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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.

ntroduction Guidelines on endoscopic resection (ER) of colorectal superficial neoplastic lesions (CSNL) recommend against biopsy sampling but many are extensively sampled prior to referral, despite the deleterious effect on ER, to exclude adenocarcinoma or high grade dysplasia (HGD), reflecting a lack of understanding of the incidence and nature of adenocarcinoma or HGD within different morphological sub-types. It is therefore important to define the significance of HGD on biopsy samples and place this in the context of the histopathological characteristics of high risk lesions.Methods ERs of large (≥2 cm) CSNL were included. Sensitivity and specificity of HGD on biopsy and higher risk morphology (laterally spreading tumour (LST) non-granular/LST mixed nodular type/IIc component) for diagnosing covert invasive adenocarcinoma and confirmed HGD after ER were calculated and compared (Mcnemar’s test). In addition, 50 high risk lesions (containing HGD or invasive adenocarcinoma) were subjected to more detailed histopathological analysis.Results Results from prior biopsy sampling were available for 291 lesions (mean size 62.8 mm). Histopathology after ER revealed HGD in 85 (29%) and invasive adenocarcinoma in 26 (9%). Sensitivity and specificity of HGD on biopsy (n=60) for invasive adenocarcinoma were 50% (95% CI 32%–68%) and 82% (95%–CI 77%–86%), and for confirmed HGD after ER were 47% (95% CI 37%–57%) and 90% (95% CI 85%–94%) respectively. Sensitivity and specificity of high risk morphology (n=124) for HGD after ER were 71% (95% CI 60%–79%) and 69% (95% CI 62%­75%) respectively. The sensitivity of high risk morphology was significantly higher than HGD on biopsy sampling (p=0.002).Detailed histopathological analysis of high risk lesions revealed invasive adenocarcinoma in 40% but a further 18% had non-invasive areas with cytological and architectural features indistinguishable from invasive adenocarcinoma. HGD was multifocal in 56%. The mean size of the focus of HGD was only 5.6 mm, and of adenocarcinoma was 11.0 mm. Mean lesion size was 53.6 mm.Conclusion Biopsy sampling of large CSNL has no value in excluding high risk lesions and morphology alone has higher sensitivity for high risk lesions. Histopathological analysis of high risk lesions reveals that areas of HGD or adenocarcinoma are very small relative to the lesion size and many contain non-invasive areas which would be cytologically indistinguishable from invasive adenocarcinoma on a biopsy. Despite this, biopsy sampling remains extremely common. Understanding of these findings and improved education regarding accurate lesion assessment may help reduce rates of inappropriate sampling.

Introduction Guidelines on endoscopic resection (ER) of colorectal superficial neoplastic lesions (CSNL) recommend against biopsy sampling, but many lesions are extensively sampled prior to referral. Although this has a deleterious effect on ER, endoscopists are often eager to exclude adenocarcinoma or high-grade dysplasia (HGD), which is seen as a marker of high-risk lesions, reflecting a lack of understanding of the incidence and nature of adenocarcinoma or HGD within different morphological sub-types. It is therefore essential to define the significance of HGD on biopsy samples of CSNL and place this in the context of the histopathological characteristics of high-risk lesions. Methods ERs of large (≥2cm) CSNL were included. Sensitivity and specificity of HGD on biopsy and higher risk morphology (laterally spreading tumour (LST) non-granular/LST mixed nodular type/IIc component) for diagnosing covert invasive adenocarcinoma and confirmed HGD after ER were calculated and compared (Mcnemar’s test). In addition, 50 high-risk lesions (defined as containing HGD or invasive adenocarcinoma) were subjected to more detailed histopathological analysis. Results Results from previous biopsy sampling were available for 291 lesions (mean size 62.8mm). Histopathological examination after ER revealed HGD in 85 (29%) and invasive adenocarcinoma in 26 (9%). Sensitivity and specificity of HGD on biopsy sampling (n=60) for invasive adenocarcinoma were 50% (95% CI 32%-68%) and 82% (95% CI 77%-86%), and for confirmed HGD after ER were 47% (95% CI 37%-57%) and 90% (95% CI 85%-94%) respectively. Sensitivity and specificity of high risk morphology (n=124) for HGD after ER were 71% (95% CI 60%-79%) and 69% (95% CI 62%-75%) respectively. The sensitivity of high-risk morphology was significantly higher than HGD on biopsy sampling (p=0.002). Detailed histopathological analysis of lesions containing HGD or adenocarcinoma (n=50) revealed invasive adenocarcinoma in 40%, but a further 18% had non-invasive areas with cytological and architectural features indistinguishable from invasive adenocarcinoma. HGD was multifocal in 56%. The mean size of the focus of HGD was only 5.6mm, and of invasive adenocarcinoma was 11.0mm. The mean lesion size was 53.6mm. Conclusion Biopsy sampling of large CSNL has no value in excluding high-risk lesions and morphology alone has higher sensitivity for high-risk lesions. Histopathological analysis of high-risk lesions reveals that areas of HGD or adenocarcinoma are very small relative to the lesion size and many contain non-invasive regions which would be cytologically indistinguishable from invasive adenocarcinoma on a biopsy. Despite this, biopsy sampling remains extremely common. Understanding of these findings and improved education regarding accurate lesion assessment may help reduce rates of inappropriate sampling.