Predictive Factors and Prevalence of Follicular ...

Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999), pp. 1156 ± 1160

Predictive Factors and Prevalence of Follicular Gastritis in Adults with Peptic Ulcer and Nonulcer Dyspepsia SPIRO S D. LADAS, MD, THEODORE ROKKAS, MD, PhD, SO TIRIOS GEORGOPO ULOS, MD, PANAGIO TA KITSANTA, MD, CHRISTO S LIATSOS, MD, PARASKEV I EUSTATHIADO U, MD, ANDREAS KARAMERIS, MD, CHARIS SPILIADI, MD, and SO TIRIO S A. RAPTIS, MD

Follicular gastritis is an important histological entity, be cause it may progre ss to overt gastric MALT lymphoma. Howeve r, there is no unive rsal agre e ment on whe the r the re is any correlation of follicular gastritis with histological feature s of the antral mucosa or on the prevale nce of follicular gastritis. To she d furthe r light on these issue s, we studie d antral biopsie s obtaine d from 735 adult patie nts, who had participate d in six conse cutive clinical trials. The y include d 348 patie nts with duode nal ulcer, 82 with gastric ulce r, and 305 with nonulce r dyspe psia. The Sydne y classi® cation system of gastritis was use d, using a score of 0 ± 3 to grade de gre e and activity of in¯ ammation, gland atrophy, intestinal metaplasia, and H. pylori colonization density. Follicular gastritis was de ® ned as prominent lymphoid follicle s with no lymphoe pithe lial lesion. None of the H. pylori-negative patie nts (N 5 159) had follicular gastritis. Among H. pylori-positive patie nts, 80/340 (23.5% ) with duode nal ulce r, 5/77 (6.5% ) with gastric ulce r, and 20/159 (12.6% ) with nonulce r dyspe psia had follicular gastritis (P , 0.001) . Multivariate discrim inant analysis selected the following four signi® cant 2 predictor variable s for follicular gastritis (Wilks l 5 0.91, x 5 70.6, df 5 4, P , 0.001) : gastritis sum score, atrophic gastritis, age of the patie nt, and disease. The prevale nce of follicular gastritis was line arly corre late d (y 5 24.55 2 0.98x, r 5 2 0.62, F 1,11 5 6.12, P 5 0.03) with the age groups of the 576 H. pylori-positive patie nts studie d. In conclusion, follicular gastritis is highly corre late d with H. pylori-cause d seve re, active gastritis. It is mostly prevale nt in the young H. pylori-infe cted patie nts with duode nal ulce r. KEY WORDS: follicular gastritis; Helicobacter pylori; duodenal ulce r; gastric ulcer; nonulcer dyspepsia; MALT lymphoma.

Follicular gastritis is characte rized by hype rplasia of lymphoid follicle s in the gastric mucosa. The close Manuscript receive d Septe mber 23, 1998; revise d manuscript re ce ived January 11, 1999; accepte d February 10, 1999. From the Gastroente rology Unit, Se cond De partme nt of Internal Medicine , Evange lismos Hospital, Athe ns Unive rsity, Athe ns; Gastroe nterology and Pathology Departmen ts, 401 Ge neral Military Hospital of Athens; and Pathology De partme nt, Evange lismos Hospital, Athens, Gre ece. Address for reprint reque sts: Dr. Spiros D. Ladas, Gastroente rology Unit, Se cond Departmen t of Internal Medicine, Athe ns Unive rsity, Evangelismos Hospital, PO B 141 27, 115 10 Athens, Gre ece.

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association of Helicobacter pylori infe ction with follicular gastritis (1, 2) sugge sts that H. pylori has antigenic prope rties that condition lymphoid tissue hype rplasia in gastric mucosa. Inde e d, regression of follicular gastritis has bee n obse rve d following H. pylori eradication (3, 4). Furthe rmore , it has recently bee n shown that follicular gastritis harbors the clonal B cell that may give rise to mucosa-assoc iate d lymphoid tissue (MALT) lymphoma (5). The refore, diagnosing se vere follicular gastritis may be of clinical importance , since it could be the ® rst ste p in ide ntiDigestive Diseases and Sciences, Vol. 44, No. 6 (June 1999)

