Menetrier's Disease A Clinicopathologic Study of Six Cases JOHN M. DAVIS, M.D., GEORGE F. GRAY, M.D., BJORN THORBJARNARSON, M.D.
Six patients with surgically treated Menetrier's disease are presented. Diffuse or focal cystic hyperplasia of mucous secreting epithelium of the fundus with antral sparing characterized the stomachs in all of these cases. In most instances the disorder was found during evaluation of non-specific complaints of pain, nausea and diarrhea. Only one patient had sufficient loss of albumin to produce severe ankle edema and four of the others had below normal serum albumin levels without associated symptoms. One patient presented with life threatening bleeding from the hyperplastic mucosa. None of the patients had an associated endocrine neoplasm. All of the patients are living and without symptoms of disease for periods ranging from three to twelve years after resection of all or part of the hyperplastic mucosa. The rationale for surgical therapy in this condition is presented.
gastric mucosa may be simply a normal variant or the result of a number of disease states, such as diffuse neoplasms, chronic infections, bezoars, varices, and motility disorders as well as hyperplasia of the mucosa. Several patterns of mucosal hyperplasia associated with different clinical syndromes are now recognized. The classification of Albo et al.1 divides gastric hyperplasia (hypertrophic gastritis) into secondary forms including Zollinger-Ellison syndrome, and two primary forms: 1) without protein loss and with acid hypersecretion, and 2) with protein loss and without acid hypersecretion. The eponym Menetrier's disease has been applied to the latter, in which the characteristic pathologic change is diffuse hyperplasia of the mucous secreting element of the mucosa, generally sparing the antrum. Since this lesion may be found in patients who have not developed clinical signs of protein loss it is more useful to define Menetrier's disease in terms of the histopathologic findings. Menetrier1° '" in 1888, described two forms of gastric YPERRUGOSITY OF THE
polyadenomas: "polyadenomes polypeux", corresponding to adenomatosis, and "polyadenomes in Submitted for publication August 26, 1976. Reprint requests: Dr. Bjorn Thorbjarnarson, 525 East 68th Street, New York, New York 10021.
From the Departments of Surgery and Pathology, The New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, New York 10021
nappe" or diffuse hyperplasia. The histologic descriptions in his paper suggest that at least some of the cases of diffuse hyperplasia were of the mucous type corresponding to the current concept of Menetrier's disease. We are reporting our experience with Menetrier's disease at The New York Hospital-Cornell Medical Center during the past 10 years. Clinical Material Since 1966, pathologic material has been examined in six cases of Menetrier's disease treated surgically at The New York Hospital-Cornell Medical Center. The clinical data are summarized in Table 1. Age and Sex. Five of the 6 patients were males. The ages ranged from 25 to 64 years, all but one being over 45 years of age. The one woman was 55 years old. Clinical Findings. All of the patients had severe symptoms referable to the upper gastrointestinal tract, but no constellation of symptoms appeared to be unique to this disorder. Nausea, poorly localized abdominal pain often described as cramping rather than burning, diarrhea and vomiting were common complaints. Duration of symptoms from onset to establishment of a diagnosis ranged from three months to five years, and in one case, symptoms attributed to a poorly documented duodenal ulcer for fourteen years may have at least in part been due to Menetrier's disease. Bleeding in the form of melena was seen in only one patient who required several transfusions as a result. This patient had previously been explored at another hospital and a pathologic diagnosis of Menetrier's disease established in the partial gastrectomy specimen. Only one patient had protein loss of sufficient magnitude to develop severe ankle edema and one
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MENETRIER'S DISEASE
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TABLE 1. Clinical Data in 6 Patients with Menetrier's Disease
Patient Age
Symptoms Physical Signs
Laboratory Data
Male 64
Nausea, vomiting 4+ ankle edema
Albumin 1.6 gm% (norm 3.8-5.0) Hct 43% (norm 47 ± 5). Guaiac Neg stool. No free acid
Grant Folds (Colonic Polyps)
Albumin 3.5 Hct 46 Guaiac neg stool. No free acid Albumin 4.4 Hct 45 Guaiac neg stool. No free acid
Gastric ulcer. probable carcinoma
Male 25
Pain None
Male
Nausea,
47
diarrhea None
Radiographic Dx. (Associated Findings)
Gastroscopy
Pre-op Dx.
Operation
Lymphoma
Subtotal Gastrectomy
Infiltrating mucinous mucosal malig.
Carcinoma
Total gastrectomy
?Gastric ulcer ?Marginal ulcer (Duodenal diverticulum. Hiatus
Not Done Cytology Norm.
Carcinoma
Subtotal Gastrectomy
Mucosal Filling defect. ?lymphoma Multiple polyps? ?Menetrier's disease (Hiatus Hernia) Submucosal tumor or polyp
Not done
Carcinoma
Subtotal Gastrectomy
?Malignant tumor
Gastric Malig.
