Review | Published: 3 April 2024
open-url

Endoscopic resection of large non-pedunculated colorectal polyps: current standards of treatment

https://doi.org/10.1136/egastro-2023-100025

Request reuse permissionopen-url
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) licenseopen-url

Abstract

Colorectal cancer is a significant public health concern, and large non-pedunculated colorectal polyps pose a substantial risk for malignancy and incomplete resection, which may lead to interval cancer. The choice of resection technique is influenced by various factors, including polyp size, morphology, location, submucosal invasion depth and endoscopist expertise. For non-cancerous superficial large non-pedunculated polyps, conventional hot or cold snare polypectomy, endoscopic mucosal resection and endoscopic submucosal dissection are common techniques for non-surgical therapeutic endoscopic resection of these polyps. This manuscript provides a comprehensive review of literature on current endoscopic resection techniques for large non-pedunculated colorectal polyps, emphasising indications, advantages, limitations and outcomes.

Introduction

Colorectal cancer (CRC) is the second most common cancer in the USA contributing to about 52 550 deaths in 2023 alone.1 It commonly initiates as a non-cancerous glandular growth in the epithelial cells of the colorectal mucosa but transforms into cancer through the adenoma-carcinoma sequence.2–4 Any colorectal lesion that measures ≥10 mm is classified as a large lesion. Large lesions pose higher risk of progressing to malignancy.5–7 Endoscopic resection techniques have revolutionised the management of large polyps, providing a less invasive alternative to surgery. As such, the development and refinement of endoscopic resection techniques have become crucial in the field of gastrointestinal endoscopy. This review aims to provide an overview of current endoscopic resection techniques for large, complex (≥20 mm) non-pedunculated colorectal polyps, including snare polypectomy, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), highlighting indications, advantages, limitations and outcomes.

The imperative of thorough resection of large colorectal polyps

About 19% of interval cancers are attributed to incomplete resections, which is particularly pronounced with larger polyps.8 Indeed, a greater rate of local recurrence in large polyps was found compared with polyps sized <10 mm (36.3% vs 12.8%, p=0.046).9 Consistently with this, a pooled analysis of eight prospective studies showed a lower risk of recurrence in polyps 10–19 mm (15.9%) compared with polyps >20 mm (19.3%).10 This could be due to a lower rate of en bloc resections (93.2% vs 100%, p<0.001), a higher rate of microscopic positive margin (54.0% vs 72.7%, p = 0.001) and high-grade dysplasia (8.1% vs 0.8%, p < 0.001) in large polyps. These findings emphasise the importance of en bloc resection of large polyps when possible or targeting least number of pieces with piecemeal resection.11 This is particularly important in cases of non-pedunculated large polyps that are more likely to be removed by piecemeal resection, increasing the risk of local adenomatous recurrence over sixfold (online supplemental material A).12

Endoscopic methods for the resection of large colorectal polyps

The current standard practice for non-malignant laterally spreading lesions (LSLs) involves endoscopic management. This method aims to eradicate adenomas, intramucosal cancer or early cancer with superficial submucosal invasion of less than 1000 µm. Alternatively, it can serve as a diagnostic tool for staging and determining the appropriate surgical or non-surgical approach.11 13 The optimal endoscopic approach for removing large polyps is determined by various factors, including the size, morphology, location, the degree of submucosal invasion and the expertise of the endoscopist. Table 1 outlines the most relevant recommendations of the US Multi-Society Task Force (USMSTF) and the European Society of Gastrointestinal Endoscopy (ESGE) guidelines.

Table 1
|
The recommendations of the most recent US and European guidelines for resecting large non-pedunculated polyps

In recent years, the EMR of superficial large non-pedunculated polyps has become the standard of care instead of surgical resection due to a very high likelihood of curative removal.14 Curative endoscopic treatment (either ESD or EMR) for suspected superficial invasive carcinoma necessitates the following histological features: (1) complete en bloc R0 resection, (2) well-differentiated adenocarcinoma (grade 1) and (3) <1000 µm submucosal invasion with no lymphovascular invasion (sm1 type).15

Preprocedure preparations

Prior to conducting an EMR/ESD procedure, endoscopists should assess the suitability of endoscopic resection, taking into consideration their own expertise and abilities. This is important to prevent unsuccessful resections that result in the formation of fibrosis, impeding subsequent endoscopic resection attempts. Box 1 outlines polyp-based prognostic factors associated with poor EMR outcomes and lesions with these characteristics should be referred for surgery or ESD.

Box 1

Poor polyp-related prognostic factors for endoscopic mucosal resection of large non-pedunculated colorectal polyps

Polyp size >20 mm.

Polyp in difficult location, namely the right colon and the ileocecal valve.

