Experience in Simultaneous Endoscopic Submucosal Dissection Treating Synchronous Multiple Primary Early Esophageal Cancers

Abstract

Objective:

Synchronous multiple primary early esophageal cancers (SMPEEC) are rare and aggressive. Early detection of esophageal cancer can improve survival rate. Endoscopic submucosal dissection (ESD) is a minimally invasive endoscopic treatment of early esophageal cancers. However, ESD for SMPEEC is little known.

We aimed to clarify the clinical outcomes of simultaneous ESD treating SMPEEC.

Methods:

We retrospectively reviewed the medical data of 34 patients, who underwent ESD for SMPEEC at Endoscopy Center of Zhongshan Hospital, Fudan University, between May 2013 and December 2014. The data of lesion size, histopathology, en bloc resection, curative resection, complication, and tumor local recurrence were analyzed.

Results:

Among 34 patients, 67 lesions were removed simultaneously in 33 cases; 2 lesions were removed in 2 operations for 1 case. For the simultaneous resection, the en bloc rate was 97.01% (65/67) and the curative resection rate was 92.54% (62/67). Postoperative stricture occurred in two cases and delayed bleeding occurred in one case. There was one local recurrence, no metastasis or procedure-related death.

Conclusions:

Simultaneous ESD as a treatment for SMPEEC is technically feasible, benefited from reducing hospitalization time and medical expenses. For the cases with risk factors of complications, simultaneous ESD needs to be avoided.

Introduction

Multiple primary esophageal cancers (MPEC) are defined as two or more cancers occurring simultaneously or successively in different parts of the esophagus.¹ MPEC are observed in 20%–30% of patients with esophageal cancer,^2,3 relatively rare and aggressive. In recent years, with the development and popularization of endoscopic technology, the discovery rate of MPEC is raising. Endoscopic submucosal dissection (ESD) has been widely used to treat early esophageal cancer^4,5 for the feature of less invasiveness. However, there are few reports about simultaneous ESD treating synchronous multiple primary early esophageal cancers (SMPEEC). The result of simultaneous ESD treating SMPEEC has not been examined in detail. In the present study, we aimed to evaluate the clinical outcomes of simultaneous ESD treating SMPEEC and summarized the experience.

Patients and Methods

Patients

We retrospectively analyzed data of early esophageal cancer at Zhongshan Hospital Fudan University between May 1, 2013, and December 31, 2015. Thirty-four patients with SMPEEC treated by ESD were enrolled in this study. Synchronous multiple esophageal cancers were diagnosed in accordance with the criteria of Warren and Gates: (1) all the lesions are malignant tumors confirmed by pathological diagnosis; (2) all the malignant lesions are separated by normal mucosa; and (3) the possibility that the second tumor represents a metastasis needs to be excluded.⁶ In this study, we focus on the patients, in whom the lesions were discovered in the same endoscopic examination.

All lesions were found during endoscopic examination. No prior treatment was given before ESD. The inclusion criteria were as follows: (1) histologically proven primary early esophageal cancer; (2) lesions followed the criteria of Warren and Gates; and (3) no lymph node or distant metastasis. Patients were excluded if they had (1) local lymph node metastasis; (2) noncorrectable coagulopathy; or (3) in agreement regarding withdrawal.

ESD procedures

The lesions were detected using white light endoscopy and narrow-band imaging (NBI). Iodine staining or NBI was used to determine the margin of the lesion. Each lesion was marked ∼5mm outside its margin with cautery using the electrosurgery unit and was injected with a saline solution (0.9% saline with a small amount of indigo carmine) into its submucosal tissue to lift the lesion. Various knives (hook knife, insulated-tip knife, hybrid knife) were used to perform mucosal incision and submucosal dissection. A hemostatic forceps was used to stop immediate bleeding. Other instruments included clips and a high-frequency generator. Carbon dioxide (CO₂) gas was used for insufflation with a CO₂ insufflator.

For simultaneous ESD treating multiple lesions, the first step is to mark both lesions, avoiding missing any of the lesions. The lesion on the anal side was resected at first. After coagulating all visible vessels on the artificial ulcer of the anal side lesion, we started resecting the oral side lesion.

