Gastric Carcinoma: Failed Adaptation to Helicobacter pylori P. SIPPONEN & K. SEPPALA Dept. of Pathology, Jorvi Hospital, Espoo, and Gastroenterology Unit, Second Dept. of Medicine, University of Helsinki, Finland

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Sipponen P, Seppala K. Gastric carcinoma: failed adaptation to Helicobacter pylori. Scand J Gastroenterol 1992;27 Suppl 193:33-38. Helicobacrer pylori is the major cause of chronic gastritis. Unlike bacterial infections in general, H. pylori acquisition causes a chronic, usually life-long infection. After acquisition, chronic inflammation (gastritis) appears and develops slowly into atrophic gastritis (with intestinal metaplasia) in a proportion of affected subjects. Inflammation and atrophy result from a failure of the immune system to eliminate the H. pylori infection. In infected stomach, several cascades of reactions are triggered which may result in impairments of structure and function of the gastric mucosa, some of which lesions also increase the risk of gastric carcinoma (CGA). A sequence of events from an early H. pylori infection into an atrophic gastritis has risen a theory that the H. pylori acquisition is a key issue in the development of GCA. Several aspects in the epidemiology and pathogenesis of GCA can be understood and explained by this infectious background. The H. pylori gastritis is unexpectedly common in patients with GCA of both intestinal or diffuse type, and the infection and gastritis precede the development of cancer. In Finland, 7U-80% of the GCA cases seem to develop in connection with an H. pylori-positivegastritis or atrophy, 1@15% develop in a normal stomach (genetically determined GCA cases?), and 1&15% are associated with an H. pylori-negative corpus-limited (autoimmune) gastritis and atrophy. Case control studies suggest that the presence of H. pylori related inflammation raises the risk of GCA twofold, and the appearance of atrophic gastritis (and intestinal metaplasia) raises further this risk 2-3 times, as compared to the risk of GCA in subjects with a normal stomach. Key words: Atrophic gastritis; chronic gastritis; gastric cancer; Helicobacter pylori Pentti Sipponen. M.D.. Depr. of Pathology. Jorvi Hospital, SF-02740 Espoo, Finland

Gastric carcinoma (GCA) is one of the most prevalent malignant tumours in the world (1,2). This is the case especially in developing countries but the GCA is still one of the prevalent malignant diseases in developed countries as well. Epidemiology of G C A shows several features which strongly suggest that some common environmental factors play a role in the pathogenesis of G C A (2.3). These features are, for instance, the association of G C A with a low socioeconomic status (4),and the unexpectedly rapid changes in the incidence of G C A which have taken place in several populations in recent decades ( 2 , s ) . Changes in exposure of the populations to some unknown carcinogens could explain these features. Another possibility is that there has occurred changes in such factors in the environment which alter the structure and function of the gastric mucosa, and which correspondingly promote and modulate the genesis of GCA. or that both of the alternatives are operating together. It has been known for a long time that chronic gastritis and its atrophic sequelae are precancerous conditions for GCA: they increase the risk gastric tumours and obviously promote the development of G C A . Recent observations that chronic gastritis is an infectious disease in origin have raised a theory that the pathogenesis of GCA is related to the Helicobacter pylori acquisition. The theory implies that H. pylori gastritis is the missing environmental factor in the GCA epidemiology. and that the infection is a key event in

the processes which may later lead to the development of G C A (6-11). Although the link between H. pylori acquisition and G C A is certainly distant and indirect, and although the causality may be an uncorrect expression, the H. pylori acquisition can trigger a sequence of phenomena in the stomach which secondarily enhance the development of G C A . Even though G C A is certainly multifactorial(12), the linkage between H. pylori gastritis and G C A can mean that the epidemiology of H . pylori gastritis predicts and determines the epidemiology of GCA in the populations. However, an important aspect to be noticed is that only a minor fraction of people with H. pylori acquisition will ever get the G C A ; that is, the H. pylori gastritis is an extremely common infection in the general population and is, therefore, a low risk factor for G C A at the individual level. FAILURE IN THE ELIMINATION OF H. PYLORI INFECTION

