INFLAMMATORY BOWEL DISEASE - PART 10 doc

There are additional histologic features which, while not diagnostic,can be helpful in favoring a diagnosis of either ulcerative colitis orCrohn’s colitis.. Unfortunately there is consid

Fig 4 Ulcerative colitis (A) Low-power view demonstrating mild crypt

archi-tectural distortion, basal lymphoplasmacytic infiltrates, and diffuse

neutro-philic infiltrates (B) (Opposite page) High-power of the same biopsy revealing

a granuloma adjacent to a ruptured crypt.

Transmural disease is another characteristic feature of Crohn’s ease, but of course this feature cannot be assessed in endoscopic biopsyspecimens Inflammation can extend into the submucosa (or evendeeper) in active ulcerative colitis, so the presence of inflammatory cells

dis-in the superficial portion of submucosa sometimes dis-included dis-in a biopsyspecimen cannot automatically be assumed to be diagnostic of Crohn’sdisease However, in ulcerative colitis, the inflammation of the overly-ing mucosa is always more severe than that of the submucosa There-fore, a biopsy that exhibits marked inflammation of the superficialsubmucosa, with relatively little active inflammation in the overlyingmucosa, would suggest a diagnosis of Crohn’s colitis

There are additional histologic features which, while not diagnostic,can be helpful in favoring a diagnosis of either ulcerative colitis orCrohn’s colitis For instance, the degree of crypt architectural distortiontends to be greater in ulcerative colitis Thus, biopsies from ulcerativecolitis patients often reveal significant mucosal atrophy with numerousbranched crypts and marked alteration of the normal parallel arrange-ment of the crypts Biopsies from patients with Crohn’s colitis, in con-trast, may exhibit only mild crypt architectural distortion with relatively

Fig 5 Early Crohn’s colitis (A) Low-power view showing a lymphoid licle (B) High-power of the same biopsy reveals an early aphthous erosion,

fol-with focal neutrophilic infiltrate directly over the lymphoid follicle.

little atrophy Moreover, biopsies from patents with active ulcerativecolitis usually exhibit significant depletion of the normal mucin content

of the crypt epithelial cells, while the mucin is often relatively preserved

in active Crohn’s disease (7) Unfortunately there is considerable

over-lap in these features in biopsies from ulcerative colitis and Crohn’scolitis patients, and their assessment is also subjective

One can also take advantage of the fact that Crohn’s disease can affectany portion of the gastrointestinal tract, while ulcerative colitis is essen-tially limited to the colon Biopsies of the terminal ileum may revealsignificant ileitis in some patients with Crohn’s disease The histologicfeatures of Crohn’s ileitis are essentially identical to those evident incolonic biopsies (Fig 6) Although some ulcerative colitis patients withpancolitis may exhibit so-called “backwash ileitis,” histologic assess-ment usually can allow distinction from Crohn’s ileitis Backwash ile-itis generally consists only of scattered neutrophils in the lamina propriaand surface epithelium, with relative preservation of the mucosal archi-tecture In Crohn’s ileitis there is usually marked distortion of normalvillous architecture at least focally, and the degree of active inflamma-tion is often greater as well Of course biopsies of the upper gastrointes-tinal tract may also be quite helpful in making a diagnosis of Crohn’sdisease if involvement can be documented Even biopsies of endoscopi-cally normal mucosa can reveal evidence of Crohn’s disease (e.g., granu-lomas and focal inflammatory cell infiltrates)

Histologic Distinction Between IBD

and Other Forms of Colitis

The histologic features of a number of other forms of colitis canoverlap with those described previously for IBD Definitive distinctionusually requires correlation with the clinical history, laboratory testresults and colonoscopic features Depending on the amount of thisclinical data made available to the pathologist, a firm histologic diagno-sis of IBD may be possible in some cases, while in others only a differ-ential diagnosis can be given The histologic appearance of each form

of colitis is discussed in the following, emphasizing features most useful

in differentiating from IBD

Histologi-Fig 6 Crohn’s ileitis There is prominent distortion of normal villous architecture.

features are quite similar to those of IBD, although in infectious colitisthe neutrophilic infiltrates tend to be more superficial (Fig 7) The keyfeatures in terms of distinction from IBD are the maintenance of normalcrypt architecture and the lack of a basal lymphoplasmacytic infiltrate

