Endoscopic treatment has been broadly applied to superficial esophageal neoplasms. Endoscopic submucosal dissection (ESD) allows for high rates of
We retrospectively reviewed 36 esophageal ESDs for superficial squamous neoplasms in 32 patients between March 2009 and August 2014 at Gangnam Severance Hospital.
The median patient age was 64 years, and 30 men were included. The indications were early squamous cell carcinoma in 26 lesions, adenoma with high-grade dysplasia in five lesions, and low-grade dysplasia in five lesions. The
Favorable clinical outcomes were observed in ESD for superficial esophageal squamous neoplasms. Esophageal ESD could be a good treatment option in terms of efficacy and safety.
Endoscopic mucosal resection (EMR) has been generally applied to early gastrointestinal cancer [
Endoscopic treatment has been broadly applied to superficial esophageal neoplasms because of its convenience and minimal invasiveness [
However, the level of difficulty in performing esophageal ESD is high because the narrow lumen obstructs the operative view, and because of movement due to heartbeat and respiration. Additionally, there is a risk of perforation related to the thin muscle wall and absence of a serosal layer. Furthermore, the lumen of the esophagus is narrow, and, therefore, post-ESD esophageal strictures occur more frequently than strictures in the stomach. When stricture occurs, multiple sessions of endoscopic balloon dilatation (EBD) are needed. Consequently, it worsens the patients’ quality of life [
As high-definition endoscopy with narrow-band imaging (NBI) was developed recently, the diagnosis of early esophageal cancer or esophageal premalignant lesions has increased. Thus, how to treat these early neoplasms has become an important issue. The existing reports on the outcomes of esophageal ESD are mainly from Japan. The aim of this report was to integrate the data from Korea where ESD has been well established. We evaluated the efficacy and safety of ESD for superficial esophageal squamous neoplasms.
We retrospectively reviewed 36 esophageal ESDs for superficial esophageal squamous neoplasms performed in 32 patients between March 2009 and August 2014 at Gangnam Severance Hospital. Superficial esophageal squamous neoplasm was defined as an adenoma with low-grade dysplasia, high-grade dysplasia, and squamous cell carcinoma limited to the mucosal layer. Adenocarcinoma was excluded in this study to focus on squamous neoplasms that account for most of the esophageal neoplasms in the Far East regions. The Institutional Review Board of Gangnam Severance Hospital approved this study (IRB no. 2-2015-0339).
The patients were evaluated by using magnifying endoscopy with NBI. We also performed chromoendoscopy with Lugol’s solution. The superficial-type neoplasms were classified macroscopically into three types: 0-I, superficial and protruding type (0-Ip, pedunculated; 0-Is, sessile); 0-II, superficial and flat type (0-IIa, slightly elevated; 0-IIb, completely flat; 0-IIc, slightly depressed); and 0-III, superficial and distinctly depressed type. All diagnoses were confirmed with pre-ESD histological evaluation through biopsy. Concerning the histological evaluation, in patients with superficial esophageal squamous neoplasms, we ascertained the tumor invasion depths and lymph node metastases by using endoscopic ultrasound (EUS) and computed tomography (CT). Also, we checked for distant metastasis through positron emission tomography (PET)-CT. ESD was not performed in patients suspected to have submucosal invasion, regional lymph node metastasis, or distant metastasis.
ESD was performed under moderate sedation with midazolam and propofol. A video endoscope (GIF-H260Z, GIF-Q260J; Olympus, Tokyo, Japan) equipped with a 4-mm transparent cap (D-201-11804; Olympus) was used (
The solution used for local submucosal injection was prepared by mixing 10% glycerol solution and 0.005 mg/mL epinephrine. In addition, hyaluronic acid (Endo-Mucoup; BMI Korea, Jeju, Korea) was used if necessary.
