New Developments to Standardise the Assessment of Mucosal Histology in Crohn’s Disease

The aim of Magro et al. is to standardise the assessment of mucosal histology in Crohn’s Disease (CD), and they propose a number of position statements. A full evaluation of CD requires ileocolonoscopy, and both severely inflamed and uninflamed segments should be biopsied. A good sampling regimen might be two biopsy pieces from the ileum and two from each of the five colon segments, submitted in separate containers. This should, of course, be accompanied by full clinical information. Pathologists will look for features of chronic and active inflammation. Only neutrophils are always abnormal and therefore define histological disease activity. There is, however, currently no validated histological disease activity score; for example, the Global Histological Activity Score (GHAS) lacks formal validation studies. The authors suggest obviating this shortcoming by the application of scores developed for Ulcerative Colitis, such as the Geboes score, the Robarts Histopathology Index and the Nancy Histological Index. There is also no widely accepted or validated definition of histological remission in CD. The authors propose absence of ulceration, erosions and mucosal neutrophils as a good definition of histological remission and a realistic endpoint after induction therapy in CD.

Gordon et al. rightly emphasise that timely identification and treatment of stricturing disease would be of major importance for CD patients. Unfortunately, strictures often become symptomatic only late in the disease course. Currently, no valid scoring system exists that can express the histopathological changes seen in developing strictures. A literature review demonstrated that the existing scoring systems are heterogeneously composed and put unequal emphasis on various features felt to be related to stricture formation. The STAR consortium addressed this problem by applying a modified RAND/UCLA exercise to establish a valid stricture histopathology scoring system. It was decided that the optimal study material was perpendicular cross-sections, one per centimetre of stricture, evaluated on H&E. In such biopsies, the thickened bowel wall in strictured areas was typically caused by widening of the muscularis mucosae and the muscularis propria. Submucosal fibrosis was difficult to rate. At present, the contribution of each layer of the bowel wall to stricturing disease remains unclear. It should be further investigated whether scoring a set of morphological parameters in each of the bowel layers and summation of these findings is the best approach.

The increased risk of development of dysplasia and carcinoma in IBD patients is an important clinical issue and a subject of ongoing research.

Currently it is controversial whether targeted biopsies can completely replace random biopsies for dysplasia surveillance in IBD. This issue has become more complex following the recent description of several non-conventional types of dysplasia in IBD. Bahceci et al. addressed this question by searching for dysplastic lesions in colectomy specimens of patients who had at least one high-definition colonoscopy prior to colectomy [3]. Dysplasia found in the colectomies was referred to as undetected if it had not been found in previous colonoscopic biopsies. The rate of undetected dysplasia was 13%, which suggests that increased random biopsies may improve the rate of dysplasia detection. Moreover, previously undetected dysplasia was more often grossly flat or invisible and showed microscopically non-conventional features (especially the hypermucinous subtype, followed by the goblet cell-deficient type and crypt cell dysplasias). This is important, given that these three subtypes have been reported to harbour molecular features of advanced neoplasia, such as aneuploidy and KRAS mutations. The authors therefore argue that the finding of non-conventional dysplasia, in particular flat/invisible lesions, should trigger more aggressive colonoscopic surveillance with increased random biopsy sampling or possibly preventive colectomy.

Detection of dysplasia in IBD is further complicated by the occurrence of cytological atypia in a context of active inflammation. These features may be sufficiently severe to warrant the designation “indefinite for dysplasia”. Biomarkers such as AMACR, Ki-67 and p53 may not be sensitive enough to detect neoplastic epithelium in these circumstances. Special AT-rich sequence-binding protein 2 (SATB2) is lost in some IBD-associated adenocarcinomas and dysplasias. Cretara et al. investigated the prevalence of SATB2 loss of expression in biopsies interpreted as indefinite for dysplasia [4]. Their observations suggest that SATB2 loss in such biopsies may be associated with an increased risk of detection of definitive dysplasia on follow-up, thus marking a patient population at high risk for disease progression.

References

1. Magro F, Sabino J, Rosini F, et al. The ECCO position on harmonisation of Crohn’s disease mucosal histopathology. J Crohns Colitis. 2022;16:876–83.
2. Gordon IO, Bettenworth D, Bokemeyer A, et al. International consensus to standardise histopathological scoring for small bowel strictures in Crohn’s disease. Gut. 2022;71:479–86.
3. Bahceci D, Lauwers GY, Choi WT. Clinicopathological features of undetected dysplasia found in total colectomy or proctocolectomy specimens of patients with inflammatory bowel disease. Histopathology. 2022;81:183–91.
4. Cretara A, Knee A, Mueller J, et al. Association between loss of SATB2 expression in inflammatory bowel disease indefinite for dysplasia and a diagnosis of definitive dysplasia on follow-up. Am J Surg Pathol. 2022;46:1137–41.