ESD

Absolute indications

Relative indications

Depth of invasion

m1, m2

m3, sm1 (≤200 μm)

EMR endoscopic mucosal resection, ESD endoscopic submucosal dissection

Barrett’s Esophagus and Esophageal Adenocarcinoma

Endoscopic resection is indicated for treatment of high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) associated with Barrett’s esophagus [25]. EMR is preferred for small lesions where en bloc resection can be achieved [28–32]. ESD is recommended for selected cases, such as lesions larger than 15 mm, poorly lifting tumors, and lesions at risk for submucosal invasion (Table 6.2) [25]. Regardless of the endoscopic resection technique, treatment is typically supplemented with an endoscopic ablation technique , such as radiofrequency ablation, in order to decrease the risk of metachronous lesions from the remaining Barrett’s epithelium [24].

Table 6.2

Indications for ESD for high-grade dysplasia and esophageal adenocarcinoma associated with Barrett’s esophagus according to the European Society of Gastrointestinal Endoscopy [25]

	Indication
Depth of invasion	sm1 (≤500 μm)
Size	>15 mm
Lifting	Poor

ESD endoscopic submucosal dissection

Procedure

Esophageal ESD is a technically challenging procedure because the narrow lumen of the esophagus limits endoscopic manipulation. In addition, the wall of the esophagus is thinner than that of the stomach, increasing the risk of perforation and mediastinitis [33]. Hence, to achieve successful outcomes, ESD should be performed in a high-volume, multidisciplinary center [34]. Before execution of the procedure in the esophagus, it is recommended to have performed at least 20–40 procedures in easier locations (distal stomach, rectum) [35, 36].

Equipment

ESD is performed in a stepwise manner, and different devices are specially designed to facilitate performance of each step [37]. Some of the equipment for ESD, such as endoscope, coagulation devices, and high-frequency electrogenerators, is similar to that used in standard endoscopy. Electrosurgical knives are unique to ESD. Choice of type of equipment requires special attention because of the complexity of the procedure [37]. Endoscopic tools and accessories for ESD are discussed elsewhere in this book and are not included in this chapter.

In regard to esophageal ESD, a straight soft distal attachment is preferred. As for knives for marking, circumferential incision, and submucosal dissection, the HookKnife (Olympus KD 620LR/KD 620UR, Tokyo, Japan), DualKnife (Olympus KD 650L/KD 650U, Tokyo, Japan), and FlushKnife (Fujinon Optical Co., Tokyo, Japan) knives are the only uncovered devices recommended for esophageal ESD [38]. The ITknife nano (Olympus KD 612L/U, Tokyo, Japan) and the Mucosectom2 (HOYA Pentax, Tokyo, Japan) are the insulated knives indicated for esophageal ESD [39, 40]. Additionally, Akahoshi et al. recently described the use of the Clutch Cutter (Fujifilm, Tokyo, Japan) for resection of SCC [41].

Preoperative Assessment

Precise patient selection and pre-procedural endoscopic evaluation of the lesion are vital to assess the extent and depth of tumor invasion and to recognize tumor margins [25, 38]. These will determine if the lesion is amenable for ESD. Standard use of the Paris classification to describe nodular lesions and the Prague criteria of all visible Barrett’s mucosa is suggested [25]. High-resolution endoscopy is recommended for detection of neoplasia and local staging [25].

Lugol chromoendoscopy is currently the gold standard technique to evaluate esophageal squamous cell carcinoma; however, lugol staining sometimes leads to patient discomfort following the procedure [45]. Therefore, recent virtual chromoendoscopy imaging techniques have been developed, such as narrow band imaging (NBI). NBI has shown to have similar sensitivity and superior specificity when compared with chromoendoscopy to predict the depth of invasion of both Barrett’s-associated neoplasia and SCC with the drawback of having a moderate interobserver agreement [46–49]. Biopsy samples of visible lesions should be obtained if malignancy is suspected [25].

High-frequency probe endoscopic ultrasound (EUS) has shown to have limited accuracy for detection of submucosal invasion in early esophageal cancer [50, 51]. However, it has been noted to be superior than computed tomography (CT) scan in assessment of nodal staging [52, 53]. Therefore, EUS is useful for locoregional staging of esophageal lesions with high risk of invasive cancer [46, 48].

Generally, monitored anesthesia care and sedation are performed for esophageal ESD. When available, general anesthesia with endotracheal intubation has the benefit of decreased risk of aspiration of secretions or blood [54].

Technique

Marking

Appropriate identification, mapping, and demarcation of the lesion are mandatory before starting the procedure [54, 55]. Circumferential marking should be carefully performed to avoid perforation of the thin wall of the esophagus. Cautery, argon plasma coagulation, or the tip of a needle-type knife can be used to mark at 3–5 mm from the edge of the lesion (Fig. 6.1).

