Chapter 22 – Mimics of Inflammatory Bowel Disease




Abstract




Histological support for a diagnosis of inflammatory bowel disease (IBD) requires characteristic features, e.g. basal plasmacytosis, architectural changes, and granulomas. Unfortunately, many conditions share histological features with IBD. One of the closest mimics is diverticular colitis, a process that occurs adjacent or close to diverticula. It often resembles ulcerative colitis (UC), but, unlike UC, it rarely involves the rectum. Another close mimic is diversion proctocolitis, which is easy to diagnose if the history is available but otherwise is often difficult to distinguish from IBD. Mucosal changes similar to those of IBD may be the result of various infections, e.g. lymphogranuloma venereum/syphilis, amoebiasis, and HIV. Other causes include mass lesions and drugs. Granulomas are a feature of Crohn’s disease but can occur in other settings. In tuberculosis, they are typically larger and more confluent than in Crohn’s disease and may show necrosis. Rarer potential mimics of IBD include common variable immunodeficiency, Behcet’s disease, graft-versus-host disease, endometriosis, and pneumatosis coli. Close attention to the clinical picture and a careful approach to colorectal biopsy assessment by the pathologist should help reduce the chance of misdiagnosis and incorrect management.





Chapter 22 Mimics of Inflammatory Bowel Disease



Roger M. Feakins



Introduction


Histological support for a diagnosis of inflammatory bowel disease (IBD) requires characteristic features, e.g. basal plasmacytosis, architectural changes, and granulomas. Unfortunately, many inflammatory conditions of the large bowel share clinical, endoscopic, and histological features with IBD. Usually, there are clinical and/or histological clues that help to steer the pathologist and clinician away from an incorrect diagnosis of IBD. However, if the clinical picture is convincing for IBD, the pathologist may wrongly suggest or support the diagnosis. Serious errors of management could be the result. For example, a patient with a severe infection such as tuberculosis or amoebiasis may receive immunosuppressive drugs, a patient with diverticular disease or another non-IBD colitis might undergo inappropriate surgery, or there may be a delay in the diagnosis of a disorder such as HIV infection or common variable immune deficiency (CVID) that requires specific treatment. Therefore, the pathologist should not be afraid to adopt a sceptical view if there is doubt. Close attention to the clinical picture and a careful approach to colorectal biopsy assessment by the pathologist should help reduce the chance of misdiagnosis of IBD.


A few entities can mimic IBD histologically particularly closely. These include diverticular colitis, diversion proctocolitis, and some chronic infections such as lymphogranuloma venereum (LGV) and syphilis. Other entities may share individual features with IBD but are less likely to lead to a confident histopathological diagnosis of IBD based on microscopic appearances alone.



Diverticular Disease and Inflammatory Bowel Disease


Diverticular disease is very common, particularly in those over 60 years of age. It typically affects the sigmoid colon in European and North American patients but can occur anywhere in the colon. It rarely involves the rectum, and this feature helps distinguish diverticular disease-associated inflammatory changes from those of IBD endoscopically and pathologically. Endoscopists are not always aware of diverticula because they may be sparse and because the mouths of diverticula are not always obvious. Inflammation of the mucosa adjacent to, or close to, the diverticula can resemble IBD histologically (Table 22.1). Histological features of this phenomenon, known as diverticular colitis, may include basal plasmacytosis, crypt distortion, epithelial mucin depletion, neutrophil activity, and Paneth cell metaplasia (Figure 22.1). Basal plasmacytosis, the feature that usually discriminates most strongly towards a diagnosis of IBD, may be prominent and diffuse in diverticular colitis. If the endoscopic and clinical findings also suggest IBD, there is a high risk of error.13 Indeed, misdiagnosis of diverticular colitis as ulcerative colitis (UC) is a well-recognised problem.




Table 22.1 Diverticular colitis and IBD




























































Diverticular colitis IBD
Clinical and macroscopic
Location


  • Typically sigmoid



  • Very rarely rectal



  • May involve any other part of colon




  • UC usually involves rectum



  • Isolated sigmoid UC is rare

Age of patient Older (usually>40 and often>60) Younger (< 40)
Diverticula


  • Usually present (occasionally not)



  • May be missed or unreported by endoscopist

May be present
Histology
Basal plasmacytosis


  • May occur



  • Sometimes prominent and diffuse, resembling IBD

Usual
Crypt distortion May be moderate/severe but typically mild Usual and may be severe
Epithelial mucin depletion Usually mild Common and may be severe
Villiform surface Rare Common
Mucosal granulomas


  • Rare



  • Cryptolytic granulomas can occur

Minority of Crohn’s biopsies
Paneth cell metaplasia May occur May occur
Neutrophil activity Common Common


UC, ulcerative colitis.





(A) Colonic mucosa adjacent to a diverticulum showing diffuse chronic inflammation and crypt distortion.





(C) Loss of the plasma cell gradient.





(C) Prominent basal plasmacytosis. In the absence of a history, these features would suggest a diagnosis of IBD, but patient age, distribution of disease, and endoscopic documentation of diverticula should reduce the risk of misdiagnosis. Crypt changes, villiform surface change, and mucin depletion tend to be less severe in diverticular colitis than in IBD.



Figure 22.1 Diverticular colitis mimicking IBD.