Wedge resection of localized lesion
Menetrier's disease (Dx previously established)
Total Gastrectomy
Favor lymphoma over Menetrier's
Biopsy-normal Cytology normal
Hernia) Male 64
Pain, nausea None
Male 64
Female 55
Dyspepsia, cramps Mucous diarrhea None Melena 2+ ankle edema
Albumin 3.6 Hct 43.5 Guaic neg stool
Albumin 3.2 Hct 43.7 Guaiac Neg stool. Albumin 3.4 Hct 35.6 (nonn 42 ± 5) Guaiac Pos stool
(Diverticulosis) Cytology nonnal ?Extrinsic mass ?Bezoar ?Polyp ?Clots (Hiatus Hernia)
possible Diffuse gastric nodularity and large folds. BiopsyMenetrier' s
Cytology-Atypia
other patient had slight ankle edema detected on physical examination. No definite abnormal physical findings in the abdomen were detected in any of the patients. Laboratory Findings. The serum albumin was profoundly lowered to 1.6 gm% (normal 3.8-5.0 gm%) in only the one patient who presented with severe ankle edema. The loss of albumin from the stomach of this patient was documented by radioactive albumin clearance studies.7 In four of the other five cases the serum albumin was slightly low (3.2, 3.4, 3.5 and 3.6 gm%) and in the remaining patient the serum albumin was normal (4.4 gm%). The patient with melena had a hematocrit of 35.6% on admission (normal female 42 ± 5%). Stool guaiac examinations were negative in the five patients who had no symptoms of gross blood loss. Radiographic and Gastroscopy Findings. Prominent, diffuse hyperrugosity was noted in all of the cases except the one in which the lesion was localized, but the changes in roentgenograms of the upper gastrointestinal tract were not sufficiently characteristic to permit a specific preoperative radiographic diagnosis. The radiographic differential diagnosis included Menetrier's disease in some instances but also lym-
phoma, carcinoma, polyposis, bezoar and blood clots. Esophageal hiatus hernia was also found in three cases and rectal polyps in two. Gastroscopy was performed in four patients. All showed an abnormal mucosa. In most instances the findings were interpreted as most consistent with a malignancy, either lymphoma or carcinoma. Biopsies were done in two cases, one of which was diagnosed as consistent with Menetrier's disease while the other was interpreted as normal. Cytologic examination of gastric washings was done in four cases, three were normal and one showed cellular atypia not diagnostic of carcinoma. The difficulty in establishing a definite diagnosis by radiography or gastroscopy has been well documented.15 Furthermore, sampling of mucosa by a small biopsy obtained during gastroscopy may often be insufficient to determine the correct diagnosis.19 Because of the nonspecificity of clinical findings, a definite diagnosis in each case was not established until operation, which was usually undertaken because of a clinical impression of probable malignancy. Surgical Treatment. The type of surgery performed on our 6 patients is outlined in Table 1. The aim of the surgery was always to remove a local lesion considered
Ann. Surg. a April 1977 DAVIS, GRAY AND THORBJARNARSON to be benign or Menetrier's disease, except once where the preoperative and intraoperative diagnosis was carcinoma. A total gastrectomy was performed in the instance of erroneous diagnosis (#2) and in the instance of massive bleeding in previously diagnosed Menetrier's disease (#6). Fig. 1. The surgery in the other four patients consisted of local excision or subtotal resection with re-establishment of continuity by gastrojejunostomy or gastroduodenostomy. Operative Findings. All of the stomachs appeared entirely normal on direct inspection with no evidence of serosal disease. In three cases, palpation did not reveal evidence of mucosal hyperplasia but in one instance the stomach was described as thickened; in one, soft polypoid tumors were felt, and in one a mass FIG. 2. The prominent rugae of the fundus in Menetrier's disease polypoid nodules of hyperplastic epithelium prolapsing into the gastrojejunostomy was felt. In the consists of confluent extend into the atrum (bottom). which do not latter instance the stomach had the consistency described as "handlihg a bag of worms". Prolapse of hyperplastic mucosal polyps into the gastroenterostomy was observed when the jejunum was opened in two cases. In three cases gastrotomy revealed enlarged polypoid folds usually involving all of the stomach except for the antrum. The entire gastric mucosa was involved in the two patients who had previously had partial gastric resections, and in the sixth case a focal polypoid mucosal fundal mass was seen. Pathologic Findings. One of the lesions was localized to 3.5 cm in diameter zone in the distal fundus. The others were diffuse and involved all of the mucosa in the two instances with previous partial gastrectomy and all of the stomachs except for the sparing of the distal part of the antrum in the remaining three cases (Figs. 2 and 3). This pattern of diffuse disease with antral sparing has been emphasized by Scott et al.17
458
FIG. 1. The picture is from a gastrointestinal series on patient #6. The gastric pouch is filled by a tumor-like mass that prolapses into the gastrojejunostomy. This patient was treated by total gastrectomy.
FIG. 3. Close-up view showing sparing of antrum.
