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A standardized imaging protocol for the endoscopic prediction of dysplasia within sessile serrated polyps (with video)

      Background and Aims

      Dysplasia within sessile serrated polyps (SSPs) is difficult to detect and may be mistaken for an adenoma, risking incomplete resection of the background serrated tissue, and is strongly implicated in interval cancer after colonoscopy. The use of endoscopic imaging to detect dysplasia within SSPs has not been systematically studied.

      Methods

      Consecutively detected SSPs ≥8 mm in size were evaluated by using a standardized imaging protocol at a tertiary-care endoscopy center over 3 years. Lesions suspected as SSPs were analyzed with high-definition white light then narrow-band imaging. A demarcated area with a neoplastic pit pattern (Kudo type III/IV, NICE type II) was sought among the serrated tissue. If this was detected, the lesion was labeled dysplastic (sessile serrated polyp with dysplasia); if not, it was labeled non-dysplastic (sessile serrated polyp without dysplasia). Histopathology was reviewed by 2 blinded specialist GI pathologists.

      Results

      A total of 141 SSPs were assessed in 83 patients. Median lesion size was 15.0 mm (interquartile range 10-20), and 54.6% were in the right side of the colon. Endoscopic evidence of dysplasia was detected in 36 of 141 (25.5%) SSPs; of these, 5 of 36 (13.9%) lacked dysplasia at histopathology. Two of 105 (1.9%) endoscopically designated non-dysplastic SSPs had dysplasia at histopathology. Endoscopic imaging, therefore, had an accuracy of 95.0% (95% confidence interval [CI], 90.1%-97.6%) and a negative predictive value of 98.1% (95% CI, 92.6%-99.7%) for detection of dysplasia within SSPs.

      Conclusions

      Dysplasia within SSPs can be detected accurately by using a simple, broadly applicable endoscopic imaging protocol that allows complete resection. Independent validation of this protocol and its dissemination to the wider endoscopic community may have a significant impact on rates of interval cancer. (Clinical trial registration number: NCT03100552.)

      Abbreviations:

      CRC (colorectal cancer), HDWL (high-definition white light), NBI (narrow-band imaging), SSA (sessile serrated adenoma), SSA-D (sessile serrated adenoma with dysplasia as determined histologically), SSA-ND (sessile serrated adenoma without dysplasia as determined histologically), SSP (sessile serrated polyp), SSP-D (sessile serrated polyp with dysplasia), SSP-ND (sessile serrated polyp without dysplasia)

      Current Knowledge

      Sessile serrated polyps (SSPs) without dysplasia (SSP-ND) account for about 8% of colorectal polyps. They may take many years to develop dysplasia and can be managed effectively by complete endoscopic resection. SSPs with dysplasia (SSP-D), conversely, are high-risk lesions. Recent evidence suggests that they may progress rapidly to colorectal cancer (CRC), particularly because they occur in people aged similar to people with serrated pathway CRC. The dysplastic areas on the surface of SSP-D may mimic conventional adenomas, risking incomplete resection by an endoscopist who does not appreciate the background serrated tissue. Incomplete endoscopic resection of SSP-D leaves a high-risk lesion in situ with the molecular changes to rapidly progress to interval cancer. A reliable and accurate method to characterize dysplasia within SSPs by using endoscopic imaging has not been demonstrated previously in a large series.

      New study findings

      In 141 SSPs, a standardized endoscopic imaging protocol for dysplasia was accurate in 95.0% (95% confidence interval [CI], 90.1%-97.6%), with a negative predictive value of 98.1% (95% CI, 92.6%-99.7%) against the criterion standard of blinded GI specialist pathologists. The protocol is simple to use and broadly applicable to any endoscopist working in a unit with high-definition endoscopes. If independently validated, and with widespread dissemination to the endoscopic community, this protocol may help reduce rates of interval cancer via reliable identification and complete resection of SSP-D.