The main distinguishing features are clinical. Features favouring diverticular colitis include anatomical location in the sigmoid colon with rectal sparing, age of presentation> 60 years, a history of diverticular disease, and absence of the typical symptoms of IBD. Histological differences include milder crypt changes, less severe mucin depletion, and absence of surface villiform change. Mucosal granulomas that are not cryptolytic (i.e. secondary to crypt rupture) are very uncommon. Examination of biopsies taken separately from the sigmoid colon and the rectum, if available, usually helps make the distinction.1, 4 Unfortunately, the sigmoid alone or the ‘rectosigmoid’ are sometimes biopsied in this circumstance, making determination of the anatomical distribution of biopsy abnormalities difficult or impossible.


There are many names for this phenomenon. The most appropriate term is ‘diverticular colitis’. Others include ‘diverticular disease-associated colitis’ and ‘diverticular-associated colitis’. Some authors distinguish ‘segmental colitis associated with diverticulosis (SCAD)’ from peridiverticular mucosal inflammation or diverticulitis and then categorise it further, e.g. as crescentic fold disease, UC-like, or Crohn’s-like. This entity (SCAD), whether distinct from diverticular colitis or not, can also resemble IBD closely.3


In resections, diverticular disease with inflammation, fibrosis, and peridiverticular abscesses can closely resemble Crohn’s disease. Granulomas may be present in resections and may be numerous.


The relationship between IBD and diverticular disease is not simple. Some patients have both diseases because both are common. There is limited evidence that IBD is more likely to develop, or to flare up, in an area of diverticular disease than elsewhere in the colon.5 Reasons may include intestinal bacterial overgrowth in the diverticular segment and stasis of bowel contents. Rarely, diverticular colitis with rectal sparing appears to evolve into IBD with rectal involvement, although it is conceivable that these are examples of UC with rectal sparing (a rare but recognised occurrence) that eventually involve the rectum (see also Chapter 26).1, 6



Diversion Proctocolitis


The term diversion proctocolitis (DPC) refers to the macroscopic and microscopic changes occurring in large bowel that is excluded from the faecal stream, usually after surgical intervention (Fact Sheet 22.1). For example, the rectum (or ‘rectal stump’ in this setting) may remain in situ after partial or subtotal colectomy with ileostomy so that bowel contents pass through the ileostomy, but not through the rectal stump. Therefore, the faecal stream is ‘diverted’ and the bowel through which the faecal stream does not pass is ‘defunctioned’. The reason for surgery is usually IBD, but DPC also occurs in patients who have had surgery and diversion for other reasons, such as chronic constipation or aganglionosis. DPC usually takes a few weeks or months to develop.




Fact Sheet 22.1 Diversion Proctocolitis


General




  • Affects bowel that is excluded from the faecal stream (‘defunctioned’ bowel)



  • Usually post-surgical, and most often a rectal stump after ileostomy and subtotal colectomy



  • IBD is the most common setting; others include motility disorders and severe constipation


Histology




  • Often resembles IBD



  • Modified by pre-existing disease



  • Relative contribution of diversion and pre-existing IBD is difficult to determine (see Fact Sheet 22.2)



  • Typical features




    • Diffuse mucosal chronic inflammation with numerous large lymphoid follicles



    • Relatively mild crypt distortion



    • Neutrophil activity (often mild)



    • Ulceration may occur



Unusual and/or Potentially Confusing Histological Features




  • Granulomas



  • Granulomatous vasculitis



  • Vascular changes, e.g. lymphocytic phlebitis



  • Filiform polyps



  • Fissures



  • Transmural chronic inflammation


The development of DPC probably relates to the absence of faecal transit and the limited availability of various energy sources, particularly butyrate and other short-chain fatty acids (SCFAs). Alteration in gut microflora reduces the generation of SCFAs. The latter are an important source of nutrition for the colonic epithelium and are necessary for the maintenance of mucosal integrity.7, 8


Typical changes of DPC include lamina propria chronic inflammation, which is usually diffuse but may be patchy or focal; crypt distortion and crypt atrophy in some settings; and aphthoid or non-aphthoid ulceration (Figure 22.2A and B).911 Prominent and numerous lymphoid follicles with germinal centres, a picture sometimes termed lymphoid follicular hyperplasia, is characteristic of DPC, and should raise the possibility of this diagnosis if clinical details are sparse and the picture does not fit with another diagnosis. However, hyperplastic lymphoid follicles are not specific as they also occur in IBD.8 In more severe examples, there may be submucosal or transmural chronic inflammation which may include lymphoid aggregates (Figure 22.2C).






(A) Diffuse chronic inflammation with prominent lymphoid follicles, crypt atrophy, and mild crypt distortion are typical.





(B) Crypt distortion is sometimes more severe, especially if the underlying diagnosis is UC.





(C) A resected diverted segment of rectum showing submucosal and transmural chronic inflammation. This more severe picture with transmural inflammation is, perhaps paradoxically, more common in UC than in other settings.





(D) Granulomas may occur in DPC, regardless of the underlying reason for the procedure, and do not necessarily indicate Crohn’s disease.





(E) Granulomatous vasculitis, with a granuloma (arrow) adjacent to an inflamed and damaged blood vessel.



Figure 22.2 Diversion proctocolitis.


