MARKED EPITHELIAL HYPERPLASIA OF THE RAT GLANDULAR STOMACH INDUCED BY LONG-TERM ADMINISTRATION OF IODOACETAMIDE

Iodoacetamide (IAA), an ulcerogenic compound, was continuously given to male Wistar rats for up to 74 weeks. No carcinomas developed but marked glandular hyperplasias were frequently observed accompanied by chronic ulcer or erosion in the fundic region. They showed pseudo-invasive growth into the submucosa, the granulomatous tissue and even into the muscle layer, but no cellular and nuclear atypia was observed in their glands. Characteristically the mucosal damage caused by chronic IAA treatment was restricted to the fundic mucosa along the limiting ridge. Abnormally regenerated mucosa in the damaged area showed pyloric gland type metaplasia, demonstrated histo-chemically by paradoxical concanavalin A-staining and high-iron diamine-Alcian blue staining for mucin. No intestinal metaplasia was observed in these mucosa.     

Sequential morphological changes of ulceration in the glandular stomach of rats induced by iodoacetamide.

Two groups of 25 male Wistar rats were given 0.1% iodoacetamide (IAM) with or without 0.4% Tween 60 in their drinking water for 12 weeks. Two or three rats from each group were sacrificed at intervals for sequential morphological observations on ulceration of gastric mucosa. The ulcers invariably developed in the fundic region adjacent to the limiting ridge, and they penetrated the muscle coats and extended to the serosal lining on continuous treatment with IAM for 9 weeks. The ulcers appeared chronic, but when IAM was discontinued the healing process began rapidly and the mucosa regenerated almost completely within six weeks. Regenerating epithelium on areas of ulcer differentiated progressively, and the renewed mucosa showed pyloric metaplasia.     

Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma.

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.     

Clinicopathological features of duodenal bulb biopsies and their relationship with upper gastrointestinal diseases

AimTo assess the prevalence of the lesions in duodenal bulb mucosa and the relationship between duodenal lesions and upper gastrointestinal diseases, including helicobacter pylori infection.MethodsClinical, endoscopic and pathological data of the cases with duodenal bulb and gastric mucosal biopsy from January 2005 to May 2017 were analyzed retrospectively.ResultsA total of 3540 patients were enrolled. The biopsy from protuberant lesions with endoscopic morphology are mostly duodenal gastric heterotopia or adenoma. The biopsy from duodenal ulcers are often observed in inflammatory changes and gastric metaplasia.Patients with gastric heterotopia had a significantly lower prevalence of chronic atrophic gastritis, intestinal metaplasia, and gastric ulcer; and much higher prevalence of gastroesophageal reflux disease and gastric fundic polyps.Patients with gastric metaplasia had been positively associated with gastroesophageal reflux disease, and negatively associated with gastric fundic polyps.There were positive correlation between helicobacter pylori infection and duodenal active inflammation, Brunner gland hyperplasia, gastric metaplasia and duodenal ulcer. However, Patients with gastric heterotopia in bulb had been negatively associated with helicobacter pylori infection.ConclusionsThe mucosa lesions in duodenal bulb were associated with concurrent gastric fundic gland polyps, gastroesophageal reflux disease, duodenal ulcer, and helicobacter pylori infection.     

SEQUENTIAL MORPHOLOGICAL CHANGES OF ULCERATION IN THE GLANDULAR STOMACH OF RATS INDUCED BY IODOACETAMIDE

Two groups of 25 male Wistar rats were given 0.1% iodoacetamide (IAM) with or without 0.4% Tween 60 in their drinking water for 12 weeks. Two or three rats from each group were sacrificed at intervals for sequential morphological observations on ulceration of gastric mucosa. The ulcers invariably developed in the fundic region adjacent to the limiting ridge, and they penetrated the muscle coats and extended to the serosal Mng on continuous treatment with IAM for 9 weeks. The ulcers appeared chronic, but when IAM was discontinued the healing process began rapidly and the mucosa regenerated almost completely within six weeks. Regenerating epithelium on areas of ulcer differentiated progressively, and the renewed mucosa showed pyloric metaplasia.     

