Surgical resection remains an essential cornerstone for patients with Thoracic esophageal squamous cell carcinoma (TESCC) . TESCC with pathological stage T3N0M0 (pT3N0M0) is a locally advanced disease with no regional lymph node or distant metastasis. Although pT3N0M0 TESCC is a homogeneous subgroup of EC, notable differences in long-term survival and local-regional recurrence were observed. The long-term 5-year overall survival (OS) of pT3N0M0 TESCC after radical (R0) resection ranges from 46–75.2%, with a local and regional recurrence rate of 16.5–38% and distant metastasis rate of 7.6–20% [17–19]. Notably, the local and regional recurrence is the major cause of treatment failure in patients with pT3N0M0 TESCC. Thus, determination of its prognostic factors is important.
In this study, we first emphasized the prognostic significance of unresected small LNs assessment for patients with pT3N0M0 TESCC who received esophagectomy. The results of univariate and multivariate factor analyses showed that unresected small LNs status, tumor grade, and postoperative adjuvant therapy are independent prognostic factors. Unresected small LNs in CT-suspect status shown a higher TR (P < 0.000) and LR (P < 0.000) rates compare with unresected small LNs in CT-negative status.
For the high lymph node spread of TESCC, the long-term survival of a patient is highly dependent on the extent of lymphadenectomy [20, 21]. Previous studies have proven that an increased extent of lymphadenectomy is associated with improved survival [22, 23]. Thus, a wide range of thresholds ranging from 6 to 20 has been reported as the optimum number of removed LNs for patients with pT3N0M0 TESCC in previous studies [17, 19, 24, 25]. However, several studies found no association between the number of removed LNs and improved survival in TESCC cases [26–29]. In this study, we used 15 LNs as a threshold to analyze the prognostic value of the number of removed LNs in patients with pT3N0M0 TESCC, as recommended by the current National Comprehensive Cancer Network guidelines . The number of removed LNs was a significant risk factor for survival in the univariate analysis but not in the multivariate analysis. Evidence indicates that the survival benefits from a higher number of removed LNs can be partly attributed to stage migration (improved staging rather than improved therapeutic benefit of the dissection itself) [31–33]. With a higher number of removed LNs, the possibility of discovering potential cancer-positive LNs will be improved, allowing more accurate staging and treatment protocols. This indicate that metastatic nodes may be among the unresected LNs.
Additionally, setting a unified threshold to represent optimum lymphadenectomy seems unreasonable for patients with different numbers of LNs before surgery. Further, overtreatment may result in increased complications and mortality, and owing to the limitations of surgical skills and the patient’s physical condition, there may still be unresected lymph nodes. Hence, the precise evaluation of unresected LNs for cancer infiltration was not only the primary determinant of accurate residual tumor (R) classification , but also meaningful for prognosis predicting and postoperative decision-making and management of EC .
Esophageal CT is currently the most commonly used method for lymph node assessment. However, the accuracy of CT is unsatisfactory when LNs greater than 10-mm diameter are considered positive for metastasis [34, 35]. An important limitation was that metastatic lymph nodes might present without an apparent enlargement in size. Furthermore, some enlarged nodes may contain no metastasis. Past reports have shown that the accuracy of CT in the diagnosis of lymph node metastasis can be 46–58% , and a false-negative rate of 11–56% was reported . Even with PET/CT, a large number of small metastatic lesions can be difficult to detect [34, 38, 39]. A previous study has reported that lowering the size criteria and combining the axial ratio (short-axis diameter/long-axis diameter) would increase sensitivity [16, 40, 41]. Therefore, in the present study, LNs were diagnosed as suspected metastatic nodes in the absence of pathological confirmation, when the short-axis diameter exceeding 5 mm and the shape of the node was round (axial ratio exceeding 0.66). However, further research is needed to determine the most accurate diagnostic method.
We retrospectively examined 294 patients with stage pT3N0M0 TESCC who received radical esophagectomy between 2009 and 2016. Among them, 84 patients (42.5%) were suspected to have metastatic unresected lymph nodes evaluated using pre- and postoperative CT and were classified into the CT-suspect group. The CT-suspect group showed significantly higher TR and LR than the CT-negative group. Further analysis found that the presence of suspected metastatic unresected small LNs was an independent prognostic factor for TR, LR, and OS. Therefore, compared with the number of removed LNs, unresected small LNs with suspected metastasis may be a better reflector for the thoroughness of lymphadenectomy and a more important prognostic factor for pT3N0M0 TESCC.
