A Rectum-Specific Selective Resection Algorithm Optimizes Oncologic Outcomes for Large Nonpedunculated Rectal Polyps.

BACKGROUND AND AIMS: Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are complementary techniques for large (≥20 mm) nonpedunculated rectal polyps (LNPRPs). A mechanism for appropriate technique selection has not been described. METHODS: We evaluated the performance of a selective resection algorithm (SRA) (August 2017 to April 2021) compared with a universal EMR algorithm (UEA) (July 2008 to July 2017) for LNPRPs within a prospective observational study. In the SRA, LNPRPs with features of superficial submucosal invasive cancer (SMIC) (<1000 µm; Kudo pit pattern Vi), or with an increased risk of SMIC (Paris 0-Is or 0-IIa+Is nongranular, 0-IIa+Is granular with a dominant nodule ≥10 mm) underwent ESD. The remaining LNPRPs underwent EMR. Algorithm performance was evaluated by SMIC identified after EMR, curative oncologic resection (R0 resection, superficial SMIC, absence of negative histologic features), technical success, adverse events, and recurrence at first surveillance colonoscopy. RESULTS: A total of 480 LNPRPs were evaluated (290 UEA, 190 SRA). Median lesion size was 40 (interquartile range, 30-60) mm. SMIC was identified in 56 (11.7%) LNPRPs. Significant differences in SMIC after EMR (SRA 1 [1.0%] vs UEA 35 [12.1%]; P = .001) and curative oncologic resection (SRA n = 7 [33.3%] vs UEA n = 2 [5.7%]; P = .010) were identified. No significant differences in technical success or adverse events were identified (all P > .137). Among LNPRPs with SMIC amenable to curative oncologic resection and which underwent ESD, 100% (n = 7 of 7) were cured. CONCLUSIONS: A rectum-specific SRA optimizes oncologic outcomes for LNPRPs and mitigates the risk of piecemeal resection of cancers.

Outcomes of Deep Mural Injury After Endoscopic Resection: An International Cohort of 3717 Large Non-Pedunculated Colorectal Polyps.

BACKGROUND & AIMS: Although perforation is the most feared adverse event associated with endoscopic mucosal resection (EMR), limited data exists concerning its management. Therefore, we sought to evaluate the short- and long-term outcomes of intra-procedural deep mural injury (DMI) in an international multi-center observational cohort of large (≥20 mm) non-pedunculated colorectal polyps (LNPCPs). METHODS: Consecutive patients who underwent EMR for a LNPCP ≥20 mm were evaluated. Significant DMI (S-DMI) was defined as Sydney DMI Classification type III (muscularis propria injury, target sign) or type IV/V (perforation without or with contamination, respectively). The primary outcome was successful S-DMI defect closure. Secondary outcomes included technical success (removal of all visible polypoid tissue during index EMR), surgical referral and recurrence at first surveillance colonscopy (SC1). RESULTS: Between July 2008 to May 2020, 3717 LNPCPs underwent EMR. Median lesion size was 35mm (interquartile range (IQR) 25 to 45mm). Significant DMI was identified in 101 cases (2.7%), with successful defect closure in 98 (97.0%) using a median of 4 through-the-scope clips (TTSCs; IQR 3 to 6 TTSCs). Three (3.0%) patients underwent S-DMI-related urgent surgery. Technical success was achieved in 94 (93.1%) patients, with 46 (45.5%) admitted to hospital (median duration 1 day; IQR 1 to 2 days). Comparing LNPCPs with and without S-DMI, no differences in technical success (94 (93.1%) vs 3316 (91.7%); P = .62) or SC1 recurrence (12 (20.0%) vs 363 (13.6%); P = .15) were identified. CONCLUSIONS: Significant DMI is readily managed endoscopically and does not appear to affect technical success or recurrence.

Incremental benefit of dye-based chromoendoscopy to predict the risk of submucosal invasive cancer in large nonpedunculated colorectal polyps.

