Histopathology of inflammatory bowel disease — Position statement of the Pathologists of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) and Italian Group of Gastrointestinal Pathologists (GIPAD-SIAPEC)

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Histopathology of inflammatory bowel disease — Position statement of the Pathologists of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) and Italian Group of Gastrointestinal Pathologists (GIPAD-SIAPEC) Vincenzo Villanacci a,∗ , Luca Reggiani-Bonetti b , Flavio Caprioli c , Luca Saragoni d , Tiziana Salviato b , Claudia Mescoli e , Gabriella Canavese f , Stefania Manenti a , Elisabetta Spada a , Luigi Baron g , Giuseppe Leoncini h , Moris Cadei a , Serena Battista i , Alessandro Armuzzi j a

Institute of Pathology, ASST Spedali Civili, Brescia, Italy Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy c Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Policlinico di Milano, and Department of Pathophysiology, Department of Transplantation, University of Milan, Milan, Italy d Department of Pathological Anatomy, AUSL Romagna, Morgagni-Pierantoni Hospital, Forlì, Italy e Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padova, Padua, Italy f Pathology Department, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy g Pathology Unit, St. Leonardo Hospital, Castellammare di Stabia, Naples, Italy h Pathology Unit, ASST del Garda, Desenzano del Garda (BS), Brescia, Italy i Institute of Pathology Azienda Ospedaliera Universitaria Integrata, Udine, Italy j IBD Unit, Presidio Columbus Fondazione Policlinico Universitario A. Gemelli IRCCS – Università Cattolica del Sacro Cuore, Rome, Italy b

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Article history: Received 28 September 2019 Accepted 8 November 2019 Available online xxx Keywords: Basal plasmacytosis Crohn’s disease Dysplasia Granulomas Histopathological report Mucosal healing Ulcerative colitis

a b s t r a c t Diagnosis of the inflammatory bowel diseases ulcerative colitis (UC) and Crohn’s disease (CD) relies mainly on the histopathological examination of endoscopic biopsies of the gastrointestinal tract. To facilitate the accurate diagnosis of these two conditions, this paper addresses key issues on the: (A) gastrointestinal biopsy procedure, (B) histomorphological characteristics of UC and CD, and (C) diagnosis of dysplasia. The 13 statements presented here represent the consensus of two groups of Italian pathologists (IG-IBD and GIPAD). © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

1. Introduction Inflammatory bowel disease (IBD) is a general term for two chronic bowel disorders: ulcerative colitis and Crohn’s disease. Distinguishing between these two entities is based on clinical, endoscopic, histological and radiological features. The histopathological examination of biopsy specimens is fundamental for making a specific diagnosis (i.e. the type of IBD), determining the state of disease activity, and evaluating the prospect of healing and risk

of relapse [1,2]. Because of the variable occurrence of diagnostic features in biopsy samples, a confident diagnosis is impossible in 10%–15% of cases. Thus, in light of the many problems and pitfalls in the histopathological diagnosis of IBD, the pathologists of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) and the Italian Group of Gastrointestinal Pathologists (GIPAD-SIAPEC) reviewed the relevant literature and defined a series of statements on the correct diagnostic approach for a precise histopathological diagnosis.

∗ Corresponding author. E-mail address: [email protected] (V. Villanacci). https://doi.org/10.1016/j.dld.2019.11.005 1590-8658/© 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Villanacci V, et al. Histopathology of inflammatory bowel disease — Position statement of the Pathologists of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) and Italian Group of Gastrointestinal Pathologists (GIPAD-SIAPEC). Dig Liver Dis (2019), https://doi.org/10.1016/j.dld.2019.11.005

