Curr Gastroenterol Rep (2014) 16:386 DOI 10.1007/s11894-014-0386-0

ESOPHAGUS (L GERSON, SECTION EDITOR)

Endoscopic Submucosal Dissection for Malignant Esophageal Lesions Hazem Hammad & Tonya Kaltenbach & Roy Soetikno

Published online: 23 March 2014 # Springer Science+Business Media New York 2014

Abstract The incidence of esophageal cancer has been increasing while the prognosis remains very poor. Endoscopic submucosal dissection (ESD) was developed in Japan for en bloc resection of early gastric cancer with excellent results. The use of ESD in early squamous cell cancer (SCC) of the esophagus in Japan has been increasing with long-term results comparable to those in early gastric cancer. The use of ESD in Barrett’s neoplasia in western countries has been challenged by the low complete resection rates and the risk of metachronous lesions from surrounding non-dysplastic Barrett’s epithelium. Efforts to combine ESD with other treatment modalities such as radiofrequency ablation in Barrett’s neoplasia and chemoradiation in SCC appear to be promising. The use of steroid therapy (local or systemic) has been demonstrated to prevent post-ESD stenosis, which is the most common complication after esophageal ESD. Keywords Endoscopy . Resection . Esophagus . Cancer Abbreviations SCC Squamous cell carcinoma EMR Endoscopic mucosal resection ESD Endoscopic submucosal dissection

This article is part of the Topical Collection on Esophagus H. Hammad Harry S. Truman Memorial Veterans Hospital, University of Missouri Hospital and Clinics, Columbia, MO, USA T. Kaltenbach : R. Soetikno Veterans Affairs Palo Alto, Stanford University School of Medicine, Palo Alto, CA, USA H. Hammad (*) Division of Gastroenterology, University of Missouri Hospital and Clinics, Five Hospital Drive, Columbia, MO 65212, USA e-mail: [email protected]

NCCN EGJ CRT ESTD IPCL

National Comprehensive Cancer Network Esophago-gastric junction Chemoradiation therapy Endoscopic submucosal tunnel dissection Intraepithelial papillary capillary loops

Introduction Esophageal cancer is the sixth common cause of cancer mortality [1]. Adenocarcinoma is the most predominant type in Europe and North America [2], while SCC remains the most common esophageal cancer worldwide, Survival from esophageal cancer is best when it is diagnosed at the earliest stage. Despite modern treatment, advanced esophageal cancer has a poor prognosis. The recent development of high definition endoscopy coupled with the increase use of image-enhanced endoscopy play an important role in the diagnosis of esophageal cancer at early stages. Early diagnosis, in turn, permits local endoscopic therapy to be performed, rather than the relatively more morbid and invasive surgical resection of the esophagus and surrounding lymph nodes. Recent data have supported the use of endoscopic treatment for superficial esophageal neoplasms [3]. Endoscopic mucosal resection (EMR) has been used extensively for treatment of small superficial SCCs and has been shown to be as effective as and less invasive than esophagectomy [4, 5]. However, EMR, irrespective of the technique used, can only remove small lesions (35 %) and should not be treated with endoscopic resection [14, 21]. The findings of lymphovascular involvement are associated with increased risk of lymph node and distant metastasis. The cumulative 5-year metastasis rates in patients with mucosal cancer with lymphovascular involvement is 47 % as compared to 0.7 % without it [22]. The National Comprehensive Cancer Network (NCCN) guidelines for indications of endoscopic treatment for early SCCs of the esophagus are included in Table 1 [23]. The indications used in Japan are included in Table 2. Barrett’s Esophagus Neoplasia The indication for ESD (or EMR) for Barrett’s esophagus neoplasia is not as developed as in SCC because Barrett’s esophagus is rare in Japan where EMR and ESD are well

ESD Technique in the Esophagus Prerequisite The ESD technique requires a high level of endoscopy. Understanding the detection, diagnosis, treatment, and the management of complications and long-term followup are prerequisites. ESD procedures take a considerably longer time than EMR. However, Takahashi et al. showed that the time required per 10 mm of excised specimens was not significantly different between EMR (22.2 min) and ESD (25.2 min)[25]. The minimum case load to perform esophageal ESD is not clear; however, most Japanese experts would recommend performing at least 50 ESDs in relatively easier locations (distal stomach or rectum) before performing the procedure in the esophagus [26]. Setting The procedure is typically conducted with the patient in deeper sedation; in patients with Barrett’s esophagus, general endotracheal intubation provides the best sedation because of the risk of aspiration due to reflux, hiatal hernia, and comorbidities (obesity and its associated diseases). Equipment High-definition endoscope equipped with waterjet function and narrow band imaging or equivalent technology is used. A variety of ESD knives have been successfully used for esophageal ESD (see below). A transparent distal attachment cap is also important to stabilize the operative field. An electrosurgical generator with adjustable settings, e.g. ERBE VIO 300D (ERBE Elektromedizin, Tubingen, Germany) is commonly used. Bleeding from submucosal

