Case 1 -

Lymphocytic gastritis Drs. Jean-François FLEJOU, Adriana HANDRA-LUCA Service d'Anatomie Pathologique, hôpital Saint-Antoine Assistance Publique-Hôpitaux de Paris Université Pierre et Marie Curie Paris, France

Clinical history 74 yrs old man. Recent anorexia and weight loss, with upper abdominal pain. Moderate arterial hypertension, no other past medical history. Under NSAIDs for vague rheumatismal pain. On upper digestive endoscopy, large eroded folds in the gastric body. Two slides of gastric biopsies are submitted: (1) body; (2) antrum. Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Histological lesions Gastric biopsies were performed in the antrum and in the fundus. They show typical features of lymphocytic gastritis. The fundic mucosa (1) shows diffuse inflammatory changes, present on all 4 specimens. There is an increased number of intraepithelial lymphocytes (IELs) in the surface and crypt epithelium, that is confirmed by immunohistochemistry. IEL number is higher than 30 per 100 epithelial cells, and IELs express CD3 and CD8. The lamina propria shows an increase in inflammatory cells, mostly lymphocytes and plasma cells. There is also focal surface erosion, with fibrin deposit and neutrophils. There is no glandular atrophy nor intestinal metaplasia. In the antrum (2), the lesions are similar, with increased IELs, but there is no erosion. There is no Helicobacter pylori (H. pylori) infection. Biopsies taken from the small intestine are normal. Diagnosis: Lymphocytic gastritis Discussion Lymphocytic gastritis was described initially by Haot et al in 1985 [1, 3, 5]. It is an uncommon form of chronic gastritis with a distinctive histological picture but still a poorly understood pathophysiology [4]. Histological and immunohistological features Diagnostic feature The diagnostic feature of lymphocytic gastritis is a marked intraepithelial lymphocytosis. The count has to be made on the surface epithelium, on 400 to 500 epithelial cells. A number of 25 IELs per 100 epithelial cells is considered as a threshold for the diagnosis of lymphocytic gastritis. However, this number is much higher in most cases, with a mean number about 50 IEL for 100 epithelial cells in most series, i.e., 10 times higher as in other types of chronic gastritis and 20 times higher as in normal mucosa. In typical cases, the surface epithelium is crowded with dark nuclei surrounded by a clear halo, typical of normal IEL. This increased number of IEL is only present in the surface and foveolar epithelium with no involvement of the glandular layer. Topography Lymphocytic gastritis can be present in the antrum and/or the body, depending upon the associated conditions and endoscopic features (see infra). Immunophenotype of IELs (8) In typical cases of lymphocytic gastritis, immunostaining is not necessary to make the diagnosis. IELs in lymphocytic gastritis have the phenotype of normal IELs: a mast majority are CD3+ T lymphocytes, and 70-80% express CD8 in the cell surface. Most of these IELs are activated cytotoxic T-lymphocytes, as shown by their expression of TIA-1, a cytotoxic granule-associated protein. B lymphocytes are absent from the epithelium in lymphocytic gastritis. Associated lesions The typical increased IELs are usually associated with a chronic inflammatory infiltrate in the lamina propria, of variable intensity, and composed of lymphocytes and plasma cells. The foveolar pits may be tortuous and elongated. In a number of cases, erosions are present. Eroded areas contain fibrin deposits and active inflammation with neutrophils, that may obscure the IEL infiltrate. Clinical and endoscopic features Lymphocytic gastritis has a frequency of 1.5% to 4% of chronic gastritis [2], and is found in about 1% of dyspeptic patients undergoing upper GI endoscopy. Although most cases have been reported in Europe and United States, lymphocytic gastritis has also been described in other parts of the world. It is seen in most cases in adults, although there have been also case reports in children. A slight female predominance is present. Associated conditions will be discussed later. They include celiac disease, Helicobacter pylori (H. pylori) infection, and to a lesser extent Crohn's disease, HIV infection, gastric lymphoma, and esophageal carcinoma. Clinical features are highly variable, from dyspepsia to the rapid development of an alarming symptomatology suggestive of a gastric neoplasm, with abdominal pain, anorexia, severe weight loss. In a small subset of patients there may be protein-losing gastroenteropathy with peripheral oedema. Endoscopic features are also variable, ranging from a normal aspect to the highly suggestive aspect of varioliform gastritis, showing enlarged gastric folds with nodules that contain central erosion. The correlation between endoscopic varioliform gastritis and lymphocytic gastritis is high in cases with diffuse and corporeal endoscopic lesions (53 of 55 cases diagnosed by endoscopy corresponding to lymphocytic gastritis in a series by Haot et al) [4] but is much weaker in antral varioliform gastritis (1 of 11 cases in the same series). On the other hand, 20 to 50% of cases of lymphocytic gastritis do not present as varioliform gastritis on endoscopy. Associated conditions Frontier cases with Ménétrier's disease Some cases presenting clinically (low acid