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Fifty shades of chronic colitis: non-infectious imposters of inflammatory bowel disease
MINI-SYMPOSIUM: PATHOLOGY OF INFLAMMATORY BOWEL DISEASE
Fifty shades of chronic colitis: non-infectious imposters of inflammatory bowel disease
Histologic features of the chronic colitis pattern C C C C
Pyloric gland metaplasia Paneth cell metaplasia* Increased lamina propria chronic inflammation Architectural distortion
Villonodular surface Abnormal crypt configuration Crypt drop-out Crypt shortfall (the basal crypts do not sit directly on the muscularis mucosae) Basal lymphoplasmacytosis (a basal layer of lymphoplasmacytic inflammation prevents the basal crypts from sitting directly on the muscularis mucosae)
Christina A Arnold Feriyl Bhaijee Dora Lam-Himlin
Abstract Chronic colitis is a common injury pattern that invokes a wide range of etiologic considerations. Any process that causes chronic mucosal injury can result in this nonspecific injury pattern. Inflammatory bowel disease is among the differential diagnoses, but it should only be rendered in the appropriate setting, after all possible mimics have been reasonably excluded. This review will detail the landscape of non-infectious IBD imposters.
*Paneth cells are normal constituents of the right and transverse colon; their presence in the descending colon, sigmoid, and rectum is never a normal finding. Box 1
most common non-infectious causes of the chronic colitis pattern are discussed below (Box 2).
Keywords chronic colitis; diversion colitis; diverticular disease; granulomatous disease sarcoid; inflammatory bowel disease (IBD); ischaemia; vasculitis
Diverticular disease Diverticular disease is one of the most commonly encountered IBD mimics. Colonic diverticula (singular: diverticulum) are blind mucosal outpouchings that are typically acquired secondary to the “Western” low-fibre diet. “Diverticular disease” is the broadest term that encompasses “diverticulosis” (diverticula lacking inflammation), “diverticulitis” (inflamed diverticula), and “segmental colitis associated with diverticulosis” (SCAD) syndrome (luminal inflammatory damage near the diverticula). Diverticular disease is extraordinarily common in countries with low-fibre diets. These diets lead to low-bulk feces with increased transit time and increased muscle bulk and intraluminal pressures. As a result, the delicate mucosa and submucosa herniate through weaknesses in the bowel wall, particularly along the vasa recti penetration points. This close association with adjacent vessels can lead to significant gastrointestinal bleeding if the diverticulitis associated inflammation extends into the neighbouring vessels. The inflammatory damage can also result in extensive adhesive disease, abdominal pain, obstruction, and fistulization to adjacent organs. Potential triggers for diverticular disease flares include impacted fecaliths, mucosal prolapse, vascular injury, altered intestinal flora, colon dysmotility, and visceral hypersensitivity.1e4 In comparison to diverticulosis and diverticulitis, much less is known about the natural history of the rarely encountered SCAD syndrome. SCAD refers to inflammatory changes restricted to the luminal segment of colon involved by diverticular disease (there are no specific requirements for inflammatory damage within the diverticula). As with diverticulosis and diverticulitis, rectal sparing is characteristic. Some experts theorize that SCAD is a result of diverticulitis that has progressed to involve the ostia and adjacent luminal mucosa. Others suggest SCAD imparts more biologically meaningful pathology and may be an important risk factor for IBD.
Introduction The chronic colitis pattern encompasses a broad range of histomorphologic features (Box 1, Figure 1). By definition, features of chronicity must be present, but not all features are required in a single case and the individual features can be present in any proportion. For example, chronic colitis can apply to a biopsy with only focal findings, such as scattered Paneth cell metaplasia, and it can also apply to a biopsy with marked chronic changes that encompass all features presented in Box 1. The chronic colitis pattern is one of the more treacherous areas in gastrointestinal (GI) pathology because the morphologic spectrum is broad, the underlying etiologies are diverse, and misclassification as IBD can result in potentially unnecessary immunosuppression, colectomy, and life-time surveillance. As a result, a prudent reporting approach involves describing the injury pattern in the top-line, and addressing the precise clinicopathologic context and specific etiologic considerations in the note. This approach can be time-consuming, but it will lead to optimal etiologic specific management, and minimize the potentially disastrous consequence of IBD misclassification. The
Christina A Arnold MD Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OIO, USA. Conflicts of interest: none. Feriyl Bhaijee MD Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA. Conflicts of interest: none. Dora Lam-Himlin MD Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA. Conflicts of interest: none.
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Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Arnold CA, et al., Fifty shades of chronic colitis: non-infectious imposters of inflammatory bowel disease, Diagnostic Histopathology (2015), http://dx.doi.org/10.1016/j.mpdhp.2015.06.014
MINI-SYMPOSIUM: PATHOLOGY OF INFLAMMATORY BOWEL DISEASE
Figure 1 (a) Test tubes in a rack: Normal colonic architecture is analogous to test tubes in a rack, where every tube (crypt) is perfectly superimposable because they are of uniform size and separated by uniform amounts of space (lamina propria). (b) Normal colonic mucosa for comparison. (c) This example of chronic colitis features non-superimposable crypts of varying size and shape, separated by variable amounts of lamina propria. Other features of chronic colitis include a villonodular surface, the crypts fall short of the muscularis mucosae (crypt shortfall) because of the intervening basal layer of lymphocytes and plasma cells (basal lymphoplasmacytosis) (asterisk), and Paneth cell metaplasia (not seen at this power).
Endoscopically, diverticulosis appears as mucosal outpouchings lacking inflammatory injury. In contrast, both diverticulitis and SCAD involve inflammatory damage restricted to a segment of colon with diverticular disease. Histologically, the chronic colitis pattern can be seen (Figure 2a and d), and it is histologically indistinguishable from IBD. Clinicians may favour Crohn disease based on the propensity of granulomatous chronic colitis with rectal sparing. Since up to 70% of patients over 80 years of age in the United States have diverticular disease, diverticular disease must be a top differential consideration of any biopsy in the left
colon displaying chronic colitis! If diverticular disease versus IBD is the clinical question, a reasonable approach is to separately submit biopsies from the diverticular zone and uninvolved bowel segments, including the rectum. Features that favour diverticular disease include inflammatory changes confined to the segment of colon with diverticula and rectal sparing.
