Sessile Serrated Adenomas/polyps Research Articles

Clinicopathological features and expression of regulatory mechanism of the Wnt signaling pathway in colorectal sessile serrated adenomas/polyps with different syndrome types.

Colorectal cancer (CRC) is the third most common cancer worldwide, with the fourth highest mortality among all cancers. Reportedly, in addition to adenomas, serrated polyps, which account for 15%-30% of CRCs, can also develop into CRCs through the serrated pathway. Sessile serrated adenomas/polyps (SSAs/Ps), a type of serrated polyps, are easily misdiagnosed during endoscopy. To observe the difference in the Wnt signaling pathway expression in SSAs/Ps patients with different syndrome types. From January 2021 to December 2021, patients with SSAs/Ps were recruited from the Endoscopy Room of Shanghai Traditional Chinese Medicine-Integrated Hospital, affiliated with Shanghai University of Traditional Chinese Medicine. Thirty cases each of large intestine damp-heat (Da-Chang-Shi-Re, DCSR) syndrome and spleen-stomach weakness (Pi-Wei-Xu-Ruo) syndrome were reported. Baseline comparison of the general data, typical tongue coating, colonoscopy findings, and hematoxylin and eosin findings was performed in each group. The expression of the Wnt pathway-related proteins, namely β-catenin, adenomatous polyposis coli, and mutated in colorectal cancer, were analyzed using immunohistochemistry. Significant differences were observed with respect to the SSAs/Ps size between the two groups of patients with different syndrome types (P = 0.001). The other aspects did not differ between the two groups. The Wnt signaling pathway was activated in patients with SSAs/Ps belonging to both groups, which was manifested as β-catenin protein translocation into the nucleus. However, SSAs/Ps patients with DCSR syndrome had more nucleation, higher β-catenin expression, and negative regulatory factor (adenomatous polyposis coli and mutated in colorectal cancer) expression (P < 0.0001) than SSA/P patients with Pi-Wei-Xu-Ruo syndrome. In addition, the SSA/P size was linearly correlated with the related protein expression. Patients with DCSR syndrome had a more obvious Wnt signaling pathway activation and a higher risk of carcinogenesis. A high-quality colonoscopic diagnosis was essential. The thorough assessment of clinical diseases can be improved by combining the diseases of Western medicine with the syndromes of traditional Chinese medicine.

Incremental Detection Rate of Dysplasia and Sessile Serrated Polyps/Adenomas Using Narrow-Band Imaging and Dye Spray Chromoendoscopy in Addition to High-Definition Endoscopy in Patients with Long-Standing Extensive Ulcerative Colitis: Segmental Tandem Endoscopic Study.

High-definition (HD) endoscopy is recommended in surveillance colonoscopy for detecting dysplasia in patients with ulcerative colitis (UC). Dye-spray chromoendoscopy (DCE) and narrow-band imaging (NBI) are often used as adjunctive techniques of white-light endoscopy (WLE) in real-world practice. However, the incremental detection ability of DCE and NBI added to HD-WLE for dysplasia and serrated lesions has not yet been evaluated using tandem endoscopy in patients with long-standing extensive UC. We enrolled patients with extensive UC for >8 years who were in clinical remission (partial Mayo score < 2) at the Samsung Medical Center in Seoul, Republic of Korea. HD-WLE was performed first. Subsequently, HD-NBI and HD-DCE with indigo carmine were performed using the segmental tandem colonoscopy technique. A total of 40 patients were eligible, and data obtained from 33 patients were analyzed. The incremental detection rates (IDRs) for dysplasia and serrated lesions were calculated. HD-WLE detected three dysplasia and five sessile serrated adenomas/polyps (SSAs/Ps). HD-NBI and HD-DCE did not detect additional dysplasia (IDR = 0%; 95% confidence interval (CI): 0-56.2%). HD-NBI identified one missed SSA/P (IDR = 7.7%; 95% CI: 1.4-33.3%), and HD-DCE detected seven missed SSAs/Ps (IDR = 53.9%; 95% CI: 29.1-76.8%). Logistic regression found that HD-DCE increased the detection of SSAs/Ps compared to HD-WLE and/or HD-NBI (odds ratio (OR) = 3.16, 95% CI: 0.83-11.92, p = 0.08). DCE in addition to HD-WLE improved the detection of SSAs/Ps, but not dysplasia, in patients with long-standing extensive UC.