H . pylori infection is the major single etiologic agent in chronic gastritis (13). Unlike bacterial infections in general. H . pylori acquisition induces a chronic inflammation (gastritis) which is long-lasting and obviously life-long (13). Spontaneous healing seems to be a rare event. Corres-

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P. Sipponen & K . Seppala

pondingly, the bacterium is demonstratable in the gastric mucosa for decades, or at least up until to the appearance of late advanced atrophic and metaplastic alterations, and of achlorhydria or hypochlorhydria. The persistence of infection may be a key issue regarding the clinical and morphological outcomes of the H. pylori acquisition. The chronicity of H. pylori infection is obviously a result from a failure of the immune system to eliminate the infection (15,16). Growth of the organisms within the mucus layer at gastric mucosal surface may be a reason for this failure. Serological and immunological responses are evoked against the bacterium but these responses fail, however, to cope effectively with the bacterium: the bacteria remain outside or in periphery of the immunological effector mechanisms, and of the innate and acquired immunity. FAILED ADAPTATION T O H. PYLORZ INFECTION

H . pylori is certainly a pathogen: the acquisition causes always an acute and/or chronic inflammation (gastritis) (17, 18). The bacterium does not exist in normal stomach, and an adaptation of the human body to H. pylori, as is the case to intaluminal bacteria in the gut, does not seem to exist. The gastric surface epithelium provides a suitable niche for the population of the pathogen without interactions with the luminal flora. In addition, the human beings seem to show a remarkable species- specific susceptibility to the H. pylori acquisition. Both the bacterium itself and the subsequent inflammation are sources of mechanisms and factors to cause tissue damages. Cytotoxins, liberation of several proteolytic and lipolytic enzymes, and production of ammonia by bacterial urease system are some of well known bacterium-related factors (17). A potent novel mechanism is further a production of tissue toxic acetaldehyde by alcohol dehydrogenase. H. pylori organisms seem to contain also this enzyme in high concentrations (R. Roine, T. Salmela, J. Hook-Nikanne, T. Kosunen, M. Salaspuro. Unpublished observations). Several immunological reactions and effector cells in the host are also activated in the If. pylori infection, resulting in liberation, for instance, of cytokines, superoxide or other free radicals, various toxins or growth factors which all may influence, regulate and modulate the differentiation, growth and function of the mucosal cells and epithelium (17). A noteworthy aspect is that the chronicity of H. pylori gastritis may accentuate the consequences of both the bacterium and inflammation related tissue injuries. Life-long duration of an on-going infection can lead to tissue damages even in such tiny injuries which in acute occasions are unlikely to cause serious or permanent tissue damages. Production of superoxide anion or other reactive free radicals from activated granulocytes or monocytes/macrophages provides a potential risk for endogenous damages of the genome in epithelial or mucosal cells. A long-lasting, active and on-going inflammation may again enhance these