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The mucosal architecture was altered so the rugae appeared not only accentuated but also nodular. In one instance, the hyperplastic mucosa did not maintain rugal folds but appeared as multiple, soft, confluent polyps prolapsed into the gastrojejunostomy (Fig. 4). A large quantity of tenaceous mucous was noted over the mucosa in all instances. Microscopically, all of the cases were characterized by thickening of the mucosa due to hyperplasia of the mucous secreting glands which were convoluted and typically dilated to form mucin filled cystic spaces in the deeper layer of the mucosa. (Fig. 5). Parietal cells appeared both relatively and absolutely diminished and in most instances none were identified. In one case, a few normal appearing glands with parietal cells were interspersed among the hyperplastic mucous glands. Intestinal metaplasia with villi was observed focally in the superficial mucosal layers. Some of the larger polypoid nodules had marked edema in the lamina propria and scattered lymphocytes were present throughout the lamina propria. In a few scattered foci, small collections of neutrophils were observed, usually at the surface or around cystic spaces; however, the degree of inflammatory infiltrates did not suggest a primary inflammatory process. The mucosa did not exhibit nuclear pleomorphism, hyperchromasia or other cytologic evidence of malignancy in any area. A moderate degree of hypertrophy of the muscularis mucosa was present and in some instances, the deeper glands were intertwined with the muscular bundles. This, in culmination with convoluted pattern of mucous glands and cysts, could possibly be misinterpreted as indicative of a well differentiated adenocarcinoma or might be regarded as evidence of the disorder of
459
FIG. 5. Photomicrograph showing thickened hyperplastic mucosa of the gastric fundus with characteristic cystic dilatation of the deeper crypts lined by mucous secreting epithelium with marked diminution of the parietal cells. Although some of the hyperplastic mucosa is thrown into papillary projections, the cells form a single layer and are uniform basally located nuclei. A few strands of the muscularis mucosa intermingle with the deepest glands. (Original magnification x32). a hamartoma. The predominance of mucin-producing epithelium rather suggests that the process is a primary hyperplasia of mucous glands and that the hypertrophy of the muscularis mucosa is a secondary phenomenon.
FIG. 4. An unusually florid example of Menetrier's disease has huge edematous polypoid masses of hyperplastic mucosa with mucin-filled cysts that prolapse into a gastrojejunostomy (Case 6) (Bottom left).
Discussion In most recent literature, the term Menetrier's disease is applied to the condition of hyperplasia of the mucous secreting elements of the gastric mucosa producing the radiographic and gastroscopic appearances of hyperrugosity and often associated with significant protein loss.17 The lesion appears to be principally an increase in number of mucous producing cells and is thus more appropriately termed hyperplasia than hypertrophy even though there may be an associated hypertrophy of the muscularis mucosa. The incidence of the disorder is difficult to estimate, particu-
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DAVIS, GRAY AND THORBJARNARSON
larly since the histopathological findings are not always well documented in the older literature. The proportion of cases with clinically significant protein loss is also uncertain. Since protein losing gastropathy due to excessive secretion is the most dramatic complication of this lesion, cases with protein loss seem to predominate in the literature. In our own experience, one of 6 patients with histologically proved Menetrier's disease had protein loss of sufficient magnitude to be symptomatic, four others had moderately decreased serum albumin without obvious clinical signs of protein loss, and only one had normal serum albumin. The etiology of the hyperplasia seen in this condition remains unknown. The demonstration of gastric secreting neoplasm in the islets of Langerhans as the cause for some cases of parietal cell hyperplasia with acid hypersecretion (Zollinger-Ellison syndrome), seems to be the basis for the idea that Menetrier's disease might also be the result of an endocrinopathy,17 perhaps one of the hypothetical APUDomas. 2 While this is perhaps the most attractive theory of etiology, at the present time neither the hormone that would induce mucous gland hyperplasia, nor the source for such a substance has been demonstrated in any case of Menetrier's disease. To our knowledge, no instance of histologically documented mucous hyperplasia has been associated with an endocrine neoplasm. In some earlier reports pancreatic adenomas were observed in cases of "giant hypertrophy of the gastric mucosa" but these were not clearly instances of Menetrier's disease as currently defined.8 Another idea that Menetrier' s disease represents an endstage of acid hypersecretory gastritis is suggested by the history of peptic ulcer in the past in some of the patients. However, there is poor documentation of ulcer and hyperacidity in these cases. Retrospective review of the history in one of our patients who carried a diagnosis of peptic duodenal ulcer for 14 years suggests that the symptoms were related to a diverticulum and possibly Menetrier's disease rather than peptic ulcer. Autoimmunity has been suggested as a basis of Menetrier's disease which shares the common finding of reduced acidity with pernicious anemia, a well established autoimmune disorder. Neither the morphologic appearance nor the clinical features of these two disorders are otherwise similar and to date there has been no proof of autoimmune basis of Menetrier's disease. A relatively neglected aspect of Menetrier's original paper has been his emphasis on the possible relationship of diffuse mucosal hyperplasia to the development of carcinoma. Chusin et al.4 concluded on the basis of review of cases reported up to 1964, that carcinoma was likely to arise in 8% of patients with all forms of
Ann. Surg.
