P133 A novel candidate pathway for development of neoplasms with serrated morphology in patients with ulcerative colitis

Abstract

Background: Patients with ulcerative colitis (UC) are at increased risk of development of colorectal cancer (CRC). CRC in patients with UC, termed colitis-associated CRC (CAC), develops through an inflammation–dysplasia–carcinoma sequence. Neoplasms with serrated morphology have been reported in UC patients; however, their features are yet to be fully elucidated. Here, we clarify the clinical, histopathological and molecular features of such neoplasms and investigate a possible novel neoplastic pathway in UC patients. Methods: We analysed seven neoplasms with serrated morphology that had been endoscopically or surgically resected from five patients with UC and compared them with those of 35 other patients with canonical CAC/dysplasias (including 13 CACs, 13 high grade and nine low grade dysplasias). We reviewed these patients' clinical features and performed morphological, histopathological and immunohistochemical analyses of these lesions. We used a laser micro-dissection system (LMD) to accurately isolate atypical glands from formalin-fixed paraffin embedded (FFPE) sections and frozen samples and precisely determine genomic alterations. Genomic DNA was eluted and gene mutations studied by using next-generation sequencing (NGS) analysis, a >2% mutation frequency being defined as positive. Results: All neoplasms with serrated morphology were located in chronically inflamed mucosa. All neoplasms were of elevated type; the median size was 15 mm (range, 5–40). Their pathological features were atypical of canonical CAC/dysplasias, sporadic sessile serrated adenoma/polyps (SSA/P) or traditional serrated adenomas (TSA). The patients with neoplasms with serrated morphology at diagnosis of UC were significantly younger than those with canonical CAC/dysplasias (median 26.4 years [range, 19.1–62.7] vs. 36.6 [15.3–66.1], p=0.06). Immunohistochemical analysis showed most neoplasms with serrated morphology and CAC/dysplasias had similar mucin expression profiles. Genomic mutations were identified in three neoplasms with serrated morphology (one adenocarcinoma in situ with SSA/P, two TSAs) by NGS. KRAS mutation was detected in all of them. APC and BRAF mutations were not detected and TP53 mutation was found in only one case (adenocarcinoma). Conclusions: In this study, neoplasms with serrated morphology in association with UC developed in chronically inflamed mucosa, and had atypical macroscopic and microscopic morphology and genomic mutations. These findings, suggest that neoplasms with serrated morphology in patients with UC do not develop through an inflammation–dysplasia–carcinoma sequence, but through an alternative novel serrated neoplasia pathway.