(6,8,9) However, these two histologic findings are difficult to assess in

poorly oriented biopsies The inflammatory changes in infectious colitismay be patchy or diffuse, so this diagnosis must be considered in thedifferential with both ulcerative colitis and Crohn’s colitis Gram stainsperformed on biopsy specimens are not useful since luminal bacteria areabundant in health Instead, confirmation of the diagnosis requires apositive stool culture, which is obtained in only a minority of cases.Without a positive stool culture, presumptive diagnosis rests on the self-limited clinical course or the resolution of symptoms with antibiotictherapy

Colitis owing to E coli O:157H7 infection is histologically more

distinctive, most often being right-sided and prominently hemorrhagic.Severe cases may be transmural and can be clinically confused with

Crohn’s disease Stool cultures must be specifically sent for E coli O:157H7 and may be negative unless obtained soon after the onset of symptoms (10,11) Colitis owing to Entamoeba histolytica infection

is often segmental and may be transmural, closely simulating Crohn’s

disease clinically (12) Stool ova and pararsites (O & P) examination

is usually diagnostic, although multiple specimens may need to beexamined If colon biopsies are obtained from the edge of an ulcer, thetrophozoites can be seen within acute inflammatory cell exudate ornecrotic debris, and highlighted with a PAS stain Clinical suspicion of

E histolytica infection should be reported to the surgical pathologist so

that a special effort is made to find the organism, which may be sparse

I SCHEMIC C OLITIS

While histologically distinctive, acute ischemic colitis may cally and colonoscopically be confused with IBD When patchy, par-ticularly if focal ulceration develops, ischemic colitis can resembleCrohn’s colitis Segmental left-sided ischemic colitis has been described

clini-in young women and has been associated with the use of oral

contracep-tives (13) Ischemia may not be considered clinically in these patients

because of their young age and atypical disease distribution nately the histologic features of acute ischemic colitis are quite charac-teristic There are only very minimal neutrophilic infiltrates, limited toareas of erosion or ulceration, and lymphoplasmacytic infiltrates are

Fortu-Fig 7 Infectious colitis Normal crypt architecture is well maintained tered neutrophils are evident within the superficial lamina propria A stool

Scat-culture grew Campylobacter jejuni.

never present Ischemia preferentially produces damage to the cial portion of the mucosa, a pattern not seen in IBD Hemorrhage anddeposits of proteinaceous material within the lamina propria are alsocharacteristic of acute ischemia and are not seen in IBD (Fig 8).Chronic ischemic colitis can result in focal ulceration or strictureformation, which can clinically and endoscopically resemble Crohn’sdisease Again, ischemia may not be considered clinically because awatershed zone may not be affected Ischemia owing to thrombosis,emboli, or vasculitis can involve any colonic segment, including so-called protected zones like the cecum and rectum Biopsies will revealsignificant crypt architectural distortion, similar to that seen in IBD, butwill also demonstrate prominent lamina propria fibrosis In addition, theneutrophilic and lymphoplasmacytic infiltrates typical of untreated IBDare never present in chronic ischemic colitis Nonetheless, focal ulcer-ation owing to chronic ischemia is sometimes misdiagnosed as Crohn’sdisease by the unwary pathologist and clinician This is particularly true

superfi-in cases with cecal superfi-involvement (solitary cecal ulceration), whereischemia may be one of several contributing factors (along with uremia,CMV infection, and/or drug toxicity)

Fig 8 Acute ischemic colitis Normal crypt architecture is maintained, although detachment of the surface epithelium and withering of the superficial portions of the crypts is evident Also note the lack of significant inflammatory cell infil- trates and the deposition of pinkish proteinaceous material in the lamina propria.

