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Best Cases from the AFIP

Mntrier Disease1
Joseph Friedman, MD Joseph Platnick, MD Salvatore Farruggia, MD Natalya Khilko, MD Kokila Mody, MD Michael Tyshkov, MD

Figures 1, 2. Mntrier disease. (1) Axial contrast materialenhanced CT image at the level of the gastric fundus shows gastric wall thickening and enhancement (arrow). (2) Axial contrast-enhanced CT image of the distal stomach reveals that the body is primarily involved and the antrum is relatively spared (arrows).

A 19-year-old white man presented to the emergency department with a 1-week history of epigastric abdominal pain, nausea, vomiting, diarrhea, and swelling of his legs and scrotum. He had a history of gastroesophageal reflux disease that was treated with a proton pump inhibitor. On chest radiographs and abdominal ultrasonographic (US) images, bilateral pleural effusions and ascites were seen. Results of routine blood analysis revealed hypoproteinemia; the protein level was 3.2 g/dL, with an albumin level of 1.6 g/dL. A stool study revealed that the 1-antitrypsin level was elevated, at 564 mg/dL. The patient underwent esophagogastroduodenoscopy, which was followed by abdominal computed tomography (CT) and upper gastrointestinal fluoroscopy. Abdominal CT was performed following oral administration of approximately 1000 mL of a

History

Imaging Findings

diatrizoate meglumine and diatrizoate sodium solution (MD-Gastroview; Tyco Healthcare Mallinckrodt, St Louis, Mo) and 100 mL of ioversol (Optiray 320, injection 68%; Tyco) with the following scanning parameters: 5-mm axial collimation, 120 kVp, 92 mAs, and a pitch of 1.5:1. CT images revealed diffusely enlarged rugal folds that were projecting into the lumen of the gastric fundus and body; the antrum was relatively spared (Figs 1, 2). The gastric wall measured 1.9 cm in the fundus, 1.7 cm in the body, and 0.4 cm in the antrum. No discrete mass was seen. Small bilateral pleural effusions and a small amount of ascites were seen in the pelvis. A barium swallow upper gastrointestinal series with small bowel follow-through depicted markedly thickened and lobulated mucosal folds that were predominantly seen in the gastric fundus

RadioGraphics 2009; 29:297301 Published online 10.1148/rg.291075216 Content Code:

1 From the Department of Radiology (J.F., J.P., S.F.), Department of Pathology (N.K., K.M.), and Department of Pediatrics, Division of Gastroenterology (M.T.), Staten Island University Hospital, 475 Seaview Ave, Staten Island, NY 10305. Received December 4, 2007; revision requested January 2, 2008 and received February 6; accepted February 8. All authors have no financial relationships to disclose. Address correspondence to J.F. (e-mail: joseph_friedman@hotmail.com).

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and body and, to a lesser extent, in the antrum (Fig 3). No discrete mass, stricture, ulceration, or obstruction was seen. The esophagus and duodenum appeared normal on abdominal CT and barium swallow images. At endoscopy, the mucosa of the distal esophagus appeared erythematous, edematous, irregular, and friable. The gastroesophageal junction appeared normal. The gastric mucosa appeared edematous, erythematous, and hemorrhagic, with severe hypertrophy of folds seen throughout the stomach (Fig 4). The extent of involvement appeared to be greater on endoscopic images than it did on radiologic images. Punch biopsies were performed in the antrum and body of the stomach. The duodenum appeared normal. Biopsy specimens obtained from all regions of the stomach, including the antrum, demonstrated foveolar hyperplasia, with elongation, a focal screwlike appearance, and cystic dilatation of the foveolae (Figs 5, 6). The hyperplastic mucosal cells were well differentiated. There was mild chronic and acute inflammation with increased eosinophils. Mild chronic nonspecific duodenitis was seen. There was no increase in intraepithelial lymphocytesa finding confirmed with CD3 immunohistochemical stainingthe presence of which would indicate celiac disease. No Giardia lamblia was identified with either hematoxylineosin or Giemsa stain, and Giemsa stain failed to reveal the presence of Helicobacter pylori. In 1888, Pierre Mntrier, a French pathologist, described certain pathologic gastric changes, which he divided into two anatomic groups. One group he called polyadenomes polypeux, which are probably the equivalent of multiple hyperplastic polyps. The other group, which he referred to as polyadenomes en nappe, were accompanied by gastric rugal hypertrophy; this is the group to which the term Mntrier disease is applied (1). Mntrier disease is listed by the Office of Rare Diseases of the National Institutes of Health as a rare disease, a designation that means it has a prevalence of less than 1 in 200,000 people. The hallmark of the disease is gastric mucosal hypertrophy, which may cause the rugae to resemble

Pathologic Evaluation

Figure 3. Fluoroscopic barium upper gastrointestinal spot view of the stomach demonstrates marked wall thickening, primarily in the fundus and body.

