MdwHrier’s Disease With Lymphocytic Gastritis: An Unusual Association With Possible Pathogenic Implications JULES HAOT, MD, WIADIMIR V. BOGOMOLETZ, MD, FRCPATH, ANNE JOURET, MD, AND PAUL MAINGUET, MD MCnCtrier’s disease is a rare form of hypertrophic or hyperplastic gastropathy, characterized by conspicuous thickening of the gastric mucosal folds and foveolar (crypt) hyperplasia. The pathogenesis of MC&trier’s disease remains unresolved. Lymphocytic gastritis is a newly described entity which corresponds endoscopically to varioliform gastritis and is marked by T-lymphocyte infiltration of the surface epithelium and crypts. Five surgical cases and one autopsy case combining the gross and microscopic features of MC&trier’s disease and lymphocytic gastritis are presented. This unusual and hitherto previously undescribed association raises the possibility of a common pathogenesis for MC&trier’s disease and lymphocytic gastritis. HUM PATHOL 22:379386. Copyright IF 1991 by W.B. Saunders Company
Lymphocytic gastritis (LG) is a newly described histopathologic entity which is characterized by a dense intraepithelial infiltration by small lymphocytes in the surface and foveolar epithelium.x-12 Clinicafly, about one third of patients with LG present with weight loss and anorexia; protein loss and peripheral edema are additional features. Endoscopically, LG corresponds to thickened gastric folds bearing small nodules with surface erosions. This unusual endoscopic picture of LG is referred to as “varioliform gastritis” and predominates in the body region of the stomach. In a prelitninary short report, we described one surgical case of hypertrophic gastropathy which combined the gross and microscopic features of MD and LG.‘:’ We present here our full series of six cases showing coexisting MD and LG. Their pathologic features are described in detail. We also review some important aspects of MD and LG, and we try to assess any possible relationship between these two diseases.
Hypertrophic or hyperplastic gastropathies are characterized by, markedly enlarged mucosal folds (IU~UP ~u,~cc~P), Involving the stomach in a more or less diffuse fashion. These gastropathies, often referred to as “giant fold disease,” are produced by a variety of different clinicopathologic conditions: ‘-’ Men&rier’s disease (MD), Zollinger-Ellison syndrome, hypertrophic hypersecretory gastropathy, diffusely infiltrative adenocarcinoma, malignant lynphoma, and ct.rtain forms of gastric polyposis (Cronkhite-(Canada syndrome). Amongst these disorders, MD represents an intriguing pathologic condition, occurring mostly in adults.“-‘i Grossly, the thickened gastric folds resemble cerebral convolutions. Microscopically, the mucosal thickening is due to elongation, tortuosity and cystic dilatation of the mucus-secreting gastric pits (cr\;pts orfo7jeokae). Patients with the clinically complete fo;-m of MD have low acid secretion and protein loss, sometimes associated with peripheral edema. Hence, MD can be considered as a protein-losing gastroenteropathy.
MATERIALS AND METHODS The only six documented cases indexed as MD in the files of the Service d’Anatomie Pathologique (Cliniques Universitaires Saint-Luc, Bruxelles. Belgium) were retrieved and carefully reviewed. The six cases included five surgical cases of‘ total gastrectomy (cases no. 1. 2, 4, 5, and 6) and one autopsy case (case no. 3). Cases no. 1,2. 3.5, and 6 have not been previously published. Case no. 4 was published as a preliminary short case report.” The clinical charts, endoscopy reports, and relevant x-ravs of these six cases were also reassessed. The pathologic reports provided a satisfactory macroscopic description of the diseased stomach in all six cases. Color transparencies of the gross specimens were also available in three cases. All six specimens had been fixed in Bouin’s fluid. Numerous blocks had been taken from the bodv and antrum in four cases: 11 in case no. 1, 12 in case no. i, 14 in case no. 4, and six in case no. 6. In case no. 3, there were two blocks from the body and one block from the antrum. Only three blocks from the body were available in case no. 5. Paraffin sections had been cut at G-km thickness and stained with hematoxylin-eosin, Masson’s trichrome, and Giemsa. Intraepithelial lymphocyte counts were performed on the hematoxyhn-eosin-stained sections from both body and antrum, whether involved by MD or unaffected. in five cases (cases no. 1. 2, 3, 4, and 6), but only from diseased body in one case (case no. 5). Using a x 400 magnification, lvmphocytes were counted in three randomly selected sites
