Helicobacter pylori and Gastric Cancer
MANFRED STOLTE, ALEXANDER MEINING
Department of Pathology, Klinikum Bayreuth, Bayreuth, Germany
Key Words. Cancer Gastritis Helicobacter pylori Prevention
A BSTRACT
Gastritis caused by infection with Helicobacter
pylori (H. pylori) is one of the most common infectious
diseases worldwide. There are data on the epidemiol-
ogy, pathophysiology, and histology of this disease that
show that H. pylori gastritis has an important role in
gastric carcinogenesis. However, it has to be considered
INTRODUCTION
Helicobacter pylori (H. pylori) is a causative agent in the
pathogenesis of chronic active gastritis of the stomach, on
which severe diseases such as duodenal and gastric ulcer may
develop [1]. The spectrum of H. pylori-associated diseases is,
however, still expanding. There is strong evidence to show that
H. pylori infection may also be associated with gastric neo-
plasms, i.e., carcinoma of the stomach and primary low-grade
B cell gastric lymphoma of mucosa-associated lymphoid tis-
sue, known as MALT lymphoma [1]. Our knowledge of the
pathogenesis of gastric neoplasms is therefore increasing, and
new approaches to the prevention of gastric cancer by antibi-
otic treatment of a precursor of this disease, namely H. pylori
gastritis, can be considered.
EPIDEMIOLOGY
Although incidence of gastric carcinoma is on the decline,
it remains the second most common cause of death from
malignant diseases. Nevertheless, incidence rates differ from
one geographical region to another, being rather high in
Japan, China, Columbia, and Costa Rica, and comparatively
low in the United States [2]. However, since there is a geo-
graphical association between gastric cancer incidence and H.
pylori prevalence rates, it has been suggested that gastritis
caused by this bacterium may represent an important factor in
gastric carcinogenesis [3, 4]. This hypothesis was confirmed
by prospective case-control studies investigating the associa-
tion between infection with H. pylori and gastric cancer which
have calculated an approximately three- to sixfold increase in
Correspondence: Prof. Dr. M. Stolte, Institut fr Pathologie, Klinikum Bayreuth, Preuschwitzerstr. 101, 95445 Bayreuth,
Germany. Telephone: 49-921-400-5600; Fax: 49-921-400-5609. Accepted for publication February 6, 1998. AlphaMed Press
1083-7159/98/$5.00/0
The Oncologist 1998;3:124-128
that only very few of those infected with H. pylori will
develop gastric cancer. Hence, it will be a main target of
future research to identify individuals who carry a greater
risk for developing gastric cancer, and therefore may
benefit from eradication of H. pylori in terms of gastric
cancer prevention. The Oncologist 1998;3:124-128
the risk of gastric cancer developing in patients infected with
the organism [5, 6]. This odds ratio increases to approxi-
mately ninefold if only patients randomized for prospective
serological case-control studies with a follow-up period of at
least 14 years are considered [7]. In addition, a recent study
from Japan in which only patients below the age of 40 were
investigated reported an odds ratio of 13.3 for developing gas-
tric cancer associated with H. pylori infection (Table 1) [8].
Nevertheless, there is a striking contrast between the
total number of persons infected with H. pylori and those
subsequently developing gastric cancer. To date, the ratio
of the prevalence of H. pylori infection to the incidence rate
of gastric cancer is approximately one to one thousand in
Germany, and even less in the United States [1]. This indi-
cates that the epidemiological role of H. pylori infection in
the development of gastric carcinoma must be seen only as
one factor in a multi-factorial process.
Diet, especially, has been mentioned to be one of these
co-factors. Authors who investigated eating habits in relation
Table 1. H. pylori and gastric cancer risk/odds ratio
Group Risk of gastric cancer
Patients infected with H. pylori 3- to 6-fold risk increase
Patients infected with H. pylori and 9-fold risk increase
randomized for prospective serological
case-control studies with a follow-up
period of at least 14 years
Only patients below age 40 13.3 odds ratio
Stolte, Meining
to gastric cancer incidence rates found that smoked food con-
taining nitrosamines and a high salt consumption in combi-
nation with a low-calcium, low-vitamin diet (especially
vitamin C, vitamin E, and -carotene) are associated with
an increased risk of developing gastric carcinoma [9, 10].
Regarding socioeconomic factors, it has been mentioned that
bad housing conditions and water supply might have a dis-
advantageous impact on gastric carcinogenesis. In particular,
the nitrate content of drinking water is believed to be of
importance [11].
PATHOLOGY
We do know that H. pylori infection is always the cause
of chronic active gastritis. Infection with the bacterium pro-
vokes an invasion of the mucosa by lymphocytes/plasma
cells (a marker for the degree of gastritis) and neutrophils
(a marker for the activity of gastritis). In addition, inflam-
mation is always accompanied by a replacement of the gas-
tric foveolae by a regenerative type of epithelium and a
decrease in the production of mucus [12]. Besides these dif-
fuse parameters, multifocal features such as intestinal meta-
plasia, atrophy, and lymphoid follicles may be found in
association with H. pylori infection.
