pylori infection rates have been documented in communities where
hygiene is poor, such as institutions for the disabled and in orphanages (Brown
2000). Other risks include bed sharing among children, which is strongly correlated
with transmission (Mendall et al. 1992; Perry et al. 2005). In contrast, attending
daycare (Wizla-Derambure et al. 2001) and school (Tindberg et al. 2001) with
infected classmates was not found to increase risk of infection.
Mechanisms of Transmission
New H. pylori infections go undetected unless they are iatrogenic or induced
experimentally. As a result, the mechanism of H. pylori transmission has been difficult to determine definitively, and the preponderance of evidence is circumstantial. Nevertheless, these data suggest that person-to-person transmission is the most
important or perhaps only means of H. pylori transmission.
The primary source of evidence to support person-to-person transmission
comes from cross-sectional data from families. Numerous studies have found
clustering of H. pylori infections within families, with infection rates highest
among first-degree relatives of infected individuals (Drumm et al. 1990; Kivi et al.
2005; Nguyen et al. 2006). Mothers seem to be more important sources for
H. pylori transmission than fathers. Studies in Japan and Germany found that
children with H. pyloriinfected mothers were significantly more likely to be
infected than children with H. pyloriseronegative mothers; no associations
were found between H. pylori infection in fathers and their children (Fujimoto
et al. 2007; Weyermann et al. 2006). A prospective study done in Japan with 9
years of follow-up supports these findings with H. pylori seroconversion occurring only in children with H. pyloriinfected mothers (Malaty et al. 2000).
DNA fingerprinting studies also support person-to-person transmission within
the family unit. H. pylori strains are more similar within families than among unrelated individuals (Bamford et al. 1993; Raymond et al. 2004). Similar fingerprints
are particularly common among siblings (Wang et al. 1993); in one study, 81% of
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siblings shared the same strain of H. pylori, compared with 56% of mothers and
their children and 0% of fathers and their children (Kivi et al. 2003).
Three possible mechanisms for person-to-person transmission of H. pylori have
been proposed: fecaloral, oraloral, and gastrooral (defined here as either transmission by vomitus, or the iatrogenic introduction of H. pylori into the stomach
through the use of infected instruments). The data in support of fecaloral transmission
are inconclusive. Although viable H. pylori have been detected in feces of both
children and adults (Kelly et al. 1994), some studies only report culturing H. pylori
from cathartic rather than normal stools (Parsonnet et al. 1999). In support of
fecaloral transmission, a study of 671 healthcare workers concluded that contact
with fecal matter was a significant risk factor for H. pylori infection (De Schryver
et al. 2006). Additionally, a prospective study found that gastroenteritis in an H.
pyloriinfected household member was associated with a fourfold increased risk of
new infection in another household member (Perry et al. 2006). In this study, however, diarrhea was not an independent risk factor for infection if vomiting was
not also present. In opposition to the fecaloral hypothesis, no excess risk for
H. pylori infection has been observed in sewage workers (Friis et al. 1996; Jeggli
et al. 2004).
Fewer data support oraloral transmission. Although H. pylori has been detected
by polymerase chain reaction from saliva and dental plaques (Krajden et al. 1989;
Mapstone et al. 1993), it has rarely been cultured from the mouth (Ferguson et al.
1993; Krajden et al. 1989; Parsonnet et al. 1999). Dental workers do not have an
increased risk for H. pylori (Malaty et al. 1992). One would anticipate high rates of
transmission of H. pylori between married couples if saliva were the source, and