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Table 1 NCCN Guidelines for Treatment of Early Esophageal Neoplasia Tis

T1a

T1b

Esophageal Squamous Cell Carcinoma

EMR or Ablation

Esophagectomy

Esophageal Adenocarcinoma

EMR or Ablation

EMR followed by ablation (preferred) or esophagectomy EMR followed by ablation (preferred) or esophagectomy

Esophagectomy

Note: Adapted from NCCN Guidelines Version 2.2013

vessels is usually controlled using the coagulation grasper and endoscopic clips. b. Procedure a. Identification of lesion: The procedure starts with tumor demarcation using conventional white-light endoscopy and image enhanced endoscopy. Magnification endoscopy can be helpful, but not required. The narrow band imaging (NBI) can assist in the determination of the border of the lesion, but for SCCs, iodine staining is a requirement. The dye is applied to the lesion by spraying the area with 1.5 % iodine solution. The lesion does not take up dye and after a few minutes becomes salmon colored (the pink sign). The stark contrast between the unstained dysplastic lesion and the stained squamous epithelium facilitates interpretation of the extent of the lesion, and its marking. The method to define the border of completely flat Barrett’s neoplasia has not yet been described. Chromoendoscopy using indigo carmine or acetic acid can also be helpful [27]. Accurate tumor demarcation could be challenging in case of Barrett’s adenocarcinoma or dysplasia due to known lateral extension of dysplasia or cancer beneath the adjacent squamous epithelium. The absence or finding of irregular vessels (IPCL) on the squamous epithelium on magnification endoscopy with NBI could be helpful in identifying subsquamous Barrett’s epithelium. Other ways include observation of small holes in the covering squamous Table 2 Japanese GI societies guidelines for indications of ESD in esophageal SCCs

Guidelines for diagnosis and treatment for esophageal cancer. Edited by Japan Esophageal Society (April 2007), Kanehara Shuppan, Tokyo (in Japanese). Courtesy of Dr. Manabu Muto, Kyoto University (August 2011)

c.

d.

e.

f.

epithelium after acetic acid staining and ultra-high resolution optical coherence tomography [28, 29]. Marking: Marking the lesion is then performed circumferentially with an electrosurgical knife, usually 3–5 mm from the lesion. Submucosal Injection: Multiple solutions have been used for esophageal ESD: glycerol, 0.5 % sodium hyaluronate, or simply normal saline. Indigo carmine is usually added to the injectant for better visualization of the stained submucosa. Circumferential resection: Circumferential mucosal incision of the lesion is performed with an electrosurgical knife. In the esophagus, the initial incision is usually performed in the distal half. Multiple electrosurgical knives have been used successfully in esophageal ESD including insulation-tip knife, hook knife [14], flex knife [30], flush knife, ball-tipped flush knife [31], triangle-tipped knife [32], Hybrid knife [33•], and Mucosectom[34]. Dissection. The last step of ESD is submucosal dissection, usually using the same knife that was used for the circumferential incision. This is usually done from the proximal to the distal end (see Figs. 1, 2). Alternative to dissection – ESD-Universal technique. Given the technical complexity, the time needed and risks involved in ESD procedures, efforts have been made to simplify the procedure by resecting the isolated lesion en bloc with a snare[35]. This technique can substitute for the more tedious, risky and time consuming submucosal dissection (see Fig. 3).

Indications

Japan Esophageal Society

Japanese Gastroenterological Endoscopy Society

Absolute

Limited to the epithelial or lamina propria layers involving ≤2/3 circumference.

Limited to the epithelial or lamina propria layers involving ≤2/3 circumferential, but smaller than 3 cm and fewer than 4 lesions.

Relative

Invades into the muscularis mucosa or submucosa, but should be clinically confirmed to be cN0M0 before the ESD.

