Detection of Mutations in Barrett's Esophagus Before Progression to High-Grade Dysplasia or Adenocarcinoma.

BACKGROUND & AIMS: Barrett's esophagus (BE) is the greatest risk factor for esophageal adenocarcinoma (EAC), but only a small proportion of patients with BE develop cancer. Biomarkers might be able to identify patients at highest risk of progression. We investigated genomic differences in surveillance biopsies collected from patients whose BE subsequently progressed compared to patients whose disease did not progress. METHODS: We performed a retrospective case-control study of 24 patients with BE that progressed to high-grade dysplasia (HGD, n = 14) or EAC (n = 10). The control group (n = 73, called non-progressors) comprised patients with BE and at least 5 years of total endoscopic biopsy surveillance without progression to HGD or EAC. From each patient, we selected a single tissue sample obtained more than 1 year before progression (cases) or more than 2 years before the end of follow-up (controls). Pathogenic mutations, gene copy numbers, and ploidy were compared between samples from progressors and non-progressors. RESULTS: TP53 mutations were detected in 46% of samples from progressors and 5% of non-progressors. In this case-control sample set, TP53 mutations in BE tissues increased the adjusted risk of progression 13.8-fold (95% confidence interval, 3.2-61.0) (P < .001). We did not observe significant differences in ploidy or copy-number profile between groups. We identified 147 pathogenic mutations in 57 distinct genes-the average number of pathogenic mutations was higher in samples from progressors (n = 2.5) than non-progressors (n = 1.2) (P < .001). TP53 and other somatic mutations were recurrently detected in samples with limited copy-number changes (aneuploidy). CONCLUSIONS: In genomic analyses of BE tissues from patients with or without later progression to HGD or EAC, we found significantly higher numbers of TP53 mutations in BE from patients with subsequent progression. These mutations were frequently detected before the onset of dysplasia or substantial changes in copy number.

Routine Anti-Helicobacter Immunohistochemical Staining is Significantly Superior to Reflex Staining Protocols for the Detection of Helicobacter in Gastric Biopsy Specimens.

BACKGROUND: The role of special stains in the detection of H. pylori is controversial; some pathologists claim that hematoxylin and eosin staining alone is adequate to detect bacteria, while others maintain that immunohistochemical staining must be used on all gastric biopsies. This study was designed to test the hypothesis that hematoxylin and eosin and histochemical special stains have similar sensitivity and that immunohistochemical staining only marginally enhances the detection rate of the organisms. MATERIALS AND METHODS: Records of all gastric biopsies examined in a large pathology laboratory between January 1, 2010 and December 31, 2014 were extracted and stratified according to the stain used for the detection of Helicobacter (1. hematoxylin and eosin only; 2. Upfront HP Blue; 3. Upfront HP Blue including reflex immunohistochemistry; 4. Upfront anti-Helicobacter immunohistochemical staining. RESULTS: Gastric biopsies from 794,859 endoscopies obtained from 622,945 unique patients were analyzed. The basic demographics of the patients in different staining groups were identical. A total of 56,955 gastric biopsy sets were stained with histochemical stains only, and 731,193 with anti-Helicobacter immunohistochemical stain; in 4409 of these, an immunohistochemical stain was also performed. In 2302 cases, only hematoxylin and eosin were performed. In this latter group, 7.0% of patients were Helicobacter-positive; in the upfront HP Blue, the prevalence was 7.8%, whereas patients with upfront immunohistochemistry had a prevalence of 10.2% (p < .0001, compared to hematoxylin and eosin only). CONCLUSIONS: There was a dramatic improvement in detection of H. pylori infection through the use of upfront immunohistochemical stains. Therefore, we contend that the routine use of IHC for all gastric biopsies is an appropriate protocol to ensure that every patient gets the right answer.

Commercially available biological mesh does not prevent stricture after esophageal mucosectomy.

BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection (EMR) offers a minimally invasive therapy for advanced esophageal dysplasia and early cancers but stricture formation limits its applicability. We aimed at assessing the efficacy of placement of a commercially available biological mesh for preventing stricture formation following esophageal EMR. METHODS: 25 swine were submitted to circumferential esophageal EMR with 10-cm extent and divided in five groups: one group with EMR only (control); one receiving an uncovered stent (stent-only group); and three groups receiving a stent covered with one of three extracellular matrices, namely small intestine submucosa (SIS group), acellular dermal matrix (ADM group), or urinary bladder matrix (UBM group). Stricture formation was evaluated with weekly esophagograms. RESULTS: The stent-only group had significantly less stricture formation and survival was extended compared with controls (4.8 vs. 2.4 weeks). Compared with stenting only, the addition of a biological mesh did not reduce stricture formation: percent reductions in esophageal diameter for the groups were SIS 86 %, ADM 94 %, and UBM 94 %, compared with 82 % in the stent-only group. CONCLUSIONS: Placement of commercially available biological meshes did not alter remodeling sufficiently to prevent stricture formation after esophageal EMR.

Preliminary results of antiscarring therapy in the prevention of postendoscopic esophageal mucosectomy strictures.

BACKGROUND: Esophageal endoscopic submucosal dissection (ESD) is an effective minimally invasive therapy for early esophageal cancer and high-grade Barrett dysplasia. However, esophageal stricture formation after circumferential or large ESD has limited its wide adoption. Mitomycin C (MMC), halofuginone (Hal), and transforming growth factor ß3 (TGF-ß3) exhibits antiscarring effects that may prevent post-ESD stricture formation. METHODS: Using endoscopic mucosectomy (EEM) technique, an 8- to 10-cm-long circumferential esophageal mucosal segment was excised in a porcine model. The site was either untreated (control, n = 6) or received 40 evenly distributed injections of antiscarring agent immediately and at weeks 1 and 2. High and low doses were used: MMC 5 mg (n = 2), 0.5 mg (n = 2); Hal 5 mg (n = 2), 1.5 mg (n = 2), 0.5 mg (n = 2); TGF-ß3 2 µg (n = 2), 0.5 µg (n = 2). The degree of stricture formation was determined by the percentage reduction of the esophageal lumen on weekly fluoroscopic examination. Animals were euthanized when strictures exceeded 80 % or the animals were unable to maintain weight. RESULTS: The control group had a luminal diameter reduction of 78.2 ± 10.9 % by 2 weeks and were euthanized by week 3. Compared at 2 weeks, the Hal group showed a decrease in mean stricture formation (68.4 % low dose, 57.7 % high dose), while both TGF-ß3 dosage groups showed no significant change (65.3 % low dose, 76.2 % high dose). MMC was most effective in stricture prevention (53.6 % low dose, 35 % high dose). Of concern, the esophageal wall treated with high-dose MMC appeared to be necrotic and eventually led to perforation. In contrast, low dose MMC, TGF-ß3 and Hal treated areas appeared re-epithelialized and healthy. CONCLUSIONS: Preliminary data on MMC and Hal demonstrated promise in reducing esophageal stricture formation after EEM. More animal data are needed to perform adequate statistical analysis in order to determine overall efficacy of antiscarring therapy.

Editorial: no bugs bugging you? Emerging insights into Helicobacter-negative gastritis.

Depending on how it is defined, between 3 and 20% of patients who have gastric biopsy specimens are diagnosed with "Helicobacter-negative gastritis." In a paper published in this issue of the Journal, data regarding use of tobacco, alcohol, nonsteroidal anti-inflammatory drugs, and proton pump inhibitors were collected from 41 patients with gastritis in whom no Helicobacters were detected by histology and culture and had negative serology. No significant associations with any of the parameters evaluated were found. Further studies are warranted to elucidate this elusive entity. Additional methods (e.g., the urea breath test and polymerase chain reaction) could be used to exclude Helicobacter infection, and a search for other candidate infectious agents (bacteria and Epstein-Barr virus) should be undertaken in those patients found to be unequivocally uninfected with Helicobacter.

