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Background & Aims: It is not clear why only a minority of patients with gastroesophageal reflux disease (GERD) develop Barrett's esophagus. We hypothesized that differences among individuals in molecular pathways activated when esophageal squamous epithelium is exposed to reflux underlie the development of Barrett's metaplasia., Methods: We used esophageal squamous cell lines from patients who had GERD with Barrett's esophagus (normal esophageal squamous [NES]-B3T and NES-B10T) and without Barrett's esophagus (NES-G2T and NES-G4T) to study effects of acid and bile salts on expression of the CDX2 gene. Bay 11-705, Ad5 inhibitor kappaB(IkappaB)alpha-SR, and site-directed mutagenesis were used to explore effects of nuclear factor-kappaB (NF-kappaB) inhibition on CDX2 promoter activity; DNA binding of the NF-kappaB subunits p50 and p65 was assessed by chromatin immune-precipitation., Results: Acid and bile salts increased CDX2 messenger RNA (mRNA), protein, and promoter activity in NES-B3T and NES-B10T cells, but not in NES-G2T or NES-G4T cells. Inhibition of NF-kappaB abolished the increase in CDX2 promoter activity. Increased CDX2 promoter activity was associated with nuclear translocation of p50, which bound to the promoter. We found CDX2 mRNA in 7 of 10 esophageal squamous biopsy specimens from patients with Barrett's esophagus, but in only 1 of 10 such specimens from patients who had GERD without Barrett's esophagus., Conclusions: Acid and bile salts induce CDX2 mRNA and protein expression in esophageal squamous cells from patients with Barrett's esophagus, but not from GERD patients without Barrett's esophagus. We speculate that these differences in acid- and bile salt-induced activation of molecular pathways may underlie the development of Barrett's metaplasia., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Esophagitis dissecans superficialis (EDS) is a term applied to a rare endoscopic finding characterized by sloughing of large fragments of the esophageal squamous mucosa that may be coughed up or vomited. Although EDS has been reported in association with certain medications and esophageal strictures, most cases remain unexplained and the histopathologic features of EDS are inadequately described. We undertook this study to define useful diagnostic criteria based on the examination of a series of well-characterized cases of EDS. To identify patients with EDS, we searched our endoscopy and pathology databases, reviewed the esophageal biopsy specimens from candidate cases, and correlated them with pertinent clinical information. Twelve patients (11 men and 1 woman) had endoscopic and histologic findings of EDS and 9 had the histologic features without the endoscopic correlates. Biopsies from confirmed EDS patients showed sloughing and flaking of superficial squamous epithelium with occasional bullous separation of the layers, parakeratosis, and varying degrees of acute or chronic inflammation. Fungal elements were identified in 3 patients, but were not associated with acute inflammation. None of the EDS patients were on bisphosphonate therapy or had bullous skin disorders. Follow-up endoscopy in 5 patients showed complete resolution of the esophageal abnormalities in 4 and mild esophagitis in one. In spite of its sometimes, dramatic presentation, EDS is a benign condition that resolves without lasting esophageal pathology. Although an association with medications, skin conditions, heavy smoking, and physical trauma has been reported, the pathogenesis of EDS remains unexplained.

Background & Aims: Reflux esophagitis is believed to be caused by the caustic effects of refluxed gastric acid on esophageal epithelial cells. However, caustic chemical injuries develop rapidly whereas esophagitis might not appear until weeks after the induction of reflux in animal models. We studied early histologic events in the development of reflux esophagitis in a rat model and performed in vitro experiments to determine whether exposure to acidified bile salts causes esophageal epithelial cells to secrete chemokines that might contribute to inflammation., Methods: At various time points after esophagoduodenostomy, the rat esophagus was removed and inflammatory changes were analyzed by histologic analyses. Human esophageal squamous cell lines were exposed to acidified bile salts to evaluate their effects on cytokine production and immune-cell migration., Results: Reflux esophagitis started at postoperative day 3 with lymphocytic infiltration of the submucosa that progressed to the epithelial surface-these findings contradicted those expected from a caustic chemical injury. Basal cell and papillary hyperplasia preceded the development of surface erosions. Exposure of squamous cells to acidified bile salts significantly increased the secretion of interleukin-8 and interleukin-1beta; conditioned media from these cells caused significant increases in the migration rates of T cells and neutrophils., Conclusions: These findings support, but do not prove, an alternative concept for the development of reflux esophagitis in which refluxed gastric juice does not directly damage the esophagus, but rather stimulates esophageal epithelial cells to secrete chemokines that mediate damage of esophageal tissue.

Increased numbers of intraepithelial lymphocytes (lymphocytosis) can be found in the esophagus, stomach, small intestine, and colon in a variety of clinical circumstances. This review, directed at practicing pathologists, portrays the normal resident lymphocyte population in the mucosa of each segment of the digestive tract and discusses the different situations that may result in quantitative or qualitative alterations of intraepithelial lymphocytes. Esophageal lymphocytosis has not been fully characterized and its clinical significance, if any, awaits definition. Thus, this diagnosis is presently discouraged. In the stomach, it is particularly important to exclude Helicobacter pylori infection and celiac sprue before diagnosing lymphocytic gastritis. Duodenal lymphocytic infiltrates, inextricably tied with alterations of the villous architecture of the mucosa, are often caused by gluten sensitivity. However, similar morphologic changes may be caused by a vast array of other conditions that must be carefully considered and excluded. Lymphocytic and collagenous colitis are most often unexplained, but their frequent association with autoimmune conditions or certain medications deserve a thorough investigation in each case. Using a combination of histologic and clinical clues, a cause for the intraepithelial lymphocytic infiltration can be identified in many instances. As some of the associated conditions are amenable to effective treatment, the importance of diligently seeking such associations before resorting to a diagnosis of primary lymphocytosis is emphasized.

