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doi:10.1111/jpc.12609

ORIGINAL ARTICLE

The association between Helicobacter pylori gastritis and lymphoid aggregates, lymphoid follicles and intestinal metaplasia in gastric mucosa of children Nursu Kara,1 Nafiye Urganci,2 Derya Kalyoncu1 and Banu Yilmaz3 1

Department of Pediatrics, 3Department of Pathology and 2Division of Pediatric Gastroenterology, Sisli Etfal Training and Research Hospital, Istanbul, Turkey

Aims: The aim of the study was to determine the topographic prevalence of lymphoid follicles, lymphoid aggregates, gastric glandular atrophy and intestinal metaplasia among children with chronic abdominal pain. The association between these lesions and age, type of gastritis and Helicobacter pylori density was also assessed. Methods: A total of 358 patients (mean age: 10, 18 ± 3, 26 years; male : female ratio: 0.92) with chronic abdominal pain who had upper gastrointestinal endoscopy were included in the study. The endoscopic and histopathological findings were documented. The prevalence of lymphoid follicles, lymphoid aggregates, atrophy and intestinal metaplasia according to the type of gastritis and their relation with H. pylori density were determined. Results: H. pylori was detected in 214 (59.8%) patients. H. pylori- positive patients were found to be significantly older than H. pylori-negative patients (P < 0.01). The endoscopy revealed that the most common finding observed was antral nodularity in H. pylori-positive patients and normal mucosal appearance in H. pylori-negative patients. Panmucosal gastritis both in the corpus and antrum and the prevalence of lymphoid follicles and lymphoid aggregates were more frequent in the H. pylori-positive group (P < 0.01). None of the patients had atrophy, whereas 11 patients had intestinal metaplasia. Although positive correlation was obtained between lymphoid lesions and H. pylori density, no significant relation was established between intestinal metaplasia, lymphoid lesions and H. pylori density. Conclusion: Lymphoid follicles and lymphoid aggregates in gastric mucosa involving both antrum and corpus significantly correlated with H. pylori infection, H. pylori density and type of gastritis in children. Key words:

children; Helicobacter pylori; intestinal metaplasia; lymphoid follicle.

What is already known on this topic

What this paper adds

1 The most common endoscopic finding observed in Helicobacter pylori-positive patients is antral nodularity. 2 H. pylori infection causes an immunological response, leading to chronic gastritis with formation of lymphoid aggregates and lymphoid follicles with germinal centres within the stomach. 3 Premalignant lesions such as gastric atrophy and intestinal metaplasia have been reported in children, and it is believed that these lesions could result in gastric cancer.

1 No correlation was established between H. pylori density and lymphoid follicles in patients with intestinal metaplasia. 2 When the prevalence of lymphoid follicles and lymphoid aggregates was evaluated according to the corpus and the antrum, no significant difference was observed. 3 H. pylori-positive patients with intestinal metaplasia are older than those without intestinal metaplasia.

Helicobacter pylori is one of the commonest chronic bacterial infections found in humans world-wide. Prevalence rates are generally much higher in developing countries compared with developed countries.1,2 The infection is typically acquired in early childhood, especially under 5 years of age,3,4 and once established, commonly persists throughout life unless treated. The prevalence of H. pylori varies by age, geographical location, Correspondence: Dr. Derya Kalyoncu, Sisli Etfal Training and Research Hospital 34270 Istanbul, Turkey. Fax: +90 212 231 22 09; email: deryakaly @hotmail.com Conflict of interest: None. Accepted for publication 24 January 2014.

ethnicity, socio-economic conditions, household crowding and infection status of family members.2–9 H. pylori infection causes chronic gastritis, gastric and duodenal ulcers, gastric glandular atrophy, intestinal metaplasia and also gastric adenocarcinoma in adults. It has been classified as a group 1 carcinogen by the World Health Organization in 1994.10 H. pylori and its relationship to gastric lymphoma are definitively established11,12 and have been identified as an aetiologic factor in gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The gastric mucosa is normally devoid of lymphoid tissue. H. pylori infection causes an immunological response, leading to chronic gastritis with formation of lymphoid aggregates and lymphoid follicles with germinal centres within the stomach. MALT lymphoma related to H. pylori infection leads

Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)

