Host-related low-prevalence gastritides: Epidemiological and clinical characterization.

INTRODUCTION: A recent consensus meeting (RE.GA.IN) addressed "host-related, low-prevalence gastritis": eosinophilic (EoG), lymphocytic (Hp-pos_LyG and Hp-neg_LyG), collagenous (CollG), and granulomatous gastritis (GrG). Our study evaluates their clinico-epidemiological characteristics. MATERIALS AND METHODS: We extracted all patients with a diagnosis of EoG, LyG, CollG, and GrG from a clinicopathological database and compared their demographics, clinical and endoscopic characteristics, associated conditions, and clinical awareness to those of all other subjects in the database (controls). RESULTS: There were 1,781,005 unique patients (median age 57 years; 55.7 % female). Hispanics were overrepresented amongst those with Hp-pos_LyG. Subjects with GrG had a high prevalence of erosions and ulcers. Clinical awareness of these conditions was dismal (<1:10,000 patients). Some clinical manifestations were more common in patients with certain gastritides (e.g., vomiting and diarrhea in CollG; anemia in LyG), but none were sufficiently distinctive to suggest a clinical diagnosis. EoG was associated with EoE; LyG had a strong association with celiac disease; CollG with microscopic colitis; and GrG with Crohn disease. CONCLUSIONS: The diagnosis of these gastritides (between <1: in 1,000 and 1 in 5000 subjects) rests on histopathology. They remain poorly characterized and clinically neglected. Yet, their associations may herald other conditions: eosinophilic gastrointestinal diseases (EGID), celiac, and Crohn disease. Patients might benefit from increased detection and characterization.

RE.GA.IN.: the Real-world Gastritis Initiative-updating the updates.

At the end of the last century, a far-sighted 'working party' held in Sydney, Australia addressed the clinicopathological issues related to gastric inflammatory diseases. A few years later, an international conference held in Houston, Texas, USA critically updated the seminal Sydney classification. In line with these initiatives, Kyoto Global Consensus Report, flanked by the Maastricht-Florence conferences, added new clinical evidence to the gastritis clinicopathological puzzle.The most relevant topics related to the gastric inflammatory diseases have been addressed by the Real-world Gastritis Initiative (RE.GA.IN.), from disease definitions to the clinical diagnosis and prognosis. This paper reports the conclusions of the RE.GA.IN. consensus process, which culminated in Venice in November 2022 after more than 8 months of intense global scientific deliberations. A forum of gastritis scholars from five continents participated in the multidisciplinary RE.GA.IN. consensus. After lively debates on the most controversial aspects of the gastritis spectrum, the RE.GA.IN. Faculty amalgamated complementary knowledge to distil patient-centred, evidence-based statements to assist health professionals in their real-world clinical practice. The sections of this report focus on: the epidemiology of gastritis; Helicobacter pylori as dominant aetiology of environmental gastritis and as the most important determinant of the gastric oncogenetic field; the evolving knowledge on gastric autoimmunity; the clinicopathological relevance of gastric microbiota; the new diagnostic horizons of endoscopy; and the clinical priority of histologically reporting gastritis in terms of staging. The ultimate goal of RE.GA.IN. was and remains the promotion of further improvement in the clinical management of patients with gastritis.

Quantification of Mucosal Mast Cells in the Gastrointestinal Tract: A Primer for Practicing Pathologists.

CONTEXT.­: Mast cells are essential components of the immune system and play crucial pathogenetic roles in several digestive diseases, including mastocytic enterocolitis and eosinophilic gastrointestinal disorders. Pathologists have rarely been asked to evaluate the distribution and density of mast cells in gastrointestinal (GI) biopsy specimens. However, such requests are becoming more common because of an increasing awareness of the role of mast cells in functional GI disease and in both esophageal and nonesophageal eosinophilic gastrointestinal disorders. OBJECTIVE.­: To provide pathologists with tools to incorporate the assessment of mast cells in the evaluation of esophageal, gastric, and intestinal specimens by developing a systematic approach to their evaluation, counting, and reporting. DESIGN.­: This study consisted of a review of the literature followed by multiple consensus sessions to decide where to count mast cells and what a countable mast cell is. RESULTS.­: We reviewed 135 papers addressing the content of mast cells in the digestive tract, selected 21 that detailed how cells were counted (microscope lens, area of high-power fields, locations evaluated, type of cells considered as countable), and summarized their data in a table. Then, drawing from both the acceptable literature and our own extensive experience, we reached a tentative consensus on: (1) the normal numbers in the different segments of the GI tract; (2) the morphology of countable mast cells; and (3) the locations and strategies for counting them. CONCLUSIONS.­: The result is a set of suggestions for reporting mast cell counts, their distribution, and their location in a way clinicians can understand and use for management decisions.