Inverse association of esophageal eosinophilia with Helicobacter pylori based on analysis of a US pathology database.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is of increasing prevalence and believed to result from allergic processes. Helicobacter pylori has been inversely associated with allergic diseases, but there is no known relationship between H pylori, EoE, and esophageal eosinophilia. We investigated the association between esophageal eosinophilia and H pylori infection. METHODS: We performed a cross-sectional study of data, collected from a US pathology database, on 165,017 patients in the United States who underwent esophageal and gastric biopsies from 2008 through 2010. Patients with and without H pylori on gastric biopsy were compared, and odds of esophageal eosinophilia were determined. RESULTS: From the data analyzed, 56,301 (34.1%) had normal esophageal biopsy specimens, 5767 (3.5%) had esophageal eosinophilia, and 11,170 (6.8%) had H pylori infection. Esophageal eosinophilia was inversely associated with H pylori (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.69-0.87). Compared with patients with normal esophageal biopsy specimens, odds of H pylori were reduced among patients with ≥ 15 eosinophils per high-power field (eos/hpf) (OR, 0.79; 95% CI, 0.70-0.88), ≥ 45 eos/hpf (OR, 0.75; 95% CI, 0.61-0.93), ≥ 75 eos/hpf (OR, 0.72; 95% CI, 0.50-1.03), and ≥ 90 eos/hpf (OR, 0.52; 95% CI, 0.31-0.87) (P for trend <.001). A similar dose-response trend was observed for increasing clinical suspicion for EoE and decreasing prevalence of H pylori. Additionally, severity of histologic effects of H pylori was inversely associated with esophageal eosinophilia. All trends held in multivariate analysis. CONCLUSIONS: In a large cross-sectional analysis, H pylori infection was inversely associated with esophageal eosinophilia. This relationship could have implications for the pathogenesis and epidemiology of EoE.

Biodegradable esophageal stent placement does not prevent high-grade stricture formation after circumferential mucosal resection in a porcine model.

BACKGROUND: Advanced esophageal dysplasia and early cancers have been treated traditionally with esophagectomy. Endoscopic esophageal mucosectomy (EEM) offers less-invasive therapy, but high-degree stricture formation limits its applicability. We hypothesized that placement of a biodegradable stent (BD-stent) immediately after circumferential EEM would prevent stricturing. METHODS: Ten pigs (five unstented controls, five BD-stent) were utilized. Under anesthesia, a flexible endoscope with a band ligator and snare was used to incise the mucosa approximately 20 cm proximal to the lower esophageal sphincter. A 10-cm, circumferential, mucosal segment was dissected and excised by using snare electrocautery. In the stented group, an 18-×120-mm, self-expanding, woven polydioxanone stent (ELLA-CS, Hradec-Kralove) was deployed. Weekly esophagograms evaluated for percent reduction in esophageal diameter, stricture length, and proximal esophageal dilation. Animals were euthanized when the stricture exceeded 80% and were unable to gain weight (despite high-calorie liquid diet) or at 14 weeks. RESULTS: The control group rapidly developed esophageal strictures; no animal survived beyond the third week of evaluation. At 2 weeks post-EEM, the BD-stent group had a significant reduction in esophageal diameter (77.7 vs. 26.6%, p < 0.001) and degree of proximal dilation (175 vs. 131%, p = 0.04) compared with controls. Survival in the BD-stent group was significantly longer than in the control group (9.2 vs. 2.4 weeks, p = 0.01). However, all BD-stent animals ultimately developed clinically significant strictures (range, 4-14 weeks). Comparison between the maximum reduction in esophageal diameter and stricture length (immediately before euthanasia) demonstrated no differences between the groups. CONCLUSIONS: Circumferential EEM results in severe stricture formation and clinical deterioration within 3 weeks. BD-stent placement significantly delays the time of clinical deterioration from 2.4 to 9.2 weeks, but does not affect the maximum reduction in esophageal diameter or proximal esophageal dilatation. The timing of stricture formation in the BD-stent group correlated with the loss radial force and stent disintegration.

A national study of Helicobactor pylori infection in gastric biopsy specimens.

BACKGROUND & AIMS: We investigated whether infection with Helicobacter pylori and signs of chronic active gastritis and intestinal metaplasia in gastric biopsy samples were inversely associated with Barrett's metaplasia. METHODS: We studied gastric biopsy samples from 78,985 unique patients. Histologic findings were correlated with sociodemographic patient characteristics using multivariate logistic regression to calculate odds ratios and 95% confidence intervals. RESULTS: H pylori infection, chronic active gastritis, and intestinal metaplasia had similar epidemiologic patterns. The presence of each, based on histology analyses, was significantly associated with that of the others. They were also characterized by similar geographic distributions within the United States. All 3 disorders were more common among men and among Medicaid patients (compared with those with other insurance) and were inversely associated with Barrett's metaplasia (less frequent in patients with Barrett's metaplasia). CONCLUSIONS: H pylori infection and associated disorders, such as chronic active gastritis and intestinal metaplasia, are inversely associated with Barrett's metaplasia.