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to malignant transformation via chronic antigenic stimulation resulting in the clonal expansion of subpopulations of B cells.13 Although it predominantly occurs in adults, MALT lymphomas also have been reported in children.14,15 The presence of lymphoid follicles, lymphoid aggregates, gastric glandular atrophy and intestinal metaplasia in children with H. pylori infection and the relationship between these lesions in children are still controversial in the literature. These are recognised risk factors for subsequent development of cancer and may be present for many years before dysplasia and malignancy develop. The aim of this study was to determine the prevalence of the precursor lesions of H. pylori associated MALT lymphoma in children and establish the relation between these lesions and type of gastritis, and H. pylori density.

Methods A total of 358 children with chronic, recurrent abdominal pain in whom upper gastrointestinal endoscopy was performed between 2004 and 2008 at the Division of Paediatric Gastroenterology of Sisli Etfal Training and Research Hospital (Istanbul, Turkey) were evaluated retrospectively. The diagnosis of chronic abdominal pain was made in children who met the following criteria: at least three episodes of abdominal pain during a 3-month period, with an intensity that interferes with the child’s everyday life and activity and required medical attention. The patients were excluded if they had H. pylori eradication therapy or treatment with antibiotics and acid suppressors within 8 weeks prior to enrolment, as this could cause falsely negative test for H. pylori.

Fig. 1 Lymphoid follicle formation in gastric mucosa (haematoxylin and eosin (H&E), ×100).

Endoscopic evaluation Endoscopy was performed by the same paediatric gastroenterologist with an Olympus GI˙F-180 and XP 18 (Olympus, Tokyo, Japan) in all of the patients during fasting under sedation with intravenous midazolam (0.1 mg/kg) or rectal midazolam 0.5 mg/kg given as premedication 30 min before endoscopy. Informed consent was taken from all of the parents before endoscopy. In each patient, biopsy specimens were taken from the body (two), antrum (two), oesophagus (one) and the duodenal bulb. Biopsy specimens were fixed in 10% formalin, embedded in paraffin and stained with haematoxylin and eosin. All of the biopsy specimens were evaluated by two blinded pathologists who were blinded to patients’ clinical conditions.

Fig. 2 Lymphoid follicle and aggregate formation in gastric mucosa (haematoxylin and eosin (H&E), ×400).

scales described in the updated Sydney scoring system on a four-point scale (0, normal/absent; 1,mild; 2, moderate; and 3, marked).16

Definitions

Statistical analysis

A lymphoid follicle was defined as an aggregate of lymphocytes with a germinal centre and lymphoid aggregates as accumulations of lymphocytes and plasma cells without a germinal centre (Figs 1,2). Intestinal metaplasia was defined as the replacement of normal differentiated gastric mucosa by another mucosa histologically identical to normal intestinal epithelium. Panmucosal gastritis was diagnosed when inflammatory cells extending into the deep gland zones were identified. Patients were considered positive for H. pylori when H. pylori was detected by at least two of the three methods: histological examination, culture and rapid urease test. H. Pylori density was scored semi-quantitatively using visual analogue

Statistical analysis was performed using the NCSS 2007 and PASS 2008 Statistical Software (NCSS, LLC, Utah, USA). All results are expressed as the mean ± standard deviation. Statistical comparisons were made using the unpaired Student’s t-tests. The analysis was conducted using Fisher’s exact test and chi-square test to analyse qualitative variables. A value of P < 0.05 was considered statistically significant.

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Results The mean age of 358 patients was 10.18 ± 3.26 (range 2–18 years) and male : female ratio was 0.92. No patients had a

Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)

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Table 1

Assessment of histopathological findings

Clinical and demographic characteristics of patients

Age (years; median) Gender (male/female) Endoscopic findings Normal Oesophagitis Gastric mucosal erosions and/or hyperaemia, gastritis, oedema Antral nodularity Gastric ulcer Duodenitis Duodenal ulcer Type of gastritis Corpus Superficial Panmucosal Antrum Superficial Panmucosal

Total patients

Helicobacter pylori (+)

H. pylori (−)

P-value

(n = 358)

(n = 214)

(n = 144)

10 (1–18) 0.92 (172/186)

11 (1–17) 0.91 (102/112)

9 (2–18) 0.94 (70/74)