Multi-Classification of Polyps in Colonoscopy Images Based on an Improved Deep Convolutional Neural Network

Achieving accurate classification of colorectal polyps during colonoscopy can avoid unnecessary endoscopic biopsy or resection. This study aimed to develop a deep learning model that can automatically classify colorectal polyps histologically on white-light and narrow-band imaging (NBI) colonoscopy images based on World Health Organization (WHO) and Workgroup serrAted polypS and Polyposis (WASP) classification criteria for colorectal polyps. White-light and NBI colonoscopy images of colorectal polyps exhibiting pathological results were firstly collected and classified into four categories: conventional adenoma, hyperplastic polyp, sessile serrated adenoma/polyp (SSAP) and normal, among which conventional adenoma could be further divided into three sub-categories of tubular adenoma, villous adenoma and villioustublar adenoma, subsequently the images were re-classified into six categories. In this paper, we proposed a novel convolutional neural network termed Polyp-DedNet for the four- and six-category classification tasks of colorectal polyps. Based on the existing classification network ResNet50, Polyp-DedNet adopted dilated convolution to retain more high-dimensional spatial information and an Efficient Channel Attention (ECA) module to improve the classification performance further. To eliminate gridding artifacts caused by dilated convolutions, traditional convolutional layers were used instead of the max pooling layer, and two convolutional layers with progressively decreasing dilation were added at the end of the network. Due to the inevitable imbalance of medical image data, a regularization method DropBlock and a Class-Balanced (CB) Loss were performed to prevent network overfitting. Furthermore, the 5-fold cross-validation was adopted to estimate the performance of Polyp-DedNet for the multi-classification task of colorectal polyps. Mean accuracies of the proposed Polyp-DedNet for the four- and six-category classifications of colorectal polyps were 89.91% ± 0.92% and 85.13% ± 1.10%, respectively. The metrics of precision, recall and F1-score were also improved by 1%~2% compared to the baseline ResNet50. The proposed Polyp-DedNet presented state-of-the-art performance for colorectal polyp classifying on white-light and NBI colonoscopy images, highlighting its considerable potential as an AI-assistant system for accurate colorectal polyp diagnosis in colonoscopy.

Comparison of some biochemical markers between early-onset and late-onset colorectal precancerous lesions: A single-center retrospective study.

ObjectiveGiven that the onset of diseases including colorectal cancer precursors is affecting younger individuals and that obesity is an important risk factor for early‐onset, we conducted a study to explore the biochemical profile of differences in serum between early‐onset patients and late‐onset colorectal precancerous lesions.MethodsA total of 1447 patients, including 469 early‐onset patients and 978 late‐onset patients, were enrolled from the First Affiliated Hospital of Nanchang University (FAHNU), of which there were 311 sessile serrated adenoma/polyps (SSA/P) and 1136 normal adenomas. The distribution of the included categorical variables was compared via Pearson's chi‐squared test, whereas continuous variables were compared by using the nonparametric Kruskal–Wallis test and anova.ResultsCompared with late‐onset patients, the levels of total bilirubin and HDL‐C were lower (p < 0.05), whereas triglyceride and uric acid levels were higher, in early‐onset patients. Interestingly, in the subgroup analysis, triglyceride and uric acid levels remained at higher levels, whereas HDL‐C remained at lower levels, in early‐onset patients than in late‐onset patients. Other characteristics, such as LDL‐C, drinking, γ‐GT, and the N/L ratio, were similar between the two groups. An additional analysis of the association of tumor size with markers showed that lower levels of HDL‐C and higher levels of uric acid were associated with increased tumor size (p < 0.05).ConclusionsEarly‐onset CRC precursor cases exhibit higher levels of triglycerides and lower levels of HDL‐C than late‐onset cases. Additionally, levels of HDL‐C are negatively associated with tumor size, whereas uric acid was positively correlated with tumor size.

Transcriptome of sessile serrated adenoma/polyps is associated with MSI-high colorectal cancer and decreased expression of CDX2.

The objective of this study was to elucidate the molecular background of sessile serrated adenoma/polyp (SSA/P) endoscopically resected with comprehensive gene expression analysis. Gene expression profiling was performed for 10 tumor-normal pairs of SSA/P. Cluster analysis, gene set enrichment analysis (GSEA), and consensus molecular subtype (CMS) classification of colorectal cancer (CRC) were applied to our transcriptome analysis. Unsupervised cluster analysis showed that the gene expression profile of SSA/Ps is different from that of adjacent normal epithelial cells, even in the very early stage of tumorigenesis. According to the CMS classification, our microarray data indicated that SSA/Ps were classified as CMS1. GSEA demonstrated a strong association between SSA/P and microsatellite instability-high (MSI-H) CRC (p < 10-5 ). Transcriptome analysis of five MSI-related genes (MSH2, MSH6, MLH1, PMS1, and PMS2) and five CRC-related genes (BRAF, KRAS, APC, TP53, and CDX2) showed that CDX2 expression was most severely decreased in SSA/P. Immunohistochemical staining confirmed that CDX2 protein was reduced compared with the surrounding mucosa. Direct sequencing of the BRAF gene showed that the BRAF V600E mutation was detected in only nine of 36 cases. In a mouse model, BRAF, APC, or CDX2 deficiency indicated that the gene expression pattern with loss of CDX2 is more similar to our SSA/Ps compared with those induced by BRAF or APC mutation. Transcriptome analysis of SSA/Ps showed characteristic gene expression with a strong resemblance to MSI-H CRC. Downregulation of CDX2 expression is an essential molecular mechanism involved in the initial stage of SSA/P tumorigenesis. (UMIN000027365).

