The impact of lymphadenectomy on lymph node recurrence after performing various treatments for esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is likely to spread to the cervical, mediastinal and abdominal lymph nodes through the lymphatic system [1]. In Japan, the recurrence rates after radical esophagectomy for ESCC are 29.0–43.0% [2‐4]. Despite improvement of lymphadenectomy, lymph node recurrence accounts for 22.0–68.0% of all recurrence [2‐7]. While some retrospective studies showed that the resection of regional lymph node recurrence had a good prognostic effect, the evidence was not strong [8‐11].

As the adoption of endoscopic resection (ER) for superficial esophageal cancer became broader, more cases of lymph node recurrence after ER were reported [12‐14]. Minasaki et al. suggested that the lymph node recurrence rate after ER of ESCC was approximately 4.0% [15]. The Japan Clinical Oncology Group (JCOG) reported a high complete response (CR) rate after radical chemoradiotherapy (CRT) for advanced ESCC (62.2%) [16]. However, their 5 year progression-free survival rate was no more than 25.6%, and lymph node recurrence after CRT for ESCC is common. In spite of the high recurrence rate, there have been few studies about the treatment of lymph node recurrence after ER and CRT.

In this study, we investigated the short- and long-term outcomes of patients who had lymphadenectomy for regional lymph node recurrence after treatment for ESCC.

The short-term outcomes of lymphadenectomy for recurrence are shown in Table 3. 17 patients (85.0%) achieved pR0. Histopathologically, seven patients had only one metastatic lymph node. Two patients had no metastatic lymph nodes. One patient had some cancer cells, but not in the lymph nodes. The rate of complications of Clavien-Dindo grade II or more was 30.0%, and that of Clavien-Dindo grade III or more was 15.0%; these included three cases of postoperative bleeding, lymphatic leakage and cervical abscess. The median hospital stay after lymphadenectomy was 4.5 days. The numbers of lymphadenectomy cases with perioperative therapy, according to initial treatment are shown in Table 4. 13 patients (85.0%) had perioperative treatment (e.g., CRT or radiation therapy [RT]) before and after lymphadenectomy for recurrence. Four patients (25.0%) had CRT as a neoadjuvant therapy. Three patients (15.0%) had RT as an adjuvant therapy, and six patients (30.0%) had CRT as an adjuvant therapy.

The long-term outcomes of lymphadenectomy for recurrence are shown in Table 3. The five-year OS and RFS rates were 50.0% and 26.7%, respectively. According to the initial treatments, the five-year OS and RFS rates were 40.0% and 25.0%, respectively for esophagectomy; 75.0% and 33.3% for ER; and 50.0% and 25.0% for CRT and CT. These OS and RFS rates are also shown using the Kaplan–Meier method in Figs. 1 and 2. The results of the univariate analysis of overall survival with a Cox proportional hazards model are shown in Table 5. There were no significant differences in OS according to the initial treatment; the hazard ratios (HRs) for esophagectomy, ER and CRT/CT were 1.00, 0.20 (p = 0.14) and 0.59 (p = 0.52), respectively. When the locations of recurrence were compared, there were no significant differences in OS; the HRs for cases involving the cervical, mediastinal and abdominal areas were 1.00, 2.47 (p = 0.22) and 5.16 (p = 0.07), respectively. When cases in which pR0 was achieved were compared with those in which pR0 was not achieved, pR0 did not significantly improve the OS; the HR of pR1-2 was 1.49 (p = 0.62). When initial Stage I and Stage II-IVB were compared (Fig. 3), the HRs for OS and RFS in patients with Stage II or more disease were 4.27 (p = 0.08) and 3.57 (p = 0.07). We also examined the re-recurrence patterns after the resection of lymph node recurrence and showed the results in Table 6. We removed three patients who could not achieve R0. Among the six patients with initial Stage I, two patients had re-recurrence; they had regional lymph node recurrence. The two patients with regional lymph node recurrence included one patient who had re-recurrence in the right supraclavicular lymph nodes within the area of lymphadenectomy for recurrence. Among the 11 patients with initial Stage II or more disease, seven patients had re-recurrence; four patients had distant recurrence and three patients had regional lymph node recurrence. The three patients with regional lymph node recurrence included one patient who had re-recurrence in the left recurrent nerve lymph node s within the area of lymphadenectomy for recurrence.