Background & Aims: Fundic gland polyps (FGPs), the most common type of gastric polyps, have been associated with prolonged proton pump inhibitor therapy and an increased risk of colon cancer. The presence of FGPs has been inversely correlated with Helicobacter pylori infection. We evaluated the prevalence of H pylori-associated gastritis, colonic polyps, and carcinomas in subjects with and without FGPs., Methods: We analyzed data collected from community-based endoscopy centers in 36 states (plus Washington DC and Puerto Rico) on patients who underwent esophagogastroduodenoscopy (EGD) and colonoscopy between April 2007 and March 2008. Of the 103,385 patients who underwent EGD during this time period, gastric biopsy samples were collected from 78,801 and colonic biopsies from 26,017. Slides of samples from Helicobacter-infected FGPs and FGPs with dysplasia were reviewed., Results: FGPs were detected in 6081 patients (67.8% women). Helicobacter infection was present in less than 0.5% patients with FGPs and 13.0% of those without FGPs (odds ratio [OR], 29.05; 95% confidence interval [CI], 20.4-41.4; P < .0001). Colonic adenomas were detected in 42.3% of women with FGPs and 33.8% of those without (OR, 1.43; 95% CI, 1.26-1.63; P < .001); there was no significant difference in colonic adenomas between men with and without FGPs., Conclusions: Women had a higher prevalence of FGPs. FGPs were associated with gastroesophageal reflux disease symptoms, gastric heterotopia, hyperplastic colonic polyps (only in men), and colonic adenomas (only in women, especially those over 60 years of age). The presence of FGPs was inversely correlated with H pylori infection, active gastritis, and gastric neoplasia.

Background and Aims: The prevalence of Helicobacter pylori infection has been decreasing in the USA, but recent data are lacking. This study evaluates the seroprevalence for anti-H. pylori antibodies in symptomatic veterans tested over the past 11 years., Materials and Methods: The same serum anti-H. pylori IgG detection system has been used at a tertiary care Veterans Affairs hospital since late 1996. Results of all tests performed from 1997 to 2007 were analyzed., Results: Of 7310 unique patients tested, 3982 (54.5%) were positive. Seropositivity declined from 70.8% in 1997 to 48.6% in 2002, then reached a plateau around 50%. A strong birth cohort effect was present, from a seropositivity of 72.7% for the veterans born before 1920 to 22% for those born between after 1980., Conclusions: Despite a constant birth cohort effect, H. pylori seropositivity among symptomatic veterans leveled down at approximately 50% after declining steadily from 1997 to 2002.

Background & Aims: Current surveillance guidelines for Barrett's esophagus (BE) recommend extensive biopsies to minimize sampling error. Biopsy practice patterns for BE surveillance in the community have not been well-described. We used a national community-based pathology database to analyze adherence to guidelines and to determine whether adherence was associated with dysplasia detection., Methods: We identified 10,958 cases of established BE in the Caris Diagnostics pathology database from January 2002-April 2007. Demographic, pathologic, and endoscopic data were recorded. Dysplasia was categorized as low grade, high grade, or adenocarcinoma. Adherence was defined as > or =4 esophageal biopsies per 2 cm BE or a ratio > or =2.0. Generalized estimating equation multivariable analysis was performed to assess factors associated with adherence, adjusted for clustering by individual gastroenterologist., Results: A total of 2245 BE surveillance cases were identified with linked endoscopy reports that recorded BE length and could be assessed for adherence. Adherence to guidelines was seen in 51.2% of cases. In multivariable analysis, longer segment BE was associated with significantly reduced adherence (3-5 cm, odds ratio [OR] 0.14, 95% confidence interval [CI] 0.10-0.19; 6-8 cm, OR 0.06, 95% CI 0.03-0.09; > or =9 cm, OR 0.03, 95% CI 0.01-0.07). Stratified by BE length, nonadherence was associated with significantly decreased dysplasia detection (summary OR 0.53, 95% CI 0.35-0.82)., Conclusions: Adherence to BE biopsy guidelines in the community is low, and nonadherence is associated with significantly decreased dysplasia detection. Future studies should identify factors underlying nonadherence as well as mechanisms to increase adherence to guidelines to improve early detection of dysplasia.

1-4% of patients who undergo gastric biopsy have gastric polyps. These lesions may be true epithelial polyps, heterotopias, lymphoid tissue, or stromal lesions. Hyperplastic polyps, which arise in patients with underlying gastritis, and fundic-gland polyps, which are associated with PPI therapy, are the most common gastric polyps; however, prevalence varies widely relative to the local prevalence of Helicobacter pylori infection and use of PPI therapy. Some polyps have characteristic topography, size, and endoscopic appearance. Approximately 20% of biopsy specimens identified endoscopically as polyps have no definite pathological diagnosis. Evaluation of the phenotype of the gastric mucosa that surrounds a lesion will provide significant information crucial to the evaluation, diagnosis and management of a patient. The presence of a gastric adenoma should prompt the search for a coexistent carcinoma. The endoscopic characteristics, histopathology, pathogenesis, and management recommendations of polyps and common polypoid lesions in the stomach are discussed in this Review.

Objectives: To use a large pathology database (Caris Diagnostics) to analyze the frequency and associations of gastric polyps in a nationwide US population., Methods: A total of 121,564 esophagogastroduodenoscopy (EGD) procedures from private practices in 36 states in the Caris Diagnostics database from 1 April 2007 to 31 March 2008 were searched for the endoscopic designations of polyp, nodule, and mass, and for the pathological diagnoses that commonly present as gastric polyps. Pertinent demographic data, clinical indications for EGD, and information regarding Helicobacter pylori infection, reactive gastropathy, chronic inactive gastritis, and intestinal metaplasia were also obtained., Results: A total of 78,909 of the 121,564 patients who underwent EGD had gastric biopsies. The prevalence of gastric polyps in the EGD population was 6.35%; 77% were fundic gland polyps, 17% hyperplastic polyps/polypoid foveolar hyperplasia, 0.69% adenomas, and 0.1% inflammatory fibroid polyps. Malignant neoplasms were slightly >2%. None of the benign gastric polyps had a significant positive association with concurrent H. pylori infection; intestinal metaplasia was detected in the background of 52.2% of carcinoids, 29.6% of adenomas, 20.1% of xanthomas, and 13% of adenocarcinomas and hyperplastic polyps. Adenomas were rarely associated with synchronous adenocarcinomas., Conclusions: The relative prevalence of fundic gland polyps in this population was much higher than that reported earlier, most likely because of the widespread use of proton pump inhibitors. H. pylori- and atrophy-associated polyps, including adenomas, were less common than in earlier series.