Front the Service d’Anatomie Pathologique, the Service de (;astro~nterologie, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium; ;and the Laboratoire d’Anatomie Pathologique. lnstitut lean (Godinot. Keims, France. Accepted tol- publication July 17. 1990. Dr H.lclt was supported by a research grant from le Fonds National de la Kecherche Scientifique Medicale Beige (Belgium). Dr Bogomoletz was wpported by a traveling grant from Shandon SA (Franc~e). Krv uwrdr: Mknktrier’s disease, hypertrophic or hyperplastk gastropathlv. Ivmphocytic gastritis, varioliform gastritis. stomach. Address correspondence and reprint requests to Jules Haot, MD. Serwce d‘Anatomie Pathologique, Cliniques Llniversitaires Saint-Luc, Avenue Hippocrate 10. 1200 Bruxelles. Belgium. (:opyright 0 1991 by W.B. Saunders Company. 0046-n I77ilJ l/204-00 11$5.00/O
379
HUMAN PATHOLOGY
Volume 22, No. 4 (April 1991)
along an uninterrupted length of 400 surface epithelial cells. The results of these three counts were pooled together and expressed as the number of intraepithelial Iymphocytes per 100 surface epithelial cells. The height of body and antral mucosa, whether involved by MD or unaffected, was measured in four cases (cases nc;. 1, 2, 4, and 6): the height of the body mucosa only, which was involved bv MD, was measured in CdSe no. 5. The hematoxylin-eosin-stained sections were projected onto a white screen by means of a slide projector (X 20 magnification). The height of the mucosa was assessed by measuring the distance between the muscularis mucosae and the surface epithelium. In addition, because of the irregular thickening of muscularis mucosae always present in MD, the combined height of the mucosa and submucosa was also measured. All these measurements were performed in the body and antrum, both in the thickened folds and interrugal spaces (situated between folds). Control material of body and antrum gastric mucosa was used when performing intraepithelial lymphocyte counts and morphologic measurements of MD cases. This control material included three stomachs obtained at postmortem less than 2 hours after death, which were macroscopically and histologically within normal limits. “Normalappearing” gastric mucosa was also used as control from two total gastrectomy specimens: one containing a small leimyosarcoma (3 cm diameter) located in the proximal fundus. and the other containing a superficial adenocarcinoma (2 cm diameter) in the antrum.
RESULTS
Clinical Data The
relevant
clinical
details
of the
six patients
combined MD and LG are shown in Table 1. The age range was 25 to 67 years (mean 36.5 years). Four patients were males and two were females. Yatients presented with one or more of the following symptoms: epigastric pain, dyspepsia, anorexia, hematemesis, and vomiting. Weight loss and peripheral edema were associated features in four cases. Laboratory investigations disclosed hypoproteinemia in four patients. In all six patients, radiologic study and endoscopic examination showed markedly thickened gastric folds, which were often described as “cerebroid” (resembling cerebral convolutions). In addition, at endoscopy, a nodular pattern was promwith
TABLE 1. Details of Six Patients With M&&trier’s Disease Combined With Lymphocytic Gastritis Case
Presenting Symptoms
Associated Features
No.
Age/Sex
1
25/F
Epigastric pain
Weight loss and perforated peptic ulcer
2
26/M
3
36/F
Dyspepsia and anorexia Hematemesis
4
67/M
5
26/M
Peripheral edema hypoalbuminemia Hypoproteinemia proteinuria Weight loss and hypoalbuminemia -
6
.50/M
Hematemesis and anorexia Epigastric pain and vomiting Epigastric pain
and and
Weight loss. peripheral edema, and hypoalbuminemia
380
inent in three cases and surface in three cases. Pathologic
erosions
were noted
Features
C;ross appeurunct3. All six specimens showed gross thickening of the gastric mucosal folds, often mimicking cerebral convolutions (Figs 1 and 2). This mucosal thickening was more prominent in the body portion of the stomach, but faded almost entirely away in the antrum, where the folds retained a fairly normal appearance. On transverse section, the thickening involved mostly the mucosa but in some cases the submucosa was also involved, with intervening furrow-like fissures corresponding to interrugal spaces (Fig 3). In addition, the antrum in case no. I contained a perforated ulcer which was situated away from the body area of thickened folds. Microscopic
features
