J Clin Pathol 1992;45:319-323 319

Helicobacter pylori infection and chronic gastritisin gastric cancer

P Sipponen, T U Kosunen, J Valle, M Riihela, K Seppala

AbstractAims: To investigate the prevalence ofHelicobacter pylori associated chronicgastritis in patients with gastric cancer.Methods: Serum IgG antibodies for Hpylori were determined in 54 consecutivepatients with gastric carcinoma. Theprevalence ofH pylori in gastric mucosawas also examined histologically(modified Giemsa) in 32 patients fromwhom adequate biopsy specimens of theantrum and corpus were available.Thirty five patients with gastrointestinaltumours outside the stomach and 48 withnon-gastrointestinal malignancies servedas controls.Results: Of the 54 patients, 38 (70%) hadH pylori antibodies (IgG) in their serum(three additional patients had H pyloriantibodies IgA, class specific but not IgGspecific). Thisprevalencewassignificantlyhigher (p < 0-05) than that (49%) in the35 controls. No differences in prevalenceof H pylori antibodies were found bet-ween gastric cancer cases of intestinal(IGCA) or diffuse (DGCA) type, boththese types showing H pylori antibodies(IgG) in 71% of the patients. In the sub-group of 32 subjects, five patients hadnormal gastric mucosa and four showedcorpus limited atrophy ("perniciousanaemia type" atrophy of type A). All ofthese nine patients had no evidence ofcurrent or previous H pylorn infection inserum (no IgG antibodies) or in tissuesections (negative Giemsa staining). Theremaining 23 patients had antral or pan-gastritis, and all had evidence of currentor previous Hpylon infection.Conclusions: H pylori associated chronicgastritis was the associated disease in75% of the patients with gastric canceroccurring equally often in both IGCAand DGCA groups. About 25% of casesseem to have a normal stomach or severecorpus limited atrophy, neither of whichshowed evidence of concomitant H pylorninfection.

The role of Helicobacter pylori infection in thepathogenesis of gastric cancer is an importantbut unresolved issue. The importance of Hpylori infection in gastric carcinoma is sup-ported by recent epidemiological observationswhich indicate that the prevalence ofH pyloriinfection and the incidence of gastric carcin-oma are significantly associated.`5 It is nowaccepted that H pylori infection is the maincause of chronic gastritis which results inmany patients in atrophy and metaplasia of

the underlying mucosa.' Both these condi-tions are known to be associated with anincreased risk of gastric carcinoma."' It hasbeen assumed that there is a sequence from Hpylori infection to gastritis and to mucosalalterations which favour the genesis of gastriccarcinoma.12But there are several problems with regard

to the association between H pylori and gastriccarcinoma. First, chronic gastritis with sub-sequent atrophy may arise without con-comitant H pylori infection.'3 This could bethe case particularly in chronic corpus gas-tritis which leads to severe corpus atrophy ofpernicious anaemia type, also well known as aprecursor to gastric carcinoma.'0 Secondly,atrophy and metaplasia are implicated in thepathogenesis of gastric carcinoma of the intes-tinal type,'4 whereas gastric carcinoma of thediffuse type, which comprises 40-50% of allcases of gastric carcinoma, does not clearlycoexist with atrophy and metaplasia, and itsassociation with gastritis and H pylori infec-tion is, therefore, less clear. Thirdly, gastriccarcinoma may also arise in gastric mucosawithout histologically demonstrable gastritisor H pylori infection, '4 suggesting that not allcases of gastric carcinoma can be related toprevious or current gastritis and H pyloriinfection.

MethodsThe series consisted of 54 consecutive patientswith gastric carcinoma diagnosed in Jorvi Hos-pital in 1988 and 1989. Cancers of cardiacregion of the stomach and those occurring inpatients who had already undergone surgery inthe stomach were excluded. Upper gastrointes-tinal endoscopy, taking biopsy specimens fromthe tumour area, was performed in all thepatients, and cancer was diagnosed his-tologically. In addition to the biopsy specimensfrom the tumour area, one to three biopsyspecimens from both antrum and corpus wereavailable from 32 (59%) patients. The meanage and the male:female ratio of the series arepresented in table 1.The presence and type of chronic gastritis,

and the prevalence of H pylori (modifiedGiemsa) in the 32 patients with biopsyspecimens taken from the antrum and corpuswere interpreted and presented according tothe Sydney system.'516