The ESD operation time was defined as the time interval between endoscopic insertion and removal. The key steps of ESD are shown in Figure 1.

FIG. 1.

Simultaneous ESD procedure for synchronous multiple primary early esophageal cancers. (A–C) Pictures of the lesion in the esophagus 30 cm from the incisors. (A) The lesion was seen after iodine staining on endoscopy. (B) The resection site following ESD. (C) The size of the resected specimen was about 2.6 × 2.4 cm. (D–F) Pictures of the lesion in the esophagus 26 cm from the incisors. (D) The lesion was seen after iodine staining on endoscopy. (E) The resection site following ESD. (F) The size of the resected specimen was about 2.1 × 2.1 cm. ESD, endoscopic submucosal dissection.

Histological evaluation

All the resected specimens were stretched smoothly by pins on a corkboard and fixed with 10% formalin for pathological evaluation. Paraffin-embedded specimens were sectioned at 2 mm intervals. Data about lesion diameter, invasion depth, curative resection, and lymphovascular invasion were collected. The histological assessment of resected specimens was performed according to the Vienna classification of gastrointestinal epithelial neoplasia⁷ and the Japanese guidelines for diagnosis and treatment of carcinoma of the esophagus.⁸

Evaluation term of treatment efficacy

En bloc resection was defined as resection in a single piece. Curative resection was defined as en bloc resection with tumor-free margins and no lymphatic and/or venous infiltration. Margin of the lesions that could not be evaluated histopathologically because of electrosurgical or mechanical damage was also diagnosed as noncurative resections.

Postoperative treatment and follow-up

After ESD, patients were admitted overnight for observing the evidence of chest pain, dyspnea, and hematemesis or signs of infection. On postoperative day 1, patients were prescribed fasting and proton pump inhibitors as routine. If there were no gastrointestinal bleeding or emphysema for 3 days after ESD, the gastric tube could be removed and patients could have a liquid diet. Follow-up endoscopic examinations were performed at 1, 3, 6, and 12 months, and annually thereafter. Patients who were at a high risk for nodal or distant metastasis had computed tomography imaging every year. For patients who were not followed up on time, a telephone follow-up was done once a year (the last telephone follow-up was October 31, 2018).

Statistical analysis

SPSS statistical software (IBM SPSS Statistics 22, IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.) was used for data analysis. Mean and standard deviation were used to describe normally distributed values and the median of values with skewed distributions.

Result

Clinical characteristics

ESD was performed successfully in all 34 patients with 69 lesions. Sixty-seven synchronous lesions from 33 patients were simultaneously treated by ESD in 1 operation; 2 synchronous lesions from 1 patient were resected on 2 operations, respectively.

Patient clinical characteristics and endoscopic outcomes are summarized in Table 1. Twenty-eighty male patients and 6 female patients were involved in the present study, with the median age of 65 years (range 46–78 years). Thirty pairs of double lesions from 30 patients were resected on 1 operation; 3 lesions from 1 patient were resected on 1 operation; 2 pairs of double lesions from 2 patients were resected as 1 piece on 1 operation. In total, 69 lesions were removed simultaneously and 67 pieces of specimen were achieved. Twelve (17.9%) lesions located in the upper esophagus; 33 lesions (47.76%) located in the middle esophagus; and 24 lesions (34.32%) located in the lower esophagus.

Table 1.

Clinical Characteristics of 34 Patients with Endoscopic Submucosal Dissection for Synchronous Multiple Primary Early Esophageal Cancers

Procedures	N = 34
Age, year, mean (SD)	62.77 (7.34)
Median (range)	63 (46–81)
Sex, male/female, n	28/6
Lesions
Number, n	69
Diameter, cm, median (range)	2.3 (0.8–6.9)
Location, n (%)
Upper esophagus	12 (17.39)
Middle esophagus	33 (47.83)
Lower esophagus	24 (34.78)
Histopathology, n (%)
HGIN	33 (47.83)
T1a	28 (40.58)
M1	6
M2	14
M3	8
T1b	8 (11.59)
SM1	5
Deeper than SM1	3
Follow-up, month, median (range)	51.3 (16–64)

ESD, endoscopic submucosal dissection; HGIN, high-grade intraepithelial neoplasia; SD, standard deviation.

