Accumulative studies have demonstrated EGJ adenocarcinoma as a separate entity from gastric or esophageal malignancies due to the unique clinicopathological characteristics and patient survival [8, 9]. The majority of EGJ carcinomas are handled by surgical intervention, including esophagectomy along with total or proximal gastrectomy, which, however, greatly attenuates postoperative living quality and is accompanied with high risk of complications. To be specific, the rate of postoperative complications is reported to be 33–39% according to a systematic review[10]. ESD is particularly suitable for patients with early-stage proximal gastric cancer, who, otherwise, are generally treated with total gastrectomy. If patients are managed with ESD, the whole stomach can be preserved, along with better life quality [11]. Due to the unknown incidence of LNM in EGJ adenocarcinoma, there is no consensus on the indication of endoscopic resection for superficial EGJ adenocarcinoma.
To our knowledge, our study is the largest one concerning LNM rates in early-stage EGJ adenocarcinoma after eliminating patients with less than 16 examined LNs. We found that the LNM rate in early-stage EGJ adenocarcinoma was as high as 18.8% (161/856). LNM rates stratified by pT stage were 8.3% (25/300)in T1a, and 24.6% (122/496) in T1b. Moreover, the rate of LNM decreased to 5.3% (2/38) in well-differentiated T1b tumors with tumor size < 3cm; and LNM rate increased to 17.9% (12/67) in poorly differentiated T1a tumors, and to 33.3% (5/15) in poorly differentiated T1a tumors with tumor size > 3cm. Overall, there is limited information concerning LNM rate in superficial EGJ adenocarcinoma. According to the study by Gertler, LNM was only detectable in pT1b tumors (18%) but not in pT1a among superficial EGJ adenocarcinoma[12], which was also similarly reported by Stein[13]. Moreover, Koufuji, et al. reported no LNM in T1 EGJ carcinoma [14]. Of the above studies, the relatively inadequate sample size might be the most significant drawbacks. Zhu, et al. reported that the overall LNM rate of superficial EGJ carcinoma was 21.75%, which is 11.41% and 26.50% in mucosal cancer and submucosal cancer, respectively. The results of the above studyare consistent with our findings and another study concerning surgically resected pT1 EGJ carcinoma [15, 16].
Previous studies have shown that tumor size, pathological differentiation, lymphovascular invasion and infiltration depth are risk factors for LNM in gastric and esophageal cancer [12, 16]. In our study, similar predictors of LNM involvement were revealed, including tumor size, differentiation type, and depth of invasion. To be specific, poor tumor differentiation (including moderately/poorly differentiated and undifferentiated) and tumor sizes exceeding 3 cm increased LNM risk. It is clear that tumor differentiation is the most potent predictor. Therefore, endoscopic intervention might be proper for low-risk patients, while, high-risk patients should be managed by surgical resection in consideration of the high risk of LNM.
Previous researches have revealed that age, T stage and tumor differentiation are independently correlated with poor prognosis [17–19] Due to the bias caused these parameters which can interfere with the comparison of ET and surgical therapy, multivariate Cox regression analysis and PSM were performed. ET and surgical therapy were associated with similar CSS in patients with early-stage EGJ adenocarcinoma. Additionally, subgroup analysis stratified by T stage also showed similar outcomes. PSM analysis also revealed consistent outcomes, which could decrease selection bias associated with diverse clinical features of ET and surgical therapy. The authors found that patients with sm1 cancers, classified by submucosal invasion of < 500µm, and tumors smaller than 3 cm had no LNMs. Nevertheless, with deep submucosal invasion of ≥ 500µm stratified by sm2 and sm3, the incidence of LNM increased to 28.6%, irrespective of tumor size. The above outcomes suggest that ESD can be safely used to treat patients with sm1 and tumor size < 3 cm, which is beyond the proposed guidelines [6, 20]. Most patients with T1b tumors should be treated by surgical intervention in consideration of high LNM rate (24.6%). Nevertheless, LNM incidence in T1b cancer with all low-risk tumor characteristics was only 5.3%. Hence, definitive ET must be cautiously determined on submucosal cancers without other high-risk characteristics. The multivariate Cox regression models showed that CSS (ET: HR 0.830, 95% CI:0.682–1.010, P = 0.062; RT: HR 4.024, 95% CI: 3.483–4.649, P < 0.001) compared with surgical therapy group. Moreover, Cox proportional hazards regression revealed no significant differences in CSS (HR = 1.112, 95% CI: 0.866–1.429; P = 0.405) between surgical therapy and ET groups after PSM. Therefore, ET might be a valid alternative to surgical therapy to treat early EGJ adenocarcinoma, especially in elderly patients.
Diagnostic ER is considered as potentially curative and also has more accurate evaluation of invasion depth than endoscopic ultrasonography (EUS)[21], which is a feasible and reasonable final step in all early-stage EGJ adenocarcinoma. Pathologic assessment on ER samples could assist further therapeutic strategies, which should simultaneously consider patient-related parameters. Moreover, multidisciplinary team involving surgeons, medical oncologists and endoscopists is necessary for clinical decision-making. For patients with older age or multiple comorbidities, a higher probability of leaving positive LNs may be acceptable for a lower morbidity procedure. Conversely, aggressive surgical therapy should be considered among young patients even with low risks of LNM.
In this population-based study, our findings are mainly based on real-world outcomes. Nevertheless, certain limitations must be acknowledged, Firstly, relevant data on lymphovascular invasion, the deep distance of submucosal invasion and macroscopic type are inaccessible in SEER database, which are potential risk factors for LNM. The absence of these variables might affect the accurate assessment of LNM. Secondly, the applied models are simplified and only use available and accepted measures, which clearly do not adequately account for all variables associated with subject outcomes. Additionally, selection biases are unavoidable in the retrospective analysis. Finally, although PSM was further performed in this study, the results must be cautiously interpreted due to the fraction of unmatched patients.