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April 1977
hypertrophic gastropathy. Their own case and a few others do appear to have been Menetrier's disease with protein loss but documentation of many of the other reported cases of carcinoma associated with hypertrophic gastritis is inadequate to establish whether these patients had Menetrier's disease or one of the other forms of gastric mucosal hyperplasia preceding the neoplasm or whether they had diffuse neoplasia only.9,16,20 Thus, a clear relationship between Menetrier's disease and carcinoma remains to be established. In fact, the natural course of untreated disease is uncertain since a few reports even suggest the possibility of complete reversibility.13 The surgical treatment for Menetrier's disease must be adapted to the individual patient. Some patients with this disorder suffer only inconsequential symptoms. In these patients the role of the surgeon is basically to establish the diagnosis. The patient who suffers from severe symptoms in the form of pain and digestive upset not controlled by conservative means may indeed benefit from surgery although it is not clear what symptoms are relieved other than reducing the hyperplastic mucosal mass. The patient with significant protein loss or bleeding should be treated surgically but there is not general agreement on what type of operation. The pathological nature of Menetrier's disease is such that usually the antrum is spared and the major diseased area is the cardia and fundus. Theoretically, therefore, the anatomically correct operation would be proximal gastrectomy with esophago-antral anastomosis as performed on a patient reported by Bruno and Ober.6 However, the high complication rate from esophago-gastrectomy has prevented the adoption of this procedure except in isolated cases. The most commonly performed operation has been subtotal gastrectomy with removal of the normal antrum and also the greater portion of hyperplastic mucosa. Usually this is sufficient to eliminate excess protein loss as in one of our patients (#1). There have been technical problems reported with this operation since the anastomosis is done between normal jejunum and a stomach with enormous mucosal fold. Indeed, complications relating to the anastomosis have been reasonably common. In rare instances localized areas of hypertrophy have been locally excised with good results. However, one of our patients who initially had a favorable response to partial gastrectomy developed prolapse of the hyperplastic mucosa into gastrojejunostomy with obstruction. Relief was only obtained by further resection and anastomosis. In another patient a local resection was possible because of the limited disease. Total gastrectomy is at times the only effective procedure. Such was the case in our patients in whom the entire
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remaining stomach was involved in a friable bleeding mucosal mass. The result in this patient and the patient who had total gastrectomy because of suspicion of cancer has been favorable, both have been asymptomatic with stabilized weight. Other surgeons have also recommended total gastrectomy for Menetrier's disease. 14,17,18 Thus, while local excision and subtotal gastrectomy may at times be sufficient to arrest protein loss or bleeding and may also often relieve other symptoms of Menetrier's disease, in circumstances of life threatening protein loss or bleeding, a more extensive operation is usually required. In our experience total gastrectomy seems to be preferred to proximal gastrectomy.
8. 9. 10. 11.
12. 13. 14. 15.
References 1. Albo, R. J., Peters, H. E., and Williams, R. R.: Giant Hypertrophic Gastritis. Am. J. Surg. 126:229, 1973. 2. Brooks, A. M., Isenberg, J. and Goldstein, H.: Giant thickening of the Gastric Mucosa with Acid Hypersecretion and Protein-losing Gastropathy. Gastroenterol. 58:73, 1970. 3. Brown, H. and Riahi, M.: Menetrier's disease or Giant Hypertrophic Gastritis. Internat. Surg. 45:403, 1966. 4. Chusin, E. L., Hirsch, R. L. and Colcher, H.: Spectrum of Hypertrophic Gastropathy. Arch. Int. Med. 114:621, 1964. 5. Cintrin, Y., Sterling, K. and Halsted, J. A.: The Mechanism of Hypoproteinemia Associated with Giant Hypertrophy of the Gastric Mucosa. New Engl. J. Med. 257:906, 1957. 6. Clinicopathologic Conference. Massive Gastrointestinal Hemorrhage. N.Y.S. J. Med. 71:1213, 1971. 7. Holman, H., Nickel, W. F., Jr., and Sleisinger, M. H.: Hypo-
16. 17. 18. 19. 20.
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proteinemia Antedating Intestinal Lesions and Possibly Due to Excessive Serum Protein Loss into the Intestine. Am. J. Med. 36:963, 1959. Kenney, F. D., Dockerty, N. D. and Waugh, J. M.: Giant Hypertrophy of Gastric Mucosa. Cancer 7:671, 1954. Matzner, M. J., Raab, A. P. and Spear, P. W.: Benign Giant Gastric Rugae Complicated by Submucosal Gastric Carcinoma. Gastroenterol. 18:296, 1951. Menetrier, P.: Des Polyadenomes Gastriques et de Leurs Rapports avec le Cancer de L'estomac. Arch. Physiol. Noim. Pathol. 1:32, 1888. Palmer, E. D.: What Menetrier Really Said. Gastrointest Endoscopy 15:83, 1968. Pearse, A. E.: The APUD cell concept and its implications in Pathology. Pathol. Ann. 9:27, 1974. Pittman, F. E., Harris, R. and Barker, H. A.: Transient Edema and Hypoproteinemia. Am. J. Dis. Child. 108:189, 1964. Roxburgh, R. A.: The Case for Total Gastrectomy in Multiple Polyposis of the Stomach. Gut 3:224, 1972. Reese, D., Hudson, J. and Dockerty, M.: Giant Hypertrophy of the Gastric Mucosa in Menetrier's Disease. A Correlation of the Roentgenographic, Pathologic and Clinical Findings. Am. J. Roentgenol. 88:619, 1962. Schindler, R.: Gastric Carcinoma and Gastritis. Am. J. Digest. Dis. 10:608, 1965. Scott, H. W., Jr., Shull, H. J., Law, D. H., IV, Burko, H. and Page, D. L.: Surgical Management of Menetrier's Disease with Protein-Losing Gastropathy. Ann. Surg. 181:765, 1975. Singh, R., Cumaraswamy, R. C., and Corrin, B.: Diffuse Hypertrophy of Gastric Mucosa (Menetrier's Disease) and IronDeficiency Anaemia. Gut 10:735, 1969. Stempien, S. J., Dagradi, A. E., Reingold, I. M., et al.: Hypertrophic Hypersecretory Gastropathy. Am. J. Digest. Dis. 9:471, 1964. Texter, E. C., Jr., Legerton, C. W., Jr., Reeves, R. J., et al.: Coexistent Carcinoma of Stomach and Hypertrophic Gastritis. Gastroenterol. 24:579, 1953.
