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Inhibitory effect of prolonged administration of tetragastrin on experimentally induced intestinal metaplasia in Wistar rats.

The effect of tetragastrin on the induction of intestinal metaplasia by intragastric administration of 5% NaOH solution was investigated in Wistar rats. The prolonged administration of tetragastrin in depot form from 1 week after NaOH treatment resulted in a significant increase in basal gastric acid secretion and a significant reduction in the incidence and number of intestinal metaplasia in experiment week 35. A histologic examination showed goblet cell metaplasia and intestinal metaplasia without Paneth cells in rats treated only with olive oil. Only goblet cell metaplasia was found in rats treated with tetragastrin. These results show that the prolonged administration of tetragastrin to rats after NaOH treatment increases gastric acid secretion and suppresses the induction of intestinal metaplasia.

Animals↗

Intestinal metaplasia of the stomach. A status report.

Intestinal metaplasia in the stomach increases the risk of gastric cancer, and the increased risk is proportional to the extent of the metaplasia. This risk could be generated by one or more mechanisms: (1) the metaplastic tissue is an early step in a multistep induction process; (2) the metaplastic tissue is an epigenetic change that raises the pH of gastric juice by replacing oxyntic mucosa, favoring the growth of a bacteria capable of generating endogenous mutagens; and/or (3) the metaplasia is only a marker for chronic gastritis due to H. pylori infection or pernicious anemia. With the last mechanism, the inflammatory response favors intramural mutagenesis that might result in metaplasia or neoplasia as independent events. Finding gene rearrangements common to both metaplastic and neoplastic tissue may establish a direct link between them, but too few have been identified to account for the large number of stomach cancers that develop in high risk populations. Histochemical and immunochemical stains that identify enzymes or mucosubstances may suggest that metaplastic epithelial cells resemble small or large intestinal cells, but they are distinctly different from both. Moreover, these stains do not indicate whether a given cytologic change is genetic or epigenetic; therefore, they cannot be used to define the relationship between metaplasia and neoplasia. It is unnecessary for practicing physicians to await resolution of this question. It can be assumed that any person with extensive metaplasia is at high risk for gastric cancer and should be subject to periodic screening. The extent of the metaplastic process is probably more important than the metaplastic subtype.

Animals↗

Transitional cell metaplasia of the uterine cervix is related to human papillomavirus: molecular analysis in seven patients with cytohistologic correlation.

BACKGROUND: Transitional cell metaplasia of the uterine cervix is an under-recognized entity in cervical pathology. The underlying etiology and biologic significance remains uncertain. The thin-layer cytology findings and association with human papillomavirus (HPV) have not been studied thoroughly. METHODS: The authors retrospectively reviewed the clinical findings, thin-layer cytology and histologic features of pure transitional cell metaplasia of the uterine cervix occurring in seven perimenopausal or postmenopausal Chinese women at Pamela Youde Nethersole Eastern Hospital, Hong Kong, during the period from January, 1998 to April, 2001. Molecular techniques for HPV screening and genotyping using polymerase chain reaction and restriction fragment length polymorphism analysis were employed in the thin-layer cytology specimens and paraffin block material. RESULTS: In all seven patients, transitional cell metaplasia represented an incidental histologic finding. It occurred in the ectocervix, transformation zone, endocervix, or vagina. Histologically, it resembled urothelium of the urinary bladder and was comprised of multilayers of mitotically inactive, immature epithelial cells with vertically aligned oval nuclei, fine chromatin, indistinct nucleoli, and conspicuous longitudinal nuclear grooves. The superficial cells were oriented more horizontally and contained pale-staining cytoplasm similar to umbrella cells. Features consistent with transitional cell metaplasia were identified in two of seven preoperative thin-layer preparations. Cytologically, the affected parabasal cells recapitulated the features that were seen in histologic sections. In addition to the bland nuclear morphology and longitudinal nuclear grooves, the cell borders appeared distinct, and the appearance of a perinuclear cytoplasmic halo was common. Sometimes, the metaplastic cells assumed a spindle shape and appeared as cohesive, streaming cell clusters. Molecular study successfully demonstrated the presence of HPV in all seven patients, mostly in the liquid-based cytology samples. In general, the viral DNA load was relatively low; and, for samples in which HPV genotyping was feasible, HPV type 58 was the prevalent genotype. CONCLUSIONS: The current study demonstrates that transitional cell metaplasia of the uterine cervix is related to HPV. It also carries a distinctive cytologic appearance in thin-layer preparations. Based on the limited follow-up data from a small number of reported patients, transitional cell metaplasia seems to run an indolent clinical course. However, its peculiar association with HPV and its possible correlation, both morphologic and histogenetic, with cervical intraepithelial neoplasia need further investigation.

