Incomplete Intestinal Metaplasia Research Articles

Relationship between Endoscopic and Histologic Gastric Atrophy and Intestinal Metaplasia

The severity of endoscopic gastric atrophy (EGA), high-stage Operative Link on Gastritis Assessment (OLGA) gastritis (i.e., stage III or IV), and extensive intestinal metaplasia (IM) with incomplete subtype have been separately reported as high-risk factors of gastric cancer (GC). The aim of this study was to evaluate the associations between these endoscopic and pathologic characteristics. A cross-sectional study was conducted on 280 patients with functional dyspepsia at the University Medical Center at Ho Chi Minh City, Vietnam. Biopsies were taken according to the updated Sydney System. EGA was assessed according to the Kimura-Takemoto classification, and gastritis stage was assessed according to the OLGA system. All of patients with high-stage OLGA gastritis (i.e., stage III or IV) clustered in the subgroup of patients with moderate-to-severe EGA: 13/126 (10.3%) in patients with moderate-to-severe EGA versus 0/154 (0%) in patients with none-to-mild EGA (p < .001). Moderate-to-severe EGA was also significantly associated with extensive IM (p < .001, OR = 28.1 (CI 95% 6.4-173.3)) and incomplete IM subtype (p < .001, OR = 36.7 (CI 95% 5.1-742.1). Extensive IM was also associated with incomplete IM subtype (p = .01). High-stage OLGA gastritis, extensive IM with incomplete subtype clustered in patients with moderate-to-severe EGA. Assessing the severity of EGA could potentially help to identify patients who should be taken systemic biopsy for evaluating GC risk.

Long Segment Inlet Patch: A Cause of Laryngopharyngeal Reflux Disease (LPRD)?

Purpose: Esophageal inlet patch is a discrete area of gastric mucosa in the proximal esophagus. Autopsy series have found 5% prevalence in the general population while endoscopic studies have reported the incidence in the general population to be between 0.4-1.0%.This discrepancy is most likely secondary to the proximal location of inlet patches, which are often missed on endoscopic examination. A 37-year-old man was evaluated for recurrent symptoms of throat pain, cough, globus sensation and postnasal drip. A previous endoscopy performed two years prior had revealed non-dysplastic Barrett's esophagus and H. pylori gastritis. Eradication of H. pylori and proton pump inhibitor (PPI) therapy had relieved cough symptoms until he self-discontinued PPI due to concern for PPI adverse effects. He reported that retreatment with PPI did not improve his symptoms. At repeat endoscopy, a 2.5 cm circumferential area of metaplastic mucosa was seen at 19-17 cm, as well as non-erosive gastritis in the antrum and body of the stomach. Barrett's esophagus was not seen endoscopically. Biopsy of the inlet patch showed gastroesophageal mucosa with active inflammation and focal incomplete intestinal metaplasia. The finding of a long-segment inlet patch with inflammatory and metaplastic (both gastric and intestinal) changes in this patient with LPRD raises the question of whether his symptoms were caused by this area of ectopic gastric tissue. Most inlet patches are found incidentally and do not cause symptoms. However, a wide range of sequelae has been attributed to inlet patch including dysphagia, H. pylori colonization, Barrett's esophagus, esophageal adenocarcinoma, globus sensation, chronic cough and LPRD. Furthermore risk factors for transformation to malignancy have not been well established. The role of medical therapy with proton pump inhibitors or treatment with endoscopic ablation is undefined.Figure: No Caption available.

Kronik Gastrit ve Tümör Çevresindeki İntestinal Metaplaziler ile Mide Kanserlerinde CDX2 Boyanma Oranlarının Karşılaştırılması

Objective: In this study, an immunohistochemical investigation was carried out into CDX2 expression in intestinal metaplasia (IM) that accompanies chronic gastritis in endoscopic biopsies and gastric cancers in resection materials.We aimed to assess differences in the intensity of CDX2 staining between groups and identify the role of CDX2 in determining the risk of cancer. Material and Methods: The endoscopic biopsies taken from 70 stomachs dia gnosed with chronic gastritis and materials resected from 54 stomachs diagnosed with adenocarcinoma have been ex - amined in our laboratory. Results: The mean CDX2 score for the tumors in the resection group was found to be statistically significantly lower compared to that for the complete and incom - plete subgroups in the endoscopic biopsy group (p<0.001). The mean CDX2 score for the comp lete subgroup was statistically significantly lower compared to that for the incomplete subgroup (p<0.05). Conclusion: The mean CDX2 score for IM in endoscopic biopsies is significantly higher compared to that in IM and tumors in the resection group. Mean CDX2 score for complete IM in the resection group is significantly higher than that for incomplete IM and tumor. Mean CDX2 score for incomplete IM and tumor exhibit similar values, which may suggest that the anticarcino - genic effect of CDX2 tends to decrease in incomplete IM and tumor and incomplete IM in an para- cancerous region is in an unstable intermediary position where it is progressing to cancer.