A dual-knife (KD-650Q; Olympus) or IT-knife 2 (KD-610L; Olympus) was used to perform the submucosal dissection with mainly the Swift coagulation mode of an electrosurgical generator (VIO 300D; Erbe Elektromedizin GmbH, Tübingen, Germany). To control bleeding, hemostatic forceps (Coagrasper, FD-410LR; Olympus) with a soft coagulation mode (60-W output) were used, and carbon dioxide (CO2) was used for the insufflation.
Full-dose intravenous proton pump inhibitors and oral sucralfate were administered to the patient immediately after the procedure. If there was no evidence of complications such as bleeding or perforation, a liquid diet was offered on the next day, and the patient was discharged in a few days. Two skilled ESD endoscopists performed all procedures.
Microperforation was defined as radiographic evidence of free air or subcutaneous emphysema during the operation, without gross perforation defects in the esophageal wall. In the case of minor bleeding in the course of the operation, hemostasis was achieved immediately by means of thermocoagulation or hemoclipping. Massive bleeding during ESD was defined as bleeding that may necessitate the termination of the operation. Delayed postoperative bleeding was defined as a decreased blood hemoglobin level >2 g/dL observed 5 days after the operation, accompanied by hematemesis or melena. In addition, post-ESD esophageal stricture was defined as dysphagia after the operation that required endoscopic treatment.
The resected specimen, attached to a small plastic board and soaked in 4% formalin, was sent to a pathologist. Then, the specimen was fixed with 100% paraffin and cut into 2-mm thickness. Finally, hematoxylin and eosin staining was performed.
Histopathologic evaluation was performed to assess the tumor size, invasion depth, lymphovascular invasion, differentiation grade, and resection margin. On the basis of the invasion depth, intraepithelial cancer (m1), cancer invading the lamina propria (m2), cancer invading the muscularis mucosa (m3), and cancer invading the submucosa (sm) were diagnosed.
For patients who had curative resection through ESD, follow-up upper gastrointestinal endoscopy with iodine staining was performed at 1, 3, and 6 months after the operation. Thereafter, it was performed every 6 months for 2 years, and on a yearly basis subsequently. For Lugol-voiding lesions, pathologic evaluation was performed through a biopsy. Chest and abdomen CT was performed 6 and 12 months after the operation. Moreover, PET-CT was performed at 12-month intervals.
In total, 32 patients (median age, 64 years; range, 42 to 82 years; 30 men) were enrolled and 36 lesions were treated with ESD. Seventeen lesions (47.2%) were located in the lower esophagus. Most of the tumors (88.9%) were macroscopic type 0-IIb. There were 26 squamous cell carcinoma lesions (72.2%) (
The median size of the resected specimen was 28 mm (range, 12 to 64), and the median tumor size was 17 mm (range, 3 to 52). Six specimens extended to more than three-fourth of the circumference of the esophageal lumen. In the case of invasion depth, there were seven m3 lesions and five sm lesions.
The total number of patients in whom R0 resection was not performed was three, including the above-mentioned patient. One patient had a positive basal margin (R1 resection), and the other patient had extension of carcinoma
In the immediate complications, microperforation was observed in two lesions (5.6%). Those two patients fully recovered with supportive medical treatment. None of the cases needed termination of ESD because of massive bleeding.
In the latent complications, delayed bleeding was observed in two lesions (5.6%), which was successfully treated with endoscopic hemostasis. Symptomatic post-ESD esophageal strictures occurred in five lesions (13.9%). The resected specimens of those patients extended to more than three-fourth of the circumference of the esophageal lumen. They were treated with EBD with or without local steroid injections. On average, EBD was performed three times (range, two to nine times), and a self-expandable metal stent was inserted as a temporary measure in two patients.
A gross perforation event during EBD occurred in one patient who had a post-ESD stricture. The patient was managed with temporary stenting and percutaneous endoscopic gastrostomy feeding. There was no procedure-related death (
Curative resection was performed in 25 patients (29 lesions, 80.6%). Noncurative resection was performed in six patients; in five of these patients, the lesion invaded the sm layer, and one patient had an m3 tumor with lymphovascular invasion.
