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Home , Colitis, Collagenous colitis, Gastritis, Lymphocytic colitis, Microscopic colitis

CASE REPORT

Collagenous : A Case Report, Morphologic Evaluation, and Review Z. Vesoulis, M.D., Gerard Lozanski, M.D., Pars Ravichandran, M.D., Edward Esber, M.D. Departments of Pathology (ZV, GL, PR) and (EE), Summa Health Systems, Akron, Ohio

dently identified by using analogous defined fea- Collagenous gastritis is rare; there are only four tures of collagenous : subepithelial collagen previous case reports. Histologic features seem to more than 10 ␮ in a patchy distribution, lamina overlap with the other “collagenous enterocoliti- propria lymphoplasmacytic infiltrates, intraepithe- des”; however, pathologic criteria are not yet estab- lial lymphocytes, and surface epithelial damage. lished for the diagnosis of collagenous gastritis. We Collagenous gastritis also seems to have the same describe an additional case of ostensible collage- spectrum of associated clinical findings as collage- nous gastritis in a patient who initially presented nous colitis, including frequent coexistence of celiac with celiac sprue and subsequently developed co- sprue, watery syndrome, and female pre- lonic manifestations of mucosal . dominance. Endoscopic of the revealed depo- sition of patchy, very thick bandlike subepithelial KEY WORDS: Celiac sprue, , Col- collagen in gastric antral mucosa, focal superficial lagenous gastritis, , Lympho- epithelial degeneration, numerous intraepithelial cytic gastritis, Mucosal ulcerative colitis. lymphocytes, and a dense lymphop- Mod Pathol 2000;13(5):591–596 lasmacytic infiltrate. Image analysis evaluation of gastric antral biopsies demonstrated a mean thick- Collagenous colitis, first described by Lindstrom in ness of subepithelial collagen of 27.07 ␮. Morpho- 1976 (1), is an inflammatory bowel lesion; diagnosis logic comparison was made with age-matched con- requires the clinical presentation of chronic watery trol groups of 10 patients who had normal gastric diarrhea, an endoscopically normal or “near nor- mucosal biopsies and 10 patients who had “chron- mal” mucosa and colon with subepithelial ic” gastritis, which revealed mean subepithelial col- collagen deposition, chronic , and ep- lagen measures of 1.37 ␮ and 1.19 ␮, respectively. ithelial degeneration. Collagenous colitis is proba- We compared these morphologic findings with bly an autoimmune disorder (2–6), although re- those of all previous case reports of collagenous cently other potential causes have been proposed gastritis and propose a pathologic definition based and include bacterial toxins, cytotoxins, nonsteroi- on the limited combined data. It seems that subep- dal anti-inflammatory drugs, infectious agents, and ithelial collagen is dramatically thickened in re- (7–10). ported cases of collagenous gastritis, with a cumu- “Collagenous” sprue was originally described as a lative mean measure of 36.9 ␮. ⌱t is also apparent variant of typical sprue with villous , prom- from this and previous reports that the thickened inent subepithelial collagen deposition, and refrac- subepithelial collagen is accompanied by a chronic toriness to a gluten-free diet (11). Some degree of or chronic active gastritis and sometimes intraepi- collagen deposition in sprue may be a common and thelial lymphocytes and surface epithelial damage. relatively nonspecific finding that occurs without Recently described associations of lymphocytic gas- alteration of the typical clinical course (12). tritis, sprue, and lymphocytic colitis as well as col- Collagen deposition in has rarely lagenous and lymphocytic colitis suggest a common been described; there are four case reports to date, pathogenesis that empirically may include collage- and no detailed pathologic descriptions or diagnos- nous gastritis in the same disease spectrum. We tic criteria have been elucidated (13–16). We de- propose that collagenous gastritis can be confi- scribe a case of collagenous gastritis that developed in association with celiac disease and ulcerative colitis. Careful morphometric comparison of this Copyright © 2000 by The United States and Canadian Academy of Pathology, Inc. case and control groups of normal gastric antral VOL. 13, NO. 5, P. 591, 2000 Printed in the U.S.A. biopsies and “chronic gastritis” cases illustrates the Date of acceptance: November 2, 1999. Address reprint requests to: Dr. Vesoulis, Department of Pathology, striking and overt subepithelial collagen deposition Summa Health Systems, 525 E. Market Street, Akron, OH 44304. that delineates this unusual lesion. We also review