The histological features of DPC often resemble IBD, regardless of the original reason for surgery. In those with no history of IBD, the histological changes in the appropriate clinical setting are very likely to reflect diversion. In those with pre-existing IBD, distinction of histological features of DPC from those of IBD is difficult. Similarly, a diagnosis of DPC is extremely difficult to make if no clinical history of diversion is given. Clues to the diagnosis of DPC in the setting of UC, rather than a diagnosis of non-diverted UC, might include very prominent lymphoid follicles and relatively mild crypt distortion (Figure 22.2A), but these features are not reliable for diagnosis as there is a range of severity of crypt changes in both DPC and UC (Figure 22.2B).


Vascular abnormalities may occur in DPC and may contribute to the histological picture.8 The rare phenomenon of enterocolic lymphocytic phlebitis (ELP) has been described in DPC and is characterised by circumferential lymphocyte-predominant inflammation in and around submucosal and/or subserosal veins with endothelial cell swelling, sometimes accompanied by necrotising phlebitis, granulomatous phlebitis, or myointimal hyperplasia.8


Granulomas can be a feature of DPC (Figure 22.2D and E). The likelihood of granuloma formation does not depend on the original reason for surgery, i.e. IBD or other indications.913 Granulomatous vasculitis is a rare occurrence in DPC but may occur both in the setting of Crohn’s disease and in the absence of pre-existing IBD (Figure 22.2E).8, 10, 14


Filiform polyps are slender elongated projections of both mucosa and submucosa and show no dysplasia.15 Filiform polyps and similar polypoid lesions may be more common in defunctioned and diverted large bowel than in other settings.15


Histological features of DPC may provide clues to the underlying diagnosis that led to surgery but rarely distinguish reliably between the possibilities. In general, the changes of diversion are more severe in the setting of UC than in Crohn’s disease or other settings. In Crohn’s disease the original histological inflammatory changes may improve after diversion, but this is not always the case.9 Paradoxically, transmural chronic inflammation (which in the non-diverted colon favours Crohn’s disease) is more common in the setting of UC than in other settings if the bowel has been defunctioned. Granulomas, as usual, are more likely in the setting of Crohn’s disease than in UC, and in some cases appear to increase in number and size in Crohn’s disease after diversion. Granulomas in Crohn’s disease are more likely to contain sarcoid-like asteroid bodies or Schaumann bodies after diversion than before, according to one report.9


Distinctions between the histological features of DPC occurring in various settings, e.g., non-inflammatory conditions, UC, and Crohn’s disease, have been documented (Fact Sheet 22.2).8, 9 However, these are observations rather than reliable ways to distinguish the underlying pathology. Usually, the histological features in biopsies and resections from a diverted segment cannot distinguish reliably between UC and Crohn’s disease.




Fact Sheet 22.2 Differences between Diversion Proctocolitis in Three Settings (Non-Inflammatory Bowel Disease, Ulcerative Colitis, and Crohn’s Disease): Observations That May Provide Clues


DPC with a Background of Non-IBD/Normal Bowel (Prototype)




  • Diffuse chronic inflammation



  • Lymphoid follicular hyperplasia



  • Minimal or no crypt distortion / variable crypt distortion



  • Aphthoid ulcers



  • Cryptitis and crypt abscesses



  • Mucin depletion



  • Cryptolytic granulomas – occasional



  • Granulomas (non-cryptolytic) – rare, but may occur


DPC in a Background of UC




  • DPC in UC is often more complex and severe than in other settings



  • UC typically becomes more severe with diversion



  • The crypt distortion of UC often persists and is more likely to be present in UC DPC than in non-UC DPC (Figure 22.2B)



  • Fissures, granulomas, and transmural chronic inflammation can occur




    • Should not prompt a revision of the original diagnosis of UC to a diagnosis of Crohn’s disease in this setting



DPC in a Background of Crohn’s Disease




  • Inflammation in Crohn’s disease typically diminishes after diversion



  • Mucosa previously spared by Crohn’s disease may become inflamed after diversion



  • Diffuse chronic inflammation and lymphoid follicular hyperplasia tend to favour DPC over Crohn’s disease, but diffuse chronic inflammation can also occur in Crohn’s disease



  • Granulomas in the setting of Crohn’s disease may be more likely to develop calcific bodies (Schaumann/asteroid) after diversion than before, but evidence is limited


Overall, histology often distinguishes poorly between the underlying disease and DPC itself. Clinical features and history are more informative.


In addition to the differences in presentation and histology, the prevalence of DPC may differ depending on the clinical setting.9 DPC is probably universal in diverted UC and diverted normal colon, while the prevalence in Crohn’s disease is less clear. Some authors have suggested reservation of the term ‘diversion proctocolitis’ for those who have unequivocal histological evidence of inflammation, distinguishing them from those with less severe changes. For example, in one study of the diverted rectum in patients who had undergone colectomy for Hirschsprung’s disease, 70% had overt histological inflammation and 30% had minimal inflammation.


Construction of a histology report is not straightforward in this setting, even when clinical details are adequate. A full clinical history is necessary, not only because the histological changes may resemble those of IBD but also because there are various indications for diversion of the faecal stream which will modify the histological picture of DPC.