BACKGROUND AND AIMS: Detailed lesion assessment of large nonpedunculated colorectal polyps (LNPCPs; ≥20 mm) can help predict the risk of submucosal invasive cancer (SMIC). Traditionally this has required the use of dye-based chromoendoscopy (DBC). We sought to assess the accuracy and incremental benefit of DBC in addition to high-definition white-light imaging (HDWLI) and virtual chromoendoscopy (VCE) for the prediction of SMIC within LNPCPs. METHODS: A prospective observational study of consecutive LNPCPs at a single tertiary referral center was performed. Before resection all lesions were assessed for the presence of a demarcated area (DA), defined as an area of disordered pit or microvascular pattern, by 2 trained endoscopists before and after DBC. Diagnostic performance characteristics were calculated with histology as the reference criterion standard, and overall agreement was calculated using the κ statistic. RESULTS: Over 39 months to March 2021, 400 consecutive LNPCPs (median lesion size, 35 mm; interquartile range, 25-45) were analyzed. The overall rate of SMIC was 6.5%. Presence of a DA had an accuracy of 91% (95% confidence interval, 87.7-93.5) for SMIC, independent of the use of DBC. The rate of interobserver agreement for presence of a DA using HDWLI + VCE was very high (κ = .96) with no benefit gained by the addition of DBC. CONCLUSIONS: The use of HDWLI and VCE is likely to be adequate for lesion assessment for the prediction of SMIC among LNPCPs. Further, the absence of a DA is strongly predictive for the absence of SMIC, independent to the use of DBC. (Clinical trial registration number: NCT03506321.).

Optical Evaluation for Predicting Cancer in Large Nonpedunculated Colorectal Polyps Is Accurate for Flat Lesions.

BACKGROUND AND AIMS: The ability of optical evaluation to diagnose submucosal invasive cancer (SMIC) prior to endoscopic resection of large (≥20 mm) nonpedunculated colorectal polyps (LNPCPs) is critical to inform therapeutic decisions. Prior studies suggest that it is insufficiently accurate to detect SMIC. It is unknown whether lesion morphology influences optical evaluation performance. METHODS: LNPCPs ≥20 mm referred for endoscopic resection within a prospective, multicenter, observational cohort were evaluated. Optical evaluation was performed prior to endoscopic resection with the optical prediction of SMIC based on established features (Kudo V pit pattern, depressed morphology, rigidity/fixation, ulceration). Optical evaluation performance outcomes were calculated. Outcomes were reported by dominant morphology: nodular (Paris 0-Is/0-IIa+Is) vs flat (Paris 0-IIa/0-IIb) morphology. RESULTS: From July 2013 to July 2019, 1583 LNPCPs (median size 35 [interquartile range, 25-50] mm; 855 flat, 728 nodular) were assessed. SMIC was identified in 146 (9.2%; 95% confidence interval [CI], 7.9%-10.8%). Overall sensitivity and specificity were 67.1% (95% CI, 59.2%-74.2%) and 95.1% (95% CI, 93.9%-96.1%), respectively. The overall SMIC miss rate was 3.0% (95% CI, 2.3%-4.0%). Significant differences in sensitivity (90.9% vs 52.7%), specificity (96.3% vs 93.7%), and SMIC miss rate (0.6% vs 5.9%) between flat and nodular LNPCPs were identified (all P < .027). Multiple logistic regression identified size ≥40 mm (odds ratio [OR], 2.0; 95% CI, 1.0-3.8), rectosigmoid location (OR, 2.0; 95% CI, 1.1-3.7), and nodular morphology (OR, 7.2; 95% CI, 2.8-18.9) as predictors of missed SMIC (all P < .039). CONCLUSIONS: Optical evaluation performance is dependent on lesion morphology. In the absence of features suggestive of SMIC, flat lesions can be presumed benign and be managed accordingly.

Impact of technical innovations in EMR in the treatment of large nonpedunculated polyps involving the ileocecal valve (with video).

