According to the latest global cancer burden data (Globocan 2020), the number of new cases of gastric cancer worldwide is 1,089,000, which ranks fifth among all malignancies, while the number of deaths is 768,000, which ranks third (1). With advances in the standard treatment of Helicobacter pylori (HP) infection, the overall incidence of gastric cancer has decreased (2). However, the incidence of gastric signet ring cell carcinoma (SRCC) continues to increase every year (3). SRCC is a histological subtype of gastric cancer defined by the presence of mucinous cells, which account for more than 50% of the tumor volume and extrude into the cellular ridges. This subtype is generally considered to have a poor prognosis (4). Clinically, SRCC is most prevalent in young women and has a high incidence of distant metastasis, which results in an unfavorable prognosis. SRCC typically demonstrates more aggressive biological behavior than other subtypes (non-SRCC) such as adenocarcinoma (5, 6). The prognosis of SRCC remains controversial in the literature. Several studies have indicated that patients diagnosed with SRCC tend to have a relatively favorable prognosis in the early stages but a poorer prognosis in the late stages compared with patients with other histological subtypes (7–9). However, several Western studies have analyzed SRCC versus non-SRCC, but the preliminary conclusions are not consistent with those of Eastern countries (10, 11). A literature review revealed that several factors, including age, tumor size, tumor-node-metastasis (TNM) stage, epidermal growth factor receptor (EGFR) status, surgical approach, radiation therapy, and chemotherapy, can influence the prognosis of SRCC patients (11–18). Therefore, it is crucial to investigate the prognostic differences and influencing factors associated with SRCC to enhance diagnostic and prognostic accuracy.

The poor prognosis of SRCC patients is attributable to a low rate of curative resection and a poor response to radiotherapy. Furthermore, the low expression of human epidermal growth factor receptor-2 (HER-2) in these patients limits the efficacy of targeted therapy for the treatment of SRCC (19, 20). The National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) do not recommend any specific treatment for SRCC in their respective clinical practice guidelines. Consequently, the development of a unique multimodal treatment regimen for SRCC is urgently needed. In clinical practice, the American Joint Committee on Cancer (AJCC) staging system has a significant impact on prognosis and serves as a key tool for clinicians in developing and implementing treatment strategies. In an era characterized by an abundance of data, data mining techniques offer an opportunity to extract potentially valuable insights from diverse sources of information. Nomograms have become common tools for assessing the prognosis of cancer patients and for personal prediction of patient survival. Nomograms have been shown to be a more appropriate clinical tool for patient management than the AJCC staging system. Prior nomograms for SRCC have made significant explorations of prognostic factors; nevertheless, either the treatment data have not been fully incorporated or the nomograms have not been fully used for the purpose of determining risk and guiding treatment strategies, thereby limiting the clinical utility of these nomograms (16, 21–30).

In this study, a nomogram was established and validated for overall survival (OS) and cancer specific survival (CSS) in SRCC patients based on important prognostic factors with publicly available data from the Surveillance, Epidemiology, and End Results (SEER) database. In addition, the concordance index (C-index), calibration plots, and decision curve analysis (DCA) were used to assess the discriminatory power and clinical utility of the nomogram. Furthermore, the nomogram was used to stratify risk and was combined with clinical treatment to predict survival and optimize the clinical management of SRCC patients.

In recent years, despite a decrease in the incidence of gastric cancer, the incidence of SRCC has increased (31). Increasing numbers of studies in Asian countries have demonstrated that the prognosis of SRCC is dependent on pathological grade and stage. These studies have shown that SRCC has a more favorable prognosis than non-SRCC in the early stages, whereas non-SRCC has a more favorable prognosis in the late stages (32–35). Nevertheless, some studies have failed to identify any significant differences between these two types of cancer (36). Regarding the diametrically opposed survival trends of SRCC in the early and late stages, some researchers have postulated that the early stage of SRCC is typified by a latent state with low invasiveness but that when tumor cells invade the muscularis propria, the tumor’s invasiveness increases and accelerates markedly, thereby increasing the risk of peritoneal metastasis (37, 38). Particularly, reduced expression of E-cadherin, which is encoded by the CDH1 gene, is associated with a lack of cell-to-cell adhesion and an elevated risk of metastasis (39–44). Given the distinct biological behaviors of SRCC in comparison to AC, and its limited clinical benefit in relation to conventional chemotherapy and targeted therapy, screening the population for potential immune benefit based on SRCC single-cell sequencing or genetic testing represents an effective strategy for harnessing the potential of immunotherapy (45, 46).

