Christine Yeh Hachem, MD; Hala El-Zimaity, MD Series Editor: Richard Goodgame, MD

Disclosures

September 27, 2007

Differential Diagnosis

The poor correlation between the endoscopic appearance of gastric mucosa and histologic abnormalities seen on biopsy is readily acknowledged.[1] Gastric mucosa that appears "normal" on endoscopy is associated with impressive and diagnostic histologic abnormalities in approximately one third of cases.[1] Conversely, "abnormal"-appearing gastric mucosa (eg, red, nodular, irregular, thickened, raised) is a nonspecific finding. These endoscopic abnormalities are compatible with many different gastropathies or gastritides and can be associated with normal histology in approximately 25% of cases.[1] For these reasons, many experts advocate taking gastric biopsies in every patient undergoing upper gastrointestinal endoscopy.[2,3] In our patient, the focal polypoid lesions combined with the more subtle diffuse gastric mucosal abnormalities strongly suggest that a significant disease is present in the patient's stomach.

Again, assuming that a single disease process is responsible for the findings, we should consider diseases that cause both diffuse gastritis or gastropathy and that are associated with focal raised, thickened, or polypoid mucosal lesions. Several types of diffuse gastritis/gastropathy are worthy of consideration.

1. Chronic H pylori gastritis is the most common type of diffuse gastritis/gastropathy.[4] Although it begins as an antral-predominant gastritis, progression to the body, fundus, and cardia of the stomach over many decades is common and well-described.[5] Over the same time course, there is progression of the depth of the associated histologic abnormalities. In the early stages, the inflammatory process and histologic changes are superficial. The now "famous" H pylori lesion -- active chronic gastritis -- refers to the polymorphonuclear leukocytes (active) infiltrating the surface epithelial cell layer and the lymphocytes (chronic) infiltrating the lamina propria. These are the diagnostic histologic features of H pylori gastritis, often seen in conjunction with the H pylori organism. However, over time, the inflammation extends to the deep glands and intraglandular area, causing progressive loss of glandular mass (atrophy). Frequently, the surface epithelium undergoes intestinal metaplasia. When H pylori gastritis is associated with large and friable lesions, there is always concern about dysplastic change or frank carcinoma in the intestinal metaplasia. It is widely believed that this sequence of events -- progression from active chronic H pylori gastritis to gastric atrophy to intestinal metaplasia to dysplasia to cancer -- is the most common pathway of adenocarcinoma development in the stomach. This malignancy is one of the leading causes of cancer death worldwide. However, the presence of 5 or 6 polypoid lesions, some >2 cm, is not compatible with either the usually flat intestinal metaplasia or the usually focal adenocarcinoma.

The host response to H pylori gastritis varies greatly.[4,5] A small subset of infected persons develops a monoclonal proliferation of B lymphocytes in response to H pylori antigen. These patients develop marginal zone-B cell lymphoma in the setting of diffuse active chronic gastritis. Multifocal lesions (ulcerations and masses) are commonly observed in this condition. Although the polypoid lesions seen in this patient do not have the typical appearance of MALT (mucosa-associated lymphoid tissue) lymphoma, the possibility should at least be considered.

2. The second most common type of diffuse gastritis/gastropathy is reactive gastropathy.[4] There are many synonyms for this condition, including reflux gastritis (because of its universal presence in the gastric mucosa after a Billroth II gastrectomy), chemical gastritis (because of its strong association with NSAID use), and type C gastritis (because it is neither type A [autoimmune] nor type B [H pylori-positive]). Histologic evaluation of reactive gastropathy shows very few inflammatory cells (thus, gastropathy rather than gastritis). The most dramatic histologic change is a corkscrew appearance of the glands in the superficial mucosa; this is called foveolar hyperplasia. The epithelial cells themselves lose intracellular mucous and develop large dark nuclei. The lamina propria can show edema, smooth muscle proliferation, and vascular congestion. The gastric endoscopic findings in a postoperative stomach or in a patient taking NSAIDs often include marked color change, irregularity, and focal raised lesions. Such large polypoid lesions as those seen in our patient would be unusual in the setting of reactive gastropathy alone. However, both H pylori and NSAIDs in a unique host could produce hyperplastic polyps. (See the discussion of hyperplastic polyps below.)

