Clinical and endoscopic characteristics of sessile serrated adenomas/polyps with dysplasia/adenocarcinoma in a Korean population: A Korean Association for the Study of Intestinal Diseases (KASID) multicenter study

Sessile serrated adenomas/polyps (SSA/Ps) are precancerous lesions that account for one-third of colorectal cancers. The endoscopic and pathologic differentiation between SSA/Ps without dysplasia (SSA/POs) and SSA/Ps with dysplasia or adenocarcinoma (SSA/PDAs) can be difficult. This study aimed to assess the clinical characteristics of SSA/PDs. This multicenter retrospective cohort study included 532 patients who underwent endoscopic resection and were pathologically diagnosed with SSA/POs and SSA/PDAs. Initially, medical, endoscopic, and histopathological records of patients who underwent endoscopic resection of SSA/POs and SSA/PDAs at eight university hospitals in Korea between January 2005 and December 2015 were reviewed. A total of 307 (57.7%) patients were detected in men and 319 (60.0%) were located in the proximal colon. Most SSA/Ps had a flat, slightly elevated, or sessile morphology. The most prevalent endoscopic findings of SSA/Ps were nodular surface (244, 45.9%), disrupted vascular pattern (232, 43.6%), altered fold contour (141, 26.5%), dome-shaped morphology (135, 25.4%), and pale color (115, 21.6%). SSA/POs were more commonly found in the proximal colon, compared to SSA/PDAs. SSA/PDAs displayed 0-Ip, Isp, IIb or IIa + IIc morphologies more frequently, while SSA/POs displayed 0-Is or IIa morphology more frequently. The frequency of a rim of debris/bubbles was significantly higher in SSA/POs, while nodular surface and disrupted vascular pattern were significantly higher in SSA/PDAs. In the univariate analysis of endoscopic features, SSA/PDAs were significantly associated with the distal colon location, 0-Isp and IIb morphologies, nodular surface, and disrupted vascular pattern. In the multivariate analysis, 0-IIb, nodular surface, and disrupted vascular pattern were significantly associated with SSA/PDAs. SSA/Ps with 0-IIb morphology, nodular surface and disrupted vascular pattern are associated with an increased risk of dysplasia or adenocarcinoma.

endoscopic and histologic analysis of ssA/ps. All patients were examined using video colonoscopes (Olympus CF-240I or CF-H260; Olympus, Tokyo, Japan). Bowel preparation was performed with polyethylene glycol electrolyte solution in all hospitals and classified according to endoscopist estimation into adequate in all cases. Two endoscopists (K.H.K. and Y.E.J.) reviewed the endoscopic findings of SSA/Ps and evaluated conventional white-light colonoscopic images. Endoscopic characteristics were evaluated using previously validated criteria defined by Tadepalli et al. 31 : nodular surface, disrupted vascular pattern, altered fold contour, dome-shaped morphology, pale color, mucus cap, and rim of debris/bubbles (Fig. 1). According to the Paris classification, the endoscopic morphologies of superficial lesions are divided into three categories: protruding (0-I), non-protruding and non-excavated (0-II), and excavated (0-III). Type 0-I lesions are further subdivided into pedunculated (0-I), sessile (0-Is), or mixed (0-Isp); Type 0-II lesions are subdivided into slightly elevated (0-IIa), flat (0-IIb), or depressed (0-IIc) 32 . The locations of the adenomas were classified as follows: the proximal colon (cecum, ascending colon, hepatic flexure, and transverse colon) and distal colon (splenic flexure of the colon, descending colon, sigmoid, and rectum). Histologic diagnoses of SSA/POs and SSA/PDAs were evaluated separately by gastrointestinal pathologists who were blinded to the knowledge of original pathologic report at each institute on the basis of the 2010 WHO classification for the presence of serrated crypts, irregularly dilated and/