591 and compare the clinical and pathologic features of strict emphasis on maintaining a gluten-free diet, other reported cases of collagenous gastritis and his diarrhea and resolved. Antiglia- attempt to derive unifying features and histopatho- din and antiendomysial antibodies were negative in logic criteria that characterize this lesion. The rela- follow-up studies. tionship and frequent co-occurrence of collagenous gastritis, collagenous and lymphocytic colitis, and sprue is also examined. MATERIALS AND METHODS Five endoscopic biopsies from the stomach, 6 CASE REPORT biopsies from the , and 15 biopsies from the colon were received in 10% buffered for- A 57-year-old Caucasian man presented with a malin and processed for histologic evaluation in the hypochromic, microcytic and loose stools typical manner. All sections were stained with he- for several months. He experienceda5lbweight matoxylin and eosin, and sections of the stomach loss and denied . His medical his- were additionally stained with Masson’s trichrome, tory was remarkable for coronary artery disease and Giemsa, and Warthin-Starry silver stains. Immu- lower extremity vascular surgery. There was no his- nohistochemical staining with a selected panel tory of food allergies, , or autoimmune dis- of antibodies, including CD3, UCHL-1(CD45ro), ease. His initial workup included an unremarkable L-26 (CD20), and ␬ and ␭, were performed on , but 4 months later, after persistence all biopsies. Immunostaining incorporated the of loose stools, continued , and anemia, streptavidin-biotin-peroxidase method after over- an upper gastrointestinal and small bowel series night incubation in humidity chambers at 4° C. A demonstrated small bowel dilation. Repeat esopha- microwave antigen retrieval method was used with gogastric duodenoscopy (EGD) with biopsy of the all antibodies. Slides were immersed in 200 mL of small intestine revealed a severe mucosal villous APK (Ventana Corp., Tucson, AZ) microwave buffer abnormality. Antigliadin IgG and IgA was elevated and heated in an 800 W microwave oven using a (Ͼ15 EIA units) and antiendomysial IgA was ele- high setting for 5 min. Fifty milliliters of deionized vated (Ͼ1:5). The patient was treated with a gluten- water was added to replace evaporated water from free diet; symptoms resolved, but intermittent heating, and slides were microwaved for an addi- flares of diarrhea continued. Strict adherence to a tional 5 min before automated immunostaining on gluten-free diet was considered questionable for the Ventana Nexes (Ventana Corp.). Control tissues this patient. Repeat upper with biopsies with established reactivity were stained concomi- revealed a persistent mild villous abnormality with- tantly. Morphometric measurements of subepithe- out significant collagen deposition. The patient was lial collagen in the hematoxylin and eosin and not rechallenged with gluten. Another colonoscopy trichrome sections of the stomach were performed was performed after the patient once again pre- on the CAS 200 image analyzer (Becton-Dickinson, sented with diarrhea. Stool cultures were negative San Jose, CA). Mean measures for each gastric frag- for bacterial , ova, and parasites, and C. ment were determined by two independent observ- difficile toxin assays were negative. Colon biopsy ers (GL and PR) using Ocular Micrometer v.1 soft- revealed a “nonspecific” increase in the inflamma- ware (Cell Analysis Systems, Elmhurst, IL). Only tory content of the lamina propria. The patient biopsy fragments with optimal orientation were continued to have intermittent bouts of moderate used in measurements to avoid the artifactual diarrhea and eventually developed bloody diarrhea. thickening introduced by tangential sections. Each Colonoscopy performed at this time revealed of the five optimally oriented gastric tissue frag- marked with granularity and ulceration of ments was measured in at least three separate areas the entire colon. Biopsies were taken from proxi- representing the thickest visually determined zones mal, transverse, and distal colon and . Pe- of subepithelial collagen. Each measurement con- rinuclear antineutrophilic cytoplasmic antibody sisted of 10 independent readings in each of the (pANCA) was positive (Ͼ1:160), and cytoplasmic three selected zones. Deposition of excessive colla- antineutrophilic cytoplasmic antibody (cANCA) gen at each point of measurement was confirmed was negative (Ͻ1:20). Serum IgA was elevated at by comparison with Masson’s trichrome stain of 682 mg/dL (range, 89 to 446 mg/dl). and IgG, IgM, parallel sections. Because there is no standard for complement C3, C4, antinuclear antibody, antithy- excessive thickness of subepithelial collagen in gas- roglobulin, and antimicrosomal antibodies were tric biopsies, we compared the test case with the negative. mean range of subepithelial collagen thickness in The patient was started on Prednisone and 10 patients’ archival gastric antral biopsies without Asacol, and his symptoms markedly improved. significant pathologic changes and 10 patients’ an- Three months after therapy with these drugs and tral biopsies with chronic gastritis (Table 1). All