Deep submucosal invasion.

High-risk morphological features under magnification endoscopy.

Prior failed resection attempts.

Size, Morphology, Site, Access (SMSA) score of 4.∗

  • ∗The SMSA polyp grading tool serves as an indicator of the complexity of endoscopic resection. This system assigns scores based on four critical factors: (1) size: <1 cm (1 point), 1–1.9 cm (3 points), 2–2.9 cm (5 points), 3–3.9 cm (7 points) and >4 cm (9 points). (2) Morphology: pedunculated (1 point), sessile (2 points) and flat (3 points). (3) Site: left (1 point) and right (2 points). (4) Access: easy (1 point) and difficult (3 points). The cumulative points obtained from these benchmarks determine the SMSA score, which, in turn, categorises polyps into four complexity levels: level 1 (4-5), level 2 (6–9), level 3 (10–12) and level 4 (>12).145

To prevent non-curative resection, it is vital to carefully inspect the lesions to identify the depth of submucosal invasion using advanced imaging techniques. The ESGE suggests using standard chromoendoscopy in the absence of advanced imaging.11 Several classification systems have been proposed to increase the accuracy of endoscopic detection of the depth of invasion, namely: Paris,16 Kudo,17 Narrow band Imaging international Colorectal Endoscopic (NICE)18 and Japan NBI Expert Team (JNET)19 classifications (table 2).

Table 2
|
Endoscopic classification systems for the detection of the depth of polyp invasion

The Paris classification 0-IIc and 0-IIa+0 IIc have increased risk of submucosal invasive carcinomas with the highest risk for uncommon Paris class 0-IIc. In a study of 1535 neoplasms, although only 15% of lesions were non-polypoid, more than half of the superficial carcinomas arose from these lesions. Additionally, non-granular lesions were found to be ten times more likely to have in situ or submucosal carcinomas compared with granular lesions of similar size.20 All lesions >20 mm had submucosal invasion with Paris type 0-IIc (flat depressed).20

The NICE classification is widely recognised as a universal standard for endoscopic polyp characterisations.18 The classification uses staining, vascular and surface patterns to distinguish between hyperplastic polyps (type 1), adenomas (type 2) and deep submucosal invasive cancer (type 3), without using magnifying endoscopy.21 NICE type 3 is compatible with Sano capillary pattern IIIA/B, Hiroshima C3 and Kudo pit pattern Vn/I for predicting deep invasion or superficial carcinoma.22–25 A study of 2123 colon lesions >10 mm showed that the NICE classification can identify the deep invasive cancer corresponding to NICE type 3 with >96% specificity and >98% negative predictive value but with a low sensitivity of 58%.26 However, NICE type 2 includes various lesions from low-grade dysplasia to T1a and cannot precisely differentiate between histology subtypes.

The JNET classification was proposed based on the NICE classification incorporating the Narrow-Band Imaging (NBI) magnifying endoscopy.19 This classification uses vessel and surface pattern to classify polyps into four categories.27 The validation studies showed types 1, 2A and 3 are highly specific for diagnosing their corresponding histology (online supplemental table 1). However, type 2B may include several subtypes including high-grade dysplasia, shallow (superficial) submucosal invasive cancer but very rarely deep submucosal invasive cancer, making the use of pit pattern characteristic in the NICE classification the standard of the diagnosis for this histological type.28 According to the previous literature, although both expert and inexperienced endoscopists could reach a high accuracy in using the JNET classification, a training session could increase the interobserver agreement and diagnostic ability.29–32

Endoscopic mucosal resection

EMR is a minimally invasive procedure that enables curative resection of large non-pedunculated polyps without invasion of lymphatic channels and vessels providing deep and wide margins surrounding polyps. Colonic LSLs≥20 mm in size are recommended to be removed with EMR if there is low likelihood of superficial submucosal invasive cancer.33 34 EMR is limited by the difficulty of en bloc resection for lesions ≥30 mm with the majority of resections performed piecemeal at that size.

Standard injection-assisted EMR

Standard EMR allows the resection of large sessile lesions by injecting a solution into the submucosa to form a cushion that prevents deep thermal injury and reduces procedure duration.11 Then, the polyp can be safely resected using snare electrocautery.11 Normal saline is the most common agent used for injecting large polyps. However, the ESGE and American Society for Gastrointestinal Endoscopy (ASGE) Technology Committee recommend that submucosal injection should be performed with agents more viscous than normal saline such as succinylated gelatin, hydroxyethyl starch, Eleview or glycerol.11 35 These agents have been shown to be associated with longer duration of submucosal cushion, faster procedure time, a lower rate of post polypectomy bleeds and a higher rate of successful and en bloc resections.36–40 Combining a submucosal injection with diluted epinephrine can further improve the visibility of the resection field, extend the duration of the submucosal cushion and reduce the risk of bleeding through vasoconstriction.41 42 The addition of a staining dye is also typically used to assist in defining the resection margin and any defects resulting from inadvertent resection of the muscularis propria.42 43

