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Microscopic heterogeneity in ulcerative colitis: implications for microscopic measurement of disease activity
  1. Noam Harpaz1,2,
  2. Samuel Ballentine1,
  3. Jean-Frederic Colombel2,
  4. Bruce E Sands2,
  5. Huabin Mabel Ko1,2
  1. 1Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  2. 2Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  1. Correspondence to Dr. Noam Harpaz, Department of Pathology, Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; noam.harpaz{at}

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Growing interest in histological measurements of inflammatory  activity to determine therapeutic efficacy and endpoints in IBD has been accompanied by progress in developing and validating scoring instruments for this purpose.1–5 Four histological grading instruments, the Geboes score, Nancy index, Robarts Histological Index (RHI) and modified Riley score, have recently demonstrated responsiveness to clinical changes based on data from a phase II trial of ozanimod.6 Further refinement of the operating characteristics of these instruments and definition of threshold values for remission can be expected.7

Less attention has been given to pre-analytical factors which might affect the histological assessment of disease activity and the definition of therapeutic endpoints, such as biopsy sampling density and target selection. Clinical consensus guidelines have thus far provided only empirical guidance. The European Crohn’s and Colitis Organisation (ECCO) guidelines for initial IBD diagnosis recommend two forceps biopsies from each of five sites in the colorectum and terminal ileum and separate biopsies from endoscopically distinct regions8 but do not address sampling density and target selection in other clinical situations. Likewise, uniform standards for biopsy sampling in therapeutic drug trials are lacking. One study has reported good endoscopic concordance between the rectosigmoid and proximal colon at baseline and after therapy9 but it is unknown whether the same can be concluded for microscopic inflammation.

One of the assumptions made in designing and interpreting biopsy studies in the setting of UC is that the characteristically continuous macroscopic distribution of inflammation in UC is similarly uniform on a microscopic scale. To test this assumption, we measured microscopic inflammation in biopsy-sized microscopic fields in colectomy specimens. Random sections of the ascending and rectosigmoid colon from 18 unselected adults with ulcerative pancolitis were scored in a series of consecutive 2.0 mm diameter (×100) microscopic mucosal fields by two pathologists using the Nancy Histological Index (NHI) to generate a score of 0–4 per field.2 10 The RHI was then used to score four individual histological parameters: chronic inflammation, lamina propria neutrophils, intraepithelial neutrophils and erosions.4 Median NHI scores and proportions of discrepant fields, that is, those with scores higher or lower by >0.5, were determined for each series. Demographic and clinical data were extracted from electronic records. Preoperative endoscopic images were not reviewed.

The subjects spanned a diverse spectrum of clinical characteristics table 1.

Table 1

Characteristics of patients with UC

A mean 70.4±24.1 microscopic fields were assessed per series. As shown in figure 1A, the mean proportions of discrepant fields in the ascending and rectosigmoid colon were 31.7 and 33.4%, respectively, and discrepancies ≥3 occurred in 11/18 (61%) and 12/18 (67%) series, respectively. The only colectomy yielding a uniform score of 0 was from a patient with clinically quiescent UC who underwent surgery for management of dysplasia. Microscopic heterogeneity was observed in all four histological parameters assessed by the RHI figure 1B, reflecting a non-uniform mucosal distribution of the individual microscopic elements on which histological measurements are based.

Figure 1

(A) NHI scores of individual ×100 microscopic fields as a proportion of total fields scored in the ascending and rectosigmoid colon. (B) Illustration of RHI and individual histological component scores in consecutive ×100 microscopic fields from rectosigmoid colon in a representative case of UC. NHI, Nancy Histological Index; RHI, Robarts Histological Index.

The median NHI scores in the ascending colon exceeded those in the rectosigmoid in 3/18 series (17%) series and the reverse occurred in 7/18 series (39%).

These observations highlight the need for prospective biopsy-based studies of patients with UC to determine optimal biopsy sampling densities and target selection for clinical and investigative purposes. Microscopic heterogeneity should also be recognised as a potential confounding factor in previously published biopsy-based studies dealing with endoscopic-histological correlations, anatomical variations and temporal dynamics of microscopic inflammation in UC.


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  • Patient consent for publication Not required.

  • Contributors All authors contributed to writing or editing the article.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests Dr NH reports personal fees from Celgene, Inc, personal fees from Abbvie, Inc, outside the submitted work; Dr BS reports personal fees from AbbVie, personal fees from Amgen, personal fees from Bristol-Myers Squibb, grants, personal fees and non-financial support from Celgene, personal fees and non-financial support from Janssen, personal fees and non-financial support from MedImmune, grants, personal fees and non-financial support from Takeda, personal fees from Akros Pharma, personal fees from Arena Pharmaceuticals, personal fees from Boehringer-Ingelheim, personal fees from Forward Pharma, personal fees from Immune Pharmaceuticals, personal fees and non-financial support from Lilly, personal fees from Shire, personal fees from Synergy Pharmaceuticals, personal fees from Theravance Biopharma R&D, personal fees from TiGenix, personal fees from TopiVert Pharma, personal fees from Receptos, personal fees from Allergan, personal fees from EnGene, personal fees from Target PharmaSolutions, personal fees from Lycera, personal fees from Lyndra, personal fees from Ironwood Pharmaceuticals, personal fees from Salix, personal fees from Vivelix Pharmaceuticals, personal fees from UCB, personal fees from Oppilan Pharmaceuticals, personal fees from Gilead, personal fees from Rheos Medicines, personal fees from Seres Therapeutics, personal fees from 4D Pharma, personal fees from Capella Bioscience, personal fees from Otsuka, personal fees from Ferring, personal fees from Protagonist Therapeutics, personal fees from Palatin Technologies, grants, personal fees and non-financial support from Pfizer, outside the submitted work. Dr JC reports grants and other from AbbVie, other from Amgen, other from Boehringer-Ingelheim, other from Arena Pharmaceuticals, other from Celgene Corporation, other from Celltrion, other from Enterome, other from Eli Lilly, other from Ferring Pharmaceuticals, other from Genentech, grants and other from Janssen and Janssen, other from Medimmune, other from Merck & Co, other from Nextbiotix, other from Novartis Pharmaceuticals Corporation, other from Otsuka Pharmaceutical Development & Commercialization, Inc, other from Pfizer, other from Protagonist, other from Second Genome, other from Gilead, other from Seres Therapeutics, other from Shire, grants and other from Takeda, other from Theradiag, other from Intestinal Biotech Development, other from Genfit, other from Zealand Pharma, outside the submitted work.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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