Aged↗

Histochemical studies of mucosubstances in metaplastic epithelium of the stomach, with special reference to the development of intestinal metaplasia.

Processes in the development of intestinal metaplasia of the stomach were investigated from the morphological and histochemical approaches using light and electron microscopic techniques. The specimens taken from 38 gastric carcinomas and 15 gastric and/or duodenal ulcers were subjected to this study. Morphological appearances of the intestinal metaplasia observed in routine examination with hematoxylin and eosin staining was able to divided into complete and incomplete metaplasia by the light and electron microscope histochemical stainings of the mucosubstances. The columnar cells at the area of the incomplete metaplasia had both the properties of the intestinal epithelia and the gastric foveolar epithelia. The incomplete as well as the complete metaplasia arose from the generative cells at the isthmus of the gland. The generative cells, however, sometimes gradually transformed to produce the complete metaplastic cells. The two processes of the development of the intestinal metaplasia were proposed and discussed.

Duodenal Ulcer↗

Cytochemical localization of alkaline phosphatase in intestinal metaplasia of the human stomach.

Alkaline phosphatase in the brush border of areas of intestinal metaplasia of human stomach was studied cytochemically. All absorptive cells in the upper part of the villi of the duodenum had strong alkaline phosphatase activity but, in areas of intestinal metaplasia, the metaplastic glands consisted of alkaline phosphatase-positive and negative absorptive cells. Alkaline phosphatase activity was found in tall dense microvilli of absorptive cells in areas of intestinal metaplasia and in the duodenum. However, in some areas of metaplastic epithelium the activity was very weak in some tall dense microvilli of absorptive cells but strong in those of neighbouring absorptive cells. No alkaline phosphatase activity was found in short sparse microvilli of absorptive cells in areas of intestinal metaplasia. The difference in alkaline phosphatase activity in microvilli of different cells in areas of intestinal metaplasia, which is not seen in the duodenum, indicates abnormal morphological and enzymatic differentiation intestinal metaplasia.

Alkaline Phosphatase↗

Effect of cigarette smoking on extent of acid-secreting area and intestinal metaplasia in the stomach.

The association of cigarette smoking and other variables with the extent of the acid-secreting area and intestinal metaplasia were investigated by multivariate analysis. Studies were made by the endoscopic Congo red-methylene blue test developed in our hospital. In this test, acid-secreting areas and areas of intestinal metaplasia could be identified as discolored areas and areas staining blue with methylene blue, respectively. In multivariate analysis, the following variables were associated with a reduction in the size of the acid-secreting area in decreasing order of importance: the smoking index and age. The following factors had little or no influence on the size of the acid-secreting area: sex, and the consumption of aspirin and nonsteroidal, nonsalicylate, antiinflammatory drugs (NSNSAIDs). In general, in patients with a high smoking index, the acid-secreting area was small. Smoking had an influence in both younger and older patients and had more influence in females than in males. Multivariate analysis also shows that the following factors were associated with an increase in the area of intestinal metaplasia in decreasing order of importance: the extent of the acid-secreting area, age, and the smoking index. The following factors had little or no influence on the area of intestinal metaplasia: the consumption of aspirin and NSNSAIDs and sex. In general, in patients with little or no acid-secreting area, the area of intestinal metaplasia was extensive. These findings indicate that smoking is associated with reduction in the size of the acid-secreting area and so in development of intestinal metaplasia.

Adult↗

The relationship between gastroesophageal reflux, intestinal metaplasia and adenocarcinoma of the esophagus.