The static submucosal injection technique involves keeping the position of the needle puncture relatively fixed, potentially leading to an inadequate submucosal bleb and difficulty during snare polypectomy. In contrast, the dynamic submucosal injection technique uses a small amount of saline to confirm needle placement within the submucosa. The remaining solution is then rapidly injected while making slight adjustments to the needle position, achieved by either pulling back the needle catheter or deflecting the endoscope tip.44 As a result, the dynamic technique produces relatively more prominent cushion than the static technique.44

Submucosal injection also aids in determining the feasibility of the resection. In fact, one significant predictor of submucosal invasion >2000 µm is the non-lifting of the lesion by submucosal injection.45 46 The ESGE recommends that if submucosal injection fails to achieve proper lifting (non-lifting sign),47 the patient must be referred to a more experienced endoscopist due to increased difficulty of resection.11 Other causes of non-lifting include invasive cancer, prior biopsy, non-granular type, prior tattoo or failed resection attempts resulting in submucosal fibrosis.46

Hot snare (HS)-EMR involves an electric current converted to heat following submucosal injection while concurrently ablating resection margins and adjacent small vessels to maintain hemostasis and preventing bleeding.48 No preferred current setting recommended as adverse event rates and resection outcomes remain similar across different modes.49 A coagulation current is particularly effective in preventing bleeds as it uses higher voltage and an interrupted cycle; however, it poses a greater risk of deep thermal injuries due to the slower rate of temperature increase. However, this approach may effectively prevent bleeding. On the other hand, a cut current involves a continuous duty cycle that results in a rapid increase in cell temperature and cell bursting, which can unintentionally lead to bleeding.50

Endoscopists should master snaring techniques before performing EMR (hot or cold). Positioning colon lesions within the snare can be difficult due to colonic peristalsis and flexure. Additionally, EMR involves capturing a larger mucosal area compared with conventional snare polypectomy, which further complicates snare placement. Therefore, selecting the appropriate snare with the right size is crucial to facilitate the snaring process, particularly for tangential polyps that tend to slip from the snare. In the case of HS-EMR, a relatively small-size snare of 15–20 mm is preferable to a large snare to decrease the risk of perforation and injury to adjacent mucosa. However, in the case of cold scare EMR (CS-EMR), a dedicated cold snare can be used to better capture the lesion.51 Snares of 10 mm are suitable for resecting remnant tissues or difficult areas that cannot be easily reached with larger snares.

Online supplementaltable 2 shows the current evidence on the outcomes of HS-EMR and CS-EMR. Currently, the availability of high-quality evidence directly comparing the efficacy of CS-EMR to HS-EMR is limited. Within the limited data, CS-EMR is noted to be particularly useful for serrated lesions.51 CS-EMR is associated with a lower rate of immediate and delayed bleeding, however, recurrence is high when the technique is applied to non-serrated LSLs.52 53 HS-EMR is, therefor, recommended for all non-serrated LSLs. A recent prospective, multicentre randomised controlled trial (RCT) (CHRONICLE trial) found that CS-EMR is superior to HS-EMR for managing large non-pedunculated polyps ≥20 mm with no macroscopic signs of malignancy, demonstrating fewer adverse events (1% vs 8%).54 However, the recurrence rate was higher than HS-EMR (24.8% vs 15%). According to a histological subanalysis, the authors concluded that sessile serrated polyps are more suitable for undergoing CS-EMR, and that Laterally spreading Tumour (LST) nodular-mixed type lesions were not due to a higher rate of residual neoplasia compared with HS-EMR (43.8% vs 16.7%). In a second prospective, multicentre, non-blinded RCT, the recurrence rate of non-pedunculated lesions ≥20mm was significantly higher in the CS-EMR group than the conventional EMR group (33.6% vs 16.7%).55 Interestingly, the recurrence was higher with CS-EMR in serrated lesions than conventional EMR, but there was no difference in other adenoma types. Adverse events and en bloc resections did not differ between the CS-EMR and conventional EMR groups.