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PREV ALENCE OF FO LLICULAR GASTRITIS

fying a group of patie nts at risk of de veloping gastric low-grade MALT lymphom a. The prevale nce of follicular gastritis has bee n studied in adult patie nts with duode nal or gastric ulcer or gastritis (1, 6 ± 10) but not in nonulce r dyspe psia. In addition, the re is no unive rsal agre ement that the histological fe ature s of the antral mucosa or the colonization density by H. pylori are correlate d with follicular gastritis (4, 6 ± 10) . To she d furthe r light on these issue s, we have studie d antral biopsie s take n from adults with duode nal ulcer (DU), gastric ulce r (GU), and nonulce r dyspe psia (NUD). The se patie nts are known to have a high prevale nce of H. pylori infe ction of the gastric mucosa.

density, and histological parameters (predictor variables) may discriminate betwee n two leve ls (present, absent) of follicular gastritis (dependent variable). The objective of this analysis is to predict the group into which a new case is most likely to fall or to obtain a small number of predictor variables for follicular gastritis. To simplify statistical analysis, a sum gastritis score was obtained by adding the grade of degree and activity of gastritis in e ach case. Discriminant analysis and not regre ssion analysis was as regarded most appropriate for our data, because follicular gastritis (dependent variable) is cate gorical and not me tric. Simple regression analysis with the best-® tting curvilinear model to our data was used to evaluate correlation of follicular gastritis prevalence with patients’ age groups, as well as the grade of H. pylori colonization of the antral mucosa with gastritis score. P , 5% was regarde d signi® cant.

MATERIALS AND METHODS

RESULTS

We used antral mucosa paraf® n tissue blocks and slides from six consecutive clinical trials of patie nts with duodenal ulcer, gastric ulcer, and nonulcer dyspepsia performed in our institutions during 1994 ± 1997. For the present study only biopsies at the e ntry of patie nts to the trials we re used. No patie nt had recently receive d H. pylori e radication or nonsteroidal antiin¯ ammatory drug the rapy. One or two antral biopsies were available from each patient. All biopsies had been obtained by using the O lympus FB-24Q biopsy forceps, which provide adequate gastric mucosa biopsy specimens (11). Biopsies were studied in sections stained with hematoxylin-e osin and Giemsa by two e xpe rienced pathologists. No special te chniques we re e mployed. For e ach biopsy, results were written in specially designed charts, including patie nts code number, age , sex, and disease (DU, GU, NUD). Histological parame te rs, such as degre e of gastritis (evident by in® ltration of the gastric mucosa by lymphocytes and plasma cells), activity of in¯ ammation (shown by in® ltration with polymorphonuclear neutrophils), glandular atrophy, and H. pylori colonization density we re also graded according to the Sydney classi® cation syste m (12) and recorded in the data chart. The following four point scales were used to grade gastritis: normal 5 0, mild 5 1, mode rate 5 2, severe 5 3; and H. pylori colonization density: absent 5 0, few 5 1, dense 5 2, heavy 5 3. The two main forms of intestinal me taplasia (complete and incomplete) were pooled and graded as present or absent. Follicular gastritis was de® ned as prominent lymphoid follicles with surrounding mantle zone and plasma cells, with no lymphoe pithelial lesion (13) . Data Analysis an d Statis tics. All data were stored in a dBASE software (Microsoft Access 97, Microsoft Corp.) and analyzed by the statistical package Statgraphics Plus 2.1 (Manugistics Inc., Statistical Graphics Corp.). Qualitative data were assessed by chi-square te st with Yate s’ correction, as appropriate . Nume rical data we re e xamined for normality. Nonnormally distributed data were analyze d by the nonparametric Kruskal-Wallis test. Multivariate discriminant analysis with a forward ste pwise selection algorithm was used to investigate whether age , sex, disease (DU, GU, NUD) , H. pylori colonization