Comparison of clinical characteristics of ssA/pos and ssA/pDAs. SSA/Ps included 370 SSA/POs and 162 SSA/PDAs. With regard to patient-related factors, no statistically significant differences were found in age, sex, smoking, alcohol, or use of NSAIDs between SSA/POs and SSA/PDAs groups. The mean BMI value was significantly higher in SSA/POs than that of SSA/PDAs (P = 0.019). With regard to lesion-related factors, SSA/ PDAs were more commonly found in the distal colon than in the proximal colon (P = 0.002). The distribution of SSA/POs and SSA/PDAs were also different according to location by subsites (P = 0.004). The proportion of rectosigmoid lesions among the subjects with SSA/PDAs (45%) was relatively higher than that among the subjects with SSA/POs (27.6%). No statistically significant differences were found in tumor size between SSA/POs and SSA/PDAs groups. The frequency of endoscopic morphology by Paris classification was different between SSA/POs and SSA/PDAs (P < 0.001). The analysis of endoscopic features showed that nodular surface and disrupted vascular pattern were more commonly found in SSA/PDAs (P < 0.001 and P = 0.006, respectively), and a rim of debris was more commonly found in SSA/POs (P = 0.023). Conventional adenomas with low-grade dysplasia were more commonly detected in SSA/PDAs than in SSA/POs (P < 0.001). Conventional adenomas with high-grade dysplasia and adenocarcinoma tended to be found more frequently in SSA/PDAs than in SSA/ POs, but the difference was not statistically significant (P = 0.090). Traditional serrated adenomas were more commonly found in SSA/POs than in SSA/PDAs (P = 0.036). With regard to procedure-related factors, polypectomy, such as cold biopsy or snare, was more frequently performed in SSA/POs, while EMR was more frequently performed in SSA/PDAs (P = 0.001). Post-procedural bleeding was more commonly found in SSA/PDAs than in SSA/POs (P = 0.006) ( Table 2).

Comparison of tumor size between SSA/POs and SSA/PDAs groups according to removal method and age groups.
The results of the comparison of tumor size between SSA/POs and SSA/PDAs groups according to removal methods are summarized in Table 5. The tumor size of SSA/Ps treated by polypectomy, such as cold biopsy or snare, was 6.2 ± 5.9 mm, by EMR, 10.6 ± 6.0 mm, by EPMR, 27.0 ± 8.3 mm, and by ESD, 27.5 ± 12.6 mm. The comparison of tumor size between SSA/POs and SSA/PDAs groups according to removal method and age groups showed statistically non-significant differences among applied removal methods (Table 5).

Discussion
SSA/Ps are considered major precursor lesions of the serrated neoplasia pathway, which account for one-third of all sporadic colorectal cancers [3][4][5][6][7][8] . SSA/Ps comprise approximately 15-25% of colorectal serrated lesions and 2-9% of all colorectal polyps. SSA/Ps have a marked predilection for the proximal colon and have predominantly a sessile or flat morphology [12][13][14][15][16][17][18][19][20] . In our study, 60.0% of SSA/Ps were localized in the proximal colon and 75.9% had sessile (0-Is) or flat morphologies (0-IIa, 0-IIb, and 0-IIa + IIc). These results are similar to those revealed by previous [12][13][14][15][16][17][18][19][20] and our studies. Histopathologically, SSA/Ps are subclassified as SSA/POs and SSA/PDAs, and SSA/PDAs accounted for about 15.1% of SSA/Ps and 0.18% of all colorectal polyps in a large cohort study 33 . In our study, the incidence of SSA/PDs was 30.4% of SSA/Ps. This result is inconsistent with that of another report 33 and may be related to the variable sample size of the current study and the previous report and the unavoidable selection bias of the present retrospective study.
Endoscopic detection of SSA/Ps is difficult because of their subtle features compared to conventional adenomas [12][13][14][15][16][17][18][19][20] . Previously, the most prevalent endoscopic features of SSA/Ps according to the criteria defined by Tadefalli et al. were mucous cap, rim of debris/bubbles, altered fold contour, and disrupted vascular pattern 31 . Another study showed that the disrupted vascular pattern, altered fold contour, or rim of debris/bubbles were most prevalent endoscopic features of SSA/Ps 21 . In our study, the main endoscopic features of SSA/Ps were nodular surface, disrupted vascular pattern, or altered fold contour.