Background and Aims: Chronic idiopathic intestinal pseudo-obstruction (CIIP) is characterised by severe impairment of intestinal propulsive motility that mimics bowel obstruction. JC virus (JCV) is a polyomavirus that can infect brain glial cells causing a fatal disease, but may also be found throughout the normal gastrointestinal tract. The hypothesis that JCV infects the myenteric plexuses of patients with CIIP was tested., Methods: 10 patients with CIIP and 61 normal specimens (30 ascending colon and 31 ileum) from patients with uncomplicated colon cancer were studied. DNA was extracted from the myenteric plexuses, and JCV T antigen (TAg) DNA and the viral regulatory region were detected by PCR and sequencing. Immunohistochemistry was performed to detect JCV viral protein expression, neuronal and glial markers. Fluorescence in situ hybridisation was performed for cellular localisation of the JCV infection., Results: Clinical studies demonstrated neurogenic impairment, and pathological analyses showed neuropathy in each patient with CIIP. JCV TAg DNA was found in the myenteric plexuses of 8/10 (80%) of the patients with CIIP and 3/31 (9.7%) of the control patients (p<0.001). All samples were JCV Mad-1 strains. Seven of the 10 CIIP specimens expressed both JCV TAg and the JCV viral protein VP1, while none of the controls expressed either. JCV infection co-localised with glial fibrillary acidic protein expression, a marker of enteric glial cells., Conclusion: JCV infection occurs in the myenteric plexuses of patients with CIIP. The JCV localisation in enteroglial cells suggests a possible pathological role for this virus in enteric neuropathy.

Proton pump inhibitors profoundly affect the stomach and have been associated with carcinoid tumors in female rats. There is now sufficient experience with this class of drugs to allow reasonable estimation of their safety in terms of cancer development in humans. Long-term use of proton pump inhibitors is associated with an increase in gastric inflammation and development of atrophy among those with active Helicobacter pylori infections. The actual risk is unknown but is clearly low. However, it can be markedly reduced or eliminated by H. pylori eradication. It is thus recommended that patients being considered for long-term proton pump inhibitor therapy should be tested for H. pylori infection and, if present, this pathogen should be eradicated. Oxyntic cell hyperplasia, glandular dilatations, and fundic gland polyps may develop in patients not infected with H. pylori, but these changes are believed to be reversible and without significant cancer risk.

This review evaluates the current evidence supporting the usefulness of gastrointestinal pathology specialists. Using the discovery of Helicobacter pylori as an example, we show that as new conditions are discovered and old ones are revisited and reclassified, an intimate alliance between clinicians, basic scientists, and pathologists is indispensable. Whilst specialised gastrointestinal pathologists (defined as someone who has received at least a year of training in a section of a pathology laboratory where only tissue from the alimentary tract and liver were examined, who has spent time in a clinical gastroenterology unit, and who has restricted his or her practice to such specimens) are usually well-represented in academic settings, their contribution is becoming increasingly recognised also in private practice. We contend that a more sophisticated or detailed diagnosis actually translate to better care, and provide numerous examples that show not only a clinical benefit to the patient and the gastroenterologist, but also a financial advantage for the payors (patients, insurances).

Atrophic gastritis (resulting mainly from long-standing Helicobacter pylori infection) is a major risk factor for (intestinal-type) gastric cancer development and the extent/topography of the atrophic changes significantly correlates with the degree of cancer risk. The current format for histology reporting in cases of gastritis fails to establish an immediate link between gastritis phenotype and risk of malignancy. The histology report consequently does not give clinical practitioners and gastroenterologists an explicit message of use in orienting an individual patient's clinical management. Building on current knowledge of the biology of gastritis and incorporating experience gained worldwide by applying the Sydney System for more than 15 years, an international group of pathologists (Operative Link for Gastritis Assessment) has proposed a system for reporting gastritis in terms of stage (the OLGA staging system). Gastritis staging arranges the histological phenotypes of gastritis along a scale of progressively increasing gastric cancer risk, from the lowest (stage 0) to the highest (stage IV). This tutorial aims to provide unequivocal information on how to consistently apply the OLGA staging system in routine diagnostic histology practice.

Objective: The findings of studies examining the prevalence and major risk factors of histological abnormalities of the gastric cardia have been inconsistent. Selection bias was possible in these studies depending on whether patients were referred for ulcer or gastroesophageal reflux disease (GERD). There have been no studies on non-patient populations. The aim of this study was to mitigate the potential effects of selection bias., Material and Methods: In a study comprising health-care workers, we distributed symptom questionnaires and invitations to undergo upper endoscopy. A single endoscopist performed standard endoscopy and biopsy examinations (2 antral, 2 corporal, and 2 cardiac biopsies). Staining was done using triple stain. Two pathologists, who were blinded to the results of the questionnaires and endoscopy, interpreted and recorded the histological findings., Results: A total of 226 participants underwent endoscopy. Gastric cardia, as defined by the presence of mucous glands, was identified in 191 subjects; mean age of the subjects was 45 years, 117 (61%) were women, and 49% were black. Active gastritis of the cardia was present in 58 (30.4%), chronic gastritis in 133 (69.6%), intestinal metaplasia (IM) in 29 (15.2%), and pancreatic metaplasia in 25 (13%). Direct (organisms) or indirect evidence (active anywhere or chronic gastritis in antrum or corpus) for Helicobacter pylori was present in all participants with active gastritis, 60% of subjects with chronic gastritis, and approximately half of those with IM of the cardia. Approximately 15% with chronic carditis had neither H. pylori nor GERD symptoms. There were also no significant differences in the prevalence of heartburn or acid regurgitation, or the use of histamine-2-receptor antagonists (H2RAs) or proton-pump inhibitors (PPIs) between groups with and without active or chronic gastritis, IM, or pancreatic metaplasia, whereas active or chronic gastritis in the antrum or corpus and H. pylori infection were more frequent (1.5- to 2-fold) among those with histological abnormalities of the cardia., Conclusions: Active and chronic gastritis as well as intestinal metaplasia of the gastric cardia are relatively common in health-care worker volunteers. Although GERD symptoms are not significantly associated with these abnormalities, H. pylori infection is a strong risk factor. However, a considerable number of participants with chronic gastritis of the cardia have neither H. pylori nor GERD.