Prospective comparison of diagnostic performance of magnifying endoscopy and biopsy for sessile serrated adenoma/polyp.

BackgroundMagnifying narrow-band imaging (M-NBI) has recently improved the accuracy of endoscopic diagnosis of gastrointestinal tumors, including colorectal polyps. However, it can be difficult to distinguish between sessile serrated adenoma/polyps (SSA/Ps) and other polyps, especially hyperplastic polyps (HPs), by histological biopsy, because diagnostic features of SSA/Ps can be detected around the colon crypt bases. We aimed to evaluate the accuracy of endoscopic diagnosis of SSA/Ps using M-NBI compared with histological biopsy.MethodsWe prospectively enrolled patients diagnosed with SSA/Ps by preoperative endoscopy and assessed the diagnostic accuracy. The primary outcome was the diagnostic accuracy of endoscopy and biopsy.ResultsBetween August 2015 and October 2017, 295 lesions were resected by polypectomy or endoscopic mucosal resection, and 79 endoscopically resected specimens that were endoscopically diagnosed as SSA/P underwent biopsy for histological examination. Two lesions were excluded because the specimens were too small for histological examination. Finally, 77 endoscopically resected specimens and 77 biopsy specimens were included in the analysis. Histopathological examination showed 67 SSA/Ps, 8 HPs, and 2 adenomas. The sensitivity, specificity and accuracy of endoscopic M-NBI diagnosis for SSA/Ps were 95.7%, 95.5% and 95.6%, respectively. The sensitivity, specificity and accuracy of histological diagnosis of a single biopsy specimen were 71.6%, 90.0% and 74.0%, respectively. The McNemar test showed significant differences between biopsy and endoscopy diagnoses (P=0.001).ConclusionThis study shows that biopsy may be avoided by using M-NBI in patients with suspected SSA/Ps.

Sessile serrated adenoma/polyp detection rate of water exchange, Endocuff, and cap colonoscopy: A network meta-analysis.

Sessile serrated adenoma/polyp (SSA/P) may contribute to interval cancer. In a recent meta-analysis, water exchange (WE) was shown to be superior to Endocuff and cap colonoscopy at adenoma and advanced adenoma detection. The strong positive correlation between adenoma detection rate (ADR), advanced adenoma detection rate (AADR), and sessile serrated adenoma/polyp detection rate (SSA/PDR) prompted us to hypothesize that WE could significantly improve SSA/PDR compared with Endocuff and cap colonoscopy. The literature was searched for all randomized controlled trials (RCTs) that reported SSA/PDR as an outcome and included the keywords colonoscopy, and water exchange, Endocuff, or cap. We performed traditional network meta-analyses with random effect models comparing SSA/PDR of each method using air insufflation as the control and reported the odds ratios (ORs) with 95% confidence interval (CI). Performances were ranked based on P-score. A total of 531 articles resulted from initial keywords search. Eleven RCTs were included in the analysis. A total of 7856 patients underwent air insufflation, WE, Endocuff, or cap colonoscopy. WE significantly increased SSA/PDR (OR 2.04; 95% CI 1.33-3.13). Endocuff (OR 1.15; 95% CI 0.94-1.41) and cap (OR 1.08; 95% CI 0.42-2.74) did not significantly impact SSA/P detection. P-scores for WE (0.96), Endocuff (0.49), cap (0.37), and air insufflation (0.17) suggested that WE had the highest SSA/PDR. The results did not change after adjusting for mean withdrawal time and indication for colonoscopy. Water exchange significantly increases SSA/PDR and is superior to Endocuff and cap colonoscopy at detecting SSA/P.

Cold snare polypectomy without submucosal injection: safety and efficacy in 615 large serrated lesions.