Diversion colitis Diversion colitis is a consequence of surgical detour of a bowel segment. Surgical diversion is performed when a diseased bowel segment is removed and the remaining bowel is insufficiently long or healthy enough to immediately re-establish continuity. Generally, after the disease bowel is removed, the proximal in situ bowel segment is diverted through the anterior abdominal wall to form an ostomy site. An ileostomy is a diversion of the small bowel, whereas, a colostomy is a diversion of the colon through the anterior abdominal wall. The bowel segment downstream from the ostomy site is left in place and excluded from the fecal stream and the critical nutrients therein (specifically shortchain fatty acids). More than 70% of patients with diversion report abdominal pain, tenesmus, rectal bleeding, and prominent rectal discharge. Endoscopic findings include mucosal friability, erosions, ulcerations, and a nodular mucosa. Corresponding histologic features include chronic colitis with florid lymphoid aggregates, conspicuous germinal centers, aphthoid lesions/ulcerations, and sometimes crypt rupture granulomata (Figure 2b and e). Diversion colitis can occur as few as 3 months following surgical diversion, and its features persist through the duration of the diversion.5 Ostomy reversal and short-chain fatty acid enemas are curative with resolution of symptoms seen as early as 2 months. Like all other causes of chronic colitis, diversion colitis can be histologically indistinguishable from IBD. Ulcerative colitis is a common clinical consideration because many diverted patients present with rectal bleeding and ulcerations. Useful red flags to the diagnosis of diversion colitis include any history of bowel surgery, such as diverticular disease, neoplasm, trauma, and ischaemia. Features that favour diversion colitis include
Top etiologic considerations of the chronic colitis pattern C C C
Diverticular disease Diversion colitis Therapeutics NSAIDs Resins Ipilimumab
C
Vascular injury Ischaemia Radiation Vasculitis
C
Autoimmune
C
Infections
C
Sarcoid Common variable immunodeficiency Chronic granulomatous disease Vasculitis
Stool pathogens Cord colitis syndrome Syphilitic and lymphogranuloma venereum colitis Others
Inflammatory bowel disease
Box 2
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MINI-SYMPOSIUM: PATHOLOGY OF INFLAMMATORY BOWEL DISEASE
Figure 2 Select IBD mimics. (a, b, c) These images feature three unique examples of chronic injury that, in isolation, are histologically indistinguishable from IBD. (d, e, f ) The corresponding lower power images provide a context for the chronic colitis: d (Lower power of panel a), Diverticular disease involves herniation of the mucosa and submucosa through the bowel wall; e (Lower power of panel b), Diversion colitis features prominent lymphoid aggregates in the excluded bowel segment; f (Lower power of panel c), Diaphragm disease is a web-like luminal protrusion and is pathognomonic for chronic NSAID usage.
prominent lymphoid aggregates restricted to the excluded bowel segment in a patient whose symptoms improved with short-chain fatty acid enemas or ostomy reversions. However, not all cases of diversion respond to such enemas, while some cases of IBD improve with this therapy.6e8 Therefore, once diversion colitis enters the clinical differential diagnosis, it would be nearly impossible to definitively distinguish diversion from IBD on histologic grounds alone. In such cases, a reasonable report would describe the pertinent findings in the top-line and discuss the etiologic possibilities in the note. Reversing the ostomy and close patient follow-up can also be a reasonable approach since diversion colitis will improve following ostomy reversion and IBD will not.
with chronic NSAID exposure, and is considered pathognomonic for NSAID related injury. The smooth, symmetrical diaphragms can be recognized endoscopically, although they are often not probe-patent (Figure 2f). Histologically, prominent submucosal fibrosis with web-like narrowing of the lumen is seen (Figure 2c). The diaphragms can eventually constrict to the size of a pin-hole and result in emergent obstruction. The background mucosa can feature chronic injury, including architectural distortion and pyloric metaplasia. While diaphragm disease is most common in the small bowel, it has also been described in the colon, perhaps related to the increasingly popular extended-release NSAID formulations. Beware that diaphragm disease may be clinically mistaken for Crohn disease based on the presence of strictures, stenosis, deep fibrosis, architectural changes, and pyloric metaplasia. Careful correlation with the clinical context, reconciliation with the medication list, and biopsies outside of the diaphragm zone can facilitate accurate diagnosis.
Therapeutics Iatrogenic injuries are increasingly encountered as the therapeutic market expands and colonoscopic procedures become more commonplace. Although the injury patterns are usually not particularly specific, therapeutics should be routine considerations of the chronic colitis pattern. The discussion below focuses on select entities with sometimes unique morphologic signatures.
Resins Resins are commonly encountered medications that facilitate ionexchange (Table 1, Figure 3). Their colourful crystalline forms can be identified throughout the GI tract and also in the lung, in cases of aspiration. At time of writing, there are only three subgroups of resins: sodium polystyrene sulfonate, sevelamer, and the bile acid sequestrants (BAS).9e12 It is important to accurately distinguish between these resins since sodium polystyrene sulfonate and sevelamer can cause of significant injury, and their appearance adjacent to mucosal injury should result in immediate clinician notification. Moreover, long-standing cases of
NSAIDs NSAIDs mediate injury via nonselective inhibition of cyclooxygenase isoenzymes. NSAIDs are notorious culprits for a variety of colonic injury patterns spanning acute colitis, ischaemic colitis, chronic colitis, ulceration, perforations, and more. Repeated cycles of deep damage and repair can result in “diaphragm disease”. This rare finding is seen in 2% of patients
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Please cite this article in press as: Arnold CA, et al., Fifty shades of chronic colitis: non-infectious imposters of inflammatory bowel disease, Diagnostic Histopathology (2015), http://dx.doi.org/10.1016/j.mpdhp.2015.06.014
MINI-SYMPOSIUM: PATHOLOGY OF INFLAMMATORY BOWEL DISEASE
Practical pointers of resins Brand name
Generic name
Route
Red flags/Indications
KayexalateÒ Sodium polystyrene sulfonate PO, Enema Hyperkalemia chronic kidney disease PO Hyperphosphatemia chronic kidney disease RenvelaÒ RenagelÒ Sevelamer Colesevelam PO Diarrhoea, hypercholesterolaemia, WelcholÒ dyslipidemia, diabetes mellitus Colestipol PO Diarrhoea, hypercholesterolaemia, ColestidÒ dyslipidemia, and pruritus LoCholestÒ Cholestyramine PO Same as above Cholestyramine PO Same as above PrevaliteÒ Cholestyramine PO Same as above QuestranÒ
Binding target Causes mucosal injury Potassium Phosphate Bile acids
Yes Possibly No
Bile acids
No
Bile acids Bile acids Bile acids
No No No
Table 1
injury can result in the chronic colitis pattern, serving as further examples of curable IBD mimics. Although resins are easily discriminated on H&E, useful diagnostic tools include an AFB special stain, a quick chart review, and awareness of pertinent red flags (Table 1, Figure 3). Red flags to consider sodium polystyrene sulfonate include potassium abnormalities or chronic kidney disease. Both its resins and its diluent have been linked to severe ulceration and ischaemia, which can be fatal.13e19 Histologically, these resins display an internal “fish-scale” pattern, are violet on H&E, and black on AFB. Sodium polystyrene sulfonate is commonly confused for sevelamer, the latter recently reported in 2013.11 Red flags to consider sevelamer include phosphate abnormalities or patients with chronic kidney disease. Like sodium polystyrene sulfonate, sevelamer also displays an internal “fishscale” pattern. Distinctive features of sevelamer include its twotoned colour on H&E with bright pink linear accentuations and a rusty yellow background; it is magenta on AFB. The BAS have been safely used for more than 90 years and do not cause mucosal injury, although the resins can be entrapped in ulcer debris. They were initially introduced to treat hypercholesterolaemia, but today they are more commonly used to treat diarrhoea. These resins are variable eosinophilic on H&E, yellow on AFB, and they lack “fish-scales”. The BAS are a large
family whose members are histologically indistinguishable from each other (Table 1). Ipilimumab colitis A history of metastatic melanoma is the clue to ipilimumab (YervoyÒ) colitis. It is one of an emerging group of biologic therapeutics whose mechanism of action is immune-mediated destruction of neoplasms.20 Specifically, ipilimumab targets the cytotoxic T-lymphocyte-associated antigen 4 found on cytotoxic T-lymphocytes and regulatory T cells. Up to 60% of patients with ipilimumab exposure report immune related adverse effects: gastrointestinal tract and skin symptoms are most common.20e22 Watery, culturenegative diarrhoea is characteristic, and endoscopic findings range from normal to marked ulcerations. Corresponding colon biopsies show chronic injury with increased apoptotic bodies, granulomata, and eosinophilia. This curable IBD mimic is effectively treated with drug cessation or optimized immunosuppression. Death due to medication is rare (1%), but only seen in cases with a delayed diagnosis or failure to recognize the diagnosis, underscoring the importance of recognizing this curable IBD mimic.
