Background
Esophageal cancer (EC) is one of the worst malignant digestive neoplasms and the sixth leading cause of cancer-related deaths around the world [
1], producing 482,300 newly diagnosed cases worldwide in 2014 [
2]. Because of the extensive network of esophageal lymphatics, early regional tumor advancement and metastasis to regional lymph nodes often occur, contributing to an 85% mortality rate [
3]. Surgeries including transhiatal esophagectomy and transthoracic approaches remain the mainstay of treatment in achieving loco-regional control in EC patients and offer the best chance for cure in early localized and locally advanced diseases [
4].
For the radical resection of EC, the most common open surgical protocols include transthoracic and transhiatal esophageal resections [
5,
6]. The Ivor Lewis (laparotomy and right thoracotomy) and Sweet approaches (through a single left-sided thoracic incision) are two most widely used transthoracic esophagectomy techniques [
5,
7,
8]. The traditional left transthoracic approach allows for less incision, less trauma, relatively small risk of perioperative complications, and good exposure of the middle-lower thoracic esophagus; however, it poses difficulties in mediastinal lymph node dissection, especially in bilateral recurrent laryngeal nerve (RLN) lymph node dissection [
9]. In contrary, right thoracotomy combined with the transabdominal approach promises better mediastinal and abdominal lymph node dissection; however, it increases the number of required abdominal incisions, aggravates trauma in patients, and poses difficulties in bilateral RLN lymph node dissection which may damage the RLN, limiting its wide range of applications [
10]. Additionally, the transcervical and transdiaphragmatic approaches without thoracotomy are limited to early-stage diseases and patients with high risks of surgery [
11‐
13].
Recently, the widely used minimally invasive esophagectomy (MIE) for the patients with EC has reduced the surgical trauma and the incidence of complications; however, this operation still requires abdominal incisions that increase trauma and may cause complications such as abdominal incision infection and hernia [
14]. Further, the application of MIE requires surgeons to learn the operation management techniques such as familiarizing laparo-thoracoscopy techniques, which may increase the difficulty of the surgery and the operating costs. Additionally, the greatest difficulty in MIE lies in the exposure of the bilateral RLN and the dissection of RLN lymph nodes dissection, which may damage the RLN and increase the operation difficulty [
9].
The application of surgical resection with the left or right transthoracic approach in patients with EC is always controversial, and the core dispute focuses on which approach can achieve better mediastinal lymph node dissection [
15]. The left thoracic approach is considered to be the main approach used in China; however, it is criticized for the limited extent of lymphadenectomy, especially in the upper mediastinum [
15,
16]. Thus, finding an effective method for upper mediastinal lymph node dissection is imperative. Video-assisted mediastinoscopy can be a useful method to expose the superior mediastinal anatomic structure and remove the superior mediastinal lymph nodes [
17]. In this study, we proposed a new surgical approach, i.e., the application of transcervical video-assisted mediastinoscopic lymphadenectomy (VAMLA) combined with the left transthoracic esophagectomy for patients with EC, and to compare its outcomes with those of esophagectomy via the right transthoracic approach. The study may offer a potential treatment option for patients with EC.
Discussion
Radical esophagectomy via either left or right transthoracic approach for patients with EC is still controversial, and which method is more efficient to achieve superior mediastinal lymph node dissection needs further discussion. Esophagectomy via the right transthoracic approach is considered as the standard surgical strategy for EC cases in western countries [
21]. On the contrary, in China and some Asian countries where EC is with a high incidence, the left transthoracic approach is used as the main surgical approach in the current status quo.
