Su1070 – Morphological and Molecular Risk Markers for Coexistent Adenocarcinoma in Low-Grade Dysplastic Areas of Highgrade Colorectal Adenomas
Creators: name: Emmanuel, Andrew
name: Diaz-Cano, Salvador J.
name: Gulati, Shraddha
name: Burt, Margaret
name: Papagrigoriadis, Savvas
name: Hayee, Bu
name: Amyn Haji
Publisher: name: figshare
Year: 2019
Subjects: subject: 111201 Cancer Cell Biology
subject: FOS: Clinical medicine
subject: FOS: Clinical medicine
subject: 111202 Cancer Diagnosis
subject: 111203 Cancer Genetics
subject: 111204 Cancer Therapy (excl. Chemotherapy and Radiation Therapy)
subject: 110307 Gastroenterology and Hepatology
subject: 111299 Oncology and Carcinogenesis not elsewhere classified

description: Introduction Safe and effective endoscopic resection (ER) relies on the endoscopic diagnosis of large lesions to predict the risk of invasive cancer. However, a detailed evaluation of histopathological features and the molecular profile of the polypoid dysplastic mucosa to predict coexistent invasive neoplasm is not available. Methods: Data from endoscopic resection of colorectal superficial neoplastic lesions performed at a UK tertiary referral center (2011-2016) were analyzed. Lesions were assessed using magnification chromoendoscopy and narrow band imaging. A subset of these lesions containing high-grade dysplasia, intramucosal cancer or invasive cancer was identified and further subjected to a detailed histopathological analysis: endoscopic type, ulceration, distribution of high-grade dysplasia, dysplastic nuclear grade, presence and distribution of necrosis, and distribution of tumor-infiltrating lymphocytes (TIL). The two areas with the highest morphological grade were microdissected from each lesion, using 5μm FFPE sections. DNA extraction and next-generation sequencing using a human clinically relevant tumor panel (Qiagen, Hiden, Germany) of 24 genes were performed for each of these areas separately. Genetic abnormalities for each locus were categorized by genetic impact according to its severity (low/moderate/high/modifier) and allele frequency. Results: ER was performed for 418 large (≥20mm) colorectal superficial neoplastic lesions (mean size 55.2mm, range 20mm-160mm), 81% being laterally spreading tumors (LST). The proportions harboring an area of invasive cancer by morphological subtype were as follows: LST non-granular 30.8%; LST granular mixed-nodular type 12.3%; LST granular homogeneous type 0.9% and Is/Isp 11.4%. The histopathological genetic evaluation was available in 70 cases; a coexistent adenocarcinoma significantly correlated with dysplastic 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). Conclusions The dysplastic stage of high-grade adenomatous polyps is characterized by multiple cooperative genetic mutations. A subset of these markers 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.