Patient selection and PSM results
Between 2013 and 2019, among the patients treated at the Gastrointestinal Cancer Center of Peking University Cancer Hospital, a total of 180 patients with gastric neoplasms containing NEC components met the inclusion criteria for the study, including 55 cases of pure NEC and 125 cases of mixed-type. Of these patients, a total of 65 patients received neoadjuvant therapy (NEC: 27, >70% G-HMiNEN: 5, G-HMiNEN: 19, <30% G-HMiNEN: 12), while the remaining 117 patients received surgery directly (NEC: 28, >70% G-HMiNEN: 8, G-HMiNEN: 43, <30% G-HMiNEN: 38). There were an insufficient number of patients in group >70% G-HMiNEN group to conduct effective statistical analysis, so we combined the >70% G-HMiNEN group with the NEC group for further analysis. We also randomly selected 785 patients with gastric adenocarcinoma who underwent radical surgery. Among them, 477 patients received neoadjuvant therapy, and the remaining 308 patients were treated with surgery directly (Figure 1).
Immunohistochemical specificity markers were utilized to identify the neuroendocrine components (Figure 2a). Syn was expressed in almost all neoplasms containing NEC components (98.3%), while the positive rates of CgA and CD56 were much lower (62.8% and 66.7%, respectively). No significant difference in the positive rate of Syn and CgA was observed between pure NEC, >70% G-HMiNEN, G-HMiNEN, and <30% G-HMiNEN (Figure 2b, 2c), only the positive rate of CD56 was found to be higher in the pure NEC group than that in the <30% G-HMiNEN group (Figure 2d).
Therefore, prior to OS comparison, PSM was performed to ensure that there were no significant differences in patient gender, age, tumor location, tumor size, pathological staging, and adjuvant chemotherapy between the two groups.
Comparison of OS between all patients with NEC components and patients with gastric adenocarcinoma in the surgical group and neoadjuvant group
Before PSM, we compared the survival curves between all patients with NEC components and patients with gastric adenocarcinoma by the Kaplan-Meier method (Figure 3). Apparently, patients with NEC components had a poorer OS than those with gastric adenocarcinoma (Figure 3a, p < 0.0001) in the surgical group. In contrast, no significant difference was observed between the patients receiving neoadjuvant therapy (Figure 3b, p = 0.1467). According to the proportion of NEC components, patients were classified into pure NEC, >70% G-HMiNEN, G-HMiNEN, and <30% G-HMiNEN. The OS was also compared between patients with adenocarcinoma and these groups, and the results were similar to the overall comparison (Figure 3c, 3d).
Before PSM, significant differences between the baseline characteristics were observed in the surgical group and the neoadjuvant group (Table 1& Table 2). To balance the clinicopathological differences between the two groups, PSM was performed to ensure that there were no significant differences in patient gender, age, tumor location, tumor size, pathological staging, and adjuvant chemotherapy between the two groups. The detailed clinicopathological characteristics before and after PSM are shown in Table 1 and Table 2.
As a result, 88 patients with NEC components and 128 patients with gastric adenocarcinoma were matched in the surgical group (Table 1). Patients with NEC components also had a poorer OS than those with gastric adenocarcinoma (Figure 3e, p=0.0133). Multivariable analysis showed that adjuvant therapy, tumor category, and TNM stage were independent prognostic factors (Table 3).
To investigate whether neoadjuvant therapy had an effect on OS, 60 patients with NEC components and 120 patients with gastric adenocarcinoma were matched in the neoadjuvant group (Table 2). Interestingly, Kaplan-Meier analysis showed that among patients receiving neoadjuvant therapy, there was still no significant difference in OS between the two groups (Figure 3f, p=0.3140).
Comparison of OS between patients with different proportions of NEC components and patients with gastric adenocarcinoma
To investigate whether the level of NEC components had an effect on OS in the surgical group, <30% G-HMiNEN, G-HMiNEN, pure NEC, and pure NEC plus >70% G-HMiNEN were compared with gastric adenocarcinoma after PSM. The results showed that even the group with the lowest proportion of NEC components, the <30% G-HMiNEN group, had a poorer OS than adenocarcinoma (Figure 4a, P = 0.0130). As expected, the G-HMiNEN, pure NEC, and pure NEC plus >70% G-HMiNEN groups, each with relatively high proportions of NEC components, had worse OS than the gastric adenocarcinoma group (Figure 4b-d, P = 0.0271, 0.0174, 0.0310). Detailed clinical information after matching is shown in Supplement Tables 1-4.
PSM was also performed in the neoadjuvant group. In contrast to the results of the surgery group, in the pure NEC group (containing the highest proportion of NEC component), there was still no significant difference in OS from gastric adenocarcinoma. The other three groups with lower NEC content were also not significantly different from gastric adenocarcinoma in terms of OS. Detailed clinicopathological characteristics before and after PSM are shown in Supplement Tables 5-8.