592 Modern Pathology TABLE 1. Computerized Image Analysis Mean 45.0 ␮ in thickness with a mean of 24.95 ␮. Subep- Measurements of Gastric Subepithelial Collagen ithelial collagen was highlighted by Masson’s a a Diagnosis Range Mean trichrome staining and was negative for amyloid by “Normal” gastric antrum (n ϭ 10)b 0.30–2.81 ␮ 1.33 ␮ Congo red and crystal violet stains. Areas contain- “Chronic” gastritis (n ϭ 10)b 0.26–2.47 ␮ 1.22 ␮ Collagenous gastritis (n ϭ 1) 13.90–45.00 ␮ 24.95 ␮ ing thickened collagen also had pronounced intra- epithelial lymphocytes and focal superficial epithe- a Paired t test, two observers. No statistically significant interobserver measurement variability (p ϭ .38). lial cell degeneration with nuclear pyknosis and b Ten patients’ gastric biopsies measured in each control group; mean spongiotic change (Fig. 2). of three biopsy fragments per patient. The thickness of subepithelial collagen in the comparison group of gastric biopsies from 10 pa- tients without abnormality ranged from 0.30 to 2.81 control cases were age-matched, and those classi- ␮ (mean, 1.33 ␮). The thickness of subepithelial fied as gastritis included seven cases that originally collagen in 10 archival cases diagnosed as chronic were diagnosed as chronic nonspecific gastritis, gastritis ranged from 0.26 to 2.47 ␮ (mean, 1.22 ␮). one case of chronic with intestinal A paired t test was performed on both observers’ , and two cases of active chronic gastritis measurements using the data analysis tool of Mi- with pylori. Studies of the colon have crosoft Excel. There was no significant difference indicated a collagen table thickness with an upper between the two observers (P ϭ .38) (Table 1). range of 3 to 7 ␮ as normal (17, 18). Lymphocytic infiltrates were distributed within superficial, pit, and glandular but were RESULTS most numerous in the superficial zone adjacent to the subepithelial collagen (Fig. 1). Intraepithelial Biopsies of the gastric antrum revealed a diffuse chronic gastritis characterized by predominantly lymphocytes were T cells as shown by positive lymphocytic and plasma cell infiltration of superfi- staining for CD3 and UCHL-1 and negative staining ␬ ␭ cial and deep mucosa, without lymphoid follicle for CD20 and and antibodies. The mean intra- formation or active inflammation. No organisms epithelial lymphocyte count was 61.5 per 100 epi- that were morphologically compatible with H. py- thelial cells when 10 random high-power fields lori were identified on routine hematoxylin and were counted in each of the five gastric biopsy eosin– or Giemsa-stained sections. Subepithelial pieces. The upper limit of normal for gastric intra- collagen in the gastric biopsies was thickened in a epithelial lymphocytes is 4 to 7 per 100 epithelial discontinuous fashion and showed entrapped cap- cells with more than 25 per 100 epithelial cells illaries. Subepithelial collagen deposition was local- considered diagnostic of lymphocytic gastritis (19). ized to the superficial epithelium and did not in- Di Giacomo et al. (20) found a mean of 40.6 intra- volve the gastric foveolae (Fig. 1). Collagen deposits epithelial lymphocytes per 100 epithelial cells in occupied 63.7% of the mucosal length of the super- children who had a diagnosis of lymphocytic gas- ficial glandular epithelium of one fragment and tritis. No atypical lymphocytes or lymphoepithelial 71.1% of the other involved fragment. Subepithelial lesions, destruction of crypt epithelium, lymphoid collagen deposition, measured by two observers in follicles, or other features of mucosal-associated two gastric mucosal fragments, ranged from 13.9 to lymphoid tissue lymphoma were identified. Only

