Digestive and Liver Disease 43S (2011) S293–S303

Chronic idiopathic inflammatory bowel diseases: The histology report Matteo Cornaggia a, *, Monica Leutner b , Claudia Mescoli c , Giacomo Carlo Sturniolo d , Renzo Gullotta e On behalf of the “Gruppo Italiano Patologi Apparato Digerente (GIPAD)” and of the “Società Italiana di Anatomia Patologica e Citopatologia Diagnostica”/International Academy of Pathology, Italian division (SIAPEC/IAP) a Department

of Laboratory Medicine, Pathology Unit, Clinica S. Carlo, Paderno Dugnano, Italy Pathology Unit, University Hospital “Ospedale Maggiore della Carità”, Novara, Italy c Department of Diagnostic Medical Sciences & Special Therapies, Pathology Unit, University of Padova, Padova, Italy d Department of Gastroenterology & Surgical Sciences, Gastroenterology Unit “R Farini”, University of Padova, Padova, Italy e Gastroenterology Unit, Clinica S. Carlo, Paderno Dugnano, Italy b S.C.

Abstract The incidence of chronic idiopathic inflammatory bowel diseases (IBD) is growing in western countries, making their histological diagnosis an everyday task for all pathologists. Reviews from the literature strongly suggest that such diagnosis cannot be performed on the histological ground alone but requires a clinical-pathological approach. Moreover, bewildering variations can be observed in the terminology employed to report either individual lesions or diagnostic categories. The aim of the present paper is to suggest a practical diagnostic algorithm summarizing the main data from the literature. Particular emphasis has been placed on minimum clinical information required and the accurate definition of individual lesions. Diagnostic categories to employ and to avoid in daily practice have furthermore been stressed. © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Crohn’s disease; GIPAD report; Ulcerative colitis

1. Introduction The diagnosis of chronic idiopathic inflammatory bowel diseases (IBD) requires a close correlation between morphol-

List of abbreviations: ALM, Adenoma-Like Mass; CD, Crohn’s disease; DALM, Dysplasia-Associated Lesion or Mass; IBD, chronic idiopathic inflammatory bowel diseases; NOS, not otherwise specified; UC, ulcerative colitis. * Correspondence to: Matteo Cornaggia, Department of Laboratory Medicine, Pathology Unit, Clinica S. Carlo, Paderno Dugnano, Via Ospedale 21, Paderno Dugnano, Milano, Italy. Tel: +39 02 99038283; fax: +39 02 99030260. E-mail address: [email protected] (M. Cornaggia).

ogy, clinical features, endoscopic appearance, imaging and laboratory data. The microscopic picture, in fact, is often composed of basic lesions that can also be observed in other diseases and only rarely appears to be pathognomonic. The histopathological diagnosis is of paramount importance in determining the choice of treatment, the prognosis and the follow-up. The aim of the diagnosis is to: 1. Differentiate IBD from other colitis. 2. Differentiate ulcerative colitis (UC) from Crohn’s disease (CD). 3. Identify dysplastic lesions.

1590-8658/$ – see front matter © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

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2. Clinical indication for biopsy A “gold standard” for IBD diagnosis has not yet been established. In fact it is based on a combination of anamnestic data, clinical evaluation, imaging and typical endoscopic and histopathologic features. Main indications leading to endoscopic investigation are symptoms like chronic diarrhoea (loose stools lasting for 6 weeks), hematochezia, abdominal pain, mucus discharge, unexplained systemic symptoms like fever and weight loss or various clinical signs like fistulae or extra-intestinal diseases (articular, cutaneous, ocular etc.) possibly associated with asymptomatic or attenuated IBD. During colonoscopy it is always important to visualize the terminal ileum and to perform a complete biopsy sampling (see later paragraph) either in normal or in pathological areas. Histological examination is in fact mandatory to perform a conclusive IBD diagnosis. In case of chronic diarrhoea with normal endoscopic appearance it is recommended that biopsies for microscopic colitis identification (lymphocytic, collagenous) be performed: two in the ascending colon and two in the sigmoid colon.