Underwater EMR

This method was initially described by Binmoeller et al.56 Before EMR, colonic air is suctioned out, and the lumen is filled with water to immerse the target lesion, removing the need for submucosal agent injection for lifting, which may paradoxically flatten the lesions, impede their measurement, reposition them in a less accessible position, and increase the likelihood of intraprocedural complications and seeding of the dysplastic tissue.56 The rate of en bloc resection achieved through Underwater EMR (U-EMR) varies in different studies, ranging up to 100% of cases, consequently resulting in a higher rate complete resection and lower recurrence in the following surveillance colonoscopes.57–67 U-EMR allows for attempting larger lesions en bloc but still struggles for lesions ≥30 mm. In a meta-analysis of 11 studies, the rate of en bloc resection was not different between U-EMR and conventional EMR for polyps >20 mm, but the risk of piecemeal resection was lower in U-EMR, although it did not reach the statistical significance (OR 3.1, p=0.13).60 Nevertheless, U-EMR increased the probability of achieving R0 resection (OR 3.1, p=0.14). Consistently, a recent meta-analysis of seven RCTs found a higher rate of R0 resections for U-EMR compared with conventional EMR (58.1% vs 44.6%; RR 1.25 (95% CI 0.99 to 1.59)).68 Another meta-analysis of seven studies estimated a higher risk of en bloc resections compared with conventional EMR for polyps ≥20 mm in size (OR 1.51, p=0.02) but not for polyps <20 mm in size (OR 1.07, p=0.80),69 which was in line with the results of the meta-analysis by Chandan et al for polyps>20mm (RR 1.21, 95% CI 1.01 to 1.44).68 In two meta-analyses, U-EMR significantly reduced local recurrences (OR 0.30, p=0.000269 ; RR 0.62, p=0.00568).

U-EMR and CS-EMR may provide benefits compared with HS-EMR.52 A controlled trial could offer additional insights into the comparison of the three techniques. A meta-analysis of 36 studies showed that the pooled R0 resection and en bloc resection rates were 90% and 82%, respectively, for U-EMR, while the pooled rate of R0 resection was 98% for CS-EMR.70 The adverse events post-U-EMR or CS-EMR were similar and lower than those of HS-EMR.70 Studies comparing the U-EMR to HS-EMR showed the advantage of U-EMR over HS-EMR.60 63 65–67 The rate of complete histological and macroscopic resection was higher in U-EMR compared with HS-EMR, although only two study reached statistical significance.63 67 The rate of polyp recurrence at the initial follow-up colonoscopy was higher in the case of HS-EMR. However, controversial en bloc resection and adverse event rates were reported in comparative studies.

Generally, U-EMR appears feasible and effective and eliminates the need for and costs of submucosal injections, but the current results require further confirmation through controlled trials.71

EMR precutting

In this method, after a submucosal injection, the mucosa is meticulously cut 5–10 mm away from the tumour using a flex knife. Subsequently, a snare is employed to remove the lesion. If the lesion exceeds the snare’s diameter, submucosal trimming is performed inward from the incision site using a flex knife before snaring. In a prospective study of 523 non-pedunculated colorectal tumours ≥20 mm, EMR– precutting (EMR-P) yielded a higher en bloc resection rate than conventional EMR (65.2% vs 42.9%), but a lower rate compared with ESD (92.7%).72 Furthermore, EMR-P had significantly higher complete resection rates than EMR (59.4% vs 32.9%), yet lower rates compared with ESD (87.6%). During follow-up colonoscopies, EMR-P showed a significantly lower recurrence rate compared with EMR (3.2% vs 25.9%), although higher than ESD (0.8%).

Adjunctive ablation techniques with EMR

Thermal ablation has reduced polyp recurrence rates, leading to the adoption of EMR combined with margin ablation as the recommended approach. Thermal ablation can be performed using snare tip soft coagulation (STSC) (Soft Coag 80W effect 4, ERBE VIO).73 Alternative techniques involve using hybrid argon plasma coagulation (h-APC) for ablating the base and margin of resection.35 A meta-analysis showed that EMR with margin ablation reduces local recurrence rates compared with EMR with incomplete ablation.74 A meta-analysis of 6 studies involving 2122 patients with LSLs >20 mm removed by EMR demonstrated that the local recurrence rate after STSC-assisted EMR is significantly lower in the first surveillance colonoscopy compared with cases with no ablation done.75 A prospective study of 390 patients with 416 LSLs≥20 mm resected by EMR demonstrated that ablation post-EMR using soft coagulation significantly reduces the risk of local recurrence compared with standard EMR without ablation (5.2% vs 21.0%, p<0.001).76 A small retrospective study of 48 patients with 59 LSLs >20 mm removed through EMR showed no local recurrence among cases with h-APC ablation post-EMR compared to the cases with no ablation (0% vs 20.7%).77 Similarly, a pilot study showed 2.2% local recurrence following h-APC-assisted EMR was likely due to ablating the nidus of recurrence in both margins and surface of the resection.78 Given that recurrence may be driven by microscopic residual polyp at the margins but also the resection base, thermal ablation of the entire resected lesion (online supplemental video 1) might become the new standard of care. Pending further studies on base ablation, endoscopists should perform margin ablation after all EMRs to reduce risk of recurrence.