      The Nature of SSPs

      SSPs account for up to 8% of colorectal polyps in a screening population.
      • East J.E.
      • Vieth M.
      • Rex D.K.
      Serrated lesions in colorectal cancer screening: detection, resection, pathology and surveillance.
      • Lash R.H.
      • Genta R.M.
      • Schuler C.M.
      Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients.
      • Carr N.J.
      • Mahajan H.
      • Tan K.L.
      • et al.
      Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma.
      They have a preponderance for the right side of the colon, are difficult to detect, and are commonly incompletely resected.
      • Pohl H.
      • Srivastava A.
      • Bensen S.P.
      • et al.
      Incomplete polyp resection during colonoscopy–results of the complete adenoma resection (CARE) study.
      They are more common than adenomas, potentially because of a lack of appreciation of the boundaries of the lesion. Recent evidence suggests that they have a long dwell time (in the order of 17 years) before the development of dysplasia. In support of this, SSP-D are found in significantly older patients, with the age of patients with SSP-D closely matching the age of individuals with serrated pathway CRC. This provides strong evidence for SSP-D as a high-risk lesion with the potential for rapid progression to cancer.
      • Bettington M.
      • Walker N.
      • Rosty C.
      • et al.
      Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma.
      Serrated pathway CRC accounts for up to 30% of CRCs
      • Bettington M.
      • Walker N.
      • Clouston A.
      • et al.
      The serrated pathway to colorectal carcinoma: current concepts and challenges.
      and is over-represented in the interval cancer subgroup.
      • Arain M.A.
      • Sawhney M.
      • Sheikh S.
      • et al.
      CIMP status of interval colon cancers: another piece to the puzzle.
      The majority of SSPs do not contain dysplasia (SSP-ND)
      • Abdeljawad K.
      • Vemulapalli K.C.
      • Kahi C.J.
      • et al.
      Sessile serrated polyp prevalence determined by a colonoscopist with a high lesion detection rate and an experienced pathologist.
      and can be managed effectively by a meticulous withdrawal technique for endoscopic detection, accurate lesion characterization, delineation of the lesion boundaries, and complete endoscopic resection. SSP-D presents a unique challenge. It is established that adenomas are more easily detected than SSPs,
      • Kahi C.J.
      • Hewett D.G.
      • Norton D.L.
      • et al.
      Prevalence and variable detection of proximal colon serrated polyps during screening colonoscopy.
      • Hetzel J.T.
      • Huang C.S.
      • Coukos J.A.
      • et al.
      Variation in the detection of serrated polyps in an average risk colorectal cancer screening cohort.
      predominantly because of their more conspicuous surface structure. SSP-D has the potential to masquerade as adenomas. Therefore if only the dysplastic portion is appreciated and resected, then a potentially rapidly progressive residual is left in situ, and CRC may ensue. In this context, the ability to accurately recognize and characterize SSP-D to achieve complete endoscopic resection is a critical component of interventions to prevent serrated pathway CRC and potentially interval cancer.
      Case reports
      • Nanda K.S.
      • Tutticci N.
      • Burgess N.
      • et al.
      Caught in the act: endoscopic characterization of sessile serrated adenomas with dysplasia.
      • Murakami T.
      • Sakamoto N.
      • Yao T.
      Sessile serrated adenoma/polyp with cytological dysplasia diagnosed accurately by magnifying chromoendoscopy.
      and a retrospective series

      Murakami T, Sakamoto N, Ritsuno H, et al. Distinct endoscopic characteristics of sessile serrated adenoma/polyp with and without dysplasia/carcinoma [abstract]. Gastrointest Endosc. Epub 2016 Sep 20.

      have described the feasibility of using endoscopic imaging to detect dysplasia within SSPs, but no systematic study exists. In this study, we prospectively evaluated the utility of a simple, widely applicable endoscopic imaging protocol to detect dysplasia within SSPs compared with histopathology.

      Methods

      Format of the study

      Over 41 months to January 2017, sequential SSPs ≥8 mm detected within the endoscopic resection practice of a single tertiary-care referral center were analyzed according to a standardized imaging protocol. Detailed patient, procedural, and lesion characteristics were recorded. Split-dose bowel preparation was used. Olympus high-definition colonoscopes were used throughout (Olympus 180/190 series, Olympus, Tokyo, Japan). Lesion size was determined with reference to an open snare of known diameter, as was any dysplastic area if present. The right side of the colon was defined as proximal to, and including, the hepatic flexure. For the purposes of this study, SSP-D describes the endoscopic determination of dysplasia within SSPs, and SSP-ND describes the endoscopic determination of no dysplasia within SSPs. Sessile serrated adenoma with dysplasia (SSA-D) and sessile serrated adenoma without dysplasia (SSA-ND) were used to describe the histologic determination of dysplasia within sessile serrated adenomas (SSA).
      All procedures were performed by endoscopists with extensive experience in endoscopic resection or by an advanced endoscopy fellow under their direct supervision. There were 8 endoscopists in total. All patients provided written informed consent. Institutional review board approval was obtained. All authors had access to the study data and reviewed and approved the final manuscript.