Gastric carcinoma was classified his-tologically into intestinal (31 patients), diffuse(21 patients), and unclassified (two patients)according to the criteria of Lauren.'7The H pylori antibodies were determined

from serum samples of all subjects usingenzyme immunoassay. The antigen was an acidextract from H pylori strain NCTC 1 1637, and

Department ofPathology, JorviHospital, 02740 Espoo,FinlandP SipponenJ ValleM RiihelaDepartment ofBacteriology andImmunology,University of Helsinki,FinlandT U KosunenGastroenterologicalUnit, SecondDepartment ofInternal Medicine,University ofHelsinki,FinlandK SeppalaCorrespondence to:Dr Pentti SipponenAccepted for publication2 October 1991

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Table 1 Prevalence ofH pylori antibodies in patients with gastric cancer and with other types ofgastrointestinal orextra-gastrointestinal cancers

H pylori antibodies n (%)

Total IgG IgA IgM Age Mean (SD) MIF

Gastric cancer 54 38 (70)* 29 (54) 3 (6) 65 (16) 26/28Cancer of gastrointestinal tractOesophagus 6 2 (33) 2 (33) 0 77 (6) 2/4Pancreas 7 2 (29) 1 (14) 0 62 (14) 4/3Colon 22 13 (59) 10 (45) 3 (14) 63 (12) 14/8All 35 17 (49) 13 (37) 3 (9) 65 (12) 20/15

Other cancers 48 26 (54) 20 (42) 1 (2) 66 (12) 34/14

*Difference to "cancer of gastrointestinal tract": p = 0-036 (X').

IgG, IgA, and IgM class antibodies weredetermined separately as described."8 The reac-tion was semiquantitatively estimated as mild(+), moderate (+ +), or strong (+ + +). Theantibody assays were performed blind withoutprior knowledge of clinical diagnosis or his-tology.

Thirty five consecutive patients with his-tologically verified cancer in gastrointestinalorgans other than the stomach and 48 patientswith non-gastrointestinal malignancies servedas controls. H pylori antibodies were deter-mined in all these subjects. The number ofpatients with different types of cancer, and thedemographic data of these series, are given intable 1.The x2 test and Student's t test were used to

calculate the significance of the differences.Kappa statistics was calculated for evaluationofconcordance between histology and serologyin the diagnosis of the Hpylori infection.

ResultsH pylori antibodies (IgG) were found in 38(70%) of the 54 patients with gastric carcinoma(fig 1, table 1). This prevalence was higher(p = 0X036; x2) than that in the control subjectswith malignant tumour of the gastrointestinaltract outside the stomach (table 1). No differ-ences were found in the prevalence ofH pyloriantibodies among the gastric carcinoma types:antibodies of IgG class were found in 71% ofboth IGCA and DGCA patients (figs 2 and 3).The prevalence of H pylori antibodies in

patients with gastric carcinoma showed a slightnegative correlation with age (table 2). Theprevalence of patients with Hpylori antibodieswas highest (80%) in the youngest age group(30-49 years) and, in contrast to the prevalenceof H pylori antibodies in the general popula-tion,'8 it tended to decrease slightly withincreasing age. Correspondingly, the patientswith gastric carcinoma and Hpylori antibodieswere also slightly younger (63 (16) years) thanthose without the antibodies (67 (18) years). Inall age groups the prevalence of H pyloriantibodies was higher in the patients withgastric carcinoma than in the controls withoutgastric carcinoma (table 2).

Details ofthe patients with gastric carcinomawith biopsy specimens available from theantrum and corpus mucosa are listed in table 3.Of these, five (16%) had a normal stomach(both antrum and corpus) and four (13%)patients had chronic corpus gastritis withsevere corpus atrophy (A type), two of themalso having pernicious anaemia. None of thesenine patients had H pylori IgG antibodies, orbacteria on histological examination (table 3).

