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Original article
Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma
  1. Mark Bettington1,2,3,
  2. Neal Walker1,2,
  3. Christophe Rosty1,2,
  4. Ian Brown2,
  5. Andrew Clouston1,2,
  6. Diane McKeone3,
  7. Sally-Ann Pearson3,
  8. Barbara Leggett1,3,4,
  9. Vicki Whitehall1,3,5
  1. 1School of Medicine, The University of Queensland, Brisbane, Queensland, Australia
  2. 2Envoi Specialist Pathologists, Brisbane, Queensland, Australia
  3. 3The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  4. 4The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
  5. 5Department of Chemical Pathology, Pathology Queensland, Brisbane, Queensland, Australia
  1. Correspondence to Dr Mark Bettington, The Conjoint Gastroenterology Laboratory, Level 7, CBCRC, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD 4006, Australia; Mark.Bettington{at}qimr.edu.au, MarkBettington{at}envoi.com.au

Abstract

Objective Sessile serrated adenomas (SSAs) are the precursors of at least 15% of colorectal carcinomas, but their biology is incompletely understood. We performed a clinicopathological and molecular analysis of a large number of the rarely observed SSAs with dysplasia/carcinoma to better define their features and the pathways by which they progress to carcinoma.

Design A cross-sectional analysis of 137 SSAs containing regions of dysplasia/carcinoma prospectively collected at a community GI pathology practice was conducted. Samples were examined for BRAF and KRAS mutations, the CpG island methylator phenotype (CIMP) and immunostained for MLH1, p53, p16, β-catenin and 0-6-methylguanine DNA methyltransferase (MGMT).

Results The median polyp size was 9 mm and 86.5% were proximal. Most were BRAF mutated (92.7%) and 94.0% showed CIMP. Mismatch repair deficiency, evidenced by loss of MLH1 (74.5%) is associated with older age (76.7 versus 71.0; p<0.0029), female gender (70% versus 36%; p<0.0008), proximal location (91% versus 72%; p<0.02), CIMP (98% versus 80%; p<0.02) and lack of aberrant p53 (7% versus 34%; p<0.001) when compared with the mismatch repair-proficient cases. Loss of p16 (43.1%) and gain of nuclear β-catenin (55.5%) were common in areas of dysplasia/cancer, irrespective of mismatch repair status.

Conclusions SSAs containing dysplasia/carcinoma are predominantly small (<10 mm) and proximal. The mismatch repair status separates these lesions into distinct clinicopathological subgroups, although WNT activation and p16 silencing are common to both. Cases with dysplasia occur at a similar age to cases with carcinoma. This, together with the rarity of these ‘caught in the act’ lesions, suggests a rapid transition to malignancy following a long dwell time as an SSA without dysplasia.

  • COLON CARCINOGENESIS
  • COLONIC NEOPLASMS
  • COLONIC POLYPS
  • COLORECTAL CANCER GENES

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Footnotes

  • Contributors MB, NW, CR, IB, AC, BL and VW collaborated to develop the study design. MB, S-AP and DM performed the experimental work. MB and NW performed the histopathological analyses. MB, S-AP, DM and VW interpreted the data. MB wrote the manuscript. NW, CR, IB, AC, BL and VW amended the manuscript.

  • Funding This project was supported by a grant from the National Health and Medical Research Council (NHMRC) of Australia (ID: 1063105). Mark Bettington received PhD scholarship funding from Cancer Council Queensland.

  • Competing interests None declared.

  • Ethics approval The ethics committee of the QIMR Berghofer Medical Research Institute (P1298).

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

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