Baselin e Data An alys is. Antral biopsie s from 735 (99.0% ) out of a total of 742 patie nts who had participate d in six consecutive clinical trials were available for study. Thre e hundre d forty-e ight patie nts (266 men, 82 women) had duode nal ulce r, 82 patie nts (55 men, 27 wome n) had gastric ulce r, and 305 patie nts (222 men, 83 wome n) had nonulce r dyspe psia. The median age of the patie nts with gastric ulcer (55, range 28 ± 78 ye ars) was signi® cantly diffe re nt from that of patie nts with duode nal ulcer (47, range 18 ± 90 ye ars) or nonulce r dyspe psia (45, range 18 ± 85 years)(Kruskal-Wallis T statistic 5 27.9, P , 0.001) . The gastric mucosa of patie nts with duode nal ulce r or gastric ulce r was more often colonize d by H. pylori (97.7 and 93.9% re spe ctive ly) as compare d with patie nts with nonulce r dyspe psia (52.1% , x2 5 212, df 5 2, P , 0.001) . Gastritis sum score (y axis) was strongly corre late d (r 5 0.88) with the grade of colonization of the antral mucosa by H. pylori (x axis) (y 5 0.37 1 2.61 x, F 1,734 5 2581, P , 0.001) . None of the H. pylorine gative (N 5 159) , but 105/576 H. pylori-positive patie nts had follicular gastritis (18.2, 95% Cl 15.1± 21.4% ). Among H. pylori-positive patie nts, follicular gastritis was found in 80/340 (23.5% , 95% Cl 19.0 ± 28.1% ) patie nts with duode nal ulcer, 5/77 (6.5% , 95% Cl 1.0 ± 12.0% ) patie nts with gastric ulce r, and 20/159 (12.6% , 95% Cl 7.4 ± 17.8% ) patie nts with nonulce r dyspe psia (x2 5 16.9, df 5 2, P , 0.001) . Factor s Pr edictin g Foll icu lar Gastr itis . Se ve n hundre d thirty-® ve case s we re use d to de ve lop a mode l to discrim inate among two le ve ls of follicu lar gastritis ( pre se nt, abse nt). Using a ste pwise se le ction algorith m, it was found that four variable s ( Wilks l 5 0.91, x2 5 70.6, df 5 4, P , 0.001) , ie , sum score of gastritis ( se ve rity plus activity score ) ,

Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999)

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Fig 1. Correlation of pre vale nce follicular gastritis (y axis) with age (x axis) in 576 Helicobacter pylori positive patie nts (age range 18 ± 90 ye ars) categorize d into 12 age groups. The re is an inve rse (y 5 24.55± 0.98x) mode rately strong corre lation (r 5 2 0.98, F 1,11 5 6.12, P 5 0.033) between the two variables.

atrophic gastriti s, age of the patie nt, and dise ase ( DU, GU, NUD) we re signi® cant pre dictors of follicu lar gastritis ( F 5 45.8, 21.4, 18.5 and 29.3, re spe ctive ly; P , 0.001) . Prevalen ce of Follicu lar Gastritis . Since it has bee n shown above that the age of the patie nts studie d is a pre dictive factor for follicular gastritis, all 576 H. pylori-positive patie nts were cate gorize d into 12 age groups ( # 25, 26 ± 30, 31± 35, 36 ± 40, 41± 45, 46 ± 50, 51± 55, 56 ± 60, 61± 65, 66 ± 70, 71± 75, $ 76 ye ars). Pre vale nce (% ) of follicular gastritis (y axis) for each age group (x axis) was the n calculate d. The be st ® tting mode l of the re gre ssion analysis was line ar (y 5 24.55 2 0.98x), sugge sting an inve rse moderate ly strong corre lation (r 5 2 0.62, F 1,11 5 6.12, P 5 0.033) betwee n the two variable s (Figure 1). DISCUSSION The normal gastric mucosa contain s scanty if any B lymphocyte s. The pre se nce of lymphoid follicle s and aggre gate s in the gastric mucosa indicate s Blymphocyte prolife ration, and it is now unde rstood as an immune re sponse to Helico bacter pylo ri infe ction ( 1, 2, 6) . The te rm follicul ar gastritis is use d to de note chronic active gastriti s with ¯ orid lymphoid follicle formation, but no lymphoe pithe lial le sion ( 13) . The importanc e of follicular gastritis is that it may progre ss to ove rt MALT lymphom a ( 14) . Re ce ntly, it has be e n shown that biopsie s take n from ce rtain patie nts with active H. pylo ri-associate d chronic gastritis have de te ctable clonal populations, but no histolog ic proof of MALT lymphom a ( 15) . It has also be e n sugge ste d that in patie nts with