Six patients with surgically treated Menetrier's disease are presented. Diffuse or focal cystic hyperplasia of mucous secreting epithelium of the fundus with antral sparing characterized the stomachs in all of these cases. In most instances the disorder was found during evaluation of non-specific complaints of pain, nausea and diarrhea. Only one patient had sufficient loss of albumin to produce severe ankle edema and four of the others had below normal serum albumin levels without associated symptoms. One patient presented with life threatening bleeding from the hyperplastic mucosa. None of the patients had an associated endocrine neoplasm. All of the patients are living and without symptoms of disease for periods ranging from three to twelve years after resection of all or part of the hyperplastic mucosa. The rationale for surgical therapy in this condition is presented.
gastric mucosa may be simply a normal variant or the result of a number of disease states, such as diffuse neoplasms, chronic infections, bezoars, varices, and motility disorders as well as hyperplasia of the mucosa. Several patterns of mucosal hyperplasia associated with different clinical syndromes are now recognized. The classification of Albo et al.1 divides gastric hyperplasia (hypertrophic gastritis) into secondary forms including Zollinger-Ellison syndrome, and two primary forms: 1) without protein loss and with acid hypersecretion, and 2) with protein loss and without acid hypersecretion. The eponym Menetrier's disease has been applied to the latter, in which the characteristic pathologic change is diffuse hyperplasia of the mucous secreting element of the mucosa, generally sparing the antrum. Since this lesion may be found in patients who have not developed clinical signs of protein loss it is more useful to define Menetrier's disease in terms of the histopathologic findings. Menetrier1° '" in 1888, described two forms of gastric YPERRUGOSITY OF THE
polyadenomas: "polyadenomes polypeux", corresponding to adenomatosis, and "polyadenomes in Submitted for publication August 26, 1976. Reprint requests: Dr. Bjorn Thorbjarnarson, 525 East 68th Street, New York, New York 10021.
From the Departments of Surgery and Pathology, The New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, New York 10021
nappe" or diffuse hyperplasia. The histologic descriptions in his paper suggest that at least some of the cases of diffuse hyperplasia were of the mucous type corresponding to the current concept of Menetrier's disease. We are reporting our experience with Menetrier's disease at The New York Hospital-Cornell Medical Center during the past 10 years. Clinical Material Since 1966, pathologic material has been examined in six cases of Menetrier's disease treated surgically at The New York Hospital-Cornell Medical Center. The clinical data are summarized in Table 1. Age and Sex. Five of the 6 patients were males. The ages ranged from 25 to 64 years, all but one being over 45 years of age. The one woman was 55 years old. Clinical Findings. All of the patients had severe symptoms referable to the upper gastrointestinal tract, but no constellation of symptoms appeared to be unique to this disorder. Nausea, poorly localized abdominal pain often described as cramping rather than burning, diarrhea and vomiting were common complaints. Duration of symptoms from onset to establishment of a diagnosis ranged from three months to five years, and in one case, symptoms attributed to a poorly documented duodenal ulcer for fourteen years may have at least in part been due to Menetrier's disease. Bleeding in the form of melena was seen in only one patient who required several transfusions as a result. This patient had previously been explored at another hospital and a pathologic diagnosis of Menetrier's disease established in the partial gastrectomy specimen. Only one patient had protein loss of sufficient magnitude to develop severe ankle edema and one
456
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Vol. 185 . No. 4
TABLE 1. Clinical Data in 6 Patients with Menetrier's Disease
Patient Age
Symptoms Physical Signs
Laboratory Data
Male 64
Nausea, vomiting 4+ ankle edema
Albumin 1.6 gm% (norm 3.8-5.0) Hct 43% (norm 47 ± 5). Guaiac Neg stool. No free acid
Grant Folds (Colonic Polyps)
Albumin 3.5 Hct 46 Guaiac neg stool. No free acid Albumin 4.4 Hct 45 Guaiac neg stool. No free acid
Gastric ulcer. probable carcinoma
Male 25
Pain None
Male
Nausea,
47
diarrhea None
Radiographic Dx. (Associated Findings)
Gastroscopy
Pre-op Dx.
Operation
Lymphoma
Subtotal Gastrectomy
Infiltrating mucinous mucosal malig.
Carcinoma
Total gastrectomy
?Gastric ulcer ?Marginal ulcer (Duodenal diverticulum. Hiatus
Not Done Cytology Norm.
Carcinoma
Subtotal Gastrectomy
Mucosal Filling defect. ?lymphoma Multiple polyps? ?Menetrier's disease (Hiatus Hernia) Submucosal tumor or polyp
Not done
Carcinoma
Subtotal Gastrectomy
?Malignant tumor
Gastric Malig.
