Surg Endosc DOI 10.1007/s00464-015-4301-z
and Other Interventional Techniques
Complete circular endoscopic resection using submucosal tunnel technique combined with esophageal stent placement for circumferential superficial esophageal lesions Li-Ping Ye1 • Hai-Hong Zheng2 • Xin-Li Mao1 • Yu Zhang1 • Xian-Bin Zhou1 Lin-Hong Zhu3
•
Received: 2 January 2015 / Accepted: 3 June 2015 Ó Springer Science+Business Media New York 2015
Abstract Background and aims At present, removing a circumferential superficial esophageal lesion (SEL) via en bloc resection is still a great challenge. Based on the previous success of submucosal tunneling endoscopic resection, this study aimed to evaluate the safety and effectiveness of complete circular endoscopic resection (CER) using a submucosal tunnel technique combined with esophageal stent placement for patients with circumferential SELs. Methods From August 2012 to June 2014, 23 patients with circumferential SELs were treated by CER using a submucosal tunnel technique combined with esophageal stent placement. The following steps were performed: (1) circular mucosa incisions were made at the anal and oral side of the lesion after marking the margin, (2) two submucosal tunnels were created from the oral to anal side using a hybrid knife, which was followed by submucosal dissection, and (3) following the completion of CER, a retrievable esophageal stent was placed to prevent postoperative stricture. Results CER using the submucosal tunnel technique combined with esophageal stent placement was
& Yu Zhang [email protected] 1
Department of Gastroenterology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical College, 150 Ximen Street, Linhai 317000, Zhejiang Province, China
2
Department of Pathology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical College, Linhai, China
3
Department of Medical Administration, Taizhou Hospital of Zhejiang Province, Wenzhou Medical College, Linhai, China
successfully performed for all 23 cases. The complete resection and success rate were 100 %, while the mean longitudinal diameter of the lesions was 65 mm. Mediastinal emphysema, pneumothorax, and postoperative stenosis were detected in 8.7 % (2/23), 4.3 % (1/23), and 17.4 % (4/23) of the cases, respectively. Pathological diagnoses of the lesions included carcinomas (13/23) and high-grade intraepithelial neoplasias (10/23). No residual or recurrent tumors were detected in any patient during the follow-up period. Conclusions CER using the submucosal tunnel technique combined with esophageal stent placement seems to be a safe and effective procedure for treating patients with SELs that result in a higher en bloc resection rate with fewer or minor complications. Keywords Superficial esophageal lesion Endoscopic resection Submucosal tunnel Esophageal stent
Endoscopic submucosal dissection (ESD) has become widely used as a minimally invasive technique for the treatment of superficial esophageal lesions (SELs) [1–3]. Although ESD offers the advantage of providing an accurate pathologic diagnosis while maintaining the normal anatomic structure of the esophagus and improving the patient’s quality of life following lesion excision, the procedure is still associated with a high complication rate, especially for some circumferential lesions [4, 5]. Therefore, most circumferential SELs are typically clinically treated by surgery. However, surgery is invasive and far from ideal for certain high-risk groups, such as elderly patients. Recently, the technique of submucosal tunneling endoscopic resection (STER) has been introduced into clinical
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practice for the treatment of upper gastrointestinal subepithelial tumors (SETs), which has been demonstrated to convey positive therapeutic effects [6–8]. Subsequently, several studies have also reported that endoscopic resection using a submucosal tunnel technique may be a feasible method for the treatment of superficial esophageal lesions [9, 10]. However, removing a circumferential esophageal lesion via en bloc resection is still a great challenge, considering the narrow lumen of the esophagus. Based on previous successes using STER during the treatment of esophageal SETs that originate from the muscularis propria (MP) layer, our center applied a complete circular endoscopic resection (CER) using submucosal tunnel techniques to the treatment of patients with circumferential SELs. This technique was combined with esophageal stent placement after complete CER for the prevention of postoperative stricture. The aim of this study was to evaluate the feasibility and safety of CER using submucosal tunnel techniques combined with esophageal stent placement for the treatment of circumferential SELs.
Endoscopic equipment and accessories The procedure was performed using a single-channel endoscope with a water jet system (Q-260 J; Olympus). Other equipment and accessories included a transparent cap (ND-201-11802, Olympus), a high-frequency electronic cutting device (ICC 200; ERBE, Tu¨bingen, Germany), argon plasma coagulator (APC 300, ERBE), an injection needle (NM-4L-1; Olympus), a hook knife (KD620LR; Olympus), an insulated-tip knife (KD-611L, IT2; Olympus), a hybrid knife (ERBE), hot biopsy forceps (FD410LR; Olympus), and carbon dioxide insufflator (Olympus). CER procedure All procedures were performed with patients under general anesthesia in the operating room. CER using the submucosal tunnel technique was performed as described below (Fig. 1): (1)
Patients and methods Study design This prospective study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by the ethical committee of the Taizhou Hospital of Zhejiang Province (Linhai, China). The inclusion criteria were as follows: (1) the lesion should be diagnosed as esophageal cancer or intraepithelial high-grade neoplasia by pathological examination; (2) the lesion should be more than three-fourths of the esophagus circumference; (3) the mucosal cancer should include the in situ lesion; and (4) there should be no lymph node or distant metastasis found by CT or endoscopic ultrasonography (EUS) with a highfrequency miniprobe (UM-2R, 12 MHz; UM-3R, 20 MHz, Olympus Optical Co., Ltd., Tokyo, Japan). Patients who could not tolerate anesthesia with tracheal intubation and those with known blood coagulation disorders (international normalized ratio [ 2.0, platelet count \ 70,000/ mm3) were excluded from the study prior to procedure. From August 2012 to June 2014, 23 patients with circumferential SELs were consecutively enrolled in this prospective study. Before the procedure, informed consent was obtained from all 23 patients. In addition, all patients were informed of the potential complications of the procedure, such as perforation, uncontrolled bleeding, stent migration, postoperative stricture, or a residual tumor or recurrence, as well as the possibility of surgical intervention in the case of severe complications. All patients consented and agreed to surgery if necessary.