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H. pylo ri gastritis analysis of B-cell clonality by polym e rase chain re action may ide ntify ce rtain patie nts with monoclonal B-cell populat ion at an e arly re ve rsible ste p in the de ve lopm e nt of MALT-oma ( 5) . The se patie nts may be ne ® t from H. pylo ri e radication the rapy. It may be argue d that be cause of the close association of H. pylori chronic active gastritis with prese nce of lymphoid follicle s in the gastric mucosa, the re is no ne ed for re porting or grading follicular gastritis, be cause its prevale nce is determined by the numbe r of biopsie s take n (16) . In this context, the te rm follicular gastritis has not be e n include d in the Update d Sydne y Syste m for classi® cation of gastritis (17). Howe ver, re cent studie s have shown a close re lationship of follicular gastritis with low-grade MALT lymphoma ( 5, 14) , sugge sting that de nse lymphoid follicle s shown in routine biopsie s should be re porte d. The se re cent de ve lopme nts on the re lationship be twe en H. pylori follicular gastritis and MALT lymphoma stre ss the ne ed for a be tter unde rstanding of the e pide miology of follicular gastritis. In the pre sent study we did not ® nd lymphocyte follicle s in any of the 159 H. pylori-negative patie nts with nonulce r dyspe psia. O ur data, the refore , agre e with publishe d re ports sugge sting that follicular gastritis is exclusive ly found in H. pylori-infe cted patie nts (6, 10) . We have also shown that follicular gastritis is most pre vale nt in patie nts with duode nal ulcer and nonulce r dyspe psia as compare d with gastric ulcer. The se results are comparable to those of Eidt and Stolte (9), who found a 46% prevale nce of lymphoid follicle s in the antral mucosa of patie nts with duode nal ulce r, but 31% in patie nts with gastric ulcer. Similar to our re sults, their patie nts with gastric ulce r were almost a decade olde r than the age of patie nts with duode nal ulce r. Multivariate discrim inant analysis of our data has shown that, among othe r factors, age is re late d to follicular gastritis. This was con® rmed by regression analysis, which showed a slow but signi® cant decrease in the pre vale nce of follicular gastritis with incre asing age . This could explain in part the lowe r incide nce of follicular gastritis found in patie nts with gastric ulcer, but othe r factors, such as host humoral and cellular immune re sponse may be involve d. To date , publishe d studie s have shown that in H. pylori-infe cted patie nts, the pre vale nce of follicular gastritis is at the range of 24 ± 72% (1, 3, 6, 8 ± 10, 14) . Howe ver, Genta and Hamne r sugge ste d that most H. pylori-infe cted patie nts have lymphoid follicle s and aggre gate s in the gastric mucosa (10) , but the y had e valuate d multiple gastric mucosal biopsie s with adDigestive Diseases and Sciences, Vol. 44, No. 6 (June 1999)

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ditional tissue se ctioning and e mploye d spe cial staining te chnique s. This variation in the prevale nce of follicular gastritis is probably due to diffe rence s in the de gre e and exte nsion of a commonly obse rved immune phe nome non. The re lative ly low pre vale nce of follicular gastritis we have found may be explaine d by the following factors. First, we have e valuate d only lymphoid follicle s and not lymphoid aggre gate s, as was the case in some publishe d studie s (9, 10) . Se condly, in our study biopsie s were proce sse d ª in routine ,º re garding the number of tissue se ctions and, furthe rmore, no spe cial staining was e mploye d. We have the re fore probably de te cted only case s with de nse follicle formation in the antral mucosa. O ur results sugge st that the re is a signi® cant ne gative corre lation of follicular gastritis pre vale nce with increasing age of H. pylori infected patie nts. To date publishe d studie s have shown a similar but not statistically signi® cant tre nd (8), or no correlation of follicular gastritis with patie nts’ age (9, 10, 16) . Howe ver, the y had evaluate d le ss than 200 H. pyloripositive case s (10, 17) and, the refore, allocation of patie nts into age groups could have re sulted in small numbe rs, invalidating furthe r statistical analysis. Anothe r important, contradictory issue is the re lationship of follicular gastritis with the activity of gastritis and the colonization density of the antral mucosa by H. pylori. Ce rtain studie s have shown positive (6, 9), but othe rs no, corre lation (7, 8, 16) . Our data lend support to earlie r publications (6, 9) and sugge st that a high gastritis score, ie, gastritis se verity and activity, are, ® rst, correlate d with dense H. pylori colonization and, second, that a high gastritis score is a pre dictive factor of follicular gastritis. Since activity and de gree of gastritis and H. pylori colonization de nsity are grade d according to four-point scale s, we sugge st that, as in our study, large numbe rs of case s should be e valuate d (6, 9) to provide valid information. Since we have e stablishe d that follicular gastritis is corre late d with seve re, active H. pylori gastritis, it may be argue d that there is no rationale for see king factors that predict follicular gastritis. Howeve r, since follicular gastritis may be a pre requisite for the de ve lopme nt of gastric low-grade MALT lymphoma (5), looking for factors that predict follicular gastritis may be of major intere st be cause certain of the se factors may be re late d to the de ve lopm ent of gastric MALT lymphoma. It will be possible , there fore , to ide ntify patie nts at risk. In this conte xt, it has be en sugge ste d that MALT lymphoma patie nts e xpre ss a signi® cantly highe r summe d gastritis score in the gastric corpus as Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999)