0.001 0.860

141 (39.3%) 33 (9.2%) 60 (16.7%)

102 (47.6%) 26 (12.1%) 44 (20.5%)

39 (27%) 7 (4.8%) 16 (11.1%)

0.001 0.633 0.061

158 (44.1%) 7 (1.9%) 69 (19.2%) 15 (4.18%)

148 (69.1%) 5 (2.3%) 60 (28%) 15 (7%)

10 (6.9%) 2 (1.38%) 9 (6.25%) 0

0.001 0.470 0.220 0.062

113 (31.5%) 146 (40.7%)

61 (28.5%) 100 (46.7%)

52 (36.1%) 46 (31.9%)

0.129 0.005

66 (18.4%) 211 (58.9%)

40 (18.7%) 138 (64.5%)

26 (18.1%) 73 (50.7%)

0.879 0.009

P < 0.01 is statistically significant.

positive family history for gastric cancer. Abnormal upper gastrointestinal endoscopic findings were observed in 217 (60.6%) patients and normal examination in 141 (39.3%) patients. H. pylori was detected in 214 (59.8%) patients. The clinical characteristics and endoscopic findings of the cases are given in Table 1. A significant difference was observed in age between H. pyloripositive and negative patients (P = 0.001). One hundred seven (26.7%) H. pylori-positive patients and 18 (21%) H. pylorinegative patients had more than one endoscopic finding. The endoscopy revealed that the most common gastroduodenal lesion observed in H. pylori positive-patients was antral nodularity, followed by duodenitis (Table 1). The antral nodularity was observed more frequently in H. pylori-positive patients than in H. pylori-negative cases (odds ratio (OR), 4.724; 95% confidence interval (CI), 2.940–7.591; P = 0.001). Superficial gastritis was observed in 113 (31.5%) patients in the corpus and 66 (18.4%) patients in the antrum. Panmucosal gastritis was observed in 146 (40.7%) patients in the corpus and 211 (58.9%) patients in the antrum significantly higher in H. pylori-positive patients than H. pylori-negative patients (OR, 1.869; 95% CI, 1.202–2.906; P = 0.005) (Table 1). The panmucosal gastritis in the corpus and in the antrum was more frequent in cases with lymphoid follicles and lymphoid aggregates than in cases without lymphoid follicles and lymphoid aggregates (OR, 5.515; 95% CI, 1.77–17.11; P = 0.001) (Tables 2,3, Fig. 3). Lymphoid follicles and aggregates were more common in H. pylori-positive patients with antral nodularity than those without antral nodularity (P < 0.05). A statistically significant difference was found between H. pylori density and lymphoid aggregates in the antrum (P =

Table 2 The distribution of lymphoid follicles according to the type of gastritis Gastritis Corpus Superficial Panmucosal Antrum Superficial Panmucosal

LF (+)

LF (−)

P-value

18 (15.9%) 34 (23.2%)

95 (84%) 112 (76.7%)

0.609 0.003*

10 (15.1%) 42 (19.9%)

56 (84.8%) 169 (80%)

0.873 0.001*

*P < 0.01 is statistically significant. LF, lymphoid follicle.

0.018). With increasing H. pylori density in the antrum, the presence of lymphoid aggregates also increased. Lymphoid follicles and H. pylori density in both the antrum and corpus were positively correlated (P < 0.01) (Table 4). Superficial gastritis was seen in three (27.2%) patients and panmucosal gastritis in eight (72.7%) patients with intestinal metaplasia. Two of 11 (18.1%) patients with intestinal metaplasia had lymphoid follicles, whereas none of them had lymphoid aggregates, and the difference was not statistically significant (P > 0.05). No significant correlation was found between intestinal metaplasia and H. pylori density in the antrum and corpus (P > 0.05) (Table 4). There was no statistically significant difference in age between patients with lymphoid aggregates and lymphoid follicles, but the difference was significant between patients with and without intestinal metaplasia (13.3 ± 1.6 and 10.1 ± 3.2, respectively; P = 0.001).

Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)

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Table 3 The distribution of lymphoid aggregates according to the type of gastritis

Table 4 Assessment of Helicobacter pylori density among lymphoid follicles, lymphoid aggregates and intestinal metaplasia

Gastritis

H. pylori density

Corpus Superficial Panmucosal Antrum Superficial Panmucosal

LA (+)

LA (−)

P-value

10 (8.84%) 17 (11.6%)

103 (91.1%) 129 (88.3%)

0.286 0.025*

6 (9%) 21 (9.95%)

60 (90.9%) 190 (90%)

0.598 0.039*

*P < 0.05 is statistically significant. LA, lymphoid aggregate.

LA (+) Corpus Antrum LF (+) Corpus Antrum IM (+) Corpus Antrum

Absent

Mild

Moderate

1 (3.7%) 1 (3.7%)

15 (55.5%) 10 (37%)

8 (29.6%) 9 (33.3%)

1 (1.9%) 1 (1%)

23 (44.2%) 18 (14.5%)

16 (30.7%) 24 (29.6%)

3 (27.3%) 2 (18.2%)

5 (45.5%) 5 (45.5%)

2 (18.2%) 2 (18.2%)

Marked

3 (11.1%) 7 (25.9%) 12 (23%) 9 (17%) 1 (9.1%) 2 (18.2%)

P-value

0.001* 0.018** 0.022* 0.001* 0.715 0.812

*P < 0.01 and **P < 0.05 are statistically significant. IM, intestinal metaplasia; LA, lymphoid aggregate; LF, lymphoid follicle.

Fig. 3 Gastric antral mucosa showing moderate chronic follicular gastritis (haematoxylin and eosin (H&E), ×200).

Discussion H. pylori infection causes an immunological response, leading to chronic gastritis with formation of lymphoid aggregates and lymphoid follicles with germinal centres within the stomach.17 Thus, MALT develops. It has been reported in studies including adults that lymphoid follicles are the precursor lesions of H. pylori-associated MALT lymphoma.18 It is still under debate in children. Some authors accepted the lymphoid aggregates in the antrum as a component of the normal gastric mucosa, whereas some emphasise that the immunological response to H. pylori infection results in formation of lymphoid aggregates and lymphoid follicles.18–21 Carpentieri et al.19 reported that although the presence of lymphoid follicles with histologic gastritis had the strongest correlation with H. pylori, lymphoid aggregates with gastritis had no significant correlation with H. pylori in children. In our study, lymphoid follicles and lymphoid aggregates both in the corpus and antrum were more frequent in patients with H. pylori-associated panmucosal gastritis. The lower rate of lymphoid follicles and lymphoid aggregates in the corpus than in the antrum can be explained by the lower intensity of inflammation, activity and grade of gastritis in the 4

corpus than in the antrum. In addition, H. pylori moves to low-acidic regions and tends to settle in the antrum. When the prevalence of lymphoid follicles and lymphoid aggregates was evaluated according to the corpus and the antrum, no significant difference was observed in this study. This can be explained by varied number and site of biopsy specimens taken (two biopsy specimens from both antrum and corpus) when compared with the other studies. It has been shown that antral nodularity may be the only endoscopic finding strongly associated with H. pylori positivity,22–25 and nodular gastritis may present as gastric manifestation of H. pylori infection that indicates gastric MALT.26 The premalignant lesions such as gastric atrophy and intestinal metaplasia have been reported in children and it has been thought that these lesions could result in development of gastric cancer.17,27 Previous studies indicated that glandular atrophy and intestinal metaplasia are rare in childhood.28,29 In the present study, 3 out of 11 patients with intestinal metaplasia had normal endoscopic examination after 2 years (triple therapy with amoxicillin, clarithromycin and lansoprazole was given), 2 patients still had intestinal metaplasia and the remaining 5 of the patients were lost to follow-up. In conclusion, the prevalence of lymphoid follicles and aggregates in gastric mucosa correlated significantly with H. pylori infection, H. pylori density and type of gastritis in children. Further, larger, prospective studies with longer follow-up are needed to clarify the clinical significance of lymphoid follicles and lymphoid aggregates in paediatric patients and the effect of eradication therapy on the disappearance of these lesions.

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The association between Helicobacter pylori gastritis and lymphoid aggregates, lymphoid follicles and intestinal metaplasia in gastric mucosa of children.

The aim of the study was to determine the topographic prevalence of lymphoid follicles, lymphoid aggregates, gastric glandular atrophy and intestinal ...
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