this is not consistently observed. Some investigators report little H. pylori concordance
among married couples (Miyaji et al. 2000; Perez-Perez et al. 1991), whereas others find a high correlation among couples even after controlling for confounding
factors (Brown et al. 2002; Singh et al. 1999; Stone et al. 2000). The strongest studies, which examined the genotype of infecting strains within couples, have not
found strong evidence of concordance; the great majority of spouses are infected
with different strains (Kuo et al. 1999; Luman et al. 2002; Suzuki et al. 1999).
The strongest data support gastricoral transmission, especially in the setting of
gastric intubation. The majority of these iatrogenic cases result from direct inoculation
of contaminated gastric contents into the stomach via incompletely cleaned
endoscopic equipment (Langenberg et al. 1990). Iatrogenic outbreaks have been
documented (Graham et al. 1988; Pardo-Mindan et al. 1989; Ramsey et al. 1979;
Tytgat 1995), and the strains of H. pylori isolated from patients using the same
endoscopy equipment have been identical. Endoscopists and endoscopy nurses are
also at increased risk for H. pylori infection (Chong et al. 1994; Lin et al. 1994).
Given the ubiquity of H. pylori infection throughout the world and the infrequency
of endoscopic examinations, direct gastricoral inoculation cannot be the primary
route of transmission. However, indirect gastricoral transmission seems plausibly
important. H. pylori has consistently been cultured in large quantities from vomitus
(Brown 2000; Leung et al. 1998; Parsonnet et al. 1999). In addition, in a prospective
study, exposure to an H. pyloriinfected individual with vomiting conferred a sixfold
37
increased risk for new infection (Perry et al. 2006). Additional data from observational
studies concluded that children exposed to emesis were significantly more likely to
be infected than children not exposed to emesis (Ito et al. 2006; Luzza et al. 2000).
Vomitus has also been implicated in transmission of H. pylori among monkeys
(Solnick et al. 2006).
Frequently, infections that are transmitted from person to person can also be
transmitted via water or other environmental vectors. Evidence for contaminated
water as a source of H. pylori transmission, however, is weak. Some studies in
developing countries have found increased risk for H. pylori infection in individuals
using, irrigating with, or swimming in, unclean water (Glynn et al. 2002; Goodman
et al. 1996; Hopkins et al. 1993; Hulten et al. 1996; Karita et al. 2003; Klein et al.
1991; Nurgalieva et al. 2002). However, the household-based clustering of H. pylori
infection in populations with municipal water sources, and the lack of concordance
of H. pylori with other waterborne diseases raises doubt about the importance of
these findings (Egemen et al. 2006; Lin et al. 2005). Although H. pylori DNA has
often been amplified from untreated water, it has been cultured only once using
immunomagnetic separation on raw sewage (Lu et al. 2002). Moreover, when
H. pylori is exposed to water or when it is under other forms of stress, it loses its
classic spiral morphology and becomes coccoid. The coccoid form of H. pylori
cannot be cultured, and it is still debated in the literature whether it is viable and
able to infect (Chen 2004; Delport and van der Merwe 2007; Sorberg et al. 1996).
Food and animal exposure have also been implicated as possible routes of
transmission, although none consistently (Brown 2000; Hopkins et al. 1993).
H. pylori naturally infects monkeys (Drazek et al. 1994; Dubois et al. 1994) and
cats (Handt et al. 1995), and has also been found in sheep and their milk (Dore
et al. 2001), and on houseflies (Grubel et al. 1997; Osato et al. 1998). Pet ownership, however, is not linked to infection (indeed, it has been found to be protective) (Graham et al. 1991; Webb et al. 1994), and animal exposure more
generally is unlikely to explain the extremely high rates of infection
worldwide.
Links Between Helicobacter pylori and Cancer