The histologic changes essentially involved the mucosal folds of the body of the stomach (Fig 4). The gastric pits showed marked elongation and tortuosity, displaying a “corkscrew” appearance. The foveolar epithelium lining these pits generally consisted of active mucus-secreting cells, although hyperplasia with nuclear pseudostratification and loss of mucus production was noted in several crypts. In addition, “crypt abscess” formation involving pits was noted in three cases (Fig 5). The body glands also showed some degree of elongation, with decrease in numbers of their acid- and pepsinogen-producing cells, these often being replaced by mucus-secreting cells. In the deeper parts of the mucosa, the pits developed cystic dilatations filled with mucus. These cystic pits appeared to push down through a much thickened muscularis mucosae. This abnormal muscularis mucosae showed irregular hyperplasia and hypertrophy, with bundles of smooth muscle fibers extending up into the lamina propria of the mucosa and reaching the surface epithelium (Fig 6). The mucosal lamina propria also contained a variable excess of lymphocytes, plasma cells, eosinophils, and neutrophils. The submucosa showed edema and vascular congestion, both probably contributing to the overall thickening of the gastric folds. The submucosa also contained thickwalled veins and a mild inflammatory infiltrate. In addition to the above characteristic changes of MD, there were also numerous intraepithelial lymphocytes which involved the surface and foveolar epithelium. producing a “nuclear crowding” appearance at low magnification (Fig 7). At higher power, these intraepithelial lymphocytes were present singly rather than in clusters and most were surrounded by a clear “halo.” The “interrugal” mucosa (the part of the body mucosa situated between the thickened folds and corresponding to the furrow-like fissures seen macroscopically) appeared much less involved by MD. Here the pits were regular and of normal length, rarely displaying cystic dilatation. The lamina propria showed a mild excess of inflammatory cells. The mus-
MENETRIERS DlSEASE/LYMPHOCYK
GASTRITIS (Haot et al)
FIGURE 1. Autopsy specimen of M&-&trier’s disease combined with lymphocytic gastritis showing coarse thickening of the mucosal folds.
cularis mucosae has not unduly thickened. However. large numbers of intraepithelial lymphocytes were consistentlv present in the surface and foveolar epithelium.
FIGURE 2. Surgical specimen of MD combined with LG showing a more “cerebroid” pattern, due to the thickened and irregular folds resembling cerebral convolutions (opened by the surgeon along the lesser curve).
‘I‘he sections of antral mucosa showed no significant histologic abnormality of the pits, glands, or muscularis mucosae. In effect, the changes of MD were absent from the antrum. Nevertheless, a striking
HUMAN PATHOLOGY
Volume 22, No. 4 [April 1991)
FIGURE 3. Transverse section of a surgical specimen of MD combined with LG. The fundus [right two thirds of the picture] shows thickened folds with intervening interrugal spaces. The antrum portion (left one third of the picture] appears fairly normal.
are in excess of our observed normal values for intraepithelial lymphocytes in surgical specimens of stomach (mean, 3.7; SD, 1.8 f-or body mucosa and mean, 3.8; SD, 1.0 for antrum mucosa). The results of the morphometric measurements are summarized in Table 3. The height of the mucosa in the thickened folds ranged from 1.3 mm to 7.5 mm (mean, 3.9 mm) for the body portion involved by MD in five cases (cases no. 1. 2, 4, 5, and 6), compared with a range of 1.3 mm in 2.6 mm (mean, 1.9 mm) for the antrum portion showing no involvement by MD in four cases (cases 1, 2, 4, and 6). The combined height of mucosa and submucosa in the thickened
intracellular infiltration by lymphocytes was again seen in the surface and foveolar epithelium. The perforated peptic ulcer in case no. 1 was histologically benign. The results of the intraepithelial lymphocyte counts are summarized in Table 2. In the five surgical cases (cases no. 1, 2, 4, 5. and 6), the numbers of intraepithelial lymphocytes per 100 surface epithelial cells ranged from 40 to 55 (mean, 48; SD, 5.4) for the body mucosa and from 28 to 50 (mean, 36.2; SD, 9.9) for the antrum mucosa. In the necropsy case (case no. 3), the lymphocyte counts were lower, 20 and 11 for body and antrum mucosa, respectively. These results
FIGURE 4. Low-power view of a full-thickness section of MD combined with LG showing thickened mucosal folds, cyst formation in depth, irregularly thickened muscularis mucosae. and edema and vascular congestion of the submucosa. Normal antrum mucosa is shown on the extreme left of the picture.