In all, 559 patients with SRCC from the SEER database were included in our study. More patients with SRCC had T4 stage, N2 stage, and stage III and IV disease, which is consistent with previous studies that have reported that SRCC is commonly diagnosed at an advanced stage. Our findings indicate that the clinical features of SRCC are distinct from those of AC. One notable difference is that, compared with AC, the age of onset of SRCC is significantly higher in individuals younger than 45 years. Additionally, a discrepancy was also noted in the gender distribution between the two cancer types. AC is typically regarded as a male-dominated cancer and accounts for approximately two-thirds of all gastric cancer cases, whereas in SRCC, approximately half of the patients are women. Previous research has indicated that younger women exhibit higher levels of estrogen receptors, which suggests that SRCC has a greater affinity for estrogen. Therefore, sex hormones are postulated to contribute to age and gender differences (47, 48).

The present study revealed that the median OS and median CSS rates of patients with SRCC were 22 months and 24 months, respectively. These rates are considerably shorter than those observed in patients diagnosed with AC, and these findings are consistent with those of previous studies. A noteworthy observation emerged from the analysis of the data on SRCC and AC following PSM. Despite the significant difference in the CSS between the two groups, the OS was not significantly different, although a difference of 11 months was observed in the median OS between the two cancers. This suggests that the shorter OS of SRCC patients before PSM may be attributed to inconsistencies in the baseline data. The relatively advanced stage of SRCC patients according to the pre-PSM baseline data may explain the poorer prognosis of these patients. To identify further potential prognostic factors, univariate and multivariate analyses were conducted, which revealed that T4 stage, N2-3 stage, metastasis, and no surgery were independent risk factors for SRCC.

Although SRCC is a highly aggressive disease, data suggest that early SRCC may be no more aggressive than early non-SRCC. Consequently, surgery remains the mainstay of treatment. Studies have shown that patients who undergo radical surgery have a better prognosis than those who undergo palliative surgery or no surgery (49, 50). Although this was an observational study, after using PSM to reduce bias, we found that surgical treatment improved OS and CSS in patients with SRCC. This suggests that surgery is the most effective treatment, at least for patients with early-stage SRCC without metastases. In addition, T stage and tumor size have been found to be independent predictors of lymph node metastasis in early SRCC, and as such, enzyme secretion detection (ESD) resection may be indicated for T1a tumors, as this approach can preserve organ function and is associated with a lower rate of cancer recurrence (22, 51, 52). Nevertheless, in patients with T1b tumors, the characteristics of signet ring cell carcinoma result in a high rate of lymph node spread, with a lymph node positivity rate exceeding 10%, even in tumors smaller than 1.0 cm. In such cases, surgery is a more thorough and advantageous treatment.

Landmark clinical trials on adjuvant treatment of gastric cancer (INT-0116 and MAGIC) revealed that chemotherapy (epirubicin, cisplatin and fluorouracil) in conjunction with surgery was associated with a superior prognosis compared with surgery alone (53–57). The efficacy of radiotherapy remains a matter of contention; the results of the ARTIST study indicated no discernible enhancement in the 5-year OS rate of gastric cancer (GC) patients undergoing adjuvant capecitabine/cisplatin chemotherapy in conjunction with radiotherapy following radical D2 surgery (58–62). A review of survival trends in patients with SRCC over the past decade has indicated an improvement in the 2-year relative survival. This improvement in survival may be attributed to the recent development of perioperative chemotherapy. A recent study demonstrated that patients with advanced SRCC treated with TEFOX chemotherapy had an OS rate of 65%, with a median survival of 14 months (63, 64). In contrast to other similar studies, our investigation concentrated on chemotherapy and surgical treatment, which are integral components of systemic therapy and are therefore more representative of medical reality. This study demonstrated that chemotherapy was not an independent protective factor. However, the combination of surgery and chemotherapy was found to be more efficacious than either treatment alone in patients at high risk and had significant prognostic implications.

