Background
Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer-related death worldwide [
1]. It is important for surgeons to determine the accurate patterns of lymph node metastasis in patients with esophageal cancer because lymph node metastasis will affect patient prognosis and decide appropriate treatment strategies [
2,
3]. However, it is controversial for surgeons to choose the best strategy for lymph node dissection.
Generally, surgeons commonly use contrast-enhanced computed tomography (CT) as a preoperative work-up to determine esophageal cancer staging. With technological developments, positron emission tomography CT (PET-CT) and endoscopic ultrasound (EUS) are regarded as additional methods to improve the diagnostic accuracy in cases of lymph node metastasis. Unfortunately, some researchers find and demonstrate lack of reliability in PET-CT and EUS staging [
4,
5]. The diagnostic accuracy of PET-CT in the context of regional lymph nodal metastasis is controversial because of the relatively low sensitivity of the technique. Furthermore, in patients with tuberculosis, false-positive lymph nodes in esophageal cancer will always be found because the specificity of nodal staging may be reduced [
6,
7]. Meanwhile, additional diagnostic methods such as EUS cannot be routinely used to screen patients and are only performed when surgeons are informed by radiologists of their suspicion of metastatic lymph nodes by contrast-enhanced CT [
8,
9].
Although surgeons prefer to choose the extended systematic nodal dissection as the best way to provide accurate pathological nodal staging and remove all possible metastasis of lymph nodes, the possibility of omitting positive lymph nodes also exists and the occurrence of postoperative complications increases. There are two opposite opinions about extended systematic nodal dissection. The benefit of extended systematic nodal dissection is under intense discussion [
10,
11]. Surgeons aim to identify an accurate strategy of lymph node dissection to improve prognosis and reduce the possibility of postoperative complications in patients with esophageal cancer.
Regional lymph node maps for esophageal cancer were revised in the 8th edition of tumor–node–metastasis (TNM) staging [
12]; lymph nodes were classified into three regions: cervical, thoracic, and abdominal. For increased accuracy, we divided the thoracic region into three regions: the upper thoracic region: 2R/2 L and 4R/4 L; the middle thoracic region: 7, 8 U, and 8 M; and the lower thoracic region: 8Lo,9R/9 L, and 15. Few studies have been performed to explore different patterns of regional lymph nodes. If strategy of lymph node dissection can be designed by obtaining accurate patterns of regional lymph nodes metastasis, patients would benefit substantially.
However, there are different clinical and pathological characteristics in each patient intraoperatively diagnosed with esophageal cancer. Many researchers have demonstrated that individual clinical parameters and the histological components of the tumor will greatly influence the occurrence of lymph node metastasis [
13‐
15]. Metastatic patterns of regional lymph nodes will be also affected by patient heterogeneity.
Therefore, the aim of the present study was to identify clinicopathologic characteristics and to develop and validate three nomograms that incorporated these risk factors to intraoperatively predict patterns of regional lymph nodes in patients with esophageal cancer. These nomograms will provide surgeons with additional guidance to make appropriate decisions for lymph node dissection and minimize damage to patients.
Discussion
The TNM staging system is used worldwide to determine proper treatment and establish prognosis for patients with esophageal cancer [
17]. With this staging system, regional lymph nodes, “N”, are an important direct guide that enables surgeons to perform lymph node dissection. Transverse penetration of the esophageal wall and flowing longitudinally in a cephalic or caudal direction are the two main patterns of lymphatic spreading in the esophagus. The longitudinal lymphatic flow of the esophagus is more plentiful than the transverse distribution [
18], so the patterns of metastatic regional lymph nodes generally include metastatic regional lymph nodes, metastatic continuous regional lymph nodes, and metastatic skipping regional lymph nodes [
19,
20].