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(2)
(3)
The lesion was carefully assessed with white light endoscopy and magnifying narrow-band imaging (NBI) and was stained using 2 % Lugol’s solution to further determine the extent of the lesion. Finally, a circumferential mark was made approximately 5 mm beyond the borders of the lesion. A submucosal injection was administered at the anal margin of the lesion, and then, a circular mucosal insection was made outside the markings into the deeper submucosal layer. This sets a limitation to avoid excessive mucosal separation. Subsequently, a circular mucosal resection was also made at the oral margin of the lesion using the same method. The first submucosal tunnel was created in the oral to anal direction of the esophagus using a hybrid knife. Using the transparent cap to expose the submucosa underneath the lesion during submucosal tunnel creation, the attachment between the mucosal and muscular layers was resected from the oral to anal side to reach the distal incision. Thereafter, a second submucosal tunnel was created in the opposite direction of the first submucosal tunnel using the same technique. During submucosal resection, repeated injections of saline solution helped facilitate resection and avoid accidental injury to the MP layer. Keeping a clear endoscopic view is the key to a successful procedure. Any minor bleeding was coagulated immediately by a hybrid knife, and pulsatile bleeding was precisely coagulated with hot biopsy forceps when the bleeding vessel was identified. Blind coagulation should be avoided, which may raise the risk of
Surg Endosc
Fig. 1 Main step of complete circular endoscopic resection using submucosal tunnel technique combined with esophageal stent placement for circumferential superficial esophageal lesion. A Endoscopic view of a lugol-negative circumferential superficial esophageal lesion. B Endoscopic ultrasonographic evaluation of the same lesion before procedure. C After marking, a circular mucosal insection was made at the anal side of the lesion. D Another circular mucosal insection was
also made at the oral side. E Tunnel creation by submucosal dissection with a hybrid knife. F Submucosal tunnel dissection from oral to anal direction to reach the distal insection. G Complete en bloc resection achieved. H An retrievable, fully covered esophageal stent positioned in the esophagus after preventive coagulation of the artificial ulcer had been performed
perforation. When reaching the anal mucosal incision, submucosal dissection was extended laterally at both sides until the lesion was completed resected. Argon plasma coagulation was used to achieve hemostasis of the wound surface after the tumor was removed.
for 1 day after the procedure. Esomeprazole (40 mg twice daily, AstraZeneca, Sodertalje, Sweden) was administered intravenously during the patient’s hospital stay and then orally for another 8 weeks. If mediastinal emphysema or pneumothorax was found during or after the procedure, conservative treatments, including the intravenous infusion of esomeprazole and antibiotics, were implemented.
A retrievable fully covered esophageal stent (Sigma, China) was used to prevent stricture. The stent length ranged from 80 to 140 mm, and the diameter ranged from 16 to 18 mm. The selection of the specific stent was used based upon the length of the mucosal defect. The insert was approximately 4 cm longer than the mucosal defect, such that approximately 2 cm of the stent extended beyond both the proximal and distal borders of the mucosal defect to reduce stent migration and prevent long-term esophageal stricture. During the procedure, bleeding that did not affect the field of view of the operation and could be managed by endoscopic methods was not considered a complication [8]. Delayed bleeding was defined as active bleeding from a post-procedure ulcer diagnosed by an emergency endoscopy or a planned follow-up [8].
Histopathological evaluation The longitudinal diameter of the resected specimens was measured from the oral edge to the anal edge. Then, the specimens were fixed in formalin, paraffin-embedded, cut into 2-mm-wide strips perpendicular to the lesion base, and evaluated by histopathological examination. Two pathologists examined the specimens to determine the histopathological diagnosis. The macroscopic types and depth of invasion were classified according to the Paris endoscopic classification of superficial neoplastic lesions [11]. En bloc resection refers to a resection that results in removal of a single piece of tissue. Resection was considered complete when the tumor was resected en bloc with tumor-free lateral and basal margins [4].
Postoperative management Postoperative observations included recording of complaints of abdominal/chest pain, dyspnea, abdominal distention, changes in vital signs, and an abdominal/chest examination. If there were no complications, an oral diet was suspended
Follow-up Endoscopy was performed when patients exhibited symptoms of dysphagia with the ingestion of solid
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foods. The esophageal stent was removed 3 months after the procedure. Subsequent surveillance endoscopy was performed to check for any residual tumors at 1, 3, and 6 months post-endoscopy. Thereafter, annual endoscopy and/or endoscopic ultrasonography was performed to check for residual or recurrent tumors in these patients.
Results Clinicopathologic features Patient information is summarized in Table 1. Among the 23 patients, 7 were women (30.4 %). The mean age was 62.3 ± 7.50 years (range 48–75 years). The median longitudinal diameter of the lesions was 65 mm (range 50–100; interquartile range 58–75). The lesions were detected in the middle esophagus in 10 cases and in the lower esophagus in 13 cases. According to the Paris endoscopic classification, 8 lesions were type IIa, 9 were type IIb, and 6 were type IIc. Therapeutic outcome All 23 circumferential SELs were completely dissected via CER. The median time required for the total procedure, which measured from the point of the initial mucosal incision to the completed placement of the esophageal stent, was 145 min (range 125–190 min), and the median time required for the tumor resection, which measured from the point of the initial mucosal incision to the completed resection of the tumor, was 89 min (range 55–125 min). The en bloc resection rate was 100 %. All specimens showed both lateral and vertical tumor-free margins. Therefore, the complete resection rate was also 100 %. All 23 lesions were evaluated by histopathology; 13 were squamous cell carcinomas and 10 were high-grade intraepithelial neoplasias (HGIN) (Fig. 2). In this study, the main complications of CER included mediastinal emphysema and pneumothorax. Two patients (2/23, 8.7 %) had complications, including one patient with mediastinal emphysema and the other one with mediastinal emphysema and right pneumothorax. These patients recovered after conservative treatment including abrosia, fluid infusion, and the intravenous infusion of antibiotics and esomeprazole. In addition, two patients experienced arterial bleeding during the procedure, which was managed successfully with endoscopic methods, such as hot biopsy forceps or argon plasma coagulation. No patient experienced delayed bleeding, secondary infection,
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or any other severe complication during hospitalization (Table 2). Clinical outcomes and additional treatment The median hospital stay after the procedure was 6 days (range 4–10 days). In this study, four patients had dysphagia at 4 and 6 weeks after the procedure, and stent migration was identified by endoscopy in all 4 patients. The other 19 patients underwent an endoscopic stent extraction procedure 3 months after the initial procedure. To date, four patients developed esophagus stricture (17.4 %), including three of the patients that experienced stent migration. All four patients with postoperative stricture were treated by endoscopic balloon dilation (EBD) a median of three times (range 1–6 times). EBD was repeated until the endoscope could smoothly pass through the lumen. No adverse events related to EBD occurred in these patients. No residual or recurrent tumors were detected in any patient during the follow-up period (median 16 months, range 5–28 months) (Fig. 3).
