Endoscopic Submucosal Dissection for Superficial Esophageal Cancer in the Remnant Esophagus After Esophagectomy

doi:10.21203/rs.3.rs-1325426/v1

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Endoscopic Submucosal Dissection for Superficial Esophageal Cancer in the Remnant Esophagus After Esophagectomy

https://doi.org/10.21203/rs.3.rs-1325426/v1

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Background and study aims

Treatment of superficial cancer in the remnant esophagus after esophagectomy is highly invasive, and early detection and minimally invasive treatment are considered necessary. We performed endoscopic submucosal dissection (ESD) for superficial cancer in the remnant esophagus and evaluated its safety and efficacy.

Patients and methods

This study involved 28 patients (33 lesions) who underwent ESD for superficial esophageal cancer in the remnant esophagus after esophagectomy from January 2007 to December 2018. The safety and efficacy of ESD were evaluated retrospectively.

Results

The average age of all 28 cases (24 men and 4 women) was 69.6 ± 5.3 years. The average duration of ESD from esophagectomy was 2826 ± 2197 days. Twenty-six of the 28 cases were treated under general anesthesia. All 33 lesions were resected en bloc. The complete resection rate was 81.8% (27/33). There were no serious adverse events such as perforation, intraoperative bleeding, postoperative bleeding, and pneumonia. The overall survival rate was 78.6% (22/28) with a mean observation period post-ESD of 1793 ± 1148 days. There was no local recurrence, lymph node metastasis, or distant metastasis.

Conclusions

The ESD procedure for superficial cancer of the remnant esophagus was performed with high rate of complete resection without serious complications. In addition, there was no local recurrence and lymph node metastasis, and so ESD for superficial cancer of the remnant esophagus can be considered a safe and effective treatment.

The incidence of metachronous esophageal cancer has been reported to be high [1–2]. In some cases, metachronous cancer may develop in the remnant esophagus even after esophagectomy for esophageal cancer. Treatment options for esophageal cancer in the remnant esophagus include endoscopy, surgery, and chemoradiotherapy. The treatment method is selected comprehensively based on the depth of the tumor and the presence or absence of lymph node metastasis, but treatment should preferably be as minimally invasive as possible to avoid damage to vital adjacent structures because the lesion is located in the cervical esophagus [3].

From the perspective of minimally invasive treatment, many endoscopy procedures are performed for treatment of superficial Esophageal Squamous Cell Carcinoma(ESCC)[4, 5]. In recent years, these treatment modalities have progressed from conventional endoscopic mucosal resection (EMR) to endoscopic submucosal dissection (ESD), which has greatly improved the complete resection rate and has improved curability [6–12].At our institution, we have been performing ESD to treat superficial esophageal cancer in the remnant esophagus. In this study, we evaluated the safety and efficacy of ESD for ESCC in the remnant esophagus.

Cases

This study included 28 patients (33 lesions) who underwent ESD for superficial esophageal cancer in the remnant esophagus after esophagectomy for esophageal cancer at our institution from January 2007 to December 2018.

Written informed consent for examination and treatment was obtained from all patients before the procedure. This retrospective study was approved by the institutional review board of Toranomon Hospital. IRB approved the research (ID 10903). The authors declare no competing interests. All methods were performed in accordance with the relevant guidelines and regulations.

After Esophagectomy

In our hospital, after esophagectomy, regular postoperative surveillance is performed. Endoscopic and CT surveillance is performed by every six months.

ESD

The indication for ESD was squamous cell carcinoma diagnosed pathologically or endoscopically and judged to have no muscle invasion, lymph node metastasis, or distant metastasis. Furthermore, Circumference of ESCC is neither whole circumference nor almost whole circumference. Endoscopic depth was diagnosed comprehensively using conventional white light endoscopy and narrow band imaging (NBI) magnification. In this study, food intake was stopped 2 days before treatment for all cases. ESD was performedusing a Dual knife, Flex knife, or Hook knife. (Olympus Tokyo, Japan) A VIO 300D(ERBE, Tübingen, Germany) was used as an electrical current source. Tumor extent was determined using iodine staining. Several marking dots were placed about 5 mm outside the lesion with soft coagulation effect 4, 50 W. Then, either Glyceol® (Chugai Pharmaceutical, Tokyo, Japan) or hyaluronic acid was injected to elevate the lesion. A mucosal incision was placed from the anal side (dry cut, effect 3, 40 W), and after a deeper cut, an oral-side incision was placed to extend the incision circumferentially. Thereafter, the submucosal layer was dissected under direct vision (swift coagulation effect 3, 40 W) and the lesion was resected en bloc. The endoscopist determined whether to treat under general anesthesia or conscious sedation in consideration of the maneuverability of the endoscope and the patient's general condition. We choose conscious anesthesia if patient can prevent the induction of vomiting reflex and we can observe oral margin of ESCC.