In addition, in the overall study cohort, the TR rate among pT3N0M0 thoracic ESCC patients was as high as 43.2%, and the LR, DM and LR with DM rates were 25.2, 11.6 and 6.5%, respectively. These results are consistent with the previous findings [26, 42].Further analysis showed that the most common area for LR was different in CT-suspect group and t CT-negative group. In contrast to previous studies , the supraclavicular lymphatic area was the most common area for LR in the CT-suspect group with a recurrence rate of 22.6%, but the mediastinal lymphatic area was the most common area for LR in the CT-negative group with a recurrence rate of 17.6%. We believe that this might be owing to the high proportion of unresected small LNs in the supraclavicular lymphatic area in the CT-suspect group. These findings suggested that CT-suspect metastatic lymph nodes should be removed as extensively as possible during the operation, or the major postoperative failure areas, such as the supraclavicular lymphatic recurrence area, and the mediastinal lymphatic recurrence area should be carefully included in the clinical target area during postoperative radiotherapy.
Currently, there are still controversies about the value and pattern of postoperative adjuvant therapy in pT3N0M0 TESCC patients. Thus, the use of postoperative chemotherapy or radiation in pT3N0M0 cases needs to be characterized in more detail, including the presence of suspicious unresected small LNs. Our previous study compared surgery alone and POCT using a propensity score matching (PSM) analysis for 582 patients with pT3N0M0 TESCC, retrospectively. After PSM, both groups had similar factors. Surgery + POCT significantly improved the 5-year OS and DFS (OS, 70.8% vs. 52.8%, P < 0.0001; DFS, 66.5% vs. 50.2%, P < 0.0001) . However, other studies have shown no survival benefit for patients who received POCT. Ando et al.  reported no survival benefit of 5-year OS for the Japan Clinical Oncology Group, with a 5‐year OS rate of 48.1% for POCT and 44.9% for surgery alone (P = 0.26). For N1 ESCC patients, the 5‐year OS was 43.7% for patients of POCT and 35.5% in surgery alone (P = 0.15). The value of adjuvant PORT in pT3N0M0 TESCC patients is also controversial, this may be related to inclusion criteria, surgical methods, extent of exposure, and radiotherapy technologies. Yang et al.  conducted a large sample-size retrospective study of PORT for pT3N0M0 TESCC, which showed that, compared with surgery alone, surgery + PORT significantly improved the 5-year OS (75.2% vs. 58.5%, P = 0.004) and DFS (71.8% vs. 49.2%, P = 0.001) rates. However, in other reports, no benefit of survival was observed. Xiao et al.  conducted a large phase III clinical trial of PORT in esophageal carcinoma and showed an improved 3-year OS in patients with pT2–3N0M0 TESCC who received PORT (64.0%) versus those who underwent surgery alone (56.0%); however, the difference was not significant. One possible reason is the inaccuracy of N staging. In most studies that show no survival benefit from postoperative adjuvant treatment, the most common surgical approach is left thoracotomy or two‐field esophagectomy. Previous studies have demonstrated that LN dissection is more complete using right thoracotomy than left thoracotomy, especially for tracheoesophageal groove and para-recurrent laryngeal nerve LNs [45, 46]. Cervical LNs were seldom resected during two‐field esophagectomy. LNs in the upper mediastinum (especially above the arch of the aorta) were usually dissected incompletely. Therefore, potential metastasis of LNs in the cervical region and upper mediastinum could not be removed intraoperatively in these studies. Therefore, postoperative chemotherapy may be insufficient, on the contrary, postoperative radiotherapy may be more effective at this time. Wang et al.  reported that postoperative adjuvant therapy (most of the patients received POCT) was not associated with OS (P > 0.05), but the presence of small LNs on preoperative CT was an independent prognostic factor for OS. In their study, all or most patients with small LNs on CT located in the upper mediastinum (especially above the arch of the aorta) underwent a limited left thoracotomy in a two‐field esophagectomy; thus, these small LNs may be unresected after surgery, indicating that no benefit of postoperative adjuvant therapy was observed in this particular study because of the unresected lymph nodes. These results suggest that unresected small LNs assessment for patients with pT3N0M0 TESCC receiving esophagectomy may be important for further postoperative treatment decisions. However, the best pattern and indicator of postoperative adjuvant therapy needs to be further studied in pT3N0M0 TESCC.