382
McNiTRIERS’ DlSEASElLYMPHOCYTlC GASTRITIS (Haot et al)
FIGURE 5. Median portion of thickened mucosa of MD combined with LG. showing hyperplastic and dilated pits (some wiW crypt abscesses). The intervening lamina contains inflammatory cells and bundles of smooth muscle fibers.
and LG. This curious and hitherto unreported combination raises a number of questions. Because MD is still an enigmatic pathologic disorder and LG is a newly described entity, it seems appropriate to review some of the essential aspects of MD and LG before discussing any possible relationship between these two diseases.
folds, in the same groups of cases, showed a range of’ 11.1 mm to 14 mm (mean, 12.4 mm) for the body and 3.3 mm to 7.7 mm (mean, 4.5 mm) for the antrum. In the interrugal spaces, all these measurements were comparativel?, lower, but the difference was mainrained berwrrn the involved body and the uninvolved antrum.
M&-&trier’s Disease
DISCUSSION
Mknktrier’s disease is a rare type of hypertrophic or hyperplastic gastropathy, I .2.5.I-1.I .5and has been re_ ported in the literature under a variety of names-at
OW six cases of “giant fold disease” of the stomach showed the histologic changes described in MD
FIGURE 6. Deep portion of thickened mucosa of MD combinecl with LG. showing mucus-secreting metaplasia of gastric glands, with disappearance of specialized cells. The thickened and irregular muscularis mucosae produces smooth muscle bundles exteiiding up into the lamina propria.
383
HUMAN PATHOLOGY
Volume 22, No. 4 (April 1991)
FIGURE 7. Typical introlepithelial lymphocytic infiltration of surface and @it epithelia of MD combined with LG.
of genuine MD on critical review. The main reason for this probable discrepancy is that strict clinical and histologic criteria of MD have not yet been accepted, albeit clearly established. Moreover, the few cases of MD recorded in children appear to represent a different disorder than that seen in adults.r7 Confusion still prevails in the literature as to the definition, classification, pathogenesis, natural history, and treatment of this enigmatic “giant fold disease” of the stomach. Nevertheless and according to most authorities in gastrointestinal pathology,‘.-‘,‘“,lX-“’ the basic gross and histologic features of MD can be delineated as follows. Macroscopically, the gastrectomy specimens
least 37 synonyms according to one review”resulting in a confused terminology. Since the original description by Menetrier in 1988,rh about 300 putative cases of MD have been reported, occurring most commonly in middle-aged males, but also in children. The main clinical symptoms are epigastric pain, weight loss, vomiting, diarrhea, and occasionally hematemesis and melena. Patients with the clinically complete form of MD have hypoor achlorhydria and an unselective loss of proteins, resulting in hypoalbuminemia and peripheral edema. However, as recently pointed out by some investigators,‘.” it is doubtful if all 300 cases, mostly single case reports and small series of few patients, represent examples 384
MENETRIERS’ DlSEASEiLYMPHOCYTlC GASTRlTlS (Haot et al]
TABLE 2.
(kse No.
lntraepithelial Lymphocyte Counts in Patients With M6n6trier’s Disease Combined With Lymphocytic Gastritis
_
Pooled kxpreswd
years, 21~2z’have been recorded. On the other hand, the 16 or so cases of MD occurring in children have been self-limited, transient, and benign, except for one case in which a gastrectomy was done.” These pediatric cases of MD have generally bern accompanied by peripheral eosinophilia, suggesting an allergic reaction or a viral infection in this age group. An interesting point of controversy has been related to the cancer risk in MD. Indeed, some investigators have considered MD a precancerous condition of the stomach.4.i However, the number of bona fide cases of histologically proven MD in which gastric carcinoma develops several years after the diagnosis is snlall, 1o.L’:5
Results of Three Lymphocyte (Zounts in Percentage of Surface Epirhrlial Cells
BOdb
Antrum
are bulky
and the diseased stomach shows marked thickening of the mucosal folds. The involved areas often resemble cerebral convolutions, with an occasional nodular or polypoid appearance. The body and greater curve of the stomach are predominantly affected. The antrum is more rarely and less markedly involved, and may be entirely spared. Histologicall,y. the striking feature of MD is foveolar hyperplasla with elongation, tortuosity. and dilatation 01‘ the gastric pits, which undergo cystic dilatation in the deeper parts of the mucosa. .i.he hod) glands show variable replacement of their specialized cells by mucus-secreting cells. The intervening lamina propria contains an excess of inflammatory cells. The muscularis mucosae is hypertrophic and hyperplastic, sending smooth muscle extensions up into the lamina propria. We have not encountered in the published series of hlD any record of lymphocytic infiltration of the surface epithelium and crypts comparable to that of’ I~(;. ‘I‘he pathogenesis of MD is still unresolved: hyor primary inflammation of perplasia, hamartoma, the gastric mucosa. i Its natural history is also unclear. since mosl reported cases in adults have included gastric resections. Two instances of spontaneous remishistologic transformasion of MD, with subsequent tion to chronic atrophic gastritis within 3 to X Morphometric Measurements of M&x%rie
Lymphocytic gastritis (LG) is a newly described histopathologic entity which is characterized by a dense intraepithelial infiltration by small lymphocytes in the surface and foveolar epithelium.x-12 Clinicafly, about one third of patients with LG present with weight loss and anorexia; protein loss and peripheral edema are additional features. Endoscopically, LG corresponds to thickened gastric folds bearing small nodules with surface erosions. This unusual endoscopic picture of LG is referred to as “varioliform gastritis” and predominates in the body region of the stomach. In a prelitninary short report, we described one surgical case of hypertrophic gastropathy which combined the gross and microscopic features of MD and LG.‘:’ We present here our full series of six cases showing coexisting MD and LG. Their pathologic features are described in detail. We also review some important aspects of MD and LG, and we try to assess any possible relationship between these two diseases.