NSAID C OLITIS

The diagnosis of NSAID colitis is often not considered by either theclinician or pathologist Patients may not be forthcoming regardingtheir usage of NSAIDs, and the endoscopist may not directly ask aboutthese agents The histologic features of NSAID colitis have not beencompletely documented, and some pathologists may not consider thepossibility, particularly if a history of NSAID use is not mentioned in thepathology requisition form Chronic NSAID use can result in the forma-tion of a focal ulcer or stricture, and therefore a diagnosis of Crohn’s

colitis might be entertained (14) NSAIDs can also produce diffuse mild

colitis, which can be confused with ulcerative colitis colonoscopically

(15,16) Histologic examination reveals mild neutrophilic infiltrates,

but maintenance of normal crypt architecture and an absence of alymphoplasmacytic infiltrate in the lamina propria, ruling out IBD Inaddition, there may be a patchy thickening of the subepithelial collagenlayer, similar to that seen in collagenous colitis However, the absence

of a significant increase in intra-epithelial lymphocytes, the presence ofcolitis colonoscopically, and the absence of a history of chronic waterydiarrhea eliminates collagenous colitis as diagnostic consideration

O THER F ORMS OF C OLITIS

Chronic radiation colitis and chronic graft vs host disease both duce crypt architectural distortion and therefore could be theoretical inhistologic differential diagnosis of treated IBD The clinical historywould obviously be important in these cases, and there are other histo-logic features of these conditions that are helpful in arriving at the cor-rect diagnosis Drugs other than NSAIDs can rarely cause colitis andmust be considered in problematic cases Distal colitis can also be pro-duced factitciously by the instillation of toxic agents via enema

pro-FULMINANT IBD AND INDETERMINANT IBD

Although a more common complication of ulcerative colitis, nant colitis and toxic megacolon can also occur in Crohn’s disease or as

fulmi-a complicfulmi-ation of vfulmi-arious infections (Shigellfulmi-a, Sfulmi-almonellfulmi-a, Cfulmi-ampylobfulmi-acter, and Clostridium) (3) Unfortunately, many of the histologic features

characteristic of either ulcerative colitis or Crohn’s disease cannot beevaluated because of the presence of very severe inflammation andnecrosis Typically a colon affected by fulminant colitis exhibitsconfluent areas of deep ulceration The remaining mucosa is severelycongested, friable, and hemorrhagic Ulceration often extends into themuscularis propria and sections from these areas may show inflamma-

tory cells extending into the serosa This transmural inflammation ismerely a reflection of the severity of the acute disease and should not byitself prompt a diagnosis of Crohn’s colitis On the other hand, lymphoidaggregates in the muscularis propria or serosal tissues away from areas

of deep ulceration are consistent with Crohn’s colitis Often in cases offulminant ulcerative colitis, the mucosa of the rectum is grossly lessaffected in comparison with the sigmoid area, leading to a false impres-sion of Crohn’s colitis However, histologic sections will show cryptarchitectural distortion, consistent with involvement by ulcerative coli-tis In some cases, a diagnosis of indeterminate colitis must be rendered

if no specific features of ulcerative colitis or Crohn’s disease can berecognized Of course, if the patient has a firm history of either ulcer-ative colitis or Crohn’s colitis before the onset of the fulminant episode,then there is no reason to change the diagnosis to indeterminate colitisfor the colectomy specimen The problematic situation arises only inpatients in whom an established diagnosis has not already been made.Considerable confusion regarding the term indeterminate colitis hasdeveloped because it has been used in several different clinical andpathologic contexts Endoscopists sometimes use the term when thefindings observed are not specific for either ulcerative colitis or Crohn’scolitis Likewise, some pathologists use the term when the histologicfeatures present in biopsy specimens do not allow clear distinctionbetween the two diseases It is probably best to restrict the term to thosecases in which it is impossible to distinguish between ulcerative colitisand Crohn’s disease, despite examination of a colectomy specimen (in

a patient without a firm pre-operative diagnosis)

ATYPICAL HISTOLOGIC FEATURES

(17) Histologic sections from these endoscopically abnormal patches

reveal changes typical of mildly active ulcerative colitis, with cryptarchitectural distortion and mild mixed inflammatory cell infiltrates Itshould be remembered, however, that cecal biopsies normally containmore intense lamina propria inflammatory cell infiltrates than are

present in biopsies from other parts of the colon In fact, rare neutrophilsmay even be present normally in cecal mucosa.