Follow-up of intestinal metaplasia in the stomach: When, how and why

Gastric cancer remains the second most frequent cause of cancer-related mortality in the world. Screening programs in some Asian countries are impractical in the majority of other countries worldwide. Therefore, follow-up of precancerous lesions is advisable for secondary gastric cancer prevention. Intestinal metaplasia (IM) is recognized as a precancerous lesion for gastric cancer, increasing the risk by 6-fold. IM is highly prevalent in the general population, being detected in nearly 1 of every 4 patients undergoing upper endoscopy. The IM prevalence rate is significantly higher in patients with Helicobacter pylori (H. pylori) infection, in first-degree relatives of gastric cancer patients, in smokers and it increases with patient age. IM is the "breaking point" in the gastric carcinogenesis cascade and does not appear to regress following H. pylori eradication, although the cure of infection may slow its progression. Gastric cancer risk is higher in patients with incomplete-type IM, in those with both antral and gastric body involvement, and the risk significantly increases with IM extension over 20% of the gastric mucosa. Scheduled endoscopic control could be cost-effective in IM patients, depending on the yearly incidence of gastric cancer in IM patients, the stage of gastric cancer at diagnosis discovered at surveillance, and the cost of endoscopy. As a pragmatic behavior, yearly endoscopic control would appear justified in all IM patients with at least one of these conditions: (1) IM extension > 20%; (2) the presence of incomplete type IM; (3) first-degree relative of gastric cancer patients; and (4) smokers. In the remaining IM patients, a less intensive (2-3 years) could be proposed.

TP53 mutation p.R337H in gastric cancer tissues of a 12-year-old male child - evidence for chimerism involving a common mutant founder haplotype: case report

BackgroundGastric adenocarcinoma is rare in children and adolescents, with about 17 cases under age 21 in the world's literature. We report a case of invasive well-differentiated metastatic gastric cancer in a Brazilian 12-year-old boy without documented familial history of cancer.Case presentationThe patient, diagnosed with metastatic disease, died seven months after surgery. DNA from intra-surgical specimens revealed a TP53 mutation at codon 337 (p.R337H) in samples with neoplastic cells (dysplasia, tumor and metastasis) but not in non-transformed cells (incomplete intestinal metaplasia and non-involved celiac lymph node). In all mutation-positive tissues, p.R337H occurred on the same background, a founder allele identified by a specific haplotype previously described in Brazilian Li-Fraumeni syndrome patients. The same mutant haplotype, corresponding to a founder mutation present in 0.3% of the general population in Southern Brazil, was found in the genome of the father. Presence of this inherited haplotype in the tumor as well as in the father's germline, suggests a rare case of microchimerism in this patient, who may have harbored a small number of mutant cells originating in another individual, perhaps a dizygotic twin that died early in gestation.ConclusionThis case represents one of the earliest ages at diagnosis of gastric cancer ever reported. It shows that cancer inheritance can occur in the absence of an obvious germline mutation, calling for caution in assessing early cancers in populations with common founder mutations such as p.R337H in Southern Brazil.

Abstract B70: Inhibition of nuclear bile acid receptor FXR as a target in prevention of esophageal adenocarcinoma