Determination of Optimal Eosinophil Thresholds for Diagnosis of Eosinophilic Gastritis and Duodenitis: A Pooled Analysis of 4 Prospective Studies.

INTRODUCTION: Consensus is lacking regarding the number of eosinophils (eos) required for the diagnosis of eosinophilic gastritis (EoG) and eosinophilic duodenitis (EoD). In addition, thresholds that require multiple high-power fields (HPFs) may not be practical for clinical use, resulting in delayed or missed diagnoses. This pooled analysis of 4 prospective studies assessed thresholds for multiple and single HPFs used to diagnose EoG and EoD. METHODS: Studies included the phase 2 ENIGMA1, the phase 3 ENIGMA2, an EoG/EoD prevalence study and a healthy volunteer study. Eos were quantified in the epithelium and lamina propria for controls and symptomatic participants. Symptomatic participants were further divided by histologic diagnosis of EoG/EoD. Peak eos counts were assessed, and the area under the receiver operating characteristic curve was analyzed to identify eos cutoffs for detection of EoG/EoD using the Youden index and sensitivity and specificity equality approaches. RESULTS: Based on the highest specificity analysis in 740 patients, the optimal eos threshold was determined to be 20 eos/HPF in 5 gastric HPFs for EoG (71% sensitivity and 94% specificity) and 33 eos/HPF in 3 duodenal HPFs for EoD (49% sensitivity and 100% specificity). For single-field analysis, the optimal eos thresholds were 33 eos/HPF (EoG) and 37 eos/HPF (EoD), both corresponding to 93% sensitivity and 93% specificity. DISCUSSION: Highly specific single gastric and duodenal HPF thresholds may have more clinical applicability than thresholds requiring multiple HPFs and could better facilitate development of practical histopathologic guidelines to aid pathologists and clinicians in the detection and diagnosis of EoG and/or EoD.

Proximity to Swine Farming Operations as a Risk Factor for Eosinophilic Esophagitis.

We aimed to determine whether residential proximity to permitted swine facilities was associated with an increased risk of eosinophilic esophagitis (EoE) by conducting a case-control study using 2 complementary data sources: 1 from a tertiary care center (n = 401 cases and 1805 controls) and 1 from a large pathology group (n = 904 cases and 4074 controls). Addresses of the subjects and swine facilities were geocoded, and adjusted odds of EoE relative to proximity to and density of swine facilities were calculated. We observed a positive association between proximity to a permitted swine facility (<1 mile) and odds of EoE (adjusted odds ratio R, 2.56; 95% CI, 1.33-4.95) in the tertiary center data; density of farms (>10 farms/census tract) was also positively associated (adjusted odds ratio, 2.76; 95% CI, 1.30-5.84). However, this association was not observed in the pathology database. Though proximity to and density of swine operations were associated with EoE, associations were sensitive to the database used.

Mast Cell Esophagitis: A Novel Entity in Patients with Unexplained Esophageal Symptoms.

It is not known whether esophageal mast cells may be a cause of unexplained esophageal symptoms. We aimed to determine the prevalence of esophageal mastocytosis in patients without other underlying causes of symptoms and assess the relationship between symptoms and mast cells. In this retrospective study, we identified adults with esophageal symptoms, a normal endoscopy, normal esophageal biopsies, and no definitive diagnosis during clinical evaluation. We quantified mast cell density (mast cells/mm2) in archived esophageal biopsies using tryptase immunohistochemistry, and compared mast cell levels by clinical features and physiologic testing. In the 87 patients identified (mean age 37, 72% female, 63% white, 92% non-Hispanic), common symptoms were dysphagia (76%), heartburn (71%), and chest pain (25%). Overall, the mean esophageal epithelial mast cell count was 83.0 ± 51.8 mast cells/mm2; 60% of patients had ≥ 60 mast/mm2, and 17% had ≥ 120 masts/mm2. There were no differences in mast cell counts by type of esophageal testing. Mast cell levels did not differ significantly by type of symptoms, atopic status, medications, smoking status, or alcohol use. There were also no major differences in clinical characteristics by mast cell quartiles or thresholds. In conclusion, esophageal mast cell infiltration was common in patients with symptoms unexplained by prior testing, and levels were higher than previously published values for patients with no underlying esophageal condition. Mast cell esophagitis could be a novel cause of unexplained esophageal symptoms in a subset of patients, though it reamins to be determined if such patients benefit from mast cell-targeted treatment.