A recent report showed that preoperative chemotherapy in patients with stage II/III esophageal squamous cell carcinoma contributed to better prognosis [
22]. However, decisions regarding neoadjuvant therapy for esophageal cancer remain a subject of controversy [
23]. Evidence suggests neoadjuvant therapy may lead to worse surgical results [
24]. This study covered cases with no preoperative adjuvant radiochemotherapy. The patients with EC were enrolled from December 2014, and radical surgery was selected for these patients using preoperative evaluation. For new-enrolled EC cases in stage II/III in later study, we will recommend preoperative neoadjuvant therapy for them. On the other hand, in this study, patients with no obvious enlarged mediastinal or cervical lymph node were included. We recommended preoperative neoadjuvant therapy or neck lymph node dissection for those patients with obvious enlarged mediastinal or cervical lymph node because direct surgical treatment was not suitable for these cases. Moreover, although only patients without enlarged nodes were included, in fact, more than 50% of dissected nodes were pathologically positive in this study. Actually, the accuracy of CT for correct assessment of lymph node metastasis is reported only about 40%, and histopathological examination of lymph node metastasis serves as the reference standard [
25]. Most cases in our study were in T2 or T3 stage. Thus, it is possible that lymph nodes were characterized as negative during preoperative evaluation while the incidence of positive lymph nodes after surgery was higher.
Lymph node dissection plays an essential role in EC radical resection [
26,
27]. Lymph node metastasis ratios and lymph node metastasis numbers are independent risk factors for EC prognosis [
28,
29]. The RLN lymph node is one of the most common metastatic and relapsing sites in EC even after radical resection, and the rates of this metastasis in upper thoracic EC are as high as 43.3% [
30,
31]. The RLN lymph node metastases are considered as independent predictors of cervical lymph node metastases [
32,
33]. Evidence showed that the 3-year survival rate was 29.3% in patients with RLN lymph node metastases after surgery, while 58.2% in patients without RLN lymph node metastases (
p < 0.05) [
34]. Thus, the RLN lymph node dissection is considered beneficial for EC patients and is the key point of lymph node dissection for EC treatment [
21,
34,
35]. However, the dissection of RLN lymph nodes is the main difficulty in EC radical surgery. Since RLN travels longer with various anatomical positions, it is pretty vulnerable during operation, and the damage will lead to hoarseness, cough, aspiration pneumonia, pulmonary infection, respiratory failure, and even death [
32]. Additionally, as bilateral RLN impaired, serious complications may occur such as life-long tracheostomy.
In the study of Matsuda et al., the total number of dissected LNs was 20.02 ± 8.16 and 27.93 ± 11.75, respectively, in the thoracic duct (TD)-preserved and TD-resected groups via right transthoracic approach [
36], which showed a little more number of dissected LNs compared with that of the control group of this study (the number of total dissected lymph nodes is 17.8 ± 8.1). However, our highly skilled surgeons had many years of experience performing surgical resection of EC. Our hospital is a professional clinical diagnosis and treatment center of esophageal cancer in China, and there is strict quality control of radical esophagectomy and lymph node dissection. Moreover, it met the National Comprehensive Cancer Network (NCCN) guidelines for esophageal cancer which indicate at least 12 lymph nodes should be removed [
37]. Although the procedure of bilateral RLN lymph node dissection via left transthoracic approach has been reported in some study [
38], the method is tough to perform and is not conducive to the widespread application. Therefore, the development of an efficient method of upper mediastinal lymph node dissection for EC radical surgery via left transthoracic approach is undoubtedly an excellent complement and optimization. The video-assisted mediastinoscopy has advantages in good exposure on the upper mediastinal anatomic structure and the dissection of the upper mediastinal lymph nodes, especially in bilateral RLN lymph node dissection [
13,
39]. Thus, the video-assisted mediastinoscopy may be a potential complement for EC radical surgery via left transthoracic approach, promoting the application of the method for EC radical surgery.
Transcervical mediastinoscopy is a relatively mature surgical procedure in thoracic surgery, which is mainly used for the diagnosis of a mediastinal mass, lymph node biopsy, and preoperative staging of lung cancer. In 1990, Buess and Becker [
39] first reported the video-assisted mediastinoscopy as a treatment for EC. According to the present research around the world, video-assisted mediastinoscopy for EC treatment is based on transcervical combined with the transhiatal operation to isolate the cervical and upper thoracic esophagus and to remove the mediastinal lymph nodes [
40,
41]. However, there is no report about the use of transcervical VAMLA auxiliary for the radical operation of EC via left transthoracic approach.