hazards. These risks may be further potentiated by deficiencies of protective vitamins and radical scavengers, as may be the case especially in subjects with gastritic and atrophic stomach. It has been emphasized that different strains of the bacterium exert reactions and damages which may vary in extent and grade (16). Production of cytotoxins is obviously dissimilar in different strains, and a heterogeneity in type and activity of toxins, enzymes, or of other virulence factors of the H. pylori organism, can modulate the outcomes of the infection. A heterogeneity may also be the case in host reactions between the affected subjects; the genetic liability to dissimilar tissue injuries, or to dissimilar reactions of the host to repair the damages, may vary between the subjects. In histology, the activity, grade of topography of gastritis and atrophy may correspondingly vary between subjects and bacterial strains. Different topographic phenotypes of gastritis can represent an equilibrium of dissimilar tissue damages and dissimilar abilities of the host to tolerate and repair the injuries (14). NATURAL COURSE O F CHRONIC GASTRITIS A number of infected subjects develop atrophy and intestinal metaplasia with time (14). The cause and mechanisms in the development of atrophy (loss of normal mucosal glands) are, however, largely unknown. The pathogenesis is obviously multifactorial, and the appearance of atrophy is a very slow process on an average. It is also an unpredictable and heterogenous with regard to the topography of the lesions (14, 15). In some patients gastritis and atrophy are limited to antrum (antral gastritis) or corpus (corpus gastritis), and in some they may occur in both simultaneously ( pangastritis). In the pathogenesis of atrophic gastritis, some environmental factors, other than the H. pylori, can also be involved. Such additional factors could be salt, diet, smoking, alcohol, duodenogastric reflux, etc. (15). In an infected stomach, these factors may promote and modulate the development of atrophy. In H. pylori gastritis in general, atrophy and intestinal metaplasia occur most often in antrum, or in antrum and corpus simultaneously. In the affection of corpus, a pylorocardial extension of the changes may occur, and some particular sites of the stomach, such as gastric angulus and small curvature, are often most extensively affected ( 19). Why this happens is unknown. Interestingly, however, these same sites are also predilection sites for GCA. Atrophy (atrophic gastritis) in H. pylori infection is often patchy, and is rarely as extensive and diffuse as is the corpus atrophy in autoimmune, corpus- limited gastritis (14, 16). Achlorhydria, pernicious anaemia, or such high fasting serum gastrin levels as commonly occur in autoimmune corpus-limited atrophy, are rare in the H. pylori associated atrophic gastritis, even though the endoscopic biopsies from corpus mucosa would indicate marked atrophic and meta-

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Gastric Carcinoma

plastic lesions. Even in advanced cases of H. pylori gastritis, atrophy may be remarkably patchy and multifocal. In the American literature (15, 20). the multifocal (metaplastic) atrophic gastritis has been considered and separated as a nosological entity. In European view (13, 14,21), the atrophic pangastritis is seen to represent a common sequela of the ordinary H. pylori acquisition. The prevalence of atrophic gastritis is high in H. pylori infected populations in general (22). In elderly, 1&30% of people may show atrophic changes (and intestinal metaplasia) either in antrum, corpus, or in both simultaneously (14,23,24). A well known fact is that the total prevalence of gastritis increases in the population with age (22.24). A less well known fact is, on the other hand, that this increase is mainly caused by an increase in prevalence of atrophic gastritis: in adulthood and elderly, the appearance of atrophic endstages of gastritis is at least as high as is the rate and appearance of people with a new, fresh H. pylori acquisition (23). The cross-sectional and follow-up studies have unambiguously shown that gastritis progresses on an average from the stage of simple inflammation ('superficial gastritis') into the stage of atrophy ('atrophic gastritis'). Studies on population-based cross-sectional data show this clearly: in statistical analyses of type and grade of gastritis and atrophy in antrum and corpus, a progressive model is the best one that fits with the observed data, and agrees with the assumption that the inflammation develops slowly and gradually into the atrophy and intestinal metaplasia with increasing age (24). This is what the direct follow-up studies indicate as well: the net result in the follow-up is an increase in prevalence of atrophy and intestinal metaplasia with time in all populations studied so far (25). RISK OF GASTRIC CARCINOMA IN GASTRITIS

The increased risk of GCA in atrophic gastritis is known for a long time. This conclusion is based on a great number of independent endoscopic and clinical studies (12,26). The follow-ups of patients with severe atrophic gastritis have shown further that gastritis and atrophy precede the formation of cancer, indicating the gastritis is hardly a consequence of the cancer or of the cancer-bearing stomach itself. In severe atrophy of antrum, the risk of GCA has been estimated to be 18 times higher than the risk in people with a non-atrophic stomach (27). In pernicious anaemia (PA) patients, who typically have a severe corpus-limited atrophy, the risk of GCA is 3-6 times higher than that in non-PA subjects (28). Cumulatively, 10-20% of elderly people with severe antral atrophy or with severe panatrophy have been estimated to get GCA in the course of time of 1-2 decades in Finland (28). In severe corpus atrophy and pernicious anaemia, the cumulative life-long risk of GCA has been estimated to be even 10% on an average (28).


