The clinical outcomes of endoscopic submucosal dissection (ESD) for undifferentiated (UD) intramucosal early gastric cancer (EGC) compared with those of surgery, regardless of lesion size, are not well known. Furthermore, there is a concern regarding the treatment plan before and after ESD in cases of UD intramucosal EGC within expanded indications.

To evaluate clinical outcomes of ESD compared with those of surgery in UD intramucosal EGC patients regardless of tumor size.

We enrolled patients with UD intramucosal EGC after ESD with complete resection or surgery from January 2005 to August 2020 who met the within or beyond expanded indications with lesion size > 2 cm (the only non-curative factor). Overall, 123 and 562 patients underwent ESD and surgery, respectively. After propensity-score matching, clinical and long-term outcomes, i.e., recurrence-free survival (RFS) and overall survival (OS), were analyzed. The multivariable Cox proportional hazard model with treatment modality and ESD indication was used to evaluate the recurrence risk.

After matching, 119 patients each were finally enrolled in the ESD and surgery groups. The median length of hospital stay was shorter in the ESD group than surgery group (4.0 vs 9.0 days, P < 0.001). Four cases of recurrence after ESD were local recurrences, all of which occurred within 1 year. Total recurrence was seven (5.9%) and two (1.7%) in the ESD and surgery groups, respectively. No difference was observed between the two groups with respect to OS (P = 0.948). However, the ESD group had inferior RFS compared with the surgery group (P = 0.031). ESD was associated with the risk of recurrence after initial treatment in all enrolled patients (hazard ratio, 5.2; 95% confidence interval: 1.0-25.8, P = 0.045).

Although OS was similar between the two groups, surveillance endoscopy was important for the ESD than for the surgery group because RFS was inferior and local recurrence was an issue.

Endoscopic submucosal dissection (ESD) is recommended as a treatment modality for early gastric cancer (EGC) because it allows curative en bloc resection and complete histopathological evaluation[1,2]. With the development of endoscopic instruments and techniques, the indication for ESD has expanded, and short- and long-term outcomes of ESD have been favorably reported in various studies[3-8]. Accordingly, ESD can be performed for patients with undifferentiated (UD) intramucosal EGC without lymphovascular invasion when the lesion size is ≤ 2 cm and there is no ulceration. Compared with surgery, ESD may be an alternative treatment option for UD intramucosal EGC within expanded indications[9-12]; however, concerns regarding lymph node (LN) metastasis in patients with UD intramucosal EGC remain[12].

Even if UD intramucosal EGC meets the criteria of expanded indications, additional surgical treatment is recommended if the lesion size alone is a non-curative factor (lesion diameter > 2 cm)[2]. In this case, physicians are concerned about determining the appropriate treatment modality and whether additional treatment should be performed. Various risk factors for LN metastasis have been reported in several surgical reports based on a lesion size of 2 cm[13-16]. Therefore, the role of ESD is limited in patients with UD intramucosal EGC because of the lesion size. However, patients may choose ESD for several reasons such as refusal of surgical treatment or older age. A recent multicenter study reported that mortality was not significantly higher in patients who underwent endoscopic resection for UD intramucosal EGC with tumor size > 2 cm as the only non-curative factor than in those who underwent additional surgery[17].

Compared with surgery, ESD can reduce the period of hospital stay after treatment and improve quality of life. To date, no study has compared long-term outcomes between ESD and surgical treatment based on propensity-score matching in patients with UD intramucosal EGC who are within or beyond expanded indications but satisfy the criteria of curative resection except for lesion size. Thus, this study aimed to evaluate the clinical outcomes and adverse events of ESD compared with those of surgery in patients with UD intramucosal EGC using propensity-score matching analysis. Furthermore, we compared long-term clinical outcomes of ESD and surgery after matching for patients with UD intramucosal EGC who are beyond the expanded indication but meet the criteria of curative resection, except for lesion sizes > 2 cm.