No association between gastric fundic gland polyps and gastrointestinal neoplasia in a study of over 100,000 patients.

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.

Lymphocytic disorders of the gastrointestinal tract: a review for the practicing pathologist.

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.

Gene expression-phenotype associations in adults with eosinophilic esophagitis.

BACKGROUND: Gene expression patterns have not been extensively examined in the context of clinical features of eosinophilic esophagitis (EoE). AIMS: To assess whether gene expression is associated with clinically defined phenotypes in adults with EoE. METHODS: This was an analysis of prospectively collected esophageal biopsies in newly diagnosed EoE patients. We determined differential gene expression with a 94 gene panel in relation to clinical features and phenotypes. These included: endoscopic findings of esophageal rings, stricture, narrowing, linear furrows, exudates, edema, and dilation; an allergic phenotype; an inflammatory phenotype, and a fibrostenotic phenotype. RESULTS: In 89 EoE cases analyzed, patients with exudates on endoscopy had multiple differences in gene expression compared to patients without exudates, though patients with exudates also had higher eosinophil counts (172 vs 106eos/hpf; p=.01). Genes associated with esophageal narrowing included CCL26 (q-value=0.028), ALOX15 (q=0.011), GRK5 (q=0.029), CPA3 (q=0.012), and TRIM2 (q=0.0027). TRIM2 was also associated with the fibrostenotic phenotype (q=0.0051). No genes were associated with the inflammatory or atopic phenotypes, or with dilation. CONCLUSIONS: Multiple genes are associated with exudates, possibly related to higher eosinophil counts. However, a number of genes, including those related to both inflammation and remodelling, are associated with esophageal narrowing. In particular, TRIM2 is associated with clinical fibrotic phenotypes.

A Gene Expression Panel is Accurate for Diagnosis and Monitoring Treatment of Eosinophilic Esophagitis in Adults.

OBJECTIVE: Eosinophilic esophagitis (EoE) can be difficult to diagnose. We aimed to evaluate whether a gene expression score could differentiate adult EoE cases from non-EoE controls and to determine whether scores normalized after treatment for EoE. METHODS: We analyzed prospectively collected esophageal biopsies from EoE patients (diagnosed as per consensus guidelines and after a proton pump inhibitor trial) and non-EoE controls. Gene expression for a previously constructed 94 gene panel was quantified for a single RNA-later preserved biopsy. For diagnosis, a summary expression score and the area under the receiver operating characteristic curve (AUC) were calculated. For treatment response (defined as <15 eosinophils per high-power field), pretreatment and posttreatment EoE samples were compared. RESULTS: For 91 EoE cases and 174 controls, gene scores for EoE cases were lower than non-EoE controls (mean 198 vs. 420; P<0.001), with an AUC of 0.927. A score ≤263 yielded a positive predictive value=91%; a score ≥349 yielded a negative predictive value=90%; only 12% of subjects had an indeterminate score (264-348) by this classification scheme. For the 89 EoE cases with paired pretreatment and posttreatment samples, overall gene scores improved after treatment from 199 to 343 (P<0.001). This normalization was seen only in cases with histological response (202 vs. 425; P<0.001); scores were unchanged in non-responders (189 vs. 226; P=0.25). CONCLUSIONS: A gene expression score has high diagnostic utility for distinguishing EoE patients from non-EoE controls in adults and can be used in clinical algorithms. Because it is highly responsive to treatment, the test could be used to monitor disease status.

Healthcare Cost of Over-Diagnosis of Low-Grade Dysplasia in Barrett's Esophagus.