In the atrophic stomach, several mechanisms may be operating upon in the pathogenesis of GCA. Such may be, for instance, colonization of the stomach by bacteria, other than H. pylori, which produce carcinogens locally or intraluminally (29). This is the case in bacteria which are capable of reducing nitrates to nitrites, leading consequently to a risk of formation of carcinogenic nitrosamines or nitrosoamides from dietary nitrogen compounds in hypochlorhydric conditions. Production of superoxides and monochloramine by activated granulocytes in H. pylori gastritis is another example of events with hypothetical risks to damage the DNA in epithelial cells. Increased cell renewal in gastritic mucosa is a further theoretical promoter mechanism giving an opportunity for malignant transformed cell lines to grow up into clinical tumours. Importance of intestinal metraplasia as a risk condition for GCA has been emphasized in several investigations in the past (29-32). Morphogenesis of the intestinal type of GCA (IGCA) shows definite links with intestinal metaplasia (30). Same morphological, histochemical and functional characteristics as are seen in intestinal metaplasia, and in intestinal epithelium in general, occur often in the IGCA tumours as well. The other major subtype of GCA, the diffuse GCA (DGCA), shows these features less frequently and its relation to atrophic gastritis, intestinal metaplasia, or to chronic gastritis in general, has been more unclear and problematic. The theory on the role and importance of H. pylori gastritis in the pathogenesis of GCA implies and anticipates that also the DGCA should be related to H. pylori gastritis. Otherwise, the role of H. pylori acquisition as a general risk state for GCA cannot be understood (6): the worldwide changes in the epidemiology of GCA cannot be explained with H. pylori acquisition without this assumption. The recent studies indicate that also the DGCA is indeed associated with the H. pylori gastritis (10, 11,33). In contrast to the association of IGCA with late atrophic and metaplastic stages of gastritis, the DGCA seems to be merely associated with early inflammatory and non-atrophic stages ('superficial gastritis') of the gastritic process (33). In consideration of chronic gastritis as a nosological entity, gastritis is more common both ICGA and DGCA patients than in matched non-cancer controls. Correspondingly, both IGCA and DGCA are unexpectedly uncommon in subjects with a normal, non-gastritic stomach. Observations on the occurrence of H. pylori infection in GCA patients is summarized in Table I. The prevalence of H. pylori varies in these investigations from 19% to 94% (8, 10, 11.33-35). The studies are, however, often handicapped by several biases, and, therefore, these investigations do not necessarily give a reliable basis for assessments of the associations of H. pylori infection with GCA. The studies are often based on a limited number of selected patients, or on demonstration of H. pylori in a small number of biopsy


P. Sipponen & K . Seppala

Table I. Prevalence (%) of H . pylori infection in gastric cancer patients Prevalence of H . pylori-positive cases Authors; year Cheng et al.; 1987 Correa & Ruiz; 1989 (a) Loffeld et al.; 1990 Parsonnet et al.; 1991 (b) Nomura et al.; 1991 (b) Sipponen et al.; 1992

No. of cases


19 156 105 109 109 54

74% 19-80% 59% 84% 94% 70%

Intestinal type

Diffuse type



45% 89% 100% 71%

Serol Histol Histol Serol Serol Serol/histol

60% 83% 93% 71 %

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a = meta-analysis;b = longitudinal, prospective study.