Incomplete resections and recurrence

Several studies show different recurrence rates ranging from 2% to 27%, emphasising the need for skillful snaring techniques to achieve complete resections and prevent recurrence.33 56 79 80 An Australian multicentre retrospective study, which followed patients undergoing piecemeal CS-EMR of 204 polyps ≥20 mm in size for a median of 8 months, found a 5.5% local recurrence rate in the initial EMR polypectomy compared with 3.5% in the second colonoscopy.81

The ASGE and ESGE recommend attempting an en bloc excision or the least number of pieces possible.11 The en bloc resections can be achieved in half of EMRs.72 82 Factors associated with failure in en bloc resection include larger polyp size (>20 mm), proximal or rectal locations and inadequate endoscopic techniques.83–85 Piecemeal resection, although allows complete resection, increases the risk of incomplete resection, positive polypectomy margins and recurrence.53 86 In a study of EMR of 252 adenomas >20 mm, 88.5% of polyps could be removed in piecemeal fashion, which resulted in a complication rate of 17.1%. Follow-up colonoscopies at 6 and 12 months revealed residual tissue in 36% and 33% of cases, respectively.87

The endoscopists can reduce the risk of recurrence through en bloc resections, inspection of the polypectomy site, extending the resection margin and margin ablation.72 83 88 One study reported a negative predictive value of 98.6 % and a 26% improvement in sensitivity for detecting local recurrence when polypectomy site was inspected with high definition white light endoscopy followed by NBI.89 The independent risk factors for recurrence include increasing polyp size (particularly >40mm), previous biopsy sampling and the number of pieces of piecemeal resection.11 13 33 85 90 A meta-analysis found that piecemeal EMR of polyps ≥10 mm was associated with a higher risk of metachronous neoplasia compared with en bloc EMR (20% vs 3%).91

EMR of lesions located in challenging areas has been associated with a higher likelihood of incomplete resections and subsequent local recurrences.33 92 93 One study reported a complete resection rate of 93.6% in 47 LSTs ≥20 mm in size involving the ileocecal valve, and surgery was avoided in 81% of the cases.92 Recommendations for adjusting EMR techniques in difficult locations include submucosal injection particularly for lesions involving <50% of the appendiceal orifice to ensure the edge of the dysplastic tissue is free of the appendix, caution with diathermy in CS-EMR or U-EMR to prevent cecal perforation and the use of retroflection or a transparent cap for ileocecal valve involvement.51

Surveillance and retreatment

ESGE and USMSTF recommend surveillance colonoscopies following EMR procedures to monitor for recurrence and assess the success of the resection. The USMSTF and ESGE suggest surveillance colonoscopies at 6 months, 18 months and 4.5 years after the initial polypectomy.11 13 During the surveillance colonoscopy, it is crucial to confirm the presence of local recurrence and assess the R0 status macroscopically using advanced endoscopic imaging and microscopically through histological analysis of systematic biopsies taken from the site of the previous resection. If remnant adenoma is suspected at the polypectomy site, the visible tissue remnants must be removed with an appropriate snare,94 followed by hot or cold avulsion thermal ablation in the same session, and the patient must be scheduled for another surveillance colonoscopy session.95 96 Any subsequent revision endoscopy may be challenging due to local fibrosis at the polypectomy site or non-lifting following submucosal fluid injection.51 LSLs are associated with high rates of synchronous missed lesions. A full and thorough colonic inspection must be performed during follow-up colonoscopies.

For the management of difficult-to-resect non-lifting lesions ≤25 mm with a fibrotic base, endoscopic full-thickness resection (EFTR) with a clip-assisted non-exposure technique can serve as a less invasive alternative to surgery.97–99 This technique is considered feasible and safe when using the over-the-scope clip system to prevent perforation. In this method, the muscle and serosa are suctioned into the cap, and then the clip is released, simulating the closure of a potential perforation.100 The rate of R0 resections ranges from 72% to 100% in various studies.97 101 In one study, 11% of patients ultimately had to undergo surgery due to adverse events or non-curative EFTR,101 a rate close to the pooled rate of post-EMR/ESD surgery reported by one meta-analysis.102 However, this relatively high rate may be deemed acceptable for the cohort of patients with ‘difficult’ resections undergoing EFTR treatment. A recent study found that EFTR is the most effective for rectal lesions,103 with a higher en bloc resection rate (90%) and lower adverse events (1.4%) compared with other colon segments.