BACKGROUND AND AIMS: The endoscopic management of large nonpedunculated colorectal polyps involving the ileocecal valve (ICV-LNPCPs) remains challenging because of its unique anatomic features, with long-term outcomes inferior to LNPCPs not involving the ICV. We sought to evaluate the impact of technical innovations and advances in the EMR of ICV-LNPCPs. METHODS: The performance of EMR for ICV-LNPCPs was retrospectively evaluated in a prospective observational cohort of LNPCPs ≥20 mm. Efficacy was measured by clinical success (removal of all polypoid tissue during index EMR and avoidance of surgery) and recurrence at first surveillance colonoscopy. Accounting for the adoption of technical innovations, comparisons were made between an historical cohort (September 2008 to April 2016) and contemporary cohort (May 2016 to October 2020). Safety was evaluated by documenting the frequencies of intraprocedural bleeding, delayed bleeding, deep mural injury, and delayed perforation. RESULTS: Between September 2008 to October 2020, 142 ICV-LNPCPs were referred for EMR. Median ICV-LNPCP size was 35 mm (interquartile range, 25-50 mm). When comparing the contemporary (n = 66) and historical cohorts (n = 76) of ICV-LNPCPs, there were significant differences in clinical success (93.9% vs 77.6%, P = .006) and recurrence (4.6% vs 21.0%, P = .019). CONCLUSIONS: With technical advances, ICV-LNPCPs can be effectively and safely managed by EMR, independent of lesion complexity. Most patients experience excellent outcomes and avoid surgery.

Previously Attempted Large Nonpedunculated Colorectal Polyps Are Effectively Managed by Endoscopic Mucosal Resection.

INTRODUCTION: Endoscopic mucosal resection (EMR) is an effective therapy for naive large nonpedunculated colorectal polyps (N-LNPCPs). The best approach for the treatment of previously attempted LNPCPs (PA-LNPCPs) is undetermined. METHODS: EMR performance for PA-LNPCPs was evaluated in a prospective observational cohort of LNPCPs ≥20 mm. Efficacy was measured by technical success (removal of all visible polypoid tissue during index EMR) and recurrence at first surveillance colonoscopy (SC1). Safety was assessed by clinically significant intraprocedural bleeding, deep mural injury types III-V, clinically significant post-EMR bleeding, and delayed perforation. RESULTS: From January 2012 to October 2019, 158 PA-LNPCPs and 1,134 N-LNPCPs underwent EMR. Median PA-LNPCP size was 30 mm (interquartile range 25-46 mm). Technical success was 93.0% and increased to 95.6% after adjusting for 2-stage EMR. Cold-forceps avulsion with adjuvant snare-tip soft coagulation (CAST) was required for nonlifting polypoid tissue in 73 (46.2%). Median time to SC1 was 6 months (interquartile range 5-7 months). Recurrence occurred in 9 (7.8%). No recurrence was identified among 65 PA-LNPCPs which underwent margin thermal ablation at SC1 vs 9 (18.0%; P < 0.001) which did not. There were significant differences in resection duration (35 vs 25 minutes; P < 0.001), technical success (93.0% vs 96.6%; P = 0.026), and use of CAST (46.2% vs 7.6%; P < 0.001), between PA-LNPCPs and N-LNPCPs. When adjusting for 2-stage EMR, no difference in technical success was identified (95.6% vs 97.8%; P = 0.100). No differences in adverse events or recurrence were identified. DISCUSSION: EMR, using auxillary techniques where necessary, can achieve high technical success and low recurrence frequencies for PA-LNPCPs.

Piecemeal cold snare polypectomy versus conventional endoscopic mucosal resection for large sessile serrated lesions: a retrospective comparison across two successive periods.

OBJECTIVE: Large (≥20 mm) sessile serrated lesions (L-SSL) are premalignant lesions that require endoscopic removal. Endoscopic mucosal resection (EMR) is the existing standard of care but carries some risk of adverse events including clinically significant post-EMR bleeding and deep mural injury (DMI). The respective risk-effectiveness ratio of piecemeal cold snare polypectomy (p-CSP) in L-SSL management is not fully known. DESIGN: Consecutive patients referred for L-SSL management were treated by p-CSP from April 2016 to January 2020 or by conventional EMR in the preceding period between July 2008 and March 2016 at four Australian tertiary centres. Surveillance colonoscopies were conducted at 6 months (SC1) and 18 months (SC2). Outcomes on technical success, adverse events and recurrence were documented prospectively and then compared retrospectively between the subsequent time periods. RESULTS: A total of 562 L-SSL in 474 patients were evaluated of which 156 L-SSL in 121 patients were treated by p-CSP and 406 L-SSL in 353 patients by EMR. Technical success was equal in both periods (100.0% (n=156) vs 99.0% (n=402)). No adverse events occurred in p-CSP, whereas delayed bleeding and DMI were encountered in 5.1% (n=18) and 3.4% (n=12) of L-SSL treated by EMR, respectively. Recurrence rates following p-CSP were similar to EMR at 4.3% (n=4) versus 4.6% (n=14) and 2.0% (n=1) versus 1.2% (n=3) for surveillance colonoscopy (SC)1 and SC2, respectively. CONCLUSIONS: In a historical comparison on the endoscopic management of L-SSL, p-CSP is technically equally efficacious to EMR but virtually eliminates the risk of delayed bleeding and perforation. p-CSP should therefore be considered as the new standard of care for L-SSL treatment.

