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The effects of different MNNG (N-methyl-N'-nitro-N-nitrosoguanidine)-doses on the stomach and the upper small intestine of the rat. II. The frequency of intestinal metaplasia.

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was given to 3 groups of male Wistar rats in different doses of 25 micrograms/ml, 50 micrograms/ml and 100 micrograms/ml with their drinking water for 32 weeks. After 50 weeks the antrum region of the stomach was investigated by serial sections. All animals showed tubules with metaplastic intestinal epithelium. The different values of metaplastic glands in the antrum region of the stomach were 187 (25 micrograms MNNG), 76 (50 micrograms MNNG) and 51 (100 micrograms MNNG). They indicate an inverse relationship of the frequency of intestinal metaplasia and the MNNG dose. As opposed to this dose-response pattern, cytotoxic alterations, regenerative hyperplastic lesions and tumours of the stomach are more frequent after medium of high MNNG doses. It is therefore suggested that the induction of intestinal metaplasia is a specific effect of the carcinogen mainly in the low dose range.

Animals↗

Gastritis, intestinal metaplasia and dysplasia versus benign ulcer in stomach and duodenum and gastric carcinoma -- a histotopographical study.

In histological examination of gastrectomy specimens from patients with duodenal ulcer, gastric ulcer, and early and advanced cancer, both chronic atrophic gastritis and intestinal metaplasia were identified in 54% of the cases with duodenal ulcer. At 90 to 100%, respectively, these mucosal changes were approximately twice as frequent with gastric ulcer and early and advanced gastric cancer. Mild dysplasia occurred in 54% of the cases with duodenal ulcer; occurred somewhat more frequently with gastric ulcer, in 75% of the cases; and in almost all cases with early and advanced gastric cancer, at 90% and 100%, respectively. Whereas 27% of the cases with duodenal ulcer, 62% with gastric ulcer, and 90% and 95% of the respective cases with early and advanced gastric cancer showed moderate dysplasia, only severe dysplasia in early gastric cancer (40%) and advanced gastric (81%) was clearly more frequent in comparison to duodenal ulcer (9%) and gastric ulcer (12%). In the cases with duodenal ulcer chronic atrophic gastritis and intestinal metaplasia were limited mostly to the antrum; with gastric ulcer and cancerous stomach disorders, they also occurred in other stomach sections. Mild and moderate dysplasia conformed to the same distribution pattern. Severe dysplasia, which was only detected in two ulcer cases, was not only substantially more frequent in cases with early and advanced gastric cancer, but also showed a clear topographic relationship to cancer localization in the stomach.

Aged↗

Induction of atypical squamous metaplasia with benzo[a]pyrene in cultured hamster tracheas.

Areas of hyperplasia were produced in hamster tracheal epithelium maintained in vitro by exposure to a suspension of benzo[a]pyrene (BP) in gelatin. Typical and atypical epiodermoid metaplasia were seen by 2 weeks. In atypical areas, cell nuclei were enlarged with prominent nucleoli, the cytoplasm contained dense bundles of tonofilaments and the cells were joined by numerous desmosomes. The peak response to the carcinogen was reached 4 weeks after the application of BP and consisted of extensive atypical epidermoid metaplasia. Tracheas treated with gelatin alone maintained a columnar epithelium for 6 weeks of culture. The characteristics of the metaplastic changes in vitro are essentially identical to those described after exposure of the hamster tracheobronchial epithelium to benzo[a]pyrene-ferric oxide in vivo.

Animals↗

Pyloric gland type adenoma of the gallbladder with squamoid spindle cell metaplasia.