specimens, and usually in biopsies from the tumour area only. However, recent longitudinal serological follow-up studies in large cohorts (10, l l ) , and the cross-sectional studies based on both histology and serology in population based samples of people, or in consecutive series of GCA patients and controls, show similar important results which indicate some noteworthy conclusions (7,10,11,33,36-39). These can be summarized as follows. First, the risk of GCA is increased in subjects with H . pylori positive gastritis in general, also in subjects with gastritis which is non-atrophic and non-metaplastic, and that this risk is further elevated when the atrophy (and intestinal metaplasia) appears. Second, the increased risk of GCA concerns both of the major subtypes of GCA; that is, both IGCA and DGCA. This implies that the GCA is associated with one and the same process; that is, with the chronic gastritis and its late atrophic sequelae. Another important conclusion from these observations is that the main difference between IGCA and DGCA may merely be a morphogenetical and histogenetical one than a nosological one; i.e., the GCA that will develop

in a gastritic stomach (‘superficial gastritis’) tends to be a DGCA whereas the GCA developing in an atrophic stomach is more likely of the IGCA subtype. Third, according to the serological follow-up studies, H. pylori infection precedes the development of GCA with years or even with decades, indicating that the H. pylori infection (and gastritis) is hardly a secondary phenomenon. THE SEQUENCE FROM H. PYLORI GASTRITIS TO GASTRIC CANCER Although a very small fraction of patients with H. pylori infection and subsequent gastritis will ever develop GCA, there seems to occur a gradual sequence of events from an early H . pylori acquisition into a late development of GCA. The critical knots (Fig. 1) in this hypothetical sequence are (i) the H. pylori is an etiologic cause of chronic gastritis which (ii) will appear as mucosal inflammation, and which will further develop into atrophic and metaplastic lesions (atrophic gastritis), in which (iii) the risk of GCA is, for one reason or another, increased. All these knots have been proven in several independent investigations.

Fig. 1 . Scheme on the multistep and multifactorial pathogenesis of gastric carcinoma. DGCA carcinoma of the diffuse type; IGCA = gastric carcinoma of the intestinal type,



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Gastric Carcinoma

The sequence is in accordance with a well known earlier concept that gastritis, and atrophic gastritis in particular, are precancerous conditions. In contrast to precancerous lesions (23), such as adenomas or dysplasias, which are neoplastic lesions in nature, and will progress into a cancer if the course of time is long enough, gastritis and its atrophic sequelae only promote the development of GCA. Approximately 6&80% of the GCA cases have been estimated to be developed in the background of H. pylori gastritis (10, 11). In a cross-sectional study on GCA patients in Finland, 7&80% of the GCA cases were developed in a gastric stomach with an H. pylori infection and only 10-15% of the GCA cases, which usually are of the DGCA subtype, occurred in a normal stomach (33). A tentative possibility is that these latter cases are genetically determined and represent variants of cancer family syndromes, or are results from an exposure of people t o some unknown specific carcinogens. Recent developments in the treatment of H. pylori infection may provide possibilities for medical interventions in prevention of GCA. However, such interventions are certainly impractical and extremely difficult t o be carried out, and, even if such efforts are successful, they would obviously not solve the problem of GCA as a whole: at least a minor part of GCAs develop without a relationship to prior H. pylori acquisition. In addition, the decline in the incidence of GCA has already been a “triumph” in recent decades, this triumph having being occurred without active attempts to interfere or intervene the disease. A theoretical explanation for this is that an improvement in environmental hygiene and a rise in socioeconomic status have dramatically lowered the rate and likelihood of the H. pylori infection in Western populations, and have correspondingly also decreased the incidence of GCA (40). This socioeconomic improvement of society may be the most effective and practical way to ‘prevent’ GCA also in developing populations in which the incidence of GCA and the rate of H. pylori gastritis are still high.

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Gastric carcinoma: failed adaptation to Helicobacter pylori.

Helicobacter pylori is the major cause of chronic gastritis. Unlike bacterial infections in general, H. pylori acquisition causes a chronic, usually l...
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