Vascular injury Long-standing vascular injuries can result in a pattern of chronic colitis that can be histologically indistinguishable from IBD.
Figure 3 Resins. (a) Sodium polystyrene sulfonate displays an internal “fish-scale” pattern, is violet on H&E, and black on AFB (not shown). (b) Sevelamer also has “fish-scales”, but displays a two-toned colour on H&E and is magenta on AFB (not shown). (c) BAS lack “fish-scales”, are eosinophilic on H&E, and yellow on AFB (not shown).
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Figure 4 Vascular injuries can also lead to the chronic colitis pattern. (a) The ischaemic colitis pattern features surface epithelial injury, mucin loss, lamina propria haemorrhage and hyalinization, and withered crypts. (b) Radiation injury is characterized by ectatic, damaged vessels in a background of hyalinization and fibrosis. On higher power, atypical stromal cells can be seen (not shown).
history of malignancy. Prostate or cervical primaries are notoriously helpful diagnostic clues to consider radiation colitis/ proctitis, but similar changes have been reported with pancreatobiliary carcinomas, and even esophageal malignancies. Additional diagnostic clues include any case of ischaemic injury, which should prompt diligent inspection of the background vessels. The classic histologic features of radiation can be subtle on biopsy, but more readily appreciated in resection specimens where the larger submucosal vessels are more easily seen. Typical features include damaged, hyalinized, and ectatic vessels in a background of hyalinization and fibrosis (Figure 4b). Additional helpful clues include atypical stromal cells with retained nuclear:cytoplasmic ratio and smudged and vacuolated chromatin.
Potential causes of chronic vascular injury include any process that compromises blood flow, such as atherosclerosis, coagulopathic disorders, thromboembolic diseases, vasculitis, radiation, amyloidosis, infections, therapeutics, mechanical compromise, and cocaine, among others. Important vascular injury patterns are detailed below. Ischaemic colitis pattern “Watershed zones” are weaknesses in the colonic blood supply due to incomplete anastomosis of the marginal arteries and suboptimal collateral circulation. The three most vulnerable sites include the ileocaecal region, splenic flexure, and the rectosigmoid. The clinical presentation is varied depending on the severity of the vascular insufficiency. Patients can be subclinical, complain of mild abdominal pain, or can present emergently with severe abdominal pain, frank gastrointestinal bleeding, and an acute abdomen. The “watershed zones” serve as the epicentre of the mucosal changes with common findings including erythema, mucosal friability, ulceration, necrosis, or perforation. Characteristic histologic features include surface epithelial injury, mucin loss, lamina propria haemorrhage and hyalinization, and withered crypts (Figure 4a). Features of chronicity can be identified in cases of gradual and longstanding vascular compromise. Like the chronic colitis pattern, the ischaemic colitis pattern is aetiologically nonspecific and may result from a diverse array of vascular insults as detailed above (atherosclerosis, vasculitis, mechanical obstruction, medications, etc). Importantly, an identical histologic injury pattern can be seen with infections, particularly those caused by Escherichia coli 0157:H7 (typically fibrin thrombi are prominent) and Clostridium difficile (characteristically exploding crypts with streaming neutrophil rich pseudomembranes are seen). In such cases, valuable diagnostic clues include pertinent stool cultures and disease distribution patterns (disease localized to watershed areas favours ischaemia).