Abstract Incidence of esophageal adenocarcinoma is increasing in the United States and other Western countries. Frequent gastroesophageal reflux or gastroesophageal reflux disease, resulting in Barrett esophagus, may be responsible for the increase. The main function of bile acid is to facilitate the formation of micelles for promotion of the processing and absorption of dietary fat. As surfactants or detergents, bile acids are potentially toxic to the cells, so their concentrations in the small intestine are tightly regulated. However, patients with frequent gastroesophageal reflux will have reflux damage caused by acid and bile acid-containing juice in the distal esophagus, with the result that normal squamous cells around the gastroesophageal junction will change to a new cell phenotype (incomplete intestinal metaplasia), because this type of cell is more resistant to acid and bile-caused injuries; therefore, Barrett esophagus is formed. This study aimed to determine the tumor-promoting effects of bile acid on esophageal cancer cells and the underlying molecular mechanisms. The data showed that different bile acids (i.e., chenodeoxycholic acid, deoxycholic acid, and lithocholic acid) induced COX-2 but inhibited RAR-β2 expression through farnesoid X receptor (FXR) expression in esophageal cancer cell lines. FXR is a nuclear receptor for bile acids functioning as a signaling molecule in the liver and the intestines and frequent gastroesophageal reflux induces FXR expression in esophageal cells. Indeed, the ex vivo data demonstrated that FXR was highly expressed in esophageal adenocarcinoma (81%) tissues and was associated with reduced RAR-β2 expression. Knockdown of FXR expression using FXR shRNA antagonized the effects of bile acid in gene expression and suppressed tumor cell viability in vitro and in nude mouse xenografts. Moreover, guggulsterone, a FXR inhibitor, was able to reduce the viability of esophageal cancer cells in time- and dose-dependent manner in vitro. Apoptosis induced by guggulsterone was through activation of caspase 8, 9, and 3. In conclusion, suppression of FXR expression using FXR shRNA or its inhibitor guggulsterone was able to suppress tumor cell growth in vitro and in vivo and induce apoptosis in vitro. This study demonstrated that inhibition of FXR could be further evaluated as a target in prevention of esophageal adenocarcinoma. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B70.

Gastric Pit Dysplasia in Adjacent Gastric Mucosa in 414 Gastric Cancers

Despite wide acceptance of the chronic gastritis-intestinal metaplasia-dysplasia-carcinoma sequence, especially for intestinal-type gastric adenocarcinoma, the precise nature of the subtle precursor lesions of gastric cancer remains to be delineated. For example, pit dysplasia with surface foveolar maturation is not well defined, nor is its prevalence and biological characteristics well characterized. We have evaluated the surrounding gastric mucosa of 414 gastric cancers for the presence of gastric pit dysplasia. We investigated its relationship with various clinicopathological and immunophenotypic features of gastric adenocarcinoma, as well as the severity and extent of any surrounding gastritis and intestinal metaplasia. p53 expression and Ki-67 proliferation index were also evaluated. We have found that 21.0% (n=87) of gastric cancer cases showed pit dysplasia in adjacent gastric mucosa. Gastric cancers with pit dysplasia were significantly associated with older age, male sex, body/fundic location, and intestinal histologic type (P<0.05). Interestingly, gastric mucin-containing intestinal metaplasia (incomplete intestinal metaplasia) was highly associated with adenocarcinoma with pit dysplasia (P=0.000). In addition, MUC6 expression in gastric adenocarcinoma was associated with pit dysplasia (P=0.036). p53 overexpression and increased Ki-67 proliferation index were more evident in gastric pit dysplasia compared with adjacent gastric mucosa. We suggest that gastric pit dysplasia is an important candidate precursor of gastric adenocarcinoma and may represent another morphologic step in the pathogenesis of gastric adenocarcinoma, especially of intestinal type. More detailed prospective studies are needed to determine the precise significance of these findings.

The expression of protein inhibitor of activated signal transducers and activators of transcription 3 in the evolutionary process of gastric cancer

Objective To study the expression of PIAS3 (protein inhibitor of activated signal transducers and activators of transcription 3) in the evolutionary process of gastric cancer. Methods Samples were taken from the endoscopic biopsy specimens of 125 patients. Gastric mucosal lesions were diagnosed in HE staining, and chronic atrophic gastritis (CAG) with intestinal metaplasia (IM) were distinguished in AB-PAS and HID-AB staining. The expressions of PIAS3 gene in different types of gastric mucosal lesions were detected by immunocytochemistry and in situ hybridization. The results were analyzed using IPP 6.0 image analysis system, from which the average optical density was obtained of positive cells. Results There were 25 patients with chronic superficial gastritis (CSG), 87 CAG (30 with complete intestinal IM, 27 with incomplete intestinal IM, 21 with complete colonic IM, 9 with incomplete colonic IM), 8 dysplasia (DYS) and 5 gastric cancer (GC). In the expressions of PIAS3 mRNA and protein, a difference was not found between the patients with CSG and those with CAG with complete or incomplete intestinal IM; however, a significant difference was statistically found among patients with CSG (or intestinal IM), complete colonic IM, incomplete colonic IM, DYS and GC, expression levels of which stepped down one by one. Conclusions There are differences in the PIAS3 expression from different stages of gastric precancerous conditions/lesions to GC, which may reveal a close relationship between expression reduction or loss of PIAS3 and gastric tumorigenesis.

