N.Y. Haboubi (�) • M.N. Safarani • F. GhafarDepartment of Surgical PathologyTrafford Healthcare NHS TrustMoorside RoadDavyhulme, Manchester M41 52L, UKE-mail: najibhaboubi@hotmail.com

N.M. ShaathDepartment of GastroenterologyRoyal InfirmaryManchester, UK

Introduction

A significant proportion of colonic biopsies in inflamma-tory conditions are not diagnostic on their own, yet histo-pathologists are still expected to deliver a definitive diag-nosis on biopsies which often are not accompanied by ade-quate clinical information. Accurate histological diagnosisand subsequently making an appropriate managementdecision require many interdependent factors such as (i)adequate clinical information for the histopathologist, (ii)standardised definitions of histopathological terms (termi-nology), and (iii) maintenance of communication betweenthe clinician and the histopathologist (multidisciplinarymeetings).

Adequate clinical information for the histopathologist

To give a meaningful pathology report, full clinical, micro-biological, endoscopic and radiological information shouldbe provided to the histopathologist. A large number of stu-dies has shown that without this information, the histopa-thologist is not able to reach the correct diagnosis [1, 2]. Ina previous study [3], our group advocated that the clinicalinformation should include:1. Duration of illness. This is of paramount importance

because the presence of clinical colitis for more than afew weeks is a strong indication of chronic disease evenin the absence of histological features of chronicity.

2. Microbiological examination of the stool. While it hasbeen suggested that at least some cases of inflammato-ry bowel disease (IBD) are initiated by bacteria [4],some others may be superimposed by infection, andwhen there are definite features of chronicity the pres-ence of cultured pathogens becomes important as itmay not indicate a spontaneous flare-up of the disease.Also, in some cases of ulcerative colitis, the flare-up is

N.Y. Haboubi • N.M. Shaath • M.N. Safarani • F. Ghafar

Improved diagnostic accuracy of inflammatory bowel disease:a clinicopathological collaborative approach

Received: 28 August 2003 / Accepted: 21 January 2004

P AT H O L O G Y C O R N E R

Abstract Although colonic biopsies have become a majorsource of information to the clinician investigating casesof inflammatory bowel diseases (IBD), there are still somedifficulties in making definitive diagnoses. This articlelooks into these challenges and possible ways of dealingwith them. We strongly recommend supplying the pathol-ogist with full clinical, radiological and endoscopic infor-mation with the request form. The pathologist may thenissue a preliminary working report, while the final reportshould be reached at the much needed regular clinico-pathological conference.

Key words Colonic biopsies • Diagnosis • Inflammatorybowel disease

Tech Coloproctol (2004) 8:117–121DOI 10.1007/s10151-004-0070-8 © Springer-Verlag 2004

due to superimposed cytomegalovirus infection [5].Both the clinician and the pathologist should be awareof this possibility.

3. Endoscopic findings. The pathologist should haveimmediate access to the endoscopy report [1]. In fact,the visual macroscopic appearance may on occasiongive a better idea of the colonic disease in cases suchas pseudomembranous colitis (PMC). The procedurealso give an indication whether the distribution ofinflammation is patchy or continuous.

4. Radiological features. These give information on thestate of the small intestine and on the extent and distri-bution of colonic disease.Endoscopists should submit the biopsies separately and

label them according to the site. These biopsies should ide-ally be placed on a piece of filter paper, submucosa face-down and placed in fixative. Best biopsies should includesubmucosa. Granulomas often appear in the submucosa incases of Crohn’s disease (CD). In our department, 3–6 sec-tions are cut routinely from each biopsy to maximise theyield of granulomas and have a better chance of examiningwell-oriented levels.

Disease activity and implication of therapy

Treatment can modify microscopic disease activity in bothulcerative colitis (UC) and CD [6, 7]. In UC, in general, mildor moderate improvement of disease activity is obtained with5-aminosalicylic acid (5-ASA) and with systemic or non-systemic steroids; in active distal UC, budesonide enemas(31.25 mg/100 ml) after 2 and 4 weeks are effective [8]. Forother drugs, such as a leukotriene biosynthesis inhibitor, themicroscopic improvement was less impressive, correlatingwell with the clinical impression [9, 10].

It is well recognised that clinical and endoscopicimprovement after treatment can occur rapidly in UC. Incontrast, histological improvement usually takes longer.This is partly explained by the persistence of architecturalabnormalities and chronic inflammation. A similar evolu-tion is noted in H. pylori-related gastritis, where neu-trophils disappear within weeks following successful erad-ication of the organisms, while chronic inflammation canpersist for months and decreases only gradually [11]. InUC, persistent microscopic evidence of inflammation iscommon in patients with sigmoidoscopically quiescentcolitis [12, 13]. In general, the visual correlation betweenendoscopy and histology is better for active than inactivedisease [14, 15] so much that endoscopy is used for stag-ing disease activity in UC. In CD, endoscopy was superiorto mucosal biopsies [16]. Furthermore, it is important tonote that some studies reported discontinuous inflamma-tion in resolving and long-standing UC [17–19].Histological study can add valuable information for dis-

118

ease activity assessment, as relapses are more frequent inpatients with persistent active inflammation [20].