Table 1 Clinical and histopathological characteristics of the 23 patients with circumferential superficial esophageal lesions Mean age (years)
62.3 ± 7.50
Gender [n (%)] Male Female Median size [mm (range)]
16 (69.6) 7 (30.4) 65 (50–100)
Lesion longitudinal diameter [mm, n (%)] B65
14 (60.9)
[65
9 (39.1)
Lesion location [n (%)] Middle
10 (43.5)
Lower
13 (56.5)
Macroscopic type [n (%)] II a
8 (34.8)
II b
9 (39.1)
II c Pathological type [n (%)]
6 (26.1) 23
Squamous cell carcinoma
13 (56.5)
High-grade intraepithelial neoplasia
10 (43.5)
Depth of invasion [n (%)]
13
M1
2 (8.7)
M2
6 (26.1)
M3
5 (19.2)
Intraepithelial carcinoma (M1); restricted within the proper mucosal layer (M2); adjacent to or invading but not beyond the muscularis mucosa (M3)
Surg Endosc Fig. 2 A The resection specimen was shown covering a 5-ml syringe and was approximately 60 mm in length. B Histological evaluation of the same specimen
Table 2 Therapeutic outcome and complications of complete circular endoscopic resection (CER) using submucosal tunnel technique combined with esophageal stent placement
Complete resection [n (%)]
23 (100)
Median total procedure time [min (range)]
145 (125–190)
Median resecting tumor time [min (range)]
89 (55–125)
Stent migration [n (%)] Complications related to CER [n (%)]
4 (17.4)
Mediastinal emphysema
2 (8.7)
Pneumothorax
1 (4.3)
Esophagus stricture
4(17.4)
Massive bleeding
0
Delayed bleeding
0
Tumor residual or recurrent tumors Median hospital stay after the procedure [days (range)]
6 (4–10)
Median follow-up period [months (range)]
16 (5–28)
Fig. 3 Follow-up after complete circular endoscopic resection: A, B The wound was completely healed with no stricture or recurrence 12 months after the procedure
Discussion Recently, in China, the detection rate of superficial esophageal carcinoma has increased, which corresponds with the recent innovations in endoscopic technology, such as image-enhanced endoscopy and magnifying endoscopy [12, 13]. Previously, surgical esophagectomy with lymph node dissection was the principal therapeutic option for these patients, even if the disease was detected at an early stage [14]. However, surgical esophagectomy is invasive
and prone to complications and increased mortality rates. In contrast, ESD has several advantages over surgical esophagectomy in terms of maintaining the normal anatomic structure of the esophagus and improving the quality of life. Due to those merits, ESD has recently become a primary therapy for treatment of patients with SELs [1–5]. However, this technique still comes with some risk of complications, such as perforation, uncontrolled bleeding, and local recurrence, especially for circumferential SELs [4, 5]. To date, effective and safe removal of
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circumferential SELs by endoscopy is still a considerable challenge for many endoscopists. The rudimentary submucosal tunneling technique was first described as a ‘‘mucosal flap safety valve’’ in porcine models [15]. Shortly thereafter, STER emerged as a treatment for esophageal SETs that originate from the MP layer, which marks the rise of a new branch of therapeutic endoscopy. Because the attachment of the mucosal and muscular layers is loose, a submucosal tunnel can easily and safely be created in the esophagus using a hybrid knife or other endoscopic knife, such as a flush knife [8, 10]. Clinically, SELs are confined to the mucosa or submucosa and do not involve the MP layer. Therefore, it can also be expected that SELs can be easily and safely resected from the MP layer. For this reason, our center has been using the CER technique to treat circumferential SELs, which we have combined with esophageal stent placement to prevent esophageal stricture after CER. In this study, a total of 23 circumferential SELs were successfully treated by CER. All lesions were resected en bloc, and the complete resection rate was 100 %. Major early complications related to CER were mediastinal emphysema and right pneumothorax (2/23, 8.7 %), and the late complication was esophageal stricture (4/23, 17.4 %). No substantial/uncontrolled bleeding, delayed bleeding, or other severe complications related to CER occurred during or after the procedure. In addition, no residual or recurrent tumors were detected in any patient during the follow-up period (range 5–28 months). Those results showed CER was a safe, effective, and feasible procedure for patients with circumferential SELs. Esophageal stricture is a main issue of endoscopy resection for patients with circumferential SELs [4, 5, 17]. Several studies reported that esophageal stents are a safe and effective tool to prevent esophageal stricture in cases where a 75 % circumference of the esophagus has been resected after ESD [18]. In a related study of 40 cases of superficial esophageal cancer with near-circumferential lesions treated by ESD, Tang et al. [4] reported that the rate of postoperative stenosis was as high as 45 %. In our study, to prevent postoperative stricture, a retrievable fully covered esophageal stent was placed in all patients after lesion removal. Although there were 4 patients that developed esophageal strictures (17.4 %) during a follow-up period of 5–28 months, the incidence of esophageal stricture was relatively low (17 %). In this study, four patients developed stent migration, and 3 of those 4 patients experienced esophagus stenosis during the follow-up. Stent migration might be affected by esophageal stent placement for preventing postoperative stricture. Thus, how to solve this problem remains something to be further studied. Additionally, EBD is an effective supplemental treatment method for esophageal stricture in patients that underwent