In terms of gastric carcinogenesis, H. pylori may act either
directly or via the inflammatory process that is provoked by
the bacterium but determined by the host. It has been reported
that H. pylori produces substances such as ammonia, phos-
pholipases, and cytotoxins, which are released into the gastric
lumen and are thought to cause epithelial damage [13]. This
damage leads to a persistent state of proliferation and regener-
ation, and thus increases the risk of malignant alterations of the
gastric stem cells at the neck region of the gastric tubes [14].
In addition, infection with H. pylori decreases secretion of
ascorbic acid into the gastric lumen [15]. Ascorbic acid (as
well as vitamin E and -carotene) serves as an anticarcinogen,
since it lowers the levels of potential mutagenic substances
such as nitrosamines or free radicals. On the other side, free
radicals in the form of NO and reactive oxygen metabolites
are produced by neutrophils and therefore determined by
the hosts immune response toward infection. Hence, in con-
clusion, there appear to be interactions among host factors,
strain factors, and disadvantageous living conditions/eating
habits which all increase the possibility of DNA damage, and
finally, the risk of developing gastric cancer (Fig. 1).
MICROBIOLOGICAL ASPECTS
To answer the question regarding why only very few
among those with H. pylori infection develop gastric cancer,
it has been suggested that there are certain strains of H.
pylori, namely those producing the CagA protein, that are
thought to play a crucial role in gastric carcinogenesis [16].
125
In our opinion, however, present data on the role of the CagA
in carcinogenesis are not convincing. Performing a
Medline data survey, we found that prior to November
1997, there were a total of 12 published case-control studies
in which the association of the CagA-status on gastric cancer
prevalence was investigated. Of these, only three studies
reported an increased odds ratio for gastric cancer if an indi-
vidual is infected with a CagA-positive strain. However, sig-
nificant odds ratios were only found for developing gastric
cancer of the intestinal but not the diffuse type. In addition, it
has been reported that the same strain factor (i.e., CagA pro-
tein) is involved in the pathogenesis of duodenal ulcers [17],
a disease which has been reported to be associated with a
reduced risk for developing gastric cancer [18]. Hence, strain
factors alone may not suffice to explain why some people
develop gastric cancer following infection with H. pylori,
whereas others develop a peptic ulcer or stay asymptomatic
the rest of their lives.
HISTOPATHOLOGICAL ASPECTS
Another factor involved in carcinogenesis might be the
different degree and distribution of gastritis in gastric carci-
noma patients. It has been shown that the extent and topo-
graphy of H. pylori-associated gastritis differs when
compared with age- and sex-matched patients having peptic
ulcer or merely gastritis. It appears that patients with gastric
cancer have much more severe gastritis in the corpus of the
stomach in contrast to the antral-predominating gastritis in
duodenal ulcer patients [19]. That pronounced gastritis in
the corpus may be involved in the development of gastric
cancer can be explained by the finding of a decrease in acid
production associated with a shift in the distribution of gas-
tritis toward the corpus [20]. This reduction in local acid
Helicobacter pylori infection
NH4+, cytotoxin,
phospholipases Inflammation
Epithelial degeneration
Production of NO &
reactive O2 metabolites
Hyperproliferation/
metaplastic changes
Salt/nitrate/ Vitamins C & E
nitrosamines calcium
DNA damage
Gastric cancer
Figure 1.
126
production might then result in the suppression of a defense
mechanism against dedifferentiated epitheliumsince atyp-
ical cells are very acid sensitiveand might thus lead to
persistence and progression of atypical cells [21].
Of interest, corpus-predominating gastric cancer pheno-
type of H. pylori gastritis also occurs more often in relatives
of gastric carcinoma patients [22]. We know, however, that
there are hereditary factors that might play a role in the devel-
opment of gastric cancer [23]. Hence, it may be speculated that
there is a genetic susceptibility influencing the expression of
gastritis and thereby increasing an individuals gastric cancer
risk. This genetic susceptibility for gastritis of the gastric can-
cer phenotype may be due to the number of acid-producing
parietal cells. If an individual inherits a comparatively low
number of parietal cells, H. pylori gastritis might manifest
predominantly in the cor-
pus and thereby increase
an individuals gastric
Since prophylactic vaccination
cancer risk.
An alternative path-
is not available, strategies need to
way could be explained be developed to identify individuals
by data of two recent
publications which report who are at a higher risk and
that in some cases there is
a crossreactivity of anti- who might therefore benefit from
bodies directed against H.
pylori with gastric pari- H. pylori eradication.
etal cells which leads to
an increase in the grade of gastritis in the corpus [24, 25].