SSA/PDAs are clinically and endoscopically similar to SSA/POs, making endoscopic differentiation difficult. A previous study showed that endoscopic features of SSA/POs tended to present as more often altered fold contour and SSA/PDAs tended to be more often characterized by a pale color and dome-shaped morphology than SSA/POs 21 . Another study reported that the incidence of any 0-Is morphologies or nodular components within the lesions was higher for SSA/PDAs than for SSA/POs 29 . Moreover, in SSA/PDAs with nodule/protrusion, the nodule/protrusion detected by endoscopy corresponded to the portion of dysplasia or carcinoma on histology 28   www.nature.com/scientificreports www.nature.com/scientificreports/ PDAs displayed pedunculated (0-Ip) or semipedunculated (0-Isp) morphologies more frequently than SSA/POs 30 . In our study, nodular surface, disrupted vascular pattern, and 0-Isp or 0-IIb morphologies were more commonly found in SSA/PDAs, while rim of debris/bubbles was more commonly found in SSA/POs in analysis of endoscopic   Polypectomy (n = 49) 6.8 ± 6.6 (43) 11.6 ± 8. www.nature.com/scientificreports www.nature.com/scientificreports/ features. On multivariate analysis, SSA/Ps with 0-IIb, nodular surface, or disrupted vascular pattern showed the significant association with the risk of dysplasia or adenocarcinoma. The analyses of sensitivity and specificity of each characteristic for SSA/PDs showed the results as follow; SSA/Ps with 0-IIb (sensitivity 1.9% and specificity 99.5%), nodular surface (sensitivity 72.2% and specificity 65.7%), and disruption of vascular pattern (sensitivity 52.5% and specificity 60.3%). Nodular surface showed a better predictive performance than others. Therefore, because SSA/Ps with these findings are likely to be accompanied by dysplasia or adenocarcinoma, they should be removed en bloc for accurate histopathological assessment and prevention of interval cancer development.
The presence of SSA/Ps was associated with the presence of synchronous advanced colorectal neoplasia [34][35][36] . In our study, 49.8% of patients with SSA/Ps had conventional adenoma with low-grade dysplasia, high-grade dysplasia, or adenocarcinoma. Furthermore, conventional adenomas with low-grade dysplasia were more commonly found in SSA/PDAs than in SSA/POs. Advanced adenomas with high-grade dysplasia and adenocarcinoma tended to be found more frequently in SSA/PDAs compared to SSA/POs. Therefore, the recognition of SSA/Ps should alert the endoscopist to meticulously inspect the remaining part of the colonic mucosa for more lesions.
In our study, SSA/Ps were resected by various techniques, including polypectomy, such as cold biopsy or snare, EMR, EPMR, or ESD as endoscopic resection of conventional adenoma [37][38][39][40] . Moreover, treatment was applied according to the tumor size, namely polypectomy was usually used for resection of SSA/Ps < 10 mm, EMR was used for SSA/Ps 10-20 mm, and ESD or EPMR was used for SSA/Ps ≥ 20 mm. In addition, the comparison of tumor size between SSA/POs and SSA/PDAs groups according to removal method and age groups showed no statistically significant differences between applied removal methods. Although the treatment strategy for SSA/Ps has not yet been established, our results showed that the principles for the management of SSA/Ps may be similar to those for conventional adenomas in clinical practice. Post-procedural bleeding was more commonly found in SSA/PDAs than in SSA/POs. This may be related to the fact that the lesions with dysplasia or adenocarcinoma present rapid growth and increased neovascularization toward the submucosa.
However, our study has some limitations. First, the study design was retrospective and nonrandomized; therefore, selection biases were unavoidable. Second, the heterogeneity of the SSA/PO and SSA/PDA groups was inevitable. For these reasons, large prospective, multicenter studies evaluating the clinical and endoscopic characteristics and outcomes of SSA/PDAs for optimal detection, complete resection, and appropriate surveillance of SSA/Ps are needed to provide more definitive evidence.
In conclusion, SSA/Ps with 0-IIb, nodular surface and disrupted vascular pattern are associated with an increased risk of dysplasia or adenocarcinoma. Therefore, these findings can be considered useful indicators in the management of SSA/Ps.