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circumferential ESD [19]. In this study, four patients that suffered from postoperative stricture were successfully treated with EBD. Residual tumors and recurrence are another issue that occurs with endoscopy resection for patients with superficial esophageal lesions, and the incidence of such events is reported to occur at a rate of 0–8.7 % [4, 20–23]. Recent studies have shown that the rate of local tumor recurrence was significantly higher for lesions with pathologically incomplete resection than with pathologically complete resection [20]. Thus, complete resection of the lesion could reduce the risk of local tumor recurrence. In this study, successful complete resection by CER was achieved in all 23 patients (13 patients with squamous cell carcinomas and 10 patients with HGIN), and no patient had tumors residual or recurrence during the follow-up (median 16 months, range 5–28 months). However, some lesions with pathologically complete resection still may be subject to recurrence. In a previous study of 40 cases of superficial esophageal cancers treated by ESD, Tang et al. [4] reported that one case (2.5 %) of local tumor recurrence was detected. If the pathologic reports reveal incomplete resection after ESD or local tumor recurrence, additional treatments, such as a second ESD procedure, esophagectomy, or radiation therapy, should be considered [20, 24]. There are some problems with the use of CER in the treatment of circumferential SELs that should be taken into consideration and are specifically addressed with our procedure. First, circular mucosa incisions were made at the anal margins of the lesion before submucosal tunnel creation, which provides a guide for the creation of a submucosal tunnel to avoid excessive mucosal separation [10]. Second, two submucosal tunnels were created before circular submucosal resection. This step helps to prevent the formation of an artificial ‘‘island’’ during lateral resection of the final one-third of the circumference, which is often associated with an obscured endoscopic view, poor submucosal lifting, and a high risk of perforation [10, 16]. In addition, submucosa elevation is maintained very efficiently by repeated injections of saline solution through the hybrid knife, which helps facilitate the separation of the attachment between the submucosal and muscular layers, while avoiding accidental injury to the underlying muscle. Using those methods, we were able to effectively complete the CER procedure for patients with circumferential SELs. The CER was technically challenging because the space of the esophagus is limited, and it is usually impossible to perform in retroflexion. Moreover, the heart beat or respiratory movements can decrease the stability of endoscopic resection [10]. In addition, the esophagus lacks a serosal layer, and there is only a thin membrane outside the MP layer. Thus, compared with other parts of the digestive tract, complications, especially perforations, are more
Surg Endosc
likely to occur during endoscopic treatment in the esophagus. For these reasons, in this study, CER was only performed by an experienced operator (Li-Ping Ye). In our endoscopy center, an endoscopic operator was granted permission to enter the study stage of the ESD technique after he/she performs more than 50 cases of endoscopic mucosal resection (EMR) for upper GI SMTs and passes the endoscopic skill examination of the corresponding level. Then, he/she has an opportunity to work as a first assistant in ESD procedures for 3 months. Unsupervised traditional ESD procedures were first attempted in gastric mucosal tumors after he/she has carried out more than 30 ESDs for gastric mucosal tumors under the close supervision of an experienced operator. Before performing esophageal ESD, an endoscopic operator in our endoscopy center usually has followed this learning process. However, there are some limitations that need to be considered for this study. One important limitation of the study was the possibility of a selection bias, as this is a single-center study. Our institution is a tertiary endoscopic center in the Zhejiang Province, and all CER procedures were performed by an experienced endoscopist. Thus, the clinical results in this study may not be generalizable to other community hospitals. In addition, there is a rather high incidence of esophageal cancer in the Zhejiang Province. This may also contribute to any selection bias. Other limitations include a fairly small sample size, the lack of randomization, and a relatively short follow-up period. For these reasons, a randomized, prospective, multicenter study will be required to fully evaluate the safety and efficiency of this technique. In conclusion, CER using a submucosal tunnel technique combined with esophageal stent placement seems to be a safe and effective technique treatment for patients with circumferential SELs. However, it should be noted that this is a single-center study with a relatively small number of patients. Therefore, a larger, randomized, controlled, and multicenter study should be pursued to confirm the safety and efficacy of our procedure. Acknowledgments This study was supported as a project of the Zhejiang province bureau of health (2013KYA226) and the TaiZhou city science and technology bureau (121ky08). Disclosures Ye, Zheng, Mao, Zhang, Zhou, and Zhu have no conflict of interest or financial ties to disclose.
References 1. Chevaux JB, Piessevaux H, Jouret-Mourin A et al (2014) Clinical outcome in patients treated with endoscopic submucosal dissection for superficial Barrett’s neoplasia. Endoscopy 20 Nov 2014 (Epub ahead of print)
2. Guo HM, Zhang XQ, Chen M et al (2014) Endoscopic submucosal dissection vs endoscopic mucosal resection for superficial esophageal cancer. World J Gastroenterol 20(18):5540–5547 3. Joo DC, Kim GH, Park do Y et a (2014) Long-term outcome after endoscopic submucosal dissection in patients with superficial esophageal squamous cell carcinoma: a single-center study. Gut Liver 8(6):612–618 4. Tang B, Bai JY, Zhao XY et al (2014) Endoscopic submucosal dissection for superficial esophageal cancer with near-circumferential lesions: our experience with 40 patients. Surg Endosc. doi:10.1007/s00464-014-3909-8 5. Shi Q, Ju H, Yao LQ, Zhou PH et al (2014) Risk factors for postoperative stricture after endoscopic submucosal dissection for superficial esophageal carcinoma. Endoscopy 46(8):640–644 6. Xu MD, Cai MY, Zhou PH et al (2012) Submucosal tunneling endoscopic resection: a new technique for treating upper GI SMTs originating from the muscularis propria layer (with videos). Gastrointest Endosc 75:195–199 7. Ye LP, Zhang Y, Mao XL et al (2013) Submucosal tunneling endoscopic resection for the treatment of esophageal submucosal tumors originating from the muscularis propria layer: an analysis of 15 cases. Dig Liver Dis 45(2):119–123 8. Inoue H, Ikeda H, Hosoya T et al (2012) Submucosal endoscopic tumor resection for subepithelial tumors in the esophagus and cardia. Endoscopy 44(3):225–230 9. Pioche M, Mais L, Guillaud O et al (2013) Endoscopic submucosal tunnel dissection for large esophageal neoplastic lesions. Endoscopy 45(12):1032–1034 10. Arantes V, Albuquerque W, Freitas Dias CA et al (2013) Standardized endoscopic submucosal tunnel dissection for management of early esophageal tumors (with video). Gastrointest Endosc 78(6):946–952 