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2. Endoscopic biopsy procedure Statement 1 For a reliable diagnosis of IBD, at least two endoscopic biopsies each should be taken from at least five sites along the ileum, colon and rectum. If Crohn’s disease is suspected, endoscopic biopsy of the upper gastrointestinal (GI) tract is also suggested. The biopsy specimens should be placed on a pre-cut cellulose acetate filter in the correct anatomical orientation. For the histopathological evaluation of features identifying ulcerative colitis and Crohn’s disease, the different segments of the ileocolonic tract should be endoscopically sampled, regardless of the severity of the inflammation. Relevant clinical, laboratory, radiological and echographic information should also be collected [3,4]. By protocol, at least two biopsies from each of the five sections of the large intestine (right colon, transverse colon, left colon, sigmoid colon and rectum) and from the terminal ileum are required [3]. In cases of suspected Crohn’s disease, in which oesophageal, gastric and duodenal involvement is possible, endoscopic and histological assessment of the upper GI tract is advised, with four biopsies of the duodenum (two in the distal and two in the proximal parts), five biopsies of the stomach (in sites recommended by the Sidney System for the classification of gastritis) [5], and two biopsies of the distal oesophagus. The orientation of biopsy specimens on pre-cut cellulose acetate filters can facilitate the histopathological identification of characteristic lesions. The use of these filters is therefore advised [3–6].

3. Histopathology of ulcerative colitis Statement 2 The histological features of UC include active inflammation (neutrophils in the lamina propria and crypts), non-active inflammation (diffuse intramucosal inflammation, basal plasmacytosis, eosinophils) and structural changes (distortion of glands, depletion of the mucinous component of the crypts). Ulcerative colitis (UC) is a chronic intestinal inflammatory disease that develops in genetically susceptible individuals probably as the result of abnormal immune responses to luminal antigens [1]. UC is limited to the colon and rectum. In about 5% of patients, mostly those with pancolitis or a history of severe attacks of the disease, toxic megacolon may be a complication [7]. Histologically, UC has a diffuse, contiguous, transmucosal distribution, with an abnormally high density of neutrophils, lymphocytes and plasma cells in the lamina propria. Based on the spread of disease, four subtypes of UC are distinguished: ulcerative proctitis, left-sided colitis, extensive colitis, and pancolitis [1,4,5]. The histological features of UC include non-active inflammation, active inflammation, and structural changes. Non-active inflammation includes the presence of lymphocytes and plasmacells in the lamina propria, at time associated to oedema and hyperaemia. These features represent the baseline of the chronic inflammatory bowel disease. Active inflammation is defined when there are neutrophils in the lamina propria, crypts or surface epithelium. Morphological changes of UC include: neutrophils penetrating the crypt epithelium (cryptitis), neutrophils occupying the crypt lumens (crypt abscesses), and neutrophils in the lamina propria and superficial epithelium. Cryptitis and crypt abscesses can cause crypt destruction, while neutrophils infiltrating the surface epithelium lead to mucosal erosions or ulcerations [5,6]. When three or more plasma cells accumulate in the mucosal lamina propria between the crypt base and the muscularis mucosae, a condition termed basal plasmacytosis is defined [7,8]. This phenomenon is limited and focal in the initial phase of UC, but later it spreads to more colonic segments [7–9]. In basal plasmacy-

