Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma

Abstract

Metaplastic cell lineages arising in response to chronic injury are precursors for the evolution of dysplasia and adenocarcinoma. Although a subtype of intestinal metaplasia has been associated with gastric adenocarcinoma, the link between this lineage and the evolution of gastric adenocarcinoma has remained unclear. Wang et al (1998) have reported that an aberrant metaplastic cell lineage with morphological characteristics similar to Brunner's glands of the duodenum develops in the fundic mucosa of mice infected with Helicobacter felis. This metaplastic lineage expresses the trefoil peptide spasmolytic polypeptide (SP). Given the epidemiological association of Helicobacter species infection with gastric cancer, we hypothesized that this SP-expressing metaplastic (SPEM) lineage may represent a precursor to or appear commensurate with gastric adenocarcinoma. The SPEM lineage was present in 68% of fundic biopsies from patients with fundic Helicobacterpylori-associated gastritis, but was absent in biopsies of fundic mucosa from patients without H. pylori infection. In a review of archival samples from 22 resected gastric adenocarcinomas, we found the SPEM lineage in 91% of cases, typically located in mucosa adjacent to the carcinoma or areas of dysplasia. Importantly, 59% of resections showed SP immunoreactivity within dysplastic cells. These data indicate a strong association of the SPEM lineage with both chronic H. pylori infection and gastric adenocarcinoma.

Figure 1.

SP staining in gastric fundic biopsies. Sect ons from biopsies of fundic mucosa from H pylon uninfected (a and b) and H. pylori infected (c and d) patients were stained for SP. All biopsies demonstrated immunoreactive parietal cells without the presence of G-cells. In noninfected patients, SP staining was confined to normal appearing mucous neck cells. In H. pylori-infected patients, nodular aggregates of SP-staining cells with the characteristics of Brunner’s gland cells (SPEM) were observed. No SPEM was observed in fundic biopsies from noninfected patients. Bar: a and c = 26 μm; b and d = 13 μm.

Figure 2.

SPEM in the gastric mucosa of resections harboring gastric adenocarcinoma, a, b, and c, Sections of gastric mucosa from regions adjacent to gross adenocarcinoma were examined for immunostaining with SP antibodies. Prominent regions of SPEM were observed in mucosa underlying regions of foveolar hyperplasia (a and b). The lineage was always observed near the bases of glands. As noted in the biopsies, the SPEM cells were large with extensive numbers of immunoreactive granules (b). c, In a region adjacent to that shown in a and b, SP staining of normal-appearing mucous neck cells was observed. Parietal cells were also observed in these sections (arrows). d, Adjacent sections were stained with anti-PSTI, demonstrating distinct PSTI immunoreactive mucous neck cells within the mucosa (arrowheads). The SPEM lineage cells at the right side of the section showed no PSTI immunoreactivity. e and f, Adjacent sections were stained with anti-pS2. Although pS2 immunostaining was observed in regions of surface cell foveolar hyperplasia (e). SPEM cells did not stain for pS 2 (f). g, Toluidine blue staining of a 0.5 μm section from a resection specimen demonstrates the numerous granules in SPEM cells. Note the presence of residual parietal cells in some SPEM-containing glands (arrows) confirming the presence of the lineage in fundic mucosa (hours). Electron microscopic examination demonstrates the presence of multiple mucous granules within the SPEM cells along with the characteristic expanded apical membrane surface without microvilli, Bars: a = 80 μm, b, c, e, and f = 40 μm; d = 20 μm; g = 13 μm, hours = 3 μm.

Figure 3.

SP immunoreactivity in areas of dysplasia contiguous with SPEM. a, In 59% of resection samples SP staining was observed in both SPEM and in contiguous regions of dysplasia. No immunoreactivity was detectable in a region of adenocarcinoma in situ adjacent to the SP-immunoreactive cells as seen in the upper right corner. b and c, At higher magnification, SP-expressing dysplastic epithelial cells are contiguous with SPEM cell-containing glands. Bar: a = 80 μm; b and c = 25 μm.