The possibility of patchy disease involvement in ulcerative colitishas already been mentioned It is now well-documented that intensivemedical therapy for symptomatic ulcerative colitis can lead to patchyhealing, resulting in an endoscopic impression of skip areas Biopsiesfrom these endoscopically normal regions, which can include the rec-tum, may reveal no disease activity, but in most cases crypt architecturaldistortion is still evident, indicating prior disease involvement In rarecases, the distortion of crypt architecture may be very subtle or simply not

apparent (18) There are also cases in which skip areas of normal mucosa

are definitely present from the onset (typically a segment in the transverse

or descending colon), and yet all other clinical and histologic features areconsistent with the diagnosis of ulcerative colitis The clinical course insuch a patient is almost always that of typical ulcerative colitis

DYSPLASIA IN IBD

The identification of dysplasia is one of the most important tasks ofthe pathologist in evaluating colonic biopsies from patients with IBD.Dysplasia is defined as an unequivocal neoplastic change in the colonicepithelium, without invasion past the basement membrane This prema-lignant change has been shown to be a useful marker of a high risk forthe presence or development of invasive adenocarcinoma, and is thebasis of surveillance colonoscopy programs The diagnostic criteria forthe diagnosis of dysplasia were established by an international group ofexpert pathologists who blindly reviewed a collection of slides showing

a range of reactive and dysplastic changes (19) The panel recognized

that significant interobserver and intraobserver variation was able, particularly in the distinction of low grade dysplasia from reactivechanges that closely resemble dysplasia The problem of interobservervariability in the diagnosis of dysplasia has in fact been confirmed in

unavoid-other studies (20–22).

A variety of technical problems can hinder the ability of pathologists

to make a reproducible diagnosis of dysplasia Small, crushed, andpoorly oriented biopsies are obviously difficult to interpret Poor fixa-tion, sectioning, and staining of the biopsies compounds the difficulty

In addition, the presence of marked active inflammation and/or ation produces cytologic alterations that closely simulate those seen indysplasia Even if large, well-oriented, and properly handled biopsiesare obtained and prepared, there are still a variety of interpretational

ulcer-obstacles that prevent a high degree of precision and accuracy in thediagnosis of dysplasia Dysplasia represents a biologic continuum whichhas been arbitrarily divided into low-grade and high-grade categories,and there will always be biopsies with features that fall at the dividingpoints between them Some pathologists have little experience in diag-nosing IBD-associated dysplasia, and therefore may be relatively unfa-miliar with the fine points of the grading scheme Also, in some biopsiesthere may be discordance between the cytologic and architectural fea-tures of dysplasia, or the focus of dysplasia may be extremely small.Clear-cut criteria for proper grading in these circumstances have not beenagreed upon For these reasons, consultation from an expert gastrointes-tinal pathologist is recommended in difficult cases and in cases where amanagement decision will be made based on the histologic diagnosis.Although a variety of more objective markers for the diagnosis of dys-plasia have been studied (e.g., flow cytometry for DNA ploidy and immu-nohistochemistry for Ki-67 and p53 protein), these techniques are not widelyavailable and have not been well validated There are also a variety of

technical and interpretative problems with these techniques (23,24).

The light microscopic diagnosis of dysplasia rests on a combination

of cytologic and architectural criteria, and the grade of dysplasia isjudged based on the severity of the cytologic and architectural abnor-

mality (19) Cytologic features of dysplasia include: increased nuclear

cytoplasmic ratio, nuclear hyperchromasia, and nuclear pleomorphism.Unfortunately these changes are similar in many respects to those ofreactive atypia caused by the presence of active inflammation Archi-tectural features, which are less affected by the presence of neutrophilicinfiltrates, include loss of normal cell and nuclear polarity, crowding ofglandular profiles, and the presence of cribiforming (back-to-backglands without intervening lamina propria) One key feature of dyspla-sia is the extension of abnormal cytologic changes from the deep aspects

of the crypts all the way to the surface epithelium (Figs 9 and 10).Optimal evaluation for the presence of this feature naturally requiresproper biopsy orientation One common situation leading to a diagnosis

of “indefinite for dysplasia” is the presence of mild cytologic atypia inthe deep aspects of the crypts, but without visible extension of thesechanges to the surface epithelium

In many cases dysplasia is diagnosed in a random biopsy of mucosawith no distinctive endoscopic appearance Dysplasia in a biopsy from

an endoscopically recognizable lesion or mass (DALM) is of particular

concern because the incidence of invasive tumor is much higher (25).