Large prolapse-related lesions of the sigmoid colon.

BACKGROUND: Large prolapse-related lesions (LPRL) of the sigmoid colon have been documented histologically but may not be readily recognized endoscopically. METHODS: Colonic lesions referred for endoscopic mucosal resection (EMR) were enrolled prospectively. Endoscopic features were carefully documented prior to resection. Final diagnosis was made based on established histologic criteria, including vascular congestion, hemosiderin deposition, fibromuscular hyperplasia, and crypt distortion. RESULTS: Of 134 large ( ≥ 20 mm) sigmoid lesions, 12 (9.0 %) had histologic features consistent with mucosal prolapse. Distinct endoscopic features were: broad-based morphology; vascular pattern obscured by dusky hyperemia; blurred crypts of varying size and shape; and irregular spacing of sparse crypts. Focal histologic dysplasia was identified in 6 of 12 lesions (50.0 %). CONCLUSIONS: LPRL of the sigmoid colon exhibit a distinct endoscopic profile. Although generally non-neoplastic, dysplasia may be present, warranting consideration of EMR.

Outcomes of thermal ablation of the defect margin after duodenal endoscopic mucosal resection (with videos).

BACKGROUND AND AIMS: Laterally spreading lesions (LSLs) in the duodenum are conventionally treated by EMR. Recurrence is commonly encountered and can be difficult to treat safely due to the unique anatomic characteristics of the duodenum. Auxiliary techniques designed to prevent recurrence have not been described. METHODS: We sought to evaluate the effectiveness of thermal ablation of the defect margin after EMR (EMR-T) in reducing recurrence at first surveillance endoscopy (SE1, scheduled at 6 months) in a single tertiary referral center. All duodenal LSLs ≥10 mm referred for EMR were eligible. After successful EMR, thermal ablation was performed using snare-tip soft coagulation around the entire circumference of the resection defect. The primary outcome was the frequency of recurrence at SE1. A previous, well-characterized, prospective cohort of duodenal LSLs ≥10 mm treated by conventional EMR was the comparator. RESULTS: Over 43 months up to October 2019, 54 LSLs underwent EMR-T. One hundred twenty-five LSLs underwent conventional EMR in the comparator group. Patient and lesion characteristics were similar between the groups. Recurrence was significantly lower in the EMR-T group compared with the conventional EMR group (1 of 49 [2.3%] vs 19 of 108 [17.6%]; P = .01). No difference in technical success, EMR-related adverse outcomes, or referral to surgery were identified between the groups. CONCLUSIONS: EMR-T significantly reduces the frequency of recurrence for duodenal LSLs. This technique is safe in the duodenum and has the potential to significantly improve the effectiveness of duodenal EMR. (Clinical trial registration number: NCT02306603.).

Snare-tip soft coagulation is effective and efficient as a first-line modality for treating intraprocedural bleeding during Barrett's mucosectomy.