      Standardized imaging protocol

      We created a standardized imaging protocol supported by our description of endoscopic features of dysplasia within SSPs
      • Nanda K.S.
      • Tutticci N.
      • Burgess N.
      • et al.
      Caught in the act: endoscopic characterization of sessile serrated adenomas with dysplasia.
      and our previous analysis of large SSP-D.
      • Burgess N.G.
      • Pellise M.
      • Nanda K.S.
      • et al.
      Clinical and endoscopic predictors of cytological dysplasia or cancer in a prospective multicentre study of large sessile serrated adenomas/polyps.
      Lesions were considered as SSPs when 1 or more of the following features were identified: mucous cap, cloud-like or finely nodular surface, indistinct border, irregular shape, and lesion paler than the surrounding mucosa (under narrow-band imaging)
      • IJspeert J.E.
      • Bastiaansen B.A.
      • van Leerdam M.E.
      • et al.
      Development and validation of the WASP classification system for optical diagnosis of adenomas, hyperplastic polyps and sessile serrated adenomas/polyps.
      (Fig. 1). Once a lesion suspected to be an SSP was detected, the endoscopist completed a structured datasheet with the study coordinator. A detailed analysis of the surface of the lesion was made by using high-resolution endoscopic imaging with high-definition white-light (HDWL) and narrow-band imaging (NBI) (Olympus). In keeping with our previous experience,
      • Nanda K.S.
      • Tutticci N.
      • Burgess N.
      • et al.
      Caught in the act: endoscopic characterization of sessile serrated adenomas with dysplasia.
      • Burgess N.G.
      • Pellise M.
      • Nanda K.S.
      • et al.
      Clinical and endoscopic predictors of cytological dysplasia or cancer in a prospective multicentre study of large sessile serrated adenomas/polyps.
      magnification was not used nor was chromoendoscopy. A careful search was made for any demarcated area with an adenomatous (Kudo III/IV, NICE II) pit pattern among the serrated tissue. If detected, the lesion was described as SSP-D, and the features of this area were described in detail. The size and number of demarcated areas was recorded. Within demarcated areas, hyper-vascularity (in comparison to the background features of the overall lesion under NBI) and Kudo pattern were described (Fig. 2, Video 1, available online at www.giejournal.org). If a demarcated area was not detected, the lesion was labeled SSP-ND. The endoscopist was then asked to provide confidence that (1) the lesion represented an SSP and (2) the lesion did or did not contain dysplasia.
      Figure thumbnail gr1
      Figure 1Surface characteristics of sessile serrated polyps (SSP). A, Multiple SSPs in a patient with serrated polyposis all covered with a mucus cap. B, SSP with relatively distinct border and a finely nodular, cloud-like surface. C, Barely perceptible SSP with an indistinct border. D, Same lesion seen under narrow-band imaging, paler than the surrounding mucosa. E, Same lesion after chromo-gelofusine injection, clearly demarcating the border. F, The final piecemeal EMR defect demonstrating the extent of the lesion.
      Figure thumbnail gr2
      Figure 2Examples of the use of a standardized imaging protocol to determine dysplasia within sessile serrated polyps (SSPs). A, A well-demarcated 25-mm SSP with dysplasia (SSP-D) in the transverse colon. B, C, Narrow-band imaging (NBI) reveals a 3-mm demarcated area (dotted white line) with a Kudo type IIIs pit pattern. D, E, Twelve-millimeter SSP-D in the ascending colon, with a 5-mm demarcated area best appreciated by using NBI (dotted white line). F, A detail of the demarcated area reveals a Kudo type IV pit pattern. G-I, Twenty-millimeter SSP-D with an indistinct border in the transverse colon and a subtle hypervascular area (dotted white line) with a borderline type III Kudo pit pattern. J-L, Twenty-millimeter SSP with indistinct border in the ascending colon, containing a demarcated area with a type IIIs Kudo pit pattern (dotted white line). All the depicted lesions were diagnosed as sessile serrated adenomas with dysplasia, as determined histologically by histopathology. SSA, sessile serrated adenoma (histologic determination); SSPs, sessile serrated polyps (endoscopic determination).

      Lesion resection

      All lesions were resected endoscopically. Our common practice is to perform en bloc cold snare polypectomy for SSPs up to 10 mm. Larger lesions predicted as SSP-ND are resected by using piecemeal cold snare polypectomy or EMR. If there is evidence of dysplasia (SSP-D), we prefer EMR, resect the suspected dysplastic area en bloc, and submit it separately for histopathologic analysis.

      Histopathologic analysis

      Resected lesions were diagnosed as SSAs based on established criteria.
      • Torlakovic E.
      • Skovlund E.
      • Snover D.C.
      • et al.
      Morphologic reappraisal of serrated colorectal polyps.
      Hematoxylin-eosin–stained sections were available and were retrieved in all cases. All specimens were reviewed by 2 independent specialist GI pathologists blinded to the endoscopic diagnosis. The type of adenoma and the presence and grade of any cytologic dysplasia were recorded. Serrated dysplasia was not considered cytologic dysplasia as per current expert opinion.

      Bettington ML, Chetty R. Traditional serrated adenoma: an update. Hum Pathol. Epub 2015 Apr 20.

      For the initial analysis, histopathology was treated as the criterion standard.
      For cases in which the histopathologic and endoscopic determination of dysplasia within an SSP were incongruent, a structured discussion between endoscopists and specialist pathologists was undertaken. A determination of the most likely correct diagnosis (SSA-ND or SSA-D) was decided by mutual agreement.

      Statistical analysis

      Statistical analysis was done by using SPSS version 23 (IBM, Armonk, NY) with a 2-tailed t test used for parametric continuous variables, Mann-Whitney U test for nonparametric continuous data, and the chi-square test for categorical variables. Only the largest demarcated area within an SSP-D was described if there was more than 1. Agreement between endoscopy and histopathologic analysis was determined by using 2 × 2 tables. For these analyses, histopathology was regarded as the criterion standard, before and after the structured discussion between specialist pathologists and endoscopists. The significance of P was regarded at <.05.