../images/442926_1_En_6_Chapter/442926_1_En_6_Fig1_HTML.jpg — Fig. 6.1

Suspicious flat lesion involving the entire circumference of the esophagus

Partial Circumferential Incision

In esophageal ESD, we prefer partial circumferential incision to prevent the escape of fluid from the submucosal layer (Figs. 6.2 and 6.3) [42]. The oral and anal incisions are made first. Mucosal incision using a FlushKnife or DualKnife along the left lateral border mucosal lesion is then performed allowing the lesion to retract away from the water pool on the gravity-dependent side. Circumferential incision of the right lateral wall is completed when approximately three-fourths of the lesion has been dissected.

../images/442926_1_En_6_Chapter/442926_1_En_6_Fig2_HTML.jpg — Fig. 6.2

Circumferential marking around the lesion

../images/442926_1_En_6_Chapter/442926_1_En_6_Fig3_HTML.jpg — Fig. 6.3

Partial circumferential mucosal incision on the proximal side of the lesion using the DualKnife and ITknife nano

Submucosal Dissection

After exposure of the submucosal layer, the lesion is then lifted with injection of a lifting solution. The submucosa can be dissected with an ITknife nano (KD 612L/U, Olympus) or HookKnife (KD 620LR/KD 620UR, Olympus) by hooking and cutting the submucosa or by contact with the tip of a DualKnife (KD 650L/KD 650U, Olympus) (Figs. 6.3 and 6.4). The Stag Beetle Knife (MD-47707; Sumitomo Bakelite Co., Ltd.) and Mucosectom2 (HOYA Pentax) have also been used for dissection.

../images/442926_1_En_6_Chapter/442926_1_En_6_Fig4_HTML.jpg — Fig. 6.4

Complete circumferential mucosal incision on the distal side of the lesion

Recently, the clip line traction method has been commonly used for submucosal dissection in esophageal ESD [56] (Figs. 6.5 and 6.6). It allows for improved exposure of submucosa allowing easier identification of the edges of exposed submucosa to direct dissection. One prospective study showed clip line traction contributed to significantly shorten the procedure time [57]. In addition, the submucosal tunneling method is proposed to keep nice visualization of submucosal layer and submucosal fluid cushion. This technique allows for safe ESD, shortening procedure time [58]. This technique can be performed with the use of the ITknife nano device even for large esophageal cancer involving complete luminal circumference (Figs. 6.7 and 6.8) [59].

../images/442926_1_En_6_Chapter/442926_1_En_6_Fig5_HTML.jpg — Fig. 6.5

Submucosal tunnel created starting on the proximal side using the distal cap of the scope and ITknife nano

../images/442926_1_En_6_Chapter/442926_1_En_6_Fig6_HTML.jpg — Fig. 6.6

An endoclip attached to the dental floss placed on the mucosal side of the specimen. Floss is pulled from the mouth in order to provide traction. The ITknife nano is then used to dissect the submucosa lateral to the tunnel

../images/442926_1_En_6_Chapter/442926_1_En_6_Fig7_HTML.jpg — Fig. 6.7

ESD ulcer defect

../images/442926_1_En_6_Chapter/442926_1_En_6_Fig8_HTML.jpg — Fig. 6.8

Opened and fixed resected specimen measuring 69 × 57 mm. Histopathology revealed SCC with the deepest invasion to the muscularis mucosae, without lymphovascular involvement, and negative margins. This represented a curative endoscopic resection

Histological Outcomes

Superficial Squamous Cell Carcinoma

Studies for ESD of SCC have revealed en bloc resection rates of 99% (83–100%), complete resection rates of 82.8% (78–100%), curative resection rates of 75.6% (69–100%), and local recurrence rates of 0.3% (0–2.6%) [18, 19, 33, 42, 43, 60–64]. Furthermore, a meta-analysis comparing ESD and EMR for resection of early SCC showed significantly higher en bloc resection rates in the ESD group than in the EMR group regardless of lesion size (97.1% vs. 49.3%), as well as higher curative resection rates (92.3% vs. 52.7%) and lower recurrence rates (0.3% vs. 11.5%) (Table 6.3) [65].