Wedge resection of localized lesion
Menetrier's disease (Dx previously established)
Total Gastrectomy
Favor lymphoma over Menetrier's
Biopsy-normal Cytology normal
Hernia) Male 64
Pain, nausea None
Male 64
Female 55
Dyspepsia, cramps Mucous diarrhea None Melena 2+ ankle edema
Albumin 3.6 Hct 43.5 Guaic neg stool
Albumin 3.2 Hct 43.7 Guaiac Neg stool. Albumin 3.4 Hct 35.6 (nonn 42 ± 5) Guaiac Pos stool
(Diverticulosis) Cytology nonnal ?Extrinsic mass ?Bezoar ?Polyp ?Clots (Hiatus Hernia)
possible Diffuse gastric nodularity and large folds. BiopsyMenetrier' s
Cytology-Atypia
other patient had slight ankle edema detected on physical examination. No definite abnormal physical findings in the abdomen were detected in any of the patients. Laboratory Findings. The serum albumin was profoundly lowered to 1.6 gm% (normal 3.8-5.0 gm%) in only the one patient who presented with severe ankle edema. The loss of albumin from the stomach of this patient was documented by radioactive albumin clearance studies.7 In four of the other five cases the serum albumin was slightly low (3.2, 3.4, 3.5 and 3.6 gm%) and in the remaining patient the serum albumin was normal (4.4 gm%). The patient with melena had a hematocrit of 35.6% on admission (normal female 42 ± 5%). Stool guaiac examinations were negative in the five patients who had no symptoms of gross blood loss. Radiographic and Gastroscopy Findings. Prominent, diffuse hyperrugosity was noted in all of the cases except the one in which the lesion was localized, but the changes in roentgenograms of the upper gastrointestinal tract were not sufficiently characteristic to permit a specific preoperative radiographic diagnosis. The radiographic differential diagnosis included Menetrier's disease in some instances but also lym-
phoma, carcinoma, polyposis, bezoar and blood clots. Esophageal hiatus hernia was also found in three cases and rectal polyps in two. Gastroscopy was performed in four patients. All showed an abnormal mucosa. In most instances the findings were interpreted as most consistent with a malignancy, either lymphoma or carcinoma. Biopsies were done in two cases, one of which was diagnosed as consistent with Menetrier's disease while the other was interpreted as normal. Cytologic examination of gastric washings was done in four cases, three were normal and one showed cellular atypia not diagnostic of carcinoma. The difficulty in establishing a definite diagnosis by radiography or gastroscopy has been well documented.15 Furthermore, sampling of mucosa by a small biopsy obtained during gastroscopy may often be insufficient to determine the correct diagnosis.19 Because of the nonspecificity of clinical findings, a definite diagnosis in each case was not established until operation, which was usually undertaken because of a clinical impression of probable malignancy. Surgical Treatment. The type of surgery performed on our 6 patients is outlined in Table 1. The aim of the surgery was always to remove a local lesion considered
Ann. Surg. a April 1977 DAVIS, GRAY AND THORBJARNARSON to be benign or Menetrier's disease, except once where the preoperative and intraoperative diagnosis was carcinoma. A total gastrectomy was performed in the instance of erroneous diagnosis (#2) and in the instance of massive bleeding in previously diagnosed Menetrier's disease (#6). Fig. 1. The surgery in the other four patients consisted of local excision or subtotal resection with re-establishment of continuity by gastrojejunostomy or gastroduodenostomy. Operative Findings. All of the stomachs appeared entirely normal on direct inspection with no evidence of serosal disease. In three cases, palpation did not reveal evidence of mucosal hyperplasia but in one instance the stomach was described as thickened; in one, soft polypoid tumors were felt, and in one a mass FIG. 2. The prominent rugae of the fundus in Menetrier's disease polypoid nodules of hyperplastic epithelium prolapsing into the gastrojejunostomy was felt. In the consists of confluent extend into the atrum (bottom). which do not latter instance the stomach had the consistency described as "handlihg a bag of worms". Prolapse of hyperplastic mucosal polyps into the gastroenterostomy was observed when the jejunum was opened in two cases. In three cases gastrotomy revealed enlarged polypoid folds usually involving all of the stomach except for the antrum. The entire gastric mucosa was involved in the two patients who had previously had partial gastric resections, and in the sixth case a focal polypoid mucosal fundal mass was seen. Pathologic Findings. One of the lesions was localized to 3.5 cm in diameter zone in the distal fundus. The others were diffuse and involved all of the mucosa in the two instances with previous partial gastrectomy and all of the stomachs except for the sparing of the distal part of the antrum in the remaining three cases (Figs. 2 and 3). This pattern of diffuse disease with antral sparing has been emphasized by Scott et al.17
458
FIG. 1. The picture is from a gastrointestinal series on patient #6. The gastric pouch is filled by a tumor-like mass that prolapses into the gastrojejunostomy. This patient was treated by total gastrectomy.
FIG. 3. Close-up view showing sparing of antrum.