Currently available data indicate a clear and probably causal relationship between long-lasting gastroesophageal reflux disease, the development of long segments with specialized intestinal metaplasia in the distal esophagus and subsequent progression to adenocarcinoma. To a lesser degree, this also appears to be the case for short segments of specialized intestinal metaplasia in the distal esophagus. In contrast, epidemiological data and classic parameters for the diagnosis of gastroesophageal reflux disease do not currently support a causal role of gastroesophageal reflux in the pathogenesis of specialized intestinal metaplasia at the gastric cardia. Despite its high prevalence and malignant potential, many questions about the prevention and management of intestinal metaplasia in the distal esophagus remain unsolved. In patients with chronic gastroesophageal reflux, current modes of medical therapy do not appear to prevent the development of intestinal metaplasia, while effective anti-reflux surgery seems to have a protective effect. Formal studies with adequate follow-up are, however, still lacking. Neither acid-suppression therapy nor anti-reflux surgery, with or without mucosal ablation, can reliably prevent the malignant degeneration of established intestinal metaplasia of the esophagus. Close endoscopic surveillance with extensive biopsies, therefore, remains mandatory in such patients, irrespective of the treatment modality.

Adenocarcinoma↗

Basal cell pseudopodia and the degree of maturation of squamous metaplasia of the uterine cervix: a morphometric quantification.

Application of morphometry to discrete processes was used to study the stroma-epithelial interface in benign proliferative processes of human cervical epithelium. This method with the use of two-dimensional transmission electron micrographs quantifies the number of pseudopodia and other features of the basal cell. The number of pseudopodia per basal cell and other basal cell features in reserve cell hyperplasia, immature squamous metaplasia, intermediate squamous metaplasia, and mature squamous metaplasia of human uterine cervix were measured. The number of pseudopodia per basal cell in reserve cell hyperplasia was 6.77 +/- 1.46 and comparable to that previously observed in advanced cervical intraepithelial neoplasia. The number of pseudopodia per basal cell in the three subtypes of squamous metaplasia ranged from 10.67 to 19.12 and was approximately half that observed in normal control epithelium. The concept of a continuum existing from reserve cell hyperplasia through immature squamous metaplasia to mature squamous metaplasia is supported with the demonstration of increasing numbers of pseudopodia per basal cell with cellular maturation.

Cell Membrane↗

Stimulation by Bt2cAMP of epidermal mucous metaplasia in retinol-pretreated chick embryonic cultured skin, and its inhibition by herbimycin A, an inhibitor for protein-tyrosine kinase.

Epidermal mucous metaplasia of cultured 13-day-old chick embryonic tarsometatarsal skin can be induced by culture in medium containing retinol (20 microM) for only 8-24 h and then in a chemically defined medium without vitamins or serum for 6 days. In the induction of mucous metaplasia, retinol primarily affects the dermal cells and a signal(s) induced in the dermis by excess retinol alters epidermal differentiation toward secretory epithelium. In this work we found that Bt2cAMP (2 mM) stimulated mucous metaplasia severalfold when added to retinol-pretreated skin but inhibited epidermal mucous metaplasia when added together with retinol. Forskolin (100 microM), an activator of adenylate cyclase, also stimulated mucous metaplasia when added to retinol-pretreated skin. On the other hand, transduction in the epidermal cells of a signal(s) induced in dermal cells by excess retinol was inhibited by herbimycin A (500 ng/ml), an inhibitor of protein-tyrosine kinases, and TPA (0.1 microM), an activator of protein kinase C. Hence these findings indicated that cAMP stimulated signal-induced mucous metaplasia, and that transduction of the signal(s) in the epidermal cells required protein-tyrosine kinase and was inhibited by protein kinase C.

Adenylyl Cyclases↗

Histopathological differences in the development of small intestinal metaplasia between antrum and body of stomach.