Vasculitis Vasculitis involving vessels supplying the gastrointestinal tract can lead to low-flow states with resultant ischaemic patterns of injury in the down-stream bowel segments. Vasculitis can lead to the chronic colitis pattern and be histologically identical to IBD, particularly vasculitis associated with granulomata, strictures, and fibrosis. To further add to the complications, Crohn disease can be associated with inflamed and damaged arterioles with fibrinoid necrosis, thrombosis, and granulomata. Since vasculitis and IBD are both managed with immunosuppression, this distinction can be difficult yet critical. For example, if a patient with Behc‚et was misdiagnosed with ulcerative colitis, an unnecessary total colectomy could follow without alleviation of symptoms. Helpful clues include a history of vasculitis, such as polyarteritis nodosa, Wegener granulomatous, ChurgeStrauss, lupus, rheumatoid arthritis, Behc‚et, or Buerger disease. The simple histologic hallmark of vasculitis is vascular based inflammatory damage. Variable fibrinoid necrosis, thrombosis, granulomatous inflammation, and eosinophilia can also be seen. Precise classification is aided by synthesizing pertinent clinical parameters (age, ANCA status, systemic involvement of other organs), character of involved inflammatory infiltrate (lymphocyte predominant, granulomatous, eosinophilic), and the type and size of involved vessels (arteries versus veins; small versus medium
Radiation Radiation-induced endothelial damage culminates in compromised vascular flow. Red flags to the diagnosis include any
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2 Makapugay LM, Dean PJ. Diverticular disease-associated chronic colitis. Am J Surg Pathol 1996; 20: 94e102. 3 Ludeman L, Shepherd NA. What is diverticular colitis? Pathology 2002; 34: 568e72. 4 Strate LL, Liu YL, Syngal S, Aldoori WH, Giovannucci EL. Nut, corn, and popcorn consumption and the incidence of diverticular disease. JAMA 2008; 300: 907e14. 5 Edwards CM, George B, Warren BF. Diversion colitis: new light through old windows. Histopathology 1999; 35: 86e7. 6 Scheppach W, Sommer H, Kirchner T, et al. Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. Gastroenterology 1992; 103: 51e6. 7 Guillemot F, Colombel JF, Neut C, et al. Treatment of diversion colitis by short-chain fatty acids. Prospective and double-blind study. Dis Colon Rectum 1991; 34: 861e4. 8 Harig JM, Soergel KH, Komorowski RA, Wood CM. Treatment of diversion colitis with short-chain-fatty acid irrigation. N Engl J Med 1989; 320: 23e8. 9 Arnold MA, Swanson BJ, Crowder CD, et al. Colesevelam and colestipol: novel medication resins in the gastrointestinal tract. Am J Surg Pathol 2014 Nov; 38: 1530e7. 10 Seminerio J, McGrath K, Arnold CA, Voltaggio L, Singhi AD. Medication-associated lesions of the GI tract. Gastrointest Endosc 2014; 79: 140e50. 11 Swanson BJ, Limketkai BN, Liu TC, et al. Sevelamer crystals in the gastrointestinal tract (GIT): a new entity associated with mucosal injury. Am J Surg Pathol 2013; 37: 1686e93. 12 Voltaggio L, Lam-Himlin D, Limketkai BN, Singhi AD, Arnold CA. Message in a bottle: decoding medication injury patterns in the gastrointestinal tract. J Clin Pathol 2014; 67: 903e12. 13 Abraham SC, Bhagavan BS, Lee LA, Rashid A, Wu TT. Upper gastrointestinal tract injury in patients receiving kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic, and histopathologic findings. Am J Surg Pathol 2001; 25: 637e44. 14 Foresti V. Intestinal obstruction due to kayexalate in a patient concurrently treated with aluminum hydroxide and morphine sulfate. Clin Nephrol 1994; 41: 252. 15 Harel Z, Harel S, Shah PS, Wald R, Perl J, Bell CM. Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: a systematic review. Am J Med 2013 Mar; 126: 264.e9e24. 16 Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams GM. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis. Surgery 1987; 101: 267e72. 17 Rashid A, Hamilton SR. Necrosis of the gastrointestinal tract in uremic patients as a result of sodium polystyrene sulfonate (Kayexalate) in sorbitol: an underrecognized condition. Am J Surg Pathol 1997; 21: 60e9. 18 Scott TR, Graham SM, Schweitzer EJ, Bartlett ST. Colonic necrosis following sodium polystyrene sulfonate (Kayexalate)-sorbitol enema in a renal transplant patient. Report of a case and review of the literature. Dis Colon Rectum 1993; 36: 607e9. 19 Wootton FT, Rhodes DF, Lee WM, Fitts CT. Colonic necrosis with Kayexalate-sorbitol enemas after renal transplantation. Ann Intern Med 1989; 111: 947e9. 20 Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711e23.
versus large vessels). For example, typical clues to Wegener granulomatosis include necrotizing, granulomatous vasculitis of small vessels, ANCA positivity, and lung and renal involvement. In contrast, ChurgeStrauss is associated with necrotizing, granulomatous, eosinophil-rich vasculitis of small vessels in patients with a peripheral eosinophilia, ANCA positivity, and lung involvement. Behc‚et is associated with HLA-B51 and is enriched in young Turkish patients with genitourinary lesions and ocular, dermatologic, and joint manifestations. Notably, while vasculitis can cause mucosal ischaemia, innocent vessels entrapped within prominent mucosal injury can appear inflamed and mimic vasculitis. In such cases, primary vascular injury should be evaluated in areas not directly subjacent to prominent mucosal injury. Sometimes, it is histologically impossible to distinguish a true vasculitis from a vasculitis mimic. In these challenging cases, reasonable approaches include a detailed note describing the findings and considerations, close clinical follow-up, and correlation with pertinent vascular imaging and serologic studies.
Autoimmune diseases Patients with autoimmune diseases can have complex, nondescript presentations that can mimic various diseases, including IBD. Granulomatous autoimmune diseases such as sarcoidosis, common variable immunodeficiency (CVID), and chronic granulomatous disease (CGD) can be particularly problematic in their overlap with Crohn disease. Sarcoidal involvement of the colon is rare with a reported prevalence of less than 1%. While helpful features in support of sarcoidosis include imaging studies showing bilateral mediastinal lymphadenopathy and elevated ACE levels, sarcoidosis (as well as IBD) is a diagnosis of exclusion. CVID can also present with granulomatous inflammation and architectural changes. Most cases of CVID lack plasma cells, making routine inspection of plasma cells worthwhile. Correlation with serum immunoglobulin levels is advised since up to 1/3 of patients have (dysfunctional) plasma cells.23 Up to 46% of autopsied patients with CGD have granulomatous colitis. Such patients also typically have a long-standing history of infections and complicated disease courses. The diagnostic evaluation of CGD includes nitroblue tetrazolium testing. Lastly, granulomatous colitis can also be seen with vascular injuries, medication related injuries, and infections.
Conclusion In summary, chronic colitis is aetiologically nonspecific. In this way, histology alone can betray the faithful pathologist if all cases of chronic colitis are attributed to IBD. To ensure proper etiologic specific management, a prudent approach is to describe the histologic feature in the diagnostic section, and carefully discuss the reasonable etiologies in the note after gathering pertinent clinicopathologic data. A REFERENCES 1 Peppercorn MA. Drug-responsive chronic segmental colitis associated with diverticula: a clinical syndrome in the elderly. Am J Gastroenterol 1992; 87: 609e12.
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21 Graziani G, Tentori L, Navarra P. Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. Pharmacol Res 2012; 65: 9e22. 22 Ku GY, Yuan J, Page DB, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 2010; 116: 1767e75. 23 Daniels JA, Lederman HM, Maitra A, Montgomery EA. Gastrointestinal tract pathology in patients with common variable immunodeficiency (CVID): a clinicopathologic study and review. Am J Surg Pathol 2007; 31: 1800e12.
Practice points C C
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Acknowledgements
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The authors would like to acknowledge Shawn Scully for figure preparation.