The nomogram, which integrates multiple parameters to assess survival probability, is more precise than the current AJCC staging system and is therefore regarded as an alternative and even a novel staging system. Previous studies have demonstrated the prognostic value of nomograms in SRCC; however, those studies either did not incorporate treatment data or they failed to fully utilize the nomogram to assess risk and inform the choice of treatment (16, 28, 29, 65). In this study, we constructed a nomogram for predicting OS and CSS in SRCC patients based on T stage, N stage, M stage, and surgical modality. We then transformed the Cox regression results into visual graphs, which increased readability of the prediction model and facilitated the assessment of OS and CSS in SRCC patients. In recent studies, several SRCC prognostic nomograms have been developed (16, 52). In comparison, the nomogram developed in this study demonstrates superior prognostic prediction performance in both internal and external validations. Furthermore, the nomogram demonstrated greater accuracy in both the C-index and AIC than did the AJCC TNM staging system. Our nomogram also enables the identification of patients with varying risk profiles, facilitating the implementation of tailored treatment approaches for this tumor type, the incidence of which continues to increase. Considering these points, patients who might not benefit from treatment should be identified. Therefore, our study classified the benefits in terms of OS according to a nomogram and explored personalized treatment strategies for SRCC patients in different risk stratification groups from the perspective of prognostic benefit. In accordance with our findings based on the new risk stratification system, it is evident that in the high-risk group, patients who underwent surgery in combination with chemotherapy exhibited a significantly higher survival rate than those who were treated with either surgery alone or chemotherapy alone. However, for the low-risk group, no discernible difference was observed in survival outcomes between those who received combination chemotherapy and those who underwent surgery. Therefore, patients with SRCC in the low-risk group may undergo surgery alone, without the necessity of chemotherapy, whereas chemotherapy plus surgery might be a better approach for patients with SRCC in the high-risk group.

SRCC is malignant and prone to submucosal infiltration and lymph node metastasis, and clinical surgeons believe that total gastrectomy can improve patient prognosis by increasing the extent of resection. The results of our study indicated that total gastrectomy did not result in superior outcomes relative to partial gastrectomy in either the low- or high-risk groups. Intraoperative pathological examination of the surgical margins was found to be an effective method for reducing residual tumor and short-term recurrence. To avoid incomplete clearance of positive lymph nodes, membrane dissection-guided laparoscopic 4d, 5, 6, and 12a lymph node clearance was found to be a safe and feasible approach. Furthermore, proximal gastrectomy confers several advantages in terms of weight maintenance, postoperative anemia and nutrition (including vitamin B12, protein, albumin and cholesterol) (66).

Notably, this study is subject to several unavoidable limitations. First, the limited data in the SEER database to collect treatment-specific information such as the strategy, sequence, and dose of chemotherapy, and extent of radical lymphadenectomy dissection, which may limit the value of that can be derived from this comprehensive risk adjustment methodologies. In addition, the database also these factors may have a significant impact on patient prognosis. Second, the PSM analysis used in this study has limitations. Propensity scores do not easily satisfy equilibrium if the sample is small. Furthermore, it does not effectively deal with selectivity bias caused by unobservable or unobservable factors. Third, retrospective analyses are inevitably susceptible to selection bias and competing risks. Attempts have been made to minimize the effects of confounding factors through the use of statistical methods such as PSM analyses, multivariate analyses, and subgroup analyses. While these techniques are designed to control for bias, they are still unlikely to eliminate all errors. The establishment of a global SRCC database will allow for more comprehensive data and the development of appropriate treatment strategies.

In conclusion, we compared the differences in basic features and prognosis between patients with SRCC and those with AC and constructed and validated a nomogram of OS and CSS for SRCC, which was more accurate than the TNM staging system. Furthermore, a subgroup analysis according to risk stratification based on the nomogram can help clinicians personalize treatment for different subgroups of SRCC patients. The results of this study highlight the necessity for prospective clinical trials to clarify the appropriate treatment for this gastric cancer subtype. It is recommended that retrospective and prospective studies be conducted using the Global SRCC Database to obtain more comprehensive data and to develop appropriate treatment strategies.