Foci of IBD-associated dysplasia that are recognizable grossly are ally described as plaque-like areas of velvety mucosa Recently there

usu-Fig 9 Ulcerative colitis with low grade dysplasia Compare the cytologic features of the non-dysplastic epithelium in the lower portion of the biopsy with the dysplastic epithelium above it Note that the dysplastic changes extend

to the surface epithelium at the top of the biopsy.

has been great interest in molecular markers that might allow betterdistinction between DALMs and sporadic adenomas (unrelated to theunderlying history of IBD) Traditionally these two types of lesionshave been separated based on clinical criteria, since there are no reliablelight microscopic features that distinguish the adenomatous (dysplas-tic) epithelium of a sporadic adenoma from the adenomatous (dysplas-tic) epithelium of a DALM Clinical findings considered to favor adiagnosis of DALM over sporadic adenoma include: age under 40–45 yr,location in a colonic segment affected by IBD, an atypical endoscopicappearance, and the presence of dysplasia in surrounding flat mucosa.Molecular techniques have been used by various investigators to ana-lyze expression of p53, β-catenin, bcl-2, and loss of heterozygosity for

p16 and at chromosomes 3p in sporadic adenomas and DALMs (26–29).

Significant differences in the expression of these markers have beendocumented, supporting the contention that both types of lesions mayexist in the colons of IBD patients Unfortunately, there is considerable

overlap in the incidence of abnormal expression of these markers, ing them unsuitable for use in routine clinical practice.

mak-PRACTICAL ENDOSCOPY GUIDELINES

As mentioned in the introductory comments for this chapter, optimalevaluation of endoscopic biopsies from IBD patients is greatly aided byclose interaction between the endoscopist and surgical pathologist Aconcise and focused summary of the patient’s clinical history and a copy

of the endoscopic report (or summary of the pertinent findings) canallow the pathologist to move from a purely descriptive report to onethat includes an interpretation and often a definitive diagnosis Orien-tation of endoscopic biopsies can be very helpful if done properly.Orientation is best performed by the endoscopist or nurse since biopsiesare difficult to orient once they have been placed in fixative Orientedbiopsies can be placed on any number of substrates, including milliporefilter paper or plain paper towel The larger the biopsy, the easier it is toorient properly A dissecting microscopy might be helpful at the outsetfor training purposes, but its use is time-consuming and unnecessary

Fig 10 Ulcerative colitis with high grade dysplasia There is a greater degree

of cytologic atypia in this biopsy that is evident in Fig 9 The nuclei are greatly enlarged and have very irregular contours There is also a loss of normal nuclear polarity.

once experience is gained Training and feedback from the pathologist

on proper orientation technique is very helpful Proper fixation is alsocritical to optimal histologic evaluation, but any standard fixative can beused (Formalin is most commonly used.) It is important that the biopsy

is immediately placed in the fixative and not allowed to dry out Thebiopsy container should be nearly filled with fixative to ensure that if it

is tipped on its side during transport the biopsy remains submerged.There are a number of indications for colonoscopy in IBD patients,including:

• Initial diagnosis of IBD (ulcerative colitis or Crohn’s disease)

• Confirmation of the diagnosis of ulcerative colitis or Crohn’s disease

• Evaluation of the extent and severity of IBD

• Re-evaluation of the histologic diagnosis of ulcerative colitis orCrohn’s disease after new or conflicting clinical data is obtained

• Surveillance for IBD-associated dysplasia

The specific steps the endoscopist can take to aid the surgicalpathologist depend on which of the above indications pertains to thepatient being evaluated These are outlined separately in the followingdiscussion The endoscopist should clearly state which of these indica-tions the colonoscopy is performed for, and can ask that specific issues

be addressed by the pathologist in the report

Initial Diagnosis of IBD

The initial endoscopy in a patient with suspected IBD is critical todetermine the correct diagnosis, since the patient is unlikely to havereceived medical therapy that might influence the histologic appear-ance The differential diagnosis usually includes infectious (bacterial)colitis, and the histologic distinction depends mainly on the cryptarchitecture and presence of a basal lymphoplasmacytic infiltrate Evalu-ation of these two features depends to a large extent on the orientation

of the biopsies, so multiple biopsies should be obtained to ensure that atleast some of them are properly oriented Multiple biopsies also increasethe likelihood that a granuloma will be identified, leading to a specificdiagnosis of Crohn’s colitis If the colitis is patchy, then biopsies fromaffected and normal mucosa should be placed in separate containers thatare labeled with the anatomic site Biopsies from normal mucosa abovethe proximal extent of endoscopically evident colitis are also helpful forhistologic verification of the extent of disease involvement These biop-sies should also be placed in a separate container labeled with the ana-tomic site If a colonoscopy is being performed, biopsies of the terminalileum should be obtained if possible