Table 1 Clinical data form to be attached to the pathology examination request in cases of suspected IBD

3. Clinical data As mentioned earlier, the clinical data are crucial for proper interpretation of the histopathological features [1–3]. The data should always be reported in the pathology examination request or submitted in separate form (Table 1). Sending a copy of the endoscopy report may be helpful, although in no way does it substitute correct and complete compilation of the pathology examination request, which must always include the precise case-specific opinion of the gastroenterologist. It is mandatory for the pathologist, especially in newly diagnosed cases, to obtain the main clinical data in order to validate the microscopic picture and to make a true clinicopathological diagnosis. If sufficient clinical information is not available the diagnosis should only be descriptive. Such information can be divided into the following categories [3,4]: 1. Clinical history. Symptoms (features and duration): diarrhoea, hematochezia and fever. Presence of major extra-intestinal diseases. Current or previous therapy, with particular emphasis on topic bowel therapies. 2. Laboratory data. Results of ongoing stool culture and faeces parasite investigations, unspecific inflammatory serological markers (erythrocyte sedimentation test and C-reactive protein), anti-neutrophil cytoplasmic antibodies (ANCAs) and antisaccharomyces cerevisiae antibodies (ASCAs). 3. Endoscopic appearance. Bowel tract examined (partial or total colonoscopy with or without terminal ileum visualization).

Description of the main lesions observed, with particular emphasis on continuous or segmental disease and the presence of diverticula. 4. Imaging. Presence and morphology of lesions in tracts not explored by endoscopy (jejunum, terminal ileum, bowel tract beyond stenotic portions).

4. Endoscopic sampling [4–7] The diagnostic accuracy has been demonstrated to increase with the number of biopsies performed and with the number of bowel tracts sampled [3,5]. Therefore, it is mandatory to perform an extensive bioptic sampling, especially in the case of newly diagnosed IBD, whereas sampling could be reduced in the follow-up examinations. It should also be noted that CD is a trans-mural disease and that therefore the diagnosis on endoscopic biopsies suffers from limitations and appears more difficult. 4.1. Optimal sampling for newly diagnosed IBD Two biopsies should be performed in the terminal ileum and in each portion of the large bowel examined (caecum,

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ascending, transverse, descending, sigmoid colon and rectum) even if the mucosa appears endoscopically normal [3,8]. 4.2. Minimum sampling during the follow-up Two biopsies should be performed in all large bowel tracts showing significant lesions and two biopsies in the rectum. In case of discordance between the initial histological diagnosis and the clinical course during the follow-up, it is mandatory to repeat a complete sampling (see previous paragraph) to settle the question. It is also strongly recommended that a critical reexamination of previous biopsies is performed and written indications of this review provided in the final report. 4.3. Sampling for the detection of dysplasia in longstanding disease (8–10 years duration) [9,10] This is a highly controversial issue since indications in the literature are very exacting and are often ignored in routine practice. The protocol, in fact, recommends that two biopsies be performed every 10 cm of large bowel examined and any suspicious lesion sampled.

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6. Histologic individual lesions [1–3,11] The diagnosis of IBD relies on the identification of variously intermingled individual histologic lesions (Table 3). These have been described since the first published papers, however their sensitivity and specificity have not yet been established. Particular emphasis should be placed on distinguishing “true lesions” from alterations caused by bowel preparation and/or endoscopic trauma (Table 4) and from “minimal changes” that fall within the normal colonic mucosa variability range. Their precise and unequivocal identification is essential to avoid diagnostic mistakes. The diagnostic reproducibility of basic lesions, in fact, has been demonstrated to significantly improve using shared diagnostic criteria [5].

7. Normal colonic mucosa [1–3,11,12] Normal colonic mucosa is characterized by a flat surface, parallel straight crypts homogeneously sized, regularly aligned and spaced, less than 10% of which are branching (Figs. 1 and 2), and whose bottom reaches the muscularis mucosae.