11. Participants in the Paris Workshop (2013) The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 58:S3–S43 12. Qin X, He S, Zhang Y et al (2014) Diagnosis and staging of superficial esophageal precursor based on pre-endoscopic resection system comparable to endoscopic resection. BMC Cancer 21(14):774 13. Lu J, Xue LY, Lu N et al (2010) Superficial primary small cell carcinoma of the esophagus: clinicopathological and immunohistochemical analysis of 15 cases. Dis Esophagus 23(2):153–159 14. Low DE (2013) Evolution in surgical management of esophageal cancer. Dig Dis 31(1):21–29. doi:10.1159/000343650 Epub 2013 Jun 17 15. Yoshizumi F, Yasuda K, Kawaguchi K et al (2009) Submucosal tunneling using endoscopic submucosal dissection for peritoneal access and closure in natural orifice translational endoscopic surgery: a porcine survival study. Endoscopy 41:707–711 16. Zhai Y, Linghu E, Li H (2014) Double-tunnel endoscopic submucosal tunnel dissection for circumferential superficial esophageal neoplasms. Endoscopy 46(Suppl 1):UCTN:E204-5 17. Mizuta H, Nishimori I, Kuratani Y et al (2009) Predictive factors for esophageal stenosis after endoscopic submucosal dissection for superficial esophageal cancer. Dis Esophagus 22(7):626–631. doi:10.1111/j.1442-2050.2009.00954.x Epub 2009 Mar 6 18. Wen J, Lu Z, Yang Y et al (2014) Preventing stricture formation by covered esophageal stent placement after endoscopic submucosal dissection for early esophageal cancer. Dig Dis Sci 59(3):658–663 19. Ezoe Y, Muto M, Horimatsu T et al (2011) Efficacy of preventive endoscopic balloon dilation for esophageal stricture after endoscopic resection. J Clin Gastroenterol 45(3):222–227 20. Tsujii Y, Nishida T, Nishiyama O et al (2015) Clinical outcomes of endoscopic submucosal dissection for superficial esophageal
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and Other Interventional Techniques
Complete circular endoscopic resection using submucosal tunnel technique combined with esophageal stent placement for circumferential superficial esophageal lesions Li-Ping Ye1 • Hai-Hong Zheng2 • Xin-Li Mao1 • Yu Zhang1 • Xian-Bin Zhou1 Lin-Hong Zhu3
•
Received: 2 January 2015 / Accepted: 3 June 2015 Ó Springer Science+Business Media New York 2015
Abstract Background and aims At present, removing a circumferential superficial esophageal lesion (SEL) via en bloc resection is still a great challenge. Based on the previous success of submucosal tunneling endoscopic resection, this study aimed to evaluate the safety and effectiveness of complete circular endoscopic resection (CER) using a submucosal tunnel technique combined with esophageal stent placement for patients with circumferential SELs. Methods From August 2012 to June 2014, 23 patients with circumferential SELs were treated by CER using a submucosal tunnel technique combined with esophageal stent placement. The following steps were performed: (1) circular mucosa incisions were made at the anal and oral side of the lesion after marking the margin, (2) two submucosal tunnels were created from the oral to anal side using a hybrid knife, which was followed by submucosal dissection, and (3) following the completion of CER, a retrievable esophageal stent was placed to prevent postoperative stricture. Results CER using the submucosal tunnel technique combined with esophageal stent placement was
& Yu Zhang [email protected] 1
Department of Gastroenterology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical College, 150 Ximen Street, Linhai 317000, Zhejiang Province, China
2
Department of Pathology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical College, Linhai, China
3
Department of Medical Administration, Taizhou Hospital of Zhejiang Province, Wenzhou Medical College, Linhai, China
successfully performed for all 23 cases. The complete resection and success rate were 100 %, while the mean longitudinal diameter of the lesions was 65 mm. Mediastinal emphysema, pneumothorax, and postoperative stenosis were detected in 8.7 % (2/23), 4.3 % (1/23), and 17.4 % (4/23) of the cases, respectively. Pathological diagnoses of the lesions included carcinomas (13/23) and high-grade intraepithelial neoplasias (10/23). No residual or recurrent tumors were detected in any patient during the follow-up period. Conclusions CER using the submucosal tunnel technique combined with esophageal stent placement seems to be a safe and effective procedure for treating patients with SELs that result in a higher en bloc resection rate with fewer or minor complications. Keywords Superficial esophageal lesion Endoscopic resection Submucosal tunnel Esophageal stent
Endoscopic submucosal dissection (ESD) has become widely used as a minimally invasive technique for the treatment of superficial esophageal lesions (SELs) [1–3]. Although ESD offers the advantage of providing an accurate pathologic diagnosis while maintaining the normal anatomic structure of the esophagus and improving the patient’s quality of life following lesion excision, the procedure is still associated with a high complication rate, especially for some circumferential lesions [4, 5]. Therefore, most circumferential SELs are typically clinically treated by surgery. However, surgery is invasive and far from ideal for certain high-risk groups, such as elderly patients. Recently, the technique of submucosal tunneling endoscopic resection (STER) has been introduced into clinical
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practice for the treatment of upper gastrointestinal subepithelial tumors (SETs), which has been demonstrated to convey positive therapeutic effects [6–8]. Subsequently, several studies have also reported that endoscopic resection using a submucosal tunnel technique may be a feasible method for the treatment of superficial esophageal lesions [9, 10]. However, removing a circumferential esophageal lesion via en bloc resection is still a great challenge, considering the narrow lumen of the esophagus. Based on previous successes using STER during the treatment of esophageal SETs that originate from the muscularis propria (MP) layer, our center applied a complete circular endoscopic resection (CER) using submucosal tunnel techniques to the treatment of patients with circumferential SELs. This technique was combined with esophageal stent placement after complete CER for the prevention of postoperative stricture. The aim of this study was to evaluate the feasibility and safety of CER using submucosal tunnel techniques combined with esophageal stent placement for the treatment of circumferential SELs.