This study documents a pyloric gland type adenoma of the gallbladder with prominent spindle cell metaplasia arising in a 61 year-old woman. A pedunculated polyp, 1.5 x 1.0 x 1.0 cm, was histologically diagnosed as a tubular adenoma. Most glandular structures showed positivity for a monoclonal antibody M2 (2B5) which indicates a differentiation to pylotic gland type. The spindle cell component displayed no apparent epithelial structures but stained mostly positive for pancytokeratin and cytokeratin (CK) 18, and focally for CK 5 + 6, CKs 7 and 19, whereas CKs 8, 13, 20, and non-epithelial markers could not be demonstrated. This suggests that the spindle cells were immature epithelial cells differentiating towards squamous and/or glandular cells. Even in spindle cell areas, the nuclear atypia was mild, and proliferating cells positive for MIB-1 (Ki-67) antigen were infrequently seen. This unique phenomenon, of which only three cases have been previously reported, is considered to represent benign squamoid spindle cell metaplasia.

Adenoma↗

Tumour-simulating squamous cell metaplasia (SCM) in necrotic areas of salivary gland tumours.

Squamous cell metaplasia (SCM) adjacent to necrotic areas of salivary gland tumours must be distinguished from other types of SCM (focal SCM in the excretory ducts of salivary glands; necrotizing sialometaplasia; focal SCM within salivary gland tumours) in respect to the tissue structure. Based on the high cellular proliferation, arcade- or cord-like pseudoneoplastic SCM develops with stellate extension in the surrounding tissue and focal inclusion of goblet cell metaplasia. This proliferative SCM resembles the cellular demarcation of radicular dental cysts. In the Salivary Gland Register 8 cases of tumor-simulating SCM could be analysed which clinically and morphologically were suspect of squamous cell or mucoepidermoid carcinoma. Five cases were localized in the parotid gland, 2 cases in the submandibular gland and 1 case in the palatinal glands. Tumour-simulating SCM was developed in pleomorphic adenomas (5 cases) and in multifocal adenomatous oncocytic hyperplasia (3 cases).

Adenoma, Pleomorphic↗

Chondro-osseous metaplasia, bone density and patellar cartilage proteoglycan content in the osteoarthritis of STR/ORT mice.

The evolution of osteoarthritis (OA) was compared in male and female STR/ORT mice and in male CBA mice with particular emphasis on the changes in para-articular structures which occur before the classical degenerative phenomena in the articular cartilage of the knee. In male STR but not female STR mice or male CBA mice, chondro-osseous metaplasia was found in the tendinous structures which surround the joint and in the major ligamentous entheses such as the patellar ligament. This change was detectable from the age of three months. By contrast, changes in the articular surfaces of the knee were never detected before four months while the total patellar proteoglycan content in male STR animals increased from three months. Line density profile measurements on radiographs of the knees revealed that changes in the bone density of the sub-chondral zone of the articular surfaces only increased in affected animals after the development of severe OA changes in the joint. It is suggested that the model of OA which develops in male STR/ORT mice is secondary to soft tissue changes, particularly chondro-osseous metaplasia in para-articular structures.

Achilles Tendon↗

Spasmolytic polypeptide-expressing metaplasia (SPEM) associated with gastric cancer in Iceland.

Recent studies have described a spasmolytic polypeptide-expressing metaplastic cell lineage (SPEM) in the gastric fundic mucosa associated with both chronic H. pylori infection and gastric adenocarcinoma. We investigated the association of SPEM both with early gastric adenocarcinoma and in biopsies taken from patients prior to diagnosis of cancer. Two cohorts were examined. First, gastric resections from 29 patients with early gastric cancer were examined. Second, biopsies taken from 18 patients prior to the diagnosis of gastric cancer were compared with their respective resection specimens as well as with control biopsies from a cohort of 19 patients diagnosed with gastritis without subsequent development of cancer. The presence of SPEM and intestinal metaplasia (IM) adjacent to and distant from the cancer was compared and spasmolytic polypeptide (SP) immunostaining within dysplastic/cancerous cells was identified. SPEM was present adjacent to cancer in all early cancer cases where the tumor was located in the body or at the body/antrum junction, and was present in the body mucosa distant from the cancer in 76% of cases. Intestinal metaplasia was found adjacent to the tumor in 76% of cases and in body sections in 52% of resections. SP immunostaining was noted within cancer cells in 62% of tumors, and within dysplastic cells in 76% of resections where dysplasia was present. SPEM was present in 82% of the biopsies obtained prior to the diagnosis of cancer, compared with only 37% in the gastritis cohort. IM was present in only 57% of biopsies. In conclusion, SPEM is strongly associated with early gastric cancers and is observed in gastric biopsies prior to the development of cancer. In addition, early gastric cancers demonstrated a high incidence of SP expression. These results suggest that SPEM merits consideration as an important pre-neoplastic gastric lesion.