Discussion

convolutions of the brain (2). The thickening of the rugae is predominantly caused by the expansion of the epithelial cell compartment of the gastric mucosa (3). Patients with Mntrier disease most often present with epigastric pain, hypoalbuminemia secondary to a loss of albumin into the gastric lumen, and an increased loss of enteric protein (4), which may manifest as an elevated fecal 1-antitrypsin level. Other signs and symptoms of Mntrier disease include anorexia, asthenia, weight loss, nausea, gastrointestinal bleeding, diarrhea, edema, and vomiting. The disease has a bimodal age distribution. The childhood form is often linked to cytomegaloviral infection and usually resolves spontaneously. It usually occurs in children younger than 10 years (mean age, 5.5 years), predominantly in boys (male-to-female ratio, 3:1) (5). The second peak occurs in adulthood, and the disease in adults tends to progress over time. The average age at diagnosis is 55, and men are affected more often than women (3). A diagnosis of Mntrier disease is made by using a combination of upper gastrointestinal fluoroscopic imaging, endoscopic imaging, and histologic analysis. On fluoroscopic images, Mntrier disease is characterized by the presence of giant rugal folds. Rugal folds should normally measure less than 1 cm in width across the fundus and 0.5 cm across the antrum, and they should be parallel to the long axis of the

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Figure 4. Endoscopic image of the body of the stomach depicts severely hypertrophic and edematous rugal folds with irregularity of the gastric mucosa.

Figures 5, 6. (5) Photomicrograph (original magnification, 4; hematoxylin-eosin stain) of a specimen taken from the gastric antrum shows gastric mucosa with elongated and tortuous pits (curved arrows) and cystic dilatation (straight arrow). (6) Photomicrograph (original magnification, 4; hematoxylin-eosin stain) of a specimen obtained during a full-thickness biopsy of gastric mucosa shows foveolar hyperplasia (straight arrow), elongated pits (jagged arrow), glandular cystic dilatation (curved arrow), and focal acute and chronic inflammation with eosinophils.

stomach. In Mntrier disease, the folds become abnormally thickened and tortuous (6). On contrast-enhanced CT images, they appear as areas of thickened mucosa that project into the gastric lumen, usually with normal gastric mucosa between the folds and a smooth serosal contour. At barium studies, enlarged and convoluted but pliable rugal folds with intervening linear strands of contrast, which represent contrast material trapped between the enlarged folds, are seen. Hypersecretion may dilute the barium and impair coating of the mucosa, thereby limiting the effectiveness of the evaluation. At endoscopy, the mucosa has an irregular, hypertrophic appearance. It is swollen, spongy,

and creased, with folds that resemble cerebral convolutions (7). Endoscopic US also has been used to evaluate gastric wall thickening. Five distinct layers can be identified in the normal gastric wall on US images. These layers correspond with the interface, mucosa, submucosa, muscularis propria, and serosa. Studies have shown that in Mntrier disease, only the second layer (the mucosa) is thickened. The mucosa also demonstrates increased echogenicity, while the submucosa and muscularis propria appear normal (8).