From Open-Type Atrophic Gastritis to Gastritis Staging

Dear Sir, We read with great interest the latest issue of Digestive Diseases and Sciences and, given our particular interests, we would like to briefly comment on three thoughtprovoking papers signed by Genta [1], Uedo [2] and, not last, by Ahn and coworkers [3]. Genta looks at the worldwide epidemiology of gastric cancer (GC) and correlates different socio-economic habits with GC risk. Addressing the etiological co-factors involved in gastric carcinogenesis, Genta notes that, ‘‘The relative influence of ... these factors on the rise and fall of GC is difficult to evaluate; since none is a sufficient cause of cancer, they must have acted synergistically’’ [1]. In this respect, without curbing the ‘‘leading’’ etiological role of H. pylori, we would like to mention that we recently documented a similar prevalence of both H. pylori and Cag-A status coexisting with impressive differences in the incidence of GC in different Siberian populations [4]. Our observation strongly supports the role of factors other than H. pylori in the etiology of ‘‘epidemic’’ GC. As Genta’s editorial suggests, such a constellation of non-Hp, environmental (?) factors should be further and more extensively addressed. Moving on to Uedo’s paper and its conclusive question, ‘‘... from the perspective of a practical endoscopist: do we need to take many biopsy specimens for assessing gastric cancer risk in... routine EGD?’’ [2], the answer is provided by the author a few lines further on: when both ‘‘gastric serology’’ (which is paid too little attention in non-Japanese clinical practice) and clinical examination consistently point to the need for an invasive diagnostic procedure (EGD), there can be no doubt that endoscopy and microscopy combined can identify patients warranting further diagnostic/therapeutic measures. Finally, Ahn and coworkers highlight the increased GC risk associated with the open phenotype of gastritis (i.e., multifocal atrophic gastritis, not restricted to the antrum) [3, 5]. The authors (who do not mention their biopsy sampling protocol) founded their conclusions on an elegant histological/immunohistochemical study, but it is worth noting that distinguishing between complete and incomplete intestinal metaplasia (IM) on the strength of H&E is only partially reliable (mucin histochemistry, i.e., high iron diamine [HID], is more appropriate). The clinical question, however, is whether we should perform (expensive and time-consuming) histochemistry and/or immunohistochemistry stains for a reliable assessment of the risk of GC. As in Ahn’s experience, when intestinalization of the gastric mucosa spreads from the antrum to the oxyntic M. Rugge (&) M. Fassan Department of Medical Diagnostic Sciences and Special Therapies, Surgical Pathology and Cytopathology Unit, University of Padua, Padua, Italy e-mail: massimo.rugge@unipd.it

Helicobacter pylori cagA and vacA Genotypes as Predictors of Progression of Gastric Preneoplastic Lesions: A Long-Term Follow-Up in a High-Risk Area in Spain

There are no established predictive markers of progression of gastric preneoplastic lesions. The aim of this study was to analyze the relationship between Helicobacter pylori cagA and vacA genotypes and progression of gastric preneoplastic lesions. This was a follow-up study that carried out in a province of Spain with a high risk of gastric cancer. A total of 312 patients who underwent upper endoscopy with gastric biopsy in 1988-1994 with diagnoses of normal mucosa, non-atrophic gastritis (NAG), non-metaplastic multifocal atrophic gastritis (MAG), and complete or incomplete intestinal metaplasia (IM), and who accepted to undergo a new biopsy during 2005-2007 or had an end point during follow-up, were included in this study. Detection and characterization of H. pylori cagA and vacA genotypes was performed directly in baseline paraffin-embedded gastric biopsy specimens by PCR followed by reverse hybridization onto a line probe assay. Inter- and intra-observer variability of histological diagnosis was assessed. Analysis was done using unconditional logistic regression. The mean age of patients was 48.5 years (45% males) and the mean of follow-up was 12.8 years. H. pylori strains harboring cagA, vacA s1, and vacA m1 genotypes were more frequently found in patients with more advanced gastric preneoplastic lesions. Infection with cagA-positive, vacA s1, and vacA m1 strains was associated with progression of gastric preneoplastic lesions (multivariate odds ratio (OR)=2.28, 95% confidence interval (CI) 1.13-4.58; OR=2.90, 95% CI 1.38-6.13; and OR=3.38, 95% CI 1.34-8.53, respectively). Infection with strains that are simultaneously cagA positive and vacA s1/m1 was associated with progression of gastric precancerous lesions with an OR of 4.80 (95% CI 1.71-13.5) in relation to those infected with cagA-negative/vacA s2/m2 strains. H. pylori genotyping may be useful for the identification of patients at high risk of progression of gastric preneoplastic lesions and who need more intensive surveillance.

