Intestinal and Diffuse Gastric Cancers Arise in a Different Background of Helicobacter pylori Gastritis Through Different Gene Involvement

Abstract

Investigation of extensively sampled nontumor gastric mucosa from 205 early gastric cancers showed Helicobacter pylori colonization in 85% of cases, including 100% of diffuse and 78% (83% in 97 cases with Swiss rolls) of glandular or mixed cancers. Intestinal metaplasia, including its type III variant, was prominent in the mucosa associated with glandular and mixed (but not diffuse) early cancers. Both glandular (usually called "intestinal") and diffuse-type cancers showed admixtures of intestinal and gastric tumor cell phenotypes. Both p53 gene mutations and p53 protein immunostaining were essentially restricted to glandular or mixed cancers and associated dysplastic lesions. Their appearance in the advanced stage of diffuse cancer was partly due to a change of the histologic pattern from glandular to diffuse during progression of some tumors. Loss of laminin, beta I integrin, or zonula adherens junctions was a common finding in both early and advanced diffuse cancer. It is concluded that two main pathways operate in gastric carcinogenesis, both starting from H. pylori gastritis and both leading to phenotypically variable, often mixed gastric/intestinal tumor growth. However, only one of the two pathways involves intestinal metaplasia, its type III variant, p53 gene alteration, and dysplasia to end in glandular cancer. In the other pathway, diffuse cancer apparently arises directly from hyperplastic, sometimes atypical necks of mostly nonmetaplastic gastric glands, through primary involvement of genes affecting cell-cell and cell-matrix junctional proteins.

Decreasing incidence of both major histologic subtypes of gastric adenocarcinoma – a population-based study in Sweden

“…But since the peri-tumour zone of most diffuse cancers lack these long-lasting intermediate steps, the importance of a preceding H. pylori infection in this subtype may be questioned. It has been suggested that H. pylori-induced chronic gastritis, involving an active renewal of gastric epithelium sensitive to oxidative carcinogenes, could be an early common starting-point in the genesis of both histologic types (Solcia et al, 1996). If genes primarily responsible for cell proliferation and differentiation are damaged, intestinal type cancer may then develop via the intermediate steps outlined above.…”

“…If genes primarily responsible for cell proliferation and differentiation are damaged, intestinal type cancer may then develop via the intermediate steps outlined above. Alternatively, if the early H. pylori-activated carcinogenic process affects genes involved in cell adhesion and basal membrane integrity, the secretory mucosal function would be retained (signet-ring cells), while prerequisites are formed for the invasiveness characterizing diffuse adenocarcinomas (Solcia et al, 1996).…”

“…The inconsistent findings regarding H. pylori's role in the genesis of the two histologic types (Solcia et al, 1996;Hansson et al, 1995;Parsonnet et al, 1993;Talley et al, 1991) may, apart from lack of statistical power, also be explained by retrospective studies of a bacteria which often spontaneously disappears from the mucosa during malignant transformation but before diagnosis of the tumour.…”

Why is the coexistence of gastric cancer and duodenal ulcer rare? Examination of factors related to both gastric cancer and duodenal ulcer

“…In addition, for gastric cancer to coexist with duodenal ulcer, an unrelated cause of mucosal atrophy must play some part, and the diffuse type of gastric cancer may be predominant in such cases [6,93,99].…”

Epigenetic alterations in gastric carcinogenesis

“…The most frequent gastric malignancy is the intestinal type, which is often preceded by sequential steps of precancerous changes, including atrophic gastritis, intestinal metaplasia, and either dysplasia or adenoma. In contrast, the diffuse type of gastric carcinoma tends to arise de novo and is infrequently associated with dysplasia or adenoma [66][67][68][69]. The sequential accumulation of alternations of APC and K-ras genes, characteristic of the colorectal adenoma-carcinoma sequence, however, does not occur frequently between adenoma and intestinal type adenocarcinoma of the stomach [27,[70][71][72][73][74][75][76][77].…”