Drug toxicity in the gastrointestinal tract is a common and serious medical problem; the number of drugs that can harm the gastrointestinal tract is impressive. The morbidity, mortality, and medical costs associated with drug toxicity, even when restricted to the gastrointestinal tract, are probably underestimated. Drug-induced gastrointestinal tract pathology is very diverse and can mimic many non-drug-related conditions. Drug toxicity, whether direct or indirect, can be restricted to a segment of the gastrointestinal tract or affect the entire gastrointestinal tract. The consequences of drug toxicity are also quite variable and can range from unimportant pathology (e.g. the relatively common and usually benign drug-induced diarrhea) at one end of the spectrum, to fatal gastrointestinal tract hemorrhage or perforation at the other end of the spectrum. Better awareness of the possibility of drug-induced gastrointestinal tract pathology, by both gastroenterologists and pathologists, and better communication between gastroenterologists, pathologists and other specialists will improve the recognition of drug-induced gastrointestinal tract pathology, and, ultimately, improve patient care. This Review focuses on the most common and well-described drug-related clinicopathologic conditions of the gastrointestinal tract. Much discussion is, therefore, dedicated to NSAIDs--the most commonly prescribed drugs and consequently the drugs most commonly associated with gastrointestinal tract toxicity.

Recent data suggest that the interaction between gastroesophageal reflux disease (GERD) and eosinophilic esophagitis can be complex, and that the notion of establishing a clear distinction between the two disorders may be too simplistic. There are at least four situations in which GERD might be associated with esophageal eosinophils: (a) GERD causes esophageal injury that results in a mild eosinophilic infiltration, (b) GERD and eosinophilic esophagitis coexist but are unrelated, (c) eosinophilic esophagitis contributes to or causes GERD, or (d) GERD contributes to or causes eosinophilic esophagitis. The high frequency of GERD described in adult patients with eosinophilic esophagitis suggests that there may be more than a chance association between the two disorders. This report discusses potential mechanisms for the complex interaction between GERD and eosinophilic esophagitis. We hope that this information will serve as a conceptual basis for future studies on the relationship between the two disorders. Whereas there are a number of plausible mechanisms whereby GERD might contribute to the accumulation of eosinophils in the esophageal epithelium, it seems prudent to recommend a clinical trial of proton pump inhibitor (PPI) therapy even when the diagnosis of eosinophilic esophagitis seems clear-cut. Furthermore, we suggest that a favorable response to PPI therapy does not preclude a diagnosis of eosinophilic esophagitis.

"Carditis" (inflammation of the gastric cardiac mucosa) may be associated with gastroesophageal reflux disease (GERD), whereas other studies argue that Helicobacter pylori could play a significant role in the chronic cardiac damage. We examined prospectively histologic features of gastric cardia, esophagitis, and H. pylori status in 204 consecutive subjects with GERD symptoms (57.3% male, 42.7% female mean age 49.2 y) undergoing upper gastrointestinal endoscopy with multiple biopsies in the distal esophagus, cardiac region, and stomach. These were assessed for esophagitis landmarks [Ismail Beigi grading (g0-3)], gastritis, and H. pylori infection (Sydney classification). The average symptom duration was 10.8 months. Endoscopy showed no erosive disease in 54.5% patients, grade "A" esophagitis in 37.6%, "B" in 8%, and "C" in 1 case. Histologic examination disclosed g0 in 8.3% patients, g1 in 78.4%, g2 in 12.8%, and g3 in 1; analysis of the cardia showed oxyntic mucosa in 27.9% patients and chronic cardiac mucosa inflammation in 72.1%. Carditis was significantly related to macroscopic esophagitis (P=0.044) and heartburn score (P=0.001). H. pylori cardiac infection was present in 27.4% cases (73.2% associated with cardiac mucosa). Gastric H. pylori infection was demonstrated in 35% patients. H. pylori in the cardiac region was associated with gastric H. pylori infection (P=0.001) and with paucity of GERD symptoms (P=0.05). A good correlation between carditis and GERD, concerning symptoms and macroscopic esophagitis was found in this study. H. pylori-related carditis is likely to be differently compared with the GERD-related type.

Background and Aims: Helicobacter pylori interact with epithelial cells resulting in activation of cellular signaling pathways leading to an inflammatory response. The pattern and timing of transcription factor activation in H pylori-infected gastric mucosa remain unclear. We investigated the roles of transcription factors in the gastric mucosa of H pylori-infected gerbils over the course of the infection., Methods: Six-week-old male Mongolian gerbils were inoculated orally with H pylori TN2GF4 or isogenic cagE mutants and examined at 1, 3, 9, and 18 months. We examined the expression of 54 transcription factors using DNA/protein arrays and electrophoretic mobility shift assays. Phosphorylation status of mitogen-activated protein kinases and IkappaB were evaluated by immunoblot and immunohistochemistry., Results: Ten transcription factors were up-regulated by H pylori infection. Six of these factors, including activator protein-1 (AP-1) and cAMP responsive element binding protein (CREB), reached maximal levels at 3 months and were strongly correlated with cellular inflammation and ulceration. Phosphorylation of extracellular signal-regulated kinase correlated with activation of AP-1 and CREB. Levels of nuclear factor-kappaB and interferon-stimulated responsive element (ISRE) peaked at 18 months and correlated with the presence of severe atrophy and with phosphorylation of Jun-N-terminal kinase (JNK), p38, and IkappaB., Conclusions: The gastric mucosal transcription factors induced by H pylori infection differed according to the phase and outcome of infection; AP-1 and CREB levels were early responders related to inflammation and ulceration, whereas NF-kappaB and ISRE were late responders related to atrophy.

