In signet ring cells, a large amount of mucin accumulates in the cytoplasm, pushing the nucleus to one side, thus giving the cell its characteristic ring shape. Generally, when more than half of the tumor cells are signet ring cells, the tumor is classified as signet ring cell carcinoma (SRCC) [2]. According to WHO standards [23], SRCC is a subtype of adenocarcinoma but differs significantly from conventional gastrointestinal adenocarcinoma in terms of clinical characteristics and prognosis [11]. In this study, we collected data from the SEER database on patients diagnosed with gastric or colorectal SRCC from 2004 to 2020. After propensity score matching between the GC and CRC groups, the differences between the two groups were not statistically significant. We then conducted LASSO regression analysis on both groups to identify independent predictive factors for SRCC metastasis. Using these independent predictors, we constructed nomogram-based prediction models, which were validated with internal cohort. Additionally, univariate and multivariate Cox regression analyses were used to identify independent risk factors for the prognosis of SRCC patients with metastasis, and stratified risk prediction models were developed and validated using the internal cohort. The discriminative ability of the models was assessed by the area under the ROC curve, and the performance of the models was evaluated using calibration curves and decision curves. The results indicated that the models' predictions were largely consistent with the actual outcomes, demonstrating good discriminative ability.

SRCC can occur in various malignancies, including breast cancer [36], bladder cancer [19], gallbladder cancer [24], and esophageal cancer [4], but its incidence is relatively low [2]. Compared to other histological types of gastric cancer, gastric SRCC is more common in females and affects younger individuals [5]. When confined to the mucosa or submucosa, its prognosis is relatively better than that of conventional adenocarcinoma. However, as it invades the gastric wall, its aggressiveness increases, along with the rates of lymph node and peritoneal metastasis. Additionally, once gastric SRCC metastasizes, the prognosis is poorer than that of other histological types of gastric cancer, regardless of the treatment method used [8]. Colorectal SRCC is less common than gastric SRCC, accounting for ~ 1% of all pathological types of colorectal cancer [2]. Also, studies indicate that married individuals tend to have better health outcomes compared to their unmarried counterparts. Specifically, in colorectal cancer cases, married individuals often exhibit better survival rates than those who are single, divorced, or widowed [9, 27]. The reason may be that married individuals may have better social support, and more likely to engage in preventive health measures. Besides, race and ethnicity significantly impact the incidence and outcomes of colorectal and gastric cancers. A study indicated that the black individuals have higher incidence rates of CRC compared to white individuals [17]. Similar differences are also observed in gastric cancer, where certain ethnic groups are at higher risk. For instance, Asian populations have been reported to have higher rates of gastric cancer compared to other racial groups in some regions [32]. Colorectal SRCC tends to be diagnosed at an earlier age compared to other pathological types of colorectal cancer [14], with an equal incidence in males and females. Tumors are often larger and more advanced at the time of diagnosis [2]. This finding is consistent with the results of our study. After the PSM of two cohorts, our research finds that the colorectal SRCC often has more advanced grade, but has older age compare to gastric SRCC. However, there was no significance for gender, marital status, tumor size, T-stage, N-stage。

