Introduction
Esophageal cancer is the seventh most common malignant tumor, ranking sixth in global cancer-associated mortality (1,2). In terms of histological subtypes, adenocarcinoma is commonly observed in Europe and the United States, whereas squamous cell carcinoma is the primary subtype in China (2,3). Early esophageal cancer is defined as cancer confined to the mucosa (T1a) or submucosa (T1b), regardless of the presence of lymph node metastasis (LNM) (4–6). In previous years, endoscopic treatment, namely endoscopic mucosal resection or endoscopic submucosal dissection (ESD), has been increasingly regarded as a treatment option for early esophageal cancer (7,8).
The proportion of early (T1) stage detection has increased due to the improvement of endoscopic detection (9). Endoscopic resection (ER) of early tumors is the first step in patient management (9,10). ER is curative in most types of intramucosal (T1a) cancer and cancer that partially invades the submucosa (T1b) (11). Esophagectomy with lymph node dissection is not clearly indicated as the first choice in patients with ‘non-curative’ or ‘potentially curative’ ER (11). Based on previous studies, esophagectomy results in a 5–10% mortality rate (12,13). However, due to high morbidity and mortality as a result of complications with esophagectomy, certain patients do not receive surgical treatment (14–17).
According to the guidelines of the European Society of Gastrointestinal Endoscopy, if there are poorly differentiated lesions, lymphovascular invasion (LVI) or positive vertical margins, further treatment is recommended (11). By contrast, the Japanese Gastroenterology Endoscopy Society recommends additional treatment for patients with submucosal infiltration following ER of esophageal cancer, but there is still no consensus on what to do in these cases (18). To date, adjuvant management following non-curative or high-risk ER is not standardized. Therefore, the present study aimed to propose an additional treatment strategy for patients with non-curative resection (non-CR) and only positive lateral margin (LM+) following ER of early esophageal squamous cell carcinoma (ESCC).
Discussion
With the advancement of endoscopic equipment, ER has been widely used to treat early esophageal cancer (23,24). Moreover, ER has been shown to be effective for early esophageal cancer and can be used to histologically evaluate submucosal infiltration and LVI (7,8). This can help decide whether to recommend additional treatment following radical (R0) ER. ER is mostly curative in early esophageal cancer (11). However, the best adjuvant treatment methods following non-CR are still unclear (11,18), so subsequent curative treatment strategies need to be established. Xu et al (25) found that repeated esophageal ESD provides an alternative choice for recurrent superficial ESCC but did not assess early repeated ESD immediately following non-CR (confirmed pathologically). The focus of the present study was to propose treatment strategies for patients with only LM+ following non-CR.
Previous studies have shown that, when considering the age and complications (diabetes, cardiovascular and cerebrovascular diseases) of patients, additional ER is an option for patients with non-CR, as the overall survival rate and incidence of adverse events of these patients are not significantly different from those of patients undergoing surgery (26,27). Toya et al (28) recommended close follow-up as an alternative to surgery as there was no difference in the cancer-specific survival rate between the patients in these two groups (close follow-up or surgery) of their study. Additional surgical treatment after non-CR considering patient age and complications is controversial (27). Similarly, the present study found that older patients were more likely to choose re-ER as subsequent therapy. Due to perioperative risks and/or short life expectancy, old age is an important reason for forgoing additional surgery following non-CR (29–31). The aforementioned studies suggested that older patients choose conservative treatment over surgical treatment.
In the research of gastric cancer, certain scholars have found that the poorer the differentiation type, the more directions of invasion the tumor has and the total length of LM affected by the tumor is significantly associated with a non-CR of residual tumor caused by LM+ (32–35). Similarly, in the present study, in patients with non-CR of ESCC, residual cancer was more common when there was a poorly differentiated histology and multiple LM+.
Certain studies have shown that patients with ESCC and deep mucosal infiltration (pT1a-m3), submucosal involvement (pT1b-m1-3) or LVI are considered to be at high risk of LNM and esophagectomy and lymph node dissection are recommended (36,37). However, in other studies, the incidence of LNM in esophageal resection specimens is 0–30%, the perioperative mortality rate is 0–14% and the incidence of serious complications is 26–43% (13,38–43). These findings are consistent with the results of the present study. In the present study, three patients who underwent additional surgery (3/13, 23.1%) had serious complications. Therefore, the present results do not support recommendations for additional surgery.
In addition, three patients (3/13, 23.1%) had LNM. Searching for accurate risk factors for LNM will help to determine whether additional surgical treatment is needed. Previous studies have shown that surgery is not the best option for patients with early esophageal cancer whose ER is non-curative (44,45). Most notably, esophagectomy with lymphadenectomy cannot prevent tumor recurrence and the 5-year survival rate of T1N1 esophageal cancer following esophagectomy is <40% (46,47). Therefore, organ preservation strategy in the management of patients with early esophageal cancer has been implemented in daily clinical practice when patients refuse or are not suitable for surgery, but evaluation of whether other alternatives can bring greater benefits is needed. The positive margin may serve a role in patient prognosis (22) but a more detailed prognostic analysis needs to be confirmed by a multicenter study with long-term follow-up.
The present study investigated the optimal treatment strategy of only LM+ ESCC with non-curative ER. Younger patients with multiple LM+ and poorly differentiated histological lesions often chose additional surgical treatment. By contrast, older patients with single LM+ involvement and well-differentiated lesions were more likely to receive re-ER. There was no recurrence or metastasis in patients who received re-ER during the limited follow-up period (36.1±24.1 months) of the study. These results suggested that additional endoscopic treatment for patients with only LM+ following ER may be sufficient to remove residual tumors. Although some scholars have suggested that ER combined with radiotherapy and chemotherapy may be effective (48,49), the present study did not include patients who had received radiotherapy and chemotherapy so similar conclusions cannot be made.
The present study had certain limitations. Firstly, it was retrospective and single center, the number of cases was small and other endoscopic treatments (such as argon plasma coagulation and laser, photodynamic and microwave coagulation therapy) were not involved. Further studies on endoscopic treatment is required to conclude whether ER is useful. Secondly, the follow-up time was short, which may lead to bias in judging recurrence and metastasis of these patients. A multicenter long follow-up study is needed to verify the results of the present study. Thirdly, additional surgery was performed more often in patients with poor prognosis and/or multiple LM+, thereby potentially affecting the results.
In conclusion, re-ER may be adequate for patients with only LM+ and non-curative ER, especially older patients and those for whom surgical treatment is not recommended. This strategy is feasible, at least in the medium-term. Further studies, including large-scale, population-based, multicenter and prospective studies, should be conducted to evaluate additional endoscopic treatment strategies for patients with LM+ early ESCC after non-curative ER.