      Results

      Population characteristics

      Over the study period, 144 SSPs were detected in 86 patients. Three SSPs in 3 patients were excluded (Supplementary Fig. 1, available online at www.giejournal.org). The mean age of patients was 64.0 years (standard deviation 15.4) and 57 of 83 (68.7%) patients were female. Forty-four of 83 (53.0%) patients had 1 SSP, 24 had 2 SSPs, 12 had 3 SSPs, 2 had 4 SSPs, and 1 had 5 SSPs included in the analysis.

      Endoscopic features of SSPs

      The median size of SSPs was 15 mm (interquartile range [IQR] 10-20). SSPs (1) were located in the right side of the colon in 77 of 141 cases (54.6%), (2) were most often Paris classification 0-IIa (119/141, 84.4%), (3) had a mucous cap (115/141, 81.6%), (4) had a finely nodular surface (84/141, 59.6%), had an indistinct border (95/141, 67.4%), and (5) were paler than the surrounding mucosa in the majority of cases (128/141, 90.8%). Endoscopic prediction that a lesion was an SSP was accurate in 141 of 141 cases (100%) compared with histopathology.
      One hundred five of 141 lesions were predicted as SSP-ND by using the standardized imaging protocol, and 36 of 141 (25.5%) were predicted as SSP-D. SSP-ND were smaller than SSP-D (15 mm, IQR 10-20 vs 20 mm, IQR 15-30; P < .001) and were more likely to be paler than the surrounding mucosa under NBI compared with SSP-D (100/105, 95.2% vs 28/36, 77.8%; P = .004). SSP-D were more likely to contain a dominant Is component than SSP-ND (3/36, 8.3% vs 0/105, 0%; P = .027). Other endoscopic features of SSPs were similar between the groups (Table 1).
      Table 1Characteristics of the lesions in the study including methods of resection split by endoscopic features of dysplasia by using the standardized imaging protocol
      SSP-ND

      n = 105
      SSP-D

      n = 36
      P value
      Patient
       Age (± SD), y60.2 (18.3)68.9 (12.8).010
       Sex, female, no. (%)79 (75.2)25 (69.4).495
      Endoscopic features
       Size, median (IQR)15.0 (10-20)20 (15-30)< .001
       Left side of colon location
      Distal to the hepatic flexure.
      50 (47.6)14 (38.9).364
       Paris classification, no. (%)
      0-Is1 (1.0)0 (0).027
      0-IIa91 (86.7)28 (77.8)
      0-IIb13 (12.4)5 (13.9)
      0-IIa/Is0 (0)3 (8.3)
       Finely nodular, cloud-like surface, no. (%)58 (55.2)26 (72.2).080
       Mucous cap, no. (%)86 (81.9)29 (80.6).857
       Indistinct border, no. (%)73 (69.5)22 (61.1).353
       Paler than surrounding mucosa,
      Using narrow-band imaging.
      no. (%)
      100 (95.2)28 (77.8).004
      Resection features
       Type of resection, no. (%)
      CSP48 (45.7)8 (22.2).042
      pCSP13 (12.4)5 (13.9)
      EMR, en bloc10 (9.5)8 (22.2)
      EMR, piecemeal34 (32.4)15 (41.7)
       Intra-procedural bleeding, no. (%)7 (6.7)4 (11.1).472
       Deep mural injury, no. (%)2 (1.9)1 (2.8)1
       Complete resection, no. (%)105 (100)36 (100)1
      Degree of dysplasia, no. (%)
      Note this comparison /28 SSP diagnosed as SSA-ND at initial histopathologic analysis.
       Low grade×26 (92.9)×
       High grade×2 (7.1)
      SSP-ND, Sessile serrated polyp without dysplasia as determined endoscopically; SSP-D, sessile serrated polyp with dysplasia as determined endoscopically; SD, standard deviation; IQR, interquartile range; CSP, cold snare polypectomy, pCSP, piecemeal cold snare polypectomy; x, not applicable.
      Distal to the hepatic flexure.
      Using narrow-band imaging.
      Note this comparison /28 SSP diagnosed as SSA-ND at initial histopathologic analysis.

      Endoscopic prediction of dysplasia

      Of the 36 of 141 (25.5%) SSPs predicted as SSP-D by using the standardized imaging protocol, 27 of 36 (75%) were predicted with high confidence (Supplementary Table 1, available online at www.giejournal.org). Larger demarcated areas within SSPs were more likely to be predicted with high confidence (median 4 mm, IQR 2-5 vs 2 mm, IQR 1.5-3; P = .010). Features of the demarcated area were described as hyper-vascular in 31 of 36 (86.1%), Kudo III pit pattern in 24 of 36 (66.7%), and Kudo IV pattern in the remaining 12 of 36 (33.3%).
      After initial histopathologic analysis, the standardized imaging protocol had a sensitivity of 92.9% (95% CI, 75.0%-98.7%), a specificity of 91.2% (95% CI, 83.9%-95.4%), and a negative predictive value of 98.1% (95% CI, 92.6%-99.7%). The accuracy was 91.4% (95% CI, 85.7%-95.1%).