The clinical characteristics and prognosis of signet ring cell carcinoma (SRCC) differ significantly from those of non-signet ring cell carcinoma. Hugen et al. [15] reported that in the colorectum, SRCC is more prone to distant metastasis to multiple organs compared to adenocarcinoma. Additionally, SRCC is more likely to metastasize to lymph nodes than mucinous adenocarcinoma and conventional adenocarcinoma. As our study found, the AJCC N stage is one of the independent predictive factors for metastasis in colorectal cancer. The mechanism underlying the increased propensity for distant metastasis in SRCC is not yet clear, but some studies Sung et al. [29] have observed that SRCC often appears as isolated cells or loose clusters under the microscope, possibly due to the loose intercellular connections that contribute to its metastatic characteristics. Signet ring cell carcinoma may be associated with genetic mutations in the CDH1 gene, which plays a crucial role in maintaining the integrity of E-cadherin [25]. Mutations in this gene lead to a loss of cohesion in the epithelial lining of transformed cells, thereby increasing the likelihood of early metastasis. At present, three biomarkers with therapeutic relevance are routinely assessed in adenocarcinoma: HER2 expression, PD-L1 expression, and deficient mismatch repair [6]. Other molecular signatures of SRCC include a higher frequency of BRAF mutations and the CpG island methylator phenotype (CIMP), reduced expression of p16 and p53, and a lower prevalence of KRAS and NRAS mutations [10]. After metastasis, SRCC progresses rapidly, necessitating adjustments in treatment plans, such as changing chemotherapy drugs or implementing neoadjuvant therapy. Therefore, early detection of metastasis is crucial. To date, no predictive model for metastasis in colorectal SRCC has been established. For gastric SRCC, only models predicting lymph node metastasis in early gastric cancer are available. You et al. [34] identified tumor size and lymphatic invasion as independent risk factors for lymph node metastasis in early gastric SRCC (AUC = 0.757, 95% CI 0.687–0.828). Other factors associated with lymph node metastasis in early gastric SRCC include tumor size, depth of invasion, lymphatic invasion, E-cadherin expression, positive mismatch repair function deficit, CA242, neutrophil to lymphocyte ratio, and macroscopic pathological type. Yang et al. [33] reported that gender, tumor size, depth of invasion, lymphatic invasion, ulceration, and immunological subtype are independent risk factors for lymph node metastasis (AUC = 0.734, 95%CI 0.643–0.826). In our study, we integrated comprehensive clinical information from a large sample in the SEER database, comparing patients with gastric and colorectal SRCC. We found that most SRCC patients had already developed metastasis at the time of tumor detection. We identified two independent risk predictors of metastasis in GC patients: age and high T stage, and three independent risk predictors in CRC patients: age, high T stage, and high N stage. These findings are consistent with previous reports. Using these independent risk predictors, we constructed predictive models via nomograms, evaluated by ROC curves, calibration curves, and DCA, demonstrating the models' good performance. This provides a valuable reference for clinicians to identify the risk of metastasis early.

Currently, there is no unified consensus on the treatment of signet ring cell carcinoma (SRCC). Most gastric SRCCs exhibit a double-layer structure (DLS), where the microscopic structure consists of two layers: the upper layer contains abundant mucin and an eccentric nucleus, while the lower layer contains small amounts of mucin and eosinophilic substances. This double-layer structure acts as a protective factor, preventing tumor invasion into lymph nodes [30]. For tumors staged as T1a, with a size ≤ 2 cm and low risk of lymph node metastasis, endoscopic submucosal dissection (ESD) can be performed [18]. Moreover, even if the above conditions are not met, if the double-layer structure is observed in ESD specimens, further surgical treatment may not be necessary [22]. However, Wang et al. [31] reported that approximately 10.3% of gastric SRCCs had lymph node metastasis, which determines whether endoscopic treatment or surgical treatment is appropriate. Surgical options include extended margin resection with D2 lymph node dissection. Despite extended margin resection, the rate of positive margins remains high. Consequently, the overall survival of gastric SRCC patients after surgical resection is lower than that of non-SRCC patients, primarily due to the higher propensity for peritoneal and lymph node metastasis and earlier recurrence in SRCC [26]. Nonetheless, surgery remains the mainstay treatment for gastric SRCC. Colorectal SRCC is relatively less common than gastric SRCC, and there are currently no large-scale clinical trials specifically targeting colorectal SRCC. However, the NCCN guidelines indicate that for stage I, II, and III colorectal cancer, surgery is the primary treatment [3]. Our study also found that surgery is associated with the prognosis of SRCC patients, and surgical treatment can improve patient survival expectations.

For advanced gastric or colorectal signet ring cell carcinoma (SRCC), the prevailing view is that these tumors are generally resistant to chemotherapy and associated with poor prognosis. Some studies have suggested that neoadjuvant chemotherapy may worsen tumor progression and prognosis due to the cytotoxicity of the chemotherapy drugs [21]. However, other studies [12] have indicated that neoadjuvant chemotherapy can benefit overall survival. Our study found that perioperative chemotherapy is beneficial for patient survival, although the indications for perioperative chemotherapy require further clarification through additional clinical trials. For patients with unresectable gastric SRCC, the docetaxel-5FU-oxaliplatin (TEFOX) regimen can be used as first-line treatment. Our study also showed that chemotherapy is an independent prognostic factor for metastatic gastric SRCC patients. Therefore, we believe that effective chemotherapy regimens could significantly improve survival rates for SRCC patients.

Our study has several strengths. We utilized a large patient population from a nationwide database in the United States, avoiding biases associated with single-institution records or limited sample sizes, thereby ensuring the validity of our models. Additionally, we employed the propensity score matching (PSM) method to eliminate the interference of disease differences in the results. However, this study also has some potential limitations. First, as a retrospective study, it is susceptible to inaccuracies. Second, the SEER database lacks precise details on treatment methods, including specific surgical procedures and chemotherapy or radiotherapy regimens. Third, the limited number of patients included in this study might introduce some bias in the results.