tosis, plasma cells intermingle with eosinophils [8]. The occurrence of eosinophils in the lamina propria, between the crypts and within the muscularis mucosae, has been associated with aggressive disease and a high risk of relapse [10,11]. Eosinophil infiltration is more visible in the early stages of the disease and in paediatric patients [10–13]. Epithelial architectural abnormalities of UC include irregular surfaces, such as a “pseudovillous surface” of the mucosa, and glandular distortion. These histological changes, which reflect chronic mucosal damage due to the duration and severity of the disease [10,14], include: crypts with irregular size and shape (e.g. branching and shortening), crypts with irregular distribution in the lamina propria, and crypts with loss of parallelism. The identification of Paneth cell metaplasia in the left colon can help in the diagnosis of long-standing UC [9,15–18]. These inflammatory features are widely found in biopsies of the colon and rectum. In some UC patients with pancolitis, the ileum too is affected by acute or chronic inflammation, with crypt abscesses and shallow ulcerations; this condition has been termed “backwash ileitis” [19]. Statement 3 The severity of inflammation in UC is histologically classified, according to the presence of inflammatory cells, as mild, moderate and severe. In UC, the severity of inflammation is histologically classified according to the presence of inflammatory cells [20–22], as follows: • In mild to moderate inflammation, the epithelium is usually intact, but the glands are irregularly arranged on a congested, oedematous background. Lymphocytes, plasma cells and eosinophils are abundant in the lamina propria. Neutrophils are often present in the glandular lumen. The intensity of inflammation can vary among biopsy specimens from the same patient, giving a range of appearances from quiescent to active inflammation. • In severe inflammation, the mucosal surface is irregular, and oedema, interstitial haemorrhage and inflammatory exudate are evident in the lamina propria. The mucosa shows heavy interstitial infiltration by lymphocytes, plasma cells, eosinophils and neutrophils, with frank erosions and exudate of neutrophils from crypt abscesses (neutrophils, eosinophils, and epithelial debris in the crypt lumens). Diffuse glandular distortion is evident. Statement 4 Histological mucosal healing is achieved when the colonic mucosa becomes free of active inflammation, erosion and crypt abscesses. Histological remission is not considered a primary goal of therapy [23]. Furthermore, histological mucosal healing cannot be determined from endoscopic evidence of mucosal healing [24,25]. Indeed, microscopic evidence of inflammation persists in 16%–100% of patients with endoscopically quiescent colitis [26]. In one report, active histological inflammation predicted clinical relapse during 12 months of follow-up, whereas endoscopic features did not [27]. Therefore, histological healing could be an endpoint in future clinical trials of new UC drugs, as previously suggested [28]. The ideal treatment goal should be complete resolution of the inflammatory process, documented by clinical, laboratory, endoscopic and histological analyses. For the correct histological evaluation of mucosal healing, the pre-analytical phase is of paramount importance [3,4]. The pathologist should receive an adequate number of biopsies (at least two per site), correctly oriented, and obtained from several sections, including the rectum and terminal ileum. The biopsies should be accompanied by a report indicating the patient’s age, disease duration, type of treatment and other relevant clinical information [29]. Histological assessment should involve the analysis of several

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microscopic sections (at least four per slide) stained with haematoxylin and eosin. A precise, globally accepted definition of histological mucosal healing does not currently exist. Histological healing has been defined as the disappearance of inflammation [30–32]. Hence, a healed mucosa has few architectural abnormalities, normally differentiated epithelial cells, no signs of active inflammation (i.e. neutrophils), and a normal density of lymphocytes and plasma cells. Thus, mucosal healing indicates a histological state in which the mucosa becomes free of active inflammation, erosions and crypt abscesses, its surface and glandular epithelial cells are intact, its general architecture is not disturbed, and the lamina propria is free of oedema, fibrosis and the accumulation of lymphocytes and eosinophils. Several histological scoring systems for disease activity and mucosal healing have been devised. These are the Riley score [27], the Geboes index [33], the Gramlich score [34], the Gupta histological activity index [35], the Robarts histopathology index [36], the Nancy histological index [37] and the Simplified Score [38,39]. Statement 5 Paediatric UC differs from adult UC in some morphological characteristics. Colonic mucosal biopsies from children with new-onset UC showed fewer histological alterations, with less aggressive epithelial injury and milder crypt distortions, than did biopsies from adults [40]. The identification of basal cell plasmacytosis can help in the diagnosis, although it can occur in a discontinuous way [41–46]. Statement 6 Histological features of pouchitis include alterations of villi, increased intraepithelial T lymphocytes, lamina propria inflammation and superimposed infections. Restorative proctocolectomy with ileal-pouch anal anastomosis is the surgical treatment of choice for patients with medically refractory UC or UC complicated by dysplasia or carcinoma; it is a treatment option for patients with Crohn’s colitis without perianal and/or small bowel disease [47]. A complication of the procedure is inflammation of the pouch, or pouchitis. Histological features of pouchitis include mucosal inflammation and villi blunting. Early pouchitis is characterized by polymorphonuclear leukocyte infiltration, crypt abscesses, ulceration and various degrees of villous atrophy [48]. Based on villi morphology and histology, the pouch mucosa can be considered normal (e.g. no active inflammation; quiescent) or inflamed (e.g. pouchitis). Three histological patterns of pouchitis have been defined [49–51]: type 1, normal villi or mild villous atrophy without or with only mild inflammation; type 2, villous atrophy with inflammatory changes; and type 3, severe villous atrophy and severe chronic inflammation. The PDAI (pouchitis disease activity index) is a useful tool to diagnose pouchitis and to assess disease severity. The PDAI includes the histological evaluation of the pouch and describes the type of inflammation (acute and chronic) and the grade of inflammation. The resulting total score defines 3 conditions: mild, moderate and severe pouchitis [52]. When inflammatory alterations are detected in an ileostomy area or in an ileal reservoir, especially when deep ulcerations are present, the original diagnosis of UC should be challenged and Crohn’s disease may be suspected [53]. It may prove useful, in such cases, to review the clinical and histopathological features of earlier colectomy samples. Features supporting the diagnosis of pouchitis include shallow inflammation without fibrosis, strictures or granulomas. In contrast, the presence of granulomas suggests an alternative diagnosis of Crohn’s disease, while viral inclusion bodies suggest pouchitis due to cytomegalovirus infection [54]. In any case it is important to keep in mind the exact site of investigation and in particular of the biopsies the afferent loop-the pouch inlet-the pouch outlet and the efferent loop, (the pouch inletoutley and efferent loop are considered the body pouch) based on