Adenocarcinoma↗

Gastric cardia intestinal metaplasia: biopsy follow-up of 85 patients.

BACKGROUND: Gastric cardia intestinal metaplasia (CIM), denoted by goblet cells is common. The frequency of persistent CIM is unknown. METHODS: 85 patients with CIM and follow-up endoscopies were prospectively identified during the time period of 10/6/94-12/21/97. The presence of goblet cells was the defining feature of CIM, other metaplastic cell types were not evaluated. AU 85 patients initially had biopsies that straddled the squamocolumnar junction (SCJ) showed CIM, an otherwise normal proximal stomach, lower esophagus, and squamocolumnar junction. The SCJ lay within the 2 cm of mucosa immediately proximal to the uppermost gastric fold and overlaid the junction of the tubular esophagus and the saccular dilatation of the stomach in all patients. The patients underwent endoscopy for many reasons. They were randomly identified based on the absence of a hiatal hernia and the presence of CIM. RESULTS: Ten of the 85 patients had CIM on repeat biopsy. Among patients with no CIM in the first repeat endoscopy, the degree of cardia inflammation decreased between the initial and first repeat endoscopy, whereas there was no change in the amount of inflammation among patients who had CIM in the first repeat endoscopy. The changes in mean inflammation score was significantly different between the two groups (P = .024). Twenty-two patients underwent a second repeat endoscopy and five had a third repeat endoscopy. Including all follow-up biopsies, six of the 85 patients (7%) had CIM. Four patients who did not have CIM on initial repeat endoscopy had CIM on their second repeat endoscopy, probably reflecting sampling issues. None of the biopsies had dysplasia. CONCLUSIONS: Cardia inflammation is a stimulus for cardia intestinal metaplasia, and a reduction in inflammation may allow the metaplastic mucosa to revert to normal.

Adult↗

Utilization of cytokeratins 7 and 20 does not differentiate between Barrett's esophagus and gastric cardiac intestinal metaplasia.

Long segment Barrett's esophagus (LSBE) is a recognized risk factor for the development of esophageal dysplasia and carcinoma. However, the risk of dysplasia arising within intestinal metaplasia below a normal-appearing Z-line (i.e., in native cardiac mucosa) is unknown. Regular endoscopic surveillance is required in patients with LSBE and is frequently performed in short segment BE (SSBE), but the need for surveillance in cardiac intestinal metaplasia (CIM) is unknown. Unfortunately IM arising in SSBE and immediately below a normal Z-line can be indistinguishable histologically on H&E stains. Previous reports suggest that the appearance of superficial CK20 immunohistochemical staining accompanied by intermediate and deep CK7 positivity is characteristic of BE, whereas CIM specimens show superficial and deep CK20 positivity and weak to absent CK7 staining. We hypothesized that CK7/20 immunostaining of metaplastic biopsies from the esophagus and stomach would allow complete differentiation of these two entities when correlated with the endoscopic appearance. We undertook an evaluation of gastric and esophageal specimens to determine whether these characteristics were valid. Cases of both BE (long and short segment) and CIM, as well as cases of gastric cardiac biopsies lacking IM, were evaluated for CK7 and CK20 and correlated with the endoscopic appearance. We observed that, although the "Barrett's" pattern of CK7/20 was maintained for many cases of BE, the sensitivity and specificity were only moderate (65% and 56%, respectively). The pattern of staining for the CIM was variable, i.e., some cases showed a CK7/20 Barrett's pattern despite a normal appearance at endoscopy. The differences between this and previous studies may be due to inaccurate visualization of SSBE on endoscopy, the development of very early SSBE cases, inter-observer variability, fixation differences, or antibody differences. Whatever the cause of the differences, if results between laboratories are not comparable, CK7/20 immunostaining cannot be used to differentiate reliably between IM present in biopsy specimens taken from above versus below the Z-line. However, further studies should be performed to determine whether the presence or absence of a Barrett's pattern of CK7/20 immunostaining could predict progression to dysplasia or carcinoma.