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Chronic colitis is aetiologically nonspecific A diagnosis of IBD should only be considered if all IBD mimics have been reasonably excluded Diverticular disease is a top consideration of chronic colitis in the left colon Diversion colitis is due to a deficiency of short-chain fatty acids in the excluded bowel segment Diaphragm disease is associated with chronic NSAID usage Sodium polystyrene sulfonate and sevelamer have “fish-scales” and are associated with mucosal injury; BAS lack “fish-scales” and do not cause mucosal injury Each mucosal biopsy and resection specimen should be carefully assessed for vascular injury Colonic granulomatous disease should prompt consideration of sarcoid, CVID, CGD, vascular injury, medication injury, infection, in addition to IBD
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Please cite this article in press as: Arnold CA, et al., Fifty shades of chronic colitis: non-infectious imposters of inflammatory bowel disease, Diagnostic Histopathology (2015), http://dx.doi.org/10.1016/j.mpdhp.2015.06.014
Fifty shades of chronic colitis: non-infectious imposters of inflammatory bowel disease
Histologic features of the chronic colitis pattern C C C C
Pyloric gland metaplasia Paneth cell metaplasia* Increased lamina propria chronic inflammation Architectural distortion
Villonodular surface Abnormal crypt configuration Crypt drop-out Crypt shortfall (the basal crypts do not sit directly on the muscularis mucosae) Basal lymphoplasmacytosis (a basal layer of lymphoplasmacytic inflammation prevents the basal crypts from sitting directly on the muscularis mucosae)
Christina A Arnold Feriyl Bhaijee Dora Lam-Himlin
Abstract Chronic colitis is a common injury pattern that invokes a wide range of etiologic considerations. Any process that causes chronic mucosal injury can result in this nonspecific injury pattern. Inflammatory bowel disease is among the differential diagnoses, but it should only be rendered in the appropriate setting, after all possible mimics have been reasonably excluded. This review will detail the landscape of non-infectious IBD imposters.
*Paneth cells are normal constituents of the right and transverse colon; their presence in the descending colon, sigmoid, and rectum is never a normal finding. Box 1
most common non-infectious causes of the chronic colitis pattern are discussed below (Box 2).
Keywords chronic colitis; diversion colitis; diverticular disease; granulomatous disease sarcoid; inflammatory bowel disease (IBD); ischaemia; vasculitis
Diverticular disease Diverticular disease is one of the most commonly encountered IBD mimics. Colonic diverticula (singular: diverticulum) are blind mucosal outpouchings that are typically acquired secondary to the “Western” low-fibre diet. “Diverticular disease” is the broadest term that encompasses “diverticulosis” (diverticula lacking inflammation), “diverticulitis” (inflamed diverticula), and “segmental colitis associated with diverticulosis” (SCAD) syndrome (luminal inflammatory damage near the diverticula). Diverticular disease is extraordinarily common in countries with low-fibre diets. These diets lead to low-bulk feces with increased transit time and increased muscle bulk and intraluminal pressures. As a result, the delicate mucosa and submucosa herniate through weaknesses in the bowel wall, particularly along the vasa recti penetration points. This close association with adjacent vessels can lead to significant gastrointestinal bleeding if the diverticulitis associated inflammation extends into the neighbouring vessels. The inflammatory damage can also result in extensive adhesive disease, abdominal pain, obstruction, and fistulization to adjacent organs. Potential triggers for diverticular disease flares include impacted fecaliths, mucosal prolapse, vascular injury, altered intestinal flora, colon dysmotility, and visceral hypersensitivity.1e4 In comparison to diverticulosis and diverticulitis, much less is known about the natural history of the rarely encountered SCAD syndrome. SCAD refers to inflammatory changes restricted to the luminal segment of colon involved by diverticular disease (there are no specific requirements for inflammatory damage within the diverticula). As with diverticulosis and diverticulitis, rectal sparing is characteristic. Some experts theorize that SCAD is a result of diverticulitis that has progressed to involve the ostia and adjacent luminal mucosa. Others suggest SCAD imparts more biologically meaningful pathology and may be an important risk factor for IBD.
Introduction The chronic colitis pattern encompasses a broad range of histomorphologic features (Box 1, Figure 1). By definition, features of chronicity must be present, but not all features are required in a single case and the individual features can be present in any proportion. For example, chronic colitis can apply to a biopsy with only focal findings, such as scattered Paneth cell metaplasia, and it can also apply to a biopsy with marked chronic changes that encompass all features presented in Box 1. The chronic colitis pattern is one of the more treacherous areas in gastrointestinal (GI) pathology because the morphologic spectrum is broad, the underlying etiologies are diverse, and misclassification as IBD can result in potentially unnecessary immunosuppression, colectomy, and life-time surveillance. As a result, a prudent reporting approach involves describing the injury pattern in the top-line, and addressing the precise clinicopathologic context and specific etiologic considerations in the note. This approach can be time-consuming, but it will lead to optimal etiologic specific management, and minimize the potentially disastrous consequence of IBD misclassification. The
Christina A Arnold MD Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OIO, USA. Conflicts of interest: none. Feriyl Bhaijee MD Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA. Conflicts of interest: none. Dora Lam-Himlin MD Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA. Conflicts of interest: none.
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Figure 1 (a) Test tubes in a rack: Normal colonic architecture is analogous to test tubes in a rack, where every tube (crypt) is perfectly superimposable because they are of uniform size and separated by uniform amounts of space (lamina propria). (b) Normal colonic mucosa for comparison. (c) This example of chronic colitis features non-superimposable crypts of varying size and shape, separated by variable amounts of lamina propria. Other features of chronic colitis include a villonodular surface, the crypts fall short of the muscularis mucosae (crypt shortfall) because of the intervening basal layer of lymphocytes and plasma cells (basal lymphoplasmacytosis) (asterisk), and Paneth cell metaplasia (not seen at this power).
Endoscopically, diverticulosis appears as mucosal outpouchings lacking inflammatory injury. In contrast, both diverticulitis and SCAD involve inflammatory damage restricted to a segment of colon with diverticular disease. Histologically, the chronic colitis pattern can be seen (Figure 2a and d), and it is histologically indistinguishable from IBD. Clinicians may favour Crohn disease based on the propensity of granulomatous chronic colitis with rectal sparing. Since up to 70% of patients over 80 years of age in the United States have diverticular disease, diverticular disease must be a top differential consideration of any biopsy in the left
colon displaying chronic colitis! If diverticular disease versus IBD is the clinical question, a reasonable approach is to separately submit biopsies from the diverticular zone and uninvolved bowel segments, including the rectum. Features that favour diverticular disease include inflammatory changes confined to the segment of colon with diverticula and rectal sparing.