Case-control study of the concurrence of coeliac disease with inflammatory bowel disease.

BACKGROUND AND AIMS: Previous studies suggested that inflammatory bowel disease (IBD) is associated with an increased prevalence of comorbid coeliac disease. Our case-control study aimed to test this association using a large histopathology database. METHODS: The Inform Diagnostics database is a repository of histopathologic records from patients distributed throughout the United States. In a case-control study among patients with bidirectional endoscopy, we compared the occurrence of coeliac disease in case subjects with IBD or microscopic colitis (MC) and control subjects without inflammatory colitis, calculating odds ratios (OR) and their 95% confidence intervals (CI) adjusted to the varying age, gender and ethnic distributions of case and control subjects. RESULTS: The study population was split into 12,816 IBD cases and 6486 MC cases, who were compared to 345,733 control subjects without colitis. A total of 2892 patients were diagnosed with coeliac disease. Of 12,816 IBD patients, 57 patients (0.4%) harboured coeliac disease compared to 0.7% (2548/345,733) in the control population. The prevalence of coeliac disease among MC patients was 4.4% (288/6486). The corresponding ORs were significantly decreased in IBD (OR: 0.50, CI: 0.38-0.64) and significantly increased in MC patients (6.78, 5.96-7.69). Further stratification of the case populations into subtypes of IBD (Crohn's disease or ulcerative colitis) and MC (collagenous or lymphocytic colitis) similarly revealed significantly decreased and increased ORs for each subtype. CONCLUSIONS: The previously reported positive association between coeliac disease and IBD may have been possibly biased by the inclusion of MC cases in the IBD patient population.

Incomplete Intestinal Metaplasia Is Rare in Autoimmune Gastritis.

BACKGROUND: Incomplete intestinal metaplasia (IM) is reportedly associated with higher gastric cancer (GC) risk than its complete variant. AGA Guidelines recommend including IM subtyping in routine pathology reports. This study assesses the prevalence of complete versus incomplete IM in gastric conditions with different GC risks. METHODS: IM subtyping (complete vs. incomplete) and grading (IM extension: G1: ≤30%; G2: >30%) were assessed in 386 patients with IM + ve gastric biopsy sets that included both antral and oxyntic samples. Cases were categorized as: (a) IM foci in otherwise normal mucosa (n = 59); (b) Helicobacter pylori gastritis (n = 138); (c) reactive gastropathy (141); and (d) autoimmune atrophic gastritis (AIG, n = 48). Odds ratios (OR) and their 95% CI were used in comparing the prevalence of incomplete IM and the correlation between subtype and IM extension. RESULTS: Incomplete IM was present in 37.7% of patients with H. pylori gastritis, 8.3% of those with AIG 5.0% of those with reactive gastropathy, and none of those with otherwise normal mucosa. Incomplete IM was strongly associated with more extensive (G2-IM) mucosal intestinalization (OR = 6.69; 95% CI = 2.77-9.40). CONCLUSION: Incomplete IM is significantly more prevalent in conditions (H. pylori gastritis) known to carry a higher risk of GC and is strongly associated with its extension. The low prevalence of incomplete IM in AIG (8.3%) and reactive gastropathy (5.2%) is in keeping with the low GC risk associated with these conditions.

Autoimmune gastritis: long-term natural history in naïve Helicobacter pylori-negative patients.