Interest in H. pylori as a potential cancer-causing agent began soon after the
pioneering discoveries of Marshall and Warren in the 1980s. It had been known for
many years that gastric adenocarcinomas often arose in areas of gastritis. Because
of its induction of chronic gastritis, investigators began almost immediately to take
interest in H. pyloris causal role in malignancy.
The first studies to examine this association were ecologic and compared
regional H. pylori incidence with regional cancer incidence (Eurogast Study 1993;
Forman et al. 1990). Many subsequent case-control studies examined the prevalence
of H. pylori in persons with and without cancer. Now, in retrospect, it is understood
that these studieswhich in a metaanalysis indicated a 1.8-fold increased risk of
38
cancer (Huang et al. 1998)underestimated the true risk. The underestimate

resulted from the loss of H. pylori infection and its serologic response as the stomach
progresses toward malignancy (Genta and Graham 1993; Masci et al. 1996; Osawa
et al. 1996). Stronger support for a role in cancer comes from nested case-control
studies. These studies examine H. pylori prevalence in stored sera obtained from
cases and matched controls years before the development of cancer. Together, these
demonstrate a stronger risk of cancer [odds ratio (OR) = 3.0; 95% CI, 2.33.8
(Helicobacter and Cancer Collaborative Group 2001)]. The risk was particularly
high when sera were drawn more than 10 years before the development of cancer
in the case (OR = 5.9; 95% CI, 3.910.3), again suggesting that diagnostic artifact
occurs when sera are obtained close to the time of cancer diagnosis. Even more
compelling data for an association between H. pylori and cancer come from longitudinal cohort studies. In a large prospective trial conducted in Japan, only those
infected with H. pylori later developed gastric cancer; 36 of 1,246 infected individuals developed gastric cancer compared with none of the 280 uninfected participants (infinite OR) (Uemura et al. 2001). A prospective study of 1,225 Taiwanese
patients confirmed this infinite OR (p = 0.015) (Hsu et al. 2007). The broad
spectrum of strongly supportive studies have led some to speculate that H. pylori is
a necessary factor in the development of gastric cancer of the distal stomach
(Brenner et al. 2004).
As a single agent, H. pylori may be responsible for as many as 5.5% of all
cancers (Parkin 2006), making it the leading infectious cause of cancer worldwide.
This figure, however, derives only from tumors of the gastric antrum and body. The
role of H. pylori in proximal tumors is more debated, in large part because of the
difficulties differentiating adenocarcinomas of the proximal stomach from those of
the gastroesophageal junction (Odze 2005; Richter 2007). Overall, H. pylori infection seems to be important for inflammation in the proximal stomach but remains
inversely related to proximal cancers of the gastric cardia and gastroesophageal
junction (Yang and Davis 1988). In a large prospective nested case-control study
of 29,133 participants aged 5069 years, H. pylori was strongly associated with
distal gastric cancer (OR = 7.9; 95% CI, 3.020.9) but inversely proportional to
proximal gastric cancers (adjusted OR = 0.31; 95% CI, 0.110.89) (Kamangar et al.
2006). This finding confirmed the results of a metaanalysis of previous nested
case-control studies that showed no increased risk for the development of proximal
gastric cancers among those infected with H. pylori (Helicobacter and Cancer
Collaborative Group 2001).
Proximal tumors often occur in the setting of GERD, and H. pylori infection is
less common in patients with these symptoms (OR = 0.60; 95% CI, 0.470.78)
(Raghunath et al. 2003). Pathophysiologically, H. pylori may prevent GERD by
decreasing gastric pH. Given the strong causal relationship between GERD and
adenocarcinoma of the esophagus (Lagergren et al. 1999), H. pylori may confer a
protective benefit for cardia tumors as well. Although incidence rates of distal gastric adenocarcinoma have declined with decreased H. pylori infection rates, it is
likely that these decreasing H. pylori infection rates observed in western countries
explain the simultaneous increase in proximal adenocarcinomas.
39
Effect Modifiers for Helicobacter pylori and Malignancy