Limited to the epithelial or lamina propria layers involving ≥2/3 circumferential.

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Fig. 1 Schematic description of the technique of ESD

Post-resection Care Patients are usually admitted for 24-h observation after ESD and kept NPO. Liquids can be started next day and slowly advanced thereafter. Patients with reflux are kept on high dose acid suppression with proton pump inhibitor for 2 months after the procedure. Routine surveillance endoscopy is done at 3 months and further therapy

Fig. 2 ESD of an early esophageal SCC (T1a). a Subtle changes noted on high definition white light endoscopy. b Demarcation of the lesion (unstained part) using chromoendoscopy with iodine staining. c Circumferential incision around the lesion. d PostESD ulcer. e Complete healing with no recurrence after 3 years

planned accordingly. Annual endoscopy should be performed thereafter to check for recurrence. Chromoendoscopy is usually performed at each follow-up endoscopy to evaluate for recurrence. Imaging with CT scan may also be needed for patients with high-risk lesion to detect any nodal or distant metastasis [25].

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Fig. 3 ESD of a small adenocarcinoma arising in long segment Barrett’s esophagus. a Subtle changes noted on high definition white light endoscopy. b Better visualization of the lesion on NBI. c Demarcation of the

lesion using chromoendoscopy with Indigo carmine. d Circumferential marking around the lesion. e Post-ESD ulcer. f Histopathology showing R0 resection of a T1b adenocarcinoma

Outcomes

long-term outcomes for 402 patients with superficial esophageal SCCs that were treated by endoscopic resection, out of which 208 patients were treated with ESD and the rest (194) with EMR. The mean follow-up time was 50 months. Additional therapies (chemotherapy and radiotherapy) were administered in 54 patients. The 5-year cause-specific survival rates of patients with M1/M2, M3, and SM cancers were 99.3, 98.0, and 85.7 %, respectively [22]. Figure 2 shows an example of curative treatment of superficial SCC with ESD.

Squamous Cell Carcinoma Excellent results have been reported with ESD of superficial esophageal SCCs in multiple studies. The en bloc resection rate ranges between 90 and 100 % [7, 12, 14, 25, 36]. Although most of these data came from Japanese series, a recent western report showed comparable results [37]. Due to the high en bloc resection rates, local recurrence after ESD is extremely rare and ranges between 0 and 3 %. Local recurrence is usually successfully treated by further endoscopic resection [7, 14, 25, 36]. At the outset, the ESD appeared relevant only for large lesions (>20 mm) that cannot be removed en bloc using different EMR techniques. However, Ishihara et al. demonstrated better en bloc resection rates when ESD is performed as compared to when EMR (with transparent cap) is used for lesions 15–20 mm in size. For smaller lesions (less than 15 mm), there was no significant difference between the en bloc resection rates for ESD and EMR, thus EMR may be most suitable [38]. Long-term results have been published on the efficacy of ESD for superficial SCCs. Ono et al. followed 84 patients after ESD of superficial SCCs for a median of 632 days. The 5-year cause-specific survival for M1 and M2 tumors (56 patients) was 100 %. For the 28 patients with M3 or SM tumors, the 5year cause-specific survival was 85 %, despite additional therapies (chemotherapy, radiotherapy and surgery) in 15 patients [36]. More recently, Yamashina et al. reported the

Barrett’s Esophagus Neoplasia Early reports for ESD of Barrett’s early carcinoma have been encouraging in Japan. Most of the studies were reporting Barrett’s adenocarcinoma among esophago-gastric junction (EGJ) tumors [39]. Yoshinaga et al. treated 24 patients with superficial adenocarcinoma located at EGJ. Fifteen of these patients had Barrett’s esophagus. The en bloc resection rate was 100 %, while 72 % of patients had curative resection and showed no local or distant recurrence during a median follow-up period of 30 months [40]. Omae et al. reported their long-term outcomes for ESD of EJG cancers in 44 patients, 13 of whom had Barrett’s esophagus (30 %). The en bloc and curative resection rates were 100 and 84 %, respectively [41]. Yamada et al. reported similar results in 53 patients with EGJ cancers. In this latter report, patients with curative resection (68 %) had 100 % 5-year cause-specific survival [42]. The largest cohort of ESD in Barrett’s neoplasia from Japan was reported by Hoteya et al. They compared 25 cases of Barrett’s adenocarcinoma to 103 EJG cancers and 1,335 non-junctional gastric cancers. The