Background: Numerous hypotheses on the cause of Napoleon Bonaparte's death have been proposed, including hereditary gastric cancer, arsenic poisoning, and inappropriate medical treatment. We aimed to determine the etiology and pathogenesis of Napoleon's illness by a comparison of historical information with current clinicopathologic knowledge., Investigations: Evaluation of Napoleon's clinical history, original autopsy reports, and of historical documents. The clinicopathologic data from 135 gastric cancer patients were used for comparison with the data available on Napoleon., Diagnosis: At least T3N1M0 (stage IIIA) gastric cancer. Napoleon's tumor extended from the cardia to the pylorus (>10 cm) without infiltration of adjacent structures, which provides strong evidence for at least stage T3. The N1 stage was determined by the presence of several enlarged and hardened regional (perigastric) lymph nodes, and the M0 stage by the absence of distant metastasis. Analysis of the available historical documents indicates that Napoleon's main risk factor might have been Helicobacter pylori infection rather than a familial predisposition., Conclusions: Our analysis suggests that Napoleon's illness was a sporadic gastric carcinoma of advanced stage. Patients with such tumors have a notoriously poor prognosis.

Objectives: To review the most recent information on the incidence, clinical course, pathology, pathogenesis, diagnosis, and treatment of rheumatoid vasculitis (RV), including the still scanty data on the use of biologics., Methods: PubMed and MEDLINE databases (1950-2006) were searched for the key words "vasculitis" and "rheumatoid arthritis"; and "rheumatoid arthritis" and "extra-articular manifestations." All relevant articles in English and French were reviewed. Additional words used in follow-up research include "anti-TNF," "rituximab," "IL-1 receptor antagonists," and "CTLA-4 Ig," all in conjunction with "vasculitis." Pertinent secondary references were also retrieved., Results: RV is an inflammatory condition of the small- and medium-sized vessels that affects a subset of patients with established rheumatoid arthritis (RA) (approximately 1 to approximately 5%). It has a vast array of clinical manifestations with a predilection for the skin (peripheral gangrene, deep cutaneous ulcers) and the peripheral nervous system (mononeuritis multiplex). Because of the lack of specific signs and symptoms, the diagnosis relies on the exclusion of other causes of similar lesions (diabetes, atherosclerosis, drug reactions, infection, neoplasias) and, ideally, on the histopathological demonstration of necrotizing vasculitis. Despite the availability of a host of promising new drugs for the treatment of RA, no clinical trials have tested their efficacy in RV; therefore, its management remains largely empirical., Conclusions: Although RV has apparently been decreasing over the last 2 decades, possibly as a consequence of the more energetic approach to the management of RA currently used, it remains an important complication of RA that needs to be promptly recognized and treated.

Although the Sydney Systems (original and updated) for the classification of gastritis have contributed substantially to the uniformity of the reporting of gastric conditions, they lack immediacy in conveying to the user information about gastric cancer risk. In this review, we summarize the current understanding of the gastric lesions associated with an increased risk for cancer, and present the rationale for a proposal for new ways of reporting gastritis. In addition to the traditional histopathological data gathered and evaluated according to the Sydney System rules, pathologists could add an assessment expressed as grading and staging of the gastric inflammatory and atrophic lesions and integrate these findings with pertinent laboratory information on pepsinogens and gastrin levels. Such an integrated report could facilitate clinicians' approach to the management of patients with gastric conditions.

Background and Aims: Patients with Helicobacter pylori gastritis are more likely to have increased duodenal intraepithelial lymphocytes (IEL); this can be reversed by H. pylori eradication. We hypothesized that: (1) H. pylori-infected celiac disease (CD) patients could have different clinicopathological features from noninfected subjects; and (2) the histopathological responses to a gluten-free diet could be different in H. pylori-infected and noninfected patients., Methods: Duodenal and gastric biopsies obtained from 80 adults with histologically and serologically confirmed CD before and after 12-18 months of a gluten-free diet were retrospectively evaluated. Gastritis was classified and scored according to the Updated Sydney System; duodenal biopsies were classified using both the Marsh-Oberhuber and a simplified classification proposed by our group., Results: At baseline, 30 patients had H. pylori infection and 50 did not; at follow-up five new infections were detected. Fifteen patients (3 H. pylori-positive and 12 negative) had lymphocytic gastritis. At baseline, a greater proportion of H. pylori-negative patients had severe villous atrophy (p < 0.01), but milder forms were more prevalent in H. pylori-positive patients (p < 0.01). After a gluten-free diet, significant improvement occurred in all duodenal features (p < 0.001), irrespective of H. pylori status; gastric variables did not change, except for lymphocytic, which resolved in 2 infected and 10 noninfected patients., Conclusions: The clinical features of CD patients are unrelated to H. pylori gastritis, and a gluten-free diet is equally effective in infected as in uninfected patients. The higher prevalence of milder duodenal lesions in CD patients with H. pylori infection suggests that lymphocytosis induced by H. pylori gastric infection becomes less obvious as profound inflammatory and structural changes alter the mucosal architecture. This study also provides further support for a pathogenetic relationship between CD and lymphocytic gastritis.

The purpose of this study was to determine whether Helicobacter pylori infection and mucosal inflammation result in gastric atrophy in Japanese children. A total of 196 patients ages 1-16 years were retrospectively studied: 131 patients were infected with H. pylori and 65 patients were uninfected. Antral (n = 196) and corpus biopsy specimens (n = 70) were investigated based on the Updated Sydney system. In both the antrum and corpus, H. pylori-infected patients showed significantly higher degrees of inflammation and activity of gastritis, compared with noninfected patients. The prevalence of grade 2 or 3 atrophy in the antrum was 10.7% in H. pylori-infected patients and 0% in the noninfected patients (P < .01) and in corpus 4.3% and 0%, respectively (P = .20). The frequency of intestinal metaplasia in the 2 study groups was 4.6% and 4.6% in the antrum and 0% and 4.2% in the corpus, respectively. Among H. pylori-infected patients, the antrum showed significantly higher degrees of H. pylori density, inflammation and activity of gastritis, and atrophy than the corpus. In the antrum, atrophy was significantly correlated with activity, whereas in the corpus, atrophy correlated with H. pylori density, inflammation, and activity. H. pylori-induced gastric inflammation can cause atrophy in Japanese children, predominantly in the antrum. It remains to be determined whether H. pylori-infected children with gastric atrophy are at increased risk for gastric cancer.