If there is pre-existing IBD, the conclusion of the report should probably be ‘diversion proctocolitis in the setting of ulcerative colitis’ or ‘diversion proctocolitis in the setting of Crohn’s disease’, etc., assuming that the histology is compatible with these conclusions. Sometimes, there is relatively mild inflammation with few crypt changes in a patient with known UC, and the pathologist could then suggest that the features support the diagnosis of DPC and that there is little evidence of UC, but such precise interpretation is usually not appropriate or reliable.


In practice, the pathologist should always be cognisant of the existence of DPC and its potential close resemblance to IBD, especially when confronted with a histological pattern resembling IBD that does not appear to conform to the clinical picture. If clinical details are sparse and the histological features raise doubts, the pathologist should be suspicious and should consider the possibility of DPC and request more clinical information.



Specific Infections


Many infections have the potential to mimic IBD clinically and endoscopically, especially if they become chronic. They may also share histological features with IBD. However, few show the classic combination of crypt changes and basal plasmacytosis that suggest or support a diagnosis of IBD. For a discussion of the differential diagnosis between IBD and acute self-limiting (infectious) colitis, please see Chapter 21. The sections that follow describe other infections that may have histological and/or clinical features suggesting IBD or similar to those of IBD.



Lymphogranuloma Venereum/Syphilis


Lymphogranuloma venereum (LGV) and syphilis involving the colon and rectum are uncommon reasons for biopsy. A few studies describe the histological features in detail.1618 Chlamydia trachomatis serotypes L1, L2, and L3 cause LGV, while Treponema pallidum causes syphilis. Clinically, underlying HIV infection is common and the patients are usually men who have sex with men (MSM). Many patients with proctocolitis in this setting receive empirical treatment with antibiotics and do not undergo mucosal biopsy. However, HIV and related infections are sometimes unsuspected clinically, and endoscopists may make a provisional diagnosis of IBD of the colon and/or rectum based on the macroscopic appearances of LGV/syphilis affecting the bowel. The rectum is typically most severely inflamed. Endoscopic resemblance to Crohn’s disease is sometimes close. If the histology also resembles IBD, unwitting collaboration between pathologist and clinician in the misdiagnosis of IBD is a risk.


Microscopically, the mucosa and submucosa in LGV and in syphilis shows chronic inflammation, often intense, with an increased density of lymphocytes, histiocytes, and plasma cells (Figure 22.3AE). Basal plasmacytosis is uncommon in LGV. However, syphilis may produce three patterns in the rectal/colonic mucosa, including a plasma cell-rich infiltrate, a lymphohistiocytic infiltrate, and a lymphoma-like infiltrate, and perineural plasma cells may occur.18






(A) Rectal mucosa in colorectal LGV showing chronic inflammation and crypt shortening, potentially resembling inflammatory bowel disease (IBD).





(B) Chronic inflammation can extend more deeply, with damage to the muscularis mucosae and fibrosis.





(C) Even if the clinical history of LGV is unknown, the absence of basal plasmacytosis and relative preservation of architecture should steer the pathologist away from a definite diagnosis of IBD.





(D) Anal mucosa in LGV showing severe chronic inflammation.





(E) Rectal mucosa involved by syphilis (Treponema pallidum) showing features resembling IBD including chronic inflammation, crypt architectural changes and crypt atrophy.


(Courtesy of Dr Laura Lamps, University of Michigan, USA).




(F) Immunohistochemistry may confirm syphilis, as in this example.


(Courtesy of Dr Laura Lamps.)


Figure 22.3 Lymphogranuloma venereum (LGV) and syphilis of the lower GI tract.


In LGV/syphilis, crypt changes are usually absent or mild (Figure 22.3C). There may be lamina propria and submucosal fibrosis. Acute inflammation in the form of cryptitis and crypt abscesses is usually mild or moderate if present. Ulceration occurs in syphilis more often than in LGV. There are variable reports of the frequency of granulomas in LGV, while giant cells and Paneth cell metaplasia are not common.16, 17 Involvement of the squamous mucosa of the anal canal by the inflammatory process may also provide a clue to the diagnosis (if anal biopsies are available) (Figure 22.3D). Anal mucosal changes may include ulceration, hyperplasia, and dense subepithelial chronic inflammation.


In a study of the discriminatory value of individual features, the following indicated LGV/syphilis rather than IBD: little or no ‘crypt centric damage’ (i.e. cryptitis, crypt abscesses, crypt distortion, and Paneth cell metaplasia); few mucosal eosinophils; and more plasma cells, endothelial swelling, and perivascular plasma cells in the submucosa. The following were not discriminatory: fibrosis, granulomas, foreign body giant cells, lymphoid aggregates, ulcers, aphthoid lesions, and neural hyperplasia (Practice Points 22.1).19




Practice Points 22.1 Clues to a Diagnosis of Lymphogranuloma Venereum/Syphilis Rather than Inflammatory Bowel Disease in Colorectal Biopsies


Useful Features Favouring LGV/Syphilis over IBD




  • Clinical setting



  • Absent or very mild crypt architectural changes



  • Absent or mild neutrophil activity



  • Sparsity of mucosal eosinophils



  • Absence of Paneth cell metaplasia



  • No basal plasmacytosis (especially in LGV)



  • Prominent submucosal plasma cells and endothelial swelling



  • Anal involvement


Features That Are Less Useful or Are Non-discriminant




  • Fibrosis



  • Granulomas



  • Foreign body giant cells



  • Lymphoid aggregates



  • Ulcers



  • Aphthoid lesions


Close analysis of the histological features should help to distinguish these conditions from IBD or, at least, to alert the pathologist and clinician to the possibility of a diagnosis other than IBD. As regards definitive histological diagnosis, silver stains or immunohistochemistry may confirm syphilis (Treponema pallidum) (Figure 22.3F) although immunohistochemistry is the more sensitive.18 Clinical tests may be more reliable. There is currently no reliable specific histological marker for LGV.