Hypertrophic or hyperplastic gastropathies are characterized by, markedly enlarged mucosal folds (IU~UP ~u,~cc~P), Involving the stomach in a more or less diffuse fashion. These gastropathies, often referred to as “giant fold disease,” are produced by a variety of different clinicopathologic conditions: ‘-’ Men&rier’s disease (MD), Zollinger-Ellison syndrome, hypertrophic hypersecretory gastropathy, diffusely infiltrative adenocarcinoma, malignant lynphoma, and ct.rtain forms of gastric polyposis (Cronkhite-(Canada syndrome). Amongst these disorders, MD represents an intriguing pathologic condition, occurring mostly in adults.“-‘i Grossly, the thickened gastric folds resemble cerebral convolutions. Microscopically, the mucosal thickening is due to elongation, tortuosity and cystic dilatation of the mucus-secreting gastric pits (cr\;pts orfo7jeokae). Patients with the clinically complete fo;-m of MD have low acid secretion and protein loss, sometimes associated with peripheral edema. Hence, MD can be considered as a protein-losing gastroenteropathy.
MATERIALS AND METHODS The only six documented cases indexed as MD in the files of the Service d’Anatomie Pathologique (Cliniques Universitaires Saint-Luc, Bruxelles. Belgium) were retrieved and carefully reviewed. The six cases included five surgical cases of‘ total gastrectomy (cases no. 1. 2, 4, 5, and 6) and one autopsy case (case no. 3). Cases no. 1,2. 3.5, and 6 have not been previously published. Case no. 4 was published as a preliminary short case report.” The clinical charts, endoscopy reports, and relevant x-ravs of these six cases were also reassessed. The pathologic reports provided a satisfactory macroscopic description of the diseased stomach in all six cases. Color transparencies of the gross specimens were also available in three cases. All six specimens had been fixed in Bouin’s fluid. Numerous blocks had been taken from the bodv and antrum in four cases: 11 in case no. 1, 12 in case no. i, 14 in case no. 4, and six in case no. 6. In case no. 3, there were two blocks from the body and one block from the antrum. Only three blocks from the body were available in case no. 5. Paraffin sections had been cut at G-km thickness and stained with hematoxylin-eosin, Masson’s trichrome, and Giemsa. Intraepithelial lymphocyte counts were performed on the hematoxyhn-eosin-stained sections from both body and antrum, whether involved by MD or unaffected. in five cases (cases no. 1. 2, 3, 4, and 6), but only from diseased body in one case (case no. 5). Using a x 400 magnification, lvmphocytes were counted in three randomly selected sites
Front the Service d’Anatomie Pathologique, the Service de (;astro~nterologie, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium; ;and the Laboratoire d’Anatomie Pathologique. lnstitut lean (Godinot. Keims, France. Accepted tol- publication July 17. 1990. Dr H.lclt was supported by a research grant from le Fonds National de la Kecherche Scientifique Medicale Beige (Belgium). Dr Bogomoletz was wpported by a traveling grant from Shandon SA (Franc~e). Krv uwrdr: Mknktrier’s disease, hypertrophic or hyperplastk gastropathlv. Ivmphocytic gastritis, varioliform gastritis. stomach. Address correspondence and reprint requests to Jules Haot, MD. Serwce d‘Anatomie Pathologique, Cliniques Llniversitaires Saint-Luc, Avenue Hippocrate 10. 1200 Bruxelles. Belgium. (:opyright 0 1991 by W.B. Saunders Company. 0046-n I77ilJ l/204-00 11$5.00/O
379
HUMAN PATHOLOGY
Volume 22, No. 4 (April 1991)
along an uninterrupted length of 400 surface epithelial cells. The results of these three counts were pooled together and expressed as the number of intraepithelial Iymphocytes per 100 surface epithelial cells. The height of body and antral mucosa, whether involved by MD or unaffected, was measured in four cases (cases nc;. 1, 2, 4, and 6): the height of the body mucosa only, which was involved bv MD, was measured in CdSe no. 5. The hematoxylin-eosin-stained sections were projected onto a white screen by means of a slide projector (X 20 magnification). The height of the mucosa was assessed by measuring the distance between the muscularis mucosae and the surface epithelium. In addition, because of the irregular thickening of muscularis mucosae always present in MD, the combined height of the mucosa and submucosa was also measured. All these measurements were performed in the body and antrum, both in the thickened folds and interrugal spaces (situated between folds). Control material of body and antrum gastric mucosa was used when performing intraepithelial lymphocyte counts and morphologic measurements of MD cases. This control material included three stomachs obtained at postmortem less than 2 hours after death, which were macroscopically and histologically within normal limits. “Normalappearing” gastric mucosa was also used as control from two total gastrectomy specimens: one containing a small leimyosarcoma (3 cm diameter) located in the proximal fundus. and the other containing a superficial adenocarcinoma (2 cm diameter) in the antrum.