After the nine patients with a normalstomach or with corpus limited severe atrophyhad been excluded 23 patients with evidence ofH pylori infection remained: 22 had IgGantibodies, one had no IgG antibodies but hadIgA antibodies and bacteria at histologicalexamination (case 14: table 3). All thesesubjects had chronic antral gastritis or pangas-tritis with or without concomitant atrophy. Inthis group there were no significant differences

Corpus gastritis Antral orsevere atrophy pangastritis

4 patients 23 patients71 +14 y * 60+15 y

Hpylori+ 0(0%) Hpylori* 22(96%

7 One,two,or three additional patients withantibodies of IgA but not of IgG class

Corpus gastritis Antral orsevere atrophy pangastritis

3 patients 1 1 patients67+15y * 67+14 y

Hpylori+ 0(0%) Hpylori+ 10(9

* I One or two additional patients withantibodies of IgA but not of IgG class

Figure I Prevalence (number and percentage) of Figure 2 Prevalence (number and percentage) ofpatients with H pylori IgG antibodies in 54 consecutive patients with Hpylori IgG antibodies in 31 cases ofcases ofgastric cancer: relation to the state of the gastric gastric cancer of intestinal type: relation to the state ofmucosa. the gastric mucosa.

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* One additional patient with antibodiesof IgA but not of IgG class

Figure 3 Prevalence (number and percentage) ofpatients with H pylori IgG antibodies in 21 cases ofgastric cancer of diffuse type: relation to the state of thegastric mucosa.

between patients with IGCA or DGCA withregard to prevalence ofHpylori antibodies (figs2 and 3): 91% and 100% of the patients hadIgG class antibodies, respectively.

In general, the prevalence of H pylori inhistological specimens agreed with the findingsof serology. Except for one, all patients withevidence ofH pylori in tissue sections also hadHpylori IgG class antibodies in serum. On theother hand, of the 22 patients with H pyloriantibodies, only 14 (64%) had the organisms intissue sections. The overall agreement betweenthe two methods for detecting H pylori infec-tion was 72% (K statistic 0A48).With regard to the failure to diagnose H

pylori infection by serology or histology in the23 patients with antral or pangastritis, atropy inthe underlying mucosa seemed to be the most

important discriminating factor (table 3). Anoticeable atrophy, particularly in corpus

mucosa, tended to indicate negative H pylorihistology (although serology was positive) inthese patients. Six out ofthe eight patients withnegative H pylori histology showed moderatecorpus atrophy; this was not seen in those withpositive H pylori histology (table 3). Corre-spondingly, the mean age tended to be higher insubjects with negative Hpylori histology (69 (9)years) than in those with a positive one (55 (16)years), indicating that the mucosal changes inthese H pylori negative subjects could havebeen of longer duration, and be at a more

advanced stage than those in H pylori positivesubjects.

DiscussionH pylori infection is common in patients withgastric carcinoma, but its prevalence variesconsiderably-from 19% to 80%.s2 192s In thisstudy the overall H pylori antibody prevalencewas 70% in 54 patients with gastric carcinoma.In the analysis of the subgroup of 32 patientswith gastric carcinoma with histological biopsyspecimens taken from antrum and corpus, andafter exclusion of the nine patients with a

normal stomach or severe corpus limitedatrophy (A type atrophy), all remaining 23patients with antral gastritis or pangastritis hadevidence of H pylori infection (22 having Hpylori IgG class antibodies, one having no IgGantibodies but showing IgA antibodies andorganisms in tissue sections). This suggeststhat H pylori associated chronic gastritis is themajor contributory factor in patients withgastric carcinoma. This type of gastritis seems

to affect about 70-75% of patients with gastriccarcinoma.The overall prevalence ofHpylori antibodies

(70%) was significantly higher in patients withgastric carcinoma than in controls (49%) whoharboured gastrointestinal malignancies otherthan gastric carcinoma. The age specificprevalence of H pylori antibodies in patientswith gastric carcinoma did not show an increasein prevalence with age as is the case in thegeneral population.'8 Even the youngest group

ofpatients with gastric carcinoma (30-49 years)had antibodies in 80% of cases, which issignificantly (p = 0-013) more than expected(39%).18 This suggests that H pylori infectionand subsequent chronic gastritis are specificallyassociated with gastric carcinoma.These observations do not necessarily pre-

clude the possibility that Hpylori infection is aconsequence of the altered luminal environ-ment in gastric cancer instead ofbeing a specificprecursor for it. On the other hand, severalearlier follow up studies have suggested thatgastritis and atrophy precede the appearance ofcancer,'4 and in addition, the specific absence ofH pylori infection in patients with gastriccarcinoma with normal stomach or in thosewith corpus limited atrophy contradicts thesuggestion that H pylori infection would besecondary to gastric carcinoma.Four patients showed severe corpus limited

atrophy, a characteristic feature of perniciousanaemia.22 In fact, two of these four subjectshad clinical evidence of pernicious anaemia.None had H pylori class IgG antibodies or