Background and study aim Cold resection is becoming the standard of care for the resection of nonpedunculated colon lesions up to 10 mm in diameter. Sessile serrated adenomas/polyps (SSA/Ps), including those ≥ 10 mm, present various characteristics that make them ideal candidates for cold snare polypectomy (CSP). Patients and methods A prospectively maintained database was searched retrospectively for consecutive patients with lesions ≥ 10 mm resected between March 2013 and March 2018. During that period, all SSA/P-appearing lesions were resected using CSP without submucosal injection, except for lesions with endoscopic suspicion of dysplasia or submucosal invasion. Patients with a pathological diagnosis of SSA/P were included in the analysis. Adverse events were recorded up to 21 days following colonoscopy. Results 615 SSA/Ps ≥ 10 mm were resected during 452 colonoscopy procedures in 379 patients (mean age 54.1 years; standard deviation [SD] 11.9 years). Mean polyp size was 13.7 (SD 5.2) mm; 122 lesions (19.8 %) were ≥ 20 mm and 479 lesions (77.9 %) underwent piecemeal resection. Immediate adverse events included persistent abdominal pain that resolved spontaneously within 2 hours in three patients (0.8 %; 95 % confidence interval [CI] 0.2 %–2.3 %). One patient with persistent intraprocedural bleeding was successfully treated with a hemostatic clip. No late adverse events were detected. Surveillance colonoscopy was performed in 293 patients (77.3 %) at 23.4 (SD 11.6) months following index colonoscopy; residual/recurrent lesions were diagnosed in 23 patients (7.8 %; 95 %CI 5.0 %–11.6 %). Conclusion CSP without submucosal injection appeared to be safe and effective for the resection of large SSA/Ps.

Role of the β-Catenin/REG Iα Axis in the Proliferation of Sessile Serrated Adenoma/Polyps Associated with Fusobacterium nucleatum.

Although sessile serrated adenoma/polyps (SSA/Ps) may arise through a pathway different from the traditional adenoma–carcinoma sequence, details of SSA/P tumorigenesis still remain unclear. Fusobacterium nucleatum (Fn) is frequently detected in colorectal cancer (CRC) tissues and may play a pivotal role in colorectal carcinogenesis. Here, we investigated the relationship between Fn and the β-catenin/REG Iα axis in SSA/Ps and their involvement in the proliferation of these lesions. Fn was detected in SSA/Ps by fluorescence in situ hybridization using a Fn-targeted probe, and expression of β-catenin, REG Iα and Ki67 was examined using immunohistochemistry. Sixteen of 30 SSA/P lesions (53.3%) were positive for Fn. Eighteen SSA/P lesions (60%) showed β-catenin immunoreactivity in the tumor cell nuclei. A significant majority of Fn-positive lesions showed nuclear expression of β-catenin (87.5%) and higher REG Iα scores and Ki67 labeling indices relative to Fn-negative lesions. The SSA/P lesions expressing β-catenin in nuclei had significantly higher REG Iα scores and Ki67 labeling indices than those expressing β-catenin on cytomembranes. The REG Iα score was positively correlated with the Ki67 labeling index in SSA/P lesions. The treatment with Wnt agonist SKL2001 promoted nuclear β-catenin translocation and enhanced REG Ia expression in Caco2 cells. Fn may play a role in the proliferation of SSA/P lesions through promotion of β-catenin nuclear translocation and REG Iα expression.

Sessile Serrated Adenoma / Polyp (SSA/P) Carcinogenic Mechanism and Gene Mutations Caused by Fusobacterium Nucleatum - Problems to be Clarified in the Future

Sessile Serrated Adenoma / Polyp (SSA/P) Carcinogenic Mechanism and Gene Mutations Caused by Fusobacterium Nucleatum - Problems to be Clarified in the Future

S100P Expression via DNA Hypomethylation Promotes Cell Growth in the Sessile Serrated Adenoma/Polyp-Cancer Sequence