Pathologic changes of endocrine cells in chronic atrophic gastritis. An ultrastructural study on peroral gastric biopsy specimens

In the course of an ultrastructural study on peroral gastric biopsy specimens that were obtained from patients with chronic atrophic gastritis, peculiar pathological changes of endocrine cells were observed and correlated with functional and hormonal data on the patients. An increased number of G (gastrin) cells was found in hypergastrinemic patients. These cells could be divided into a "light" (probably hyperfunctioning) and a "dark" (probably exhausted) type. The light type of cell was prominent regardless of the concomitant gastrin blood levels. The G cells found within the fundic region were always localized within the areas of pyloric metaplasia. Focal micronodular proliferation of antral enterochromaffin cells (EC) was often seen. A proliferation of the closed type of endocrine cells of the fundic mucosa was observed only in patients with elevated gastrin concentrations. In the present study, these cells were identified as enterochromaffin-like cells (ECL). No substantial changes were found in the D and D1 cells. The endocrine cells seen in metaplastic intestinal epithelium exhibited ultrastruct characteristics of at least three different types of intestinal endocrine cells (EC, L, and S cells).     

Morphological findings of different areas of gastric mucosa in patients with achlorhydria,extreme hypochlorhydria,Normochlorhydria and their relationship to serum gastrin level: Evidence for two different types of gastritis

Summary The morphological changes of gastric mucosa taken from different areas have been studied in patients of approximately the same age with achlorhydria, extreme hypochlorhydria and normochlorhydria. The serum gastrin level and parietal cell antibodies were determined in the achlorhydric patients. In the latter the diffuse gastritis was localized in the corpus-fundic area, while the changes in the antral region were few and occurred mostly in the superficial zone. In normochlorhydric patients however, the diffuse gastritis was localized in the antral region, with only few changes at the corpus-fundic area. In patients with extreme hypochlorhydria either the fundic or the antral region was involved. Besides the diffuse gastritis intestinal metaplasia, pseudopyloric metaplasia, and atrophy of mucosa were also observed, although much less commonly. The increase of gastrin level could not be related to a definite morphological pattern in the gastric mucosa.It can be assumed that each of the two types of gastritis has a different natural history; the antral site of gastritis cannot be transformed into the fundic site, nor can the fundic site be transformed into the antral site.Parts of this study were presented at the Fifth World Congress of Gastroenterology, Mexico, 1974     

Duodenal gastric heterotopia,sporadic or fundic gland polyp-associated,frequently carries β-catenin mutation

Duodenal gastric heterotopia (DGH) is a benign asymptomatic condition assumed to be of congenital origin. Since DGH is often associated with fundic gland polyps (FGPs) that frequently carry a somatic β-catenin gene mutation, we examined whether DGH, either sporadic or FGP-associated, is attributable to alterations of the Wnt/β-catenin pathway. Genetic analysis revealed frequent somatic β-catenin gene mutations in DGH; some of which showed the same mutation pattern as coexisting FGPs. All missense mutations were confined to codons 32, 33, and 37. No such mutations were observed, however, in any of the specimens from focal gastric foveolar metaplasia (GFM). Therefore, DGH is not a mere congenital lesion due to aberrant migration of normal gastric mucosa or a simple reactive metaplasia after regenerative stimuli of the duodenal mucosa, but a distinct condition based upon molecular genetic changes in the Wnt/β-catenin pathway.     

Intestinal metaplasia of the regenerative epithelia in 549 gastric ulcers

Histopathologic changes in the regenerative epithelia of 549 foci of gastric ulcer were studied. About 70 per cent of the regenerative epithelia revealed intestinal metaplasia of the so-called complete or incomplete type. Parietal cells and chief cells were occasionally observed in the regenerative epithelia of ulcers located in fundic gland areas or at fundopyloric gland borders. It is possible that the regenerative epithelium frequently reverts to intestinal epithelium during the regenerative process, later redifferentiating into normal gastric mucosa or remaining as intestinal metaplasia and that, thus, only a few foci of intestinal metaplasia are precancerous lesions.     

Mucosal changes of the gallbladder in anomalous union with the pancreatico-biliary duct system

Histological examination of the gallbladder mucosa was made on a total of 39 patients with anomalous union of the pancreatico-biliary duct system. The most characteristic finding was mucosal hyperplasia of the gallbladder. Measurement of the height of the mucosa revealed that 15 cases (38.5%) showed mucosal hyperplasia composed of ordinary gallbladder epithelium without any metaplastic changes, including two cases of primary mucosal hyperplasia of the gallbladder. The other finding was metaplastic changes which were observed in 26 cases in various degrees, of whom 16 cases showed only focal metaplasia. These findings indicate that metaplasia frequently occurred in the gallbladder but the distribution of metaplasia was relatively focal in anomalous union with the pancreatico-biliary duct system. In our present materials there were nine cases of gallbladder adenocarcinoma and based on our classification, they were divided into seven cases of metaplastic type and two cases of non-metaplastic type. This ratio was not different from that of usual gallbladder carcinoma not complicated by this anomaly. These results indicate that the reflux of pancreatic juice into the gallbladder by anomalous union with the pancreatico-biliary duct system may cause two different effects on the gallbladder mucosa, the first being a proliferative effect resulting in mucosal hyperplasia and the other being chronic irritation causing metaplastic changes. The relation between these changes and the pathogenesis of gallbladder carcinoma is briefly discussed.     