In our study, we accurately divided the thoracic region into three: the upper thoracic region; the middle thoracic region; and the lower thoracic region. Metastatic regional lymph nodes are defined as the location of positive lymph nodes (> 1) that correspond to the position of the esophageal tumor. Metastatic continuous regional lymph nodes are defined as positive lymph nodes (> 1) also found in the adjacent region besides the positive lymph nodes (> 1) in the corresponding position of the esophageal tumor. Metastatic skipping regional lymph nodes are defined as positive lymph nodes (> 1) found in the other regions by the absence of regional lymph node metastasis in the corresponding position of the esophageal tumor.
However, in clinical practice, although extended systematic nodal dissection is regarded as the best treatment for patients, the possibility of omitting positive lymph nodes also exists and a high occurrence of postoperative complications makes it difficult for surgeons to choose the best strategy of lymph node dissection [
21,
22]. Surgeons face a dilemma about how to perform lymph node dissection and they must make this decision based on their experience [
23,
24]. Surgeons aim to obtain additional guides for accurate lymph node dissection.
Fortunately, nomograms, which can more accurately predict metastatic lymph nodes and provide superior stratification compared with traditional methods, have been developed and validated in several types of cancer [
25,
26]. In our study, a total of 693 patients were analyzed retrospectively following radical three-incision esophagectomy. Nomograms that were reasonably effective in predicting metastasis for different patterns of regional lymph nodes based on independent risk factors were constructed and validated. Our nomograms showed more accurate prediction, with AUC values of 0.737, 0.738, and 0.707 in the training cohort and 0.728, 0.668, and 0.657 in the validation cohort, respectively. Moreover, the calibration curves indicate a good consistency between the predicted outcomes and actual outcomes of lymph node metastasis. In addition, DCA demonstrated that these novel nomograms display an improved overall benefit and superior clinical utility compared with contrast-enhanced CT.
Using nomograms, the patterns of metastatic regional lymph nodes can be estimated. The possibility of metastasis of regional lymph nodes will increase when patients are younger, have deeper tumor invasion, and present with lymph–vascular space invasion. Metastasis risks of regional lymph node can be evaluated using nomograms within the range from 10 to 80% (Fig.
1a). By using ROC curve, the cut-off value is 35%. Metastasis risk of regional lymph node more than 35% is defined as high level risk. To assess the pattern of metastatic continuous regional lymph nodes, the possibility of metastasis of continuous regional lymph nodes will increase when patients are younger, have an APTT of < 26.6, and are in a condition of neural invasion. Metastasis risks of continuous regional lymph nodes can be evaluated using nomograms within the range from 5 to 50% (Fig.
1b). By using ROC curve, the cut-off value is 10%. Metastasis risks of continuous regional lymph nodes more than 10% is defined as high level. To assess the pattern of metastatic skipping regional lymph nodes, the possibility of metastasis of skipping regional lymph nodes will increase when patients have an increased tumor length and are in a condition of lymph–vascular space invasion. Metastasis risks of skipping regional lymph nodes can be evaluated using nomograms within the range from 5 to 30% (Fig.
1c). By using ROC curve, the cut-off value is 10%. Metastasis risks of skipping regional lymph nodes more than 10% is defined as high level.
Nomograms can provide surgeons with an important guide for making decisions about the strategy for lymph node dissection. If we find that the predictive metastasis risk of continuous or skipping regional lymph nodes is high, then extended systematic nodal dissection must be performed to avoid omitting positive lymph nodes. If we find that the predictive metastasis risk of continuous and skipping regional lymph nodes is low and that of regional lymph nodes is high, then we can only perform systemic regional lymph node dissection corresponding to the position of the esophageal tumor. If we find that the predictive metastasis risk of continuous and skipping regional lymph nodes is low and that of regional lymph nodes is also low, we can only perform regional lymph node sampling corresponding to the position of the esophageal tumor. By using the nomogram, we can probably decrease damage to patients and achieve the goal of high-accuracy treatment.
There are some limitations in the present study. This study was a single institution retrospective research and demonstrates the necessity for further prospective studies. It is necessary to perform further prospective studies with multicenter trials to comprehensively evaluate nomograms in the context of predicting intraoperative metastasis of different regional lymph nodes in patients diagnosed with esophageal cancer.
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