INTRODUCTION: Published reports have demonstrated that many Barrett's esophagus patients are over-diagnosed as low-grade dysplasia (BE-LGD). We performed an analysis of the surveillance and treatment costs associated with the over-diagnosis of BE-LGD. METHODS: As the principal cost variables, we used endoscopic and histologic procedures performed during the recommended surveillance intervals for patients with BE-LGD, the national average Medicare reimbursement for the Current Procedural Terminology codes of the procedures performed, and a spreadsheet-based tool we created to determine the overall healthcare cost associated with the over-diagnosis of BE-LGD in the US population. RESULTS: The average excess cost (range) for every patient in the US who is over-diagnosed with BE-LGD is estimated to be $5557 ($3115 to $8072). The principal contributors to the excess cost of over-diagnosis of BE-LGD in these patients are: endoscopy ($2626 to $4639), pathologist biopsy review ($275 to $2185), and esophagogastroduodenoscopy-guided endoscopic ablation ($214 to $1249). CONCLUSIONS: The healthcare cost of over-diagnosis of BE-LGD is significant. To reduce the overall healthcare cost impact of over-diagnosis of BE-LGD, strict adherence to the recommendations of the American Gastroenterological Association, American College of Gastroenterology, and American Society for Gastrointestinal Endoscopy that pathology review of all BE biopsy specimens be performed by a gastrointestinal pathologist is warranted.

Helicobacter infections with rare bacteria or minimal gastritis: Expecting the unexpected.

BACKGROUND: The routine use of special stains for detection of Helicobacter remains controversial. AIMS: To determine the frequency of histologically atypical Helicobacter infection. METHODS: All gastric biopsies received at a large pathology reference laboratory over a 6-month period were stained for Helicobacter, and the histologic and clinicopathologic parameters evaluated. RESULTS: Amongst 7663 Helicobacter-positive biopsies, 823 (10.7%) did not show typical chronic active gastritis with numerous Helicobacter organisms, and were therefore considered histologically atypical. Rare Helicobacter pylori organisms accounted for 58.0% of all atypical infections; the next most common atypical Helicobacter infection was that with minimal or no gastric inflammation (23.3% of atypical infections). Patients in these groups did not differ demographically from those with other forms of atypical or typical Helicobacter infection, although a small subgroup (6%) was more likely to have had a previously treated infection. CONCLUSIONS: In many of these atypical infections, Helicobacter would not have been suspected based on the histologic findings alone, and would have been missed without routine special stains. Performing a sensitive stain could prevent additional testing and allow prompt treatment of the affected patients, thus substantially reducing the risk for peptic ulcer and gastric cancer and preventing the transmission of the infection to family members.

Anatomic distribution of sessile serrated adenoma/polyp with and without cytologic dysplasia.

CONTEXT: Sessile serrated adenomas/polyps (SSA/Ps) have been increasingly studied during the last 10 years. However, their detailed anatomic distribution pattern has not been studied, especially given newer (broader) criteria for the diagnosis. OBJECTIVES: To characterize the anatomic distribution of SSA/P with and without cytologic dysplasia and to assess the demographics of these patients in a nationwide database. DESIGN: We retrospectively analyzed the database of Miraca Life Sciences Research Institute for a 1-year period. Patients with a diagnosis of SSA/P, SSA/P with low-grade cytologic dysplasia (SSA/P-LGD), SSA/P with high-grade cytologic dysplasia (SSA/P-HGD), or SSA/P with adenocarcinoma (SSA/P-ACA) were retrieved, and patients' age, sex, and specific anatomic location were analyzed. RESULTS: A total of 11,201 patients were identified, of which 10,646 (95.0%) had SSA/P, 514 (4.6%) had SSA/P-LGD, 39 (0.35%) had SSA/P-HGD, and 2 (0.018%) had SSA/P-ACA. All SSA/Ps and more advanced lesions were significantly more common in the proximal colon-SSA/P (61.2%), SSA/P-LGD (61.2%), SSA/P-HGD (80%), and SSA/P-ACA (100%)-than in either the transverse (18.8%, 17.8%, 10.0%, and 0%, respectively) or the distal (19.9%, 21.0%, 10.0%, and 0%, respectively) colon, P < .001. Sessile serrated adenoma/polyp with cytologic dysplasia was most commonly found in the ascending colon (LGD, 31.6%) and cecum (HGD, 37.5%). Advanced SSA/Ps were disproportionally more common among older women. CONCLUSIONS: Sessile serrated adenomas/polyps with and without cytologic dysplasia and carcinoma are predominantly found in the cecum and ascending colon, whereas there is low prevalence in both the transverse and distal colon. Confirmation of previously published data regarding demographics of advanced lesions among a different cohort and including newer (broader) criteria suggests these criteria are valid.