FIGURE 1. Subepithelial collagen deposition in collagenous gastritis localized only to the superficial glandular epithelium (arrowheads) (hematoxylin and eosin ϫ 200). Right, gastric antral surface epithelium showing many intraepithelial lymphocytes (arrowheads) and marked thickening of subepithelial collagen (arrow) (hematoxylin and eosin ϫ 400).

Collagenous Gastritis (Z. Vesoulis et al.) 593 FIGURE 4. Colonic mucosal biopsy with changes consistent with FIGURE 2. Antral mucosa showing subepithelial collagen with active ulcerative colitis, including irregular glandular morphology, entrapped capillary containing red blood cells (arrowhead) and distribution and variable gland size in association with diffuse active overlying epithelium with intraepithelial lymphocytes, karyorrhectic colitis, crypt abscesses (arrowhead), and marked lamina propria ϫ fragments, and spongiotic epithelial degenerative change (large inflammation (hematoxylin and eosin 40). arrowhead) (hematoxylin and eosin ϫ 400).

lar epithelium. Patchy neutrophilic infiltration of rare intraepithelial lymphocytes could be found in crypt epithelium and crypt abscesses was conspic- the control group biopsies and therefore were not uous (Fig. 5). No granulomas except for rare mucin quantified granulomas associated with ruptured crypts were Sections of the and showed identified. Additional findings included Paneth cell almost total villous atrophy, crypt hyperplasia with metaplasia and a thickened muscularis mucosa in prominent mitotic activity, marked mononuclear the left colon biopsies. No significant subepithelial cell infiltrates of the lamina propria, and numerous collagen deposition was identified in biopsies of the intraepithelial lymphocytes with patchy degenera- small bowel or colon. tion of surface enterocytes characteristic of celiac sprue (Fig. 3). Neither neutrophils nor collagen was DISCUSSION conspicuous in the small bowel biopsies. Sections of the colon showed a diffuse active colitis pattern A spectrum of ostensible immune-mediated in- of inflammation involving the mucosa from the flammatory bowel diseases were present in this pa- cecum, transverse, and rectosigmoid colon. The tient, including collagenous gastritis associated mucosa showed atrophic features with irregular with lymphocytic gastritis, celiac disease, and - crypt architecture, variable size, and irregular spac- ative colitis. The histologic findings of intraepithe- ing of atrophic glands (Fig. 4). A dense chronic lial lymphocytic infiltrates and epithelial injury inflammatory infiltrate with basal plasmacytosis throughout the gastric and intestinal biopsy mate- occupied the lamina propria continuously in most rial and the serologic presence of several autoanti- biopsy fragments. Numerous intraepithelial lym- bodies, including antigliadin, antiendomysial, and phocytes were identified in the superficial glandu- pANCA, are unifying features. Recently, reports have shown overlap of both related and seemingly