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The pathologic findings of Mntrier disease include increased mucosal thickness caused by hyperplasia of epithelial cells, deeper gastric pits (foveolae), and cystic dilatation of the stomach body and fundus that causes enlarged mucosal folds (composed of a submucosal core and thickened mucosa) to form (9). A massive increase in surface and foveolar mucin-secreting cells is also seen, with a reduction in the numbers of parietal and chief cells that causes a decrease in gastric acid secretion (10). In 1976, Olmsted et al (9) studied the distribution of enlarged gastric folds in 13 patients with Mntrier disease. They found that the antral portion of the stomach was involved in 46% of cases, and they concluded that the previously accepted idea that the antrum is spared was invalid. Instead, a diagnosis of Mntrier disease should be considered when gastric rugal enlargement is seen in any region. However, gastric fold thickening, the most characteristic finding of Mntrier disease, is nonspecific; because of this, a differential diagnosis usually must be generated. Although overlap between the conditions certainly exists, one feature of Mntrier disease that helps set it apart from other conditions is the degree of fold thickening; Mntrier disease tends to produce the greatest and perhaps the most impressive thickening. The differential diagnosis of Mntrier disease is broad and includes infectious causes (eg, cytomegalovirus, histoplasmosis, and H pylori), infiltrative diseases (eg, sarcoidosis and amyloidosis), malignancy (eg, Zollinger-Ellison syndrome, lymphoma, and gastric carcinoma), and varices. Some features that may help narrow the differential diagnosis include the location of involvement, fold pliability, the presence of associated ulcers, and additional extragastric findings. Overall, H pylori gastritis is probably the most common cause of fold thickening. In fact, H pylori has been isolated in about 50% of patients with enlarged gastric folds (11). Cytomegaloviral infection, which is common and often asymptomatic, has been linked to the childhood form of Mntrier disease and must be differentiated from cytomegaloviral gastritis, which frequently occurs in patients who have a compromised immune system and is distinguished by gross ulceration, perforation, and hemorrhage (12).

A neoplasm should be considered when the gastric folds exhibit rigidity or when there are associated masses or ulcers. A diagnosis of Zollinger-Ellison syndrome can be made with more confidence when the small bowel is involved and when ulcers, especially postbulbar ulcers, are present in addition to the gastric fold thickening. Ulcers are unusual in Mntrier disease but common in Zollinger-Ellison syndrome (13). The fold thickening associated with Mntrier disease tends to be most pronounced on or along the greater curvature, unlike that associated with lymphoma, which usually affects the distal stomach and lesser curvature. Splenomegaly or extrinsic compression of the gastric lumen by enlarged nodes may provide additional clues in diagnosing lymphoma. Varices tend to have a more serpentine form, are changeable in size and shape, and are confined to the regions of the cardia and fundus. In amyloidosis, the folds tend to exhibit more nodular thickening. On CT images and double-contrast barium studies, the normal lumen may be underdistended and mimic abnormally thickened folds. To confirm this finding, additional effervescent granules, barium, or other contrast material may be administered orally to further distend the lumen. The constellation of findings from the clinical examination, radiologic imaging, and laboratory and pathologic analyses should help further differentiate Mntrier disease from other entities. Mntrier disease has been associated with an increased risk for thromboembolic disease. An increased risk for gastric malignancy has been hypothesized but is uncertain: A 10%15% increase in risk was reported (2); however, a study of 43 patients with Mntrier disease found no cases of malignancy over a 10-year follow-up period (14). Therapeutic approaches include the use of anticholinergics, prostaglandins, proton pump inhibitors, prednisone, histamine-2 blockers, and a high-protein diet, all of which have produced varying results (10,15,16). Patients in whom pharmacologic therapy failed or who experienced intractable pain or persistent loss of protein, and patients in whom malignancy could not be excluded, have undergone subtotal or total gastrectomy with good long-term results (2,10). The etiology of Mntrier disease is unknown. Fieber (17) described multiple possible causes of hypertrophic mucosal changes in the stomach, including bacterial infections, toxins, and