compare d to the gastritis patie nts (18) and that the H. pylori CagA status may be re late d to MALT lymphoma (19, 20) . In conclusion, our data sugge st that follicular gastritis is highly corre late d with H. pylori-induce d se ve re, active gastritis and that the prevale nce of follicular gastritis is slowly re duce d with incre asing age . Since follicular gastritis may give rise to MALT lymphoma, studie s on the evolution of follicular gastritis following H. pylori e radication the rapy (3, 4, 16) are imperative . REFERENCES 1. Wyatt JJ, Rathbone BJ: Immune response of the gastric mucosa to Cam pylobacter pylori. Scand J Gastroente rol 23( suppl 142) :44 ± 49, 1988 2. Stolte M, E idt S, Ohnsmann A: Cam pylobacter pylori: Unte rschiedliche auswirkunge n auf die Mage nschleimhaut. In Second Cam pylobacter pylori Symposium 1988. R Ottenjann, W Schmidt (e ds). Stuttgart, Thie me, 1990, pp 38 ± 50 3. Di Napoli A, Pe trino R, Boero M, Bellis D, Chiandussi L: Quantitative asse ssment of histological changes in chronic gastritis after eradication of Helicobacter pylori. J Clin Pathol 45:796 ± 798, 1992 4. Genta RM, Le w GM, Graham DY: Change s in the gastric mucosa following e radication of Helicobacter pylori. Mod Pathol 6:281± 289, 1993 5. Zucca E, Bertoni F, Rogge ro E, Bosshard G, Cazzaniga G, Pedrinis E, Biondi A, Cavalli F: Mole cular analysis of the progression from Helicobacter pylori-associated chronic gastritis to mucosa-associate d lymphoid-tissue lymphoma. N Engl J Me d 338:804 ± 810, 1998 6. Stolte M, Edit S: Lymphoid follicles in antral mucosa: Immune response to Cam pylobacter pylori? J Clin Pathol 42:1269 ± 1271, 1989 7. Arista-Nasr J, Reye r-De vesa S, Fonse ca-Solis D: Follicular gastritis and its association with Helicobacter pylori infection. Re v Inve st Clin 44:369 ± 372, 1992 8. Ze rbib F, V iale tte G, Cayla R, Rude lli A, Sauvet P, Be chade D, Seurat P, Lamouliatte H: Follicular gastritis in adults. Re lations with Helicobacter pylori, histological and e ndoscopic aspe cts. Gastroe nterol Clin Biol 17:529 ± 534, 1993 9. Eidt S, Stolte M: Prevalence of lymphoid follicles and aggre gate s in Helicobacter pylori gastritis in antral and body mucosa. J Clin Pathol 46:832± 835, 1993 10. Genta RM, Hamne r WH: The signi® cance of lymphoid follicle s in the interpretation of gastric biopsy specimens. Arch Pathol Lab Med 118:740 ± 743, 1994 11. Dane sh BJZ, Burke M, Newmans J, Aylott A, Whit® e ld P, Cotton PB: Comparison of weight depth and diagnostic ade quacy of specimens obtained with 16 different biopsy force ps designed for upper gastrointe stinal endoscopy. Gut 26:227± 231, 1985 12. Price AB: The Sydne y system: Histological division. J Gastroente rol He patol 6:209 ± 222, 1991 13. Wotherspoon AC, Doglioni C, Diss TC, Pan L, Moschini A, deBoni M, Isaacson PG: Re gression of primary low-grade B-ce ll gastric lymphoma of mucosa-associated lymphoid tissue

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Houston 1994. Classi® cation and grading of gastritis. The updated Sydney system. Am J Surg Pathol 20:1161± 1181, 1996 18. Me ining A, Stolte M, Hatz R, Lehn N, Mie hlke S, Morgne r A, Bayerdorffe r E: Differing degre e and distribution of gastritis in Helicobacter pylori-associate d disease. V irchows Arch 431:11± 15, 1997 19. Eck M, Schmauû er B, Haas R, Greine r A, Czub S, MullerHe rmelink HK: MALT-type lymphoma of the stomach is associated with Helicobacter pylori strains expressing the CagA protein. Gastroe nterology 112:1482± 1486, 1997 20. Withere ll HL, Hanse n S, Jellum E, Ore ntreich N, V ogelman JH, Parsonnet J: Risk for gastric lymphoma in persons with CagA 1 and CagA 2 Helicobacter pylori infection. J Infect Dis 176:1641± 1644, 1997

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