Barrett Esophagus↗

Apoptotic activity is increased in parallel with the metaplasia-dysplasia-carcinoma sequence of the bronchial epithelium.

A high level of apoptotic activity and an independence of apoptosis from the expression of p53 and bcl-2 have been observed in non-small-cell lung carcinoma. We examined 44 samples of normal, metaplastic and premalignant (i.e. mild, moderate and severe dysplasias and carcinoma in situ) bronchial epithelia to evaluate whether differences in the apoptotic activity could already be seen in the stages preceding squamous cell carcinoma of the lung (SQCLC). Apoptotic cells and bodies were visualized by 3' end labelling. The expression of p53 and members of the bcl-2 gene family, such as bcl-2, bax and mcl-1, were determined immunohistochemically with specific antibodies. The relative number of apoptotic cells and bodies [apoptotic index (AI%)] was already increased threefold as the normal bronchial epithelium changed to squamous metaplasia, and the AIs of the dysplastic lesions were about four times higher than those of the normal epithelium. Apoptosis was significantly associated with cell proliferation, as determined by proliferating cell nuclear antigen (PCNA) immunohistochemistry. However, the extent of apoptosis did not correlate with the expression of p53, bcl-2, bax and mcl-1. We conclude that, in the metaplasia-dysplasia-carcinoma sequence in the lung, the elevation of the AI% is an early event associated with cell proliferation activity, but is independent of the expression of p53, bcl-2, mcl-1 and bax.

Apoptosis↗

Altered transcription of the stem cell leukemia gene in myelofibrosis with myeloid metaplasia.

An increased number of circulating CD34+ hematopoietic progenitors with a prominent proliferation of the megakaryocytic (MK) population are the hallmarks of the myeloproliferation in myelofibrosis with myeloid metaplasia (MMM). Analyzing the potential contribution of the stem cell leukemia (SCL) gene in MMM myeloproliferation was doubly interesting for SCL is expressed both in primitive-uncommitted progenitor cells and erythroid/MK cells, its transcription differentially initiating from promoter 1b and 1a, respectively. Our results show that: (i) the expression of SCL transcript is increased in peripheral blood mononuclear cells (PBMCs) from patients; (ii) SCL gene transcription is altered in MMM CD34+ progenitor cells sorted into CD34+CD41+ and CD34+CD41- subpopulations. Actually, in patients, SCL transcription initiated at promoter 1b is restricted to primitive CD34+CD41- progenitor cells, while it is detectable in both cell subsets from healthy subjects; (iii) the full-length isoform of SCL protein is present in patients' CD34+ cells and in PBMC; in the latter the SCL-expressing cells mainly belong to the MK lineage in which its sublocalization is both nuclear and cytoplasmic, which contrasts with the sole nuclear staining observed in normal MK cells. Our demonstration of altered expression and transcription of SCL in patients' hematopoietic cells emphasizes the possible contribution of this regulatory nuclear factor to the hematopoietic dysregulation, which is a feature of myelofibrosis with myeloid metaplasia.

Antigens, CD↗

Fatty acid synthase is highly expressed in carcinoma, adenoma and in regenerative epithelium and intestinal metaplasia of the stomach.

AIMS: To investigate the relation of fatty acid synthase (FAS) expression to the clinicopathological characteristics of gastric cancers and gastric tumorigenesis. METHODS AND RESULTS: FAS expression was examined immunohistochemically in 626 gastric cancers, 51 gastric adenomas, and non-neoplastic epithelium contiguous with cancer tissue including normal foveolae, intestinal metaplasia, regenerative epithelium, and gastric glands. FAS expression was found in more than 70% of gastric cancers. Interestingly, it occurred preferentially in differentiated carcinomas, male cases, and in patients over 51 years old. Although previous reports showed that FAS expression is closely related to cancer progression, in gastric cancers FAS expression had no relationship with prognosis, cancer progression as indicated by depth of invasion, venous and lymphatic permeation, and distant metastasis. Gastric tubular adenoma and intestinal metaplasia, which are thought to be associated with well-differentiated gastric carcinomas, showed a frequency of FAS expression similar to that of differentiated carcinomas; however, normal foveolae and gastric glands showed no or less FAS expression. CONCLUSIONS: FAS expression occurs at the early stage of tumorigenesis and plays important roles in the formation of precancerous foci rather than in the progression of carcinoma of the stomach.