Diversion colitis Diversion colitis is a consequence of surgical detour of a bowel segment. Surgical diversion is performed when a diseased bowel segment is removed and the remaining bowel is insufficiently long or healthy enough to immediately re-establish continuity. Generally, after the disease bowel is removed, the proximal in situ bowel segment is diverted through the anterior abdominal wall to form an ostomy site. An ileostomy is a diversion of the small bowel, whereas, a colostomy is a diversion of the colon through the anterior abdominal wall. The bowel segment downstream from the ostomy site is left in place and excluded from the fecal stream and the critical nutrients therein (specifically shortchain fatty acids). More than 70% of patients with diversion report abdominal pain, tenesmus, rectal bleeding, and prominent rectal discharge. Endoscopic findings include mucosal friability, erosions, ulcerations, and a nodular mucosa. Corresponding histologic features include chronic colitis with florid lymphoid aggregates, conspicuous germinal centers, aphthoid lesions/ulcerations, and sometimes crypt rupture granulomata (Figure 2b and e). Diversion colitis can occur as few as 3 months following surgical diversion, and its features persist through the duration of the diversion.5 Ostomy reversal and short-chain fatty acid enemas are curative with resolution of symptoms seen as early as 2 months. Like all other causes of chronic colitis, diversion colitis can be histologically indistinguishable from IBD. Ulcerative colitis is a common clinical consideration because many diverted patients present with rectal bleeding and ulcerations. Useful red flags to the diagnosis of diversion colitis include any history of bowel surgery, such as diverticular disease, neoplasm, trauma, and ischaemia. Features that favour diversion colitis include
Top etiologic considerations of the chronic colitis pattern C C C
Diverticular disease Diversion colitis Therapeutics NSAIDs Resins Ipilimumab
C
Vascular injury Ischaemia Radiation Vasculitis
C
Autoimmune
C
Infections
C
Sarcoid Common variable immunodeficiency Chronic granulomatous disease Vasculitis
Stool pathogens Cord colitis syndrome Syphilitic and lymphogranuloma venereum colitis Others
Inflammatory bowel disease
Box 2
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Figure 2 Select IBD mimics. (a, b, c) These images feature three unique examples of chronic injury that, in isolation, are histologically indistinguishable from IBD. (d, e, f ) The corresponding lower power images provide a context for the chronic colitis: d (Lower power of panel a), Diverticular disease involves herniation of the mucosa and submucosa through the bowel wall; e (Lower power of panel b), Diversion colitis features prominent lymphoid aggregates in the excluded bowel segment; f (Lower power of panel c), Diaphragm disease is a web-like luminal protrusion and is pathognomonic for chronic NSAID usage.
prominent lymphoid aggregates restricted to the excluded bowel segment in a patient whose symptoms improved with short-chain fatty acid enemas or ostomy reversions. However, not all cases of diversion respond to such enemas, while some cases of IBD improve with this therapy.6e8 Therefore, once diversion colitis enters the clinical differential diagnosis, it would be nearly impossible to definitively distinguish diversion from IBD on histologic grounds alone. In such cases, a reasonable report would describe the pertinent findings in the top-line and discuss the etiologic possibilities in the note. Reversing the ostomy and close patient follow-up can also be a reasonable approach since diversion colitis will improve following ostomy reversion and IBD will not.
with chronic NSAID exposure, and is considered pathognomonic for NSAID related injury. The smooth, symmetrical diaphragms can be recognized endoscopically, although they are often not probe-patent (Figure 2f). Histologically, prominent submucosal fibrosis with web-like narrowing of the lumen is seen (Figure 2c). The diaphragms can eventually constrict to the size of a pin-hole and result in emergent obstruction. The background mucosa can feature chronic injury, including architectural distortion and pyloric metaplasia. While diaphragm disease is most common in the small bowel, it has also been described in the colon, perhaps related to the increasingly popular extended-release NSAID formulations. Beware that diaphragm disease may be clinically mistaken for Crohn disease based on the presence of strictures, stenosis, deep fibrosis, architectural changes, and pyloric metaplasia. Careful correlation with the clinical context, reconciliation with the medication list, and biopsies outside of the diaphragm zone can facilitate accurate diagnosis.
Therapeutics Iatrogenic injuries are increasingly encountered as the therapeutic market expands and colonoscopic procedures become more commonplace. Although the injury patterns are usually not particularly specific, therapeutics should be routine considerations of the chronic colitis pattern. The discussion below focuses on select entities with sometimes unique morphologic signatures.
Resins Resins are commonly encountered medications that facilitate ionexchange (Table 1, Figure 3). Their colourful crystalline forms can be identified throughout the GI tract and also in the lung, in cases of aspiration. At time of writing, there are only three subgroups of resins: sodium polystyrene sulfonate, sevelamer, and the bile acid sequestrants (BAS).9e12 It is important to accurately distinguish between these resins since sodium polystyrene sulfonate and sevelamer can cause of significant injury, and their appearance adjacent to mucosal injury should result in immediate clinician notification. Moreover, long-standing cases of
NSAIDs NSAIDs mediate injury via nonselective inhibition of cyclooxygenase isoenzymes. NSAIDs are notorious culprits for a variety of colonic injury patterns spanning acute colitis, ischaemic colitis, chronic colitis, ulceration, perforations, and more. Repeated cycles of deep damage and repair can result in “diaphragm disease”. This rare finding is seen in 2% of patients
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Practical pointers of resins Brand name
Generic name
Route
Red flags/Indications
KayexalateÒ Sodium polystyrene sulfonate PO, Enema Hyperkalemia chronic kidney disease PO Hyperphosphatemia chronic kidney disease RenvelaÒ RenagelÒ Sevelamer Colesevelam PO Diarrhoea, hypercholesterolaemia, WelcholÒ dyslipidemia, diabetes mellitus Colestipol PO Diarrhoea, hypercholesterolaemia, ColestidÒ dyslipidemia, and pruritus LoCholestÒ Cholestyramine PO Same as above Cholestyramine PO Same as above PrevaliteÒ Cholestyramine PO Same as above QuestranÒ
Binding target Causes mucosal injury Potassium Phosphate Bile acids
Yes Possibly No
Bile acids
No
Bile acids Bile acids Bile acids
No No No
Table 1
injury can result in the chronic colitis pattern, serving as further examples of curable IBD mimics. Although resins are easily discriminated on H&E, useful diagnostic tools include an AFB special stain, a quick chart review, and awareness of pertinent red flags (Table 1, Figure 3). Red flags to consider sodium polystyrene sulfonate include potassium abnormalities or chronic kidney disease. Both its resins and its diluent have been linked to severe ulceration and ischaemia, which can be fatal.13e19 Histologically, these resins display an internal “fish-scale” pattern, are violet on H&E, and black on AFB. Sodium polystyrene sulfonate is commonly confused for sevelamer, the latter recently reported in 2013.11 Red flags to consider sevelamer include phosphate abnormalities or patients with chronic kidney disease. Like sodium polystyrene sulfonate, sevelamer also displays an internal “fishscale” pattern. Distinctive features of sevelamer include its twotoned colour on H&E with bright pink linear accentuations and a rusty yellow background; it is magenta on AFB. The BAS have been safely used for more than 90 years and do not cause mucosal injury, although the resins can be entrapped in ulcer debris. They were initially introduced to treat hypercholesterolaemia, but today they are more commonly used to treat diarrhoea. These resins are variable eosinophilic on H&E, yellow on AFB, and they lack “fish-scales”. The BAS are a large
family whose members are histologically indistinguishable from each other (Table 1). Ipilimumab colitis A history of metastatic melanoma is the clue to ipilimumab (YervoyÒ) colitis. It is one of an emerging group of biologic therapeutics whose mechanism of action is immune-mediated destruction of neoplasms.20 Specifically, ipilimumab targets the cytotoxic T-lymphocyte-associated antigen 4 found on cytotoxic T-lymphocytes and regulatory T cells. Up to 60% of patients with ipilimumab exposure report immune related adverse effects: gastrointestinal tract and skin symptoms are most common.20e22 Watery, culturenegative diarrhoea is characteristic, and endoscopic findings range from normal to marked ulcerations. Corresponding colon biopsies show chronic injury with increased apoptotic bodies, granulomata, and eosinophilia. This curable IBD mimic is effectively treated with drug cessation or optimized immunosuppression. Death due to medication is rare (1%), but only seen in cases with a delayed diagnosis or failure to recognize the diagnosis, underscoring the importance of recognizing this curable IBD mimic.