      Cases with disagreement between histologic and endoscopic determination of dysplasia within SSP

      In 12 of 141 cases (8.5%), there was disagreement between endoscopic and histopathologic determination of dysplasia within specific SSPs. In each case, endoscopic and histologic images of the procedure were retrieved, and a structured discussion between endoscopists and the specialist histopathologists was undertaken (Fig. 3).
      Figure thumbnail gr3
      Figure 3Examples of cases with incongruent endoscopic imaging and initial histopathologic analysis. Area of interest ringed in white. A, B, A 30-mm sessile serrated polyp with dysplasia (SSP-D) with a 3-mm hypervascular demarcated area. Thinner tissue sections revealed a small 2-mm focus of dysplasia. Final diagnosis was sessile serrated adenoma with dysplasia as determined histologically (SSA-D). C, D, A 30-mm SSP-D with a 3-mm demarcated area, type IIIs Kudo pit pattern. No dysplasia was detected despite further tissue sections, so failure to retrieve the correct specimen was suspected because the endoscopic appearances were convincing. Final diagnosis was SSA-D. E, F, A 15-mm sessile serrated polyp without dysplasia (SSP-ND). Histopathology revealed a focus of dysplasia. On further inspection of the images, a demarcated area was visible and was likely under-appreciated by the endoscopist because of over-distension of the colon. Final diagnosis was SSA-D. G, H, A 20-mm SSP-ND. Histopathology revealed small, multifocal areas of dysplasia. Lack of a clear transition zone from dysplastic to nondysplastic sessile serrated polyp (SSP) was judged responsible for this error. Final diagnosis was SSA-D. I, J, A 15-mm sessile serrated polyp with dysplasia (SSP-D). Histopathology revealed no evidence of dysplasia despite further tissue sections. A borderline type II-O/IIIs Kudo pit pattern was judged to be responsible for this error. Final diagnosis was sessile serrated adenoma without dysplasia as determined histologically (SSA-ND). K, L, A 35-mm SSP-D. A small focus of traditional serrated adenoma within the SSP was detected at histopathology review, likely corresponding to the demarcated area (photomicrograph in C). Final diagnosis was SSA-ND (no conventional dysplasia

      Bettington ML, Chetty R. Traditional serrated adenoma: an update. Hum Pathol. Epub 2015 Apr 20.

      ). M, N, A 25-mm SSP-D. No dysplasia was detected at histopathology despite additional sections, however a 1.5-mm perineurioma was detected. It was judged likely that this pathology elevated and stretched the lesion surface, creating the appearance of a demarcated area (D). Final diagnosis was SSA-ND. O, P, A 25-mm SSP-D at the appendiceal orifice. No dysplasia was detected at histopathology review. The appearance of a demarcated area created by the colon contour was judged to be responsible for this error. Final diagnosis was SSA-ND.
      In 5 of 12 cases (41.7%), a consensus was reached that the endoscopic imaging was correct. Causes for histopathologic error were not errors in retrieval and/or processing of the specimen in 4 of 5 cases (80.0%), and a small area of dysplasia missed between tissue slices in 1 case of 5 (20.0%).
      In 7 of 12 cases (58.3%), a consensus was reached that the histopathologic assessment was correct. Causes for endoscopic error were a demarcation area created by an alternative pathology in 3 of 7 cases (42.9%) (traditional serrated adenoma in 1 of 3 and a perineurioma in 2 of 3) (Fig. 4), colon morphology in 2 of 7 cases (28.6%), a borderline type II-O/III Kudo pit pattern in 1 of 7 cases (14.3%), and multifocal dysplasia with no transition point in 1 of 7 cases (14.3%).
      Figure thumbnail gr4
      Figure 4Examples of cases in which histopathologic features other than dysplasia created a demarcation zone, causing the endoscopist to predict dysplasia when none was present. A, Typical sessile serrated polyp with dysplasia (SSP-D) with a transition zone from dysplastic mucosa (D) to nondysplastic serrated tissue (ND) marked by the arrow (H&E, orig. mag. ×2). B, A higher magnification of A (H&E, orig. mag. ×4). C, Endoscopically predicted SSP-D (corresponding to K and L). A small focus of traditional serrated adenoma was detected at histopathology (arrow), likely corresponding to the demarcated area in the endoscopic image. Final diagnosis was sessile serrated adenoma without dysplasia as determined histologically (SSA-ND) (H&E, orig. mag. ×4). D, Endoscopically predicted SSP-D (corresponding to M and N) (H&E, orig. mag. ×5). The photomicrograph shows a focal perineurioma (arrow) measuring 1.5 mm across within the SSA-ND. This elevated and stretched a focal area of the lesion, creating the appearance of a demarcated area. Final diagnosis was SSA-ND (H&E, orig. mag. ×4). E, Magnification of area shown by arrow in D (H&E, orig. mag. ×10).
      After the results of consensus opinion were taken into consideration, the standardized endoscopic imaging protocol demonstrated a sensitivity of 93.9% (95% CI, 78.4%-98.9%), specificity of 95.4% (95% CI, 89.0%-98.3%), negative predictive value of 98.1% (95% CI, 92.6%-99.7%), and an accuracy of 95.0% (95% CI, 90.1%-97.6%) for the prediction of dysplasia within SSPs (Table 2).
      Table 2Accuracy of the endoscopic assessment of dysplasia within serrated lesions ≥8 mm before and after discussion with the specialist histopathologists
      Before discussionHistopathologic assessment
      Endoscopic assessmentSSA-ND (113)SSA-D (28)
       SSP-ND (105)103 (98.1%)2 (1.9%)
       SSP-D (36)10 (27.8%)26 (72.2%)
      Accuracy of endoscopic assessment of dysplasia (before discussion)
       Sensitivity92.9% (95 CI, 75.0%-98.7%)
       Specificity91.2% (95% CI, 83.9%-95.4%)
       Negative predictive value98.1% (95% CI, 92.6%-99.7%)
       Accuracy91.4% (95% CI, 85.7%-95.1%)
      After discussionHistopathologic assessment
      Endoscopic assessmentSSA-ND (108)SSA-D (33)
       SSP-ND (105)103 (98.1%)2 (1.9%)
       SSP-D (36)5 (13.9%)31 (86.1%)
      Accuracy of endoscopic assessment of dysplasia (after discussion)
       Sensitivity93.9% (95% CI, 78.4%-98.9%)
       Specificity95.4% (95% CI, 89.0%-98.3%)
       Negative predictive value98.1% (95% CI, 92.6%-99.7%)
       Accuracy95.0% (95% CI, 90.1%-97.6%)
      SSA-ND, Sessile serrated adenoma without dysplasia as determined histologically; SSA-D, sessile serrated adenoma with dysplasia as determined histologically or by structured discussion; SSP-ND, sessile serrated polyp without dysplasia as determined endoscopically; SSP-D, sessile serrated polyp with dysplasia as determined endoscopically; CI, confidence interval.