Adverse events associated with standard EMR

Adverse events tend to be more prevalent during the EMR of complex and difficult polyps.104 The common adverse event of EMR is bleeding in up to 24% of the cases.102 105 106 The risk of bleeding during and after EMR increases with patients’ anticoagulant usage, less experienced endoscopists, proximal location of the lesion, larger polyp size and the need for piecemeal resections.102 105 Kim et al found that the risk of post-EMR bleeding was 15 times higher in piecemeal and en bloc resections of polyps ≥40 mm in size compared with en bloc resections of polyps <40 mm.85 The literature is inconclusive about the effect of hot or cold-snare on post-EMR bleeding. There is growing evidence that hot-snare EMR may reduce immediate bleeding but could be linked to a higher rate of delayed bleeding.52 53 107 A multicentre retrospective study reported a 6.5% intraprocedural bleeding in patients whose large polyps were removed with cold snare piecemeal EMR; all cases were self-limiting and could be managed with supportive or immediate endoscopic measures.81 Likewise, another study reported that piecemeal EMR resulted in 5.1% delayed bleeding and 3.4% deep mural injury, while piecemeal cold snare polypectomy (CSP) resulted in no complication.53 In contrast to these results, a meta-analysis showed no difference between the delayed bleeding after cold and hot-snare EMR.70 An RCT of 918 large polyps ≥20 mm in size found that closing the resection defect with clips after EMR reduced the risk of delayed bleeding from 7.1% to 3.5% for the right-colon polyps (p=0.015).108 Hence, the ASGE Technology Committee recommends using soft coagulation with the tip of a snare to control intraprocedural bleeding.35 But other methods such as hot biopsy forceps, monopolar haemostatic forceps, bicap probes, APC and endoscopic clips can also be used.

Perforation (eg, deep mural injury or resection of muscularis propria) is rare and less than 2%.102 105 109 There is no evidence about the effect of hot-snare or cold-snare or U-EMR on the likelihood of perforation.52 60 65 Postpolypectomy coagulation syndrome is also a rare complication after electrocoagulation of the mucosa and the muscularis layer causing an inflammation of the peritoneum without evidence of perforation. It may occur in <1% of cases and is associated with polyp larger size and flatter morphology that require extensive vertical force for capturing the polyp within the snare efficiently.35 110 Treatment is generally supportive with good prognosis.110

Endoscopic submucosal dissection

ESD was first described in 1988 as an endoscopic technique for treating early gastric neoplasia and then was adopted for the endoscopic treatment of large colonic lesions.111 ESD can be used for removing superficial polyps with limited invasion based on depressed morphology (0-IIc), T1 (SM) invasion, complex morphology (0–Is or 0–IIa+Is), irregular surface pattern in chromoendoscopy, or the presence of a large protruding or bulky component, and rectosigmoid location. It can also be used for non-granular nodular mixed LSTs, particularly if the lesions are larger than 20 mm, or for lesions that otherwise cannot be optimally (ie, en bloc resections) and curatively removed by EMR or standard snare polypectomy.15 90 105 112 113 The use of ESD is justified, especially for polyps in the rectum, where the risk of submucosal invasion is high.

Standard ESD

The ESGE recommends that ESD be performed only after obtaining sufficient experience in evaluating the eligibility of polyps and applying the technical methods.15 ESD should be performed using therapeutic endoscopes to allow superior suctioning capabilities and high definition endoscopes (eg, high-magnification endoscopes, virtual chromoendoscopy or NBI) to better determine the tumour’s invasive characteristics, polyp morphology and delineate tumour margin.114 115 For optimal visualisation in ESD, a distal tip cap and an endoscope capable of focusing within 1 cm of the distal tip provide a substantial advantage.

The ASGE Technology Committee recommends a stepwise approach for performing ESD as follows: (1) marking the perimeter of the lesion with cautery. (2) Injecting a lifting agent into the submucosa around the perimeter of the lesion. (3) Circumferential incision using an ESD knife.(4) Injection and dissection of the submucosa until the specimen has been completely resected.(5) Coagulation of intraprocedural bleeding using haemostatic forceps or an electrosurgical knife.35 Multiple techniques have been described to facilitate ESD such as the pocket creation method, gravity assistance and the use of traction methods (eg, clip with line, external forceps, clip and snare, internal traction, double scope and magnetic anchor).116 A combination of these techniques can be performed to facilitate the procedure and the use of traction should be encouraged.