Vascular injury Long-standing vascular injuries can result in a pattern of chronic colitis that can be histologically indistinguishable from IBD.
Figure 3 Resins. (a) Sodium polystyrene sulfonate displays an internal “fish-scale” pattern, is violet on H&E, and black on AFB (not shown). (b) Sevelamer also has “fish-scales”, but displays a two-toned colour on H&E and is magenta on AFB (not shown). (c) BAS lack “fish-scales”, are eosinophilic on H&E, and yellow on AFB (not shown).
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Figure 4 Vascular injuries can also lead to the chronic colitis pattern. (a) The ischaemic colitis pattern features surface epithelial injury, mucin loss, lamina propria haemorrhage and hyalinization, and withered crypts. (b) Radiation injury is characterized by ectatic, damaged vessels in a background of hyalinization and fibrosis. On higher power, atypical stromal cells can be seen (not shown).
history of malignancy. Prostate or cervical primaries are notoriously helpful diagnostic clues to consider radiation colitis/ proctitis, but similar changes have been reported with pancreatobiliary carcinomas, and even esophageal malignancies. Additional diagnostic clues include any case of ischaemic injury, which should prompt diligent inspection of the background vessels. The classic histologic features of radiation can be subtle on biopsy, but more readily appreciated in resection specimens where the larger submucosal vessels are more easily seen. Typical features include damaged, hyalinized, and ectatic vessels in a background of hyalinization and fibrosis (Figure 4b). Additional helpful clues include atypical stromal cells with retained nuclear:cytoplasmic ratio and smudged and vacuolated chromatin.
Potential causes of chronic vascular injury include any process that compromises blood flow, such as atherosclerosis, coagulopathic disorders, thromboembolic diseases, vasculitis, radiation, amyloidosis, infections, therapeutics, mechanical compromise, and cocaine, among others. Important vascular injury patterns are detailed below. Ischaemic colitis pattern “Watershed zones” are weaknesses in the colonic blood supply due to incomplete anastomosis of the marginal arteries and suboptimal collateral circulation. The three most vulnerable sites include the ileocaecal region, splenic flexure, and the rectosigmoid. The clinical presentation is varied depending on the severity of the vascular insufficiency. Patients can be subclinical, complain of mild abdominal pain, or can present emergently with severe abdominal pain, frank gastrointestinal bleeding, and an acute abdomen. The “watershed zones” serve as the epicentre of the mucosal changes with common findings including erythema, mucosal friability, ulceration, necrosis, or perforation. Characteristic histologic features include surface epithelial injury, mucin loss, lamina propria haemorrhage and hyalinization, and withered crypts (Figure 4a). Features of chronicity can be identified in cases of gradual and longstanding vascular compromise. Like the chronic colitis pattern, the ischaemic colitis pattern is aetiologically nonspecific and may result from a diverse array of vascular insults as detailed above (atherosclerosis, vasculitis, mechanical obstruction, medications, etc). Importantly, an identical histologic injury pattern can be seen with infections, particularly those caused by Escherichia coli 0157:H7 (typically fibrin thrombi are prominent) and Clostridium difficile (characteristically exploding crypts with streaming neutrophil rich pseudomembranes are seen). In such cases, valuable diagnostic clues include pertinent stool cultures and disease distribution patterns (disease localized to watershed areas favours ischaemia).
Vasculitis Vasculitis involving vessels supplying the gastrointestinal tract can lead to low-flow states with resultant ischaemic patterns of injury in the down-stream bowel segments. Vasculitis can lead to the chronic colitis pattern and be histologically identical to IBD, particularly vasculitis associated with granulomata, strictures, and fibrosis. To further add to the complications, Crohn disease can be associated with inflamed and damaged arterioles with fibrinoid necrosis, thrombosis, and granulomata. Since vasculitis and IBD are both managed with immunosuppression, this distinction can be difficult yet critical. For example, if a patient with Behc‚et was misdiagnosed with ulcerative colitis, an unnecessary total colectomy could follow without alleviation of symptoms. Helpful clues include a history of vasculitis, such as polyarteritis nodosa, Wegener granulomatous, ChurgeStrauss, lupus, rheumatoid arthritis, Behc‚et, or Buerger disease. The simple histologic hallmark of vasculitis is vascular based inflammatory damage. Variable fibrinoid necrosis, thrombosis, granulomatous inflammation, and eosinophilia can also be seen. Precise classification is aided by synthesizing pertinent clinical parameters (age, ANCA status, systemic involvement of other organs), character of involved inflammatory infiltrate (lymphocyte predominant, granulomatous, eosinophilic), and the type and size of involved vessels (arteries versus veins; small versus medium
Radiation Radiation-induced endothelial damage culminates in compromised vascular flow. Red flags to the diagnosis include any
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2 Makapugay LM, Dean PJ. Diverticular disease-associated chronic colitis. Am J Surg Pathol 1996; 20: 94e102. 3 Ludeman L, Shepherd NA. What is diverticular colitis? Pathology 2002; 34: 568e72. 4 Strate LL, Liu YL, Syngal S, Aldoori WH, Giovannucci EL. Nut, corn, and popcorn consumption and the incidence of diverticular disease. JAMA 2008; 300: 907e14. 5 Edwards CM, George B, Warren BF. Diversion colitis: new light through old windows. Histopathology 1999; 35: 86e7. 6 Scheppach W, Sommer H, Kirchner T, et al. Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. Gastroenterology 1992; 103: 51e6. 7 Guillemot F, Colombel JF, Neut C, et al. Treatment of diversion colitis by short-chain fatty acids. Prospective and double-blind study. Dis Colon Rectum 1991; 34: 861e4. 8 Harig JM, Soergel KH, Komorowski RA, Wood CM. Treatment of diversion colitis with short-chain-fatty acid irrigation. N Engl J Med 1989; 320: 23e8. 9 Arnold MA, Swanson BJ, Crowder CD, et al. Colesevelam and colestipol: novel medication resins in the gastrointestinal tract. Am J Surg Pathol 2014 Nov; 38: 1530e7. 10 Seminerio J, McGrath K, Arnold CA, Voltaggio L, Singhi AD. Medication-associated lesions of the GI tract. Gastrointest Endosc 2014; 79: 140e50. 