      Endoscopic resection

      En bloc cold snare polypectomy was the most common form of resection for SSPs (56/141, 39.7%). Piecemeal cold snare polypectomy (18/141, 12.8%) was principally used for large, nondysplastic SSPs. EMR was preferred for SSP-D (20/28, 71.4% vs 47/113, 41.6%; P = .005). Endoscopic resection was judged to be complete in all cases.

      Discussion

      Recent data show that SSA-ND has a long dwell time before the development of dysplasia and progression to CRC.
      • Bettington M.
      • Walker N.
      • Rosty C.
      • et al.
      Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma.
      Standardized description of their endoscopic features
      • IJspeert J.E.
      • Bastiaansen B.A.
      • van Leerdam M.E.
      • et al.
      Development and validation of the WASP classification system for optical diagnosis of adenomas, hyperplastic polyps and sessile serrated adenomas/polyps.
      has enabled their reliable detection, and they can be managed effectively by complete endoscopic resection. Conversely, SSA-D are high-risk lesions. Once they have acquired specific molecular changes (commonly hyper-methylation of MLH1
      • Sheridan T.B.
      • Fenton H.
      • Lewin M.R.
      • et al.
      Sessile serrated adenomas with low- and high-grade dysplasia and early carcinomas.
      ), the available evidence suggests they progress rapidly to CRC.
      • Bettington M.
      • Walker N.
      • Rosty C.
      • et al.
      Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma.
      • Arain M.A.
      • Sawhney M.
      • Sheikh S.
      • et al.
      CIMP status of interval colon cancers: another piece to the puzzle.
      It is established that SSPs often are incompletely resected.
      • Pohl H.
      • Srivastava A.
      • Bensen S.P.
      • et al.
      Incomplete polyp resection during colonoscopy–results of the complete adenoma resection (CARE) study.
      Although this may be of little consequence for SSP-ND, incomplete resection of SSP-D may be responsible for a significant proportion of interval CRC, perhaps primarily because of a failure to appreciate the nature or extent of the lesion. For example, SSP-D may be mistaken for adenomas with the endoscopist not appreciating the surrounding serrated component, which may then be left in situ. In this study we have demonstrated that a simple, broadly applicable, endoscopic imaging protocol can accurately determine the presence of dysplasia within SSPs in a large prospective cohort. This protocol therefore allows the suitably trained endoscopist to reliably recognize SSP-D, precisely delineate its extent, and ensure its complete endoscopic resection.
      Contemporary colonoscopists with high adenoma detection rates report serrated lesion detection rates of approximately 8%,
      • Abdeljawad K.
      • Vemulapalli K.C.
      • Kahi C.J.
      • et al.
      Sessile serrated polyp prevalence determined by a colonoscopist with a high lesion detection rate and an experienced pathologist.
      and the serrated lesion detection rate is emerging as an important quality measure for colonoscopists. This success has, in large part, been because of studies defining
      • Hazewinkel Y.
      • López-Cerón M.
      • East J.E.
      • et al.
      Endoscopic features of sessile serrated adenomas: validation by international experts using high-resolution white-light endoscopy and narrow-band imaging.
      • Kimura T.
      • Yamamoto E.
      • Yamano H.-O.
      • et al.
      A novel pit pattern identifies the precursor of colorectal cancer derived from sessile serrated adenoma.
      and standardizing the endoscopic features of SSPs. A recent international consensus
      • IJspeert J.E.
      • Bastiaansen B.A.
      • van Leerdam M.E.
      • et al.
      Development and validation of the WASP classification system for optical diagnosis of adenomas, hyperplastic polyps and sessile serrated adenomas/polyps.
      suggests an accuracy of 0.93 (95% CI, 0.87-0.98) in discriminating SSPs from non-SSPs after training. Among the cohort of tertiary-care center endoscopists in this study, SSPs were correctly identified in all cases. We confirmed that the features of SSPs in the WASP classification
      • IJspeert J.E.
      • Bastiaansen B.A.
      • van Leerdam M.E.
      • et al.
      Development and validation of the WASP classification system for optical diagnosis of adenomas, hyperplastic polyps and sessile serrated adenomas/polyps.
      were common and can be used readily to identify SSPs, particularly a clouded or finely nodular surface, indistinct border, and a lesion paler than the surrounding mucosa by using NBI.
      Modern endoscopic imaging allows reliable visualization to the level of the individual colon mucosal gland, permitting differentiation of so-called neoplastic pit patterns from non-neoplastic patterns.
      • Kudo S.
      • Hirota S.
      • Nakajima T.
      • et al.
      Colorectal tumours and pit pattern.
      The detection of a demarcated area of disordered pit pattern within a regular neoplastic pattern has emerged as a predictor of submucosal invasive cancer.
      • Kudo S.-E.
      • Kashida H.
      Flat and depressed lesions of the colorectum.
      Multiple case reports have described the feasibility of using endoscopic imaging
      • Nanda K.S.
      • Tutticci N.
      • Burgess N.
      • et al.
      Caught in the act: endoscopic characterization of sessile serrated adenomas with dysplasia.
      or chromoendoscopy
      • Murakami T.
      • Sakamoto N.
      • Yao T.
      Sessile serrated adenoma/polyp with cytological dysplasia diagnosed accurately by magnifying chromoendoscopy.
      to describe demarcated areas of dysplasia within SSPs. A recent Japanese still-image–based study

