Zollinger-Ellison syndrome

A 39-year-old white woman presented with a 4-day history of abdominal pain, nausea, vomiting, and diarrhea and a 30-lb weight loss during a 3-month period. Her medical history included several gastrointestinal examinations for chronic abdominal pain, the cause of which was never identified. Previous gastric biopsy specimens showed Helicobacter pylori-associated gastritis. Physical examination revealed a mildly tender abdomen, especially over the epigastrium. The patient's serum albumin level was 4 g/dL, and her hemoglobin level was 11.7 g/dL.

Endoscopic ultrasonography showed thickened gastric rugal folds suggestive of gastric lymphoma. Endoscopic ultrasound-guided fine-needle aspiration biopsy of the folds was performed and showed no evidence of malignancy. We decided that the patient should undergo intraoperative endoscopy with a full-thickness gastric biopsy. The intraoperative endoscopy showed enlarged gastric folds in the body and fundus, especially along the greater curvature (Figure 1).

Full-thickness biopsy specimens showed elongated foveolar epithelium with foveolar mucous cell hyperplasia and cystic dilation of foveolar glands (Figure 2). There was mild chronic inflammation with focal intraepithelial lymphocytosis. Giemsa-stained sections were negative for H pylori-like organisms. The patient's symptoms continued, and approximately 1 month later, a therapeutic gastrectomy was performed (Figures 3 and 4).

What is your diagnosis?

Pathologic Diagnosis: Ménétrier Disease

The multiple causes of diffuse mucosal hypertrophy in the stomach include benign variation of normal size, hyperplasia of the parietal cells (Zollinger-Ellison syndrome), hyperplasia of surface-foveolar cells (Ménétrier disease), hypertrophie gastritis, gastric lymphomas, and rarely diffuse-type adenocarcinomas (so-called linitis plastica). Patients with Zollinger-Ellison syndrome may present with similar clinical symptoms and endoscopie findings, as this patient did; however, microscopic examination of such patients shows parietal cell hyperplasia, sometimes enterochromaffin-like cell hyperplasia and absence of foveolar cell hyperplasia. In hypertrophie gastritis, there is usually considerable chronic inflammation and glandular atrophy. Gastric lymphomas, especially the low-grade mucosa-associated lymphoid tissue lymphoma, usually have symptoms that simulate chronic gastritis and present endoscopically as thickened convolutions, as seen in this case (Figure 1). However, histologically, these cases exhibit infiltrating monotonous atypical lymphocytes in mucosa and submucosa with effacement and loss of glands. These findings are not present in this case. Extensive sampling and examination of the gastrectomy specimen did not reveal carcinoma cells. Our patient's findings are consistent with Ménétrier disease.1

Ménétrier disease, originally described in 1888 as "polyadenomes en nappe" by the French physician Ménétrier, is a rare disorder characterized by diffuse hyperplasia of the surface and foveolar mucous cells of the stomach. Ménétrier disease is usually limited to the corpus or fundic region but rarely may extend into the antrum.1,2 The disease is associated with normal or reduced gastric acid and protein loss from the mucosa, resulting in hypoalbuminemia. Definitive diagnosis requires enlarged gastric rugae due to hyperplasia of the foveolar mucous cells in the proximal part of the stomach that is not associated with significant inflammation, the absence of hyperplasia of other epithelial elements, such as parietal cells, the absence of excess acid production, and the presence of protein loss from the mucosa, leading to reduced serum albumin levels. In the early and healing phases of disease, the morphologic features can exist without significant functional consequences.1

Ménétrier disease commonly affects adults between the ages of 30 and 60 years, 75% of whom are men.1 Patients usually present with epigastric pain, substantial weight loss, nausea, vomiting, gastrointestinal bleeding, and diarrhea.3 Pathogenesis of the disease is not fully understood but is thought to involve elevated levels of transforming growth factor α in gastric mucous cells. Transforming growth factor α binds to the epidermal growth factor receptor on gastric mucous cells, which increases gastric mucous production, increases cell renewal, and inhibits acid secretion. Other studies have implicated cytomegalovirus in children and infection with H pylori,4 but the evidence for these explanations is not overwhelming.

The relation of Ménétrier disease to cancer remains a major point of controversy. However, in studies that relate the 2, adequate histologie confirmation has been lacking. Furthermore, gastric resection soon after the diagnosis of Ménétrier disease has been the usual treatment in the past, so in these instances cancer risk could not be assessed.2

Pathologic features of Ménétrier disease include pronounced hyperplasia of the foveolar (pit) mucous cells. The foveolae are greatly elongated, often tortuous, and cystic in appearance and mainly composed of mature mucous cells with little evidence of active regeneration or mitosis.15 The cystic glands may also extend into the superficial submucosa, which may present as gastritis cystica profunda.'1 Typically, there is no ulceration. Inflammatory cells in the epithelial layer and lamina propria are sparse, and intestinal metaplasia is uncommon. Chief and parietal cells may be markedly reduced in numbers but may also be unaffected. Glands show no signs of dysplasia.1,5 A total gastrectomy may be necessary to alleviate symptoms.

In summary, Ménétrier disease, also known as hypertrophic gastropathy, presents clinically as nonspecific chronic diarrhea, abdominal pain, and weight loss. It can be confused with some malignant conditions, such as lymphoma and carcinoma, endoscopically, radiographically, and grossly. Microscopic identification of the characteristic morphologic features of Ménétrier disease is diagnostic.

References

1. Ming SC, Goldman H, eds. Pathology of the Gastrointestinal Tract. 2nd ed. Baltimore,' Md: Williams & Wilkins; 1998:578-583.

2. Day DW, Jass IR, Price AB, et al, eds. Morson and Dawson's Gastrointestinal Pathology. 4th ed. Maiden, Mass: Blackwell Science Ltd; 2003:221-222.

3. Meuwissen SG, Ridwan BU, Hasper HJ, lnnemee G. Hypertrophie protein-losing gastropathy: a retrospective analysis of 40 cases in The Netherlands: The Dutch Menetrier Study Group. Scand I Gastroenterol Supp/. 1992; 194:1-7.

4. Burdick JS, Chung EK, Tanner G, et al. Treatment of Menetrier's disease with a monoclonal antibody against the epidermal growth factor receptor. N Engl I Med. 2000;343:1697-1701.

5. Odze R, Goldblum IR, Crawford eds. Surgical Pathology of the Gl Tract, Liver, Biliary Tract, and Pancreas. Philadelphia, Pa: Saunders; 2004:274-276.

6. Fenoglio CM, Noffsinger AE, Lantz PE, et al. Gastrointestinal Pathology: An Atlas and Text. Philadelphia, Pa: Lippincott and Raven; 1999:208-213.

Ken Spengel, DO; Mojtaba Olyaee, MD; Fang Fan, MD, PhD

Accepted for publication September 9, 2004.

From the Departments of Pathology and Laboratory Medicine (Drs Spengel and Fan) and Castroenterology (Dr Olyaee), The University of Kansas Medical Center, Kansas City.

The authors have no relevant financial interest in the products or companies described in this article.

Corresponding author: Ken Spengel, DO, Department of Pathology, The University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160-7410 (e-mail: kspengel@kumc.edu).

Reprints not available from the authors.

Copyright College of American Pathologists Mar 2005
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