In this background, it is crucial for the histopathologistto be aware of the timing of biopsies in relation to theonset of current clinical activity of the disease and whetherthe patient has received or is receiving therapy. However,the picture is further complicated when we take into con-sideration variations to patients’ responses to variousforms of treatment.

The pathologist must realise that there are mimics ofchronic IBD. Chronic-phase radiation damage is one ofthem [21]. Other differential diagnoses include ischaemiaileal pouch mucosa after restorative proctocolectomy,pseudomembranous, obstructive, diversion, collagenousand infective colitides, specially due to immunosuppres-sion [22].

Terminology

When the clinician and the pathologist work as a team,histopathological terms must be understood by the clini-cian to allow proper understanding of the report. In ourinstitution, the histopathological terms include [3]: (i) Diffuse versus focal

- Diffuse inflammation is defined when most of thesingle biopsy or all fragments from one anatomicalregion are inflamed.

- Focal inflammation is defined when only part of asingle biopsy is inflamed or, in cases of severalfragments from one anatomical region, some areinflamed and others are normal.

(ii) Active versus chronic - Active inflammation is defined when there is infil-

tration of neutrophils in the surface epithelium,crypts, or lamina propria with or without formationof crypt abscesses. In the setting of IBD, cryptabscesses have no diagnostic value.

- Chronic inflammation is defined when there is one ormore of the following features of chronicity: cryptdistortion, villous configuration of the epithelial sur-face, Paneth’s cell, ulcer-associated lineage cell meta-plasia and the condensation of lymphocytes and plas-ma cells in the deeper part of the lamina propria.

(iii) Continuous or discontinuous- Continuous is defined when biopsies from consecu-

tive regions starting from the rectum are abnormal.- Discontinuous is defined when at least one of a

series of biopsies from one anatomical site is normalbut proximal and distal biopsies are abnormal. Thisfeature in our hands excludes ulcerative colitis.

(iv) Presence or absence of granuloma [3, 23]. Granulomasbecome diagnostic of Crohn’s disease only when theyare well-formed, of the sarcoid type and observed in the

N.Y. Haboubi et al.: Diagnostic accuracy of IBD

Trafford Healthcare NHS Trust Department of Histopathology

Surname: Forename: Sex: Date of birth:Consultant: GP: Source: Case note no:Pathologist: Lab number: Copy for:

V Disease history

Total duration: ——————————— days/months

Duration type: Persistent � Remittent �Previous biopsy: Yes � No �Treatment:

- Surgery:

- Radiotherapy:

- Chemotherapy:

- Medicines:

- Other:

VI Additional information (if appropriate)

� Other disease(s) present� Previous gastrointestinal surgery� Familial history

VII Clinical impression: …………………………………

Differential diagnoses:i)ii)iii)

VIII Microscopy

Focal � Continuous � Discontinuous �

Activity: Absent � Mild � Moderate � Severe �

Features of chronicity: Present � Absent �

Differential diagnosis:

Crohn’s disease � Ulcerative colitis �Infective colitis � Transient colitis �Microscopic, collagenous, lymphocytic colitis �

Other comments:…………………………………………………………………………………………………………………..…...

………………………………………………………………………………………………………………………………..….….…..

III Radiological features

Procedure(s): Findings:1)

2)

Radiologist’s impression:

IV Laboratory and microbiology

1- Stool test:2- Stool culture:3- Blood test:

I Present clinical episode

Date of onset: / / Duration: days

Main symptoms:1) Diarrhoea Watery � Bloody �

2)

3)

4)

N.Y. Haboubi et al.: Diagnostic accuracy of IBD 119

Fig. 1 Pattern-based report to be presented to the pathologist together with the biopsy request form

II Endoscopy findings

Procedure: Date: / /

Biopsy site(s):

Mucosal features:

Extent of disease:

Pattern: Focal � Segmental � Continuous � Skip �Pancolitis �

Severity: Mild � Moderate � Extensive �Suspicion of neoplasia: �

setting of inflammatory bowel disease. There is a largenumber of aetiological factors of granuloma in theintestine, and Crohn’s disease is only one of them [24].

Our system, like that of others [25, 26], does not en-courage the use of terms such as mild inflammatory chan-ges and non-specific chronic colitis [27, 28].