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The mucosal architecture was altered so the rugae appeared not only accentuated but also nodular. In one instance, the hyperplastic mucosa did not maintain rugal folds but appeared as multiple, soft, confluent polyps prolapsed into the gastrojejunostomy (Fig. 4). A large quantity of tenaceous mucous was noted over the mucosa in all instances. Microscopically, all of the cases were characterized by thickening of the mucosa due to hyperplasia of the mucous secreting glands which were convoluted and typically dilated to form mucin filled cystic spaces in the deeper layer of the mucosa. (Fig. 5). Parietal cells appeared both relatively and absolutely diminished and in most instances none were identified. In one case, a few normal appearing glands with parietal cells were interspersed among the hyperplastic mucous glands. Intestinal metaplasia with villi was observed focally in the superficial mucosal layers. Some of the larger polypoid nodules had marked edema in the lamina propria and scattered lymphocytes were present throughout the lamina propria. In a few scattered foci, small collections of neutrophils were observed, usually at the surface or around cystic spaces; however, the degree of inflammatory infiltrates did not suggest a primary inflammatory process. The mucosa did not exhibit nuclear pleomorphism, hyperchromasia or other cytologic evidence of malignancy in any area. A moderate degree of hypertrophy of the muscularis mucosa was present and in some instances, the deeper glands were intertwined with the muscular bundles. This, in culmination with convoluted pattern of mucous glands and cysts, could possibly be misinterpreted as indicative of a well differentiated adenocarcinoma or might be regarded as evidence of the disorder of
459
FIG. 5. Photomicrograph showing thickened hyperplastic mucosa of the gastric fundus with characteristic cystic dilatation of the deeper crypts lined by mucous secreting epithelium with marked diminution of the parietal cells. Although some of the hyperplastic mucosa is thrown into papillary projections, the cells form a single layer and are uniform basally located nuclei. A few strands of the muscularis mucosa intermingle with the deepest glands. (Original magnification x32). a hamartoma. The predominance of mucin-producing epithelium rather suggests that the process is a primary hyperplasia of mucous glands and that the hypertrophy of the muscularis mucosa is a secondary phenomenon.
FIG. 4. An unusually florid example of Menetrier's disease has huge edematous polypoid masses of hyperplastic mucosa with mucin-filled cysts that prolapse into a gastrojejunostomy (Case 6) (Bottom left).
Discussion In most recent literature, the term Menetrier's disease is applied to the condition of hyperplasia of the mucous secreting elements of the gastric mucosa producing the radiographic and gastroscopic appearances of hyperrugosity and often associated with significant protein loss.17 The lesion appears to be principally an increase in number of mucous producing cells and is thus more appropriately termed hyperplasia than hypertrophy even though there may be an associated hypertrophy of the muscularis mucosa. The incidence of the disorder is difficult to estimate, particu-
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larly since the histopathological findings are not always well documented in the older literature. The proportion of cases with clinically significant protein loss is also uncertain. Since protein losing gastropathy due to excessive secretion is the most dramatic complication of this lesion, cases with protein loss seem to predominate in the literature. In our own experience, one of 6 patients with histologically proved Menetrier's disease had protein loss of sufficient magnitude to be symptomatic, four others had moderately decreased serum albumin without obvious clinical signs of protein loss, and only one had normal serum albumin. The etiology of the hyperplasia seen in this condition remains unknown. The demonstration of gastric secreting neoplasm in the islets of Langerhans as the cause for some cases of parietal cell hyperplasia with acid hypersecretion (Zollinger-Ellison syndrome), seems to be the basis for the idea that Menetrier's disease might also be the result of an endocrinopathy,17 perhaps one of the hypothetical APUDomas. 2 While this is perhaps the most attractive theory of etiology, at the present time neither the hormone that would induce mucous gland hyperplasia, nor the source for such a substance has been demonstrated in any case of Menetrier's disease. To our knowledge, no instance of histologically documented mucous hyperplasia has been associated with an endocrine neoplasm. In some earlier reports pancreatic adenomas were observed in cases of "giant hypertrophy of the gastric mucosa" but these were not clearly instances of Menetrier's disease as currently defined.8 Another idea that Menetrier' s disease represents an endstage of acid hypersecretory gastritis is suggested by the history of peptic ulcer in the past in some of the patients. However, there is poor documentation of ulcer and hyperacidity in these cases. Retrospective review of the history in one of our patients who carried a diagnosis of peptic duodenal ulcer for 14 years suggests that the symptoms were related to a diverticulum and possibly Menetrier's disease rather than peptic ulcer. Autoimmunity has been suggested as a basis of Menetrier's disease which shares the common finding of reduced acidity with pernicious anemia, a well established autoimmune disorder. Neither the morphologic appearance nor the clinical features of these two disorders are otherwise similar and to date there has been no proof of autoimmune basis of Menetrier's disease. A relatively neglected aspect of Menetrier's original paper has been his emphasis on the possible relationship of diffuse mucosal hyperplasia to the development of carcinoma. Chusin et al.4 concluded on the basis of review of cases reported up to 1964, that carcinoma was likely to arise in 8% of patients with all forms of
