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Histological and molecular diversity and heterogeneity of precancerous lesions associated with inflammatory bowel diseases
  1. Xianyong Gui1,2,
  2. Martin Köbel2,
  3. Jose GP Ferraz3,
  4. Marietta Iacucci4,
  5. Subrata Ghosh4,
  6. Shuhong Liu2,
  7. Young Ou2,
  8. Marco Perizzolo2,
  9. Robert J Winkfein2,
  10. Peter Rambau2,
  11. Douglas J Demetrick2
  1. 1 Pathology, University of Washington School of Medicine, Seattle, Washington, USA
  2. 2 Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  3. 3 Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  4. 4 NIHR Biomedical Research Centre, Institute of Translational Medicine, University of Birmingham, Birmingham, Birmingham, UK
  1. Correspondence to Dr Xianyong Gui, Pathology, University of Washington School of Medicine, Seattle, Washington, USA; xgui{at}


Aims Inflammatory bowel disease (IBD)-associated precancerous lesions may be adenomatous or non-adenomatous with various histomorphologies. We aim to validate the newly proposed classification, to explore the neoplastic nature of the non-adenomatous lesions and to elucidate the molecular mechanisms underlying the different histomorphologies.

Methods 44 background precursor lesions identified in 53 cases of surgically resected IBD-associated colorectal and ileal carcinomas were reviewed for the histomorphological features (classified into adenomatous, mucinous, sessile serrated adenoma (SSA)-like, traditional serrated adenoma-like, differentiated, eosinophilic and serrated not otherwise specified (NOS)) and analysed for a key panel of colonic cancer-related molecular markers.

Results Approximately 60% of the lesions were adenomatous, of which some had mixed serrated, mucinous or eosinophilic changes. The remaining non-adenomatous lesions, including all other types except SSA-like type, mostly showed mixed features and focal adenomatous dysplasia. KRAS mutation and p53 mutant-type expression were found in about half cases across all types, while PIK3CA mutation only in some of adenomatous and eosinophilic lesions and MLH1/PMS2 loss in a subset of adenomatous, mucinous and eosinophilic but not in differentiated and serrated lesions. SAT-B2 or PTEN loss and IMP3 overexpression were seen in a small subset of lesions. No BRAF, NRAS or EGFR gene mutation was detected in any type. Certain molecular-morphological correlations were demonstrated; however, no single or combined molecular alteration(s) was specific to any particular morphological type.

Conclusions IBD-associated precancerous lesions are heterogeneous both histologically and molecularly. True colitis-associated adenomatous lesions are unlikely conventional adenomas. Non-adenomatous lesions without frank cytologic dysplasia should also be regarded as neoplastic.

  • inflammatory bowel disease
  • colorectal cancer
  • genetics
  • oncogenes
  • gut pathology

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  • Handling editor Runjan Chetty.

  • Correction notice The paper has been corrected since it appeared Online First. The author Marco Perizzolo's name was mispelled as 'Perrizzolo' and has been corrected.

  • Contributors XG designed the study, performed the pathology review, selected and collected the tissue samples for study, read the immunohistochemistry, analyse the entire data and wrote the manuscript which was reviewed by all coauthors. MK provided some antibodies and read the immunohistochemistry. PFR read the immunohistochemistry. JF, MI and SG performed clinical and endoscopic data review. SL and YO performed the tissue punching, TMA construction and immunohistochemistry. MP and RJW performed molecular testing and analysed the results. DJD helped study design and reviewed molecular testing results.

  • Funding This study was supported by an internal research fund (RS17-612) from Calgary Laboratory Services (now Alberta Public Laboratories).

  • Competing interests None declared.

  • Patient consent for publication Not required.

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

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.