We comparatively analyzed the long-term outcomes of patients who underwent ESD and surgery for UD intramucosal EGC with complete resection regardless of lesion size using propensity score-matched analysis. ESD was similar to surgery in terms of OS; however, RFS in the ESD group was lower than that in the surgery group. In both the groups, LN metastasis was absent during the follow-up period, and only one case of distant metastasis was observed in the surgery group. ESD was advantageous because of shorter hospital stays and fewer late complications compared with surgery. Although complete resection was performed for patients with UD intramucosal EGC, ESD was identified as a recurrence risk factor in terms of treatment modality compared with surgery. In patients with lesion size > 2 cm as the only non-curative factor, there was a difference in RFS depending on the treatment modality, with ESD having an inferior outcome.

In our study, there was a clear bias in the patient population depending on treatment modality. Before matching, patients in the ESD group were older and had a higher ASA physical status score, fewer lesions located in the upper third of the stomach, and lower signet ring cell carcinoma rate than those in the surgery group. While the expanded indication proposed by Gotoda et al[19] is based on the pathology of specimens, clinicians should select the treatment modality for EGC based on gross and pathological findings. However, this method sometimes makes it difficult to determine a treatment modality in clinical practice. Besides, there are cases in which patients beyond the expanded indication of ESD refuse surgery and thus undergo ESD in hopes of endoscopic resection instead of surgery. In contrast, there are a significant number of patients who meet the expanded indications and undergo surgery. As a result, patients and lesion characteristics are not the same between patients who undergo ESD and those who undergo surgery. Our results suggested that patients were hesitant to undergo surgery if they were older or if their ASA physical status score was high. For this reason, selection bias was inevitable in this study group. Therefore, we performed propensity-score matching analysis to reduce selection bias owing to treatment modality.

With the development of ESD techniques and instruments and the accumulation of various clinical outcomes, the scope of ESD has been gradually expanding. However, issues regarding the role of ESD in patients with UD intramucosal EGC are continuously raised. Currently, the ESD criteria for UD intramucosal EGC are strict. ESD is performed only when the lesion has no ulceration and is ≤ 2 cm and when it satisfies the complete resection conditions of negative resection margins and the absence of lymphovascular and perineural invasion in the final pathological examination[2]. Lesion size > 2 cm is a non-curative factor, and various studies have reported a difference in LN metastasis based on lesion size of 2 cm[13,14,15,20]. However, in cases of UD-EGC with a lesion size > 2 cm, LN metastasis was reported to be 0% (0/54) when neither ulceration nor lymphovascular invasion was present[16], all of which were from surgical studies. To our knowledge, only one study analyzed LN metastasis in patients who underwent endoscopic resection for UD intramucosal EGC with lesion size > 2 cm. Yang et al[17] reported an incidence of 1.1% (2/176), which showed no increase in mortality during observation after ESD based on Cox regression analysis. Similar results were also obtained in our study. LN metastasis was not observed among 119 patients who underwent ESD. However, 71.4% (5/7) of the total recurrence cases had a lesion size > 2 cm, which revealed a higher recurrence rate than that in patients with a lesion size ≤ 2 cm (11.9% vs 2.6%). Furthermore, patients with lesion size > 2 cm in the ESD group had a lower RFS than those in the surgery group.

The results of our analysis after matching for UD intramucosal EGC patients with complete resection, irrespective of lesion size, showed that RFS was inferior in the ESD group compared with the surgery group. However, no LN metastasis or distant metastasis was identified during the follow-up period. In other words, all recurrence cases occurred in the stomach, all were treated successfully after recurrence, and no further recurrences occurred during the follow-up period. However, taking ESD into account over surgery as the preferred treatment for UD intramucosal EGC irrespective of lesion size should be carefully considered. LN metastasis was not observed; however, local recurrence was found in four patients (4/119, 3.4%), all of whom had an initial tumor size > 2 cm that occurred less than a year after initial treatment, and surgery as a rescue treatment was performed because endoscopic treatment was impossible. In the study by Yang et al[17], the local recurrence rate was 2.3% (4/176), and one case had LN metastasis. Therefore, ESD must overcome the problem of local recurrence, which does not need to be considered in surgery. Furthermore, we should consider the why local recurrence occurs even after complete resection. The initial pathologic evaluation could have been incorrect or a new cancer may have occurred. We repeated the pathologic evaluation for these cases; however, the initial diagnosis did not change. Additional studies and data accumulation are required to examine why local recurrence occurs within a short period, although complete or curative resection is performed after the initial pathologic evaluation. In this study, in the 212 patients considered, the margin negative resection rate in the ESD group before matching was 92.0% (195/212). This was similar to previous studies where endoscopic resection was performed in UD EGC[21-26].