Most people infected with H. pylori will remain free of symptoms and will never
develop gastric cancer in their lifetimes. Host genetic factors, bacterial variation,
and diet and environmental cofactors all have significant roles in the variable evolution and presentation of H. pylori infection.
Genetic Factors
Approximately 10% of gastric cancers cluster in families but only a small portion
of these cancers result from known hereditary cancer syndromes. Other genetic
factors have been investigated that might influence the consequences.
Notably, the intensity and type of immune response to infection with H. pylori
is determined by host genetics. In 2000, El-Omar demonstrated that specific
polymorphisms of interleukin (IL)-1, an important inflammatory cytokine and
potent inhibitor of gastric acid secretion, contribute to intestinal-type stomach
cancer progression (El-Omar et al. 2000). These findings have now been extensively replicated worldwide. Polymorphisms in tumor necrosis factor (TNF)-
(Machado et al. 2003), IL-1 receptor antagonist (El-Omar et al. 2000), and IL-10
(El-Omar et al. 2003) also influence intestinal-type gastric cancer evolution
whereas polymorphisms in the IL-8 promotor have been linked to diffuse-type
cancer (Lee et al. 2005). Individuals unfortunate enough to possess polymorphisms
in IL-1, TNF-, and IL-10 have a 27-fold increased risk for the development of
gastric cancer (El-Omar et al. 2003).
Human leukocyte antigen (HLA) genotypes have been variably linked to gastric
cancer, with different HLA types associated with cancer or cancer protection in
different regions of the world (Garza-Gonzalez et al. 2004; Hirata et al. 2007; Li
et al. 2005; Perri et al. 2002; Quintero et al. 2005; Watanabe et al. 2006).
Bacterial Factors
Variations in H. pylori genes confer different risks of cancer development. H. pylori
can undergo point mutations and chromosomal rearrangements (Blaser and Berg
2001) and, consequently, there is an impressive degree of genetic diversity, even
within a single host (Cooke et al. 2005; Israel et al. 2001; Kim et al. 2004).
Approximately half of all strains of H. pylori contain a 40-kb DNA virulence cassette
known as the pathogenicity island (PAI) (Stein et al. 2002; Yamazaki et al. 2003).
This cassette, which is discussed in detail elsewhere in this book, encodes a Type
IV secretion system that injects the CagA protein into the host epithelial cell.
H. pylori possessing this cassette produce greater gastric inflammation and a higher
risk of intestinal-type malignancies than strains that do not contain this gene (Chow
et al. 1998; Parsonnet et al. 1997). A metaanalysis published in 2003 showed that
40
CagA is an independent risk factor for distal gastric cancers (OR = 1.64; 95% CI,
1.212.24) (Huang et al. 2003).
Certain genotypes (the s1 and m1 genotypes) of the vacA gene, a gene that
encodes a vacuolating cytotoxin, are associated both with the presence of a viable
pathogenicity island and with the development of cancer (Con et al. 2007). Other
polymorphic bacterial factors linked to cancer contribute to H. pylori adherence to
gastric epithelial cells (babA), bacterial invasion into the gastric glands, and persistence
of infection within the gastric lumen.
From an epidemiologic perspective, global distribution of the more pathogenic
genotypes might help to explain disease distribution (Bravo et al. 2002; Kersulyte
et al. 2000). For example, in Asia, a region with high gastric cancer incidence,
nearly all strains of H. pylori possess the PAI, whereas the rates are closer to 50%
in the United States and Europe (Covacci et al. 1999). In addition to regional
differences in the presence of the PAI, polymorphisms within the PAI vary
geographically and may relate to disease pathogenesis (Yamaoka et al. 2000).
Also being mapped to determine population effects are the vacA genotypes; less
virulent strains with vacA s2 genotype are extremely rare in Asia, whereas they
comprise 20%40% of strains in North America, northern Europe, and Australia
(Van Doorn et al. 1999). Recently, an H. pylori genotype database has been developed
to assess the breadth of gene sequences in isolates entered worldwide (Ahmed
et al. 2007); this database will enable a broader understanding of the genetics of
virulence and disease. Such an understanding will be complicated, however, by
the existence of multiple genotypes of varying pathogenicity within individual
hosts (Matteo et al. 2007).
Environmental Factors
Although diet has been extensively studied in gastric carcinogenesis, it is not well
studied in the setting of H. pylori infection. A prospective cohort study in
Scandinavia demonstrated a protective effect of vitamin C and beta-carotene in
individuals infected with H. pylori (Ekstrom et al. 2000). This finding was initially
supported in a prospective study from Colombia that demonstrated that H. pylori
eradication and increased dietary vitamin C and beta-carotene independently
prevented progression of preneoplastic lesions to cancer (Correa et al. 2000). Longterm follow-up from this trial, however, showed that the benefits of vitamin C and
beta-carotenebut not of H. pylori eradicationdisappeared when participants
were followed up for a longer period of time (Mera et al. 2005).
Increased dietary salt may also increase gastric cancer risk. As mentioned above,
before the discovery of H. pylori, salt was linked to gastric cancer in humans. In animal
models, increased dietary salt in the setting of H. pylori augments gastric carcinogenesis (Fox et al. 2003). In humans, a study of 2,476 participants followed prospectively for 14 years, the years yielded a significant relationship between increased salt
consumption and the development of gastric cancer, but only in subjects who were
both infected with H. pylori and had atrophic gastritis (Shikata et al. 2006).
41
Another area of increasing interest is the possibility of coinfection with other