De novo expression of CD44 variants in sporadic and hereditary gastric cancer

CD44 is the major ubiquitously expressed cell surface receptor for hyaluronate. The CD44 gene encodes several protein isoforms due to extensive alternative splicing and post-translational modifications. Some of these CD44 variable isoforms have been foreseen as key players in malignant transformation and their expression is highly restricted and highly specific, unlike the canonical CD44 standard isoform. In this study, we aimed at dissecting the mRNA splicing pattern of CD44 in normal stomach and gastric cancer (GC) cell lines (n=9) using cloning and quantitative mRNA amplification assays. Moreover, we assessed the RNA levels and protein expression pattern of relevant splicing forms in distinct premalignant and malignant gastric lesions (sporadic (n=43) and hereditary (n=3) forms) using real-time RT-PCR and immunohistochemistry. We also explored the association of CD44 and E-cadherin expression by immunohistochemistry, as E-cadherin has a pivotal functional role in GC. We established the pattern of CD44 variant forms in normal stomach and gastric malignancy. We observed that although exon v6-containing isoforms were rarely expressed in normal gastric mucosa, they became increasingly expressed both in gastric premalignant (hyperplastic polyps, complete and incomplete intestinal metaplasia, low- and high-grade dysplasia) and malignant lesions (cell lines derived from GCs, primary sporadic GCs and hereditary diffuse GCs (HDGCs)). Moreover, we verified that whenever E-cadherin expression was absent, exon v6-containing CD44 isoforms were overexpressed. The lack of expression of CD44 isoforms containing exon v6 in the surface and foveolar epithelia of normal stomach and, its de novo expression in premalignant, as well as in sporadic and hereditary malignant lesions of the stomach, pinpoint CD44 v6-containg isoforms as potential biomarkers for early transformation of the gastric mucosa. Further, our results raise the hypothesis of using CD44v6 as a marker of early invasive intramucosal carcinoma in HDGC CDH1 mutation carriers that lack CDH1 expression in their tumors.

Gastric cancer occurrence in preneoplastic lesions: A long‐term follow‐up in a high‐risk area in Spain

There are no established criteria to classify patients into high or low risk of progressing to gastric cancer (GC). The aim of the study was to identify predictors of GC occurrence among patients with gastric preneoplastic lesions. A prospective and retrospective follow-up study was carried out in a province in Spain with one of the highest risk of GC. The study included 478 patients who underwent gastric biopsy in 1988-1994 with diagnoses of normal mucosa, nonatrophic gastritis (NAG), non-metaplastic multifocal atrophic gastritis (MAG) and complete or incomplete intestinal metaplasia (IM) and who accepted to undergo a new biopsy during 2005-2007 or had an event during follow up. Inter- and intra-observer variability of histological diagnosis was assessed. Analysis was done using Cox proportional hazards risk (HR) models. The mean age of the patients was 50 years, 47% were males and the mean follow-up time was 12.8 years. During follow-up, 23 GC (4.8%) were diagnosed (21 adenocarcinomas and 2 lymphomas) with an incidence of 3.77 per 1,000 person per year. The incidence rate of GC for those with incomplete IM was 16.5 per 1,000 person years. Out the 21 adenocarcinomas, 16 had an incomplete IM in the baseline diagnosis. Incomplete IM (HR 11.3; 95% CI 3.8-33.9) and a family history of GC (HR 6.1; 95% CI 1.7-22.4) were the strongest risk factors for gastric adenocarcinoma. Subtyping of IM and family history of GC may be useful for the identification of high-risk patients who need more intensive surveillance.