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this anatomical distinction in the typical pouchitis in the pouch body we have severe villous atrophy, active and/or chronic inflammatory infiltrates, crypt abscesses and erosions and ulcerations; in pre-pouch or CD-like pouchitis may have: segmental inflammation of the pouch body and/or afferent limb, strictures at the pouch/inlet/outlet or in the afferent limb, the presence of 1 or more fistulas and in some cases granulomas in this last condition is mandatory the distinction with a previous Crohn disease [47]. The small portion of rectum not surgically removed (rectal stump or cuff), located between the anastomosis and dentate line and created as a result of ileal pouch-anal anastomosis, can also be affected by UC. This condition, called “cuffitis”, requires surveillance for dysplasia [55,56]. Statement 7 The UC histopathological report should clearly describe the morphological elements mandatory for diagnosis: grade of inflammation, basal plasmocytosis, and crypt architecture. The UC histopathological report should comprehensively describe the different morphological elements of the diagnosis, including: (a) location and grade of inflammation, (b) presence of basal plasmacytosis with intermingling eosinophils, and (c) architectural distortion of crypts. The diagnosis should be written in clear, specific terms, avoiding generic terms such as “chronic colitis” and “aspecific colitis”. When the diagnostic features are evident, a diagnosis of UC can be confident.

4. Histopathology of Crohn’s disease Statement 8 The histological features of Crohn’s disease include sectorial active inflammation (neutrophil-mediated epithelial glandular injury), nonactive inflammation (transmucosal inflammation, plasmacells and eosinophils), granulomas, and sectorial architectural distortion of glands. Crohn’s disease (CD) generally involves the terminal ileum, but can affect all segments of the GI tract [2,56]. At disease onset most patients have an inflammatory phenotype, while subsequently about half of them develop complications such as stenosis, fistulae, strictures and abscesses requiring surgery [56]. The inflammation in CD is typically segmental and asymmetric, with a transmural distribution pattern (i.e. not limited to the lamina propria) [56–58]. A correct orientation of the biopsy on filters is essential for determining the pattern of inflammation [59]. The cellularity is polymorphic, with lymphocytes, plasma cells, eosinophils and neutrophils. Because the CD inflammatory infiltrate has a transmural and segmental distribution, basal plasmacytosis is not a characteristic feature of this disease (while it is for UC). Neutrophils are indicative of inflammation even when present exclusively in the stroma without attacking glands, causing cryptitis, or inducing microabscesses. The presence of deep transmural lymphoid aggregates, corresponding to areas of mucosal ulceration, is a particular morphological characteristic of CD that is often seen at disease onset. As described in statement 2 of UC, non-active inflammation includes the presence of lymphocytes and plasmacells in the lamina propria, at time associated to oedema and hyperaemia. This condition is the baseline of the chronic inflammatory bowel disease, and differs from the active inflammation that includes neutrophils in the lamina propria. Architectural distortion in CD can be focal, i.e. affecting only some of the biopsy specimens from a patient. In one study of 39 CD patients, non-caseating granulomas were found in 15%–36% of rectal biopsies from each patient [60]. Granulomas are localized aggregates of inflammatory cells including macrophages and T lymphocytes, and should be distinguished from aggregates of histiocytes found near glands or broken crypts. For this purpose, it is useful to obtain additional sections