Since these autoantibodies are found in only a proportion of
infected individuals, it may be speculated that their appear-
ance is influenced at least to some extent by hereditary fac-
tors. Further studies may help to prove this association. That
autoimmune gastritis is associated with an increased risk of
gastric carcinoma has been known for many years and has
also been confirmed more recently [26, 27]. However, we
know that infection with H. pylori induces severe inflamma-
tion with destruction of the corpus glands (preatrophic
stage), which finally leads to complete atrophy of the corpus
(atrophic stage). This latter stage of atrophy and loss of acid
production not only increases the risk of gastric carcinoma, but
also represents unfavorable living conditions for H. pylori
[21, 28]. In some cases, therefore, H. pylori may no longer be
detectable even though infection with the organism induced
the mucosal damage. Yet, after the histopathological diagno-
sis of preatrophy and histological or even serological diag-
nosis of H. pylori infection, antimicrobial therapy should be
initiated, since our own observations showed that eradicating
H. pylori not only inhibits a further progression of autoim-
mune gastritis but also leads to normalization of the gastric
glands [29].
Helicobacter pylori and Gastric Cancer
PREVENTION OF GASTRIC CANCER BY CURE OF THE
H. PYLORI INFECTION?
After what has been reported about the association
between gastric cancer and H. pylori infection, it sounds rea-
sonable that prevention of H. pylori infection might serve to
decrease gastric cancer incidence. However, prophylactic
vaccination is not available to date. Thus, one of the main
aims for future studies will be to investigate the extent to
which gastric cancer associated with H. pylori infection can
be prevented by antibiotic treatment of the organism. There
are, however, only very few persons predisposed to develop
gastric cancer among those infected with H. pylori. In addition,
there are the problems with treatment regimens subscribed
against the infection: they cost money, they have a number
of side effects, and widespread uncritical use may give rise
to the major problem of
increasing antibiotic resis-
tance rates. Hence, certain
strategies need to be devel-
oped to identify individu-
als who are at a higher risk
and who might therefore
benefit from H. pylori
eradication.
Relevant important
data have recently been
reported by Uemura et al.
[30]. In a group of patients
with endoscopically resected early gastric cancer and subse-
quent eradication of H. pylori, no secondary carcinoma devel-
oped during the follow-up period, while in the group with
persistent H. pylori infection, 9% developed secondary can-
cers. Hence, prevention of secondary cancer appears possi-
ble by treating the H. pylori infection and should therefore
be performed in individuals following early resection for
gastric cancer.
Since there is certainly a hereditary risk for gastric can-
cer, it may also be advisable to eradicate H. pylori in per-
sons with a family history of gastric cancer [31]. This
procedure might help to avoid one factor that increases the
risk of gastric cancer.
But who else besides the above-mentioned persons
might benefit from H. pylori eradication in terms of gastric
cancer prevention? To date, data on certain strain and host
factors are not convincing. Although it has been suggested
that serological screening for CagA-status or pepsinogen
A/C levels indicates an increased gastric cancer risk, it is
still equivocal whether these methods are useful for identi-
fying those persons with H. pylori infection who might
indeed benefit from H. pylori eradication in terms of gastric
cancer prevention.
Stolte, Meining
A much broader approach may be given by the use of
histopathological examinations of the gastric mucosa. It may
be speculated that routine histopathology alone suffices not
only to enable reliable detection of a neoplasm but also pro-
vides predictive information about the outcome of H. pylori
gastritis in terms of cancer development. We know from
Correas model that multifocal atrophy arising in H. pylori
gastritis is a precancerous condition leading to gastric carci-
noma of the intestinal type [32]. Hence, an individual carries
an increased risk of gastric cancer if atrophy is detected in
gastric biopsy specimens. Subsequent cure of the H. pylori
infection may help to stop this process. However, carcinomas
of the diffuse type are not included in Correas model.
Precancerous conditions for this type of gastric cancer have
not yet been identified.
Another argument against Correas hypothetical
sequence derives from data published by Hattori from Japan
[33]. Analyzing gastric microcarcinomas of the intestinal
type (diameters <5 mm), he found no precursor lesions in the
tumor margins. Hence, he concluded that intestinal metapla-
sia, dysplasia, and carcinomas arise coincidentally. This
implies that no precursor is present for each of them. In addi-
tion, in disagreement with the role of intestinal metaplasia as
a precancerous lesion stands the finding that intestinal meta-
plasia is found in almost every patient with duodenal ulcer.
However, the distribution of intestinal metaplasia/gastric
atrophy in these patients is not as expanded as in cancer
patients, which attributes to the fact that it is only found in
routine gastric biopsies of approximately 20% of duodenal
ulcer patients. We do know, however, that a history of duo-
denal ulcer disease protects from gastric cancer [18]. Hence,
it may be speculated that intestinal metaplasia/gastric atrophy
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