Induction of intestinal metaplasia in the rat gastric mucosa by local X-irradiation

Attempts were made to learn about an optimal condition for the induction of intestinal metaplasia in the gastric mucosa. The gastric region of 5-week-old female Wistar rats was irradiated with 500 rad of X-ray daily for 6 times (Group I) or with 1,000 rad of X-ray every two days for 3 times (Group III). In addition, the effect of immunization by allogeneic stomach antigen on the intestinalization was studied in rats irradiated with 500 rad of X-ray daily for 6 times (Group II). In a group of rats (Group II) injected with allogeneic stomach antigen and X-irradiated the process of intestinalization was more accelerated as compared to that in rats treated with X-ray (Group I). The similar results were obtained in rats irradiated with 1,000 rad of X-ray 3 times (Group II). Intestinal metaplasia developed more later in the fundic gland mucosa which became usually atrophic due to the loss of parietal cell mass. There was an intimate association among the parietal cell loss in the fundic gland, a rise in pH value and the development of intestinal metaplasia. In all groups, no case of gastric adenocarcinoma was detected during observation period up to 52nd week.     

Histopathological study of porcine gastric mucosa with and without a spiral bacterium ("Gastrospirillum suis").

Tightly spiralled bacteria ("Gastrospirillum suis") were seen in the pyloric mucosa of the stomach of 13 (10.8%) of 120 pigs that appeared clinically healthy at slaughter and in the fundic mucosa of three (5.0%) out of 60 pigs. The spiral organism could not be cultured from any pig. Chronic gastritis was observed in the pyloric mucosa of 53 (44.2%) of 120 pigs and in the fundic mucosa of 7 (11.7%) of 60 pigs. The 13 pigs with spiral bacteria in the pyloric region comprised one animal (7.7%) with normal pyloric mucosa, two (15.4%) with "borderline gastritis", and 10 (76.9%) with chronic gastritis--in one instance accompanied by signs of activity (numerous polymorphonuclear cells). The three pigs with spiral bacteria in the fundic mucosa comprised two animals with a normal fundic region and one with "borderline gastritis". The presence of the spiral bacterium was significantly associated with pyloric gastritis (p = 0.013) and with numbers of lymphoid follicles (p = 0.014).     

Emergence of spasmolytic polypeptide-expressing metaplasia in Mongolian gerbils infected with Helicobacter pylori

Spasmolytic polypeptide (TFF2)-expressing metaplasia (SPEM) is observed in mucosa adjacent to human gastric cancer and in fundic glands showing oxyntic atrophy in Helicobacter felis-infected mice. Mongolian gerbils infected with Helicobacter pylori (Hp) develop goblet cell intestinal metaplasia and adenocarcinoma, but the presence of SPEM has not been studied in gerbils. We therefore have sought to examine the development of metaplastic mucosal changes in Hp-infected Mongolian gerbils. Mongolian gerbils were assigned to either uninfected controls or infected with Hp at 17 weeks of age. The animals were killed at 17, 20, 26, 31, 41 and 56 weeks of age. Stomach sections were stained using antibodies for TFF2, intrinsic factor, H/K-ATPase, BrdU and MUC2. Dual immunofluorescence staining for TFF2 with intrinsic factor and for TFF2 with MUC2 was performed. In uninfected animals, no SPEM or intestinal metaplasia was observed. Infected gerbils developed SPEM initially in the intermediate zone along the lesser curvature and subsequently spread out towards the greater curvature. In the earlier stages of infection, SPEM glands demonstrated TFF2 and intrinsic factor double staining cells. However, after 35 weeks of infection, the number of double staining SPEM cells decreased. While early in infection SPEM organized in straight glands, in the later stages of infections, SPEM glands became distorted or dilated along with the development of gastritis cystica profunda that was TFF2 positive. Goblet cell intestinal metaplasia developed only late in the infection. Dual staining for TFF2 and MUC2 showed glands containing both SPEM- and MUC2-positive goblet cell intestinal metaplasia. SPEM develops early in Hp infection in Mongolian gerbils, and alterations in gland morphology arise from SPEM glands during the course of gastric infection with goblet cell intestinal metaplasia developing subsequent to SPEM.     