RESULTS
Clinical Data The
relevant
clinical
details
of the
six patients
combined MD and LG are shown in Table 1. The age range was 25 to 67 years (mean 36.5 years). Four patients were males and two were females. Yatients presented with one or more of the following symptoms: epigastric pain, dyspepsia, anorexia, hematemesis, and vomiting. Weight loss and peripheral edema were associated features in four cases. Laboratory investigations disclosed hypoproteinemia in four patients. In all six patients, radiologic study and endoscopic examination showed markedly thickened gastric folds, which were often described as “cerebroid” (resembling cerebral convolutions). In addition, at endoscopy, a nodular pattern was promwith
TABLE 1. Details of Six Patients With M&&trier’s Disease Combined With Lymphocytic Gastritis Case
Presenting Symptoms
Associated Features
No.
Age/Sex
1
25/F
Epigastric pain
Weight loss and perforated peptic ulcer
2
26/M
3
36/F
Dyspepsia and anorexia Hematemesis
4
67/M
5
26/M
Peripheral edema hypoalbuminemia Hypoproteinemia proteinuria Weight loss and hypoalbuminemia -
6
.50/M
Hematemesis and anorexia Epigastric pain and vomiting Epigastric pain
and and
Weight loss. peripheral edema, and hypoalbuminemia
380
inent in three cases and surface in three cases. Pathologic
erosions
were noted
Features
C;ross appeurunct3. All six specimens showed gross thickening of the gastric mucosal folds, often mimicking cerebral convolutions (Figs 1 and 2). This mucosal thickening was more prominent in the body portion of the stomach, but faded almost entirely away in the antrum, where the folds retained a fairly normal appearance. On transverse section, the thickening involved mostly the mucosa but in some cases the submucosa was also involved, with intervening furrow-like fissures corresponding to interrugal spaces (Fig 3). In addition, the antrum in case no. I contained a perforated ulcer which was situated away from the body area of thickened folds. Microscopic
features
The histologic changes essentially involved the mucosal folds of the body of the stomach (Fig 4). The gastric pits showed marked elongation and tortuosity, displaying a “corkscrew” appearance. The foveolar epithelium lining these pits generally consisted of active mucus-secreting cells, although hyperplasia with nuclear pseudostratification and loss of mucus production was noted in several crypts. In addition, “crypt abscess” formation involving pits was noted in three cases (Fig 5). The body glands also showed some degree of elongation, with decrease in numbers of their acid- and pepsinogen-producing cells, these often being replaced by mucus-secreting cells. In the deeper parts of the mucosa, the pits developed cystic dilatations filled with mucus. These cystic pits appeared to push down through a much thickened muscularis mucosae. This abnormal muscularis mucosae showed irregular hyperplasia and hypertrophy, with bundles of smooth muscle fibers extending up into the lamina propria of the mucosa and reaching the surface epithelium (Fig 6). The mucosal lamina propria also contained a variable excess of lymphocytes, plasma cells, eosinophils, and neutrophils. The submucosa showed edema and vascular congestion, both probably contributing to the overall thickening of the gastric folds. The submucosa also contained thickwalled veins and a mild inflammatory infiltrate. In addition to the above characteristic changes of MD, there were also numerous intraepithelial lymphocytes which involved the surface and foveolar epithelium. producing a “nuclear crowding” appearance at low magnification (Fig 7). At higher power, these intraepithelial lymphocytes were present singly rather than in clusters and most were surrounded by a clear “halo.” The “interrugal” mucosa (the part of the body mucosa situated between the thickened folds and corresponding to the furrow-like fissures seen macroscopically) appeared much less involved by MD. Here the pits were regular and of normal length, rarely displaying cystic dilatation. The lamina propria showed a mild excess of inflammatory cells. The mus-
MENETRIERS DlSEASE/LYMPHOCYK
GASTRITIS (Haot et al)
FIGURE 1. Autopsy specimen of M&-&trier’s disease combined with lymphocytic gastritis showing coarse thickening of the mucosal folds.