secretion and protein loss) and endoscopically (giant gastric folds) as Ménétrier's disease show histologically lymphocytic gastritis in addition to the classical features of Ménétrier's disease. On the other hand, many authors have reported an association between lymphocytic gastritis and protein-losing gastropathy. It appears therefore that there is an overlap between lymphocytic gastritis and Ménétrier's disease, with a spectrum of lesions ranging from pure lymphocytic gastritis to classical Ménétriers's disease, trough intermediate lesions of "hypertrophic" lymphocytic gastritis. Collagenous gastritis Collagenous gastritis is a very uncommon form of chronic gastritis with about 20 cases reported in the literature to date. Its aetiology is unknown, and it is defined histologically by the presence on gastric biopsies of a thickened subepithelial collagen band in association with an increased number of inflammatory cells in the lamina propria. In view of the relationship between the two types of microscopic colitides, i.e. lymphocytic colitis and collagenous colitis, there is a possibility that collagenous and lymphocytic gastritis are linked in some way. In a series of 6 cases we have reported, an increased number of IELs was present in the stomach in 2 cases [6]. Lymphocytic gastritis and celiac disease Celiac disease is an important cause of lymphocytic gastritis. Approximately half of the patients with celiac disease and a flat duodenal mucosa meet the criteria of lymphocytic gastritis. Conversely, significantly higher IEL counts are found in the duodenal mucosa of patients with lymphocytic gastritis and half of them have evidence of abnormal small intestinal permeability. These data indicate that in some cases lymphocytic gastritis represents a reaction of the gastric mucosa to gluten ingestion. Links with H. pylori infection In most published series, H. pylori infection is present in a minority of cases (20 to 40%) of lymphocytic gastritis. Moreover, in H. pylori-positive cases with lymphocytic gastritis, H. pylori colonization is often minimal or focally localized mainly in the corpus. Conversely, the majority of adult patients with lymphocytic gastritis will have positive levels of serum anti-H. pylori antibodies. This may be due to the cytotoxic effects of activated T lymphocytes on H. pylori leading to reduction or even complete elimination of the bacteria. Differential diagnosis The histological picture of lymphocytic gastritis is distinctive, and once the pathologist is aware of this entity, the diagnosis is easily made in most cases. Diagnostic difficulties may occur in cases with multiple erosions, due to non specific inflammatory changes (necrosis, polymorphs etc.) that may obscure the increase in IELs. Celiac disease and Ménétrier's disease are not differential diagnoses but associated or linked conditions in most cases. In gastric MALT lymphomas there is epithelial destruction by the lymphoid infiltrate, which does not occur in lymphocytic gastritis, and the neoplastic lymphoid cells are CD20 positive and CD3 negative. In chronic active H. pylori gastritis, the surface and crypt epithelium may be infiltrated by neutrophils, but the number of IEL is usually less than 5 per 100 epithelial cells. Evolution and treatment Spontaneous resolution of the disease is possible, but in most cases, lymphocytic gastritis follows a protracted course and must be considered a chronic disease. Patients with ulcers and/or erosions are treated with proton pump inhibitors (PPI). But in cases associated with other conditions, the main part of the treatment is directed against those conditions: gluten-free diet in celiac disease, and antibiotics with PPI in H. pylori gastritis. Very interestingly, it has been reported in the only randomized-controlled anti-H. pylori trial of lymphocytic gastritis that the healing rate was comparable high irrespective of the H. pylori status at baseline [7]. References Dixon MF, Wyatt JI, Burke DA, Rathbone BJ. Lymphocytic gastritis: relationship to Campylobacter pylori infection. J Pathol 1988;154:125-132. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney system. Am J Surg Pathol 1996;20:1161-1181. Haot J, Delos M, Wallez N, Hardy N, Lenzen B, Jouret-Mourin A. Intraepithelial lymphocytes in inflammatory gastric pathology. Acta Endoscopica 1986;16:61-63. Haot J, Jouret A, Mainguet P. Lymphocytic gastritis. In : Graham DY, Genta RM, Dixon MF. Gastritis. Lippincott, Philadelphia , 1999. pp109-117. Jones EA, Fléjou J-F, Potet F, Muzeau F, Molas G, Rotenberg A, Goldfain D. Lymphocytic gastritis: a clinicopathological study of 32 patients. Eur J Gastroenterol Hepatol 1990;2:367-372. Lagorce-Pages C, Fabiani B, Bouvier R, Scoazec J-Y, Durand L, Fléjou J-F. Collagenous gastritis. A report of six cases. Am J Surg Pathol 2001;25:1174-1179. Madisch A, Miehlke S, Neuber F, Morgner A, Kuhlisch E, Rappel A, Lehn N, Bayerdörffer E, Seitz G, Stolte M. Healing of lymphocytic gastritis after Helicobacter pylori eradication therapy – a randomized, double-blind, placebo-controlled multicentre trial. Aliment Pharmacol Ther 2006;23:473-479. Oberhuber G, Bodingbauer M, Mosberger I, Stolte M, Vogelsang H. High proportion of Granzyme B-positive (activated) intraepithelial and lamina propria lymphocytes in lymphocytic gastritis. Am J Surg Pathol 1998;22:450-458.