Crypt distortion in the colon, which is one of the majorhistological features in diagnosing chronic IBD, is usuallynot present in the early phase of IBD [29]. Crypt distortionwas not found among patients presenting within 2 weeks ofthe onset of colitis. In one prospective study, it was absentin 22% of cases examined within 121-300 days followingthe first attack of colitis [30]. Another retrospective studysuggested that the development of crypt distortion takes 2months [2]. These studies suggested that sometimes there isdissociation between the histological features and the dura-tion of the disease. It has become, therefore, necessary tohave clinical data available at the time of interpretation ofthese biopsies. However, these data are often unavailable atthat time, resulting in problems in interpretation. Ideallysequential biopsies are required after the baseline biopsy,and multiple biopsies are recommended.

Bently et al. [31] recently reported that in Crohn’s dis-ease, while rectal biopsies in the hands of experts were24% accurate for reaching a diagnosis, this figure rose to64% when multiple colonoscopic biopsies were examined.The figures, however, were much closer in UC, indicatingthat in CD multiple biopsies significantly enhance diag-nostic accuracy.

Multidisciplinary meetings

Like others [32], we strongly believe that biopsy speci-mens on their own have limited diagnostic value in diseasedifferentiation in IBD.

The limited clinical data provided to the pathologistputs greater weight on the pathologists’ shoulders [27].Most colonic biopsies in inflammatory conditions have nodiagnostic or pathognomonic histological features becauseone histological pattern can be seen in many diseases andone disease can produce many patterns. These are the mainfactors that may lead to a wrong diagnosis and thereforeless effective management. Due to the fact that the clini-cian requires a working diagnosis, our group suggested toproduce a pattern-based report (Fig. 1) with a differentialworking diagnosis and to reach the final diagnosis in aclinicopathological conference where more data would beavailable [3]. We believe that the responsibility of takingdiagnostic decisions falls equally on both the clinician andthe pathologist [25]. One study from Southampton, UK,showed that, after establisment of the clinicopathologicalmeetings, the clinical management changed in over 40% ofcases [33].

120 N.Y. Haboubi et al.: Diagnostic accuracy of IBD

Conclusions

There are grey areas in reporting colonic mucosal biopsies.These can be minimised by following a more efficientmethodology. The process of reaching the final diagnosisshould include the following steps:1. Provide full, relevant data to the pathologist. It is of

paramount importance that histology request formsshould be redesigned to include specific clinical fea-tures such as duration of symptoms, the severity, typeand duration of relevant medical and surgical treat-ments used and, if any, endoscopic findings. In thisaspect, we are currently auditing the use of a unifiedrequest form. Short of that, a copy of the endoscopicreport must accompany the request form. We found thatthe information on the endoscopy report is significant-ly more accurate than that given on the request forms.

2. Where the diagnosis is not clear-cut, a pattern-basedreport with a differential diagnosis is initially issuedwhere: (i) commonly understood terminology shouldbe used, and (ii) confusing terms such as non-specificchronic colitis should be avoided.

3. The final diagnosis should be discussed and reached inregular clinicopathological meetings.

Acknowledgement We are grateful to Mrs. Irving for typing themanuscript.

References

1. Haboubi NJ, Schofield PF (1994) Large bowel biopsies in coli-tis. Aclinico-pathological correlation. J Royal Soc Med 87:16–17

2. Theodossi A, Spiegelhalter DJ, Jass J et al (1994) Observervariation and discriminatory value of biopsy feature in inflam-matory bowel disease. Gut 35:961–968

3. Haboubi NJ, Schofeld PF (2000) Reporting colonic mucosalbiopsies in inflammatory conditions: a new approach. Colo-rectal Dis 2:66–72

4. Tamboli CP, Neut C, Desreumaux P, Colombel JF (2004) Dy-sbiosis in inflammatory bowel disease. Gut 53:1–4

5. Wada Y, Matsui T, Matake H et al (2003) Intractable ulcera-tive colitis caused by cytomegalovirus infection. Dis ColonRectum 46(10):S59–S65

6. Odze R, Antonioli D, Peppercorn M, Goldman H (1993) Ef-fect of topical 5-aminosalicylic acid (5-ASA) therapy on rec-tal mucosal biopsy morphology in chronic ulcerative colitis.Am J Surg Pathol 17:869–875

7. Danielsson A (1995) Non-systemic steroid as enemas in thetreatment of ulceration colitis. In: Tytgst GNJ, BartelsmanJFWM, Van Deventer SJH (eds) Infilammatory bowel dis-ease. Kluwer Academic, Dordrecht, pp 647–656

8. Gimes P, Du Boulay C, Smith CL, Holdstock G (1986) Re-lationship between disease activity and colonoscopic findingsin patients with colonic inflammatory bowel disease. Gut27:92–95