Table 2 Prevalence of patients with H pylori antibodies (positive) of class IgG in gastric carcinoma and other cancerpatients (relation to age)

Age group (years)

30-49 50-69 70+ All

Gastric carcinoma patientsTotal 10 19 25 54H pylori positive 8 (80%) 13 (68%)t 17 (68%)* 38 (70%)$

Patients with cancer other than gastric carcinomaTotal 9 38 37 84

H pylori positive 5 56%) 22 (58%)tt 16 (43%)t 43 (51%)**

*one additional patient had H pylori antibodies of IgA class but not of IgG;ttwo additional patients had H pylori antibodies of IgA class but not of IgG;tthree additional patients had H pylori antibodies of IgA class but not of IgG;ttfour additional patients had Hpylori antibodies of IgA class but not of IgG;**six additional patients had H pylori antibodies of IgA class but not of IgG.

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Table 3 H pylori infection in histology and serology in 32 patients with gastric carcinoma: relation to morphologicalstate of antral and corpus mucosa

Hpylori SerologyGastric H pyloricarcinoma Type* Age (y) Sex Antrumt Corpust Histology IgG IgA IgM

1 IGCA 32 M 0 02 DGCA 67 M 0 0 - - - -

3 DGCA 38 M 0 0 - - - -

4 DGCA 74 F 0 0 - - - -

5 DGCA 69 M 0 0 - - + -

6 IGCA 52 F 0 4 - - -7 IGCA 69 M 1 4 - -

8 IGCA 81 F 1 4 - - +9 uncl 81 F 0 4 - - - -10 IGCA 67 M 1 1 + + ++ -11 IGCA 71 F 1 1 + ++ - -12 IGCA 70 M 3 0 + +++ - -13 IGCA 31 M 2 1 + +±++ +±14 IGCA 69 F 2 0 + - + + +15 IGCA 86 M 4 2 + + + + -16 DGCA 41 M 1 1 + + + +17 DGCA 56 F 3 2 + + + - -

18 DGCA 61 F 1 1 + + + + + + -19 DGCA 43 F 1 1 + + + + + -

20 DGCA 38 M 1 1 + +21 DGCA 57 M 1 1 + + +22 DGCA 44 F 2 1 + + + + + -

23 DGCA 59 F 1 1 + + + -

24 DGCA 39 F 1 0 + + + + + -

25 IGCA 64 F 1 3 - + + + + -

26 IGCA 66 M 4 3 - + + -

27 IGCA 83 M 1 1 - +28 IGCA 70 M 4 3 - + + + +29 IGCA 60 F 3 3 - + + + + -

30 DGCA 82 F 1 1 - + ++ + +31 DGCA 58 F 1 3 - + + + +32 DGCA 70 F 4 3 - +

Abbreviations:*IGCA, DGCA, uncl = intestinal, diffuse and unclassified;tgrade of chronic gastritis; 0 = normal mucosa; 1 = chronic gastritis without atrophy; 2-4 = chronic gastritis with mild,moderate, or severe atrophy (and metaplasia), respectively.

bacteria in tissue sections, confirming theearlier observations that H pylori infection israrely seen in pernicious anaemia or in severecorpus limited atrophy.'323 Current dataindicate that in Finland about 5% of gastriccarcinoma cases are associated with pemiciousanaemia, and that about another 5% could beassociated with severe corpus limited atrophy(A type) without concomitant anaemia.