organisms influencing the outcome of H. pylori in humans. By mitigating the Th1
inflammatory response, helminths could theoretically reduce gastric inflammation and cancer incidence. This reduction of inflammation has been observed in
animals coinfected with H. pylori felis and helminths (Fox et al. 2000) and has
also been suggested in small ecologic studies of humans (Mitchell et al. 2002;
Whary et al. 2005). The clinical significance of these findings is now an intense
area of investigation.
Unanswered Epidemiologic Questions

Although much has been learned about H. pylori and its relationship to gastric cancer since 1982, some critical questions remain unresolved and additional research
is needed.
Why Do Males Have Higher Risk for Cancer?

More men than women develop gastric cancer. In fact, distal, noncardia gastric
cancers is on average twice as common among men compared with women (Crew
and Neugut 2006). This higher incidence of gastric cancer observed among men is
partially explained by higher H. pylori infection rates. A metaanalysis of large,
population-based studies found that male gender was significantly associated with
H. pylori infection (OR = 1.16; 95% CI, 1.111.22), although this difference was
not observed in studies of children sufficient to explain the differences in cancer
incidence (De Martel and Parsonnet 2006). Other cofactors beyond H. pylori infection such as smoking, alcohol, increased dietary salt, or even a protective effect of
female hormones have not been demonstrated to explain the differences observed
(Ferreccio et al. 2007; Lindblad et al. 2005). Understanding gender differences in
gastric cancer would provide insights into carcinogenesis more generally.
Is There an African Enigma?

Although H. pylori infection has a significant role in gastric cancer development,
higher H. pylori infection rates are not always associated with higher gastric cancer
rates. As early as 1992, Holcombe noted that despite high rates of H. pylori infection and H. pyloriassociated gastritis in Nigeria, gastric cancer was uncommon;
they termed this the Africa enigma (Holcombe 1992). Additional research has
noted a similar pattern of high H. pylori infection rates and low gastric cancer incidence in India, Bangladesh, Pakistan, and Thailand (Miwa et al. 2002; Singh and
42
Ghoshal 2006). Some have maintained that microbial coinfection with helminths
explains these paradoxic H. pylori responses (Whary et al. 2005). For example,
several human studies have found shifts in H. pylori immunoglobulin (Ig)G
antibodies in helminth-infected populations to IgG1 rather than IgG2 (Mitchell
et al. 2002; Whary et al. 2005), indicating differentand possibly less inflammatoryimmunologic response to gastric infection. Others maintain that dietary
factors, host genetics, or bacterial factors explain these observations (Ghoshal et al.
2007; Louw et al. 2001; Singh and Ghoshal 2006). Still others aver there is no
African enigma, only low life expectancy among the poorest individuals, deficient
cancer reporting, and H. pylori diagnostic artifact (Agha and Graham 2005). It is
unlikely, however, that anyone would argue that host response to infection does not
vary from individual to individual. Understanding this variability across populations
could be the key to identifying attainable cancer intervention strategies.
Can Treatment of Helicobacter pylori Prevent Cancer?

