Collagenous Gastritis and Collagenous Colitis: a Report with Sequential Histological and Ultrastructural ﬁndings

Gut 1999;44:881–885 881

CASE REPORTS Gut: first published as 10.1136/gut.44.6.881 on 1 June 1999. Downloaded from

Collagenous gastritis and collagenous colitis: a report with sequential histological and ultrastructural ﬁndings

A B Pulimood, B S Ramakrishna, M M Mathan

Abstract Collagenous gastritis, an extremely rare entity, The case is reported of a young adult man and the more commonly encountered colla- with collagenous gastritis, an extremely genous colitis are both characterised by the rare disorder with only three case reports deposition of a subepithelial collagen band in in the English literature, who subse- the mucosa. Only three cases of collagenous quently presented with collagenous colitis. gastritis have been reported in the English Sequential gastric biopsies showed a nota- literature. One occurred in isolation1, one with ble increase in thickness of the subepithe- synchronous collagenous colitis and collagen- lial collagen band. Ultrastructural study ous duodenitis,2 and the third with synchro- of gastric and rectal mucosa showed the nous lymphocytic colitis.3 We report, with characteristic subepithelial band com- ultrastructural findings, the case of a young posed of haphazardly arranged collagen adult man who presented initially with features fibres, prominent degranulating eosi- of collagenous gastritis and was subsequently nophils, and activated pericryptal fibro- found to have collagenous colitis. blasts. (Gut 1999;44:881–885) Case report

Keywords: collagenous gastritis; collagenous colitis; A 20 year old man presented with a two year http://gut.bmj.com/ stomach; colon history of epigastric pain, vomiting, easy fatiguability, and malaise. The symptoms were noticed after an acute febrile illness, the treatment details of which are not known. Physical examination disclosed pallor and angular stomatitis. Routine blood and stool examination showed a haemoglobin level of 6.3 g/dl, a total white blood cell count of 8.5 × on September 27, 2021 by guest. Protected copyright. 106/dl with 13% eosinophils, and hookworm ova in the stools. On upper gastrointestinal endoscopy, diVuse nodularity of the gastric mucosa was seen with no abnormalities in the oesophagus or duodenum. Biopsy specimens from the body and antrum of the stomach were obtained for routine histopathological examination. Rigid sigmoidoscopy performed at the same time gave normal results and biopsy specimens were not taken. The patient was Wellcome Trust treated with H receptor blockers, antihelmin- Research Laboratory, 2 Christian Medical thics, and oral iron, but he continued to have College and Hospital, recurrent symptoms over the next four years. Vellore 632004, India Upper endoscopy repeated at three months A B Pulimood and three years after the initial presentation B S Ramakrishna continued to show the same findings. On both M M Mathan occasions, biopsy samples from the gastric Correspondence to: body and antrum were processed for routine Dr A B Pulimood, histopathology, and on the second time the Department of Surgery, samples were also fixed in glutaraldehyde for School of Surgical Sciences, The Medical School, ultrastructural study. University of Newcastle, Six years after the onset of the illness, the Newcastle upon Tyne NE2 patient presented with diarrhoea and weight 4HH, UK. Figure 1 Antral mucosa obtained in the year of loss of two months duration. Stool occult blood presentation showing atrophic gastritis and diVuse fibrosis Accepted for publication of the lamina propria. The surface epithelium is lifted oV. at this time was strongly positive (3+). On 19 August 1998 Trichrome stain. upper endoscopy and sigmoidoscopy, the 882 Pulimood, Ramakrishna, Mathan Gut: first published as 10.1136/gut.44.6.881 on 1 June 1999. Downloaded from

Figure 2 Gastric mucosa obtained in the year of presentation (A) and three years (B) and four years (C) later showing a collagen band (*) below the surface epithelium, which is seen to increase in length and thickness in (B) and (C). Entrapped inﬂammatory cells and capillaries are also seen. Trichrome stain. gastric mucosa continued to show diVuse nodularity. The rectal mucosa still did not show any abnormality. Biopsy specimens were obtained from the antrum, duodenum, and rectum for histopathological study and from the antrum and rectum for ultrastructural study.