VAMLA combined with radical operation via left transthoracic approach for EC has the following potential advantages: (1) not only retaining the benefits of the traditional esophagectomy via the left transthoracic approach but also achieving the superior mediastinal lymph nodes and bilateral RLN lymph node dissection without increasing surgical incisions; (2) satisfactory exposure of the upper mediastinal anatomical structure, in particular, the exposure of bilateral RLN ,and better lymph node dissection; (3) achieving the cervical and upper thoracic esophageal dissociation simultaneously; and (4) less trauma and bleeding, as well as less postoperative pain and complications.
Our results indicated that the total number of dissected lymph nodes and the numbers of upper mediastinal lymph nodes and RLN lymph nodes were significantly higher in the study group than that in the control group, while the number of dissected abdominal lymph nodes was similar in both groups. It suggested that VAMLA combined with radical operation via left transthoracic approach for EC was not inferior to esophagectomy via the left transthoracic approach in the dissection of abdominal lymph nodes. Furthermore, it has distinct advantages in dissecting the upper mediastinal lymph nodes, especially for the RLN lymph node. In this study, the RLN lymph node metastatic rate was 25% (7/28), namely four cases of right RLN lymph node metastasis and three cases of left RLN lymph node metastasis, which was similar with that reported in domestic and foreign relevant literature [
13,
34].
There were no significant differences in postoperative complications including respiratory system complications, arrhythmia, chylothorax, anastomotic fistula, postoperative hospital stay, and vocal cord paralysis between the two groups. Four patients (14%, 4/28) in the study group were subjected to RLN paralysis, and the symptom in three of them significantly alleviated after 3 months of operation. The incidence of nerve palsy, however, has been reported to be 3.1–22.5% in other studies [
42]. The possible reason is that the right transthoracic approach is not sufficient for the RLN isolation which limits the resection of lymph nodes, while VAMLA did not increase the risk of RLN damage due to its profits in the exposure of this area although the uncovered time of RLN lasts the entire operation. A study also showed that intraoperative application of single-chamber tracheal tube EMG signal and EZ to monitor the RLN could reduce the frequency of RLN injury [
43]. Meanwhile, it also should be noticed that the mediastinoscopy operation by itself causes the incidence of complications approximately 0.5%, including injury of superior vena cava, azygos vein, innominate artery, and other large vascular damage (mediastinal infection, tracheoesophageal injury, and misdiagnosed parathyroid risk) [
44]. Nevertheless, as long as the surgeons are meticulous and well trained, VAMLA is a very safe operation.
In the present study, VAMLA was used to make up the deficiency of the dissection of recurrent laryngeal nerve lymph nodes (RLN LNs) in esophagectomy via left transthoracic approach. Although the Ivor Lewis approach is the most routinely performed approach by most surgeons [
45], we also need to perform esophagectomy via left transthoracic approach on some patients in clinical, such as the patients with right-sided chest empyema, right chest surgeries, or severe right chest adhesions and patients with combined pulmonary nodules at the left lung that need to be removed and determine pathology. VAMLA with esophagectomy via the left transthoracic approach undoubtedly shows its advantages and importance. So, in the development of this new strategy, we have made a few improvements, mainly in the exposure procedures of RLN. As a new protocol, VAMLA with esophagectomy via left transthoracic approach possesses good learnability and popularization, although it requires a period of mediastinoscope learning curve and the related experience of esophagectomy. Apart from the experience of surgeons, the selection of EC patients to receive this novel operation bases on their clinical stage, and all the patients under cT3N1M0 will be suitable for this protocol. However, VAMLA combined with esophagectomy via left transthoracic approach still has some shortcomings, such as positional change during surgery, the requirement of video-assisted mediastinoscopy instruments, and skilled surgeons. Besides, more meticulous operating are also needed because the manipulating space is limited, and fractional resection of large lymph nodes is sometimes needed. Moreover, a limitation of this study was the relatively short period of follow-up, and the efficacy of this surgery on the prognosis in EC patients needs further follow-up study. Finally, it has been reported that 38.3–56.5% of the RLN LN metastases accompanied by the supraclavicular lymph node metastasis, which means RLN LN should be considered an important indication for supraclavicular lymph node dissection [
32,
38]. However, the group of positive RLN LNs cases in this study did not undergo the cervical lymph node dissection, and the significance needs further investigations.