Inflammatory reaction patterns and molecular genetics in high-grade 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: 111202 Cancer Diagnosis
subject: FOS: Clinical medicine
subject: FOS: Clinical medicine
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 The grading of both neoplastic and dysplastic lesions is based on morphological and genetic changes of the epithelial cells. The inflammatory stromal changes are frequent findings that can contribute to the neoplastic progression, and their correlation is not fully established in high-grade adenomas of the colon as predictors of coexistent invasive malignancy. Methods: Data from endoscopic resection (ER) of colorectal superficial neoplastic lesions performed at a UK tertiary referral center (2011-2016) were analyzed. 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; the extension of TIL positively correlated with the presence of coexistent adenocarcinoma, and multifocal intraluminal necrosis and high nuclear grade. The presence of multifocal high-grade dysplasia was driven by different cooperative sets of genetic abnormalities regarding the TIL pattern: high-impact (TP53), and moderate impact (FLT4, ERBB2, RET/RAS/RAF/ERK) for an interface pattern, and high-impact (TP53, PDFGRA, FGFR3), and moderate impact (TP53, ERBB2, KRAS, RET/FGFR3) for an interstitial pattern. Conclusions A more extensive lymphocytic response contributes to the progression of adenomatous polyps and is associated with morphological changes of increased risk of adenocarcinoma (multifocal necrosis and high nuclear grade and abnormal TP53). An interface pattern expresses proliferative (receptor kinase) and vascular (FLT4) profile and the interstitial pattern outlines predominantly stromal (PDGFRA, FGFR3) features.