Background/Aims: Sessile serrated adenomas/polyps (SSA/Ps) are a putative precursor lesion of colon cancer. Although the relevance of DNA hypermethylation in the SSA/P-cancer sequence is well documented, the role of DNA hypomethylation is unknown. We investigated the biological relevance of DNA hypomethylation in the SSA/P-cancer sequence by using 3-dimensional organoids of SSA/P. Methods: We first analyzed hypomethylated genes using datasets from our previous DNA methylation array analysis on 7 SSA/P and 2 cancer in SSA/P specimens. Expression levels of hypomethylated genes in SSA/P specimens were determined by RT-PCR and immunohistochemistry. We established 3-dimensional SSA/P organoids and performed knockdown experiments using a lentiviral shRNA vector. DNA hypomethylation at CpG sites of the gene was quantitated by MassARRAY analysis. Results: The mean number of hypomethylated genes in SSA/P and cancer in SSA/P was 41.6 ± 27.5 and 214 ± 19.8, respectively, showing a stepwise increment in hypomethylation during the SSA/P-cancer sequence. S100P, S100α2, PKP3, and MUC2 were most commonly hypomethylated in SSA/P specimens. The mRNA and protein expression levels of S100P, S100α2, and MUC2 were significantly elevated in SSA/P compared with normal colon tissues, as revealed by RT-PCR and immunohistochemistry, respectively. Among these, mRNA and protein levels were highest for S100P. Knockdown of the S100P gene using a lentiviral shRNA vector in 3-dimensional SSA/P organoids inhibited cell growth by >50% (p < 0.01). The mean diameter of SSA/P organoids with S100P gene knockdown was significantly smaller compared with control organoids. MassARRAY analysis of DNA hypomethylation in the S100P gene revealed significant hypomethylation at specific CpG sites in intron 1, exon 1, and the 5′-flanking promoter region. Conclusion: These results suggest that DNA hypomethylation, including S100P hypomethylation, is supposedly associated with the SSA/P-cancer sequence. S100P overexpression via DNA hypomethylation plays an important role in promoting cell growth in the SSA/P-cancer sequence.

S0312 Increased Incidence of Sessile Serrated Adenoma/Polyp and Colorectal Cancer Detection in Veterans With Elevated Charlson Comorbidity Index and Positive Fecal Immunochemical Test

INTRODUCTION: The fecal immunochemical test (FIT) is widely used as a screening method for colorectal cancer (CRC). The Charlson Comorbidity Index (CCI) is the most widely comorbidity index used by researchers. There have been no studies to date correlating colonoscopy findings after positive FIT based on CCI. The primary aim of our study was to determine if CCI influences colonoscopy findings (adenoma or cancer) in patients with a positive FIT from a Veterans Affairs hospital in the Inland Empire of Southern California. METHODS: The VA Loma Linda Healthcare System electronic medical record was queried for all patients having FIT between October 1, 2014 and September 30, 2015. Inclusion criteria were positive FIT and completion of colonoscopy. Data collected included demographic information, endoscopist performing colonoscopy, type and quality of preparation, withdrawal time, Endocuff use, adenoma size and location along with calculated CCI score. Primary outcome measures were adenoma detection rate (ADR), advanced adenoma detection rate (AADR), sessile serrated adenoma/polyps (SSA/P), CRC, preparation quality and duration of colonoscopy based on CCI. Statistical analysis was performed with R software with Mann-Whitney test, chi-square, Fisher’s exact test, logistic regression and linear regression analysis as indicated. RESULTS: During the study period, 7778 FIT tests were distributed. Of those distributed, 638 patients (8%) were positive and met the study criteria. 380 (59.5%) underwent diagnostic colonoscopy, comprising the study group. The average age was 66 years old. The overall prevalence of ADR, AADR, SSA/P, ASSA/P and CRC was 64.4%, 25%, 13.95%, 2.6% and 3.42% respectively. Multivariate analysis showed higher CCI score was associated with higher CRC (OR = 1.2, P = 0.05) and SSAP incidence (OR = 1.16, P = 0.01) respectively. There was no significant difference in CCI observed in any other parameter assessed. CONCLUSION: For every one-unit elevation, CCI score increased the frequency of diagnosis with either a sessile serrated adenoma/polyp or CRC by a minimum of 16%. CCI may be predictive in FIT outcomes at colonoscopy among veteran patients.Table 1Table 2

Comparison of different virtual chromoendoscopy classification systems for the characterization of colorectal lesions.

Background and AimCommonly used classifications for colorectal lesions (CLs) include the Narrow Band Imaging (NBI) International Colorectal Endoscopic (NICE) and Japan NBI Expert Team (JNET) classifications. However, both lack a sessile serrated adenoma/polyp (SSA/P) category. This has been addressed by the modified Sano's (MS) and Workgroup serrAted polypS and Polyposis (WASP) classifications. This study aims to compare the accuracy of wNICE and wJNET (WASP added to both) with the stand‐alone MS classification.MethodsPatients undergoing colonoscopy at an Australian tertiary hospital who had at least one CL detected were prospectively enrolled. In the exploratory phase, CLs were characterized in real time with NBI and magnification using all classifications. In the validation phase, CLs were assessed with both NBI and Blue Laser Imaging (BLI) by four external endoscopists in Japan. The primary outcome was the comparison of wJNET and MS. Secondary outcomes included comparisons among all classifications and the calculation of interrater reliability.ResultsA total of 483 CLs were evaluated in real time in the exploratory phase, and four sets of 30 CL images (80 on NBI and 40 on BLI) were scored in the validation phase. For high‐confidence diagnoses, MS accuracy was superior to wJNET in both the exploratory (86% vs 79%, P < 0.05) and validation (85% vs 69%, P < 0.05) phases. The interrater reliability was substantial for all classifications (κ = 0.74, 0.69, and 0.63 for wNICE, wJNET, and MS, respectively).ConclusionsMS classification achieved the highest accuracy in both the exploratory and validation phases. MS can differentiate serrated and adenomatous polyps as a stand‐alone classification.