Adenoma↗

Enhanced expression of decay-accelerating factor and CD59/homologous restriction factor 20 in intestinal metaplasia, gastric adenomas and intestinal-type gastric carcinomas but not in diffuse-type carcinomas.

AIMS: Variable expression of the complement regulatory proteins, decay-accelerating factor, CD59/homologous restriction factor 20 (HRF20) and membrane cofactor protein has been shown in human gastrointestinal malignancies, but their expression in gastric cancer has not been fully described. Thus, we immunohistochemically defined the distribution of these proteins in human normal gastric mucosa, intestinal metaplasia, adenomas and gastric cancers. METHODS AND RESULTS: Gastric tissues were obtained by endoscopic biopsy or surgical resection and stained with mouse monoclonal antibodies to decay-accelerating factor, CD59/HRF20, and membrane cofactor protein. In the normal gastric mucosa, membrane cofactor protein was diffusely stained on the basolateral surface of epithelial cells, whereas the expression of decay-accelerating factor and CD59/HRF20 was inconspicuous. In intestinal metaplasia, adenoma and intestinal-type gastric carcinoma cells, decay-accelerating factor and HRF20 were intensely stained on the apical surface; membrane cofactor protein retained its location on the basolateral surface. In diffuse-type gastric carcinomas, the expression of decay-accelerating factor, CD59/HRF20 was lost, but membrane cofactor protein was present on the tumour cell surface. CONCLUSIONS: These findings suggest that membrane cofactor protein plays a primary role in the regulation of complement activation in normal and neoplastic gastric cells and that the expression pattern of the complement regulatory proteins is closely related to gastric carcinoma development.

Adenoma↗

CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia.

BACKGROUND & AIMS: The intestine-specific caudal-related homeobox transcription factor CDX2 seems to play a key role in intestinal development and differentiation. Inactivation of one Cdx2 allele predisposes mice to develop colon polyps, and loss of CDX2 expression is a feature of some poorly differentiated colon carcinomas in humans. Conversely, aberrant CDX2 expression is often seen in intestinal metaplasias in the stomach and esophagus and in some gastric carcinomas. To better understand CDX2 function, we sought to define CDX2-regulated genes. METHODS: HT-29 colon cancer cells with minimal endogenous CDX2 expression were engineered to express exogenous CDX2, and gene expression changes relative to control cells were assessed using high-density oligonucleotide arrays. RESULTS: The gene for liver intestine (LI)-cadherin (cadherin 17) was strongly induced by CDX2 in HT-29. In other colorectal cancer lines, endogenous CDX2 and LI-cadherin expression were well correlated. Activation of a ligand-regulated form of CDX2 rapidly induced LI-cadherin gene expression, even in the presence of protein synthesis inhibitor. Analysis of the 5'-flanking region of the LI-cadherin gene defined 2 CDX2 responsive elements, and chromatin immunoprecipitation assays indicate CDX2 binds to the elements. In primary colorectal cancers and intestinal metaplasias in the stomach, CDX2 and LI-cadherin expression were tightly correlated. CONCLUSIONS: CDX2 regulates LI-cadherin gene expression in normal, metaplastic, and neoplastic tissues of the gastrointestinal tract via binding to elements in the 5'-flanking region of the gene. Given the well-established roles of cadherins in morphogenesis and differentiation, LI-cadherin may be a key factor mediating CDX2 function in intestinal cell fate determination.

Animals↗

Decreased expression of Fas (CD95/APO1) associated with goblet cell metaplasia in Barrett's esophagus.