This study used mucin immunohistochemistry to investigate differences in the properties of intestinal metaplasia between the antrum and body of the stomach in 28 resected specimens. Intestinal metaplasia was classified as: (1) small intestinal metaplasia (SIM) with a tubule, including CD10-positive brush border on a background of MUC5AC-/ HGM-negative cells; or (2) goblet cell metaplasia (GCM) with MUC2-positive and CD10-negative cells. In the antrum, frequencies of SIM and GCM were nearly equal irrespective of metaplasia grade. Frequency and length of remnant pyloric gland for SIM were significantly greater in the antrum than in the body. In the proliferative zone, there existed a lower level in SIM than in non-intestinalized tubules. These findings suggest that the proliferative zone shifts from the neck zone toward the bottom of the tubule during the SIM process in the antrum. In the body, however, the grade of SIM grade was significantly higher than that of GCM. The proliferative zone was located higher in the fundic gland, pseudopyloric gland and SIM, in that order. Almost all remnant pyloric glands for SIM were negative for pepsinogen I. These facts indicate that SIM in the body originates in a proliferative zone that shifted downward to an area near the bottom of the tubule, with atrophic pyloric glands originating from pseudopyloric gland metaplasia.

Aged↗

Inflammation and intestinal metaplasia of the gastric cardia: the role of gastroesophageal reflux and H. pylori infection.

BACKGROUND & AIMS: Whether inflammation of the cardia indicates gastroesophageal reflux disease (GERD) and/or is a manifestation of pangastritis caused by Helicobacter pylori infection is unknown. The aim of this study was to evaluate the relationship between cardia inflammation, H. pylori infection, and cardia intestinal metaplasia in patients with and without GERD. METHODS: Patients with GERD were compared with controls undergoing endoscopy for a variety of other conditions. Endoscopic biopsy specimens from the distal esophagus and cardia, fundus, and antrum were evaluated for inflammation, H. pylori infection, and intestinal metaplasia. RESULTS: Neither the prevalence of H. pylori infection (controls, 48%; GERD, 41%) nor cardia inflammation (controls, 41%; GERD, 40%) differed between groups. All 11 controls and 22 of 23 patients with GERD (96%) and cardia inflammation had H. pylori infection. Esophagitis was more common among GERD patients (33%) than controls (7%; P = 0.01). Cardia intestinal metaplasia was more common among controls (22%) than GERD patients (3%; P = 0.01); all had cardia inflammation, 7 had H. pylori infection, and 6 had metaplasia elsewhere in the stomach. CONCLUSIONS: The prevalence of cardia inflammation is similar in patients with and without GERD and is associated with H. pylori infection (P < 0.001). Cardia intestinal metaplasia is associated with H. pylori-related cardia inflammation (P = 0.01) and intestinal metaplasia elsewhere in the stomach, indicating that it is distinct from Barrett's esophagus.

Adult↗

Gastric metaplasia of the duodenum: identification by an endoscopic selective mucosal staining technique.

BACKGROUND: To understand the pathophysiology of duodenal ulcer disease, it is important to identify and quantitate gastric metaplasia of the duodenum. Methylene blue dye is absorbed well by intestinal mucosa, but not by gastric mucosa. Our aim was to validate a methylene blue staining technique for measurement of gastric metaplasia in the duodenum. METHODS: Eight subjects with chronic duodenal ulcer disease and seven subjects with other upper intestinal disorders underwent duodenal methylene blue staining after application of a mucolytic agent. Biopsy specimens were obtained from blue-stained and pale unstained areas and assessed for gastric metaplasia histologically. RESULTS: Pink or pale unstained duodenal areas had more gastric surface cell metaplasia than blue-stained areas. Unstained duodenum was also more likely to have extensive (more than 25% of the biopsy specimens) gastric metaplasia (60%) than blue-stained areas (9%). Subjects with duodenal ulcer disease had more unstained mucosa than controls. CONCLUSION: Methylene blue staining of the duodenum is useful to identify and quantitate gastric metaplasia.

Aged↗

Value of cytology in detecting intestinal metaplasia and associated dysplasia at the gastroesophageal junction.