Technical success of standard ESD and associated adverse events

The standardisation of ESD techniques significantly reduces the adverse events, especially perforation, and enhances the rate of complete and en bloc resections.117 ESD is especially beneficial for achieving en bloc resections for LSLs≥20 mm in size; thus, it provides a higher chance of histological evaluation of complete and curative resection. Kobayashi et al showed that the implementation of ESD significantly increased the en bloc resection rate compared with the period when surgery was the standard of care (76.5% vs 35.0%, p<0.001).118 In a prospective Japanese study of 290 patients who underwent ESD for removing colorectal neoplasms and were followed for a median of 38.7 months, approximately 90% and 75% of resections were achieved en bloc and R0, respectively.119 Only 2% of resections had local recurrence, all of which had been removed piecemeal. The 5-year survival prognosis was up to 100% after ESD.119 In this study, the rate of R0 resections was close to that reported in a meta-analysis of Asian studies (88%) which was significantly higher than that reported in European studies (65%).120 This might be explained by the fact that ESD is not commonly performed in Western countries because of technical difficulties, prolonged hospitalisations and high endoscopic complication rates. Furthermore, an extensive study of 877 patients with macroscopic complete endoscopic resection of T1 cancer revealed that the incomplete resection rate was 3.4% and that piecemeal resection was an independent risk factor for incomplete resection.121

Intraprocedural bleeding may happen particularly in rectal lesions but can be easily managed using coagulation current delivered through the ESD knife or haemostatic forceps in case of significant bleeding.122 Kobayashi et al also reported that post-ESD immediate and delayed bleedings occurred in 4.5% and 1.3% of patients, respectively, but could be successfully managed endoscopically. Another uncommon adverse outcome is perforation, which is mostly managed non-surgically during the colonoscopy using clip closure. In the above-mentioned Japanese study, only one patient had perforation (0.3%), which is lower than a pooled estimate of 4.8% in a meta-analysis.120 The management of adverse events was briefly explained in online supplemental material B.

A meta-analysis reported 10% and 36% local recurrence rates for non-evaluable and positive horizontal margins, respectively.123 There was almost a threefold higher likelihood of local recurrence with positive horizontal margins.123 A non-evaluable or positive vertical margin was associated with a nearly fourfold higher local recurrence rate.123

ESD is considered curative when an R0 en bloc resection is performed in Sm1 cancers without high risk features. Prognostic factors that would warrant surgery in patients who underwent ESD include poor tumour differentiation, lymphovascular invasion and high-grade tumour budding.124 125 When at least one of these risk factors is present, endoscopic resection is not considered curative and surgical intervention is recommended.126 In such cases, a multidisciplinary team must determine the next treatment step.127 An eight-study meta-analysis found that deep submucosal invasion was not an independent risk factor for lymph node metastasis while poor differentiation, high-grade tumour budding and lymphovascular invasion were found to have a direct association.128 Consequently, it has been suggested that opting for local excision in T1 sm2 cancers via ESD might be a more favourable alternative to surgery to avoid surgical overtreatment, morbidity and mortality, however, more confirmatory studies are required.

After resection, it is necessary to ensure the histological complete resection with negative vertical and horizontal margins. Subsequently, patients with T1 sm1 cancers must undergo several sessions of surveillance colonoscopy at appropriate intervals. Generally, there is a low risk of local recurrence after curative endoscopic resection of T1 sm1 cancers (<1%).129 Further research must be conducted to establish the risks associated with endoscopic resection of T1 cancers. Currently, the standard of treatment for lesions with morphological characteristics suggesting deep mucosal invasion (ie, Paris class III, JNET type 3, NICE type III, Kudo pit pattern V/Vn) is radical surgery since the risk of lymph node metastasis is high.

Simplified or hybrid ESD

Toyonaga et al described hybrid ESD, a modified version of the standard ESD technique, involves marking and incising the lesion using ESD with partial submucosal dissection, followed by snare resection of the remaining tissue using EMR.130 This method can be performed for lesions less than 3–4 cm in size, which are difficult to reach in the submucosal layer (online supplemental material C).130 In this method, the snare polypectomy is performed after circumferential incision and submucosal dissection using a Flex knife or Flush knife. Additionally, it can serve as a bridging procedure to full ESD for en bloc resection of larger lesions compared with those resected with standard EMR. This approach aims to minimise submucosal dissection to shorten the procedure time, which is often the most challenging aspect.122 131

The body of literature reports controversially on the effectiveness of the hybrid ESD. Initial studies showed that hybrid ESD is less effective than ESD.132–134 However, recent evidence, including an RCT, suggests that hybrid ESD is as effective and safe as ESD for treating colorectal neoplasia.135 136 The overall procedure time of hybrid ESD was reported statistically significantly lower than conventional ESD but higher than EMR.130 Recently, a 16-study meta-analysis showed a shorter procedure duration, fewer complications and no difference in recurrence for hybrid ESD vs conventional ESD; however, hybrid ESD was associated with a lower en bloc resection rate compared with conventional ESD (p<0.001).137

What is the most appropriate procedure?