HIV Infection


HIV infection can cause mild colorectal mucosal chronic inflammation. This usually comprises a lamina propria chronic inflammatory infiltrate with lymphoid aggregates, mild epithelial mucin depletion, and minimal crypt changes (Figure 22.4).20 Epithelial cell apoptoses may be present. The changes may be patchy and may resemble Crohn’s disease histologically, although crypt changes tend to be mild or absent. HIV-related infections also require consideration, particularly LGV and syphilis (see earlier). A clinical history and exclusion of all other causes are necessary before diagnosing HIV-related inflammation. The term ‘Crohn’s disease’ is not advisable in this setting, unless a diagnosis of idiopathic Crohn’s disease is appropriate for other reasons.






(A) Colorectal mucosa from HIV-positive patients with no obvious colorectal infection sometimes shows mild lamina propria chronic inflammation, epithelial mucin depletion, and minimal crypt distortion, potentially resembling Crohn’s disease. An incorrect diagnosis of IBD is possible if no clinical history is available.





(B) Absence of basal plasmacytosis is a clue that the diagnosis is not IBD.



Figure 22.4 HIV-related changes.



Tuberculosis


Tuberculosis (TB) is caused by Mycobacterium tuberculosis and may involve the bowel (among multiple other sites) (Figures 18.12, 19.7, 22.5, and 27.4). It affects the terminal ileum and proximal colon most often, potentially mimicking Crohn’s disease. Histologically, TB causes mucosal ulceration, inflammation, and granulomas. There may be crypt distortion. In a resection specimen, the diagnosis may be easy, particularly if there are necrotising granulomas (Figure 22.5B and C). However, reliable distinction from Crohn’s disease can be difficult and in a biopsy is often impossible. The clinical setting is very important, including the patient’s risk factors for TB. The nature of the granulomatous infiltrate in a biopsy sample may be helpful. Compared to Crohn’s disease, the granulomas in TB are likely to be more numerous, larger (>400 μm in diameter), and more confluent (Practice Points 22.2 and Figure 22.5D). They are more likely to contain Langhans giant cells and to have a lymphoid cuff around them. Central necrosis excludes Crohn’s disease unless minimal, but is unusual in mucosal biopsies from TB cases.2123 Similarly, special stains for mycobacteria such as Ziehl–Neelsen are usually negative in the mucosa affected by TB and accordingly are almost always unhelpful. However, the pathologist may perform the stains ‘for completeness’ or as a result of encouragement from clinical teams. Further analysis of tissue using techniques such as PCR is not useful in practice.






(A) Ileocaecal ulceration and inflammation with mural thickening in a patient with TB, resembling Crohn’s disease.





(B) Transmural inflammation in a resection specimen may also resemble Crohn’s disease.





(C) Granulomas in the wall and in lymph nodes may show necrosis, virtually excluding Crohn’s disease.





(D) Necrosis is unusual in tuberculous granulomas of the colorectal mucosa. However, the granulomas in TB tend to be more numerous, larger, and more confluent than in Crohn’s disease and are more likely to contain Langhans giant cells.



Figure 22.5 Tuberculosis (TB) of the bowel.




Practice Points 22.2 Tuberculosis Mimicking Inflammatory Bowel Disease


Features of TB That Resemble Crohn’s Disease




  • Ileocaecal location (common)



  • Granulomas (usually present in TB; not always present in Crohn’s disease)


GI Granulomas in TB Compared to Granulomas in Crohn’s Disease




  • Larger (>400 μm)



  • Confluent



  • More numerous (e.g. 10 or more per biopsy site)



  • More likely to have Langhan’s giant cells



  • More likely to have a lymphoid cuff



  • Ulcers lined by conglomerate epithelioid histiocytes



  • Necrosis (virtually diagnostic if caseating, but necrosis is rare in GI biopsy samples)



  • Acid fast bacilli on Ziehl–Neelsen stain (rare in GI biopsy samples)


Additional Features of TB in Resections




  • Small serosal tubercles



  • Relative lack of fissuring



Sarcoidosis


Very rarely, sarcoidosis is complicated by an ileitis and/or colitis that may resemble Crohn’s disease clinically and pathologically. Both diseases are characterised by granulomas, although GI involvement in both diseases may lack granulomas. In sarcoidosis, calcified inclusions (e.g. asteroid bodies and Schaumann bodies) within granulomas or within multinucleate cells are more common than in Crohn’s disease but they are not specific (Figure 22.6). Typically, GI sarcoidosis does not cause mucosal architectural changes. In resections, sarcoidosis lacks the transmural chronic inflammation, deep fissures, and fistulas of Crohn’s disease.24, 25 Furthermore, the clinical picture is usually dissimilar, including more widespread systemic involvement in sarcoidosis. Lymph nodes, lungs, and liver often show numerous closely packed granulomas in sarcoidosis, while in Crohn’s disease there are few or no granulomas. Very rare examples of apparently coexistent lower GI sarcoidosis and IBD have been reported.25, 26





Figure 22.6 Inclusion bodies in GI tract granulomas or giant cells may raise the possibility of sarcoid but are not specific. This example is from a patient with ileocolonic Crohn’s disease.