Table 6.3

Histological outcomes of ESD for early esophageal neoplasia

Histological subtype	N, lesions	Procedure time range, min	En bloc resection rate, % [95% CI] (range)	R0 resection rate, % [95% CI] (range)	Curative resection rate, % [95% CI] (range)	Local recurrence rate, % [95% CI] (range)	Reference
SCC	970	24–160	99 (83.3–100)	82.8 (78–100)	75.6 (69–100)	0.3 (0–2.6)	[18, 19, 33, 42, 43, 61–64, 85, 88]
BE-HGD or EAC	524	86.4–128.5	92.9 [90.3–95.2]	74.5 [66.3–81.9]	64.9 [55.7–73.6]	0.17 [0–0.3%]	[28–30, 44, 68, 84, 96]

Histological subtype

N, lesions

Procedure time range, min

En bloc resection rate, % [95% CI] (range)

R0 resection rate, % [95% CI] (range)

Curative resection rate, % [95% CI] (range)

Local recurrence rate, % [95% CI] (range)

Reference

SCC

970

24–160

99 (83.3–100)

82.8 (78–100)

75.6 (69–100)

0.3 (0–2.6)

[18, 19, 33, 42, 43, 61–64, 85, 88]

BE-HGD or EAC

524

86.4–128.5

92.9 [90.3–95.2]

74.5 [66.3–81.9]

64.9 [55.7–73.6]

0.17

[0–0.3%]

[28–30, 44, 68, 84, 96]

ESD endoscopic submucosal dissection, SCC squamous cell cancer, BE Barrett’s esophagus, HGD high-grade dysplasia, EAC esophageal adenocarcinoma, CI confidence interval

Barrett’s Esophagus-Associated High-Grade Dysplasia or Early Adenocarcinoma

A recent meta-analysis evaluated the safety and efficacy of ESD in the treatment of early BE neoplasia [66]. It included 11 studies, of which 10 were cohort studies and 1 was a randomized controlled trial. Seven studies were from Europe, 3 from Asia, and 1 from the United States. Mean lesion size was 27 mm (20.9–33.1), and average procedure time was 107.5 minutes (86.4–128.5). The pooled en bloc resection rate was 92.9% (95% confidence interval (CI), 90.3–95.2%), while the R0 and curative resection rates were 74.5% (95% CI, 66.3–81.9%) and 64.9% (95% CI, 55.7%–73.6%), respectively (Table 6.2). Interestingly, the authors found significant heterogeneity in R0 and curative resection rates [66]. Variation has been attributed to infiltrated lateral margins that were not evident before endoscopic resection, highlighting the importance of detailed pre-procedural evaluation. This meta-analysis reported highly favorable outcomes and safety profiles, comparable to those in gastric and colorectal ESD from Asia and Europe [66].

Two recent multicenter analyses demonstrated the efficacy and safety of ESD in the West for resection of BE-HGD and EAC. The multicenter retrospective analysis from five academic tertiary referral centers in the United States reported en bloc and curative resection rates of 96% and 70%, respectively. Early bleeding was noted in 6% of the patients, perforation in 2.1%, and strictures in 15% [67]. The European analysis from three centers, which included large (≥2 cm), nodular, or fibrotic lesions, revealed similar outcomes. The en bloc resection rate was 90.8% and curative resection rate 65.8%. The learning curve portraying en bloc resection revealed that it plateaued after 30 procedures, providing evidence of better outcomes with experience. Rate of bleeding was 1.4%, perforation 0%, and stricture 2.1% [68]. These findings highlight the potential role of ESD for the assessment and management of neoplastic lesions associated with BE and provide reassurance on the safety of the technique when performed by experts in high-volume centers.

Post-ESD Recommendations

Squamous Cell Cancer

The risk of lymph node metastasis in SCC lesions limited to the lamina propria is almost 0, while those invading the muscularis mucosa carry a risk of metastasis of 8–15%, and those invading the submucosal layer to 200 um or less have a risk of 11–53% [69–72]. Based on the risk of lymph node metastasis, the following post-treatment recommendations are suggested by the ESGE based on histological outcomes after ESD:

1.

A resection is considered curative if en bloc R0 resection is achieved, with a depth < m2, without lymphovascular invasion [72, 73].
2.

Multidisciplinary discussion is advisable in the case of an en bloc resection of a well-differentiated m3/sm1 lesion (≤200 μm) without lymphovascular invasion [69–71].
3.

Further treatment, in the form of surgery or chemoradiotherapy, is recommended in case of a poorly differentiated tumor, with lymphovascular invasion, positive vertical margins, or a depth > sm2 (>200 μm) [25, 73].
4.

If a positive horizontal margin is the only high-risk criteria, endoscopic surveillance and retreatment are reasonable options [33, 42, 43, 55, 74].

High-Grade Dysplasia and Esophageal Adenocarcinoma Associated with Barrett’s Esophagus

A recent multicenter retrospective Japanese study found that lesions with lymphovascular involvement, poorly differentiated type, and size >30 mm were independently associated with detection of metastasis of adenocarcinoma of the esophagus. If none of these were present in mucosal and submucosal neoplasms (1–500 μm), the risk of metastasis was very low [75]. Therefore, after detailed histopathologic examination of resected ESD sample, the ESGE recommends the following:

1.