Therapeutic endoscopists always consider that a sufficient lateral margin can reduce the possibility of local recurrence. While it would be best to secure as much safety margin as possible, the operator should consider the duration of intervention, acute complications (bleeding or perforation), or delayed complications (bleeding, stricture). These considerations may be more prominent in UD EGC. A recently published study mentioned that local recurrence may be related to sequential molecular changes in various cancer-related proteins in histological margin-free endoscopically resected EGCs[27]. In this study, a tumor-free distance of 5.5 mm was considered insufficient as a safety margin. Besides, a subepithelial spread beneath the normal mucosa may exist in UD EGC, especially in signet ring cell cancer, and this subepithelial spread could reach up to 6 mm[28]. These studies suggest that securing sufficient margin in the endoscopic resection of UD EGC using the ESD method might reduce the rate of local recurrence. In the endoscopic resection of UD EGC using the ESD method, the endoscopically predicted and the actual size of the lesion is often different. In the Japanese algorithm, an additional biopsy was recommended from the surrounding mucosa of UD EGC to accurately evaluate the margin of the lesion[29]. In addition, other studies have reported that narrow-band imaging with magnifying endoscopy may help in accurately predicting the tumor extent in UD EGC[30]. Prospective randomized studies are required to evaluate whether the various attempts to accurately determine the tumor margin and resection with sufficient margin can reduce the rate of local recurrence.

In our study, all recurrence cases in the ESD group occurred in the lower or middle third of the stomach, except for one case (6/7, 85.7%). Although it is difficult to judge because of only a small number of recurrence cases, there is a report that incidence increased in the middle and lower third of the stomach in metachronous cancer after ESD[31]. This may be why fewer synchronous or metachronous recurrences were observed in the surgery group. In our study, 16.8% of patients underwent total gastrectomy after matching (20/119). Since the portion of the remnant stomach is small, even in patients who have undergone subtotal gastrectomy, surgery can be advantageous in terms of recurrence. In our study, only one recurrence occurred in the upper third of the stomach in the ESD and surgery groups. It is challenging to select ESD as the initial treatment option if surgical treatment is performed as a rescue treatment in a short period, given that ESD has a probability of local recurrence. Therefore, our results suggest that ESD should not be actively recommended to patients with UD intramucosal EGC with lesion size > 2 cm even without ulceration on preoperative workup.

This study had some limitations. First, this was a retrospective single-center study. A randomized study is required to compare long-term outcomes of ESD and surgery, but this is difficult to perform for UD intramucosal EGC. Second, baseline characteristics and tumor information were different between the groups; however, we analyzed the data after propensity-score matching to minimize the difference between baseline characteristics and reduce selection bias of treatment modality. Third, the number of patients with UD intramucosal EGC with lesion size > 2 cm was significantly lower in the pre-matching ESD group than in the surgery group (43 vs 233 patients). Although the data were corrected as much as possible with propensity-score matching, most ESD patients were assigned after matching; thus, selection bias could exist. Finally, although we confirmed survival based on data from the National Cancer Center registry, we did not check the cause of the death in all patients who died. Therefore, we did not evaluate gastric cancer-related deaths in both groups after follow-up loss.

In conclusion, ESD is a treatment modality for stomach preservation with fewer late complications and shorter hospital stays than surgery. For patients with UD intramucosal EGC, if the lesion size is the only non-curative factor, ESD may be an alternative treatment option when surgery is not possible. However, all cases of local recurrence were identified within 1 year in our study, all of which were cancer, although LN metastasis was not observed after ESD. Therefore, even for complete resection, endoscopic surveillance is essential. Especially in cases with lesion sizes > 2 cm, endoscopic surveillance should be more thoroughly performed.

We would like to thank Cho W, Medical Information & Media Center, Ajou University School of Medicine for providing editing services for images and illustrations.