      Murakami T, Sakamoto N, Ritsuno H, et al. Distinct endoscopic characteristics of sessile serrated adenoma/polyp with and without dysplasia/carcinoma [abstract]. Gastrointest Endosc. Epub 2016 Sep 20.

      conducted retrospectively among 41 SSP-D derived a set of endoscopic lesion characteristics (reddishness, double elevation, and central depression), which predicted dysplasia or serrated cancer. The inclusion of serrated cancer, use of still images, and derivation of highly subjective predictors limits the widespread applicability of this method of determining SSP-D.
      We used features derived from our previous studies
      • Nanda K.S.
      • Tutticci N.
      • Burgess N.
      • et al.
      Caught in the act: endoscopic characterization of sessile serrated adenomas with dysplasia.
      • Burgess N.G.
      • Pellise M.
      • Nanda K.S.
      • et al.
      Clinical and endoscopic predictors of cytological dysplasia or cancer in a prospective multicentre study of large sessile serrated adenomas/polyps.
      in addition to our anecdotal observations to develop a standardized imaging protocol to determine dysplasia within SSP. Dysplasia commonly appears as a transition from type II open pits typical of SSP to type III or type IV pits typical of tubular or tubulovillous adenoma. The transition stands out to the observer and creates a demarcated area, particularly under NBI. This area often is hypervascular or dark (under NBI) compared with the surrounding serrated tissue. When the imaging protocol was applied prospectively to the 141 lesions in this study, the accuracy of determining dysplasia was very high (95%) as was the negative predictive value (98%).
      Incomplete resection of a rapidly progressive high-risk lesion such as SSP-D is likely responsible for a proportion of interval cancers after colonoscopy. In this scenario, the endoscopist, distracted by the adenomatous pit pattern of an SSP-D, resects only the dysplastic portion, leaving part of a lesion with the mutations, allowing rapid progression to CRC in situ. The ability to determine accurately, by using endoscopic imaging, whether a given colon lesion is an SSP-D allows real-time appreciation of its high-risk nature as well as the full extent of the lesion, guarding against incomplete resection. It also allows selection of a safe method of endoscopic resection. Dysplastic lesions should be resected by established techniques, that is, EMR. In particular, the dysplastic focus should be removed en bloc and submitted separately for histopathology to avoid missing a focus of submucosal invasive cancer. At our center, we routinely perform piecemeal cold snare polypectomy for large SSPs without endoscopic evidence of dysplasia, aiming to avoid the risks of electrocautery, especially delayed bleeding from the right side of the colon. Prospective randomized studies (compared with EMR) are required to determine the safety and utility of this technique. The 5 patients who underwent piecemeal cold snare polypectomy for SSP-D in this study were elderly, and therefore avoidance of electrocautery risk was prioritized.
      Another potential benefit of an accurate endoscopic imaging protocol to detect and characterize SSP-D concerns patients with multiple SSPs (including those meeting criteria for serrated polyposis syndrome), requiring several colonoscopic sessions to clear the colon. The majority of these lesions may take many years to develop the molecular changes required to become CRC. Endoscopic determination of dysplasia allows the endoscopist to prioritize high-risk lesions for resection.
      Real-time analysis notwithstanding, histopathology remains an imperfect criterion standard in the study of dysplastic areas within SSPs. Dysplastic foci often are small (median 3 mm diameter in this study). These small foci may not be retrieved or may be destroyed during tissue processing. They may lie undiscovered between tissue sections, which can be as wide as 3 to 5 mm.
      The majority of endoscopic errors in determining SSP-D were due to an alternative lesion mimicking the appearance of a demarcated area or the colon contour hiding the presence of a nodule. Overall, 10 of 12 cases (83.3%) with a discrepancy between endoscopic and histologic findings were endoscopically predicted as SSP-D, whereas histology determined SSA-ND. Although 5 of 10 such cases (50%) were later determined to be histologic error, the clinical relevance of these discrepancies should be played down because it is the ability to endoscopically determine a lack of dysplasia that matters clinically.