The lesions of 12 cases (17.9%) were located in the upper esophagus, lesions of 33 cases (47.76%) were located in the middle esophagus, and lesions of 24 cases (34.32%) were located in the lower esophagus. Of all 69 lesions, 36 were carcinoma, and 33 were high-grade intraepithelial neoplasia.

Treatment outcomes of ESD

In this study, only 1 patient was operated twice to remove the 2 double lesions. So, we focused on assessment of simultaneous ESD treating synchronous early esophageal cancer through the following study, excluding the case that was not resected during the same operation (Table 2). The median operation time was 60 minutes (range 36–197 minutes). The median hospitalization time was 3 days (range 2–14 days). The median diameter of the resected lesion was 2.3 cm (range 0.8–6.9 cm). The en bloc resection rate was 97.01% (65/67) and curative resection rate was 92.53% (62/67).

Table 2.

Treatment Strategy and Outcomes of 33 Patients with Synchronous Multiple Primary Early Esophageal Cancers

No. of procedures	N = 33
Lesions removed simultaneously, n	67
Patient with double lesions, n	30
Patient with triple lesions, n	1
Two lesions on one specimen, n	2
En bloc resection rate (%)	97.01% (65/67)
Curative resection rate (%)	92.53% (62/67)
Operation time, minutes, median (range)	60 (36–197)
Complications, n (%)	3 (9.09)
Stricture	2
Delayed bleeding	1
Hospitalization time, day, median (range)	3 (2–14)
Recurrence, n (%)	1 (3.03)
Metastasis, n (%)	0
Additional treatment, n (%)	3 (9.09)
Surgery	2
Radiotherapy	1

A small amount of intraoperative bleeding occurred in all cases and was treated by electrocoagulation or coagrasper successfully. Delayed bleeding was observed in 1 patient and cured by endoscopy. Esophageal strictures occurred in 2 cases. Both patients were treated with endoscopic balloon dilation (EBD) for 3 times and 2 times. The EBD treatment was successful when the endoscopy could smoothly pass through the esophageal stricture. The treatment success rate was 100% and no adverse events related to EBD. The main clinical characteristics of the cases with complication are summarized in Table 3.

Table 3.

Clinical Characteristics of the 3 Patients with Complication

No.	1	2	3
Sex	Male	Male	Male
Age (year)	61	81	59
Size (cm)	5.8/6.1	3.3/3.3	3.8/4
Procedure time (minutes)	162	125	107
Invasion depth	M1/M3	M2/M2	SM1/SM1
En bloc resection	Yes/yes	No/no	Yes/yes
Curative resection	Yes/no	Yes/yes	No/no
Complications	Delayed bleeding	Stricture	Stricture
Therapeutic intervention	Endoscopic treatment and intravenous antibiotics	EBD 3 times	EBD 2 time
Hospitalization time (day)	8	4	14

EBD, endoscopic balloon dilation.

Long-term outcomes

In the present study, the median follow-up time was 51.3 (range 16–64) months. Of the 34 patients, 3 were lost to follow-up. Local recurrence was observed in one case. Additional surgery was applied to 2 patients and radiotherapy was administered to 1 patient. None of the patients had distant metastasis or treatment-related deaths.

Discussion

SMPEEC are much less than a single primary esophageal cancer. The ratio of simultaneous MPEC reported is quite different, about 0.8%–26%.^1,2 So far, nearly all lesions involved in the reports of MPEC are advanced and usually treated by surgery. Esophagectomy is invasive, less cost-effective, and makes patients to suffer a low quality of life. With the improvement of endoscopic diagnosis and treatment, ESD has become the main option treating early cancer in the digestive tract. For the perioperative safety and excellent short- and long-term outcomes,^9,10 ESD has been performed worldwide However, in those studies, the population of the SMPEEC was very small. Few studies have specifically focused on the application of ESD for SMPEEC.