Pathological evaluation

The resected specimens were fixed in formalin and microtomed into 2-mm slices. Each section was examined to assess the tumor depth and presence or absence of vascular invasion. Complete resection was defined as en bloc resection with tumor-negative vertical and lateral margins.

Evaluation items

The clinical course of ESD was evaluated retrospectively. Regarding ESD technique, we evaluated short-term and long-term outcomes. For short-term outcomes, we evaluated the en bloc resection rate, complete resection rate, perforation, massive intraoperative bleeding, postoperative bleeding, pneumonia, and time to start of the meal. Long-term outcomes were the rates of overall survival, local recurrence, lymph node metastasis, distant metastasis rate, and postoperative stenosis. Then, the diagnostic accuracy of the tumor depth was examined. Tumor depth was divided into three categories, T1a-EP / LPM, T1a-MM / SM1, and SM2 for endoscopic and pathological depth diagnosis.

Procedure time was defined as the time from the start of incision to resection of the lesion. Massive intraoperative bleeding was defined as a decrease in hemoglobin of 2 g/dL compared with preoperative levels. Postoperative bleeding was defined as hematemesis, melena, and other clinical features of anemia (defined as a decrease in hemoglobin of ≥ 2 g/dL) compared with preoperative levels) that warranted emergency endoscopy for hemostasis.

Statistical analysis

Data were analyzed using the unpaired t-test, Chi-squared test, or Mann-Whitney U-test as appropriate. A P value less than 0.05 was considered significant. All statistical analyses were performed using EZR.

The characteristics of all 28 patients are shown in Table 1 and results of ESD for ESCC in the remnant esophagus are shown in Table 2. The details of clinicopathological feature of ESD are shown in Table 3. There is one lesion spreading the esophageal entrance. Furthermore, there is two cases lesions spreading to anastomosis.

Table 1

Clinical characteristics of study participants.
Patients (Lesions)	28 (33)
Median age, years (± SD)	69.6 ± 5.3
Sex (Male/Female)	24/4
reconstruction organ	Gastric tube 19, Ileum 6, Jejunum 2, sigmoid colon1

Table 2

Results of ESD for superficial esophageal cancer in the remnant esophagus.
Adverse events
Post ESD bleeding	0
Perforation	0
Delayed perforation	0
Post ESD stricture	2

Table 3

The details of clinicopathological feature of ESD.
n = 33
mean tumor size (mean ± SD)	17.8 ± 10.8
Pathological result
mean specimen size (mean ± SD)	27.9 ± 10.5
Circumference
≦ 1/4	17
1/4<,≦1/2	12
1/2<,≦3/4	3
3/4<	1
lymohovascular invasion(negative/positive)	33/0
Lateral margin(negative/unknown/positive)	27/3/3
Vertical margin(negative/unknown/positive)	33/0/0

The 28 cases (24 men and 4 women) had an average age of 69.6 ± 5.3 years. Average duration of ESD from esophagectomy was 2826 ± 2197 days. Reconstruction methods were gastric tube reconstruction in 19 cases, ileocecal reconstruction in 6 cases, jejunal reconstruction in 2 cases, and sigmoid colon reconstruction in 1 case. The reconstruction routes were pre-sternal route in 2 cases, retrosternal route in 15 cases, and posterior mediastinal in 11 cases. Chemotherapy or radiotherapy was administered in 10 cases before and after surgery.