Treatment of H. pylori infection to prevent gastric cancer is an appealing prevention
strategy and numerous studies have indicated it is also likely to be cost effective
(Fendrick et al. 1999; Mason et al. 2002; Parsonnet et al. 1996; Roderick et al.
2003). Yet, to date, no randomized, prospective trials have shown that eradication
of existing infection prevents cancer. Several studies, however, show tantalizing
evidence that such treatment might work. A nonrandomized, nonblinded trial of
H. pylori eradication in Japanese patients with early gastric cancer showed significantly lower rates of cancer relapse in patients who received eradication therapy than
those who did not (Uemura et al. 1997); this finding has been supported by larger
retrospective analyses (Nakagawa et al. 2006) but has yet to be supported by a
randomized clinical trial. Randomized trials of preneoplastic conditions indicate
that H. pylori therapy may improve the overall pathology of the stomach, decreasing atrophic gastritis and intestinal metaplasia (Correa et al. 2000; Ley et al. 2004;
Sung et al. 2000). Although an improvement in histopathology has been reported
in only a minority of subjects, the study with longest follow-up indicates that the
differences between treated and untreated subjects may become increasingly evident
as years pass (Mera et al. 2005).
The one randomized trial of cancer prevention completed to datea study
conducted in Chinawas underpowered for the final endpoint of gastric cancer
(Parsonnet and Forman 2004). Among a subset of participants, however, eradication
did show a benefit; i.e., among participants who had no preneoplastic lesions in
their first endoscopy, there was a decreased incidence of gastric cancer after active
treatment (Wong et al. 2004). Further randomized trials are underway. Given the
difficulties of conducting these trials and the decreasing incidence of gastric cancer
worldwide, however, it is possible none will ever be completed successfully. In the
absence of clinical trial support, there is yet no policy in place in any country to
screen populations for infection and treat all infected individuals. Instead, consensus
43
groups have recommended screening and treating those at highest risk: i.e., those
with a family history of cancer, with prior gastric surgery, or with documented
atrophic gastritis (Malfertheiner et al. 2007).
What Is the Best Approach to Helicobacter pylori Prevention?

