The Histopathology of Nonsteroidal Anti-inflammatory Drug-Associated Colitis

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1 The Histopathology of Nonsteroidal Anti-inflammatory Drug-Associated Colitis NealS. Goldstein, M D, a n d A. Noel Cinenza, MD Key Words: NSAID; Colon; Colitis; Inflammatory bowel disease; Microscopic colitis; Lymphocytic colitis; Collagenous colitis; Focal colitis We describe the histologic findings of biopsies performed on specimens from 14 patients with nonsteroidal antiinflammatory drug (NSAID) associated colitis. Thirteen patients had endoscopially patchy colitis with small erosions in different parts of the colon. One patient had diffuse colitis extending from the rectum to the midtransverse colon. Histologically, 8 patients had a mixed inflammatory infiltrate, 4 had predominantly neutrophilic inflammation, and 2 had predominantly lymphocytic inflammation. Seven patients had erosions. Eight patients had crypt architectural disarray, but none had crypt architectural distortion or granulomas. The histology ofnsaidassociated colitis is similar in our experience to that of Crohn disease and infectious-type colitis. It shares no features with ulcerative colitis. Given the widespread use ofnsaids, pathologists should consider NSAIDassociated colitis along with Crohn disease and infectious-type colitis in the histologic differential diagnosis of focal active colitis. Nonsteroidal antiinflammatory drugs (NSAIDs) are a widely used group of pharmaceutical agents. In addition to being distributed by prescription, NSAIDs also are distributed as over-the-counter products and are a component of many different drug formulations. Thus, many patients may unknowingly ingest NSAIDs, which can cause a variety of colonic abnormalities including colitis, ulcers, and strictures (webs). Although the clinical entity of NSAID-associated colitis is well recognized, its histopathology is poorly documented. Most descriptions of NSAID-associated colitis are short, textual, and confined within case reports or small series, and many authors have classified the changes as nonspecific. We report the histologic findings in colonic biopsy specimens from 14 patients with NSAID-associated colitis to enable pathologists to recognize this condition and distinguish it from other forms of colitis. Materials and Methods Fourteen patients were identified from the surgical pathology files of William Beaumont Hospital and records from the Monthly Surgical Pathology-Gastroenterology Clinicopathologic Conference from August 1994 through July All patients were taking NSAIDs at the time of their biopsies. All patients had a resolution of their signs and symptoms following the cessation of NSAID ingestion. No medications were used to treat the colitis, and no patient had prior colitis or diverticulitis. All patients had stool cultures performed at the time of biopsy, and none of the cultures grew enteric pathogenic microorganisms. The following histologic features were examined: 1. Pattern of injury, categorized as either diffuse or focal. Diffuse injury was defined as a similar degree of inflammation in all the biopsy fragments procured from 622

2 the same region of the colon. Focal injury was defined as a heterogeneous pattern, with 1 or several biopsy fragments procured from the same region of the colon appearing distinctly different from other fragments. 2. Crypt architectural distortion, defined as crypt atrophy, branching, or focal shortening above the muscularis mucosae. This feature was categorized as either present or absent. 3. Crypt disarray, defined as variation in crypt distribution or size without crypt branching or focal shortening. This feature was categorized as either present or absent. 