Of the 28 cases, 26 cases were treated under general anesthesia with tracheal intubation, and 2 cases were treated under conscious sedation. In 10 cases, endoscopic treatment of coexisting pharyngeal cancer was performed at the same time, and so ESD was performed with laryngeal elevation in the supine position. In 1 case, it was difficult to approach the lesion via an antegrade approach, so the artificial fistula was surgically opened and treated with a retrograde approach [13]. The average procedure time was 43.2 ± 45.3 min. Extubation on the day of ESD was impossible in 1 patient due to laryngeal edema following ESD for pharyngeal cancer, but was successfully done on another day.

The preoperative diagnosis of tumor depth was T1a-EP/LPM in 30 lesions, T1aMM/SM1 in 2 lesions, and SM2 in 1 lesion. Postoperative pathological diagnosis of the tumor depth was T1a-EP/LPM in 30 lesions, T1aMM/SM1 in 2 lesions, and SM2 in 1 lesion. The diagnostic accuracy of preoperative diagnosis was 87.9% (29/33). (Table 4) The average tumor diameter was 17.8 ± 10.8 mm, and the average specimen diameter was 27.9 ± 10.5mm. No lymphovascular invasion was observed in this study.

Table 4

Diagnostic accuracy of tumor depth in this study
		Endoscopic diagnosis
		EP/LPM	MM/SM1	SM2
Pathological diagnosis	EP/LPM	28	2	0
	MM/SM1	2	0	0
	SM2	0	0	1
Diagnostic accuracy: 87.9% (29/33)

Short-term outcomes

All 33 lesions in this study were resected en bloc. The complete resection rate was 81.8% (27/33). Among the 6 cases of incomplete resection, there were 3 cases with tumor-positive lateral margins and 3 cases with unclear lateral margins. One of the three lesions with positive lateral margins invaded the anastomosis. There were no cases of tumor-positive vertical margins. There were also no serious adverse events such as perforation, massive intraoperative bleeding, postoperative bleeding, and pneumonia. The average time from ESD to resumption of food intake was 2.4 ± 1.3 days.

Long-term outcomes

The overall survival rate was 78.6% (22/28) with a mean observation period post-ESD of 1793 ± 1148 days. Kaplan-Meier analysis revealed a 3-year and a 5-year overall survival rate of 87.5% and 58.3%, respectively (Fig. 1). There were 3 deaths due to other cancers and 3 deaths due to pneumonia. There were no deaths from esophageal cancer. There was no local recurrence, lymph node metastasis, or distant metastasis.

For prevention of stenosis, local steroid injection was administered in 3 cases and oral steroid administration in 1 case. Postoperative stenosis was observed in 1 case. The stenosis was improved after 5 times Balloon dilatation (12–15 cm).

Compared with conventional EMR, ESD has a high complete resection rate and high curability [14]. For this reason, it has been performed not only in the stomach [15, 16], esophagus, and colon, but also in various organs such as the pharynx and duodenum in recent years. ESD is also useful for cancer that develops in the gastrointestinal tract after surgery. Lesions in the postoperative gastrointestinal tract are often particularly difficult to resect using conventional EMR due to the anastomosis and subsequently narrow lumen [17]. However, with ESD, incision and dissection can be performed under direct vision, and the complete resection rate is high even for lesions that occur in the postoperative gastrointestinal tract.

Most cancers in the remnant esophagus after esophagectomy are located in the cervical esophagus, where endoscopic observation is difficult due to the pharyngeal reflex and the contraction or bending of the digestive tract [18]. General anesthesia may be required to adequately observe the target lesion [19]. In fact, in this study about 90% of treatment procedures were performed under general anesthesia. The remaining 10% were treated with conscious sedation, but in all these cases the distance from the esophageal entrance to the lesion was maintained. If it is difficult to observe the target lesion adequately at the time of endoscopic examination, treatment under general anesthesia should be considered necessary [19]. In addition, the postoperative gastrointestinal tract has a reduced peristaltic function, so the possibility of food retention is higher than that of the normal gastrointestinal tract. In this study, food intake was stopped 2 days before treatment for all cases. Therefore, no residual food contents were observed in any case at the time of treatment. It was considered important to set an appropriate fasting period before the endoscopy. In our hospital, after esophagectomy, regular postoperative surveillance is performed. Endoscopic and CT surveillance is performed by every six months. Many cases of ESCC are detected in relatively early stage, probably because the observation range is short. Esophageal cancer in the remnant esophagus is difficult in terms of diagnosis as well as treatment. In diagnosis, both detection and diagnosis of invasion depth may be challenging. In this study, the average period from esophagectomy to ESD was 2800 days, and cancer may develop even a long time after surgery. Endoscopic follow-up after surgery for esophageal cancer should therefore be performed carefully even after a long time.