H. pylori and its related diseases are disappearing spontaneously worldwide.
Acceleration of the organisms disappearance through primary prevention, however,
could save myriad lives. Because the preponderance of evidence supports personto-person transmission of H. pylori, efforts to improve hygiene and handwashing
may be effective strategies for gastric cancer prevention. These methods have the
added advantage of preventing other enteric infections, and of proven feasibility.
Consuming a diet high in vegetables and fruit and low in salt may also be an effective way to reduce stomach cancer rates (World Cancer Research Fund and
American Institute for Cancer Research 1997), but effectuating dietary change can
be an onerous challenge.
A vaccine for H. pylori is another appealing primary prevention strategy for gastric cancer. The precedent for a vaccine to prevent cancer has already been established with the hepatitis B vaccine to prevent hepatomas and HPV vaccine to
prevent cervical cancer. Unfortunately, the development of an H. pylori vaccine has
proved to be more difficult than the hepatitis B and HPVvaccines. Although an enormous amount has been learned about the immune response to H. pylori infection
(Suerbaum and Michetti 2002), there are as yet no known correlates of protective
immunity for infection or reinfection in humans. In mouse models, infection can be
prevented with a variety of vaccines (Arora and Czinn 2005). The human response
to H. pylori is more complicated, however, and no vaccine has yet reached efficacy
trials in humans (Kabir 2007). Should a vaccine appear, it is likely to be a cost-effective approach to cancer prevention (Rupnow et al. 1999; Rupnow et al. 2001).
In considering H. pylori prevention, however, it is also important to assess
whether there may be downsides to the strategy. Recent observational data suggest
that H. pylori might provide some protection against acute diseases of childhood.
Theoretically, by upregulating the systemic Th1 immune response, infection might
assist in combating common childhood infections. A small amount of evidence
supports this; H. pylori infection has been linked to protection from both diarrheal
disease (Perry et al. 2004)a leading cause of death in children worldwideand
tuberculosis (Perry et al. 2007). In addition, some argue that absence of H. pyloris
Th1 stimulation in young children has fostered increases in asthma and other allergic
diseases (Chen and Blaser 2007; Kosunen et al. 2002; Pessi et al. 2005). Finally, in
adults, an ever-increasing amount of data indicates that the absence of H. pylori
promotes both GERD and its long-term consequenceadenocarcinoma of the
esophagus (Cremonini et al. 2003; de Martel et al. 2005).
Although there is no doubt that the areas of the world that have spontaneously
lost H. pylori from their resident flora experience greater life expectancy and
44
decreased morbidity than those in which it persists, we have, in the past, always let
nature take its course. With a vaccine, we would be in a position to precipitate
the loss of H. pylori even from regions of the world where acute infectious diseases
run rampant. One would be prudent, then, to ask whether the survival of H. pylori
in these microbial ecologies provides a survival advantage to children that counterbalances the risks of gastric adenocarcinoma later in life.
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Chapter 2

Epidemiology of Gastric Cancer

Gastric Cancer Epidemiology

T.C. Wang et al. (eds.) The Biology of Gastric Cancers,

Classifications of Adenocarcinomas of the Stomach

Incidence of Gastric Cancer

2 Epidemiology of Gastric Cancer and H. pylori

Trends Over Time

Differences in Epidemiology of Various Tumor Types

Mortality and Case Fatality

2 Epidemiology of Gastric Cancer and H. pylori

Risk Factors for Gastric Cancer, Excluding Helicobacter pylori

1996), this depressed socioeconomic status is confounded by increased usage of

2 Epidemiology of Gastric Cancer and H. pylori

of Hiroshima and Nagasaki, a greater than expected number of gastric tumors

Helicobacter pylori Epidemiology

2 Epidemiology of Gastric Cancer and H. pylori

Prevalence and Incidence by Region

1995). Incidence of infection is highest in early childhood; the majority of infections

Risk Factors for Infection

2 Epidemiology of Gastric Cancer and H. pylori

least in part, of socioeconomic differences. In the United States, non-Hispanic

2 Epidemiology of Gastric Cancer and H. pylori

Links Between Helicobacter pylori and Cancer

cancer (Huang et al. 1998)underestimated the true risk. The underestimate

2 Epidemiology of Gastric Cancer and H. pylori

Effect Modifiers for Helicobacter pylori and Malignancy

2 Epidemiology of Gastric Cancer and H. pylori

Another area of increasing interest is the possibility of coinfection with other

Unanswered Epidemiologic Questions

Why Do Males Have Higher Risk for Cancer?

Is There an African Enigma?

Can Treatment of Helicobacter pylori Prevent Cancer?

2 Epidemiology of Gastric Cancer and H. pylori

What Is the Best Approach to Helicobacter pylori Prevention?

2 Epidemiology of Gastric Cancer and H. pylori

2 Epidemiology of Gastric Cancer and H. pylori

2 Epidemiology of Gastric Cancer and H. pylori

2 Epidemiology of Gastric Cancer and H. pylori

2 Epidemiology of Gastric Cancer and H. pylori

2 Epidemiology of Gastric Cancer and H. pylori

2 Epidemiology of Gastric Cancer and H. pylori

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