Fas ligand (FasL) has been shown to induce apoptosis in cells expressing its receptor Fas. We have recently shown that Fas ligand is overexpressed in all cases of Barrett's metaplasia (BM) with dysplasia and esophageal adenocarcinomas, and in a few cases of BM negative with dysplasia. The aim of this work was to determine the status of Fas expression in BM with and without dysplasia or carcinoma. Formalin-fixed and paraffin-embedded tissue sections from esophageal biopsies and esophagectomy specimens with BM, with and without dysplasia and carcinoma, were immunostained for Fas and FasL using the immunoperoxidase technique. The percentage of positive cells in each case was evaluated and compared with the degree of dysplasia. When Fas expression was assessed in glands with goblet cell metaplasia, Fas immunoreactivity was either undetected or present in less than 10% of the cells in 85% of the cases, and only 1 (4%) of the 28 cases examined showed Fas immunoreactivity in more than 25% of the cells. When we compared Fas expression in goblet cell-containing glands with glands of gastric cardia phenotype, we found that in the 26 cases of BM with or without dysplasia Fas was completely undetectable in goblet cell-containing glands in 15 (58%) of the cases but was undetectable in only 3 (12%) of the glands with gastric cardia phenotype (P = .002). Fas is usually undetectable or is expressed at a low level in BM with or without dysplasia or carcinoma. Fas expression in goblet cell-containing glands is less frequent than in glands with gastric cardia phenotype in the same specimens. BM with dysplasia or carcinoma overexpress FasL, so decreased Fas expression may protect BM with dysplasia and carcinoma from self-destruction while allowing them to evade immune surveillance.

Adenocarcinoma↗

Cartilaginous metaplasia in calcified diabetic peripheral vascular disease: morphologic evidence of enchondral ossification.

The mechanism of arterial calcification is not clear. We examined histological sections of major arteries from lower extremities of two patients with longstanding type II (or non-insulin-dependent) diabetes mellitus, and found morphological evidence of cartilaginous metaplasia and ectopic ossification with associated severe medial arterial calcification and atherosclerosis. Hematoxylin and eosin, alcian blue, and toluidine blue stains were applied for the demonstration of cartilage cells and their specific matrix proteins, and immunohistochemical studies for type II collagen. To our knowledge, cartilaginous metaplasia has not previously been described in medium-sized human muscular arteries. This observation supports the hypothesis that active enchondral ossification may be a pathway leading to arterial calcification in diabetic obstructive peripheral vascular disease.

Arteries↗

Oncocytic metaplasia of canine palatine ductal epithelium.

Oncocytic metaplasia of palatine gland ducts was demonstrated by light and electron microscopy in seven out of 54 dogs. Oncocytes were recognized as distinct swollen epithelial cells with bright eosinophilic cytoplasm, small dark nuclei and scattered microvilli at the luminal surface. Their cytoplasm contained numerous tightly packed mitochondria, which varied in size and shape. Some oncocytes formed nodular hyperplastic foci that were easily recognized by low-power light microscopy. Oncocytic metaplasia appears to be a common incidental finding in palatine ductal epithelium of older dogs.

Aging↗

Esophageal squamous metaplasia: nudging the esophageal carcinoma morphogenetic paradigm.

The concept regarding esophageal squamous metaplasia, its existence, origin and the role it plays in the etiology of esophageal carcinoma, needs some urgent attention. Explanations regarding the presence of metaplastic squamous epithelial cells on esophageal smears, from asymptomatic high-risk patients undergoing screening for esophageal carcinoma, are difficult to find. The presence of squamous metaplastic cells on smears from the esophagus collected by us since 1983, from rural Transkei populations, is a regular finding and warrants some discussion. Cellular material from the esophageal lumen is collected with a gelatine encapsulated sponge brush for cytological evaluation. Each full-length, 'blind' sampling procedure produces a mixture of single cells, sheets, small groups as well as microbiopsies. Some very well preserved and excellent examples of esophageal epithelium undergoing or in a state of squamous metaplasia are a regular find.

Black People↗