FIGURE 3. Jejunal mucosa with total villous atrophy, intraepithelial FIGURE 5. Colonic mucosal biopsy with active ulcerative colitis lymphocytes (arrowhead), and diffuse plasma cell infiltrates of the changes including a dense plasmacytic infiltrate (large arrowhead) and lamina propria (hematoxylin and eosin ϫ 200). active cryptitis (small arrowhead) (hematoxylin and eosin ϫ 400).

594 Modern Pathology unrelated forms of inflammatory bowel disease, in- been demonstrated in collagenous colitis (26–28). cluding various forms of collagenous and lympho- Collagen deposition in collagenous gastritis may cytic colitis, sprue, Crohn’s disease, and ulcerative have a similar pathogenesis considering the close colitis (17, 21–25). Associated clinical and patho- morphologic similarities to collagenous colitis. logic features of these chronic inflammatory bowel However, if the mechanism of collagen deposition diseases suggest overlapping causes or a similar is simply reparative and related to mucosal injury, pathogenesis. Serum autoantibodies and histocom- then why is some degree of collagen deposition not patibility locus antigens are described in cases of described in reactive gastropathies, nonspecific ulcerative colitis, collagenous and lymphocytic co- gastritis, H. pylori gastritis, or other forms of gastric litis, celiac sprue, and lymphocytic gastritis. mucosal insult? Undoubtedly, the mechanism is Collagenous gastritis seems to be a very rare or more complex and probably involves immune- underrecognized entity; only four other cases have mediated phenomenon related to the intraepithe- been reported since 1989. A summary of the clinical lial T-lymphocyte infiltrates, epithelial injury, and presentation and pathologic findings of these cases antibody production. is presented in Table 2. All reported cases have No reports of collagenous gastritis have appeared shown a subepithelial collagen layer significantly in the pathology literature, and no detailed patho- thickened in a range of 20 to 30 times that of normal logic definition has been elaborated. With the use mucosa. of morphometric comparison to normal and “gas- The mechanism of collagen deposition in pa- tritis” mucosa, it is a reasonable assertion that sub- tients who have collagenous gastritis is unknown. epithelial collagen deposition exceeding 10 ␮, anal- One postulated mechanism of collagen deposition ogous to collagenous colitis criterion, can in collagenous colitis is that the collagenous band confidently identify collagenous gastritis. We are represents a sequel to inflammation and mucosal aware of no other condition in which excessive injury. Deposition of type III collagen, a repair-type subepithelial collagen in a bandlike distribution has collagen produced by subepithelial fibroblasts, has been described. Summary data of the five reported

TABLE 2. Summary of Collagenous Gastritis Case Reports

Case Report Current Report Grossman 1996 (15) Stolte 1990 (16) Colletti 1989 (14) Borchard 1989 (13) Age 57 35 75 15 67 Sex Male Female Female Female Female Clinical Diarrhea, rectal Abdominal distension, Watery Intermittent Watery diarrhea presentation , watery diarrhea diarrhea for gastric pain for for2y 6mo 1y Endoscopy Gastric Diffuse gastric edema, Not reported Erythema, Normal endoscopy erythema, nodularity nodularity, duodenal hemorrhagic atrophy, mucosa rectosigmoid erythema and exudate Diffuse chronic Patchy surface damage, Active chronic Patchy, Active chronic gastritis nonspecific gastritis gastritis superficial gastritis active chronic gastritis Collagen Antrum surface Surface epithelium avg. Antrum, body Antrum surface Location not epithelium, 20–30 ␮ surface epithelium specified mean 27 ␮ epithelium avg. 60 ␮ 30–60 ␮ 25–30 ␮ Lymphocytic Yes Not reported Not reported Not reported Not reported gastritis Significant IgA, gliadin, Antigliadin G,A negative Not reported IgG,A,M,E, ANA, No serum labs endomysial parietal cell autoantibodies titers and IF elevated, negative pANCA Associated Celiac sprue, Lymphocytic colitis Collagenous Normal Collagenous sprue, diseases mucosal colitis, sprue esophageal, collagenous ulcerative duodenal, colitis colitis colon biopsies Treatment Asacol, gluten , famotene, Not given Ranitidine, restriction sulfasalazine sucralfate, furazolidane Course Resolution of Resolution of diarrhea Not given No clinical/ Residual gastric diarrhea and only pathologic collagen at gastrointestinal resolution rebiopsy bleeding