11 Swanson BJ, Limketkai BN, Liu TC, et al. Sevelamer crystals in the gastrointestinal tract (GIT): a new entity associated with mucosal injury. Am J Surg Pathol 2013; 37: 1686e93. 12 Voltaggio L, Lam-Himlin D, Limketkai BN, Singhi AD, Arnold CA. Message in a bottle: decoding medication injury patterns in the gastrointestinal tract. J Clin Pathol 2014; 67: 903e12. 13 Abraham SC, Bhagavan BS, Lee LA, Rashid A, Wu TT. Upper gastrointestinal tract injury in patients receiving kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic, and histopathologic findings. Am J Surg Pathol 2001; 25: 637e44. 14 Foresti V. Intestinal obstruction due to kayexalate in a patient concurrently treated with aluminum hydroxide and morphine sulfate. Clin Nephrol 1994; 41: 252. 15 Harel Z, Harel S, Shah PS, Wald R, Perl J, Bell CM. Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: a systematic review. Am J Med 2013 Mar; 126: 264.e9e24. 16 Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams GM. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis. Surgery 1987; 101: 267e72. 17 Rashid A, Hamilton SR. Necrosis of the gastrointestinal tract in uremic patients as a result of sodium polystyrene sulfonate (Kayexalate) in sorbitol: an underrecognized condition. Am J Surg Pathol 1997; 21: 60e9. 18 Scott TR, Graham SM, Schweitzer EJ, Bartlett ST. Colonic necrosis following sodium polystyrene sulfonate (Kayexalate)-sorbitol enema in a renal transplant patient. Report of a case and review of the literature. Dis Colon Rectum 1993; 36: 607e9. 19 Wootton FT, Rhodes DF, Lee WM, Fitts CT. Colonic necrosis with Kayexalate-sorbitol enemas after renal transplantation. Ann Intern Med 1989; 111: 947e9. 20 Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711e23.
versus large vessels). For example, typical clues to Wegener granulomatosis include necrotizing, granulomatous vasculitis of small vessels, ANCA positivity, and lung and renal involvement. In contrast, ChurgeStrauss is associated with necrotizing, granulomatous, eosinophil-rich vasculitis of small vessels in patients with a peripheral eosinophilia, ANCA positivity, and lung involvement. Behc‚et is associated with HLA-B51 and is enriched in young Turkish patients with genitourinary lesions and ocular, dermatologic, and joint manifestations. Notably, while vasculitis can cause mucosal ischaemia, innocent vessels entrapped within prominent mucosal injury can appear inflamed and mimic vasculitis. In such cases, primary vascular injury should be evaluated in areas not directly subjacent to prominent mucosal injury. Sometimes, it is histologically impossible to distinguish a true vasculitis from a vasculitis mimic. In these challenging cases, reasonable approaches include a detailed note describing the findings and considerations, close clinical follow-up, and correlation with pertinent vascular imaging and serologic studies.
Autoimmune diseases Patients with autoimmune diseases can have complex, nondescript presentations that can mimic various diseases, including IBD. Granulomatous autoimmune diseases such as sarcoidosis, common variable immunodeficiency (CVID), and chronic granulomatous disease (CGD) can be particularly problematic in their overlap with Crohn disease. Sarcoidal involvement of the colon is rare with a reported prevalence of less than 1%. While helpful features in support of sarcoidosis include imaging studies showing bilateral mediastinal lymphadenopathy and elevated ACE levels, sarcoidosis (as well as IBD) is a diagnosis of exclusion. CVID can also present with granulomatous inflammation and architectural changes. Most cases of CVID lack plasma cells, making routine inspection of plasma cells worthwhile. Correlation with serum immunoglobulin levels is advised since up to 1/3 of patients have (dysfunctional) plasma cells.23 Up to 46% of autopsied patients with CGD have granulomatous colitis. Such patients also typically have a long-standing history of infections and complicated disease courses. The diagnostic evaluation of CGD includes nitroblue tetrazolium testing. Lastly, granulomatous colitis can also be seen with vascular injuries, medication related injuries, and infections.
Conclusion In summary, chronic colitis is aetiologically nonspecific. In this way, histology alone can betray the faithful pathologist if all cases of chronic colitis are attributed to IBD. To ensure proper etiologic specific management, a prudent approach is to describe the histologic feature in the diagnostic section, and carefully discuss the reasonable etiologies in the note after gathering pertinent clinicopathologic data. A REFERENCES 1 Peppercorn MA. Drug-responsive chronic segmental colitis associated with diverticula: a clinical syndrome in the elderly. Am J Gastroenterol 1992; 87: 609e12.
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21 Graziani G, Tentori L, Navarra P. Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. Pharmacol Res 2012; 65: 9e22. 22 Ku GY, Yuan J, Page DB, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 2010; 116: 1767e75. 23 Daniels JA, Lederman HM, Maitra A, Montgomery EA. Gastrointestinal tract pathology in patients with common variable immunodeficiency (CVID): a clinicopathologic study and review. Am J Surg Pathol 2007; 31: 1800e12.
Practice points C C
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Acknowledgements
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The authors would like to acknowledge Shawn Scully for figure preparation.
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Chronic colitis is aetiologically nonspecific A diagnosis of IBD should only be considered if all IBD mimics have been reasonably excluded Diverticular disease is a top consideration of chronic colitis in the left colon Diversion colitis is due to a deficiency of short-chain fatty acids in the excluded bowel segment Diaphragm disease is associated with chronic NSAID usage Sodium polystyrene sulfonate and sevelamer have “fish-scales” and are associated with mucosal injury; BAS lack “fish-scales” and do not cause mucosal injury Each mucosal biopsy and resection specimen should be carefully assessed for vascular injury Colonic granulomatous disease should prompt consideration of sarcoid, CVID, CGD, vascular injury, medication injury, infection, in addition to IBD
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Please cite this article in press as: Arnold CA, et al., Fifty shades of chronic colitis: non-infectious imposters of inflammatory bowel disease, Diagnostic Histopathology (2015), http://dx.doi.org/10.1016/j.mpdhp.2015.06.014