No different from a single primary early esophageal cancer, early detection is the key point that SMPEEC can be treated by ESD. Misdiagnose is likely to delay the timing of treatment and cost patients' opportunity to receive minimally invasive treatment. In reducing the rate of missed diagnosis for early esophageal cancer, Lugol's chromoendoscopy or NBI combined with magnifying endoscopy is better than standard endoscopy. Shimizu et al.¹¹ reported that in high-risk patients, with the application of standard endoscopy, there was a missed diagnosis rate, of early esophageal cancer, as high as 45%. A combination of different endoscopic screening techniques is an effective way to reduce missed diagnosis rate; furthermore, endoscopists need to build the awareness of the possibility of multiple lesions.

For those MPEC and precancerous lesions meeting the indications of endoscopic treatment, there are two types of treatment strategies: (1) performing two or three ESD during one operation and (2) performing ESD in different operations.

In this study, lesions of 33 patients were resected in 1 operation. In 2 patients, 2 lesions were resected in 1 piece of specimen. The en bloc resection rate (97.01%) and the curative resection rate (92.53%) were similar to the previous result in Japan (en bloc resection rate 93%–100%; curative resection rate 84.5%–97%).^5,12

The rate of major complications observed in this study was 9.09%, a little higher than the complication rate of a single ESD in the esophagus (0%–10%).^13,14 In total, one delayed bleeding and two postoperative strictures were observed. The delayed bleeding was cured by endoscopy. Two patients suffered postoperative stricture. One patient had an M2 lesion exceeding 3/4 of the esophageal circumference. The other one had a lesion deeper than SM1 exceeding 2/3 of the esophageal circumference. It was reported that wound surface of resection >3/4 of the esophageal circumference was a main risk factor for stricture^15,16 and the stricture rate was about 70%–90%.^16–18 The invasion depth is another risk factor for stricture.¹⁹ All the stricture cases in our study were treated successfully by repeated endoscopic balloon dilatation.

Local recurrence occurred in one case, because of noncurative resection of one lesion. A multicenter retrospective study in Japan showed that the local recurrence rate of esophageal mucosal lesions after ESD was about 1.9%–9.4%.^5,19 The complication rate and local recurrence rate in our study were comparable with those data.

Further treatments, including esophagectomy or radiotherapy, were recommended for 3 patients with an invasion depth of SM2. Two patients had esophagectomy and 1 patient had radiotherapy. Thirty-one patients successfully avoided esophagectomy, which greatly improved the quality of life, while reducing mental and financial burden on those patients. Therefore, we considered performing two or three ESD during one operation as a feasible treatment for SMPEEC.

The lesions of 1 patient were resected in 2 operations. The two lesions were large, 2.7 and 3.5 mm in diameter, respectively. Furthermore, these two lesions were close to each other. If the two lesions were resected in one operation, we can predict that the operation time would be long and easily cause a complication, such as postoperative stricture or bleeding. Under the situation that the operation is complex or patients had risk factor for complications, resecting the lesion in a different operation would be a wise choice. Although performing ESD by stages will increase the number of operations, it will correspondingly shorten the time of each operation, reducing the incidence of complications. From our experience, 4 weeks is a good option to be the interval time between two operations. Because 4 weeks is long enough for the surgical wound to be healed⁵ and the left lesion would not worsen in the pathological stage and prognosis.

There are some limitations of this study. Overall, we included only 34 patients. The small sample size may cause bias error. Also, there was no comparison with ESD for single esophageal cancer or comparison with surgery. To confirm our study, a large sample size and comparison with single esophageal cancer or other treatments are warranted.

Conclusion

Simultaneous ESD is a feasible option to treat synchronous esophageal cancer. It may reduce hospitalization time and overall medical expenses by the resection of multiple lesions in one operation. For the cases with risk factors of complications, simultaneous ESD needs to be avoided. Furthermore, physicians should be aware of the coexistence of two or more lesions of the esophagus during the initial examination.

Footnotes

Acknowledgments

The project was supported by the Shanghai Engineering and Research Center of Diagnostic and Therapeutic Endoscopy (16DZ2280900), National Natural Science Foundation of China (81672329), Shanghai Municipal Health System Outstanding Academic Leaders Foundation Program (2017BR010), and Jianfeng Project of Xuhui Provincial Commission of Health and Family Planning (SHXH201701). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.

Disclosure Statement

No competing financial interests exist.

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