Yersinia


Yersiniosis is a common cause of diarrhoea. The agents responsible are Yersinia enterocolitica (YE) and Yersinia pseudotuberculosis (YP). Their clinical and pathological features are similar. Usually the infection is self-limiting but it may persist, especially in immunocompromised patients. The ileum, right colon, and appendix are preferentially affected, and there may be clinical and pathological resemblance to Crohn’s disease. In particular, there may be granulomas. Some show central necrosis, stellate abscesses, or a perigranulomatous lymphoid cuff, allowing their distinction from the granulomas of Crohn’s disease (Figures 18.5 and 19.9). However, some granulomas in Yersinia infection show none of these features. Mucosal abnormalities also include cryptitis, giant cells, and ulceration. The basal plasmacytosis and crypt architectural changes of IBD are not usually a feature. Nevertheless, distinction from Crohn’s disease, and indeed from intestinal TB, can be very difficult or impossible in a biopsy and even in a resection specimen and may eventually depend on a combination of histological, clinical, microbiological, and serological findings.22



Amoebiasis


Amoebiasis is most likely to affect the right colon, sigmoid, and/or rectum. The prevalence of amoebiasis varies considerably according to geographical location. Amoebiasis of the GI tract may become chronic and may persist for months or years prior to the development of invasive disease. Clinically, it may mimic IBD and TB.27 This is a more important problem in higher prevalence areas of the world such as Central America, South America, Asia, and Southern Africa than it is elsewhere. Treatment with anti-inflammatories may worsen amoebiasis. Therefore, distinction from IBD is important. Immunosuppressive drugs given mistakenly for presumed IBD could precipitate the onset of invasiveness,27 allow the development of fulminant disease, or facilitate dissemination.28 Unfortunately, stool specimens, bowel biopsies, and serology may be negative.


Endoscopically, amoebiasis is characterised by ulcers that are often discrete and induce fewer changes than typical IBD in the adjacent mucosa. Other patterns include haemorrhagic colitis and membranes.28, 29 Ulcers and discontinuity can mimic Crohn’s disease macroscopically, while fulminant amoebic colitis can resemble the fulminant colitis of IBD.


Histologically, the trophozoites are characteristic and diagnostic. They are typically 25 to 40 μm in diameter and have a small, round or ovoid, pale and often eccentric nucleus that has a central karyosome resembling a nucleolus and they have pale foamy periodic acid–Schiff (PAS)-positive cytoplasm containing ingested red cells (Figures 18.20 and 22.7A). They stain negatively for macrophage markers such as CD68. However, trophozoites may not be present. Indeed, some authors suggest that their absence is common.30 When acute and chronic forms are compared, there are trophozoites in all biopsies of acute cases and in a minority of biopsies of chronic cases.29 Other features that favour amoebiasis over IBD include ulcers that contain necrotic debris, mucin, blood clot, and proteinaceous material,28 neutrophils in the lamina propria, and neutrophils in the surface epithelium.30, 31 Neutrophil cryptitis and crypt abscesses also occur but are not specific.






(A) Trophozoites with ingested red cells and pale small ovoid nucleus are diagnostic of amoebiasis but are not always present, and not always identified even if present.





(B) The mucosa in amoebiasis occasionally shows basal plasmacytosis.





(C) Crypt distortion if present in amoebiasis is usually mild, as in this example, but more severe distortion can occur. Paneth cells are numerous.





(D) Paneth cell metaplasia favours IBD over other causes but may be present in amoebiasis. The combination of basal plasmacytosis, crypt changes, Paneth cell metaplasia, and endoscopic features of IBD can result in an incorrect clinicopathological diagnosis of IBD.



Figure 22.7 Amoebiasis resembling inflammatory bowel disease (IBD).


In amoebic colitis, histological features similar to those of IBD may be present. The chronic inflammatory infiltrate may extend deeply into the mucosa and occasionally is associated with well-developed basal plasmacytosis resembling the inflammation of IBD (Figure 22.7B). There may also be crypt distortion (Figure 22.7C) (particularly adjacent to ulcerated mucosa), Paneth cell metaplasia (Figure 22.7C and D), and epithelial mucin depletion (especially superficially). Rarely, there is well-developed crypt branching (Practice Points 22.3).30, 31




Practice Points 22.3 Amoebiasis and Inflammatory Bowel Disease


Considerations




  • GI amoebiasis can mimic IBD clinically and histologically.



  • Amoebiasis can coexist with IBD.



  • Inappropriate immunosuppression (with IBD drugs) can exacerbate amoebiasis and may precipitate invasiveness.