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to exclude the presence of fragmented crypts adjacent to areas of non-necrotizing granulomatous inflammation. Necrosis is usually not present in CD biopsies, while non-necrotizing epithelial granulomas are associated with a more aggressive phenotype. Patients in whom granulomatous lesions are found during surgery have a high risk of recurrence [61–66]. Neuronal hyperplasia of the submucosal plexuses is characteristic of CD. Infiltration of eosinophils or T lymphocytes into the submucosal or intramuscular plexus (ganglionitis) should be reported, when present at the resection margins of the surgical specimen, as this finding is prognostic of disease recurrence [62,66]. Early CD mucosal lesions are mainly found in the ileum [67,68]. The lesions usually have a focal distribution over a regular morphological background of villi. They are caused by the focal penetration of neutrophils and eosinophils into the enterocytic epithelium. Statement 9 A diagnosis of extracolonic CD requires distinctive histopathological features such as non-necrotizing granulomas in the mucosa. Besides the main ileocolonic localization of CD, other affected areas include the anus, appendix, non-ileal small intestine, stomach, oesophagus and oropharynx mucosa [68–72]. In the non-ileal small intestine, including the duodenum, the most severe CDinduced damage occurs proximal to the ligament of Treitz and includes erosion, increased numbers of lamina propria plasma cells and neutrophils, crypt abscesses and pyloric gland metaplasia, often in the absence of granulomas; intraepithelial neutrophils can be observed. The patient’s clinical history helps in the diagnosis. Gastric CD more frequently involves the distal portion of the stomach, including the antrum, and is characterized by the deep infiltration of inflammatory cells into the pits and glands [68–72]. Granulomas are almost always associated with focal active gastritis. Oropharyngeal histological manifestations include chronic inflammation, granulation tissue and well-formed, nonnecrotizing granulomas [69]. Statement 10 Paediatric CD is histopathologically different from adult CD. According to one retrospective study, the finding of a granuloma in at least one extra-ileal site was more common in paediatric than adult cases [69]. Several studies have documented that paediatriconset CD is different from adult-onset CD [73–75]. Very early onset CD (<6 years) tends to localize in the colon, while CD that develops in older children tends to have an ileocolonic distribution. The lesions in paediatric CD include crypt distortion (even minimal and focal), sectorial acute inflammation (moderate or severe), and granulomas (more frequent than in adults) [74,75]. Moreover, localization of CD in the upper gastrointestinal tract (duodenum, stomach, oesophagus) is more frequent in children than in adults. Statement 11 The CD histopathological report should clearly describe the morphological elements mandatory for diagnosis: a sectorial distribution of inflammation, basal plasmocytosis, and granulomas. The CD histopathological report should comprehensively describe the different morphological elements of the diagnosis, including: (a) a sectorial distribution of active inflammation and architectural crypt distortion; (b) presence of basal plasmacytosis with intermingling eosinophils; and (c) presence of granulomas. When these features are evident, a diagnosis of CD can be confident.

5. Dysplasia and cancer risk in IBD Statement 12 Dysplasia in IBD is diagnosed on the detection of cytoarchitectural alterations and is classified mainly as low and high grade, while doubtful lesions are considered “indefinite for dysplasia”. The risk of cancer is greater in the colorectal mucosa than in the ileal mucosa.