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hypertrophic gastropathy. Their own case and a few others do appear to have been Menetrier's disease with protein loss but documentation of many of the other reported cases of carcinoma associated with hypertrophic gastritis is inadequate to establish whether these patients had Menetrier's disease or one of the other forms of gastric mucosal hyperplasia preceding the neoplasm or whether they had diffuse neoplasia only.9,16,20 Thus, a clear relationship between Menetrier's disease and carcinoma remains to be established. In fact, the natural course of untreated disease is uncertain since a few reports even suggest the possibility of complete reversibility.13 The surgical treatment for Menetrier's disease must be adapted to the individual patient. Some patients with this disorder suffer only inconsequential symptoms. In these patients the role of the surgeon is basically to establish the diagnosis. The patient who suffers from severe symptoms in the form of pain and digestive upset not controlled by conservative means may indeed benefit from surgery although it is not clear what symptoms are relieved other than reducing the hyperplastic mucosal mass. The patient with significant protein loss or bleeding should be treated surgically but there is not general agreement on what type of operation. The pathological nature of Menetrier's disease is such that usually the antrum is spared and the major diseased area is the cardia and fundus. Theoretically, therefore, the anatomically correct operation would be proximal gastrectomy with esophago-antral anastomosis as performed on a patient reported by Bruno and Ober.6 However, the high complication rate from esophago-gastrectomy has prevented the adoption of this procedure except in isolated cases. The most commonly performed operation has been subtotal gastrectomy with removal of the normal antrum and also the greater portion of hyperplastic mucosa. Usually this is sufficient to eliminate excess protein loss as in one of our patients (#1). There have been technical problems reported with this operation since the anastomosis is done between normal jejunum and a stomach with enormous mucosal fold. Indeed, complications relating to the anastomosis have been reasonably common. In rare instances localized areas of hypertrophy have been locally excised with good results. However, one of our patients who initially had a favorable response to partial gastrectomy developed prolapse of the hyperplastic mucosa into gastrojejunostomy with obstruction. Relief was only obtained by further resection and anastomosis. In another patient a local resection was possible because of the limited disease. Total gastrectomy is at times the only effective procedure. Such was the case in our patients in whom the entire
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remaining stomach was involved in a friable bleeding mucosal mass. The result in this patient and the patient who had total gastrectomy because of suspicion of cancer has been favorable, both have been asymptomatic with stabilized weight. Other surgeons have also recommended total gastrectomy for Menetrier's disease. 14,17,18 Thus, while local excision and subtotal gastrectomy may at times be sufficient to arrest protein loss or bleeding and may also often relieve other symptoms of Menetrier's disease, in circumstances of life threatening protein loss or bleeding, a more extensive operation is usually required. In our experience total gastrectomy seems to be preferred to proximal gastrectomy.
8. 9. 10. 11.
12. 13. 14. 15.
References 1. Albo, R. J., Peters, H. E., and Williams, R. R.: Giant Hypertrophic Gastritis. Am. J. Surg. 126:229, 1973. 2. Brooks, A. M., Isenberg, J. and Goldstein, H.: Giant thickening of the Gastric Mucosa with Acid Hypersecretion and Protein-losing Gastropathy. Gastroenterol. 58:73, 1970. 3. Brown, H. and Riahi, M.: Menetrier's disease or Giant Hypertrophic Gastritis. Internat. Surg. 45:403, 1966. 4. Chusin, E. L., Hirsch, R. L. and Colcher, H.: Spectrum of Hypertrophic Gastropathy. Arch. Int. Med. 114:621, 1964. 5. Cintrin, Y., Sterling, K. and Halsted, J. A.: The Mechanism of Hypoproteinemia Associated with Giant Hypertrophy of the Gastric Mucosa. New Engl. J. Med. 257:906, 1957. 6. Clinicopathologic Conference. Massive Gastrointestinal Hemorrhage. N.Y.S. J. Med. 71:1213, 1971. 7. Holman, H., Nickel, W. F., Jr., and Sleisinger, M. H.: Hypo-
16. 17. 18. 19. 20.
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proteinemia Antedating Intestinal Lesions and Possibly Due to Excessive Serum Protein Loss into the Intestine. Am. J. Med. 36:963, 1959. Kenney, F. D., Dockerty, N. D. and Waugh, J. M.: Giant Hypertrophy of Gastric Mucosa. Cancer 7:671, 1954. Matzner, M. J., Raab, A. P. and Spear, P. W.: Benign Giant Gastric Rugae Complicated by Submucosal Gastric Carcinoma. Gastroenterol. 18:296, 1951. Menetrier, P.: Des Polyadenomes Gastriques et de Leurs Rapports avec le Cancer de L'estomac. Arch. Physiol. Noim. Pathol. 1:32, 1888. Palmer, E. D.: What Menetrier Really Said. Gastrointest Endoscopy 15:83, 1968. Pearse, A. E.: The APUD cell concept and its implications in Pathology. Pathol. Ann. 9:27, 1974. Pittman, F. E., Harris, R. and Barker, H. A.: Transient Edema and Hypoproteinemia. Am. J. Dis. Child. 108:189, 1964. Roxburgh, R. A.: The Case for Total Gastrectomy in Multiple Polyposis of the Stomach. Gut 3:224, 1972. Reese, D., Hudson, J. and Dockerty, M.: Giant Hypertrophy of the Gastric Mucosa in Menetrier's Disease. A Correlation of the Roentgenographic, Pathologic and Clinical Findings. Am. J. Roentgenol. 88:619, 1962. Schindler, R.: Gastric Carcinoma and Gastritis. Am. J. Digest. Dis. 10:608, 1965. Scott, H. W., Jr., Shull, H. J., Law, D. H., IV, Burko, H. and Page, D. L.: Surgical Management of Menetrier's Disease with Protein-Losing Gastropathy. Ann. Surg. 181:765, 1975. Singh, R., Cumaraswamy, R. C., and Corrin, B.: Diffuse Hypertrophy of Gastric Mucosa (Menetrier's Disease) and IronDeficiency Anaemia. Gut 10:735, 1969. Stempien, S. J., Dagradi, A. E., Reingold, I. M., et al.: Hypertrophic Hypersecretory Gastropathy. Am. J. Digest. Dis. 9:471, 1964. Texter, E. C., Jr., Legerton, C. W., Jr., Reeves, R. J., et al.: Coexistent Carcinoma of Stomach and Hypertrophic Gastritis. Gastroenterol. 24:579, 1953.
