Clinical Research Regarding the Ratio of Lymph Node Metastasis and the Reasonable Extent of Lymphadenectomy in Middle Third Thoracic Esophageal Squamous Cell Carcinoma

Discussion

The lymphatic drainage of the esophagus is quite extensive, with longitudinal drainage along the submucosa and transverse drainage via a direct route through the esophageal wall. It was suggested in our study that there was a significant correlation in comparison of the prognosis of EC with each of the following: tumor infiltration, degree of differentiation of tumor cells, and LMR. Feng et al.^[2] found that there was significant difference in lymph node involvement between tumors with invasion into the mucosa or submucosa and tumors with cellular infiltration into the muscular layer. Siewert et al.^[3] found that the degree of differentiation of EC was an independent influential factor on LM: the higher the degree of differentiation was, the lower the LMR. These results are similar to those findings in a number of previous reports ^[4-6]. Therefore, a general consensus has been reached that there is a clear cut correlation in comparison of LM with each of depth of tumor infiltration and degree of differentiation of tumor cells.

The available T-stage standard of EC is based on the depth of tumor infiltration, without considering tumor size. Many authors have held the belief that there is a positive correlation between the LMR of EC and the size of tumor. Rong et al.^[7] believed that there were significant differences in the RLNM between patients with tumor size > 5 cm and patients with tumor size < 5 cm. Eloubeidi et al.^[8] found that tumor size could be regarded as an independent factor which influenced the prognosis of EC patients. However, it was shown in the study of An et al.^[9] that size of tumor had no effect on LM. Wang et al.^[10] also found that when depth of tumor infiltration is equal, tumor size did not affect LM. Therefore, further studies are needed to prove the influence of tumor size on T-staging and prognosis in EC.

At present, surgery combined with other therapy is the primary choice of treatment for EC patients, while tumor staging and extent of the surgery are the main factors affecting the treatment outcome. In China and overseas, there has not yet been a unified standard regarding the scope of lymphadenectomies. It is thought that LM to the superior mediastinum and base of neck mainly occur in EC patients whose tumors are localized to the superior thoracic segment and that metastasis to the inferior mediastinal and abdominal lymph nodes mainly present in patients whose tumors are localized to the inferior thoracic segment. In addition, LM may occur in patients with tumors located in the middle thoracic segment, following the route of lymphatic drainage both superiorly and inferiorly. Retrograde metastasis may also occur if there is a lymphatic blockage. Based on the points mentioned above, extensive lymphadenectomy of EC has increasingly been recommended. Since the 1980’s, Japanese surgeons have taken the lead in performing modern 2-field lymphadenectomies in EC patients, i.e., the scope of the lymphadenectomy extended to the superior mediastinum from the middle and inferior mediastinum, and upper abdomen, then resulting in the extensive 3-field lymphadenectomy including the neck, thorax and abdomen. It was found in our study that the LMR of the superior mediastinum in EC patients whose tumor was localized to the middle thoracic mediastinum was 43.4%, in which the metastatic ratio of the single superior mediastinum was 28.7%, and that of the single left superior mediastinum was 7.8%. Therefore, concerning modern 2-field lymphadenectomy, if merely the conventional 2-field lymphadenectomy was performed in patients with middle thoracic EC, i.e., the standard mediastinal plus abdominal lymphatic scavenge, there would be an advancement of tumor stage in 28.7% of the patients, and an inadequate scope of lymph node clearance in 43.4% of the patients. If merely the extended mediastinal plus abdominal lymphadenectomy was performed in these patients, there would be an advancement of tumor stage in 7.8% of the patients, and an inadequate scope of lymph node clearance in 14.0% of the patients. Whether 3-field lymphadenectomy should or should not be performed in these EC patients remains controversial at present. On the one hand, it has been widely accepted that 3-field nodal clearance may increase the accuracy rating of the staging and lower the rate of local relapse^[11,12]. On the other hand, this extensive excision may result in an increased postoperative complication and death rate.

There is at present no prospective report on a large sample and randomized control study of the survival rate of patients with 3-field nodal clearance. Most authors have believed that 3-field scavenge could increase the survival rate of EC patients^[13-15]. However, Watanabe et al.^[16] found that the 5-year survival rate of EC patients was higher in the group with the modern 2-field lymphadenectomy than in the other 2 groups, suggesting that the key point of the extended lymphadenectomy is the precise dissection of the lymph nodes surrounding the bilateral RLNs area, instead of a scavenge of the lymph nodes surrounding the neck. Law et al.^[17] found that there was no significant difference in comparison of the relapse and survival rates between patients undergoing 3-field and patients undergoing 2-field lymphadenectomies, suggesting that 2-field clearance is enough for the scope of the lymphadenectomy in EC patients. Therefore, further randomized control studies with large study samples are needed in addition to investigation on whether 3-field lymph node clearance can improve the survival rate for EC patients.

In the EC staging system which has been used, the amount, frequency and region of LM are not included when a tumor is staged in patients with positive lymph nodes. Therefore, this results in differences in the prognosis of patients with the same staging. In our study, the COX model multifactorial analysis of the clinicopathologic data was conducted in 129 patients with middle thoracic esophageal squamous cancer, showing that the tumor size, degree of tumor cell differentiation, depth of tumor infiltration, and RLNM of the tumor have significant influence on prognosis. In the study, the patients with N1 stage disease were divided into 2 groups based on RLNM, i.e., the 1-, 3- and 5-year survival rates were 77.4%, 44.2% and 31.0%, respectively in the N1 (A) group and 61.4%, 30.7% and 6.8%, respectively in the N1 (B) group, indicating that the 5-year survival rates were significantly higher in the patients with N1 (A) than those in the patients with N1 (B) (P = 0.047). Hsu et al.^[18] defined N staging as N0 (no LM), N1 (≤ 4 positive lymph nodes or RLNM ≤ 20%), N2 (> 4 positive lymph nodes or RLNM > 20%) and found that there was also an apparent decrease in survival rate among patients in the 3 groups, with a retroposition of the N stages. The result had statistical significance. An et al.^[9] classified 217 patients receiving 3-field nodal scavenge into 4 groups, i.e., no LM, having LM in Zone 1, in Zone 2, and in Zone 3, and found that there were significant differences in 5-year survival rate among the patients in the 4 groups. The outcome of the study by Shimada et al.^[15] was similar to that from An’s study. Zhang et al.^[19] conducted a retrospective analysis of 1,146 EC patients and found that the 5-year survival rates were respectively 59.79%, 33.38%, 14.28%, 6.26% and 2.98% in EC patients with 5 different grades of disease which included the number of the metastasized nodes of 0, 1, 2, 3 and ≥ 4. There were statistical differences in the overall survival curve; however, there was no significant difference in survival in 3 of the 5 grades, i.e., 2, 3 and ≥ 4 metastasized nodes. Therefore, the prognosis of EC patients not only depends on whether there are positive nodes, but also closely relates to the number of the metastasized nodes and the frequency of LM.

To summarize the above, the LM of EC is in close relation with the depth of tumor infiltration, degree of differentiation of tumor cells and size of tumor, and LM is the important factor affecting the prognosis of the EC patients. The current TNM staging fails to thoroughly reflect the prognosis of these patients. Therefore, concerning the surgical treatment for the EC patients, extensive lymphadenectomy is needed to enhance the accuracy of staging and the extent of the radical excision. The improvement of the current N-staging of EC is also expected.