Collagenous Gastritis (Z. Vesoulis et al.) 595 cases of collagenous gastritis show a mean subep- 8. Giardiello FM, Hansen F, Lazenby AJ, Hillman DB, Milligan ithelial collagen thickness of 36.9 ␮ (Table 2). In our FD, Bayless TM, et al. Collagenous colitis in setting of non- control group data, the mean thickness of collagen, steroidal anti-inflammatory drugs and antibiotics. Dig Dis Sci 1990;35(2):257–60. even in severe active chronic gastritis, rarely ex- 9. Jarnerot G, Tyck C, Bohr J, Erikson S. Collagenous colitis and ceeded 3 ␮. We propose that the diagnosis of col- fecal stream diversion. Gastroenterology 1995;109:449–55. lagenous gastritis also requires biopsy evidence of 10. Ridell RH, Tanaka M, Mazzolini G. Non-steroidal anti- gastritis, epithelial injury, and intraepithelial lym- inflammatory drugs as a possible cause of collagenous coli- phocytes, analogous to collagenous colitis, al- tis: a case control study. Gut 1992;33:683–6. 11. Weinstein WM, Saunders DR, Tytgat GN, Rubin CE. Collag- though other case reports have not entirely docu- enous sprue—an unrecognized type of malabsorption. mented some of these features. It is interesting that N Engl J Med 1970;283:1297–301. three of the five reported cases had coexisting 12. Bossart R, Henry K, Booth CC, Doe WF. Subepithelial colla- sprue, three had collagenous or lymphocytic colitis, gen in intestinal malabsorption. Gut 1975;16:18–22. four were female, and three presented with watery 13. Borchard F, Niederau C. Kollagene gastroduodenitis. Dtsch diarrhea. This apparently common association with Med Wschr 1989;114:1345. 14. Colletti RB, Trainer T. Collagenous gastritis. Gastroenterol- a similar clinical syndrome and morphologically ogy 1989;97:1552–5. similar lesions in other parts of the gastrointestinal 15. Grossman GM, Myers S, Harpaz N. Collagenous gastritis tract empirically suggests overlapping pathologic associated with lymphocytic colitis. J Clin Gastroenterol features. Appropriate therapy for collagenous gas- 1996;22(2):134–7. tritis has not been established, and resolution with 16. Stolte M, Ritter M, Borchard F, Koch-Scherner G. Collage- specific therapy has not be documented. nous gastroduodenitis on collagenous colitis. Endoscopy 1990;22:186–7. Probably an insufficient number of cases of col- 17. Bogomoletz WV. Collagenous, microscopic and lymphocytic lagenous gastritis have been reported to extrapolate colitis. An evolving concept. Virchows Arch 1994;424:573–9. consistent clinical, laboratory, endoscopic, and 18. Lee E, Schiller LR, Vendrell D, Santa Ana C, Fordtran JS. pathologic findings. However, even with the few Subepithelial collagen table thickness in colon specimens reported cases, the dramatically thickened gastric from patients with and collagenous co- subepithelial collagen does seem to be a morpho- litis. Gastroenterology 1992;103:1790–6. 19. Haot J, Hamichi L, Wallez I, Manguet P. 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596 Modern Pathology