AWE-02 Morphological and molecular markers for coexistent adenocarcinoma in low-grade dysplastic areas of high-grade colorectal adenomas

IntroductionSuccessful endoscopic resection (ER) relies on endoscopic diagnosis to predict the risk of invasive cancer. However, a detailed evaluation of histopathological features and the molecular profile of the dysplastic mucosa to predict coexistent invasive cancer is not available.MethodsER of large colorectal adenomas (2011–2016) were analysed. A subset containing high-grade dysplasia, intramucosal cancer or invasive cancer was identified and subjected to detailed histopathological analysis: ulceration, distribution of high-grade dysplasia, dysplastic nuclear grade, presence/distribution of necrosis, and distribution of tumour-infiltrating lymphocytes (TIL). Microdissection, DNA extraction and next-generation sequencing using a human clinically relevant tumour panel of 24 genes were performed separately for two areas with the highest morphological grade from each lesion.ResultsER was performed for 418 large (≥20 mm) adenomas. Histopathological genetic evaluation was available in 70 high grade cases. Coexistent adenocarcinoma significantly correlated with adenomatous mucosa featuring ulceration, mixed interface/interstitial TIL, multifocal high nuclear grade, infiltrative edges, and multifocal intraluminal necrosis. Multifocal intraluminal necrosis and high nuclear grade in the adjacent low-grade dysplastic mucosa were driven by cooperative genetic abnormalities of high-impact (FLT4), moderate impact (KRAS/NRAS for infiltrative edges, FLT4, TP53, ERBB2), and low impact (FGFR3, PDGFA).ConclusionsThe dysplastic stage of high-grade adenomas is characterized by multiple cooperative genetic mutations. A subset of these identify a risk of coexistent adenocarcinoma with a close correlation between genetic markers of angiogenesis (FLT4), receptor activation (RAS/ERBB2), genome maintenance (TP53) and stromal reaction (FGFR3, PDGFRA) with morphological features defined by high nuclear grade, intraluminal necrosis, and inflammatory stromal reaction.