BACKGROUND : Intraprocedural bleeding (IPB) during multiband mucosectomy (MBM) for Barrett's neoplasia can obscure the endoscopic field. Current hemostatic devices may affect procedure continuity and technical success. Snare-tip soft coagulation (STSC) as a first-line therapy for primary hemostasis has not previously been studied in this setting. METHODS: Between January 2014 and November 2019, 191 consecutive patients underwent 292 MBM procedures for Barrett's neoplasia within a prospective observational cohort in two tertiary care centers. A standard MBM technique was performed. IPB was defined as bleeding obscuring the endoscopic field that required intervention. The primary outcome was the technical success and efficacy of STSC. RESULTS: IPB occurred in 63 MBM procedures (21.6 %; 95 % confidence interval 17.3 % - 26.7 %). STSC was attempted as first-line therapy in 51 IPBs, with the remainder requiring alternate therapies because of pooling of blood. STSC achieved hemostasis in 48 cases (94.1 % by per-protocol analysis; 76.2 % by intention-to-treat analysis). No apparatus disassembly was required to perform STSC. CONCLUSIONS: STSC is a safe, effective, and efficient first-line hemostatic modality for IPB during MBM for Barrett's neoplasia.

Optical evaluation: the crux for effective management of colorectal neoplasia.

Advances in minimally invasive tissue resection techniques now allow for the majority of early colorectal neoplasia to be managed endoscopically. To optimize their respective risk-benefit profiles, and, therefore, appropriately select between endoscopic mucosal resection, endoscopic submucosal dissection, and surgery, the endoscopist must accurately predict the risk of submucosal invasive cancer and estimate depth of invasion. Herein, we discuss the evidence and our approach for optical evaluation of large (⩾ 20 mm) colorectal laterally spreading lesions.

Endoscopic mucosal resection is effective for laterally spreading lesions at the anorectal junction.

OBJECTIVE: The optimal approach for removing large laterally spreading lesions at the anorectal junction (ARJ-LSLs) is unknown. Endoscopic mucosal resection (EMR) is a definitive therapy for colorectal LSLs. It is unclear whether it is an effective modality for ARJ-LSLs. DESIGN: EMR outcomes for ARJ-LSLs (distal margin of ≤20 mm from the dentate line) in comparison with rectal LSLs (distal margin of >20 mm from the dentate line) were evaluated within a multicentre observational cohort of LSLs of ≥20 mm. Technical success was defined as the removal of all polypoid tissue during index EMR. Safety was evaluated by the frequencies of intraprocedural bleeding, delayed bleeding, deep mural injury (DMI) and delayed perforation. Long-term efficacy was evaluated by the absence of recurrence (either endoscopic or histologic) at surveillance colonoscopy (SC). RESULTS: Between July 2008 and August 2019, 100 ARJ-LSLs and 313 rectal LSLs underwent EMR. ARJ-LSL median size was 40 mm (IQR 35-60 mm). Median follow-up at SC4 was 54 months (IQR 33-83 months). Technical success was 98%. Cancer was present in three (3%). Recurrence occurred in 15.4%, 6.8%, 3.7% and 0% at SC1-SC4, respectively. Among 30 ARJ-LSLs that received margin thermal ablation, no recurrence was identified at SC1 (0.0% vs 25.0%, p=0.002). Technical success, recurrence and adverse events were not different between groups, except for DMI (ARJ-LSLs 0% vs rectal LSLs 4.5%, p=0.027). CONCLUSION: EMR is an effective technique for ARJ-LSLs and should be considered a first-line resection modality for the majority of these lesions.

Juvenile polyposis syndrome.

Juvenile polyposis syndrome is a rare autosomal dominant syndrome characterized by multiple distinct juvenile polyps in the gastrointestinal tract and an increased risk of colorectal cancer. The cumulative life-time risk of colorectal cancer is 39% and the relative risk is 34. Juvenile polyps have a distinctive histology characterized by an abundance of edematous lamina propria with inflammatory cells and cystically dilated glands lined by cuboidal to columnar epithelium with reactive changes. Clinically, juvenile polyposis syndrome is defined by the presence of 5 or more juvenile polyps in the colorectum, juvenile polyps throughout the gastrointestinal tract or any number of juvenile polyps and a positive family history of juvenile polyposis. In about 50%-60% of patients diagnosed with juvenile polyposis syndrome a germline mutation in the SMAD4 or BMPR1A gene is found. Both genes play a role in the BMP/TGF-beta signalling pathway. It has been suggested that cancer in juvenile polyposis may develop through the so-called "landscaper mechanism" where an abnormal stromal environment leads to neoplastic transformation of the adjacent epithelium and in the end invasive carcinoma. Recognition of this rare disorder is important for patients and their families with regard to treatment, follow-up and screening of at risk individuals. Each clinician confronted with the diagnosis of a juvenile polyp should therefore consider the possibility of juvenile polyposis syndrome. In addition, juvenile polyposis syndrome provides a unique model to study colorectal cancer pathogenesis in general and gives insight in the molecular genetic basis of cancer. This review discusses clinical manifestations, genetics, pathogenesis and management of juvenile polyposis syndrome.