Both ESD and EMR can be used to resect large polyps with curative intent with their respective advantages and disadvantages (figure 1). However, it is worth noting that the applicability of ESD is restricted to specific indications. Typically, in cases where superficial signs of submucosal invasive cancers are observed, ESD is the preferrable endoscopic resection method.11 13 90 Also, ESD offers an improved likelihood of achieving adequate histopathological assessment and mitigates the risk of subsequent surgery when compared with the piecemeal EMR. Nonetheless, ESD is complex and time-consuming and may increase the risk of adverse events such as perforation in the absence of adequate technical skills.117 138 In addition, ESD should be avoided in areas with limited endoscope manoeuvrability due to risk of adverse events.117

Figure 1
Figure 1

Flow chart for the management of large non-pedunculated colorectal polyps. The figure was derived from ‘International consensus on the management of large (≥20 mm) non-pedunculated colorectal polyps: A World Endoscopy Organisation Delphi study’; Djinbachian et al, 2023; Under review). DM, distant metastasis; EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection; JNET, Japan NBI Expert Team; LNM, lymph node metastasis; NBI, Narrow-Band Imaging.

According to the recent meta-analyses, ESD is associated with higher rates of en bloc resection, curative resection, lower rates of lateral margin involvement and recurrence than EMR, but it also leads to higher rates of complications and longer procedural time.120 139 A varying rates of en bloc resection in ESD procedures (43%–97%) and EMR procedures (0%–94%) have been reported across studies of both techniques.140 Similar to an earlier publication,141 ESD was more likely to achieve en bloc resections than EMR procedures in two recent meta-analyses (pooled estimate: 90.8% vs 33.0%140 and 93.7% vs 37.7%142). These pooled estimates for ESD are slightly higher than those of reported in the previous meta-analyses, but can be due to improvement in technique and learning curve of the endoscopists over time.84 102 One meta-analysis revealed an R0 resection rate of 85.0% and 64.6% in the ESD and the EMR group,140 respectively, while another extensive meta-analysis reported lower R0 resection rate for EMR (36.4%) (ESD=86.4%).142 Additionally, ESD showed a higher curative resection rate than EMR (93.6% vs 84 %), that is probably due to inclusion of larger >30 mm polyps in the EMR group.142 This is anticipated to reduce the need for additional surgery following a curative ESD. Despite a relatively low complication rate with both interventions, ESD had a higher perforation rate (5.9% vs 1.2% and 5.1% vs 1.7%142). On the other hand, ESD has a lower bleeding rate than EMR.142 (9.6% vs 2.8%; 4.3% vs 3.6%; ESD vs EMR). Of note, most complications could be sufficiently managed endoscopically. The local recurrence rate for ESD was significantly lower than that for EMR (13.9% vs 1.3%140 and 12.6% vs 1.1%142), which might be due to piecemeal resection by EMR technique.

The most important criterion for choosing a removal technique for large non-pedunculated polyps must be the endoscopists’ experience. Rönnow et al retrospectively evaluated 301 cases of ESD and reported that the en bloc resection rate improved from 60% during the first period to 98% during the last period, indicating the importance of experience for the success of the ESD procedure.143 Reflecting this, meta-analyses investigating post-ESD surgery rates were 7.8% in older studies but recently have improved to 4.2%.102 Given the necessity of endoscopist expertise, ESD is more common in Asia.144

Given the current state of endoscopy in the world, ESD should play a role for en bloc resection of lesions at higher risk of submucosal invasion (JNET 2B, granular mixed, non-granular) and for rectal lesions. In centres where there is high expertise, and where ESD can be performed quickly and safely with appropriate use of traction, ESD indications can be expanded to lower risk lesions. In centres where ESD expertise is lower, or when providing en bloc resections will result in delay in care and the risk of surgery (eg, low volume, high costs of hospitalisation), piecemeal EMR should be preferentially performed over surgery. This should be even at the risk of performing piecemeal EMR for lesions at higher risk of submucosal invasion as it does not prevent definitive surgical treatment in the low chance of piecemeal resection of a T1 CRC.

Conclusion

In conclusion, snare polypectomy, EMR and ESD are established techniques for endoscopic resection to completely remove large polyps, overcoming the limitations associated with surgery. For polyps ≥20 mm in size, ESD and EMR are effective techniques for achieving high rates of R0 resection, en bloc resection and low rates of adverse events and local recurrence. The decision on the appropriateness of a procedure must be based on individual patient and polyp criteria. Both techniques require expertise; however, ESD is a more complex procedure. ESD is also time-consuming and requires hospitalisation. Further randomised studies are needed to comprehensively compare ESD, EMR and surgery to determine the most suitable method for individual patients.