Short-segment Barrett’s esophagus and cardia intestinal metaplasia: A comparative analysis

to investigate the endoscopy and histology of short-segment Barrett's esophagus (SSBE) and cardia intestinal metaplasia (CIM), and their correlation with Helicobacter pylori (H. pylori) gastritis and gastroesophageal reflux disease (GERD). biopsy specimens were taken from 32 SSBE patients and 41 CIM patients with normal appearance of the esophagogastric junction. Eight biopsy specimens from the lower esophagus, cardia, and gastric antrum were stained with hematoxylin/eosin, Alcian blue/periodic acid-Schiff, Alcian blue/high iron diamine and Gimenez dye. Results were graded independently by one pathologist. the SSBE patients were younger than the CIM patients (P < 0.01). The incidence of dysplasia and incomplete intestinal metaplasia subtype was higher in SSBE patients than in CIM patients (P < 0.01). H. pylori infection was correlated with antral intestinal metaplasia (P < 0.05), but not with reflux symptomatic, endoscopic, or histological markers of GERD in CIM patients. SSBE was correlated with reflux symptomatic and endoscopic esophagitis (P < 0.01), but not with H. pylori infection and antral intestinal metaplasia. dysplasia risk is significantly greater in SSBE patients than in CIM patients. CIM is a manifestation of H. pylori-associated and multifocal atrophic gastritis, whereas SSBE may result from GERD.

Sonic hedgehog and CDX2 expression in the stomach

Sonic hedgehog (Shh) is an essential regulator of patterning processes throughout development, and CDX proteins act as the master regulators for intestinal development and differentiation. Shh and CDX2 seem to be interdependently linked with cellular differentiation through different signal cascades. We have recently shown that the loss of Shh and aberrant expression of CDX2 in Helicobacter pylori (H. pylori)-associated atrophic gastritis can be modified by H. pylori eradication prior to incomplete intestinal metaplasia. On the other hand, abnormal signaling of the hedgehog pathway has been reported in gastric cancer, especially diffuse-type cancer and advanced gastric cancer, and Shh acts as a proliferation factor in both the normal mucosa and malignant lesions. CDX2 expressed in the early stage of gastric carcinogenesis is associated with the intestinal phenotypic region and thus with a better outcome. However, it remains unclear how Shh and CDX2 are involved with intestinal transformation and further carcinogenesis.

Prevalence and distribution of gastric intestinal metaplasia and its subtypes

Background and study aims Intestinal metaplasia, especially type III intestinal metaplasia is considered to be a precursor of gastric cancer and because of this it is suggested that these patients should be followed up by gastroscopy. Our aim was to find out the prevalence of intestinal metaplasia and its subtypes, the appearance of intestinal metaplasia in different parts of the stomach, and the correlation of intestinal metaplasia with other histological and endoscopic findings. Patients and methods A total of 505 consecutive patients, with a mean age ± S.D. of 54 ± 16 years, had two biopsies taken from the antrum, two from the corpus, and, in 272 cases, two from the angulus of the stomach during routine upper gastrointestinal endoscopy. Histological specimens were examined according to the updated Sydney system and the ones with incomplete intestinal metaplasia were further stained for sulphomucin visualisation to divide these into types II and III. Results The overall prevalence of intestinal metaplasia was 19%. The prevalence of type III intestinal metaplasia was 2.8%, type II intestinal metaplasia was 4.4%, and complete intestinal metaplasia was 11%. Intestinal metaplasia was found most frequently in the antrum and also in the angulus. There was no type III intestinal metaplasia in the corpus. Intestinal metaplasia was found more frequently in patients with atrophic gastritis than in other patients ( p < 0.01). The patients with type III intestinal metaplasia were older than the patients without intestinal metaplasia (mean age of 73 versus 51 years). None of the patients with a totally normal appearing stomach in upper gastrointestinal endoscopy had type II or type III intestinal metaplasia. Conclusion The relatively high overall prevalence of intestinal metaplasia was found in patients referred for gastroscopy in a region of low prevalence of Helicobacter pylori infection and low incidence of gastric cancer. Intestinal metaplasia was most often found in the antrum and angulus. Type III intestinal metaplasia was more prevalent in older patients and intestinal metaplasia was more frequently found in patients with atrophic gastritis. Normal appearing endoscopic finding seems to exclude type II and III intestinal metaplasia.