cularis mucosae has not unduly thickened. However. large numbers of intraepithelial lymphocytes were consistentlv present in the surface and foveolar epithelium.
FIGURE 2. Surgical specimen of MD combined with LG showing a more “cerebroid” pattern, due to the thickened and irregular folds resembling cerebral convolutions (opened by the surgeon along the lesser curve).
‘I‘he sections of antral mucosa showed no significant histologic abnormality of the pits, glands, or muscularis mucosae. In effect, the changes of MD were absent from the antrum. Nevertheless, a striking
HUMAN PATHOLOGY
Volume 22, No. 4 [April 1991)
FIGURE 3. Transverse section of a surgical specimen of MD combined with LG. The fundus [right two thirds of the picture] shows thickened folds with intervening interrugal spaces. The antrum portion (left one third of the picture] appears fairly normal.
are in excess of our observed normal values for intraepithelial lymphocytes in surgical specimens of stomach (mean, 3.7; SD, 1.8 f-or body mucosa and mean, 3.8; SD, 1.0 for antrum mucosa). The results of the morphometric measurements are summarized in Table 3. The height of the mucosa in the thickened folds ranged from 1.3 mm to 7.5 mm (mean, 3.9 mm) for the body portion involved by MD in five cases (cases no. 1. 2, 4, 5, and 6), compared with a range of 1.3 mm in 2.6 mm (mean, 1.9 mm) for the antrum portion showing no involvement by MD in four cases (cases 1, 2, 4, and 6). The combined height of mucosa and submucosa in the thickened
intracellular infiltration by lymphocytes was again seen in the surface and foveolar epithelium. The perforated peptic ulcer in case no. 1 was histologically benign. The results of the intraepithelial lymphocyte counts are summarized in Table 2. In the five surgical cases (cases no. 1, 2, 4, 5. and 6), the numbers of intraepithelial lymphocytes per 100 surface epithelial cells ranged from 40 to 55 (mean, 48; SD, 5.4) for the body mucosa and from 28 to 50 (mean, 36.2; SD, 9.9) for the antrum mucosa. In the necropsy case (case no. 3), the lymphocyte counts were lower, 20 and 11 for body and antrum mucosa, respectively. These results
FIGURE 4. Low-power view of a full-thickness section of MD combined with LG showing thickened mucosal folds, cyst formation in depth, irregularly thickened muscularis mucosae. and edema and vascular congestion of the submucosa. Normal antrum mucosa is shown on the extreme left of the picture.
382
McNiTRIERS’ DlSEASElLYMPHOCYTlC GASTRITIS (Haot et al)
FIGURE 5. Median portion of thickened mucosa of MD combined with LG. showing hyperplastic and dilated pits (some wiW crypt abscesses). The intervening lamina contains inflammatory cells and bundles of smooth muscle fibers.
and LG. This curious and hitherto unreported combination raises a number of questions. Because MD is still an enigmatic pathologic disorder and LG is a newly described entity, it seems appropriate to review some of the essential aspects of MD and LG before discussing any possible relationship between these two diseases.
folds, in the same groups of cases, showed a range of’ 11.1 mm to 14 mm (mean, 12.4 mm) for the body and 3.3 mm to 7.7 mm (mean, 4.5 mm) for the antrum. In the interrugal spaces, all these measurements were comparativel?, lower, but the difference was mainrained berwrrn the involved body and the uninvolved antrum.