Helicobacter pylori-negative gastritis: seek, yet ye shall not always find.

Since its recognition as the causative agent for most cases of gastritis, the prevalence of Helicobacter pylori-induced gastritis has been declining, in part due to the deliberate and inadvertent use of various medications. As a result, pathologists find themselves facing cases of gastritis in which, based upon history and histology, there are expected but undetectable H. pylori organisms. This review explores the 2 possibilities of false-negative and true-negative gastritides, including when and how to search for H. pylori, explanations for absent organisms in cases of true H. pylori gastritis, and other causes of gastritis that may mimic H. pylori infection. The latter group includes reactive gastropathy with focal activity, focally active gastritis and carditis, autoimmune gastritis, granulomatous gastritis, lymphocytic gastritis, and other infections.

Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients.

BACKGROUND AND AIMS: Sessile serrated adenomas (SSAs) are recognised as precursors to microsatellite unstable adenocarcinomas. This study attempts to estimate the progression rate of SSAs based upon the epidemiology of a large cohort as well as identify relationships to other colorectal polyps. METHODS: Pathological reports generated at Caris Diagnostics from 290 810 colonoscopic specimens on 179 111 patients were analysed using computerised algorithms. RESULTS: SSAs with or without dysplasia/carcinoma (SSA+/-) were identified in 2416 specimens from 2139 patients (54% women). The distribution of SSA+/- was: right-sided (81.2%); left-sided (11.2%); both right- and left-sided (3.2%); not specified (4.3%). There were 1816 (85%) patients without dysplasia (SSA-), 257 (12%) with low-grade dysplasia (SSA-LD), 45 (2%) with high-grade dysplasia (SSA-HD) and 21 (1%) with adenocarcinoma (SSA-CA). The difference in median age between almost all groups was significant (SSA-=61 years versus SSA-LD=66 years (p<0.001) vs SSA-HD=72 years (p=0.002) vs SSA-CA=76 years (p=0.07, NS)). Women comprised 53% of the SSA- group (968/1816), 57% of the SSA-LD group (147/257), 69% of the SSA-HD group (31/45) and 76% of the SSA-CA group (16/21), being more likely to have high-grade dysplasia (OR 1.94, 95% CI 1.03 to 3.67) and adenocarcinoma (OR 2.80, 95% CI 1.02 to 7.68). CONCLUSIONS: 1.7% of patients with mucosal polyps had SSAs (with and without dysplasia), more commonly in women and primarily in the right colon. Dysplasia or carcinoma was identified in 15% of patients and significantly disproportionately among women. Based on significant age differences between groups, there appears to be a stepwise progression of dysplasia and carcinoma in SSAs over 10 to 15 years, a period two to three times longer than that for conventional adenomas.

Significant increase in IgG4+ plasma cells in gastric biopsy specimens from patients with pernicious anaemia.

AIM: To investigate the presence of IgG4+ plasma cells in gastric mucosal biopsy samples from patients with atrophic gastritis (AG) and a history of pernicious anaemia (PA) (AG+PA+). METHODS: Gastric mucosal biopsy specimens from 46 patients with AG+PA+ were investigated. As controls, we evaluated specimens from patients with AG but no history of PA (AG+ PA-) (n=25), normal histology (n=25), mild chronic inactive gastritis (MCIG) (n=25) or Helicobacter pylori gastritis (HP) (n=25). IgG4+ plasma cells were detected by two immunohistochemical methods: (1) using a monoclonal antibody, the average of the three most cellular high-power fields was counted in areas with the highest density of IgG4+ plasma cells; (2) using a dual-chromagen stain for both IgG4 and CD138 (plasma cell marker), the number of IgG4+ cells per 200 CD138+ plasma cells was counted. The latter was used to ensure that the number of IgG4+ cells was not simply related to the degree of inflammation (density of plasma cells). RESULTS: Identical results were obtained with the two staining methods. Increased numbers of IgG4+ plasma cells were present in 37% of patients with AG+PA+, but in none with AG+PA-, MCIG, HP or normal gastric biopsy results (100% specific, p=0.0001). CONCLUSION: IgG4+ plasma cells may play a role in the pathogenesis of PA and may be a useful marker for its diagnosis.