Nucleolar organizer regions in gastric carcinoma and its precursor stages

A silver technique for nucleolar organizer regions (AgNOR) was applied to sections from 156 gastric biopsies and gastrectomy specimens. These included normal controls, normal gastric mucosa from carcinoma-bearing stomachs, intestinal metaplasia types I and III, dysplasia and carcinoma. AgNOR counts gradually increased from normal, through intestinal metaplasia, to carcinoma. This finding supports the chronic atrophic gastritis-intestinal metaplasia-dysplasia-carcinoma sequence concept for gastric carcinogenesis. Normal gastric mucosa was different from all lesions, including normal mucosa from carcinoma-bearing stomachs. Significantly higher AgNOR counts were observed in tumours compared to all other lesions except dysplasia. Dysplasia differed from intestinal metaplasia type I but not from type III. Eighty-five per cent of metaplasia cases overlapped with carcinoma and 19% with normal controls. The spread of AgNOR values in intestinal metaplasia reinforces the concept that this lesion is a heterogeneous entity reflecting a dynamic and continuous process. The AgNOR technique may contribute to the assessment of the stage of evolution of 'borderline' lesions.     

Application of parietal cell autoantibody to histopathological studies

Parietal cell antibody (PCA) from the serum of a patient with type A gastritis was used for the immunohistochemical demonstration of human parietal cells not only in frozen sections but in paraffin-embedded biopsy specimens. The antigenicity was occasionally lost in paraffin sections of routine surgical materials. With the indirect immunoperoxidase technique, PCA clearly detected antigenic substances on the intracytoplasmic canalicular structures and focally on the apical plasma membranes. These intracellular localization patterns differed from those of intrinsic factor, which was present on fine vesicular structures along the intracytoplasmic canaliculi and apical plasma membranes. A few PCA-reactive cells were further demonstrated in normal pyloric glands, atrophic fundic glands with pseudopyloric gland metaplasia and cystic changes, a hamartomatous polyp in the fundic mucosa, and in heterotopic gastric mucosa in the duodenum. Developing parietal cells in the newborn stomach were also visualized by PCA. In one of 16 surgical specimens of gastric cancer, abortive gland lumens formed by the cancer cells were focally positive with PCA. Immunostaining with PCA was, therefore, a useful tool for the detection of pathological alterations of human parietal cells in routine histopathology specimens.     

Increased apoptosis in gastric mucosa adjacent to intestinal metaplasia

BACKGROUND: The biological processes involved in the development of gastric mucosal atrophy and intestinal metaplasia are still incompletely understood. Reports testing the hypothesis that apoptosis leads to atrophy have yielded conflicting results. The availability of new antibodies for the detection of apoptotic cells in tissue sections has facilitated the analysis of the role of apoptosis in the gastritis-atrophy-intestinal metaplasia sequence. METHODS: Archival material from 40 gastric resection specimens with normal mucosa (n = 5), chronic active gastritis (n = 17), or intestinal metaplasia (n = 18) was studied. Immunohistochemistry was performed using antibodies directed against cleaved cytokeratin 18 and active caspase 3. Slides were scored on a 0-3 scale for the presence of apoptotic cells. RESULTS: Normal gastric mucosa contained low numbers of apoptotic cells at the surface epithelium (mean score, 0.20). This number was significantly increased in cases with chronic gastritis (mean score, 1.06) and in those with intestinal metaplasia (mean score, 2.56). Within the intestinal metaplasia cases, 44 different foci of intestinal metaplasia were identified. In 39 of these 44 areas, concentrations of apoptotic cells were seen immediately adjacent to the foci of intestinal metaplasia, but not in the metaplastic epithelium itself. CONCLUSIONS: Apoptosis is uncommon in normal gastric mucosa. Chronic inflammation and intestinal metaplasia are associated with increased apoptosis, but occur mainly at the mucosal surface and not in the deeper layers. These findings do not support the concept that apoptosis underlies the loss of gastric glands and leads to atrophy, but the observed concentration of apoptotic epithelial cells adjacent to foci of intestinal metaplasia could be related to heterogeneity of epithelial damage, causing apoptosis, to which intestinal metaplasia is a response.     