OBJECTIVE: Autoimmune gastritis (AIG) is an immunomediated disease targeting parietal cells, eventually resulting in oxyntic-restricted atrophy. This long-term follow-up study aimed at elucidating the natural history, histological phenotype(s), and associated cancer risk of patients with AIG consistently tested H. pylori-negative (naïve H. pylori-negative subjects). DESIGN: Two-hundred eleven naïve H. pylori-negative patients (tested by serology, histology, molecular biology) with AIG (F:M=3.15:1; p<0.001) were prospectively followed up with paired biopsies (T1 vs T2; mean follow-up years:7.5 (SD:4.4); median:7). Histology distinguished non-atrophic versus atrophic AIG. Atrophy was further subtyped/scored as non-metaplastic versus metaplastic (pseudopyloric (PPM) and intestinal (IM)). Enterochromaffin-like-cell (ECL) status was categorised as diffuse versus adenomatoid hyperplasia/dysplasia, and type 1 neuroendocrine tumours (Type1-NETs). RESULTS: Over the long-term histological follow-up, AIG consistently featured oxyntic-predominant-mononuclear inflammation. At T1, PPM-score was greater than IM (200/211 vs 160/211, respectively); IM scores increased from T1 to T2 (160/211 to 179/211), with no changes in the PPM prevalence (T1=200/211; T2=201/211). At both T1/T2, the prevalence of OLGA-III-stage was <5%; no Operative Link on Gastritis Assessment (OLGA)-IV-stage occurred. ECL-cell-status progressed from diffuse to adenomatoid hyperplasia/dysplasia (T1=167/14 vs T2=151/25). Type1-NETs (T1=10; T2=11) always coexisted with extensive oxyntic-atrophy, and ECL adenomatoid-hyperplasia/dysplasia. No excess risk of gastric or other malignancies was found over a cumulative follow-up time of 10 541 person years, except for (marginally significant) thyroid cancer (SIR=3.09; 95% CI 1.001 to 7.20). CONCLUSIONS: Oxyntic-restricted inflammation, PPM (more than IM), and ECL-cell hyperplasia/neoplasia are the histological AIG hallmarks. Compared with the general population, corpus-restricted inflammation/atrophy does not increase the GC risk. The excess of GC risk reported in patients with AIG could plausibly result from unrecognised previous/current H. pylori comorbidity.

The Occurrence of Gastritis in Microscopic Colitis and Inflammatory Bowel Disease.

Multiple studies have shown that Helicobacter pylori infection is associated with a lower prevalence of inflammatory bowel disease (IBD).1,2 Besides chronic active gastritis (CAG) resulting from gastric infection with H pylori, pathologists have noticed another form of CAG, which is unrelated to H pylori infection and seems to cluster in patients with IBD.3-5 The aim of the present study was to compare the prevalence of H pylori-negative and H pylori-positive CAG in patients with IBD, and microscopic colitis (MC).

Do General Pathologists Assess Gastric and Duodenal Eosinophilia?

CONTEXT.­: Eosinophilic diseases of the gastrointestinal tract (EGIDs), eosinophilic gastritis (EoG), and eosinophilic duodenitis (EoD) are rarely suspected clinically and infrequently detected by pathologists. OBJECTIVE.­: To determine whether histories of allergic or eosinophilic disorders and requests to rule out EoG and EoD affect pathologists' awareness of eosinophils in gastrointestinal biopsies. DESIGN.­: Thirty-one community-based pathologists were given 16 sets of biopsies from gastric and duodenal mucosa with elevated eosinophils, Helicobacter pylori gastritis, atrophic gastritis, normal stomach and duodenum, lymphocytosis, and celiac disease. Participants were assigned to 3 groups: group A did not receive histories of allergic or eosinophilic conditions; group B received similar histories plus a clue of possible allergic or eosinophilic conditions; and group C received the same histories as B and was asked to rule out EoG/EoD. A list of gastric and duodenal diagnoses and a space for comments were provided. Results were analyzed descriptively. RESULTS.­: Pathologists correctly diagnosed most noneosinophilic gastrointestinal disorders, indicating competence in gastrointestinal pathology. With respect to EoG and EoD, pathologists in group C performed significantly better that those in groups A and B. The combined odds ratio with 95% CI was 12.34 (2.87-53.04), P < .001, for A versus C and 4.02 (1.60-10.09), P < .02, for B versus C. CONCLUSIONS.­: Most pathologists neither reported gastric/duodenal eosinophilia nor diagnosed EoG/EoD, even when provided histories of eosinophilic disorders. Requests to rule out EoG/EoD resulted in only 4 of 11 participants evaluating and counting eosinophils in some cases. Simple evidence-based histopathologic criteria are needed before pathologists can be expected to consider and diagnose EGIDs.