Medical error is a subject that receives increasing attention from physicians, legislators and attorneys. Taking the lead from a personal event in the author's career, the article focuses on errors in the practice of anatomic pathology. It discusses the difficulties of objectively separating true diagnostic mistakes from the great variability of informed opinions that exists in pathology; such variability makes the definition of error particularly arduous. Some of the possible causes of diagnostic errors and ways to deal with their potentially disastrous consequences are also discussed.

Reactive or chemical gastropathy is the constellation of endoscopic and histological changes caused by chemical injury to the gastric mucosa. Its diagnosis rests on the histopathological demonstration of nonspecific elementary lesions that may occur simultaneously or separately in different degrees and various proportions. These lesions include foveolar hyperplasia, interfoveolar smooth muscle fibers, erosions, edema, and hyperemia, in the absence of significant inflammation. Their respective occurrence in a set of gastric biopsies can be placed on a spectrum of diagnostic certainty that is never absolute because each of such changes can and does occur in other conditions. Although a correlation between histological evidence of chemical gastropathy and clinical manifestations, particularly risk of bleeding, is yet to be documented, reporting the suspicion of drug-induced gastric damage may help clinicians to identify patients that might benefit from change, reduction, or discontinuation of certain medications.

Chronic gastritis is an inflammatory condition of the gastric mucosa that may include structural alterations of the glandular compartment. The semiquantitative scoring systems advocated in the Sydney Systems and the subsequent Atrophy Club Guidelines remain essential for the recognition of the spectrum of the lesions detectable in gastric inflammatory disease. Most practicing pathologists, however, find them too cumbersome to use in their routine diagnostic activities. In this article, we propose a reporting system for chronic gastritis in staging and grading. Staging would convey information on the topography and extension of the gastric atrophic changes, whereas grading should represent the semiquantitative assessment of the combined severity of both mononuclear and granulocytic inflammation. This system could offer gastroenterologists a more immediate perception of the overall condition of the gastric mucosa while also providing useful information about gastric cancer risk.

Gastric cancer remains the second most frequent and lethal malignancy worldwide, with a wide range of incidence rates in different populations. Reducing its incidence is a priority in many high-risk countries, and screening programmes are often advocated as an option. An effective screening programme should have the following characteristics: (i) the disease should be common in the population, otherwise the individual benefit will not offset the risk, cost and inconvenience of screening of the rest of the population; (ii) the diagnostic test(s) used should be safe, simple, inexpensive and reliable; and (iii) effective treatment should be available. With respect to gastric cancer, these conditions are not fulfilled completely in any population and therefore population-based screening does not appear to be a viable approach to the prevention of this neoplasia. In contrast, gastroscopic screening in selected high-risk subjects would seem appropriate. A more effective strategy, particularly in high-incidence populations, could be the widespread screening and treatment for Helicobacter pylori infection. This could result in the virtually complete elimination of chronic gastritis and its associated conditions, including most peptic ulcers, primary gastric B-cell lymphomas and a major portion of gastric epithelial tumours.

Background & Aims: White people in the United States are several-fold more affected by esophageal adenocarcinoma than black people. It remains unknown whether this racial discrepancy reflects a higher prevalence of gastroesophageal reflux disease (GERD) symptoms or a higher degree of esophageal damage., Methods: A cross-sectional survey followed by endoscopy was performed among employees at a VA medical center. The association between race and GERD symptoms and erosive esophagitis was analyzed in logistic regression analyses controlling for demographic, clinical, and histologic variables., Results: A total of 496 of 915 people (54%) returned interpretable questionnaires, and endoscopy was performed in 215 participants. The mean age was 45 years, and 336 (68%) were women. Racial distribution was 43% black, 34% white, and 23% other races. Heartburn occurring at least weekly was reported in 27%, 23%, and 24% of these racial groups, respectively. The age-adjusted prevalence of heartburn or regurgitation was not significantly different among the groups. Erosive esophagitis was found in 50 of 215 participants (23%); 31 of these cases were mild. Only one person had Barrett's esophagus (0.4%). For weekly heartburn or regurgitation, black participants had significantly less frequent erosive esophagitis than white participants (24% vs. 50%; P = 0.03). With multiple adjustments, black participants had a persistently lower risk of esophagitis (adjusted odds ratio, 0.22-0.46; P < 0.001)., Conclusions: White and black people in the United States have a similarly high prevalence of GERD symptoms. However, black people have a lower prevalence of esophagitis for the same frequency of GERD symptoms. Barrett's esophagus was rare in this study, even among those with frequent symptoms.

Objective: The clinical course of gastroesophageal reflux disease (GERD) in children without comorbid illness (neurological deficits, congenital esophageal anomalies, chronic obstructive airway conditions) is unclear. Whether GERD in childhood progresses or predisposes to GERD in adulthood remains unknown., Methods: We identified a cohort of individuals endoscopically diagnosed with GERD in childhood between 1990 and 1996. We excluded patients with comorbid illnesses. Eligible persons were contacted by telephone in person or through a household member and requested to complete a validated (in adults) symptom questionnaire between February 2001 and February 2003. Respondents were invited to undergo an upper endoscopy or to share results of any endoscopic examination performed within the past 12 months. We calculated the proportion of persons with GERD symptoms (monthly, weekly), and with current use of antisecretory medications (histamine-2-receptor antagonists [H2RA], proton pump inhibitors [PPI])., Results: A total of 207 persons satisfied the inclusion and exclusion criteria and were contacted. Of those, 80 (39%) completed the questionnaire and 14/80 (18%) had an upper endoscopy. The mean age of participants was 20 years (SD = 4, range 10-40); most were Caucasian (73%), and 60% were female. GERD was documented at a mean age of 5 years (approximately a 15-yr duration of follow-up). Most participants (64/80, 80%) had at least monthly heartburn and/or acid regurgitation reported within the past 12 months; 18/80 (23%) reported at least weekly symptoms, and an additional three patients were asymptomatic but taking antisecretory therapy (H2RA or PPI). If all nonresponders were considered free of symptoms, then at least 31% had monthly symptoms, and 9% had weekly symptoms. Overall, 24 (30%) were currently taking either H2RA or PPI, and 19 patients had undergone fundoplication. There were no statistically significant differences between those who reported monthly GERD symptoms, weekly GERD symptoms, or no GERD symptoms as far as demographic features, age of GERD onset, receipt of fundoplication, or current GERD treatment. At endoscopy, three patients had mild to moderate erosive esophagitis., Conclusions: GERD in otherwise normal children can persist through adolescence and adulthood in a significant proportion of patients who continue to have GERD symptoms and signs, and use antisecretory medications. Childhood GERD is a risk factor for GERD in adolescence and adulthood.