Some previous studies showed that the complication rate of lymphadenectomy for recurrence was 8.0–21.1% [8‐11]. When these results are compared with our results, the complication rate in our study was slightly higher in comparison to previous studies. Four of six patients who had complications had esophagectomy, and three of them had CRT before lymphadenectomy for recurrence (lymphatic leakage, aspiration pneumonia and mediastinal abscess [n = 1 each]). We suspect that tissues were scarred and weakened from previous operations and CRT, which led to postoperative complications. We should carefully perform lymphadenectomy in cases after esophagectomy and CRT. The pR0 rate after lymphadenectomy for recurrence was nearly the same as the rate reported by Watanabe et al. (78.9%) and Nakamura et al. (88.2%) [8‐10]. In addition, they reported median postoperative hospital stays of seven days and 10.5 days, respectively. In our study, the length of postoperative hospital stay was shorter in comparison to those previous studies.

Nakamura et al. reported that the median survival time of 22 patients who received CRT for lymph node recurrence after esophagectomy for ESCC was 20.3 months [10]. This study also showed that the rate of lymph node recurrence did not differ to a statistically significant extent between lymphadenectomy and CRT. In our study, the median survival time of patients who received lymphadenectomy for recurrence after esophagectomy for ESCC was 17.0 months. This result may suggest that the efficiency of lymphadenectomy for recurrence after esophagectomy for ESCC is limited. The combination of lymphadenectomy and adjuvant therapy may be needed at least, because eight of the 11 patients who received esophagectomy as an initial treatment also received CRT or RT.

There are few case reports about treatment for regional lymph node recurrence after ER for ESCC [12‐14]. We performed lymphadenectomy for 5 patients with lymph node recurrence after ER for ESCC. Our study could not demonstrate that the prognosis of patients who received ER as an initial treatment for ESCC was significantly better in comparison to patients who had esophagectomy and CRT/CT; however, the results might imply the possibility that patients who received ER had a better prognosis. In addition, the interval from ER to lymph node recurrence was longer than from other initial treatments to lymph node recurrence. As Kanda et al. and Ono et al. reported lymph node recurrence two years after ER, regular and long-term follow-up are required to enable early intervention [17, 18].

In our study, we could not show a prognostic difference between initial Stage I and Stage II-IVB. However, patients with Stage I disease tended to show a better prognosis in comparison to those with higher disease stages. Ozawa et al. reported that the 5-year OS rates of patients with pStage I disease who had recurrence after esophagectomy for ESCC was 9.3%, which represents a poor prognosis [19]. Approximately 25% of the cohort of that study was composed of patients with distant metastatic recurrence; thus, we cannot simply compare the results with ours. However, the 5-year OS rate of patients with pStage I disease who had regional lymph node recurrence was 83.3%, which is a valuable result, even considering the unmatched cohort. Our results suggest that lymphadenectomy can lead to a good prognosis in patients diagnosed with pStage I ESCC who have regional lymph node recurrence.

The present study was associated with some limitations. This was a retrospective single-arm analysis of a limited number of cases. The indication of lymphadenectomy was based on the surgeons’ experience; thus, it is likely that there was a selection bias. We lacked information about some confounding factors, such as the performance status, the medical and social history, and the histopathological type. In addition, we could not perform a multivariate analysis because of the small study population. There is the possibility that we could not correctly assess the efficacy of lymphadenectomy itself because most of the patients who received lymphadenectomy also received some adjuvant therapy.

Lymphadenectomy can be expected to be effective in the treatment of regional recurrence after the initial treatment of ESCC. In particular, patients with regional lymph node recurrence after initial treatment for Stage I ESCC had a good prognosis; thus, we should consider lymphadenectomy for these cases.