In this study, the diagnostic accuracy of tumor depth was as high as 87%. For all cases, diagnosis was by using NBI magnification during the detection and diagnosis of tumor depth. Iodine staining is sometimes difficult to use because the remnant esophagus is close to the larynx and in such cases, NBI magnification may be useful for the diagnosis [20] in the remnant esophagus. In our hospital, there are little cases of using EUS, because patients with the remnant esophagus after esophagectomy have high risk of aspiration. In this study, the complete resection rate was about 80%. Although there were no cases of tumor-positive vertical margins, in 6 cases the lateral margin was positive or unclear. Compared with other reports of esophageal ESD, the resection rate with tumor-negative margins was considered to be low, possibly attributable to two reasons. First, it was considered that scar or fibrosis was present at the anastomosis site, making it difficult to resect with negative margins. Second, because the cervical esophagus has a high incidence of post-ESD stenosis, it was considered to have a low negative margin rate because it was resected close to the lesion. However, no local recurrence was observed in the average observation period of 2033 ± 1146 days, and thus local control by ESD was considered good. ESD for cervical esophageal lesions has been reported to have a higher likelihood of postoperative stenosis than other sites. However, in this study the mean tumor diameter was found at a relatively small stage of 17.8 mm, and stenosis was prevented, for example, by steroid therapy. Systemic steroid administration [21] and intralesional steroid injection [22, 23] obstructs esophageal stricture after ESD [24]. Unlike ESD of cervical ESCC, ESD of remnant esophagus requires treatment of the anastomotic site. It is the factor of technical difficulty. One of the three lesions with positive lateral margins, which the specimen size is 30 mm x 30 mm, invaded the anastomosis. There was only one case of stenosis. In this one case, stenosis was improved with 5 dilatations, but stenosis of the cervical esophagus was difficult to control, thus suggesting that stenosis prevention should be implemented as much as possible.

There are several limitations to this study. It is the retrospective study design with a small number of single-center facilities. In addition, it is a study of a single group of ESD in the remnant esophagus. In the future, we would like to search usefulness for ESD in the remnant esophagus by comparison study.

This study is based on procedures performed by a skilled endoscopist. Although the technical difficulty of ESD in the remnant esophagus is thought to be high, it was considered necessary to verify what skill level of endoscopist will be required to perform this procedure in the future. Second, it is not clear whether the lesion site is the cervical or upper thoracic esophagus. The definition of cervical esophagus thus needs to be unified.

In this study, ESD for superficial cancer of the remnant esophagus often required general anesthesia, the en bloc resection rate was high, and no serious complications were observed, indicating that the technique is feasible. Pathologically, the rate of tumor-positive lateral margins was relatively high, but no residual or local recurrence was observed and local control was good. Thus, ESD is a safe and useful treatment for superficial cancer of the remnant esophagus after esophagectomy.

Disclosures

Drs. Satoshi Nakamura, Daisuke Kikuchi, Toshiro Iizuka, Yugo Suzuki, Kosuke Nomura, Yorinari Ochiai, Junnosuke Hayasaka, Masami Tanaka, Hiroyuki Odagiri, Satoshi Yamashita, Akira Matsui, Yu Ohkura, Shusuke Haruta, Masaki Ueno, Harushi Udagawa and Shu Hoteya have no conflicts of interest or financial ties to disclose.

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No competing interests reported.

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Endoscopic Submucosal Dissection for Superficial Esophageal Cancer in the Remnant Esophagus After Esophagectomy

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Version 1

Abstract

Figures

Introduction

Patients/material And Methods

Cases

After Esophagectomy

ESD

Pathological evaluation

Evaluation items

Statistical analysis

Results

Short-term outcomes

Long-term outcomes

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1