The identification of dysplasia in IBD patients has an impact on their management, mainly because dysplasia is associated with the development of colorectal carcinoma [76–79]. The risk of colorectal carcinoma in patients with colonic IBD is greater than in the general population [76,79] and is higher in patients with UC than in those with CD, probably due to the different colonic segments involved in the two diseases [76–80]. The increased risk of colorectal cancer in IBD is related to disease duration, becoming significant after 8–10 years of evolution and is associated to chronic inflammation, high Nancy index, family history of colorectal cancer, and previous diagnosis of colorectal cancer (>50 years) [76]. In a meta-analysis from 2001, the probability of colorectal cancer in patients with UC increased with the duration of disease [81]; this result was confirmed in a recent meta-analysis [82]. A Danish study reported that the risk of colorectal cancer in UC decreased over time, from 1.34 in 1979–1988 to 0.57 in 1999–2008, while in CD patients the risk was stable at 0.85 [83]. On the other hand, a study from the United States found that the incidence of colorectal cancer in IBD patients was essentially stable over time from 1998 to 2010, being about 60% higher than in the general population [84]. Additional studies are needed to clarify if the cancer risk in IBD is changing and, if so, if this is due to surveillance programs or new treatments such as biological drugs. Risk factors for dysplasia include a macroscopically large extent of inflammation, pancolitis and primary sclerosing cholangitis [76,85,86]. The risk of colon cancer in paediatric IBD patients remains controversial, but much less than in IBD overall [87]. The distribution of cancer sites in UC includes the left colon and the rectum, followed by the right colon, while in CD the sites involved by malignancy include the ileum, jejunum, large bowel and the ileostomy site [87]. Dysplasia should be distinguished into low and high degrees, using the cytoarchitectural morphological criteria of the World Health Organization [88]. In low-grade dysplasia, crypt architecture shows minimal distortion and the cytological atypia is limited to the lower half of the crypts. Cytologically, the nuclei have slight hyperchromasia and the nuclear membrane has irregular edges. Dystrophic goblet cells (hypermucinous dysplasia) may be evident. High-grade dysplasia is characterized by greater architectural complexity. The cells show more atypia, with marked nuclear pleomorphism, an irregular nuclear membrane, and a macronucleolus with greater loss of polarity in the crypts and consequently greater nuclear stratification. Cytoarchitectural alterations that do not fully fall into dysplastic lesions or are not hyperplastic-regenerative abnormalities secondary to inflammation or medical treatment are considered “indefinite for dysplasia”. Dysplasia may be seen in mucous areas without significant macroscopic changes (flat mucosa) or in polypoid lesions [89–93]. For the histopathological diagnosis of high-grade dysplastic lesions there is fairly high interobserver concordance, but for lowgrade dysplastic lesions and indefinite dysplasia the interobserver variability is high [93]. A concordance study involving four pathologists and 38 cases of dysplasia found fair agreement (k = 0.4) [94]. A more recent study found low agreement for samples of indefinite dysplasia ( = 0.25), while samples that were negative for dysplasia had high agreement ( = 0.82) and those with high-grade dysplasia had the highest agreement ( = 1.0) [95]. Therefore, for unclear samples, the diagnosis should be confirmed by a second opinion of an expert pathologist. Overall, the sensitive detection of preneoplastic (dysplastic) lesions and a diagnostic approach with low interobserver variability between pathologists are essential in the management of IBD patients, in order to decrease the risk of progression towards invasive, neoplastic lesions. Statement 13 The histopathological report on dysplasia in CD or UC should clearly describe the morphological elements mandatory for diagnosis: grade of