5. Biopsy handling The use of cellulose acetate films is highly recommended because it allows proper mucosal sample orientation, whereas the use of blotting paper should be discouraged owing to sample handling and possible artefacts. Samples from each anatomical site should be adequate in size (presence of muscularis mucosae), carefully handled in order to avoid crushing artefacts, immediately fixed in neutral buffered formalin and unequivocally identified [6,7]. The diagnosis of IBD can be performed, in most cases, using sections stained with haematoxylin and eosin. There is no gold standard rule concerning the number of histological sections to be examined although the diagnostic accuracy has been demonstrated to increase with serial sectioning, with particular reference to granuloma identification in CD [7]. Special staining techniques may help in the differential diagnosis (Table 2).

Table 2 Special techniques for the differential diagnosis of IBD • • • • •

PAS for fungi identification. Giemsa and Warthin-Starry for bacteria identification. Masson Trichrome for basement membrane evaluation. Ziehl Nielsen for mycobacteria identification. Immunohistochemical reactions for T lymphocytes (CD3) and viral antigen detection (cytomegalovirus and herpes virus). • PCR for mycobacteria identification and typifying.

Table 3 Individual histologic lesions in IBD 1. Mucosal architecture alterations 1.1. Mucosal surface alterations 1.2. Crypt distortion 1.3. Atrophy 2. Epithelium breakings 2.1. Erosions 2.2. Ulcers 2.3. Aphthous ulcers 2.4. Pseudomembranes 3. Epithelium alterations 3.1. Mucin depletion 3.2. Paneth cell metaplasia 3.3. Pseudopyloric metaplasia 3.4. Dysplasia/Intraepithelial neoplasia 4. Inflammatory infiltration 4.1. Neutrophil polymorphs 4.2. Lymphoplasmacytic 4.3. Basal plasma cell infiltration 4.4. Granulation tissue-like inflammation 4.5. Epithelioid granulomas 4.6. Increase in lymphoid follicles

Table 4 Alterations caused by bowel preparation and/or endoscopic trauma • • • • • • •

Epithelial sloughing Acute haemorrhagic foci Edema Pseudolipomatosis Decrease in intracellular mucus Mitosis increase Presence of occasional neutrophils in the surface epithelium, especially above lymphoid follicles, and in the crypts (15/100 enterocytes). Diffuse lymphoplasmacellular infiltration.

Focal or diffuse lesions. Possible rectal sparing.

Haematoxylin and eosin. CD3 antibodies.

Collagenous colitis [12,16]

Chronic diarrhoea lasting several months. Normal colonoscopy. Use of drugs.

Thick continuous sub-epithelial collagenous band (>10 μm). Superficial epithelium damage. Lymphocytes and neutrophil polymorphs granulocytes infiltrating superficial epithelium.

Focal or diffuse lesions. Possible recto-sigmoid sparing.

Haematoxylin and eosin. Masson’s trichrome.

Drug-induced colitis [17]

Use of nonsteroid antiinflammatory drugs, chemotherapeutic agents and vasoactive drugs.

Ischemic-like lesions. Microscopic colitis. IBD-like colitis. Graft versus host-like lesions. Cathartic colon lesions.

Focal or diffuse lesions

Haematoxylin and eosin.

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Table 5 (continued) Disease

Clinical information

Individual histologic lesions

Gross lesion distribution

Histological techniques

Diversion colitis [11,12]

Previous surgery creating a blind intestinal loop.

Cryptitis and/or crypt abscesses. Diffuse lymphoplasmacellular infiltration. Lymphoid follicles hyperplasia.

Blind intestinal loop.

Haematoxylin and eosin.

Diverticular diseaseassociated colitis [11,12]

Protean symptoms.

Mild/severe lymphoplasmacellular infiltration. Cryptitis and/or crypt abscesses. Crypt distortion. Mucin depletion.

Bowel tracts affected by diverticula.

Haematoxylin and eosin.

Eosinophilic colitis [12]

Diarrhoea. Rectal bleeding. Abdominal distension. Anorexia. Vomiting.

Rich eosinophilic granulocyte infiltration in the absence of other lesions (>10 eosinophils/HPF).

Focal lesions. Prevailing left colon involvement.

Haematoxylin and eosin.