9. Hawkey CJ, Dube LM, Rountree LV, Linnen PJ, Lancasten JF(1997) A trial of zileuton versus mesalazine or placebo in themaintenance of remission of ulcerative colitis. Gastroentero-logy 112:718–724

10. Robert WG, Simson TJ, Berlin RG et al (1997) Leukotrienes inulcerative colitis: results of a multicenter trial of a leukotrienebiosynthesis inhibitor, MK-591. Gastroenterology 112:725–732

11. Ectors N, Deiessen A, Gebose K (1998) Reversibilite deslesion histologiques. Acta Endoscopica 28:221–232

12. Truelove SC, Witts LJ (1995) Cortisone in ulcerative colitis;final report on a therapeutic trial. Br Med J 29:1041–1048

13. Powell-Tuck, Day DU, Buckell NA, Wadsworth J, Lennard-Jones J (1982) Correlation between defined sigmoidoscopicappearances and other measurements of disease activity inulcerative colitis. Dig Dis Sci 27:533–537

14. Gebose K, Riddell R, Ost A, Jensfelt B, Persson T, Lofber R(2000) A reproducible grading scale for histopathologicalassessment in ulcerative colitis. Gut 47:404–410

15. Quinn PG, Binion DG, Connors PJ (1994) The role of endo-scopy in inflammatory bowel disease. Med Clin North Am78:1331–1352

16. Smedth K, Olaison G, Franzen L, Sjodahl R (1996) The endo-scopic picture reflects transmural inflammation better than en-doscopic biopsy in Crohn’s disease. Eur J Gastroenterol He-patol 8:1189–1193

17. D’Haens F, Geboes K, Peeters M, Baert, Ectors N, RutgeertsP (1997) Patchy caecal inflammation associated with distalulcerative colitis: a prospective study. Am J Gastroenterol92:1275–1279

18. Bernstein C, Shanahan F, Anton P, Weinstien W (1995) Pat-chiness of mucosal inflammation in treated ulcerative colitis.Gastrointestinal Endoscopy 42:232–237

19. Kleer C, Appleton H (1998) Ulcerative colitis: patterns of in-volvement in colorectal biopsies and changes with time. Am JSurg Path 22(8):983–989

20. Riley SA, Mani V, Goodman MJ, Dutt S, Herd ME (1991)Microscopic activity in ulcerative colitis: what does it mean?Gut 32:174–178

N.Y. Haboubi et al.: Diagnostic accuracy of IBD 121

21. Haboubi NJ, Kaftan S, Scofield PF (1992) Radiation colitis isanother mimic of chronic inflammatory bowel disease. J ClinPathol 45:272

22. Shepherd NA (1991) Pathological mimics of chronic inflam-matory bowel disease. J Clin Pathol 44:726–733

23. Shepherd NA (2002) Granuloma in the diagnosis of intestinalCrohn’s disease: a myth exploded? Histopathology 41:166–168

24. Shepherd NA (2002) Granulomas in the diagnosis of Crohn’sdisease: a myth exploded? Histopathology 41:166–168

25. Jenkins D, Balstitis B, Gallivan S et al (1997) Guidelines forthe initial biopsy diagnosis of suspected chronic idiopathicinflammatory bowel disease. The British Society of Gastroen-terology. J Clin Path 50:93–105

26. Tanaka M, Riddell RH, Saito H, Soma Y, Hidaka H, Kudo H(1999) Morphologic criteria applicable to biopsy specimens:an effective distinction of inflammatory bowel disease fromother forms of colitis and of Crohn’s disease from ulcerativecolitis. Scand J Gastroenterol 1:56–67

27. Haboubi NY, Kamal F (2001) Non-specific colitis, is it a jus-tifiable diagnosis? Colorectal Dis 3:263–265

28. Tsang P, Rotterdam H (1999) Biopsy Diagnosis of colitis.Possibilities and pitfalls. Am J Surg Pathol 23(4):423–430

29. Gebose K (2001) Pathology of inflammatory bowel disease(IBD): variability with time and treatment. Colorect Dis 3:2–12

30. Schumacher G, Kollberg B, Sandstedt B (1994) A prospectivestudy of first attacks of inflammatory bowel disease and infec-tious colitis. Scand J Gastroenterol 29:318–332

31. Bentley E, Jenkins D, Campbell F, Warren B (2002) Howcould pathologists improve the initial diagnosis of colitis?Evidence from an international workshop. J Clin Path55:955–960

32. Shirandana S, Hordijk ML, Tenkute FWJ, Probert CSJ, May-berry JF (1991) Differential diagnosis of inflammatory boweldisease. A comparison of various diagnostic classifications.Scand J Gastroenterol 26:167–173

33. McBroom MH, Ramsay AD (1993) The clinicopathologicalmeeting. A means of auditing diagnostic performance. Am JSurg Pathol 17:75–80