Although regenerating gene (Reg) protein is reported to have a trophic effect on gastric epithelial cells, its involvement in human gastric diseases is not clear. We have recently shown that both gastrin and gastric mucosal inflammation enhance Reg gene expression in the fundic mucosa in rats. This study was designed to clarify whether Reg protein is involved in Helicobacter pylori-induced gastritis and whether Reg gene expression is linked to serum gastrin levels in this condition. Mongolian gerbils were inoculated with an H. pylori strain isolated from a gastric cancer patient. Four weeks later, some of the gerbils with H. pylori infection were eradicated by lansoprazole, amoxicillin, and clarithromycin. The time courses of changes in Reg gene expression, serum gastrin levels, gastric acidity, and histopathologic factors were examined. Four weeks after H. pylori infection, gastritis started spreading to the fundic mucosa, and gastric acidity started reducing. Serum gastrin levels and Reg mRNA expression in the fundus were significantly increased 6 weeks after infection. Reg mRNA expression in the fundus correlated significantly with both serum gastrin levels and the severity of fundic mucosal inflammation. After H. pylori eradication, serum gastrin levels and fundic mucosal inflammation were normalized, and the increase in Reg mRNA expression was abolished. The Reg gene is associated with hypergastrinemia and fundic mucosal inflammation and may be involved in H. pylori-induced gastritis.

We investigated the expression of cyclooxygenase-2 (COX-2) and COX-1 mRNAs during longterm Helicobacter pylori infection of the Mongolian gerbil (18 months) as well as the effect of eradication therapy and the cag pathogenicity island on COX mRNA expression. COX mRNA levels were determined by reverse transcription-polymerase chain reaction. Pyloric channel ulcers were noted in one of 10 gerbils (10%) at 3 months, 33% at 6 months, 50% at 9 months, 17% at 10 months, 40% at 12 months and 25% at 18 months after inoculation of parental strains. Nineteen of 21 gerbils had successful H. pylori eradication and showed significant reduction of inflammation and no ulcerations. There were no significant differences in COX-1 mRNA expression between the groups. COX-2 mRNA expression was significantly increased 1 and 3 months after inoculation and then decreased to basal levels. In control animals, COX-2 mRNA expression was significantly higher at 12 and 18 months compared to younger animals. cagE knockout mutants did not induce gastric inflammation and induced significantly lower COX-2 mRNA expression compared to parental strains. COX-2 mRNA was induced early in H. pylori infection and then declined. COX-2 mRNA expression was also induced with aging.

Rebamipide stimulates the generation of endogenous prostaglandins in the gastric mucosa and is reported to accelerate ulcer healing. This review discusses whether rebamipide can prevent Helicobacter pylori infection, reduce inflammation, accelerate healing after eradication, promote ulcer healing, and prevent progression of preneoplastic lesions. Furthermore, we evaluate its usefulness in other inflammatory conditions of the gastrointestinal tract. We conclude that rebamipide is an important candidate for long-term suppression of gastro-intestinal inflammation, particularly if reducing the complications of H. pylori infection without eradicating the organism becomes accepted. If its ability to accelerate mucosal normalization is confirmed, rebamipide could be added to eradication regimens. Little information exists on whether such therapy could help limit the development of pre-neoplastic lesions. In light of the dearth of effective drugs to control inflammation in idiopathic inflammatory bowel disease, the potential of any promising new and safe compound deserves to be fully explored. The next step is to devise a targeted plan of translational research, so that results from the bench may be used to design rigorously controlled international clinical trials.

Objective: The aim of this study was to determine the effect of 6-12 months of treatment with esomeprazole on the histopathology of the gastric mucosa., Methods: Two identically designed, randomized, placebo-controlled trials of esomeprazole 40, 20, or 10 mg daily for up to 6 months, as well as a noncomparative, multicenter trial of esomeprazole 40 mg daily for up to 12 months, were conducted in 1326 patients with healed erosive esophagitis (1294 negative for Helicobacter pylori [H. pylori]). Gastric biopsy samples were obtained before treatment and on completion of (or discontinuation from) the trials. Samples were evaluated for the presence of H. pylori, characteristics of acute gastritis or atrophic gastritis, and enterochromaffin-like cell pathology., Results: During treatment with esomeprazole, the number of patients with an improvement in gastric histological scores was typically greater than or equal to the number who worsened. Gastric histological scores worsened for each corporal or antral characteristic of gastritis in <6.2% of patients. Histological scores with esomeprazole and placebo were similar throughout the 6-month trials. Only one among 1326 patients treated with esomeprazole (H. pylori negative) had evidence of treatment-emergent atrophic gastritis. On final biopsy, 5-12% of patients had abnormal enterochromaffin-like cell scores (simple, linear, or micronodular hyperplasia). There were no instances of enterochromaffin-like cell dysplasia, carcinoids, or neoplasia., Conclusions: Patients with healed erosive esophagitis receiving esomeprazole for up to 12 months had minor fluctuations in gastric histological scores, similar to those experienced in untreated populations. Use of esomeprazole did not raise any safety concerns with respect to the development of atrophic gastritis, or cause clinically significant changes in enterochromaffin-like cells.