4- Amount of lymphoplasmacytic infiltrate in the lamina propria, categorized as normal, mildly increased, or markedly increased. The normal constituent mucosal inflammatory cell population consisted of a sprinkling of lymphocytes and plasma cells between crypts and occasional lymphoid follicles. Lymphoplasmacytic inflammation was mildly increased when the pink areolar lamina propria connective tissue was obscured by inflammatory cells, but no crypt disarray was evident. Markedly increased lymphoplasmacytic inflammation had crypt disarray resulting from inflammatory cell expansion of the lamina propria. 5. Lymphocytes in the surface or crypt epithelium, categorized as absent, mildly increased, or markedly increased. The normal surface or crypt epithelium contained rare intraepithelial lymphocytes (IELs). Mildly increased IELs consisted of focal clusters or a mild diffuse increase in intraepithelial lymphocytes, producing IEL counts between 10 and 20 surface epithelial cells per 100 surface epithelial cells, which is less than the diagnostic minimum for lymphocytic colitis.1"3 Markedly increased IELs consisted of more than 20 IELs per 100 surface epithelial cells, which conforms to the descriptions and photographs of typical lymphocytic colitis. 6. Amount of neutrophilic lamina propria inflammation, graded as absent, mildly increased, or markedly increased. The normal lamina propria contained no neutrophils. Mildly increased neutrophilic inflammation was considered present in cases of single or small clusters of neutrophils in the lamina propria between crypts and no infiltration of the crypt or surface epithelium. Neutrophils were markedly increased when they formed microabscesses in the lamina propria or crypt abscesses. 7. Erosions, categorized as either present or absent. 8. Subsurface epithelial collagen band thickening, categorized as either absent or present. Although not measured, a normal subsurface collagen layer thickness was defined as less than the thickened subsurface collagen band of collagenous colitis Pericryptal fibroblastic sheath thickness, categorized as either normal or thickened. A normal thickness was defined as less than the diameter of 1 erythrocyte. 10. Apoptotic bodies in the surface epithelium, defined as either normal or increased. Normal apoptotic bodies/nuclear debris was defined as 3 or fewer foci in the surface epithelium between adjacent crypts. 11. Granulomas, categorized as either present or absent. Results Clinical Findings Of the 14 patients, 9 were female and 5 were male. The median patient age was 59 years (range, years; standard deviation, 16.1 years). Eleven patients had abdominal pain or cramps and intermittent bloody nondiarrheal stools. Four of those patients also had anemia. Four patients presented with mild bloody diarrhea. Ten patients had been "chronically" ingesting NSAIDs for time periods of more than 3 months. Three patients had been ingesting NSAIDs for periods of 1 to 3 months. One patient had ingested high doses of prescription NSAIDs for 2 weeks. The colitis was patchy in 13 patients and diffuse in 1. The patchy colitis predominantly involved the rectosigmoid in 6 patients, transverse colon in 2 patients, cecum in 2 patients, ascending colon in 1 patient, and entire colon in 2 patients. Two patients with predominantly rectosigmoid disease also had lesions in the cecum and descending colon, respectively. All 13 patients were described as having regions of mucosal erythema and friability, with smallgeographic or aphthous ulcers. One patient had diffuse colitis and ulcers that homogeneously involved the rectum with extension to the midtransverse colon. Pathologic Findings Of the 14 patients, 13 had colitis that was patchy upon microscopic examination, identical to the endoscopic appearance. These biopsy specimens, which were all procured from the same region of the colon, manifested a heterogenous pattern of injury: some fragments were normal, whereas others showed colitis. Most of the biopsy fragments that showed colitis were also involved in a patchy distribution. In 7 of the specimens with patchy colitis, the inflammatory infiltrate contained a mixture of lymphocytes, plasma cells, and neutrophils. Six of the 7 specimens had mildly increased inflammation, and the seventh had markedly increased inflammation. Crypt disarray was present in 4 specimens. Two of the 6 mildly inflamed biopsy specimens also contained focal, mildly increased surface IELs llmage II llmage