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dysplasia, single or multiple foci of dysplasia, and grade of infiltration in the submucosa. The histological report should be precise in the definition of dysplasia, and should clearly report the degree of cellular atypia (lowor high-grade dysplasia). The localization of dysplasia and number of foci in biopsy fragments should be specified. For advanced lesions with infiltrating patterns (adenocarcinoma), the report should indicate the level of infiltration when feasible (e.g. submucosal invasion) and the presence of unfavourable factors such as tumour budding and lymphovascular invasion. 6. Conclusions The histological diagnosis of IBD requires specific pathological competences. The identification of particular histomorphological features is fundamental for the precise definition of UC, CD and their clinical variants. The statements in this paper underline key points for the correct methodological approach to an IBD diagnosis and to its histopathological reporting by pathologists. Conflict of interest We declare no conflict of interests and no financial support. Acknowledgements Special thanks go to AITIC (Italian Association of Laboratory Technicians) for scientific support regarding the methodological handling of biopsy samples and to AMICI Onlus (National IBD Patients’ Association) for administrative support. The authors also thank Valerie Matarese for editing the manuscript. References [1] Gajendran M, Loganathan P, Jimenez G, Catinella AP, Ng N, Umapathy C, et al. A comprehensive review and update on ulcerative colitis. Dis Mon 2019;(March), pii: S0011-5029(19)30031-8. [2] Gajendran M, Loganathan P, Catinella AP, Hashash JG. A comprehensive review and update on Crohn’s disease. Dis Mon 2018;64(February (2)):20–57. [3] Magro F, Langner C, Driessen A, Ensari A, Geboes K, Mantzaris GJ, et al. European consensus on the histopathology of inflammatory bowel disease. J Crohns Colitis 2013;7(November (10)):827–51. [4] Langner C, Magro F, Driessen A, Ensari A, Mantzaris GJ, Villanacci V, et al. The histopathological approach to inflammatory bowel disease: a practice guide. Virchows Arch 2014;464(May (5)):511–2. [5] Price AB. The Sydney system: histological division. Gastroenterol Hepatol 1991;6:209–22. [6] DeRoche TC, Xiao SY, Liu X. Histological evaluation in ulcerative colitis. Gastroenterol Rep (Oxf) 2014;2(August (3)):178–92. [7] Caprilli R, Latella G, Vernia P, Frieri G. Multiple organ dysfunction in ulcerative colitis. Am J Gastroenterol 2000;95(May (5)):1258–62. [8] Villanacci V, Antonelli E, Reboldi G, Salemme M, Casella G, Bassotti G. Endoscopic biopsy samples of naïve “colitides” patients: role of basal plasmocytosis. J Crohns Colitis 2014:1438–43. [9] 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(January (1)):55–67. [10] Zezos P, Patsiaoura K, Nakos A, Mpoumponaris A, Vassiliadis T, Giouleme O, et al. Severe eosinophilic infiltration in colonic biopsies predicts patients with ulcerative colitis not responding to medical therapy. Colorectal Dis 2014;16(December (12)):O420–30. [11] Leoncini G, Villanacci V, Marin MG, Crisafulli V, Cadei M, Antonelli E, et al. Colonic hypereosinophilia in ulcerative colitis may help to predict the failure of steroid therapy. Tech Coloproctol 2018;22(December (12)):941–6. [12] Geboes K, Dewit O, Moreels TG, Faa G, Jouret-Mourin A. Inflammatory bowel disease. In: Jouret-Mourin A, editor. Colitis. Springer; 2018. p. 119. [13] Canavese G, Villanacci V, Antonelli E, Cadei M, Sapino A, Rocca R, et al. Eosinophilia-associated basal plasmacytosis: an early and sensitive histologic feature of inflammatory bowel disease. APMIS 2017;125(March (3)):179–83. [14] Feakins RM. Inflammatory bowel disease biopsies: updated British Society of Gastroenterology reporting guidelines. J Clin Pathol 2013;66(December (12)):1005–26. [15] Stange EF, Travis SP, Vermeire S, Reinisch W, Geboes K, Barakauskiene A, et al. European evidence-based consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohns Colitis 2008;2:1–23.

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Please cite this article in press as: Villanacci V, et al. Histopathology of inflammatory bowel disease — Position statement of the Pathologists of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) and Italian Group of Gastrointestinal Pathologists (GIPAD-SIAPEC). Dig Liver Dis (2019), https://doi.org/10.1016/j.dld.2019.11.005