Most gastric polyps, adenocarcinomas, carcinoids, and B cell lymphomas arise on a gastric mucosa damaged by long-standing chronic gastritis. The most common form of chronic gastritis is caused by infection with Helicobacter pylori. All patients with H. pylori infection develop lymphoid aggregates with germinal centers that interact intimally with the gastric mucosa (mucosa-associated lymphoid tissue [MALT]); these follicles are the condition sine qua non for the development of primary B cell mantle lymphomas, also known as MALT lymphomas. As the infection progresses, atrophy of the gastric mucosa develops in a subset of patients, which is replaced by an intestinal-type epithelium (intestinal metaplasia). On this background, dysplasia and adenocarcinomas of the intestinal type may develop. When atrophy is sufficiently severe to impair acid production, the gastrin-producing cells of the antrum increase their secretion of gastrin and stimulate endocrine cells in the corpus, which may eventually proliferate, become dysplastic, and give raise to carcinoids. This development is more frequent in advanced cases of autoimmune gastritis associated with pernicious anemia. On this background, there is also extensive epithelial hyperplasia and the formation of hyperplastic or inflammatory polyps, a small percentage of which may become dysplastic and progress to adenocarcinoma. Chronic exposure of the corpus mucosa to pancreaticoduodenal secretions ("bile reflux") causes reactive mucosal changes that may predispose to neoplasia. Thus, the progression of inflammation to atrophy to metaplasia, and in some cases chronic chemical injury, may give rise, at different times and under the influence of other, unknown stimuli, to most types of gastric tumors. Other types of gastritis, including lymphocytic and granulomatous gastritis, are rare and have not been associated with gastric neoplasia. Awareness of these associations, appropriate treatment policies, and implementation of endoscopic surveillance programs would dramatically reduce the incidence of most types of gastric neoplasms and would allow the detection of many tumors at a stage when endoscopic resection or conservative treatment would still be possible.

Helicobacter pylori(H. pylori) are an organism that can be confidently recognized by histology. Using histological specimens, we can both identify infection and assess pathological condition associated with H. pylori. For the precise diagnosis, biopsies should be taken from suitable sites(greater curvature of antrum and corpus) and the valuable requirements are to recognize several pathologic findings of H. pylori--infected gastric mucosa(epithelial changes and neutrophilic infiltration together with mononuclear cell infiltration) and to use special staining methods for H. pylori(i.e. Giemsa staining, Gimenez staining, silver staining, and immunostaining) in addition to HE staining.

Background: Relatives of gastric cancer patients have an increased risk of gastric cancer, possibly related to genetically-related strains of Helicobacter pylori or a common environment., Methods: The pattern of gastritis and H. pylori from gastric cancer patients and their first-degree relatives were compared using detailed DNA fingerprints and vacA, cagA, and iceA genotyping., Results: Sixteen index cases from Korea, the US, or Colombia and their 38 first-degree relatives (brothers, sisters, sons and daughters) were studied. No definite, or consistent, relationship between the pattern of gastritis and the relatedness of the H. pylori strain was observed (i.e. relatives could have an identical or a totally different pattern of gastritis regardless if they were infected with identical or highly similar organisms). For example, three elderly siblings of an index case with atrophic pangastritis had identical H. pylori isolates and environments in childhood and yet two had antral predominant nonatrophic gastritis, which is typically associated with duodenal ulcer instead of gastric cancer., Conclusions: The results of this study are not consistent with the hypothesis that specific virulence factors or similar H. pylori strains correlate with a specific histologic pattern or outcome even among those sharing the same environment in childhood.

Continuing attempts have been made to classify pathogenic strains within bacterial populations based on DNA fingerprints and to identify virulence factors in H. pylori. We studied 287 H. pylori isolates from patients with duodenal ulcer or gastric cancer from three different geographic regions. DNA fingerprints were generated using REP-PCR and analyzed by cluster analysis. The status of three candidate virulence factors-vacA polymorphism, cagA and iceA,-were examined by PCR amplification. Cluster analysis of the REP-PCR fingerprints showed clustering by geographic region but not by disease presentation. cagA was detected in 91.3% of the isolates. Differences in vacA subtypes were observed among the three geographic regions. There was no association between iceA subtypes and clinical outcome. We conclude that geographic differences among the H. pylori strains exist in single gene allelic variants as well as in the conserved noncoding regions such as REP sequences throughout the entire bacterial genome. We did not detect any association between disease presentation and H. pylori genotypes using either DNA fingerprinting or candidate single gene virulence factors.

Background: Expression of the angiogenic factor platelet-derived endothelial cell growth factor is induced in some gastric carcinomas. Whether angiogenesis is induced early in the development of gastric pre-neoplastic lesions and whether Helicobacter pylori infection affects platelet-derived endothelial cell growth factor expression is not known., Aim: To assess whether chronic gastritis, intestinal metaplasia, gastric dysplasia and gastric carcinomas express platelet-derived endothelial cell growth factor and whether Helicobacter pylori infection might affect the expression of platelet-derived endothelial cell growth factor in these lesions., Patients and Methods: Patients with gastric carcinomas, atrophic gastritis with associated intestinal metaplasia, dysplasia and controls without infection or carcinoma were studied., Results: Platelet-derived endothelial cell growth factor was detected by immunohistochemistry in 9 out 19 gastric carcinomas (45%). Only focal immunostaining was detected in intestinal metaplasia adjacent to dysplasia and in dysplastic cells. Of the tumours, 90% contained platelet-derived endothelial cell growth factor-positive interstitial cells. A significant correlation was found between active Helicobacter pylori infection and a larger number of platelet-derived endothelial cell growth factor-positive interstitial cells in areas of intestinal metaplasia (p<0.05)., Conclusion: Helicobacter pylori infection does not influence the expression of platelet-derived endothelial cell growth factor, once gastric cancer has developed. However, Helicobacter pylori infection may increase the extension of expression of platelet-derived endothelial cell growth factor by infiltrating interstitial cells in premalignant lesions, such as intestinal metaplasia, which may help create a favourable environment for tumour development. This may possibly be due to non-specific increase in recruitment of inflammatory cells caused by Helicobacter pylori infection. Further studies, with a larger number of samples, are now needed in order to confirm this finding.