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. 1999 Jun;44(6):789–799. doi: 10.1136/gut.44.6.789

Effect of Helicobacter pylori infection and its eradication on cell proliferation, DNA status, and oncogene expression in patients with chronic gastritis

G Nardone 1, S Staibano 1, A Rocco 1, E Mezza 1, F D'Armiento 1, L Insabato 1, A Coppola 1, G Salvatore 1, A Lucariello 1, N Figura 1, G De Rosa 1, G Budillon 1
PMCID: PMC1727537  PMID: 10323879

Abstract

BACKGROUND—Helicobacter pylori, the main cause of chronic gastritis, is a class I gastric carcinogen. Chronic gastritis progresses to cancer through atrophy, metaplasia, and dysplasia. Precancerous phenotypic expression is generally associated with acquired genomic instability.
AIM—To evaluate the effect of H pylori infection and its eradication on gastric histology, cell proliferation, DNA status, and oncogene expression.
METHODS/SUBJECTS—Morphometric and immunohistochemical techniques were used to examine gastric mucosal biopsy specimens from eight controls, 10 patients with H pylori negative chronic gastritis, 53 with H pylori positive chronic gastritis, and 11 with gastric cancer.
RESULTS—All patients with chronic gastritis were in a hyperproliferative state related to mucosal inflammation, regardless of H pylori infection. Atrophy was present in three of 10 patients with H pylori negative chronic gastritis and in 26 of 53 with H pylori positive chronic gastritis, associated in 18 with intestinal metaplasia. DNA content was abnormal in only 11 patients with atrophy and H pylori infection; eight of these also had c-Myc expression, associated in six cases with p53 expression. Fifty three patients with H pylori positive chronic gastritis were monitored for 12 months after antibiotic treatment: three dropped out; infection was eradicated in 45, in whom cell proliferation decreased in parallel with the reduction in gastritis activity; atrophy previously detected in 21/45 disappeared in five, regressed from moderate to mild in nine, and remained unchanged in seven; complete metaplasia disappeared in 4/14, and markers of genomic instability disappeared where previously present. In the five patients in whom H pylori persisted, atrophy, metaplasia, dysplasia, and markers of genomic instability remained unchanged.
CONCLUSIONS—Chronic H pylori infection seems to be responsible for genomic instability in a subset of cases of H pylori positive chronic atrophic gastritis; eradication of H pylori infection can reverse inflammation and the related atrophy, metaplasia, and genomic instability.


Keywords: H pylori infection; atrophic gastritis; genomic instability; eradication therapy

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Figure 1  .

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Distribution of histological and immunohistochemical features and DNA content in 53 H pylori positive patients with chronic gastritis. *16 complete and two incomplete.     

Figure 2  .

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Immunohistochemical expression of proliferating cell nuclear antigen (PCNA) in gastric crypt sections (as indicated on the figure; a mean of five well oriented crypts for each patient) of patients with functional dyspepsia, H pylori negative chronic gastritis, or H pylori positive chronic gastritis, with or without complete intestinal metaplasia (IM), before and after H pylori eradication. LI, labelling index, expressed as percentage of PCNA positive nuclei; C, controls with functional dyspepsia; nCG, H pylori negative chronic gastritis; pCG IM−, H pylori positive chronic gastritis without intestinal metaplasia; pCG IM+, H pylori positive chronic gastritis with complete intestinal metaplasia; IM−, chronic gastritis without intestinal metaplasia after H pylori eradication; IM+, chronic gastritis with intestinal metaplasia after H pylori eradication. †Three patients dropped out; intestinal metaplasia disappeared in four subjects.

Figure 3  .

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Proliferating cell nuclear antigen (PCNA) immunostaining of the gastric mucosa. (A) H pylori negative chronic gastritis with expression of PCNA in the nuclei of the cells of the glandular neck; (B) H pylori positive chronic gastritis; (C) H pylori positive chronic gastritis with intestinal metaplasia; (D) H pylori positive chronic gastritis after successful eradication treatment; (E) invasive gastric cancer showing high levels of PCNA positivity. Note the low labelling index of PCNA in the adjacent normal mucosa. Original magnifications: A, × 250; B, × 150; C × 400; D, × 250; E, × 150.

Figure 4  .

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Silver stained nucleolar organiser regions (AgNORs) in gastric mucosa. (A) H pylori negative chronic gastritis: small to medium-sized AgNORs in the nuclei. (B) H pylori positive chronic gastritis: medium-sized irregular AgNORs in the nuclei. (C) H pylori positive chronic gastritis, after eradication treatment. (D) Gastric cancer: large, irregular and sometimes unusually shaped AgNORs in neoplastic cells. Original magnification: A, B, C and D, × 1000, oil immersion.

Figure 5  .

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bcl-2 protein expression. (A) H pylori negative chronic gastritis: moderate bcl-2 expression. (B) H pylori positive chronic gastritis. (C) H pylori positive chronic gastritis with dysplasia: low bcl-2 expression. (D) H pylori positive chronic gastritis: moderate expression of bcl-2 protein in areas of intestinal metaplasia. (E) Nodal metastasis from gastric cancer: negative for bcl-2 protein in gastric cancer cells. Original magnifications: A, × 250; B, × 250; C, × 400; D, × 250; E, × 100.

Figure 6  .

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Representative DNA ploidy patterns in Feulgen stained sections of gastric mucosa. (A) H pylori positive chronic gastritis with moderate dysplasia: mild degree of aneuploidy. (B) H pylori positive chronic gastritis not responsive to eradication therapy without dysplasia: mild degree of aneuploidy. (C) Aneuploid pattern in gastric cancer (image analysis Quantimet 500C).   

Figure 7  .

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c-Myc expression. (A) H pylori positive chronic gastritis: low to moderate positivity for c-Myc expression. (B) H pylori positive chronic gastritis with intestinal metaplasia: moderate degree of positivity for c-Myc protein. (C) Gastric cancer: positivity for neoplastic cells for c-Myc protein. Original magnifications: A, × 400; B × 400; C × 100. 

Figure 8  .

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p53 protein expression. (A) H pylori positive chronic gastritis: sparse low positivity for p53 protein. (B) H pylori positive chronic gastritis with intestinal metaplasia: positivity for p53 protein in areas of intestinal metaplasia. (C) Gastric cancer: high positivity for p53 protein. Original magnifications: A, × 250; B, × 250; C, × 100. 

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