Histological Features of IBD That May Occur in Amoebiasis




  • Basal plasmacytosis



  • Crypt distortion



  • Prominent crypt branching (rarely)



  • Mucin depletion



  • Paneth cell metaplasia


Features Favouring Amoebiasis over IBD




  • Trophozoites (diagnostic of amoebiasis)




    • Foamy pale cytoplasm



    • Ingested red blood cells



    • Small round or ovoid pale nucleus



    • CD68-negative (distinguishing them from macrophages)




  • Ulceration with necrotic material, mucin, red blood cells, debris



  • Neutrophils in surface epithelium



  • Neutrophils in lamina propria



  • Absence of well-developed chronic features (basal plasmacytosis, crypt changes)


Amoebiasis may coexist with IBD (see Chapter 23). In a report from Turkey (an area with a high prevalence of amoebiasis), there was amoebic infection in almost 10% of patients with UC, compared to 3% of Crohn’s patients and less than 2% of the population.32 Distinction of the histological changes caused by amoebiasis from those caused by IBD is then difficult (Figure 23.7A). Rare reports describe evolution of amoebiasis into IBD.33



Other Infections


Chronic or recurrent Clostridioides difficile infection may occasionally cause crypt architectural changes that can resemble IBD. Schistosomiasis can elicit granulomas around which there may be an inflammatory reaction, but it rarely causes other IBD-like changes (Figure 22.8).





Figure 22.8 Schistosomiasis can cause granulomas, potentially mimicking Crohn’s disease. However, other histological features of IBD are not usually present, and the Schistosomal ova (arrow) are often detectable histologically.


(Courtesy of Dr V. Simanskaite, London, UK.)


Mass Lesion


Mucosal abnormalities similar to those of IBD may occur overlying, or adjacent to, a space-occupying lesion. Diverticular disease is a common cause. Crypt changes and lamina propria chronic inflammation can also be apparent adjacent to or overlying other masses, e.g. primary or secondary carcinoma, endometriosis (see later), and pneumatosis coli (see later).34



Behçet’s Disease


Behçet’s disease is a systemic illness. The diagnosis requires oral ulceration plus any two of the following: genital ulceration; specific lesions of the eye; specific lesions of the skin; and a positive pathergy test (an excessive reaction to minor skin injury). The underlying pathogenesis is an abnormality of blood vessels (vasculitis and lymphocytic phlebitis).8


Lower GI tract involvement by Behçet’s disease is rare and is preferentially ileocaecal. In terms of presentation and response to treatment, it can resemble IBD (particularly Crohn’s disease, given the anatomical location). According to some experts, Behçet’s disease may be a form of Crohn’s disease or IBD, but this is a controversial suggestion. Macroscopically, ulceration is common in Behçet’s disease. Colorectal mucosal microscopic findings are not specific. The most common histological finding in Behçet’s disease is ulceration, which may be severe, with a background of normal or mildly inflamed mucosa.35, 36 Crypt distortion could occur adjacent to ulcerated mucosa. Occasionally, a vasculitis of small veins or venules may be apparent. When compared directly in one study, UC was more likely than Behçet’s disease to show crypt loss, neutrophil polymorphs, and goblet cell mucin depletion.37 Granulomas favour Crohn’s disease over Behçet’s disease and are unusual in the latter. Chronic changes can occur but basal plasmacytosis and crypt distortion (unless adjacent to ulceration) are uncommon (Practice Points 22.4 and Figure 22.9).




Practice Points 22.4 Behçet’s Disease and Inflammatory Bowel Disease


Considerations




  • Behçet’s disease is rare and there is a risk of misdiagnosis as another disease.



  • Behçet’s disease can resemble Crohn’s disease clinically and respond to the same therapy.



  • There may be some overlap between Behçet’s disease and Crohn’s disease, but this is a controversial and difficult area.



  • Ileocolonic Behçet’s disease is impossible to diagnose on histology alone.


Pathological Features of Behçet’s Disease That May Mimic Crohn’s Disease




  • Ileocaecal location



  • Ulceration



  • Crypt distortion (adjacent to ulcers)



  • Transmural chronic inflammation (in resections)


Histological Features That Are Rare in Behçet’s Disease and Help to Favour IBD




  • Basal plasmacytosis



  • Crypt loss



  • Mucin depletion





Figure 22.9 Behçet’s disease of the GI tract is very rare, is preferentially ileocaecal, and may cause ulceration. Lamina propria inflammation and crypt distortion may occur, as in this example, but crypt atrophy, basal plasmacytosis, and significant mucin depletion are rare. Distinction depends mainly on the clinical history.



Radiation Damage


The effects of radiation on the colorectal mucosa can mimic IBD (see Chapter 3). Chronic radiation damage can cause mucosal architectural distortion, and the rectum is often involved. Accordingly, there is the potential for confusion with distal or rectal UC, and particularly with quiescent UC. Fibrosis and vascular ectasia are typical of radiation damage, but UC can also show fibrosis and, less often, vascular ectasia. Basal plasmacytosis is unusual in radiation damage but can occur; furthermore, its absence does not exclude chronic UC (Figures 3.2, 3.4, 3.17, and 3.19). Essentially, a histological diagnosis of radiation proctocolitis requires clinical information.



Ischaemia


Chronic ischaemia may also cause a degree of crypt distortion, potentially mimicking IBD (Figures 6.6 and 22.10) (see also Chapter 6). Typically, ischaemia also causes fibrosis and hyalinisation of the lamina propria that is often more severe than that seen in radiation damage or longstanding IBD. Ischaemia may also cause ulceration, acute inflammation, crypt epithelial cell attenuation, crypt withering, crypt dropout, lamina propria haemorrhage, and haemosiderin-laden macrophages. The upper part of the crypt may show more damage than the crypt base. Basal plasmacytosis is unusual but can occur (Figure 22.10). The other histological features of ischaemia should allow distinction, but the clinical details are also necessary for accurate diagnosis. Patients are typically older than patients with IBD and they often have other clinical evidence of ischaemia, e.g. ischaemic heart disease, peripheral vascular disease, or cerebrovascular accident. Anatomical location of disease at, or around, the splenic flexure is typical of ischaemia and is uncommon in IBD. However, ischaemia can involve any site, including the rectum in isolation or the rectum in addition to other sites.





Figure 22.10 Ischaemic colitis may cause crypt distortion and mucin depletion. Mild basal plasmacytosis is rarely also present, as in this example. Clinical features and other histological changes, e.g. haemorrhage, crypt withering, and fibrosis, should allow distinction from inflammatory bowel disease.



Mucosal Prolapse


Mucosal prolapse syndrome can present as macroscopic prolapse, solitary rectal ulcer, colitis cystica profunda, a rectal polyp, an anorectal (inflammatory cloacogenic) polyp, or various endoscopic mucosal abnormalities (see also Chapter 26).38 Biopsies are most often rectal. Typical histological features include fibrosis; vertical smooth muscle fibres in the lamina propria, that appear to originate in the muscularis mucosae and pass upwards vertically between the crypts; thickening, splaying, and disorganisation of the muscularis mucosae39; crypt architectural abnormalities such as diamond-shaped and angulated crypts;40 surface erosion; and vascular ectasia. Other features include mild inflammation, epithelial mucin depletion, haemorrhage, epithelial serration, and a villous surface. There may be mild epithelial atypia.38, 40 The submucosa may contain misplaced epithelium and may show fibrosis.38, 39


The clinical and/or pathological features of mucosal prolapse may suggest IBD. A clinical history of rectal bleeding (which is quite common in prolapse) together with a biopsy showing crypt distortion, fibrosis, epithelial mucin depletion, regenerative epithelial atypia, and mild inflammation, may misdirect the pathologist and clinician towards an erroneous diagnosis of IBD (Figure 22.11). Rarely, there is a plasma cell-rich lamina propria inflammatory infiltrate including basal plasma cells. Features favouring mucosal prolapse include a polypoid appearance in many cases; the absence of significant lamina propria inflammation; absence of basal plasmacytosis; and the presence of vertical smooth muscle fibres, fibrosis, erosion, epithelial hyperplasia, and characteristic diamond-shaped crypts (Practice Points 22.5).40





Figure 22.11 Mucosal prolapse may resemble longstanding inflammatory bowel disease if there is crypt distortion and fibrosis. Features suggesting mucosal prolapse include diamond-shaped crypts and vascular ectasia, as in this example, and vertical smooth muscle fibres (not readily apparent here).




Practice Points 22.5 Mucosal Prolapse and Inflammatory Bowel Disease


Features of Mucosal Prolapse That May Incorrectly Suggest IBD




  • Crypt distortion



  • Fibrosis



  • Mucin depletion



  • Chronic inflammation (rarely)


Features Supporting a Diagnosis of Mucosal Prolapse




  • Polypoid lesion



  • Diamond-shaped crypts



  • Vertical smooth muscle fibres



  • Surface erosion



  • Vascular ectasia


Other Features That Can Occur in mucosal prolapse




  • Epithelial serration



  • Villous surface



  • Mild epithelial atypia



  • Submucosa: misplaced epithelium and fibrosis



Acute Graft-versus-Host Disease


Graft-versus-host disease (GvHD) (see also Chapter 4) may occur in patients who have had haematopoietic stem cell transplantation or, less commonly, other forms of transplantation such as liver or kidney.41, 42 GvHD may be acute or chronic.


The microscopic feature that points most directly to a diagnosis of acute GvHD, rather than to IBD or other conditions, is a significant increase in crypt epithelial cell apoptoses. However, apoptoses are not specific and can also occur in drug-induced colitides, infection, and IBD.4143 In IBD, an increase in apoptotic bodies can be seen in untreated disease (mean count, 2.4 per 100 crypts compared to 0.94 in normal mucosa) (Figure 21.10) although higher numbers may occur in post-treatment IBD if the mucosa remains inflamed (mean count, 13.1). IBD in remission has an apoptosis count similar to that of normal mucosa (1.4 per 100 crypts).43 Therefore, the presence of increased apoptoses alone may not be reliably discriminant. In the setting of suspected GVHD, a count of more than 6 apoptoses per 10 contiguous crypts may support a diagnosis of GvHD.41


Acute GvHD shares some other features with IBD but rarely resembles it closely (Table 22.2). Crypt loss or ‘dropout’ leads to wider spaces between crypts and may affect contiguous crypts (Figure 22.12A),42 and crypt distortion may also occur. However, basal plasmacytosis is not usually a feature.41, 44 Indeed, the lamina propria inflammatory infiltrate is not usually intense or plasma cell-rich and is often mainly lymphocytic, with or without neutrophils and eosinophils (Figure 4.6). Paneth cell metaplasia, a characteristic feature of IBD, can also occur in GvHD (Figure 22.12B).45


Sep 2, 2020 | Posted by in GASTROENTEROLOGY | Comments Off on Chapter 22 – Mimics of Inflammatory Bowel Disease
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