Endoscopic equipment and accessories The procedure was performed using a single-channel endoscope with a water jet system (Q-260 J; Olympus). Other equipment and accessories included a transparent cap (ND-201-11802, Olympus), a high-frequency electronic cutting device (ICC 200; ERBE, Tu¨bingen, Germany), argon plasma coagulator (APC 300, ERBE), an injection needle (NM-4L-1; Olympus), a hook knife (KD620LR; Olympus), an insulated-tip knife (KD-611L, IT2; Olympus), a hybrid knife (ERBE), hot biopsy forceps (FD410LR; Olympus), and carbon dioxide insufflator (Olympus). CER procedure All procedures were performed with patients under general anesthesia in the operating room. CER using the submucosal tunnel technique was performed as described below (Fig. 1): (1)
Patients and methods Study design This prospective study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by the ethical committee of the Taizhou Hospital of Zhejiang Province (Linhai, China). The inclusion criteria were as follows: (1) the lesion should be diagnosed as esophageal cancer or intraepithelial high-grade neoplasia by pathological examination; (2) the lesion should be more than three-fourths of the esophagus circumference; (3) the mucosal cancer should include the in situ lesion; and (4) there should be no lymph node or distant metastasis found by CT or endoscopic ultrasonography (EUS) with a highfrequency miniprobe (UM-2R, 12 MHz; UM-3R, 20 MHz, Olympus Optical Co., Ltd., Tokyo, Japan). Patients who could not tolerate anesthesia with tracheal intubation and those with known blood coagulation disorders (international normalized ratio [ 2.0, platelet count \ 70,000/ mm3) were excluded from the study prior to procedure. From August 2012 to June 2014, 23 patients with circumferential SELs were consecutively enrolled in this prospective study. Before the procedure, informed consent was obtained from all 23 patients. In addition, all patients were informed of the potential complications of the procedure, such as perforation, uncontrolled bleeding, stent migration, postoperative stricture, or a residual tumor or recurrence, as well as the possibility of surgical intervention in the case of severe complications. All patients consented and agreed to surgery if necessary.
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(2)
(3)
The lesion was carefully assessed with white light endoscopy and magnifying narrow-band imaging (NBI) and was stained using 2 % Lugol’s solution to further determine the extent of the lesion. Finally, a circumferential mark was made approximately 5 mm beyond the borders of the lesion. A submucosal injection was administered at the anal margin of the lesion, and then, a circular mucosal insection was made outside the markings into the deeper submucosal layer. This sets a limitation to avoid excessive mucosal separation. Subsequently, a circular mucosal resection was also made at the oral margin of the lesion using the same method. The first submucosal tunnel was created in the oral to anal direction of the esophagus using a hybrid knife. Using the transparent cap to expose the submucosa underneath the lesion during submucosal tunnel creation, the attachment between the mucosal and muscular layers was resected from the oral to anal side to reach the distal incision. Thereafter, a second submucosal tunnel was created in the opposite direction of the first submucosal tunnel using the same technique. During submucosal resection, repeated injections of saline solution helped facilitate resection and avoid accidental injury to the MP layer. Keeping a clear endoscopic view is the key to a successful procedure. Any minor bleeding was coagulated immediately by a hybrid knife, and pulsatile bleeding was precisely coagulated with hot biopsy forceps when the bleeding vessel was identified. Blind coagulation should be avoided, which may raise the risk of
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Fig. 1 Main step of complete circular endoscopic resection using submucosal tunnel technique combined with esophageal stent placement for circumferential superficial esophageal lesion. A Endoscopic view of a lugol-negative circumferential superficial esophageal lesion. B Endoscopic ultrasonographic evaluation of the same lesion before procedure. C After marking, a circular mucosal insection was made at the anal side of the lesion. D Another circular mucosal insection was
also made at the oral side. E Tunnel creation by submucosal dissection with a hybrid knife. F Submucosal tunnel dissection from oral to anal direction to reach the distal insection. G Complete en bloc resection achieved. H An retrievable, fully covered esophageal stent positioned in the esophagus after preventive coagulation of the artificial ulcer had been performed
perforation. When reaching the anal mucosal incision, submucosal dissection was extended laterally at both sides until the lesion was completed resected. Argon plasma coagulation was used to achieve hemostasis of the wound surface after the tumor was removed.
for 1 day after the procedure. Esomeprazole (40 mg twice daily, AstraZeneca, Sodertalje, Sweden) was administered intravenously during the patient’s hospital stay and then orally for another 8 weeks. If mediastinal emphysema or pneumothorax was found during or after the procedure, conservative treatments, including the intravenous infusion of esomeprazole and antibiotics, were implemented.
A retrievable fully covered esophageal stent (Sigma, China) was used to prevent stricture. The stent length ranged from 80 to 140 mm, and the diameter ranged from 16 to 18 mm. The selection of the specific stent was used based upon the length of the mucosal defect. The insert was approximately 4 cm longer than the mucosal defect, such that approximately 2 cm of the stent extended beyond both the proximal and distal borders of the mucosal defect to reduce stent migration and prevent long-term esophageal stricture. During the procedure, bleeding that did not affect the field of view of the operation and could be managed by endoscopic methods was not considered a complication [8]. Delayed bleeding was defined as active bleeding from a post-procedure ulcer diagnosed by an emergency endoscopy or a planned follow-up [8].
Histopathological evaluation The longitudinal diameter of the resected specimens was measured from the oral edge to the anal edge. Then, the specimens were fixed in formalin, paraffin-embedded, cut into 2-mm-wide strips perpendicular to the lesion base, and evaluated by histopathological examination. Two pathologists examined the specimens to determine the histopathological diagnosis. The macroscopic types and depth of invasion were classified according to the Paris endoscopic classification of superficial neoplastic lesions [11]. En bloc resection refers to a resection that results in removal of a single piece of tissue. Resection was considered complete when the tumor was resected en bloc with tumor-free lateral and basal margins [4].
Postoperative management Postoperative observations included recording of complaints of abdominal/chest pain, dyspnea, abdominal distention, changes in vital signs, and an abdominal/chest examination. If there were no complications, an oral diet was suspended
Follow-up Endoscopy was performed when patients exhibited symptoms of dysphagia with the ingestion of solid
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foods. The esophageal stent was removed 3 months after the procedure. Subsequent surveillance endoscopy was performed to check for any residual tumors at 1, 3, and 6 months post-endoscopy. Thereafter, annual endoscopy and/or endoscopic ultrasonography was performed to check for residual or recurrent tumors in these patients.