Qualitative and quantitative alterations in the parietal cell domain in chronic gastritis

Hematoxylin and eosin (H&E) is not an optimal stain to discriminate between parietal and chief cells in gastric biopsies; modified Giemsa (G) and toluidine blue (TB) were found more suitable stains to characterize these two cell phenotypes. Sixty-eight well-oriented sections from the fundic mucosa were stained with H&E, and with G or TB. With G or TB the normal fundic mucosa clearly displayed a parietal cell domain (PCD) and a chief-cell domain (CCD). The continuity of these two cell domains was assessed in the entire section at ×4 magnification and the thickness of the PCD. The total mucosal thickness (TMT) was measured in three different HPF at ×20 magnifications. Qualitative observations indicated that the PCD and CCD were (a) continuous in normal fundic mucosa or having slight chronic gastritis, (b) fragmented in moderate chronic gastritis, in focal glandular atrophy or focal IM or (c) absent in severe chronic gastritis, including autoimmune gastritis and extensive IM. Quantitative measurements showed that the thickness of the PCD in chronic gastritis could be (a) normal, (b) reduced by partial destruction of the parietal cell population by chronic inflammation, or (c) absent, in extensive IM or total glandular atrophy (p < 0.05). Toluidine blue gave a better contrast between the two cell phenotypes than modified Giemsa stain. Future studies might elucidate whether qualitative and quantitative studies of toluidine blue-stained sections of the fundic mucosa are useful in monitoring the results of therapy in individual patients with chronic gastritis.     

Well-differentiated adenocarcinoma mimicking complete-type intestinal metaplasia in the stomach.

We describe extremely well-differentiated intestinal-type adenocarcinomas of the stomach which mimic complete-type intestinal metaplasia. It is often difficult to discriminate such neoplastic lesions from inflamed or regenerative changes of intestinal metaplasia histologically. The aim of this study was to elucidate the clinicopathologic features of this unique carcinoma. Eight cases of gastric carcinoma of this type that were invasive beyond the muscularis mucosae were selected for mucin histochemical and immunohistochemical analyses. The carcinomas showed the following features: (1) predominant cells that had differentiated to mature neoplastic cells, with features of small intestinal absorptive cells (complete-type intestinal metaplastic cells), which have sialomucin, MUC2-positive cells, and brush border features detected by CD10 (56C6) staining; (2) neoplastic tubules in the mucosa showing branching, tortuous, anastomosing, and plexiform structures, which were more pathognomonic than the cytological features; (3) lesions distributed predominantly in the middle third of the stomach and surrounded by the fundic mucosa; and (4) zonal distribution of Ki-67-positive proliferative cells like those of intestinal metaplasia in the lower third to half of the cancerous tubules in the mucosa. The lesions consisted mainly of illusory carcinoma; however, there were foci of pathognomonic elements in some areas of the tumors. Several biopsy samplings of the lesion would ensure the histopathologic diagnosis. This unique lesion forms a subgroup of intestinal-type carcinomas of the stomach and is suggested to have a close link with complete-type intestinal metaplasia, previously ignored as a precancerous lesion.     

Tubulovillous adenoma of the urinary bladder.

We report a case of vesical tubulovillous adenoma that occurred in a background of protracted chronic cystitis with intestinal-type glandular metaplasia and extensive cellular atypia (dysplasia) in the flat mucosa. Flow cytometry analysis showed DNA aneuploidy in the adenoma. Increased expression of the tumor suppresser gene, p53, and also of cellular proliferation markers (proliferating cell nuclear antigen and MIB-1) were detected in the villous adenoma and in the dysplastic regions of the flat metaplastic mucosa. These findings provide insight into the biology of intestinal metaplasia and also lend support to the theory of the chronic irritation-metaplasia-dysplasia-carcinoma sequence.     

A HISTOPATHOLOGICAL STUDY OF DIFFUSE HYPERPLASIA OF GASTRIC ARGYROPHIL CELLS

The present study includes a histopathological and immunohistochemical study of 4 cases of diffuse hyperplasia of gastric argyrophil cells. The mode of proliferation of these cells and the production of hormone by these cells have been documented. The distribution of microacinar nests composed of argyrophil cells was thought to be related to chronic gastritis in which there are atrophy of mucosa and intestinal metaplasia. In the case in which these nests were found only in the corpus ventriculi, there was intestinal metaplasia throughout the stomach. On the other hand, in the case in which these nests appeared only in the pyloric area, atrophy of the mucosa with mild intestinal metaplasia was observed only in the pyloric area. The microacinar nests composed of argyrophil cells were distributed in the deep mucosa at the basal portion of the glands in the area with intestinal metaplasia. Serial sections revealed a sprout composed of argyrophil cells budding from the gland with intestinal metaplastic changes. The sprout buds out from the growth zone of glands with Intestinal metaplasia and then becomes isolated and gives rise to reactive hyperplasia. The peptide hormone contained in these cells differs according to the mucosal environments. Cells containing gastrin were observed in the pyloric area, but not in the corpus ventriculi where there was marked intestinal metaplasia. The cells in this area were assumed to contain other hormones.