Pathology http://gut.bmj.com/ LIGHT MICROSCOPY Gastric biopsy specimens obtained at the time of presentation and three months later showed diVuse chronic gastritis of the body and antrum with focal moderate to severe atrophy of glands, in both the body and the antrum. The foci of atrophy were associated with notable fibrosis of the lamina propria and smooth on September 27, 2021 by guest. Protected copyright. muscle upgrowth from the muscularis mucosa Figure 4 Electron micrograph showing subepithelial (fig 1). The surface epithelium in these areas collagen band (*) in the gastric mucosa composed of haphazardly arranged collagen fibres. Original was partly detached and there was neutrophilic magnification × 4000. infiltration of both the epithelium and the lamina propria. In the mucosa away from the sites of atrophy, short bands of hyalinised laries, lymphocytes, and eosinophils (fig 2A), collagen 15–43 µm thick, with entrapped capil- were seen below the surface epithelium or at the level of the foveolae. These bands of collagen stained blue with the trichrome stain and negative for amyloid with congo red stain. The epithelium overlying these bands appeared normal in some areas and shortened and detached in others. There was no increase in intraepithelial leucocytes. Modified Giemsa stain did not show any evidence of Helicobacter pylori. Gastric biopsy samples obtained three and four years after presentation also showed chronic gastritis with foci of atrophy and subepithelial collagen bands. The width of these bands ranged from 23 to 225 µm (fig 2B,C) and they extended over greater lengths of the mucosa than the bands seen in the earlier specimens. The cellularity of the lamina Figure 3 Rectal mucosa showing chronic colitis and a propria and the degree of atrophy were similar subepithelial collagen band (trichrome stain). to that seen in the previous samples. H pylori Collagenous gastritis and collagenous colitis 883

were not seen. Duodenal biopsy specimens showed only mild chronic inﬂammation. Rectal biopsy specimens obtained after the

onset of watery diarrhoea showed a mild Gut: first published as 10.1136/gut.44.6.881 on 1 June 1999. Downloaded from chronic colitis with patchy subepithelial collagen bands 20–30 µm thick (fig 3). In some areas the band was located deeper in the mucosa. The surface epithelium was shortened in foci over the deposited collagen and showed a few intraepithelial leucocytes. The lamina propria had a mild infiltrate of plasma cells, lymphocytes, eosinophils, and neutrophils. Crypt architecture was preserved and there were no other significant findings.

ULTRASTRUCTURAL STUDY Ultrastructural examination of the gastric Figure 6 Electron micrograph of an eosinophil in the biopsy specimens obtained three and four years gastric lamina propria showing degranulation with fusion after the first presentation showed a patchy of adjacent granule chambers (*). Original magnification subepithelial band of haphazardly arranged × 7000. collagen fibres (fig 4). Capillaries, lymphocytes, eosinophils, mast cells, and fibroblasts were seen entrapped in this band. The overlying surface epithelium showed focal decrease in mucous granules, widening of intercellular spaces, and detachment from the basement membrane in some areas. Fibroblasts entrapped in the subepithelial collagen bundles and located around foveolae and glands did not show significant alterations. Many of the entrapped eosinophils and those present in the superficial and deep lamina propria showed evidence of prominent degranulation: by necrosis and release of granules, by piecemeal degranulation (partial or complete loss of individual granule contents), or by the http://gut.bmj.com/ fusion of granule chambers with each other and the surface membrane to release contents, a Figure 7 Electron micrograph showing reduplication of process similar to anaphylactic degranulation glandular basement membrane in gastric mucosa (*). × of mast cells45 (figs 5 and 6). Mast cells Original magnification 6000. entrapped in the collagen band and located in the lamina propria also showed evidence of

degranulation, predominantly of the piecemeal on September 27, 2021 by guest. Protected copyright. type5 (ﬁg 5).

Figure 8 Electron micrograph showing an activated pericryptal ﬁbroblast in the rectal mucosa with prominent Golgi (G) and dilated rough endoplasmic reticulum (R). Original magniﬁcation × 11 000.

There was atrophy of glands, and the deep lamina propria showed large collagen bundles composed of uniformly oriented fibres. Some of these glands showed reduplication of their Figure 5 Electron micrograph of an eosinophil (E) and a basement membranes (fig 7), a finding that was mast cell (M) in the lamina propria of gastric mucosa showing degranulation adjacent to collagen bundles (C). also noted in superficial and deep blood Original magnification × 4000. vessels. 884 Pulimood, Ramakrishna, Mathan