Behçet syndrome [11]

Uveitis. Arthritis. Cutaneous lesions (erythema nodosum and/or others). Apthous stomatitis. Genital ulcers.

Deeply penetrating aphtoid ulcers. Submucosal small vessels vasculitis.

Ileo-cecal region involvement.

Haematoxylin and eosin.

9.7. Diagnostic categories to be avoided [18]

Table 6 Examples of histopathological report

9.7.1. Indeterminate colitis The term was originally proposed for surgical cases showing a histological picture typical of either UC or CD and it was later used in the same sense for biopsies. In such cases it appears, on the contrary, more correct to use the term ’chronic idiopathic inflammatory bowel disease NOS’.

Unequivocal diagnosis

Highly suggestive diagnosis

• Histopathological description • Histopathological features

• Histopathological description • Histopathological features highly

9.7.2. Chronic colitis This term has no scientific basis in that it does not identify any clinical-pathological entity and is therefore wholly devoid of any clinical value. Its use must be absolutely banned.

10. Writing a report According to the level of diagnostic certainty achieved, three different types of diagnosis can be written up. 1. Unequivocal diagnosis (Table 6) – Histopathological description (optional) 1. – Type of observed disease: ulcerative colitis, Crohn’s disease or chronic idiopathic inflammatory bowel NOS. – Assessment of disease activity. – Assessment of dysplasia. 2. Highly suggestive diagnosis (Table 6) – Histopathological description 1. – Statement assessing the subjective grade of probability supporting the diagnosis of the disease: ulcerative coli-

diagnostic for ulcerative colitis • Active disease • Dysplasia absent

suggestive of Crohn’s disease • Active disease • Dysplasia absent

Note: a complete sampling of the ileo-colic mucosa should be performed to validate the diagnosis.

tis, Crohn’s disease or chronic idiopathic inflammatory bowel NOS. – Assessment of disease activity. – Assessment of dysplasia. – Explanatory note clarifying the causes preventing attainment of a definitive diagnosis (incomplete sampling and/or insufficient clinical data). 3. Descriptive diagnosis The mere description of histological findings should only be reserved to cases showing definitive abnormal microscopic features that, however, do not fit into any specific disease entity. Its use should be restricted to cases where the pathologist wants to pass on the presence of abnormal findings that need further investigation.

11. Clinical impact of the histopathological diagnosis 1 Although the histopathological description may seem superfluous, it can be useful in subsequent examinations to assess the "level of certainty," even if the slides are not available. It is therefore strongly recommended in cases of highly suggestive diagnosis.

Histological diagnosis, as previously stated, appears of paramount importance in the diagnostic algorithm for patients with clinical aspects highly suggestive for IBD.

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Table 7 Histopathological diagnosis of IBD: its application in the clinico-therapeutic algorithm • Endoscopic typical lesions and

Conflict of interest The authors have no conflicts of interest to disclose.

Specific therapy for IBD.

unequivocal histopathologic diagnosis. • Endoscopic typical lesions and highly

References

suggestive histopathologic diagnosis. • Endoscopic typical lesions and

negative histopathologic diagnosis. • Endoscopic typical lesions absent and unequivocal or highly suggestive histopathologic diagnosis. • Endoscopic typical lesions absent and

negative histopathologic diagnosis.

Clinico-endoscopic and histopathologic follow-up without specific therapy for IBD. Diagnosis of IBD unlikely: investigate different causes of patient symptoms.

However, it should be critically evaluated according to the endoscopic appearance in order to establish a therapeutic strategy. Table 7 summarizes the main possible clinical implications. Two items of the histopathological report appear to be particularly significant: • Disease activity: some data in the literature seem to indicate that a higher relapse frequency is associated with cases exhibiting clinical-endoscopic remission still showing microscopic activity [19]. • Presence of dysplasia leading to relevant clinical treatments as summarized in Fig. 13 [20].

Acknowledgements The authors wish to thank Mr. Alan Povall for revising the manuscript.

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Fig. 13. Recommended algorithm for dysplasia treatment (modified from Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 8th ed. [20].)

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