Confirmation of the Diagnosis

of Ulcerative Colitis or Crohn’s Disease

In this circumstance, the patient is likely to have received medicaltherapy for IBD, which can alter the histologic appearance of the biop-sies (e.g., producing patchy healing) Submission of slides from anyprevious endoscopy performed at an outside institution can be veryvaluable to the pathologist in interpretation of the current material.Biopsies should be submitted in a manner similar to that discussedpreviously for the initial diagnosis of IBD

Evaluation of the Extent and Severity of IBD

In this situation, the diagnosis of either ulcerative colitis or Crohn’sdisease has already been established Biopsies from the involvedsegment(s) of colon can be submitted together in a single container.Biopsies from normal segments should be submitted separately so thatthe histologic extent of disease can be accurately determined Biopsiesfrom the cecum and ascending colon should be placed in a separatecontainer labeled as such because mucosa from these sites normallycontain scattered Paneth cells, while their presence in more distal colonicbiopsies is indicative of IBD Ileal biopsies can also be placed in thiscontainer unless there is active disease in both the cecum/ascendingcolon and ileum In that case, the ileal biopsies may exhibit ulcerationand/or severe villous blunting to the point where they can be confusedwith biopsies of colonic origin Likewise, colonic biopsies may exhibit

a villiform metaplasia that creates a resemblance with ileal mucosa

Re-evaluation of the Diagnosis

of Ulcerative Colitis or Crohn’s Disease

In some patients, new clinical findings may lead to a reconsideration

of an established diagnosis of either ulcerative colitis or Crohn’s colitis.For instance, a patient carrying a diagnosis of ulcerative colitis maydevelop perianal skin tags or a fistula It is also possible that during aroutine colonoscopy to document the extent or severity of disease atypi-cal endoscopic features are unexpectently discovered (e.g., aphthous-type ulcers in an ulcerative colitis patient) In these types of circumstances,the patient may very well be receiving medical therapy, which canalter the histologic appearance The list of current medications should

be made available to the surgical pathologist, as well as slides from anyprevious endoscopy performed at outside institutions The new clinical

or endoscopic data that has put the established diagnosis in doubt shouldalso be concisely communicated It is critical that biopsies from normal

and affected areas in placed in separately designated containers Ilealbiopsies should be performed if possible.

Surveillance for Dysplasia in IBD Patients

Various proposals have been made regarding the minimum number

of biopsies obtained during surveillance colonoscopy, but no standardhas been accepted nationally If significant active colitis is evident at thetime of colonoscopy, biopsies should be postponed until after a trial ofmedical therapy Some pathologists may not be comfortable diagnosingdysplasia in the face of active inflammation (because of possible con-fusion with reactive atypia), and a diagnosis of “indefinite for dyspla-sia” is made much more often in this situation than in patients withquiescent disease

Biopsies of polyps and possible DALMs should be placed in separatecontainers labeled to anatomic site Biopsies of the mucosa surroundingthe lesion should be placed in another labeled container These biopsiesare helpful in documenting whether the lesion, if adenomatous, is aris-ing in a background of normal mucosa (which supports a diagnosis ofsporadic adenoma) or of IBD (which favors a diagnosis of IBD-associ-ated dysplasia)

Random biopsies can be placed in separate containers by level (e.g.,

90 cm, 80 cm, 70 cm, etc.) or grouped into regions (e.g., right colon, leftcolon, rectosigmoid), depending on institutional preference In Crohn’sdisease patients, it may be possible to perform a right hemicolectomy ifthe random biopsy with dysplasia is known to be from the proximalcolon Also, knowledge of the site of origin of a random biopsy diag-nosed as “indefinite for dysplasia” would allow numerous follow-upbiopsies to be obtained from that same segment of the colon

ACKNOWLEDGMENT

Color photographs provided through an unrestricted educational grantfrom Procter & Gamble Pharmaceuticals, as well as grants from Shire USInc., Prometheus Laboratories Inc., and Salix Pharmaceuticals Inc

REFERENCES

1 Riddell RH Pathology of Idiopathic Inflammatory Bowel Disease In: tory Bowel Disease (4th ed) (Kirsner JB and Sorter RG, eds), 1995 Williams & Wilkins, Baltimore, pp 517–552.