One patient whose lesion invaded the sm layer did not undergo additional treatment because this patient has a history of radiotherapy for breast cancer and refused additional treatment. The other five patients (15.6%) had additional treatment for esophageal cancer after ESD (CCRTx in three patients, radiation therapy in one patient, and surgery in one patient). The patient who underwent esophagectomy was found to have lymph node recurrence at 24 months after the operation, and additional CCRTx was performed. Thereafter, the patient was followed without recurrence.
There was no recurrence or disease-specific mortality during a median follow-up of 31 months (
ESD has been broadly applied to superficial esophageal neoplasms, and related studies have been performed mostly in Japan. Recently, there was a report of a small series in Korea [
The results showed an
The most critical point in endoscopic treatment for gastrointestinal cancer is that the cancer should be completely cured with endoscopic resection. To satisfy this expectation, R0 resection needs to be performed, and at the same time, regional lymph node metastasis or distant metastasis should not exist. Unlike stomach cancer or colorectal cancer, esophageal cancer is accompanied by lymph node metastasis in the early stage, and this should be understood well before planning the treatment strategy.
According to previous studies, regional lymph node metastasis occurred in 8% to 18% of patients with m3 invasion and 17% to 53% of patients with sm1 invasion [
In their study of m3 or sm1 superficial esophageal carcinoma patients, Higuchi et al. [
We considered the curative resection complete if there was no lymphovascular invasion in the resected specimen of the patients who had m3 invasion, and regional lymph node metastasis was not observed on EUS, CT, and PET-CT. In this study, seven patients had m3 invasion, and among the patients, one patient had lymphovascular invasion. The patient who had m3 layer and lymphovascular invasion underwent CCRTx as an additional treatment. The other six patients without lymphovascular invasion did not undergo additional treatment but were closely followed. Local or distant recurrence was not observed with the six patients in 44 months. However, there is no current standard guideline for m3 squamous cell carcinoma without lymphovascular invasion after
Patients with sm invasion, regardless of the presence of lymphovascular invasion, are inappropriate candidates for ESD. According to previous studies, one factor that can predict sm invasion is gross tumor shape. Endo analyzed the invasion depth according to gross shape in superficial esophageal cancer. Flat-type (llb) tumors showed sm invasion in 0% (0 of 12), whereas type l, lla, llc, lll, and combined lesions showed sm invasion in 100% (53 of 53), 66.7% (4 of 6), 38.4% (30 of 78), 100% (21 of 21), and 97.7% (42 of 43), respectively [
In this study, one patient showed extension of carcinoma
In this study, five of the six patients who had noncurative resection underwent additional treatment, and one patient from that group underwent esophagectomy but showed lymph node recurrence. Then, the patient underwent CCRTx. In light of this case, surgery as an additional treatment is not the best option. Considering the surgical risk, chemotherapy or CCRTx needs to be applied depending on the patient. To date, no study has determined which modality is appropriate for patients who undergo noncurative resection as an additional treatment. Further study on this issue is necessary.
If the muscular layer is injured during SD, perforation could occur because the esophagus does not have a serosal layer. In such cases, perforation could result in mediastinitis, and therefore, esophageal ESD is considered a risky procedure. In this study, gross perforation did not occur; however, microperforation and accompanying subcutaneous emphysema and mediastinitis occurred in two patients (5.6%). In previous studies, the rate of perforation during ESD was 2.6% to 6.9%, which is comparable to that of this study [
Esophageal ESD has lower morbidity and mortality rates than surgery; however, the candidates need to be chosen with consideration of the above complications. As previously stated, the advanced liver cirrhosis patient whose ESD had been stopped had a high tendency for bleeding as a result of thrombocytopenia and prolonged prothrombin time. Severe bleeding obstructed the operative view, and microperforation occurred as a result. Moreover, if mediastinitis had occurred, recovery from infection might have been difficult. Therefore, the procedure had to be stopped. After the procedure, preventive antibiotics were started. Mediastinitis did not occur but delayed bleeding occurred 10 days after the procedure. This candidate was inappropriate for esophageal ESD, and this case indicates the importance of careful candidate selection.