3. All other causes of diffuse gastritis/gastropathy are much less common. Autoimmune gastritis should be suspected when there is chronic gastritis atrophy or intestinal metaplasia predominantly in the gastric body.[4] Autoimmune gastritis is often found in the evaluation of patients with pernicious anemia and in association with antibodies to intrinsic factor and parietal cells. In the past, autoimmune gastritis was considered distinct from H pylori gastritis -- it was assumed that the former was purely immunologic and the latter was purely infectious. However, when some patients were found to have both typical autoimmune gastritis and H pylori infection, questions were raised regarding such a dichotomy.[6] There is convincing evidence that some patients have all the features of autoimmune gastritis as a consequence of H pylori infection.[7,8] The best evidence for this is the normalization of serum B12 and hemoglobin concentrations after treatment of H pylori infection.[9] Our patient is obviously prone to autoimmune disease, given his active rheumatoid arthritis and other autoantibodies. He also has hypergastrinemia, suggesting that he has hypochlorhydria. Thus, the diffuse gastric mucosal abnormalities could be due to autoimmune gastritis, regardless of the presence or absence of H pylori.

But what about our patient's focal polypoid lesions? Are they compatible with autoimmune gastritis, reactive gastropathy, or H pylori gastritis? Seventy-five percent of all gastric polyps are hyperplastic polyps.[10] Microscopic examination of these polyps shows variable features, including elongated and dilated surface glands with chronically inflamed lamina propria. Hyperplastic polyps can be associated with any form of longstanding gastric inflammation or injury, including H pylori gastritis, autoimmune gastritis, or reactive gastropathy. Regression of hyperplastic polyps has been associated with eradication of H pylori infection.[11] If any of these forms of gastritis/gastropathy are the gastric mucosal pathologic condition in our patient, the most likely diagnosis of the polypoid lesions would be hyperplastic polyps.

4. Lymphocytic gastritis is another form of diffuse gastritis; it is associated with both H pylori infection and celiac sprue.[12] This form of gastritis can be associated with a variety of endoscopic abnormalities,[4] including some of the abnormalities seen in our patient. In moderate disease, the endoscopic examination shows chronic erosions: raised lesions topped with a small break or depression in the mucosa.[13] This is termed "varioliform gastritis" and strongly resembles the lesion seen in Figure 7. The most severe forms of lymphocytic gastritis have large mucosal folds that resemble those seen in Ménétrièr's disease, both clinically and endoscopically. The large gastric folds are frequently due to foveolar hyperplasia, as in the case of reactive gastropathy or hyperplastic polyps. The diagnosis of lymphocytic gastritis depends on histologic demonstration of large numbers of normal-appearing lymphocytes infiltrating not only the lamina propria, but also the surface and glandular epithelial cells. In most cases, there is an intraepithelial lymphocyte for every 2 to 3 surface and glandular epithelial cells.[4]

5. Crohn's disease is rarely associated with endoscopic abnormalities in the stomach, but histologic abnormalities of the normal-appearing gastric mucosa may occur in approximately 50% of patients.[4,14,15] As in the intestine, Crohn's disease of the stomach is usually a focal or multifocal process. Patients with Crohn's disease in the small bowel or colon may have "focally enhanced gastritis" seen in one area of a low-power microscopic field and normal gastric mucosa in adjacent areas.[14,15] Granulomas are seen in about 10% of Crohn's disease patients with gastric involvement if numerous biopsies are taken.[14,15] Although hyperplastic and inflammatory polyps can occur whenever there is a chronic source of inflammation and injury to the gastric mucosa, the polypoid lesions seen in our patient have not been described in Crohn's disease of the stomach.

6. A last type of diffuse gastritis that should be considered in the differential diagnosis is eosinophilic gastritis. In this disease, an endoscopically abnormal gastric mucosa with erythema, irregularity, or frank ulceration is found on microscopic examination to have abundant eosinophils infiltrating the mucosa. Usually no specific cause is identified. Sometimes it is associated with a systemic autoimmune disease, such as scleroderma or polymyositis.[4] In addition, eosinophilic gastritis may rarely be seen in the setting of an acute illness due to Anisakis larva invading the gastric mucosa.[16] Eosinophilic gastritis may also be related to food allergy.[17] The idiopathic form is usually part of a localized or diffuse eosinophilic gastroenteritis, a steroid-responsive gastrointestinal disease that shares some clinical features with Crohn's disease.[4]

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