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rates of en bloc and curative resection for Barrett’s adenocarcinoma (64 and 48 %, respectively) were significantly lower than the rates for EJG cancers and non-junctional gastric cancers. The rates of submucosal and lymphovascular invasion were also significantly higher in Barrett’s adenocarcinoma. However, in patients with curative resection, the 5-year cause-specific survival rate was 100 %. The high rate of incomplete resection in patients with Barrett’s adenocarcinoma is typically due to the sub-epithelial extension of the tumor, which is difficult to recognize pre-operatively [43]. Initial results of ESD in the western countries were discouraging with very low en bloc and curative resection rates including in Barrett’s esophagus. For example, Rosch et al. showed en bloc resection rate of only 25 % for mucosal lesions [44, 45]. More recently, Neuhaus et al. combined ESD with radiofrequency ablation (RFA) of any residual Barrett’s tissue after ESD. They performed ESD on 30 patients with Barrett’s esophagus who had visible lesions containing high-grade dysplasia or mucosal adenocarcinoma with a median lesion size of 2 cm. En bloc resection was achieved in 90 % of the cases. Complete (R0) resection was histologically confirmed in 39 % of the patients only. Minor delayed bleeding occurred in 2 patients. RFA was offered to all patients with residual intestinal metaplasia and was performed in 8 patients without complications. Complete remission of neoplasia was seen in 96 % of the patients after a median follow up of 17 months. They concluded that ESD is feasible and can be used in combination with RFA with excellent rate of response [33•]. Complications The most feared complication of esophageal ESD is perforation. However, this is a relatively rare complication (0–4 %) [7, 12, 14, 20, 25, 36], and perforation after ESD has been treated successfully with conservative management (endoscopic closure, NPO, fluid replacement, and intravenous antibiotics) with excellent results. Radiologic evidence of pneumomediastinum (mediastinal emphysema) without overt perforation can happen in up to 30 % of patients after ESD. The clinical outcome is usually similar to patients with no pneumomediastinum [46]. Insufflation of CO2 rather than air during esophageal ESD has been shown to significantly reduce post-procedural pneumomediastinum (0 vs. 6.6 %) [47]. Muscle layer exposure during ESD is a significant risk factor for perforation. Endoscopic closure with clips is typically used when muscle layer injury is observed. Esophageal stenosis is the most common complication after ESD, and is of higher incidence following ESD compared to EMR. The rate of esophageal stricture after ESD ranges between 7 and 18 % [14, 36, 46, 48]. The most important predictors of postoperative stricture after ESD are the circumferential mucosal defect (>71 %) and the circumferential size of the tumor (> 59 %) [49]. Post-ESD strictures

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are usually treated with endoscopic balloon dilation. The dilation may need to be repeated several times depending on the response to the initial dilation. Prophylactic balloon dilation in the first week after endoscopic resection (as early as 3 days post-ESD) and repeated weekly until the mucosal defect was completely healed was shown to be effective to prevent stricture formation after resections exceeding 75 % of the esophageal circumference [50]. Prophylactic endoscopic triamcinolone injection at days 3, 7 and 10 post-ESD has been studied in 41 patients who had semi-circumferential mucosal defects (>3/4 of the esophageal circumference) after ESD. The total dose of triamcinolone ranged from 18 to 62 mg depending on the size of the resection. Submucosal steroid injection decreased the rate of stricture formation (19 vs. 75 %) as well as the number of required endoscopic balloon dilations (EBD) (1.7 vs. 6.6). There were no side effects or complications [51•]. Such a preventive measure is better than dilation after the formation of stricture. Dilation of post-ESD stricture carries a significant risk of perforation; up to 9 % in a recent study by Takahashi et al. Risk factors for perforation were multiple dilations or stricture location in the lower esophagus [52]. Another option for treatment of post-ESD stricture is oral prednisolone therapy. The efficacy of this strategy was demonstrated in a study that compared pre-emptive esophageal balloon dilation (starting on the third day post-ESD) or oral prednisolone therapy (started with 30 mg/day on the third day post-ESD and tapered gradually for 8 weeks) for patients who underwent complete circular or semicircular ESD for esophageal SCCs involving >75 % of the lumen. The number of endoscopic balloon dilation sessions required for the preemptive dilation group was significantly higher than the prednisolone therapy group (average 15.6 vs. 1.7, respectively, P

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