A resection is considered curative if en bloc R0 resection of a mucosal lesion is achieved [29, 76].
2.

A multidisciplinary discussion is advised in the case of an en bloc resection of a well-differentiated sm1 tumor (≤500 μm) without lymphovascular invasion [77].
3.

Surgery is recommended if lymphovascular invasion, poorly differentiated histology, depth > 500 μm, or positive vertical margins are found [25, 29, 76].
4.

Endoscopic surveillance or retreatment are recommended if horizontal margins are positive, and there are no other high-risk criteria [25, 28, 29, 76].

Surveillance After Curative ESD

Evidence for the most effective follow-up interval after esophageal ESD is lacking. However, based on the risk of recurrence rates of Barrett’s-associated neoplasia after endoscopic resection that range from 11% to 30%, close endoscopic follow-up and an ablation technique are recommended after excision [78, 79]. Per experts’ practice, a 3-monthly approach for 1 year, and yearly thereafter, is suggested [80]. For the case of superficial squamous cell cancer, high-resolution endoscopy and biopsies of suspicious areas at 3 and 6 months, and annually thereafter, are recommended [25].

Adverse Events

Management of the potential complications associated with ESD is vital for performing successful procedures [38]. The perceived rate of adverse events is higher for ESD when compared to EMR, because of the longer procedure times and its technically challenging nature. However, a significant difference in the complication rates has been noted only for esophageal strictures [28, 64, 74, 81]. No mortality has been observed after esophageal ESD procedures.

Bleeding

Bleeding, defined as ≥2 g/dL drop in hemoglobin, has been noted in 0–22.8% of esophageal ESD case series, with a mean of 2.5% [19, 28, 29, 32, 33, 42, 43, 55, 60, 61, 63, 67, 82–86]. It usually presents during the procedure or within the first 24 hours. According to a recent systematic review, bleeding was controlled conservatively in 95% of cases and required intervention in less than 10% of cases [81]. Delayed bleeding after esophageal ESD is rare, being reported in 0–5.2% of patients.

Perforation

Perforation has been noted in 0–4% of ESD procedures for resection of squamous cell carcinoma and HGD and EAC associated with BE [19, 28, 29, 32, 33, 42, 43, 55, 60, 61, 63, 67, 82–86]. Small perforations can be successfully treated with endoscopic clip placement, while large perforations may require urgent surgical intervention [25, 64]. Given the resection of the submucosa (the strength layer) in ESD and the lack of serosa in the esophagus, endoscopic salvage and, to a lesser degree, primary surgical repair of larger defects are challenging. In those patients who develop mediastinal emphysema without a recognizable perforation, it might be beneficial to provide conservative treatment [63].

Stricture

An esophageal stricture after ESD is defined as a stenosis that limits the passage of a gastroscope. It develops in 12–17% of patients [87, 88]. This complication creates additional challenges in patients who may need adjuvant therapy, such as radiotherapy, where the development of a stricture may be a relative contraindication. A circumferential extent ≥75% of the lumen and greater invasion depth (>T1m2) have been associated with occurrence of strictures [18]. In light of its high prevalence, several interventions have been proposed to prevent this complication [89]. Currently, the first-line options are oral or locally injected steroids [89–94]. A randomized controlled trial is ongoing to rigorously evaluate the efficacy of stricture prevention in both methods [95]. Alternatives include prophylactic endoscopic balloon dilation, self-expandable metal stents, local injection of botulinum toxin, and oral tranilast [90, 96, 97]. In addition, promising approaches, including tissue-shielding resection sites with carboxymethyl cellulose, polyglycolic acid sheets followed by fibrin glue, as well as autologous cell sheet transplantation, are currently under investigation [98–103].

Future

Randomized controlled trials addressing the efficacy and safety of ESD for Barrett’s HGD and EAC are needed, especially from Western endoscopists. Further investigation is needed for lifting solutions with submucosal dissecting properties that may decrease the technical difficulty of ESD, promoting its universalization. Prevention of adverse events by way of tissue-shielding techniques and endoscopic suturing is a promising field of research.

Conclusion

ESD is an established technique for treatment of early esophageal squamous cell carcinoma. Compared with EMR, ESD has higher rates of en bloc, curative, and R0 resections, resulting in lower local recurrence rates. Adoption of ESD for removal of HGD and EAC associated with Barrett’s esophagus has been restricted by its technical complexity, limited training opportunities, a high risk of adverse events, long procedure times, and suboptimal reimbursement. However, promising fields include the development of techniques to prevent adverse events and decrease the technical difficulty of ESD.