Abstract IA35: Molecular characterization of sessile serrated adenoma/polyps: A risk factor for higher colorectal cancer that further associates with endometrial polyps in female African Americans

Abstract Colorectal cancer is the third leading cause of cancer-related deaths in the United States, and rates are highest among African Americans (AAs). Sessile serrated adenoma/polyps (SSA/Ps) may be precursors to up to 30% of all colorectal cancers. Flat and mucinous features make SSA/Ps difficult to detect and diagnose. As such, there is a need for specific sensitive molecular biomarkers for an accurate and reliable diagnosis. Our aim was to assess the diagnostic value of molecular biomarkers that may distinguish SSA/Ps from benign hyperplastic polyps (HPs) among AA SSA/P patients. We conducted a retrospective study of all colonoscopies (n=12,085) performed at Howard University Hospital (2010-2015), which confirmed 4,070 AA patients with polyps, including 252 with SSA/Ps. Gene expression and mutation frequency profiles were analyzed in a total of 47 patients (62 specimens: 29 SSA/Ps, 26 HPs, 3 tubular adenomas, and 4 normal tissues). We tested 4 transcripts (MUC6, FSCN1, SEMG1, and TRNP1) using qRT-PCR. MSI and BRAF mutations were analyzed. CIMP analysis was performed using CACNA1G, IGF2, NEUROG1, RUNX, SOCS, and MLH1. In a parallel study, we assessed the association between endometrial polyp occurrence in patients with different types of colorectal lesions. MUC6, SEMG1, TRNP1, and FSCN1 were significantly more expressed in SSA/Ps vs. HPs (P&amp;lt;0.05; fold differences of 37.2, 10.7, 5.8 and 2.5, respectively). BRAF mutation was found in 55.6% of SSA/Ps vs. 12.0% in HPs (P = 0.001). The frequency of CIMP was higher in SSA/Ps but not statistically significant, while MSI was more prevalent in HPs (P &amp;gt; 0.05). There was a higher loss of MLH1 expression in HPs than SSA/Ps (42.9% showing expression vs 70.3% IHC staining &amp;gt;=2 in HPs and SSA/Ps). The SSA/Ps in our AA study were primarily distal (67%). In female patients, SSA/Ps associated with the higher frequency of endometrial polyps (8% vs. 2% in controls, p=0.003). Our results show that MUC6-SEMG1-TRNP1 expression and BRAF mutation have the strongest correlation with SSA/Ps. The distal location might help explain why MSI and CIMP may not be optimal molecular biomarkers in African American patients with SSA/Ps. These markers may be of high relevance for the diagnosis of ambiguous lesions and will benefit patients’ management for scheduling follow-ups based on the nature of index lesions. Females with colon lesions of the SSA/Ps type might benefit from a screening for an endometrial polyp in an age-independent manner. Citation Format: Hassan Ashktorab, Saman Azam, Babak Shokrani, Edward Lee, Taraneh Arjomand, Priyanka Kanth, Don Delker, Adeyinka Laiyemo, John Caretheres, Mehdi Nouraie, Hassan Brim. Molecular characterization of sessile serrated adenoma/polyps: A risk factor for higher colorectal cancer that further associates with endometrial polyps in female African Americans [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr IA35.

Associations between molecular characteristics of colorectal serrated polyps and subsequent advanced colorectal neoplasia.