Ultrastructural study of the rectal biopsy local abnormality of the pericryptal collagen specimens obtained after the onset of watery sheath; (c) autoimmune injury.6–8 The histo- diarrhoea also showed a subepithelial band of logical and ultrastructural ﬁndings in our case

haphazardly arranged collagen fibres. The appear to concur with the first two theories. Gut: first published as 10.1136/gut.44.6.881 on 1 June 1999. Downloaded from overlying surface epithelium did not show any The initial and all subsequent gastric biopsy significant alterations. Pericryptal fibroblasts specimens from our patient showed a non- were enlarged (fig 8), with prominent rough progressive patchy atrophic gastritis. This was endoplasmic reticulum, well developed Golgi, associated with neutrophilic infiltration of the large mitochondria, and occasional lipid bod- mucosa and thin subepithelial collagen band ies. Eosinophils in the mucosa showed evi- deposition in the first two sets of biopsy dence of piecemeal degranulation. Mast cells samples, but absent neutrophils and a notice- did not show any significant alterations. There ably thickened collagen band in the next two was focal duplication of basement membranes, obtained three and four years later. These find- both of crypts and blood vessels. ings suggest that the original stimulus for the atrophic gastritis and the collagen band Discussion deposition was possibly the same, but once Collagenous gastritis is an extremely rare triggered, the subepithelial collagen deposition disorder and little is known about its aetio- continued to progress irrespective of the course pathogenesis and natural history. The three of gastritis in the rest of the mucosa. This previous reports described this condition (a)in would imply that a local defect was responsible isolation,1 (b) with synchronous lymphocytic for the specific subepithelial collagen deposi- colitis,2 and (c) with synchronous collagenous tion, and, as the periepithelial fibroblastic colitis and collagenous duodenitis.3 This is the sheath is the source of collagen in this zone, the first report of a case presenting initially with defect would in all probability lie in the collagenous gastritis and subsequently with functioning of these cells. Activated fibroblasts features of collagenous colitis. were noted in the rectal mucosa of our patient, The clinical, endoscopic, and histological as described in previous ultrastructural features in our case are similar to those reports,79and an inherent metabolic defect in described by Colletti and Trainer.1 Both these pericryptal fibroblasts, either in their patients were young and presented with production or breakdown of collagen, would epigastric pain and gastrointestinal bleeding. also explain the synchronous or metachronous Our patient, however, presented with chronic occurrence of collagenous colitis and collagen-

anaemia which did not improve with H2 recep- ous gastritis in this and other patients. tor blockers, antihelminthic treatment, and Collagenous colitis is occasionally associated iron supplements, suggesting chronic blood with lymphocytic colitis, and they have been

loss. This was unlike the acute upper gastro- postulated to be diVerent stages of the same http://gut.bmj.com/ intestinal bleeding seen in the patient described disorder.6 Lymphocytic gastritis on the other by Colletti and Trainer. Our endoscopic hand has been reported in only one patient finding of gastric nodularity had been noted in with collagenous colitis10 and was not described two of the three previous reports,13 but in any of the previous reports of collagenous involvement of the mucosa was more extensive gastritis. in our case. Histologically also, atrophic gastri- The gastric mucosa of our patient showed tis and deposition of the subepithelial collagen prominent degranulating eosinophils in the band was seen in both the body and antral lamina propria on ultrastructural study. This on September 27, 2021 by guest. Protected copyright. biopsy specimens of our patient, unlike the observation was also made in one of the earliest previous report1 where only the body was reports of collagenous colitis.11 At the light involved. microscopic level, authors have described the There was an eightfold increase in thickness increase in mucosal eosinophils in patients with of the subepithelial collagen band noted in the collagenous gastritis and colitis.1–3 12–16 Eosi- gastric mucosa of our patient in the three year nophils are known to produce tissue damage period between the initial and the last two sets and are associated with some fibrosing of biopsies. The linear extent of the band was disorders.6 It is possible that they may play a also increased in the second set of samples. The role in the aetiopathogenesis of collagenous simultaneous notable increase in thickness of disorders of the gastrointestinal tract, although the gastric collagen band and the onset of their activation could also be a byproduct of a symptomatic involvement of the colon in this non-specific inflammatory response. young man suggests that histologically the dis- The gastric mucosa of this patient also ease was probably progressing. Colonic/rectal showed many degranulating mast cells. Mast biopsy specimens from the period before the cells are believed to play a role in wound healing onset of diarrhoea, however, were not available and fibrotic disorders of the skin,17 heart,18 and to rule out definitely pre-existing disease. The lung.19 In the appendix mild mucosal fibrosis fact that the thickness of the rectal collagen was associated with a threefold increase in mast band seen within two months of the onset of cell numbers.20 Mast cells induce migration and diarrhoea was similar to that in the gastric proliferation of fibroblasts17 and also stimulate mucosa at the time of initial presentation also collagen synthesis.21 It is possible that the suggests that the disease process in the colon mediators released by the degranulating mast was still in its early stages. cells in the gastric mucosa of our patient could Three major theories have been postulated have contributed to the pathogenesis of the for the pathogenesis of the subepithelial thickening collagen band. Mast cell activation, collagen band: (a) inflammatory origin; (b) through the release of eosinophil chemotactic Collagenous gastritis and collagenous colitis 885