Tissue sampling is essential for detecting intestinal metaplasia in the distal esophagus (Barrett's esophagus), because symptoms and endoscopy are not reliable in making this diagnosis. The utility of cytology in this process is unknown. All adult patients having elective upper gastrointestinal endoscopy over a 6-month period were invited to participate in a prospective study whose aim was to determine the prevalence of intestinal metaplasia in the distal esophagus in an adult population with diverse upper gastrointestinal symptoms. Clinical data and endoscopic findings were recorded. Brush cytology and biopsy specimens were obtained from both sides of the apparent squamocolumnar junction. The cytology specimens were processed routinely, stained with the Papanicolaou technique, and reviewed blinded to the clinical information and the histological findings in the corresponding biopsy specimens. One hundred fifty-five patients (81 women, 74 men; 137 whites, 11 blacks, 7 others; mean age, 52 years) were included. Glandular epithelium/cells were present on both histology and cytology in 147 specimens. Thirty-two patients (22%) showed intestinal metaplasia on histology. Of the cytology specimens from these 32 patients, 6 contained definite goblet cells (19%), 7 probable goblet cells, and 19 no goblet cells. Goblet cells and probable goblet cells were observed on cytology in 7 and 11 additional specimens, respectively. One was from a patient known to have intestinal metaplasia in the esophagus. Follow-up endoscopy with biopsy was performed in two of these latter 18 patients and did not show intestinal metaplasia. One case of high-grade dysplasia, two of low-grade dysplasia, and three indefinite for dysplasia were diagnosed on histology. All three cases of dysplasia were also identified on cytology. The three indefinite cases on histology were considered reactive in two and unremarkable in one on cytology. Low-grade dysplasia was diagnosed on cytology alone on two cases. Follow-up endoscopy with biopsy was performed in one patient, and low-grade dysplasia was found. Cytology using the Papanicolaou stain is not as sensitive and specific as histology for detecting intestinal metaplasia in the distal esophagus. However, it may be at least as useful as tissue sampling in detecting dysplasia.

Adult↗

Cytokeratin subsets can reliably distinguish Barrett's esophagus from intestinal metaplasia of the stomach.

The histological distinction between intestinal metaplasia involving the distal esophagus (Barrett's esophagus [BE]) and intestinal metaplasia of the stomach has important clinical implications and can be difficult even with the use of histochemical mucin stains. Cytokeratin (CK) 7 and 20 are cytoplasmic structural proteins that show restricted expression in normal and malignant epithelia of the gastrointestinal tract. The aim of this study was to determine the use of CK7 and 20 expression in the histological distinction of BE from gastric intestinal metaplasia. CK7 and 20 immunostaining was performed on randomly selected surgical resection (n = 31) and biopsy specimens (n = 34) from patients with long-segment BE and gastric resection specimens (n = 11) and gastric cardia biopsy specimens (n = 13) in patients with histological evidence of intestinal metaplasia. A unique pattern of immunoreactivity designated the Barrett's CK7/20 pattern showed superficial CK20 staining and strong CK7 staining of both superficial and deep glands in 29 of 31 (94%) esophageal resection specimens and 34 of 34 (100%) esophageal biopsy specimens form patients with long-segment BE. A Barrett's CK7/20 pattern was not observed in gastric cardia biopsy specimens (n = 13) or gastric resection specimens (n = 11) in patients with histological evidence of intestinal metaplasia. The sensitivity, specificity, and positive predictive value of a Barrett's CK7/20 pattern for a diagnosis of long-segment BE was 97%, 100%, and 100%, respectively. CK7 and 20 reactivity patterns can reliably identify the location of intestinal metaplasia in the esophagus and stomach using histological material from both routine endoscopic biopsy and surgical resection specimens.

Barrett Esophagus↗

Intestinal metaplasia of the gastric mucosa in autopsies of Chilean adults.

The frequency and characteristics of intestinal metaplasia of the stomach were studied in autopsy material of 68 Chilean adults, with ages ranging from 30 to 79 years. Metaplasia was found in 76.5% of the cases, which is in agreement with the high frequency of metaplasia reported from other geographic areas of high incidence for gastric cancer. Of those stomachs with metaplasia, 90.4% had involvement of the lesser curvature, 88.5% of the antral region, and only 3.8% did not show the condition in those two areas. The metaplasia extended to less than half of the length of the mucosa in 85.6% of the sections with this change, showing that it is mainly a patchy and multifocal condition. In subjects older than 50 years, intestinal metaplasia was more extended and severe, and involved with a relative higher frequency the greater curvature and both anterior and posterior walls of the stomach.

Adult↗

Morphology and histogenesis of squamous cell metaplasia of the rat lung after chronic exposure to a pyrolized pitch condensate and/or carbon black, or to combinations of pyrolized pitch condensate, carbon black and irritant gases.