3 Goldstein and Cinensa / NSAID COLITIS. -»» **v I #1*r*5'* «*. r-^ 4 i Image I I A, Mildly increased, mixed inflammation with small central erosion. There is slight crypt architectural disarray but no distortion (H&E, x192). B, Neutrophils emanate from the center of the erosion. The surface epithelium has regenerative changes including mucin depletion, cuboidal shapes, nucleomegaly, and prominent nucleoli (H&E, x364). C, This section is off the surface epithelium between two crypts from the left portion of A. Focal, mildly increased intraepithelial lymphocytes are present (H&E, x600). Image 21 Markedly increased, mixed inflammation with several neutrophilic collections in the surface epithelium (A, H&E, x192; B, H&E, x288). 624

4 Four specimens had predominantly neutrophilic inflammation: 2 were mildly increased, and the other 2 were markedly increased. Two of the 4 had crypt disarray I Image 31. Two specimens had predominantly lymphoplasmacytic inflammation: 1 was mildly increased, and the other was markedly increased. One of these specimens had focal mild increased surface IELs llmage 41. One biopsy fragment had crypt disarray. The 1 patient with diffuse colitis had markedly increased mixed inflammation with crypt disarray and erosions that was identical to the mixed inflammation found after biopsies of tissue from patients with endoscopically patchy colitis. None of the specimens, including the specimen with diffuse colitis, had crypt architectural distortion, granulomas, markedly increased surface or crypt intraepithelial lymphocytes, thickened subsurface collagen layer or pericryptal fibroblastic sheath, or increased surface epithelial apoptotic bodies. Additionally, none of the biopsies had the features of ischemia, which include crypt withering, fibrin thrombi, and lamina propria edema. Discussion Nonsteroidal antiinflammatory drugs are well known to cause colonic disease. All formulations have been associated with it. They have been associated with colitis, segmental ischemia, bleeding from diverticula, eosinophilic allergic colitis, collagenous colitis, discrete ulcers, diaphragm-like strictures, and relapse of inflammatory bowel disease.3-6' Some authors have stated that NSAID-associated colitis has a nonspecific histologic appearance Although this statement may be true for biopsy specimens that show extensive ulceration and marked inflammation, its lack of precision contributes little to the advancement of knowledge in gastrointestinal surgical pathology. We found that NSAIDassociated colitis most commonly had a histology of patchy mild to moderate inflammation that was either predominantly lymphoplasmacytic, neutrophilic, or mixed and was usually associated with slight crypt disarray and focal erosions. None of the biopsy specimens, including those from the patient with endoscopically diffuse disease, had either crypt architectural distortion or granulomas in any of the fragments. These results are similar to those of other studies One report noted NSAID-induced granulomatous inflammation.10 Our results suggest that NSAID-associated colitis can be grouped with the other colitides that cause patchy inflammation and crypt disarray without crypt distortion. The other colitides that can have this histologic appearance and enter into diagnostic consideration are Crohn colitis and infectious-type colitis, the latter including antibiotic-associated colitis and so-called acute self-limited colitis We are not Image 31 Mildly increased, predominantly neutrophilic inflammation. The inflammation is extremely focal. No crypt architectural distortion is present (A, H&E, x184; B, H&E, x600). Am J Clin Pathol 1998;110:

5 Goldstein and Cinenza / NSAID COLITIS Image 41 A, Mildly increased, predominantly lymphocytic inflammation. No crypt disarray or distortion is present (H&E, x184). B, A mild intraepithelial lymphocyte infiltrate is evident that is focal and limited to the areas of endoscopic colitis. Other biopsy specimins from endoscopically normal colon were normal (H&E, x288). aware of any specific histologic features that would allow the distinction between these 3 diseases in the context of biopsies showing focal active colitis. NSAID-associated colitis is not rare In one study, cases of NSAID-associated colitis accounted for 10% of new colitis patients.27,48 Given the overlap of histologic features in these entities and its high prevalence, it is important that pathologists consider NSAID-associated colitis before definitively diagnosing either Crohn disease or infectious-type colitis. The lack of crypt architectural distortion in all our cases suggests that NSAID-associated colitis, even when diffuse, is distinguishable histologically from ulcerative colitis. Chronic ulcerative colitis almost always has some crypt distortion and a predominantly lymphoplasmacytic inflammatory infiltrate with variable numbers of neutrophils. An absence of crypt architectural distortion or predominance of neutrophils makes the diagnosis of ulcerative colitis unlikely.62,63 Some of the biopsies with predominantly or mixed lymphoplasmacytic inflammation also had a mild increase in surface IELs. The distribution and amount of surface IELs was too focal and mild to be categorized histologically as lymphocytic colitis.2-5,7,8 Nevertheless, the features of the most heavily inflamed areas of these NSAID-associated colitis biopsies and those of lymphocytic colitis overlapped. NSAIDs have been linked to collagenous colitis.3,5-7,41 These foci may be the earliest lesions of lymphocytic/collagenous colitis. The changes we ascribe to NSAID use are also histologically similar to some of the focal active colitis lesions described by Greenson and colleagues.64 Although none of their patients were known to be receiving NSAID therapy at the time their biopsies were performed, it is possible that some 626 of them may have unknowingly ingested NSAIDs, given their wide distribution in many pharmacologic products. In summary, NSAID-associated colitis most commonly has histologic features of focal colitis with varying degrees of activity, crypt disarray, and a mild intraepithelial lymphocytosis but no crypt architectural distortion. These histologic features are similar to those in some cases of Crohn colitis and infective-type colitis. Pathologists should consider NSAIDassociated colitis before labeling a patient as having inflammatory bowel disease, especially if the patient has coexistent diseases that may be conducive to NSAID ingestion. From the Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan. Address reprint requests to Dr Goldstein: Department of Anatomic Pathology, 3601 W13 Mile Rd, Royal Oak, MI Acknowledgment: We thank John Watts, MD, for his editorial comments. References 1. Carpenter HA, Tremaine WJ, Batts KP, et al. Sequential histologic evaluations in collagenous colitis: correlations with disease behavior and sampling strategy. Dig Dis Sci. 1992;37: Lazenby AJ, Yardley ]H, Giardiello FM, et al. Lymphocytic ("microscopic") colitis: a comparative histopathologic study with particular reference to collagenous colitis. Hum Pathol. 1989;20: Slywestrowicz T, Kelly JK, Hwang WS, et al. Collagenous colitis and microscopic colitis: The watery diarrhea-colitis syndrome. Am J Gastroenterol. 1989;84:

6 4- Bogomoletz WV. Collagenous, microscopic, and lymphocytic colitis. An evolving concept. Virchows Archiv. 1994;424: Bowling TE, Price AB, Al-Adnani M, et al. Interchange between collagenous and lymphocytic colitis in severe disease with autoimmune associations requiring colectomy: a case report. Gut. 1996;38: Giardiello FM, Hansen FC III, Lazenby AJ, et al. Collagenous colitis in setting of nonsteroidal antiinflammatory drugs and antibiotics. DigDis Sri. 1990;35: Goff JS, Barnett JL, Pelke T, et al. Collagenous colitis: histopathology and clinical course. Am J Gastroenterol. 1997;92: Lazenby AJ, Yardley JH, Giardiello FM, et al. Pitfalls in the diagnosis of collagenous colitis: experience with 75 cases from a registry of collagenous colitis at The Johns Hopkins Hospital. Hum Pathol. 1990;21: Pimentel RR, Achkar E, Bedford R. Collagenous colitis: A treatable disease with an elusive diagosis. Dig Dis Sci. 1995;40: Baert F, Hart J, Blackstone MO. A case of diclofenac-induced colitis with focal granulomatous change. Am ] Gastroenterol. 1995;90: Bjarnason I, Hayllar J, MacPherson AJ, et al. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology. 1993;104: Bridges AJ, Marshall JB, Diaz-Arias AA. Acute eosinophilic colitis and hypersensitivity reaction associated with naproxen therapy. Am J Med. 1990;89: Buchman AL, Schwartz MR. Colonic ulceration associated with the systemic use of nonsteroidal antiinflammatory medication. J Clin Gastroenterol. 1996;22: Campbell K, Steele RJ. Non-steroidal anti-inflammatory drugs and complicated diverticular disease: a case control study. Br J Surg. 1991;78: Carratu R, Parisi P, Agozzino A. Segmental ischemic colitis associated with nonsteroidal antiinflammatory drugs. J Clin Gastroenterol 1993;16: Carson J, Notis WM, Orris ES. Colonic ulceration and bleeding during diclofenac therapy. New Engl J Med. 1990;323:135. Letter. 17. Clements D, Williams GT, Rhodes J. Colitis associated with ibuprofen. BMJ. 1990;301:987. Letter. 18. Corder A. Steroids, non-steroidal anti-inflammatory drugs and serious septic complications of diverticular disease. BMJ. 1987;295:1238. Letter. 19. D'Haens G, Breysem Y, Rutgeerts P, et al. Proctitis and rectal stenosis induced by nonsteroidal antiinflammatory suppositories. J Clin Gastroenterol. 1993; 17: Evans JMM, McMahon AD, Murray FE, et al. Non-steroidal anti-inflamatory drugs are associated with emergency admission to hospital for colitis due to inflammatory bowel disease. Gut. 1997;40: Faucheron J-L, Pare R. Nonsteroidal anti-inflammatory druginduced colitis. Int J Colorectal Dis. 1996;11: Fellows IW, Clarke JMF, Roberts PF. Non-steroidal antiinflammatory drug-induced jejunal and colonic diaphragm disease: a report of two cases. Gut. 1992;33: Foutch PG. Diverticular bleeding: are nonsteroidal antiinflammatory drugs risk factors for hemorrhage and can colonoscopy predict outcome for patients? Am J Gastroenterol. 1995;90: Gargot D, Chaussade S, d'alteroche L, et al. Nosteroidal antiinflammatory drug-induced colonic strictures: two cases and literature review. Am J Gastroenterol. 1995;90: Gibson GR, Whitacre EB, Ricotti CA. Colitis induced by nonsteroidal anti-inflammatory drugs. Report of four cases and review of the literature. Arch Intern Med. 1992;152: Gleeson MH, Ramsay D, Hutchinson S, et al. Colitis associated with non-steroidal anti-inflammatory drugs. Lancet. 1994;344:1028. Letter. 27. Gleeson MH, Lim SH, Spencer D. Non-steroidal antiinflammatory drugs, salicylates, and colitis. Lancet. 1996;347: Graham DY, Smith JL. Gastroduodenal complications of chronic NSAID therapy. Am J Gastroenterol. 1988;83: Hebuterne X, Dreyfus G, Franti G, et al. Nonsteroidal antiinflammatory drug-induced colitis and misoprostol. Dig Dis Sci. 1996;41: Hollingworth J, Alexander-Williams J. Non-steroidal antiinflammatory drugs and stercoral perforation of the colon. Ann R Coil Surg Engl. 1991;73: Hooker GD, Gregor JC, Ponich TP, et al. Diaphragm-like strictures of the right colon induced by indomethacin suppositories: evidence of a systemic effect. Gastrointest Endosc. 1996;44: Hovde O, Farup PG. NSAID-induced irreversible exacerbation of ulcerative colitis. J Clin Gastroenterol. 1992;15: Huber T, Ruchti C, Halter F. Nonsteroidal antiinflammatory drug-induced colonic strictures: a case report. Gastroenterology. 1991;100: Kapur KC, Williams GT, Allison MC. Mesalazine induced exacerbation of ulcerative colitis. Gut. 1995;37: Kaufmann HJ, Taubin HL. Nonsteroidal anti-inflammatory drugs activated quiescent inflammatory bowel disease. Ann Intern Med. 1987;107: Kaufman HL, Fischer AH, Carroll M, et al. Colonic ulceration associated with nonsteroidal anti-inflammatory drugs. Dis Colon Rectum. 