Inflamma-2 Lewin KJ, Riddell RH, Weinstein WM Inflammatory bowel Diseases In: trointestinal Pathology and Its Clinical Implications 1992 Igaku-Shoin, New York, pp 812–989.

Gas-3 Whitehead R (ed) Gastrointestinal and Oesphageal Pathology (2nd ed) Churchill Livingstone: New York, 1995, pp 589–632.

4 Surawicz CM, Belic L Rectal biopsy helps distinguish acute self limited colitis from idiopathic inflammatory bowel disease Gastroenterology 1984;86:104–113.

5 Nostrant TT, Kumar NB, Appelman HD Histopathology differentiates acute limited colitis from ulcerative colitis Gastroenterology 1987;92:318–328.

self-6 Schumacher G, Sandstedt B, Kollberg B A prospective study of first attacks of inflammatory bowel disease and infectious colitis Scand J Gastroenterol 1994;29:265–274.

7 Tanaka M Riddell RH, Saito H, Soma Y, Hidaka H, Kudo H Morphologic criteria applicable to biopsy specimens for effective distinction of inflammatory bowel disease from other forms of colitis and of Crohn’s disease from ulcerative colitis Scand J Gastroenterol 1999;34:55–67.

8 Kleer CG, Appelman HD Ulcerative colitis: pattern of involvement in colorectal biopsies and changes with time Am J Surg Pathol 1998;22:983–989.

9 Schumacher G, Kolberg B, Sandstedt B A prospective study of first attacks of inflammatory bowel disease and infectious colitis Histologic course during the

1 st year after presentation Scand J Gastroenterol 1994;29:318–332.

10 Griffin PM, Olmstead LC, Petras RE Escherichia coli O157:H7-associated colitis:

a clinical and histological study of 11 cases Gastroenterology 1990;99:142–149.

11 Ilnyckyj A, Greenberg H, Berstein CN Escherichia coli O157:H7 infection icking Crohn’s disease Gastroenterology 1997;112:995–999.

mim-12 Ellyson JH, Bezmalinovic Z, Parks SN, Lewis Jr FR Necrotizing amebic colitis:

a frequently fatal complication Amer J Surg 1986;152:21–26.

13 Deana DG, Dean PJ Reversible ischemic colitis in young women: association with oral contraceptive use Am J Surg Pathol 1995;19:454–462.

14 Gargot D, Chaussade S, d’Alteroche L, et al Non-steroidal anti-inflammatory induced colonic strictures: two cases and literature review Am J Gastroenterol 1995;90:2035–2038.

drug-15 Bjarnason I, Hayllar J, Macpherson AJ, Russell AS Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans Gastroenter- ology 1993;104:1832–1847.

16 Davies NM Toxicity of nonsteroidal anti-inflammatory drugs in the large tine Dis Colon Rectum 1995;38:1311–1321.

intes-17 D’Haens G, Geboes K, Peeters M, Baert F, Ectors N, Rutgeerts P Patchy cecal inflammation associated with distal ulcerative colitis: a prospective endoscopic study Am J Gastroenterol 1997;8:1275–1279.

18 Kim B, Barnett JL, Kleer CG Appelman HD Endoscopic and histological ness in treated ulcerative colitis Amer J Gastroenterol 1999;94:3258–3262.

patchi-19 Riddell RH, Goldman H, Ransohoff DF, et al Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications Hum Pathol 1983;14:931–968.

20 Dixon MF, Brown LJ, Gilmour HM, et al Observer variation in the assessment

of dysplasia in ulcerative colitis Histopathology 1988;13:385–397.

21 Melville DM, Jass JR, Morson BC, et al Observer study of the grading of sia in ulcerative colitis: comparison with clinical outcome Human Pathol 1989;20:1008–1014.

dyspla-22 Eaden J, Abrams K, McKay H, et al Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative coli- tis J Pathol 2001;194:152–157.

23 Löfberg R, Broström O, Karlen P, et al DNA aneuploidy in ulcerative colitis: reproducibility, topographic distribution, and relation to dysplasia Gastroenter- ology 1992;102:1149–1154.