Female Wistar rats were exposed to different concentrations of a pyrolized pitch condensate and/or carbon black particles and/or a combination of irritant gases for 18 hours/day, 5 days/week for 10 months, followed by a clean air period of up to 20 months. Bronchiolo-alveolar hyperplasia and squamous metaplasia were important components of the resulting lesions. Squamous metaplasia and associated hyperplasia was investigated by routine histology, scanning and transmission electron microscopy, and by immunohistochemical detection of various cytokeratins (CKs). Intensely CK positive squamous metaplasia lacking a distinct stratum spinosum was distinguishable from squamous metaplasia with a distinct stratum spinosum that reacted weakly CK positive or CK negative. The CK positive type was histologically characterized by narrow intercellular spaces, the weakly CK positive or CK negative type had markedly enlarged intercellular spaces. Differentiated hyperplastic epithelium and the normal lung parenchyma reacted CK negative. In poorly differentiated hyperplasia of the alveolar type associated with squamous metaplasia scattered cells with characteristics of squamous differentiation were detected. Ultrastructurally these cells showed increased amounts of filament bundles and immunohistochemically a positive reaction with the CK antibody. These cells were regarded as precursor stages of squamous metaplasia of the lung periphery in rats.

Animals↗

Genetic instability in intestinal metaplasia is a frequent event leading to well-differentiated early adenocarcinoma of the stomach.

To understand the development of well-differentiated adenocarcinoma in the stomach, we examined genetic instability in 31 patients with stage Ia gastric cancer. Triplets of tissue specimens (normal/metaplasia/tumour) from 33 lesions were examined for microsatellite instability (MSI) and loss of heterozygosity (LOH), using nine microsatellite loci. Frameshift mutations in the transforming growth factor beta receptor type II (TGF-betaRII) (A)(10), Bcl-2-associated X protein (BAX) (G)(8), hMSH3 (A)(8) and hMSH6 (C)(8) genes were also studied. In this study, a high incidence of MSI (MSI-H) was defined as samples containing 30% or more MSI positive loci, and a low incidence of MSI (MSI-L) as samples which had less than 30% MSI. MSI-L was observed in 19 cancerous lesions (58%), and MSI-H in three (9%). Eleven intestinal metaplasia lesions (33%) showed MSI-L, but no metaplasia lesions exhibited MSI-H. Frameshift mutation was observed in only one cancerous lesion (3%) at the (A)(10) tract of TGF-betaRII. In contrast, LOH was observed in 24 cancerous lesions (73%), and in 15 (45%) of intestinal metaplasia lesions. Intriguingly, these alterations tend to be coincident between metaplasia and cancerous lesions in the same sets of specimens, and there was no case that showed alterations in metaplasia, but not in cancerous lesions. These findings suggest that metaplasia and well-differentiated adenocarcinoma in the stomach may have the same molecular backgrounds, and that these two lesions may be chronologically connected.

Adenocarcinoma↗

Prospective evaluation of intestinal metaplasia and dysplasia within the cardia of patients with Barrett's esophagus.

The prevalence of cardia versus noncardia gastric intestinal metaplasia in patients with Barrett's esophagus was assessed prospectively. Four-quadrant biopsies were obtained from the cardia from 119 consecutive patients with Barrett's esophagus and 64 control patients. Gastric surveillance biopsies were obtained in 108 of the Barrett's patients and 58 control patients. There was a significantly greater prevalence of cardia intestinal metaplasia in short-segment Barrett's (10.2%), but not traditional Barrett's (3.3%), compared to control patients (0%) (P = 0.009). Dysplastic changes were significantly more frequent in the metaplastic epithelium within the esophagus than in the cardia (P < 0.0001). A significantly greater prevalence of noncardia intestinal metaplasia compared to cardia intestinal metaplasia was found in each of the three groups of patients; however, the prevalence of noncardia intestinal metaplasia between short-segment, traditional, and control patients was not significantly different. Cardia intestinal metaplasia was an infrequent finding in patients with Barrett's esophagus and appears to develop independently from that in the remainder of the stomach.

Adenocarcinoma↗