CDX2 expression is progressively decreased in human gastric intestinal metaplasia, dysplasia and cancer

Intestinal metaplasia is a key event in multistep gastric carcinogenesis. CDX2, a master regulator of intestinal phenotype, was shown to play a tumor-suppressive role in colon cancer. However, it was reported to be expressed in nearly all gastric intestinal metaplasia and many gastric cancers. As CDX2 is differentially expressed in normal stomach and intestine, we sought to relate the CDX2 expression to gastrointestinal differentiation along gastric carcinogenesis. The expression of CDX2 protein in gastric intestinal metaplasia, dysplasia and cancer was examined and related to their gastrointestinal differentiation. CDX2 expression was significantly decreased in incomplete intestinal metaplasia, which expresses both gastric mucins (MUC5AC and MUC6) and intestinal mucin (MUC2), compared with complete intestinal metaplasia, which expresses intestinal mucin (MUC2) only. Although incomplete intestinal metaplasia morphologically resembles colon, its CDX2 expression was apparently lower than that in the normal colon. Moreover, CDX2 expression was progressively reduced in gastric dysplasia and cancer. The CDX2 expression in gastric cancer was also inversely correlated with the expression of gastric mucins. As incomplete intestinal metaplasia is associated with higher risk of gastric cancer, its lower CDX2 expression compared with that in complete intestinal metaplasia and normal colon epithelium resolved the current contradiction between the tumor-suppressive role of CDX2 in the colon and the high prevalence of CDX2 in intestinal metaplasia. Further decrease of CDX2 expression in gastric dysplasia and cancer suggests that CDX2 plays a similar anticarcinogenic role in intestinal metaplasia as it does in colon. Intestinal metaplasia or dysplasia with low expression of CDX2 may serve as predictive markers for gastric cancer.

Morphologic Features are Useful in Distinguishing Barrett Esophagus From Carditis With Intestinal Metaplasia

Barrett esophagus (BE) and carditis with intestinal metaplasia (CIM) differ in their risk of malignancy and implications for patient management, but are difficult to distinguish in mucosal biopsies from the gastroesophageal junction region. The present study was performed to evaluate the role of routine morphology in distinguishing BE from CIM in mucosal biopsies and to assess the degree of interobserver variability in recognizing morphologic parameters that are of significance in making this distinction. Several morphologic features, including presence of crypt disarray and atrophy, incomplete and diffuse intestinal metaplasia, multilayered epithelium, squamous epithelium overlying columnar crypts with intestinal metaplasia, hybrid glands, and esophageal glands/ducts, were significantly associated with a diagnosis of BE. The latter 3 features were observed exclusively in BE biopsies. Furthermore, multiple BE-associated morphologic features were often present together in BE but not CIM biopsies. There was substantial agreement (kappa=0.6) among expert gastrointestinal pathologists for distinguishing BE from CIM even in the absence of clinical/endoscopic information. The interobserver agreement in recognition of BE-associated morphologic features ranged from almost perfect for some features like esophageal glands/ducts (kappa=0.83) to slight for multilayered epithelium (kappa=0.17). In conclusion, our findings indicate that several morphologic features are helpful in distinguishing BE from CIM. The combined presence of multiple BE-associated morphologic features can be used in making this distinction with a high degree of accuracy. Larger prospective studies need to be performed to validate these findings and evaluate the reproducibility of this approach in routine clinical practice.

Re‐expression of sonic hedgehog and reduction of CDX2 after Helicobacter pylori eradication prior to incomplete intestinal metaplasia

Loss of Sonic Hedgehog (Shh) and aberrant CDX2 expression are early changes correlating with the presence of intestinal metaplasia that occur in the gastric mucosa prior to neoplastic transformation. The aim of this study was to compare the improvement in corpus gastritis with Shh and CDX2 expression after H. pylori eradication between subjects at high risk for gastric cancer and controls. The usefulness of serum pepsinogen levels as a predictor of resolved corpus gastritis was also examined. Seventy patients with endoscopic resection for early gastric cancer and 30 controls were studied. Expression of Shh and CDX2 were evaluated by immunostaining. Serum levels of pepsinogen I before eradication in the patients scored as having improvement of corpus atrophy were significantly higher than in the patients without improvement (<0.01). Residual inflammation at the corpus lesser curve was more frequently detected in the cancer group than in the controls (OR 4.6 95% C.I. 1.6-13.5) and in the mucosa with incomplete intestinal metaplasia rather than in those without incomplete intestinal metaplasia (OR 7.6 95% C.I. 2.4-24.3). Atrophy, expression of Shh and CDX2 at the corpus lesser curve significantly improved in mucosa without incomplete intestinal metaplasia (p < 0.01), but not in mucosa with incomplete intestinal metaplasia. In conclusion, H. pylori eradication prior to development of incomplete intestinal metaplasia improves corpus gastritis and may prevent gastric cancer. Pepsinogen I may be a useful marker in patients with a residual higher risk of gastric cancer after H. pylori eradication.