factor and the resulting eosinophilic infiltrate with transition to collagenous colitis. Schweiz Med Wochen- schr 1993;123:1487–90. could also indirectly play a role in the laying 11 Bamford MJ, Matz LR, Armstrong JA, et al. Collagenous down of excessive collagen. colitis: a case report and review of the literature. Pathology 1982;14:481–4. Gut: first published as 10.1136/gut.44.6.881 on 1 June 1999. Downloaded from 12 Jessrun J, Yardley JH, Giardiello FM, et al. Chronic colitis 1 Colletti RB,Trainer TD. Collagenous gastritis. Gastroenterol- with thickening of the subepithelial collagen layer (colla- ogy 1989;97:1552–5. genous colitis). Hum Pathol 1987;18:839–48. 2 Stolte M, Ritter M, Borchard F, et al. Collagenous 13 Lazenby AJ, Yardley JH, Giardiello FM, et al. Pitfalls in the gastroduodenitis on collagenous colitis. Endoscopy 1990;22: diagnosis of collagenous colitis: experience with 75 cases 186–7. from a registry of collagenous colitis at the Johns Hopkins 3 Groisman GM, Meyers S, Harpaz N. Collagenous gastritis Hospital. Hum Pathol 1990;21:905–10. associated with lymphocytic colitis. J Clin Gastroenterol 14 Bogomoletz WV. Collagenous, microscopic and lym- 1996;22:134–7. phocytic colitis. An evolving concept. Virchows Arch 1994; 4 Dvorak AM. Ultrastructural studies on mechanisms of 424:573–579. human eosinophil activation and secretion. In: Gliech GJ, 15 Gremse DA, Boudreaux CW, Manci EA. Collagenous coli- Kay AB, eds. Eosinophils in allergy and inflammation.New tis in children. Gastroenterology 1993:104:906–9. York: Marcel Dekker, 1994:159–209. 16 Wardlaw A. The eosinophil: new insights into its function in 5 Dvorak AM. Ultrastructural analysis of human mast cells human health and disease. 1996; :355–7. and basophils. In: Marone G, ed. J Pathol 179 Human basophils and mast 17 Levi-SchaVer F, Weg VB. Mast cells, eosinophils and fibro- cells: biological aspects. Chemical immunology. Basel: Karger, 1995;61:1–33. sis. Clin Exp Allergy 1997;27(suppl):64–70. 6 Jawahari A, Talbot IC. Microscopic, lymphocytic and colla- 18 Li OY, Raza-Ahmad A, MacAulay MA, et al. The genous colitis. Histopathology 1996;29:101–10. relationship of mast cells and their secreted products to the 7 Hwang WS, Kelly JK, ShaVer EA, et al. Collagenous colitis: volume of fibrosis in post transplant hearts. Transplantation a disease of pericryptal fibroblast sheath? JPathol 1992;53:1047–51. 1986;149:33–40. 19 Inoue Y, King TE, Tinkle SS, et al. Human mast cell basic 8 Stampel DA, Friedman LS. Collagenous colitis: pathophysi- fibroblast growth factor in pulmonary fibrotic disorders. ologic conditons. Dig Dis Sci 1991;6:705–11. Am J Pathol 1996;149:2037–54. 9 Widgren S, Jlidi R, Cox JN. Collagenous colitis: histologic, 20 Stead RH, Franks AJ, Goldsmith CH, et al. Mast cells, morphometric, immunohistochemical and ultrastructural nerves and fibrosis in the appendix: a morphological studies. Report of 21 cases. Virchows Arch 1988;413:287– assessment. J Pathol 1990;161:209–19. 96. 21 Cairns JA, Walls AF. Mast cell tryptase stimulates the 10 Christ AD, Meier R, Bauerfeind P, et al. Simultaneous synthesis of type I collagen in human lung fibroblasts. J occurrence of lymphocytic gastritis and lymphocytic colitis Clin Invest 1997;99:1313–21. http://gut.bmj.com/ on September 27, 2021 by guest. Protected copyright.