Results Clinicopathologic features Patient information is summarized in Table 1. Among the 23 patients, 7 were women (30.4 %). The mean age was 62.3 ± 7.50 years (range 48–75 years). The median longitudinal diameter of the lesions was 65 mm (range 50–100; interquartile range 58–75). The lesions were detected in the middle esophagus in 10 cases and in the lower esophagus in 13 cases. According to the Paris endoscopic classification, 8 lesions were type IIa, 9 were type IIb, and 6 were type IIc. Therapeutic outcome All 23 circumferential SELs were completely dissected via CER. The median time required for the total procedure, which measured from the point of the initial mucosal incision to the completed placement of the esophageal stent, was 145 min (range 125–190 min), and the median time required for the tumor resection, which measured from the point of the initial mucosal incision to the completed resection of the tumor, was 89 min (range 55–125 min). The en bloc resection rate was 100 %. All specimens showed both lateral and vertical tumor-free margins. Therefore, the complete resection rate was also 100 %. All 23 lesions were evaluated by histopathology; 13 were squamous cell carcinomas and 10 were high-grade intraepithelial neoplasias (HGIN) (Fig. 2). In this study, the main complications of CER included mediastinal emphysema and pneumothorax. Two patients (2/23, 8.7 %) had complications, including one patient with mediastinal emphysema and the other one with mediastinal emphysema and right pneumothorax. These patients recovered after conservative treatment including abrosia, fluid infusion, and the intravenous infusion of antibiotics and esomeprazole. In addition, two patients experienced arterial bleeding during the procedure, which was managed successfully with endoscopic methods, such as hot biopsy forceps or argon plasma coagulation. No patient experienced delayed bleeding, secondary infection,
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or any other severe complication during hospitalization (Table 2). Clinical outcomes and additional treatment The median hospital stay after the procedure was 6 days (range 4–10 days). In this study, four patients had dysphagia at 4 and 6 weeks after the procedure, and stent migration was identified by endoscopy in all 4 patients. The other 19 patients underwent an endoscopic stent extraction procedure 3 months after the initial procedure. To date, four patients developed esophagus stricture (17.4 %), including three of the patients that experienced stent migration. All four patients with postoperative stricture were treated by endoscopic balloon dilation (EBD) a median of three times (range 1–6 times). EBD was repeated until the endoscope could smoothly pass through the lumen. No adverse events related to EBD occurred in these patients. No residual or recurrent tumors were detected in any patient during the follow-up period (median 16 months, range 5–28 months) (Fig. 3).
Table 1 Clinical and histopathological characteristics of the 23 patients with circumferential superficial esophageal lesions Mean age (years)
62.3 ± 7.50
Gender [n (%)] Male Female Median size [mm (range)]
16 (69.6) 7 (30.4) 65 (50–100)
Lesion longitudinal diameter [mm, n (%)] B65
14 (60.9)
[65
9 (39.1)
Lesion location [n (%)] Middle
10 (43.5)
Lower
13 (56.5)
Macroscopic type [n (%)] II a
8 (34.8)
II b
9 (39.1)
II c Pathological type [n (%)]
6 (26.1) 23
Squamous cell carcinoma
13 (56.5)
High-grade intraepithelial neoplasia
10 (43.5)
Depth of invasion [n (%)]
13
M1
2 (8.7)
M2
6 (26.1)
M3
5 (19.2)
Intraepithelial carcinoma (M1); restricted within the proper mucosal layer (M2); adjacent to or invading but not beyond the muscularis mucosa (M3)
Surg Endosc Fig. 2 A The resection specimen was shown covering a 5-ml syringe and was approximately 60 mm in length. B Histological evaluation of the same specimen
Table 2 Therapeutic outcome and complications of complete circular endoscopic resection (CER) using submucosal tunnel technique combined with esophageal stent placement
Complete resection [n (%)]
23 (100)
Median total procedure time [min (range)]
145 (125–190)
Median resecting tumor time [min (range)]
89 (55–125)
Stent migration [n (%)] Complications related to CER [n (%)]
4 (17.4)
Mediastinal emphysema
2 (8.7)
Pneumothorax
1 (4.3)
Esophagus stricture
4(17.4)
Massive bleeding
0
Delayed bleeding
0
Tumor residual or recurrent tumors Median hospital stay after the procedure [days (range)]
6 (4–10)
Median follow-up period [months (range)]
16 (5–28)
Fig. 3 Follow-up after complete circular endoscopic resection: A, B The wound was completely healed with no stricture or recurrence 12 months after the procedure
Discussion Recently, in China, the detection rate of superficial esophageal carcinoma has increased, which corresponds with the recent innovations in endoscopic technology, such as image-enhanced endoscopy and magnifying endoscopy [12, 13]. Previously, surgical esophagectomy with lymph node dissection was the principal therapeutic option for these patients, even if the disease was detected at an early stage [14]. However, surgical esophagectomy is invasive
and prone to complications and increased mortality rates. In contrast, ESD has several advantages over surgical esophagectomy in terms of maintaining the normal anatomic structure of the esophagus and improving the quality of life. Due to those merits, ESD has recently become a primary therapy for treatment of patients with SELs [1–5]. However, this technique still comes with some risk of complications, such as perforation, uncontrolled bleeding, and local recurrence, especially for circumferential SELs [4, 5]. To date, effective and safe removal of
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circumferential SELs by endoscopy is still a considerable challenge for many endoscopists. The rudimentary submucosal tunneling technique was first described as a ‘‘mucosal flap safety valve’’ in porcine models [15]. Shortly thereafter, STER emerged as a treatment for esophageal SETs that originate from the MP layer, which marks the rise of a new branch of therapeutic endoscopy. Because the attachment of the mucosal and muscular layers is loose, a submucosal tunnel can easily and safely be created in the esophagus using a hybrid knife or other endoscopic knife, such as a flush knife [8, 10]. Clinically, SELs are confined to the mucosa or submucosa and do not involve the MP layer. Therefore, it can also be expected that SELs can be easily and safely resected from the MP layer. For this reason, our center has been using the CER technique to treat circumferential SELs, which we have combined with esophageal stent placement to prevent esophageal stricture after CER. In this study, a total of 23 circumferential SELs were successfully treated by CER. All lesions were resected en bloc, and the complete resection rate was 100 %. Major early complications related to CER were mediastinal emphysema and right pneumothorax (2/23, 8.7 %), and the late complication was esophageal stricture (4/23, 17.4 %). No substantial/uncontrolled bleeding, delayed bleeding, or other