M&-&trier’s Disease
DISCUSSION
Mknktrier’s disease is a rare type of hypertrophic or hyperplastic gastropathy, I .2.5.I-1.I .5and has been re_ ported in the literature under a variety of names-at
OW six cases of “giant fold disease” of the stomach showed the histologic changes described in MD
FIGURE 6. Deep portion of thickened mucosa of MD combinecl with LG. showing mucus-secreting metaplasia of gastric glands, with disappearance of specialized cells. The thickened and irregular muscularis mucosae produces smooth muscle bundles exteiiding up into the lamina propria.
383
HUMAN PATHOLOGY
Volume 22, No. 4 (April 1991)
FIGURE 7. Typical introlepithelial lymphocytic infiltration of surface and @it epithelia of MD combined with LG.
of genuine MD on critical review. The main reason for this probable discrepancy is that strict clinical and histologic criteria of MD have not yet been accepted, albeit clearly established. Moreover, the few cases of MD recorded in children appear to represent a different disorder than that seen in adults.r7 Confusion still prevails in the literature as to the definition, classification, pathogenesis, natural history, and treatment of this enigmatic “giant fold disease” of the stomach. Nevertheless and according to most authorities in gastrointestinal pathology,‘.-‘,‘“,lX-“’ the basic gross and histologic features of MD can be delineated as follows. Macroscopically, the gastrectomy specimens
least 37 synonyms according to one review”resulting in a confused terminology. Since the original description by Menetrier in 1988,rh about 300 putative cases of MD have been reported, occurring most commonly in middle-aged males, but also in children. The main clinical symptoms are epigastric pain, weight loss, vomiting, diarrhea, and occasionally hematemesis and melena. Patients with the clinically complete form of MD have hypoor achlorhydria and an unselective loss of proteins, resulting in hypoalbuminemia and peripheral edema. However, as recently pointed out by some investigators,‘.” it is doubtful if all 300 cases, mostly single case reports and small series of few patients, represent examples 384
MENETRIERS’ DlSEASEiLYMPHOCYTlC GASTRlTlS (Haot et al]
TABLE 2.
(kse No.
lntraepithelial Lymphocyte Counts in Patients With M6n6trier’s Disease Combined With Lymphocytic Gastritis
_
Pooled kxpreswd
years, 21~2z’have been recorded. On the other hand, the 16 or so cases of MD occurring in children have been self-limited, transient, and benign, except for one case in which a gastrectomy was done.” These pediatric cases of MD have generally bern accompanied by peripheral eosinophilia, suggesting an allergic reaction or a viral infection in this age group. An interesting point of controversy has been related to the cancer risk in MD. Indeed, some investigators have considered MD a precancerous condition of the stomach.4.i However, the number of bona fide cases of histologically proven MD in which gastric carcinoma develops several years after the diagnosis is snlall, 1o.L’:5
Results of Three Lymphocyte (Zounts in Percentage of Surface Epirhrlial Cells
BOdb
Antrum
are bulky
and the diseased stomach shows marked thickening of the mucosal folds. The involved areas often resemble cerebral convolutions, with an occasional nodular or polypoid appearance. The body and greater curve of the stomach are predominantly affected. The antrum is more rarely and less markedly involved, and may be entirely spared. Histologicall,y. the striking feature of MD is foveolar hyperplasla with elongation, tortuosity. and dilatation 01‘ the gastric pits, which undergo cystic dilatation in the deeper parts of the mucosa. .i.he hod) glands show variable replacement of their specialized cells by mucus-secreting cells. The intervening lamina propria contains an excess of inflammatory cells. The muscularis mucosae is hypertrophic and hyperplastic, sending smooth muscle extensions up into the lamina propria. We have not encountered in the published series of hlD any record of lymphocytic infiltration of the surface epithelium and crypts comparable to that of’ I~(;. ‘I‘he pathogenesis of MD is still unresolved: hyor primary inflammation of perplasia, hamartoma, the gastric mucosa. i Its natural history is also unclear. since mosl reported cases in adults have included gastric resections. Two instances of spontaneous remishistologic transformasion of MD, with subsequent tion to chronic atrophic gastritis within 3 to X Morphometric Measurements of M&x%rie