SMAD4 immunohistochemistry reflects genetic status in juvenile polyposis syndrome.

PURPOSE: Juvenile polyposis syndrome (JPS) can be caused by a germline defect of the SMAD4 gene. Somatic inactivation of SMAD4 occurs in pancreatic and colorectal cancers and is reflected by loss of SMAD4 immunohistochemistry. Here, SMAD4 immunohistochemistry as a marker of SMAD4 gene status and the role of SMAD4 in the adenoma-carcinoma sequence in neoplastic progression in JPS are studied. EXPERIMENTAL DESIGN: Twenty polyps with a SMAD4 germline defect and 38 control polyps were studied by SMAD4 immunohistochemistry. Inactivation of the SMAD4 wild-type allele was studied in dysplastic epithelium and in areas with aberrant SMAD4 expression. APC, beta-catenin, p53, and K-ras were studied to evaluate the adenoma-carcinoma sequence. RESULTS: Nine of 20 polyps with a SMAD4 germline defect showed loss of epithelial SMAD4 expression. Loss of heterozygosity of SMAD4 was found in five polyps and a somatic stop codon mutation was found in two polyps without loss of heterozygosity. Remarkably, somatic inactivation of epithelial SMAD4 did not always coincide with dysplasia and aberrant p53 staining was found in four of six dysplastic polyps with normal SMAD4 staining. One K-ras mutation was found in nine juvenile polyps with dysplasia. No evidence for Wnt activation was found. CONCLUSIONS: SMAD4 immunohistochemistry mirrors genetic status and provides a specific adjunct in the molecular diagnosis of JPS. However, epithelial SMAD4 inactivation is not required for polyp formation and is not obligatory for neoplastic progression in JPS. Instead, different routes to neoplasia in JPS caused by germline SMAD4 mutation seem to be operative, including somatic loss of SMAD4 and p53 inactivation without somatic loss of SMAD4.

Increased cyclooxygenase-2 expression in juvenile polyposis syndrome.

BACKGROUND & AIMS: Gastrointestinal juvenile polyps may occur in juvenile polyposis syndrome (JPS) or sporadically. JPS is an autosomal-dominant condition caused by a germline defect in SMAD4 or BMPR1A in 50% to 60% of cases, and is characterized by multiple juvenile polyps, predominantly in the colorectum. JPS has an increased risk of gastrointestinal malignancy but sporadic juvenile polyps do not. Cyclooxygenase-2 (COX-2) expression is increased in gastrointestinal tumorigenesis and familial adenomatous polyposis. Inhibition of COX-2 leads to regression of colorectal adenomas in familial adenomatous polyposis patients and inhibits gastrointestinal tumorigenesis. To investigate the role of COX-2 in juvenile polyps, we compared the expression of COX-2 in juvenile polyps from a well-defined group of juvenile polyposis patients and sporadic juvenile polyps. METHODS: COX-2 expression was assessed in 24 genetically well-defined JPS patients and 26 patients with sporadic juvenile polyps using tissue microarray analysis. Two additional markers, Hu-antigen R, a stabilizer of messenger RNA, and CCAAT/enhancer-binding protein beta, a transcription factor, both associated with increased COX-2 expression, also were investigated. RESULTS: Increased COX-2 expression in JPS patients was noted compared with patients with sporadic juvenile polyps (P < .001). Also, JPS patients with a BMPR1A germline defect had higher COX-2 expression than did JPS patients in whom no germline mutation was detected. High COX-2 levels correlated with increased cytoplasmic Hu-antigen R expression in JPS polyps (P = .022), but not in sporadic juvenile polyps. CONCLUSIONS: Juvenile polyposis and sporadic juvenile polyps show distinctive expression profiles of COX-2 that may have clinical implications.