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Friedman et al 301 3. Coffey RJ, Washington MK, Corless CL, Heinrich MC. Menetrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach. J Clin Invest 2007;117:7080. 4. Burns B, Gay BB Jr. Mntrier disease of the stomach in children. Am J Roentgenol Radium Ther Nucl Med 1968;103:300306. 5. Shah SS, Ludwig S. Pediatric complaints and diagnostic dilemmas: a case-based approach. Philadelphia, Pa: Lippincott Williams & Wilkins, 2004. 6. Palmer WE, Bloch SM, Chew FS. Menetrier disease. AJR Am J Roentgenol 1992;158:62. 7. Sleisenger MH, Feldman M, Friedman LS, Brandt LJ. Sleisenger & Fordtrans gastrointestinal and liver disease: pathophysiology, diagnosis, management. Philadelphia, Pa: Saunders Elsevier, 2006. 8. Songur Y, Okai T, Watanabe H, Motoo Y, Sawabu N. Endosonographic evaluation of giant gastric folds. Gastrointest Endosc 1995;41:468474. 9. Olmsted WW, Cooper PH, Madewell JE. Involvement of the gastric antrum in Mntrier disease. AJR Am J Roentgenol 1976;126:524529. 10. Harrison TR, Braunwald E. Harrisons principles of internal medicine. New York, NY: McGraw-Hill Health Professions Division, 2001. 11. Halpert RD, Feczko PJ. Gastrointestinal radiology. St Louis, Mo: Mosby, 1999. 12. Sferra TJ, Pawel BR, Qualman SJ, Li BU. Menetrier disease of childhood: role of cytomegalovirus and transforming growth factor alpha. J Pediatr 1996; 128:213219. 13. Mettler FA. Essentials of radiology. Philadelphia, Pa: Elsevier Saunders, 2005. 14. Searcy RM, Malagelada JR. Mntrier disease and idiopathic hypertrophic gastropathy. Ann Intern Med 1984;100:565570. 15. Kelly DG, Miller LJ, Malagelada JR, Huizenga KA, Markowitz H. Giant hypertrophic gastropathy (Mntrier disease): pharmacologic effects on protein leakage and mucosal ultrastructure. Gastroenterology 1982;83:581589. 16. Meuwissen SG, Ridwan BU, Hasper HJ, Innemee G. Hypertrophic protein-losing gastropathy. A retrospective analysis of 40 cases in The Netherlands. The Dutch Menetrier Study Group. Scand J Gastroenterol Suppl 1992;194:17. 17. Fieber SS. Hypertrophic gastritis: report of two cases and analysis of fifty pathologically verified cases from the literature. Gastroenterology 1955;28:3969. 18. Dempsey PJ, Goldenring JR, Soroka CJ, et al. Possible role of transforming growth factor alpha in the pathogenesis of Mntrier disease: supportive evidence from humans and transgenic mice. Gastroenterology 1992;103:19501963. 19. Burdick JS, Chung E, Tanner G, et al. Treatment of Mntrier disease with a monoclonal antibody against the epidermal growth factor receptor. N Engl J Med 2000;343:16971701.

neurogenic, emotional, congenital, endocrine, and mechanical causes. Allergy appears to be the most common cause of the pediatric form of the disease. The mucosal changes in Mntrier disease are hypothesized to be secondary to an overproduction of transforming growth factor , a polypeptide that is normally secreted by gastric epithelium and that increases the production of gastric mucus and inhibits acid secretion. Elevated levels of this polypeptide, which lead to increased epithelial growth factor receptor signaling, have been found in the gastric mucosae of patients with Mntrier disease (18). Current molecular treatment options focus on the use of monoclonal antibodies against the epithelial growth factor receptor and have shown promising results (19). During 2 weeks of hospitalization, our patient was given 20 mg of furosemide daily, 30 mg of lansoprazole twice daily, intravenous albumin infusions (25 g every other day), and a high-protein diet. He gradually improved; vomiting and diarrhea completely resolved, and abdominal pain was mild and usually occurred only after meals. On the day he was discharged, there was no edema present, but there was mild epigastric tenderness at palpation of the abdomen. His serum albumin level had increased from that at admission, to 2.2 g/dL. The patient was discharged and instructed to continue lansoprazole therapy and to follow a high-protein diet. After the patients discharge, close follow-up was maintained by the pediatric gastroenterologist. The patient continued to experience short mild episodes of epigastric pain following meals, with no vomiting or edema. His serum albumin level was maintained above 2 g/dL. Follow-up endoscopy 2 weeks after discharge revealed similar fold thickening with less prominent inflammatory changes. A full-thickness biopsy at that time showed hyperplastic mucosal cells with foveolar hyperplasia and acute and chronic inflammatory changes, findings indicative of no significant change.

References
1. Menetrier P. Des polyadenomes gastriques et de leurs rapports avec le cancer de lestomac. Arch Physiol Normal Pathol 1888;1:232262. 2. Sundt TM 3rd, Compton CC, Malt RA. Mntrier disease. A trivalent gastropathy. Ann Surg 1988;208: 694701.