      Given the accuracy of the standardized imaging protocol in predicting SSP-D among a group of expert endoscopists, independent validation of these findings is necessary before dissemination of learning materials to the wider endoscopic community. Complementary efforts should include dissemination of validated criteria to accurately identify SSPs. The support of international societies will be vital in this endeavor.
      The strengths of this study include a large, previously unstudied cohort of patients with SSP, which were systematically described and prospectively collected. Involvement of multiple endoscopists and review of all specimens by 2 blinded specialist histopathologists minimized bias in analysis of the protocol and the histopathologic analysis. The standardized imaging protocol is simple and can be generalized widely because the majority of endoscopy units will have the equipment required to implement it.
      The drawbacks of the study include the collection of cases from a single center. In addition, SSPs were detected within a tertiary-care resection cohort, potentially biasing the type of lesion seen in the everyday practice of a screening endoscopist. In particular, the mean size of SSPs in a screening populations is about 10 mm, according to a recent study,
      • Abdeljawad K.
      • Vemulapalli K.C.
      • Kahi C.J.
      • et al.
      Sessile serrated polyp prevalence determined by a colonoscopist with a high lesion detection rate and an experienced pathologist.
      as compared with the median size in this study of 15 mm. The experience described here with larger SSPs may be a stepping stone to understanding the problem and elucidating the imaging signs of dysplasia in smaller lesions. In addition, not only is SSP-D rare in screening populations (0.6% of all polyps in 1 study
      • Abdeljawad K.
      • Vemulapalli K.C.
      • Kahi C.J.
      • et al.
      Sessile serrated polyp prevalence determined by a colonoscopist with a high lesion detection rate and an experienced pathologist.
      ), but if an SSP is small, the endoscopist is more likely to appreciate the lesion as a whole rather than be drawn to the dysplastic focus as such.
      In conclusion, we have demonstrated that dysplasia within SSPs can be predicted accurately by using a standardized endoscopic imaging protocol. This simple protocol allows the appropriately trained endoscopist to characterize SSP-D fully–particularly the extent of the lesion–with a view to achieving complete resection. Given that SSP-Ds are strongly implicated in interval cancers after colonoscopy, independent validation of this protocol and its dissemination to the wider endoscopic community may have profound clinical consequences.

      Appendix

      Figure thumbnail fx1
      Supplementary Figure 1Recruitment and flow through the study. ER, endoscopic resection; SSP, sessile serrated polyp; HDWL, high-definition white light; NBI, narrow-band imaging; SSP-ND, nondysplastic SSP as determined endoscopically; SSP-D, dysplastic SSP as determined endoscopically; CSP, cold snare polypectomy; pCSP, piecemeal cold snare polypectomy; SSA-ND, sessile serrated adenoma without dysplasia as determined histologically; SSA-D, sessile serrated adenoma with dysplasia as determined histologically.
      Supplementary Table 1Characteristics of dysplastic demarcated areas within 36 sessile serrated polyps with dysplasia detected within the study period, split by the endoscopist’s confidence in the presence of dysplasia
      Total

      n = 36
      Low confidence

      n = 9
      High confidence

      n = 27
      P value
      Endoscopic features of demarcated area
       Size (median, IQR), mm3 (2-5)2 (1.5-3)4 (2-5).010
       Hypervascular, no. (%)31 (86.1)8 (88.9)23 (85.2)1.000
       Highest Kudo, no. (%)
      III24 (66.7)6 (66.7)18 (66.7)1.000
      IV12 (33.3)3 (33.3)9 (33.3)
      Histologic outcome
       SSA-D before discussion, no. (%)26 (72.2)4 (44.4)22 (81.5).627
       SSA-D after discussion, no. (%)31 (86.1)6 (66.7)25 (92.6).088
      IQR, Interquartile range; SSA-D, sessile serrated adenoma with dysplasia as determined histologically Before and after discussion refer to the discussion of cases between the endoscopist and the specialist pathologists.

      Supplementary data

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