In the subgroup of 32 patients with biopsyspecimens taken from antrum and corpus, fivedid not show gastritis, atrophy, or signs ofprevious or current H pylori infection (no IgGantibodies; no evidence of the organism inbiopsy specimens from antrum and corpus),suggesting that probably 10-20% of gastriccarcinoma cases developed in a histologicallynormal stomach. Notably, four out of the fivepatients had gastric carcinoma of the diffusetype (DGCA) and were relatively young. Theymay represent genetically determined cases ofgastric carcinoma and may not be attributableto H pylori infection or gastritis. Hereditaryfactors have been suggested as important in thepathogenesis of some cases of gastric carcin-oma, especially those of DGCA.2425There was rather good concordance between

the findings in tissue sections and serumsamples in the detection ofH pylori infection.All except one with positive Hpylori histologyhad H pylori IgG class antibodies. The overallagreement between the two methods wastherefore 72% (K statistic 048). All gastriccarcinoma cases with antral or pangastritisprobably represent H pylori associated gas-tritis: all such patients showed either positiveserology or histology forH pylori infection.IgA and IgM class antibodies showed a

worse concordance with H pylori in tissuesections than those of IgG class. Antibodies of

IgM class were present only occasionally andthose of IgA class gave several false negativeand positive results compared with prevalenceof H pylori in tissue sections. IgG antibodiescould be the best determinant of H pyloriinfection in patients with gastric carcinoma.The histological demonstration of H pylori

may be difficult in a severely atrophic stomach,particularly in corpus atrophy.'3 Positiveserology, however, often occurs in suchpatients, indicating previous or latent H pyloriinfection.26 As the infection resolves the num-ber of mucosal lesions increases, resulting insampling errors in histology (and also later in areduction in the serological response). Ourobservations support this; severe corpusatrophy was the main lesion in those in whomHpylori were not seen in tissue sections but inwhom serum antibodies were present.An important finding is that the prevalence of

H pylori infection and gastritis seems to affectgastric carcinoma of both intestinal (IGCA)and diffuse (DGCA) type, these types covering80-90% of all gastric carcinoma cases in gen-eral.'427 In fact, the prevalence of H pyloriantibodies was slightly higher (100% v 91%)(figs 2 and 3) in patients with DGCA than inthose with IGCA; when the patients with anormal stomach and those with corpus limitedatrophy were excluded, the overall prevalenceofHpylori antibodies was 71% in both.

Several earlier studies have indicated thatthere are important clinical, histological, anddemographic differences between IGCA andDGCA."7 For instance, DGCA occurs moreoften in young subjects than IGCA, butequally often in males and females; IGCAtends to be twice as common in males than infemales. Histologically, IGCA frequentlyshows features of intestinal metaplasia in the

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malignant mucosa whereas such features aretypically absent in DGCA-that is, DGCAoccurs more often in non-atrophic, non-meta-plastic stomach than IGCA.2"3'

In spite ofthe above differences, both types ofcancer seem to share common epidemiologicalfeatures. Both are prevalent in populationswith a high incidence of gastric carcinoma butthey also seem to occur equally rarely incountries with a low incidence of gastric carcin-oma."' The pronounced decline in incidenceof gastric carcinoma, which has occurredthroughout the world over the past fewdecades,35 36 seems to affect both types of gastriccarcinoma, suggesting that both types musthave similar common aetiological factors andpathogenic mechanisms.The association of H pylori infection and

gastritis with both IGCA and DGCA suggeststhat H pylori associated chronic gastritis is thecommon general background factor for gastriccarcinoma. One hypothesis is that the mor-phogenesis of gastric carcinoma into differenthistological subtypes follows the natural courseof chronic gastritis in the population.i 7Inflammation advances gradually and slowly(within years or sometimes decades) towardsatrophy (and metaplasia) in both antrum andcorpus. The morphogenesis of gastric carcin-oma of the intestinal type may be particularlypromoted by an atrophic (metaplastic) stomachand that of the diffuse type by a non-atrophic,gastritic stomach.

It is therefore assumed that after initiation ofcancer (a gene based event) the morphogenesisof gastric carcinoma into different histologicaltypes depends on the stage in the natural courseof gastritis from inflammation to atrophy. Thisassumption would make it understandable whyboth types of gastric carcinoma share similarepidemiological features: the development ofboth IGCA and DGCA depends on theoccurrence and course of H pylori associatedchronic gastritis and its sequelae in the generalpopulation.

In conclusion, H pylori associated chronicgastritis seems to be the background lesion inpatients with gastric carcinoma in about 75%of cases. In the remainder it is associated with a

normal stomach or with a corpus limitedatrophy (atrophy ofA type) in which coexistentH pylori infection is absent. We further con-

clude that H pylori related gastritis is alsoassociated with both IGCA and DGCA, andsuggest that chronic gastritis promotes thegenesis of both these major cancer types.

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