BRAF mutation and DNA hypermethylation have linked sessile serrated adenomas/polyps (SSA/Ps) to serrated colorectal cancer (CRC) in cross-sectional studies, but they have not been evaluated in a longitudinal study. We aimed to evaluate the associations between molecular markers of serrated polyps and subsequent advanced colorectal neoplasia. Study subjects included Kaiser Permanente Washington members aged 20-75years who received an index colonoscopy between 1/1/1998 and 12/31/2007 and had hyperplastic polyps (HPs) or SSA/Ps according to study pathology review. Polyps from index colonoscopies were removed and assayed for BRAF mutation, CpG island methylator phenotype (CIMP), and MLH1 methylation. Pathology reports and biopsies from the subsequent lower gastrointestinal endoscopy through 1/1/2013 were reviewed for advanced colorectal neoplasia. We identified additional incident CRC cases through linkage to the Seattle-Puget Sound Surveillance Epidemiology and End Results registry. We used generalized estimating equations to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for subsequent advanced colorectal neoplasia, comparing index serrated polyps with different molecular markers. We included 553 individuals with index serrated polyps (420 HPs and 133 SSA/Ps) and 795 subsequent endoscopies. The prevalence of BRAF-mutant, CIMP-high, and MLH1-methylated serrated polyps were 51%, 4%, and 2%, respectively. BRAF and CIMP were not associated with subsequent advanced colorectal neoplasia. MLH1-methylated SSP/As were significantly more likely to have subsequent advanced neoplasia (OR = 4.66, 95% CI 1.06-20.51). Our results suggest that BRAF-mutant and CIMP-high serrated polyps are not associated with subsequent advanced colorectal neoplasia. Among SSA/Ps, MLH1 methylation may be an important marker to identify high-risk CRC precursors.

Computer aided detection for laterally spreading tumors and sessile serrated adenomas during colonoscopy.

Evidence has shown that deep learning computer aided detection (CADe) system achieved high overall detection accuracy for polyp detection during colonoscopy. The detection performance of CADe system on non-polypoid laterally spreading tumors (LSTs) and sessile serrated adenomas/polyps (SSA/Ps), with higher risk for malignancy transformation and miss rate, has not been exclusively investigated. A previously validated deep learning CADe system for polyp detection was tested exclusively on LSTs and SSA/Ps. 1451 LST images from 184 patients were collected between July 2015 and January 2019, 82 SSA/Ps videos from 26 patients were collected between September 2018 and January 2019. The per-frame sensitivity and per-lesion sensitivity were calculated. (1) For LSTs image dataset, the system achieved an overall per-image sensitivity and per-lesion sensitivity of 94.07% (1365/1451) and 98.99% (197/199) respectively. The per-frame sensitivity for LST-G(H), LST-G(M), LST-NG(F), LST-NG(PD) was 93.97% (343/365), 98.72% (692/701), 85.71% (324/378) and 85.71% (6/7) respectively. The per-lesion sensitivity of each subgroup was 100.00% (71/71), 100.00% (64/64), 98.31% (58/59) and 80.00% (4/5). (2) For SSA/Ps video dataset, the system achieved an overall per-frame sensitivity and per-lesion sensitivity of 84.10% (15883/18885) and 100.00% (42/42), respectively. This study demonstrated that a local-feature-prioritized automatic CADe system could detect LSTs and SSA/Ps with high sensitivity. The per-frame sensitivity for non-granular LSTs and small SSA/Ps should be further improved.

Patterns of polyp histology: predictors of peril in the mucosa.

Precursor colonic polyps of varied subtypes correlate with the known neoplastic pathways. When patients present with synchronous pre-malignant polyps of multiple histologies, multiple genetic mechanisms are likely to be active, potentially resulting in a more unstable, tumourigenic mucosa. We hypothesized that patients with a combination of sessile serrated adenomas/polyps (SSA/Ps), hyperplastic (HP) polyps and adenomas would be at highest risk of developing dysplasia/cancer compared to SSA/Ps alone, due to the synergistic effect of multiple active carcinogenic pathways. A prospective colonoscopy database was examined for patients with a history of SSA/P. Patients were placed into four groups based on patterns of polyp histology as follows: (i) only SSA/Ps; (ii) SSA/P + HP; (iii) SSA/Ps + adenomas; and (iv) SSA/Ps + HP + adenomas. These groups were compared in terms of the numbers, size, location and histology of polyps and personal or family history of colorectal cancer. A total of 374 patients were included. The average age was 70 years (range 21-88), and 43% were male. There was a trend towards the most aggressive neoplastic pattern in group 4, associated with a tendency to larger SSA/Ps, more villous architecture in the adenomas and more high-grade dysplasia in both types of polyps. It was also associated with multiplicity of both SSA/Ps and adenomas. No SSA/Ps existing in the absence of adenomas had cytological dysplasia. The combination of SSA/Ps, HP and adenomas in the colorectal epithelium seems to be a marker for aggressive carcinogenesis and suggests that accurate and effective surveillance is important to manage this risk.

DNMT3B Oncogenic Activity in Human Intestinal Cancer Is Not Linked to CIMP or BRAFV600E Mutation.