severe complications related to CER occurred during or after the procedure. In addition, no residual or recurrent tumors were detected in any patient during the follow-up period (range 5–28 months). Those results showed CER was a safe, effective, and feasible procedure for patients with circumferential SELs. Esophageal stricture is a main issue of endoscopy resection for patients with circumferential SELs [4, 5, 17]. Several studies reported that esophageal stents are a safe and effective tool to prevent esophageal stricture in cases where a 75 % circumference of the esophagus has been resected after ESD [18]. In a related study of 40 cases of superficial esophageal cancer with near-circumferential lesions treated by ESD, Tang et al. [4] reported that the rate of postoperative stenosis was as high as 45 %. In our study, to prevent postoperative stricture, a retrievable fully covered esophageal stent was placed in all patients after lesion removal. Although there were 4 patients that developed esophageal strictures (17.4 %) during a follow-up period of 5–28 months, the incidence of esophageal stricture was relatively low (17 %). In this study, four patients developed stent migration, and 3 of those 4 patients experienced esophagus stenosis during the follow-up. Stent migration might be affected by esophageal stent placement for preventing postoperative stricture. Thus, how to solve this problem remains something to be further studied. Additionally, EBD is an effective supplemental treatment method for esophageal stricture in patients that underwent
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circumferential ESD [19]. In this study, four patients that suffered from postoperative stricture were successfully treated with EBD. Residual tumors and recurrence are another issue that occurs with endoscopy resection for patients with superficial esophageal lesions, and the incidence of such events is reported to occur at a rate of 0–8.7 % [4, 20–23]. Recent studies have shown that the rate of local tumor recurrence was significantly higher for lesions with pathologically incomplete resection than with pathologically complete resection [20]. Thus, complete resection of the lesion could reduce the risk of local tumor recurrence. In this study, successful complete resection by CER was achieved in all 23 patients (13 patients with squamous cell carcinomas and 10 patients with HGIN), and no patient had tumors residual or recurrence during the follow-up (median 16 months, range 5–28 months). However, some lesions with pathologically complete resection still may be subject to recurrence. In a previous study of 40 cases of superficial esophageal cancers treated by ESD, Tang et al. [4] reported that one case (2.5 %) of local tumor recurrence was detected. If the pathologic reports reveal incomplete resection after ESD or local tumor recurrence, additional treatments, such as a second ESD procedure, esophagectomy, or radiation therapy, should be considered [20, 24]. There are some problems with the use of CER in the treatment of circumferential SELs that should be taken into consideration and are specifically addressed with our procedure. First, circular mucosa incisions were made at the anal margins of the lesion before submucosal tunnel creation, which provides a guide for the creation of a submucosal tunnel to avoid excessive mucosal separation [10]. Second, two submucosal tunnels were created before circular submucosal resection. This step helps to prevent the formation of an artificial ‘‘island’’ during lateral resection of the final one-third of the circumference, which is often associated with an obscured endoscopic view, poor submucosal lifting, and a high risk of perforation [10, 16]. In addition, submucosa elevation is maintained very efficiently by repeated injections of saline solution through the hybrid knife, which helps facilitate the separation of the attachment between the submucosal and muscular layers, while avoiding accidental injury to the underlying muscle. Using those methods, we were able to effectively complete the CER procedure for patients with circumferential SELs. The CER was technically challenging because the space of the esophagus is limited, and it is usually impossible to perform in retroflexion. Moreover, the heart beat or respiratory movements can decrease the stability of endoscopic resection [10]. In addition, the esophagus lacks a serosal layer, and there is only a thin membrane outside the MP layer. Thus, compared with other parts of the digestive tract, complications, especially perforations, are more
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likely to occur during endoscopic treatment in the esophagus. For these reasons, in this study, CER was only performed by an experienced operator (Li-Ping Ye). In our endoscopy center, an endoscopic operator was granted permission to enter the study stage of the ESD technique after he/she performs more than 50 cases of endoscopic mucosal resection (EMR) for upper GI SMTs and passes the endoscopic skill examination of the corresponding level. Then, he/she has an opportunity to work as a first assistant in ESD procedures for 3 months. Unsupervised traditional ESD procedures were first attempted in gastric mucosal tumors after he/she has carried out more than 30 ESDs for gastric mucosal tumors under the close supervision of an experienced operator. Before performing esophageal ESD, an endoscopic operator in our endoscopy center usually has followed this learning process. However, there are some limitations that need to be considered for this study. One important limitation of the study was the possibility of a selection bias, as this is a single-center study. Our institution is a tertiary endoscopic center in the Zhejiang Province, and all CER procedures were performed by an experienced endoscopist. Thus, the clinical results in this study may not be generalizable to other community hospitals. In addition, there is a rather high incidence of esophageal cancer in the Zhejiang Province. This may also contribute to any selection bias. Other limitations include a fairly small sample size, the lack of randomization, and a relatively short follow-up period. For these reasons, a randomized, prospective, multicenter study will be required to fully evaluate the safety and efficiency of this technique. In conclusion, CER using a submucosal tunnel technique combined with esophageal stent placement seems to be a safe and effective technique treatment for patients with circumferential SELs. However, it should be noted that this is a single-center study with a relatively small number of patients. Therefore, a larger, randomized, controlled, and multicenter study should be pursued to confirm the safety and efficacy of our procedure. Acknowledgments This study was supported as a project of the Zhejiang province bureau of health (2013KYA226) and the TaiZhou city science and technology bureau (121ky08). Disclosures Ye, Zheng, Mao, Zhang, Zhou, and Zhu have no conflict of interest or financial ties to disclose.
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