Feasibility and cost‐effectiveness of using magnification chromoendoscopy and pepsinogen serum levels for the follow‐up of patients with atrophic chronic gastritis and intestinal metaplasia

The follow-up of patients with atrophic chronic gastritis or intestinal metaplasia may lead to early diagnosis of gastric cancer. However, to-date no cost-effective model has been proposed. Improved endoscopic examination using magnification chromoendoscopy together with non-invasive functional assessment with pepsinogen serum levels are accurate in the diagnosis of intestinal metaplasia (extension) and minute dysplastic lesions. The aim of this study was to assess the feasibility and cost-effectiveness of a follow-up model for patients with atrophic chronic gastritis and intestinal metaplasia based on gastric mucosal status using magnification chromoendoscopy and pepsinogen. A cohort of patients with lesions as severe as atrophic chronic gastritis were followed-up according to a standardized protocol using magnification chromoendoscopy with methylene blue and measurement of serum pepsinogen I and II levels. A single node decision tree and Markov chain modeling were used to define cost-effectiveness of this follow-up model versus its absence. Transition rates were considered time-independent and calculated using primary data following cohort data analysis. Costs, quality of life and survival were estimated based on published data and extensive sensitivity analysis was performed. A total of 100 patients were successfully followed-up over 3 years. Seven cases of dysplasia were diagnosed during follow-up, all among patients with incomplete intestinal metaplasia at baseline, six of whom had extensive (pepsinogen I to II ratio <3) incomplete intestinal metaplasia. For those individuals with atrophic chronic gastritis or complete intestinal metaplasia, a yearly measurement of pepsinogen levels or an endoscopic examination on a 3-yearly basis would cost 455 euros per quality-adjusted life year (QALY) gain. Endoscopic examination and pepsinogen serum level measurement on a yearly basis would cost 1868 euros per QALY for patients with extensive intestinal metaplasia. The follow-up of patients with atrophic chronic gastritis or intestinal metaplasia is both feasible and cost-effective if improved accurate endoscopic examination of gastric mucosa together with non-invasive assessment of gastric mucosal status are used to identify individuals at high-risk for development of gastric cancer.

Smoking, Helicobacter pylori Virulence, and Type of Intestinal Metaplasia in Portuguese Males

High-virulence Helicobacter pylori strains and smoking increase the risk of gastric precancerous lesions. However, its association with specific types of intestinal metaplasia has been poorly studied. We aimed to quantify the association between different types of intestinal metaplasia (complete, incomplete, and mixed) and these two risk factors. Male volunteers (n = 227) underwent an upper digestive endoscopy and completed symptoms and lifestyle questionnaires. A histologic diagnosis was assigned based on the lesions found in any of the biopsy specimens (antrum, body, or incisura). H. pylori vacA and cagA were directly genotyped by multiplex PCR and reverse hybridization. Each participant's smoking status at the time of endoscopy was assessed. Logistic and multinomial logistic regression models were fitted (including H. pylori virulence, smoking, age, and education as independent variables) using normal/chronic nonatrophic gastritis as the reference category. Compared with never smokers infected with low-virulence strains, the risk of intestinal metaplasia was increased in subjects infected with high-virulence strains [odds ratio (OR), 5.74; 95% confidence interval (95% CI), 1.68-19.63] and in ever smokers (OR, 3.54; 95% CI, 1.30-9.61). In ever smokers infected with high-virulence H. pylori strains, the risk of intestinal metaplasia was further increased (OR, 8.61; 95% CI, 3.07-24.17). Infection with high-virulence strains significantly increased the risk of incomplete (OR, 9.81; 95% CI, 2.39-40.31) and mixed (OR, 3.28; 95% CI, 1.51-7.14) intestinal metaplasia. Complete (OR, 2.82; 95% CI, 1.01-7.88) and mixed (OR, 2.97; 95% CI, 1.12-7.84) intestinal metaplasia were more frequent among ever smokers. High-virulence H. pylori strains and smoking are differentially associated with the complete and incomplete types of intestinal metaplasia, suggesting divergent pathways in gastric carcinogenesis.