SummaryApproximately 10% of human colorectal cancer (CRC) are associated with activated BRAFV600E mutation, typically in absence of APC mutation and often associated with a CpG island methylator (CIMP) phenotype. To protect from cancer, normal intestinal epithelial cells respond to oncogenic BRAFV600E by activation of intrinsic p53 and p16-dependent tumor suppressor mechanisms, such as cellular senescence. Conversely, CIMP is thought to contribute to bypass of these tumor suppressor mechanisms, e.g. via epigenetic silencing of tumor suppressor genes, such as p16. It has been repeatedly proposed that DNMT3B is responsible for BRAFV600E-induced CIMP in human CRC. Here we set out to test this by in silico, in vitro, and in vivo approaches. We conclude that although both BRAFV600E and DNMT3B harbor oncogenic potential in vitro and in vivo and show some evidence of cooperation in tumor promotion, they do not frequently cooperate to promote CIMP and human intestinal cancer.

Validation of serrated polyps (SPs) in Swedish pathology registers

BackgroundLittle is known about the natural history of serrated polyps (SPs), partly due to the lack of large-scale epidemiologic data. In this study, we examined the validity of SP identification according to SNOMED (Systematised Nomenclature of Medicine) codes and free text from colorectal histopathology reports.MethodsThrough the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study, we retrieved data on SPs from all pathology departments in Sweden in 2015–2017 by using SNOMED codes and free-text search in colorectal histopathology reports. Randomly selected individuals with a histopathology report of SPs were validated against patient charts using a structured, retrospective review.ResultsSPs were confirmed in 101/106 individuals with a histopathology report of SPs, yielding a positive predictive value (PPV) of 95% (95%CI = 89–98%). By year of diagnosis, the PPV was 89% (95%CI = 69–97%), 96% (95%CI = 81–99%) and 97% (95%CI = 89–99%) for individuals diagnosed before 2001 (n = 19), between 2001 and 2010 (n = 26) and after 2010 (n = 61), respectively. According to search method, the PPV for individuals identified by SNOMED codes was 100% (95%CI = 93–100%), and 93% (95%CI = 86–97%) using free-text search. Recorded location (colon vs. rectum) was correct in 94% of all SP histopathology reports (95%CI = 84–98%) identified by SNOMED codes. Individuals with SPs were classified into hyperplastic polyps (n = 34; 32%), traditional serrated adenomas (n = 3; 3%), sessile serrated adenomas/polyps (SSA/Ps) (n = 70; 66%), unspecified SPs (n = 3, 3%), and false positive SPs (n = 5, 5%). For individuals identified by SNOMED codes, SSA/Ps were confirmed in 49/52 individuals, resulting in a PPV of 94% (95%CI: 84–98%). In total, 57% had ≥2 polyps (1: n = 44, 2–3: n = 33 and ≥ 4: n = 27). Some 46% of SPs (n = 71) originated from the proximal colon and 24% were ≥ 10 mm in size (n = 37). Heredity for colorectal cancer, intestinal polyposis syndromes, or both was reported in seven individuals (7%). Common comorbidities included diverticulosis (n = 45, 42%), colorectal cancer (n = 19, 18%), and inflammatory bowel disease (n = 10, 9%).ConclusionColorectal histopathology reports are a reliable data source to identify individuals with SPs.

Elevated Risk for Sessile Serrated Polyps in African Americans with Endometrial Polyps.

Colorectal and endometrial lesions increase with age. It is not known if these two precursor lesions in sporadic cases associate with each other. To determine the association between colorectal polyps and endometrial polyps (EP) in African Americans. We reviewed records of patients referred to gynecology clinics and had colonoscopy at Howard University Hospital from January 2004 to December 2015. We defined cases as all patients who had EP and underwent colonoscopy. For controls, we used EP-free patients who underwent colonoscopy. Logistic regression analysis was used to assess the association between colon polyps and EP. The median age was 60years in 118 Cases and 57years in 664 Controls. The overall colorectal polyps prevalence in the two groups was not statistically different (54% in controls vs. 52% in cases, P = 0.60). Sessile serrated adenoma/polyps (SSPs) were more frequent in cases (8% vs. 2% in controls, P = 0.003). Sigmoid and rectal locations were more prevalent in controls than cases. In multivariate analysis and after adjusting for age, diabetes mellitus (DM), and BMI, SSPs were associated with EP occurrence with an odds ratio of 4.6 (CI 1.2-16.7, P = 0.022). Colorectal polyp prevalence was similar in EP patients compared to EP-free controls. However, we observed a significant association between higher-risk SSPs in patients with EP. The prevalence of smoking and DM was higher in these patients. Females with EP might benefit from a screening for colonic lesions in an age-independent manner.