During the long-term follow-up, post-ESD stricture after esophageal ESD is a critical complication that affects patients’ quality of life. According to recent studies, post-ESD stricture occurred in 5% to 17.2% of patients [
The conventional method that has been adopted to prevent post-ESD stricture is EBD. EBD is simple and conventional; however, it generally should be performed in multiple sessions, and there is a perforation risk [
In conclusion, this study shows favorable clinical outcomes in ESD for superficial esophageal squamous neoplasms, and reveals that esophageal ESD is a relatively safe, technically feasible, and effective treatment. Additional treatment needs to be considered after assessing the tumor invasion depth, presence of R0 resection, and presence of lymphovascular invasion. Additionally, in patients who undergo widespread circumferential resection, paying attention to prevent strictures is important. Although further massive studies with long-term follow-up are needed, ESD should be considered as the useful treatment option for superficial esophageal squamous neoplasms.
Endoscopic submucosal dissection of a superficial squamous cell carcinoma. (A, B) A slightly erythematous, flat lesion that is not stained with Lugol’s solution. (C, D) Submucosal dissection is made with a dual-knife after local submucosal injection. (E, F) The lesion is completely resected.
Additional treatment and follow-up of 36 superficial squamous neoplasms in 32 patients who underwent endoscopic submucosal dissection (ESD). RTx, radiotherapy; LN, lymph node; CCRTx, concurrent chemoradiation therapy.
Clinicopathologic Features of the Patients and Tumors
Characteristic | No. (%) |
---|---|
No. of patients (no. of lesions) | 32 (36) |
Age, yr, median (range) | 64 (42–82) |
Sex | |
Male | 30 (93.8) |
Female | 2 (6.2) |
Tumor location | |
Upper third of the esophagus | 3 (8.3) |
Middle third of the esophagus | 13 (36.1) |
Lower third of the esophagus | 17 (47.2) |
Esophagogastric junction | 3 (8.3) |
Tumor morphology | |
Type 0-ls | 1 (2.8) |
Type 0-lla | 2 (5.6) |
Type 0-llb | 32 (88.9) |
Type 0-llc | 1 (2.8) |
Tumor pathology | |
Low-grade dysplasia | 5 (13.9) |
High-grade dysplasia | 5 (13.9) |
Squamous cell carcinoma | 26 (72.2) |
Treatment Outcomes
Characteristic | Value |
---|---|
Specimen size, mm | 28 (12–64) |
Tumor size, mm | 17 (3–52) |
Circumference of the resected specimen | |
<1/2 | 21 (60) |
<3/4 | 8 (22.9) |
>3/4 | 6 (17.1) |
ESD procedure time, min | 36.5 (10–240) |
Tumor depth | |
Low-grade dysplasia | 5 (13.9) |
High-grade dysplasia | 5 (13.9) |
Epithelial layer (m1) | 6 (16.7) |
Lamina propria (m2) | 8 (22.2) |
Muscularis mucosa (m3) | 7 (19.4) |
Submucosal layer (sm) | 5 (13.9) |
35/36 (97.2) | |
R0 resection | 33/36 (91.7) |
Length of hospitalization, day | 4 (3–13) |
Values are presented as mean (range) or number (%).
ESD, endoscopic submucosal dissection.
Complications
Variable | Value |
---|---|
Immediate complications | |
Microperforation | 2/36 (5.6) |
Massive bleeding during ESD | 0/36 (0) |
Latent complications | |
Delayed bleeding | 2/36 (5.6) |
Post-ESD esophageal stricture | 5/36 (13.9) |
EBD or EBD+local steroid injections | 5 |
No. of EBD sessions | 3 (2–9) |
Temporary SEMS | 2 |
Values are presented as number (%) or mean (range).
ESD, endoscopic submucosal dissection; EBD, endoscopic balloon dilatation; SEMS, self-expandable metal stent.