1996;39: Keating JP, Mcllwaine J. Simultaneous small and large bowel ulceration associated with short term NSAID use. N Z Med J. 1993;106:438. Letter. 38. Lee FD. Drug-related pathological lesions of the intestinal tract. Histopathobgy. 1994;25: Pucius RJ, Charles AK, Adair HM, et al. Diaphragm-like strictures of the colon induced by non-steroidal antiinflammatory drugs. Br J Surg. 1993;80: Ravi S, Keat AC, Keat ECB. Colitis caused by non-steroidal anti-inflammatory drugs. Postgrad Med J. 1986;62: Riddell RH, Tanaka M, Mazzoleni G. Non-steroidal antiinflammatory drugs as a possible cause of collagenous colitis: a case-control study. Gut. 1992;33: Sacanella E, Munoz F, Cardellach F, et al. Massive hemorrhage due to colitis secondary to nonsteroidal anti-inflammatory drugs. Postgrad Med J. 1996;72: Schweizer W, Halter F, Huber T, et al. Diaphragm-like strictutes of the colon induced by non-steroidal antiinflammatory drugs. Br J Surg. 1993;80:1627. Letter. 44- Sheers R, Williams WR. NSAIDs and gut damage. Lancet. 1989;2:1154. Letter. 45. Spirnak JP, Monahan DW. Colonic diaphrams associated with long-term use of nonsteroidal antiinflammatory drugs. AJR. 1993;160: Am J Clin Pathol 1998;110:

7 Goldstein and Cinenza / NSA1D COLITIS 46. Stamm C, Burkhalter CE, Pearce W, et al. Benign colonic ulcers associated with nonsteroidal antiinflammatory drug ingestion. Am J Gastroenterol. 1994;89: Sturgeon JB, Bhatia P, Hermens D, et al. Exacerbation of chronic ulcerative colitis with mesalamine. Gastroenterology. 1995;108: Tanner AR, Raghunath AS. Colonic inflammation and nonsteroidal anti-inflammatory drug administration. An assessment of the frequency of the problem. Digestion. 1988;41: Uribe A, Johansson C, Slezak P, et al. Ulcerations of the colon associated with naproxen and acetylsalicylic acid treatment. Gastrointest Endosc ;3 2: Walt RP, Hawkey CJ, Langman MJ. Colitis associated with non-steroidal anti-inflammatory drugs. BMJ. 1984;288:238. Letter. 51. Whitcomb DC, Martin SP, Trellis DR, et al. "Diaphragm-like" stricture and ulcer of the colon during diclofenac treatment. Arch Intern Med. 1992;152: Whitcomb DC. Pathophysiology of nonsteroidal antiinflammatory drug-induced intestinal strictures. Gastroenterology. 1995;105: Zanelli G, Smethurst P, Burke M, et al. Clinicopathological features of nonsteroidal antiinflammatory drug-induced small intestinal strictures. Gastroenterology. 1988;94: Guslandi M. Pathogenesis of NSAID colitis. Dig Dis Sci. 1996;41: Lee FD. Importance of apoptosis in the histopathology of drag related lesions in the large intestine. J Clin Patfiol. 1993;46: Am J Clin Pathol 1998;110: Seldenrijk CA, Morson BC, Meuwissen SGM, et al. Histopathological evaluation of colonic mucosal biopsy specimens in chronic inflammatory bowel disease: diagnostic implications. Gut. 1991;32: Tanaka M, Riddell RH. The pathological diagnosis and differential diagnosis of Crohn's disease. Hepatogostroenterology. 1990;37: Iliffe GD, Owen DA. Rectal biopsy in Crohn's disease. Dig Dis Sci. 1981;26: Surawicz CM, Meisel JL, Ylvisaker T, et al. Rectal biopsy in the diagnosis of Crohn's disease: value of multiple biopsies and serial sectioning. Gastroenterology. 1981;80: Goldman H, Antonioli DA. Mucosal biopsy of the rectum, colon, and distal ileum. Hum Pathol. 1982;13: Price AB, Morson BC. Inflammatory bowel disease. The surgical pathology of Crohn's disease and ulcerative colitis. Hum Pathol 1975;6: Nostrant TT, Kumar NB, Appelman HD. Histopathology differentiates acute self-limited colitis from ulcerative colitis. Gastroenterology. 1987;92: Surawicz CM, Haggitt RC, Husseman M, et al. Mucosal biopsy diagnosis of colitis: acute self-limited colitis and idiopathic inflammatory bowel disease. Gastroenterology. 1994;107: Greenson JK, Stern RA, Carpenter SL, et al. The clinical significance of focal active colitis. Hum Pathol. 1997;28: