A distinct form of colorectal cancer: signet ring cell carcinoma

Introduction

Globally, colorectal cancer (CRC) ranks fourth in incidence and second in mortality among all cancers (1). The global annual incidence is approximately 1.09 million cases, with a mortality of about 550,000 (2). Colorectal signet ring cell carcinoma (SRCC) represents a rare histologic subtype of CRC, accounting for approximately 1% of all cases (3). The entity was first described in the medical literature by Saphir and Laufman in 1951 (4). Owing to its rarity, many pathological aspects of SRCC have not been fully elucidated. The limited case volume also hampers comprehensive clinical investigation.

SRCC represents a distinct pathological entity with clinical and pathological profiles divergent from colorectal adenocarcinoma (COAD), SRCC has a worse survival prognosis, which may be attributed to some of its special features, including atypical symptoms and delayed clinical manifestations (5). Therefore, the study of the particular clinical features of SRCC should be paid more attention and go more in-depth. At present, some studies have explored the pathological characteristics of SRCC, but controversies still exist. Meanwhile, these studies have some non-negligible shortcomings, such as not excluding the effect of multiple tumors (6,7).

The Surveillance, Epidemiology, and End Results (SEER) program is a source for epidemiologic information on the incidence and survival rates of cancer in the United States (8). There is a certain degree of authority and authenticity of its data. Our study obtained a large number of data from SEER, analyzed the pathological characteristics of SRCC from different aspects, and analyzed the influence of some traditional pathological characteristics on survival outcomes. Despite its widespread application in prognostic evaluation for numerous cancers, the AJCC staging system exhibits a well-documented survival paradox in colon cancer (9-11). Therefore, our study fully and comprehensively analyzed the pathological features of SRCC patients, and on this basis, developed an effective nomogram for predicting the overall survival (OS). We present this article in accordance with the TRIPOD reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2429/rc).

Methods

Patient selection

Patients diagnosed as CRC by histopathology were screened for our research from the SEER database during 2013 to 2018. Among them, 66.3% of patients with adenocarcinoma (n=145,474), about 1% of patients with signet ring cell carcinoma (n=2,298), and about 32.7% of patients with other types of CRC (n=71,346). We excluded patients with unknown TNM stage and survival time. Even more strictly, we excluded patients with tumors of multiple origin. A total of 49,405 patients were included in the final analysis, with the cohort made up of 842 SRCC (ICD-O-3, 8490) and 48,563 COAD patients (Figure 1). This investigation was conducted in full compliance with the ethical standards set forth by the Declaration of Helsinki and its subsequent amendments.

Figure 1 Flowchart for creation of the SEER patient dataset. SEER, Surveillance, Epidemiology, and End Results; TNM, tumor-node-metastasis.

Statistical analysis

Analyses were performed using SPSS software (version 24.0, Chicago, USA) and R software (version 4.1.0). The best cut-off value of LNR (positive lymph node ratio) was determined by X-tile software (version 3.6.1, Yale University School of Medicine, US). χ² tests was performed to assess associations between patient groups (SRCC vs. COAD) and various prognostic factors, such as age, sex, race, tumor grade, TNM stage, metastatic sites, and treatment. To address the considerable difference in the number of SRCC and COAD patients, we conducted propensity score matching (PSM) to reduce possible selection bias. Matching was based on the following variables: age, sex, and race. Survival analyses for OS and cause-specific survival (CSS) were performed with the Kaplan-Meier method, and differences between groups were compared using the log-rank test. Forest plots were utilized to compare the impact of different treatment strategies. The identification of prognostic factors was performed via Cox proportional hazards regression, reporting hazard ratios (HRs) and 95% confidence intervals (CIs). Candidates identified in univariate analysis (P<0.05) were incorporated into the multivariable model. Statistical significance was defined as a two-sided P value <0.05, and factors that retained significance in either analysis were considered independent predictors.

Utilizing the identified high-risk factors, a prognostic nomogram was developed. The model’s performance was appraised through the concordance index (C-index) and visually represented with a calibration plot for a graphical comparison of predicted versus actual survival. Moreover, the prognostic power of the nomogram was benchmarked against the AJCC TNM staging system by comparing both receiver operating characteristic (ROC) curves and decision curve analysis (DCA). A two-sided alpha level of 0.05 was applied for all statistical tests to determine significance.

Results

Patient characteristics

A total of 49,405 patients were included for analysis, with 842 SRCC patients (1.7%) and 48,563 COAD patients (98.3%). Patients over 60 years old comprised the majority in both COAD (63.91%) and SRCC (55.59%) subtypes. In patients under 60 years old, SRCC (44.41%) was higher than COAD (36.09%), that indicated a higher incidence of SRCC in younger populations. SRCC tumors were markedly more poorly differentiated than COAD tumors (62.71% vs. 14.12%). Furthermore, advanced-stage disease was more prevalent in the SRCC cohort: 37.88% presented with AJCC stage III (vs. 31.35% for COAD) and 45.25% with stage IV (vs. 25.94%). Conversely, this aggressive profile was also reflected in a higher incidence of lymph node metastasis (N2: 38.84% vs. 15.15%) and distant metastasis (M1: 45.25% vs. 25.94%). In terms of treatment, SRCC received less surgery (75.30% vs. 81.35%) and radiotherapy (9.98% vs. 18.00%) than COAD, received more chemotherapy than COAD patients (61.52% vs. 50.25%). As for tumor location, they also showed some differences: SRCC was more common in the right colon (56.89% vs. 32.12%), while COAD was more common in the rectosigmoid (28.15% vs. 51.80%). Lastly, there was no difference in race, sex and marital status between COAD and SRCC (P>0.05) (Table 1). PSM was employed to mitigate potential confounding from the imbalanced sample sizes. The clinicopathological characteristics were subsequently analyzed and are presented in Table 1. The comparative results between SRCC and COAD remained robust after PSM. In light of the unique characteristics of SRCC, its specific prognostic factors—including patterns of organ metastasis, extent of lymph node metastasis, and efficacy of treatment strategies—merit further investigation.

Survival comparisons between SRCC patients and COAD patients after PSM

OS was calculated for both COAD and SRCC cohorts to compare prognosis. CSS was also determined to mitigate the potential confounding effect of deaths from other causes. Compared with COAD, the median survival time of patients with SRCC was significantly shorter (17 vs. 59 months). The 1-year survival rate of patients with COAD was 83.49%, the 3-year survival rate was 63.53%, and the 5-year survival rate was 46.9%. While the corresponding rate of patients with SRCC was only 57.83%, 30.99% and 5.9%, respectively. The OS and CSS survival curves between COAD and SRCC patients were shown in Figure 2A-2D, which suggested patients with SRCC exhibited a worse survival prognosis.

Figure 2 Survival comparisons. (A) OS among COAD and SRCC patients after PSM; (B) CSS among COAD and SRCC patients after PSM; (C) OS among COAD and SRCC patients with and without metastatic after PSM; (D) CSS among COAD and SRCC patients with and without metastatic after PSM. COAD, colorectal adenocarcinoma; CSS, cause-specific survival; OS, overall survival; PSM, propensity score matching; SRCC, colorectal signet ring cell carcinoma.

Metastasis comparisons between SRCC patients and COAD patients after PSM

Compared to COAD, SRCC patients presented more advanced M stage (45.25% vs. 25.94%) and more advanced N stage (38.84% vs. 15.15% in N2). Accordingly, our subsequent analysis focused on five potential sites of metastasis: distant lymph nodes, liver, bone, lung, and brain. Metastasis to the peritoneum was excluded from this analysis owing to insufficient data. Both bone and distant lymph node metastases were far more common in SRCC than in COAD patients. This difference was particularly pronounced for distant lymph node metastasis (63.7% vs. 47.6%; P<0.001), though also statistically significant for bone metastasis (3.3% vs. 3.1%; P=0.002). In contrast, SRCC patients with liver or lung metastases were significantly fewer than those with COAD (7.5% vs. 19.5%, P<0.001; 3.7% vs. 6.7%, P<0.001, respectively). No difference was observed in brain metastases because of the small number of cases. Detailed information was shown in Table 2.

Lymph node positive rate (LNR) grouping: a more optimized way to evaluate lymph node metastasis of SRCC

In SRCC patients, lymph node metastasis was higher than liver metastasis and lung metastasis, that may be closely related to poor prognosis. Our study calculated LNR (the number of positive lymph nodes divided by the total number of lymph nodes examined) for each patient. And we determined the best cut-off value of LNR for 0.23 and 0.69 by X-tile [no positive lymph node detection defined as negative; low positive group (LNR ≤0.23); middle positive group (0.23< LNR ≤0.69); high positive group (LNR >0.69)]. Figure 3A,3B showed the OS and CSS survival curves of SRCC patients with different LNR groups, suggesting that the more the LNR, the worse the survival prognosis (P<0.001). Then, receiver operating characteristic (ROC) analysis demonstrated a superior predictive ability for the lymph node ratio (LNR; AUC =0.780) over the AJCC N stage (AUC =0.648) (Figure 3C). The outcomes indicated that LNR had a better value than AJCC N stage.

Figure 3 Overall survival across LNR categories and the ROC curve of LNR. (A) CSS of different LNR grouping for SRCC; (B) OS of different LNR grouping for SRCC; (C) ROC of LNR and AJCC N stage. AJCC, American Joint Committee on Cancer; CSS, cause-specific survival; LNR, lymph node positive rate; N, node; OS, overall survival; ROC, receiver operating characteristic; SRCC, colorectal signet ring cell carcinoma.

The value of different treatment strategies for SRCC patients

The survival prognosis of SRCC patients is poor, and the selection of appropriate treatment strategies is particularly important to prolong the survival time. Our analysis found surgery combined with chemotherapy and radiotherapy was the best treatment for patients with SRCC (HR =0.113; 95% CI: 0.076–0.170; P<0.001), followed by surgery only (HR =0.147; 95% CI: 0.110–0.196; P<0.001), and chemotherapy only was the worst (HR =0.380; 95% CI: 0.281–0.514; P<0.001) (Figure 4A). Then, for SRCC patients with lymph node metastasis, surgery combined with chemotherapy and radiotherapy was still the best treatment (HR =0.125; 95% CI: 0.073–0.213; P<0.001), and chemotherapy only was the worst (HR =0.433; 95% CI: 0.251–0.749; P=0.003) (Figure 4B). For SRCC patients with organ metastasis, surgery combined with chemotherapy and radiotherapy was the best treatment (HR =0.168; 95% CI: 0.076–0.368; P<0.001), but surgery only was the worst (HR=0.432; 95% CI: 0.295–0.631; P<0.001) (Figure 4C). Radiotherapy alone was not included in the analysis due to few patients.

Figure 4 The value of different treatment strategies. (A) Prognostic analysis of different therapy for SRCC; (B) prognostic analysis of different therapy for SRCC patients with lymph metastasis; (C) prognostic analysis of different therapy for SRCC patients with organ metastasis. CI, confidence interval; SRCC, colorectal signet ring cell carcinoma.

LNR and treatment strategies were independent prognostic factors for OS in patients with SRCC

To examine factors associated with OS in patients with SRCC, we conducted univariate and multivariate Cox regression analysis. Univariate Cox regression analysis showed that age, tumor site, tumor size, tumor grade, AJCC stage, LNR, treatment, CEA, perineural invasion (PI), tumor deposits (TD), lymph node dissection was associated with OS (P values are all <0.05) (Table 3). After incorporating the above factors into the multivariate Cox regression analysis, we found that age, tumor site, tumor size, AJCC stage, LNR, treatment, CEA, PI were independent risk factors for OS.

Nomogram development and validation

Based on the above multivariate Cox regression analysis results, we included LNR and treatment strategies to construct OS nomogram (Figure 5). We found that AJCC stage contributed the most to survival outcomes, followed by treatment strategies and then LNR group. Internal validation was performed using 1,000 bootstrap resamples, assessed by the C-index and calibration plots. The nomogram for OS demonstrated good discriminative ability, yielding a C-index of 0.769 (95% CI: 0.760–0.778). Furthermore, the calibration curve demonstrated excellent agreement between the predicted and observed OS (Figure 6A-6C). Then, to further compare the nomogram with AJCC TNM stage, in ROC, nomogram (AUC =0.839) in OS showed a larger area than AJCC TNM stage (AUC =0.772) (Figure 6D); in DCA, nomogram in OS showed superior power than AJCC TNM stage (Figure 6E). In summary, the nomogram model showed better predictive ability and stability compared with AJCC TNM stage.

Figure 5 Nomogram predicting 1-, 3-, and 5-year OS rate of SRCC patients. CEA, carcinoembryonic antigen; LNR, lymph node positive rate; OS, overall survival; PI, perineural invasion; SRCC, colorectal signet ring cell carcinoma.

Figure 6 Nomogram validation. The calibration curve for predicting patient survival of (A) 1-, (B) 3- and (C) 5-year OS in the primary cohort after 1,000 bootstrap internal validation; (D) ROC comparison of OS nomogram and AJCC TNM stage; (E) DCA comparison of OS nomogram and AJCC TNM stage. AJCC, American Joint Committee on Cancer; DCA, decision curve analysis; OS, overall survival; ROC, receiver operating characteristic; TNM, tumor-node-metastasis.

Discussion

Epidemiologic data in the United States over the past three decades showed an overall decline in CRC incidence. From 1975 to 2010, the overall age-adjusted incidence of CRC demonstrated a significant downward trend, with an average annual percentage change (AAPC) of −0.92% (95% CI: −1.14 to −0.70). On the contrary, the proportion of young patients and the incidence of SRCC gradually increased (12). SRCC is defined as a pathological entity distinct from COAD, exhibiting a unique disease profile encompassing its clinical manifestations, pathological features and biological behavior.

Compared to COAD, we found a higher proportion of patients with SRCC in the population less than 60 years of age, indicated a higher incidence of SRCC in younger patients. This is consistent with the study of Benesch MGK et al., who found that SRCC had an earlier mean age of onset of 3.5 years (13). In terms of tumor location, SRCC was more prone to the right colon. Although rectal cancers account for 30% of all CRCs, rectal SRCC is relatively rare (14,15). This distribution difference is not fully explained at present, and the most convincing explanation is the embryological and genetic differences between the right and left colon (16). Then, Colorectal SRCC showed a higher risk biological behavior, compared with COAD, with worse tumor grade, more advanced AJCC stage and more metastasis (included lymph nodes and distant organs). This risky biological behavior may be directly related to its poor prognosis. Some studies suggested SRCC cells were mostly in the form of single cells or loose clusters, which led to a lack of intercellular adhesion, making it easier to spread (5,17). But that didn’t fully illuminate this high-risk biological behavior. In some research on molecular characteristics, it was found that the oncogenic and tumor suppressor genes and signaling pathways of SRCC were significantly different from COAD, which may be the key factor leading to its high-risk biological behavior. For example, as a tumor suppressor gene, SMAD4 could regulate tumor transcription and cell growth, and the loss of SMAD4 expression was closely related to chemotherapy resistance and poor prognosis. Deletion of the SMAD4 gene appeared to be more common in patients with SRCC than COAD (18,19). It is worth noting that SRCC patients had unique transfer mode. Patients with SRCC had more lymph node and bone metastases, while patients with COAD had more liver and lung metastases. It requires us to be more inclined to evaluate these specific sites of metastasis in the preoperative examination and the postoperative review. This was confirmed by the large-scale autopsy study of Hugen et al, which found that the most common metastatic sites in SRCC patients were the peritoneum and lymph nodes (20). But unfortunately, we haven’t obtained data of peritoneal metastasis.

Combined treatment mode is still preferred for SRCC patients. Surgical treatment combined with chemotherapy and radiotherapy is the most effective treatment for SRCC patients with or without lymph nodes and distant organ metastases. But individualized treatment is still a priority. A study conducted by Fu et al. found that SRCC patients might benefit little from the resection of primary and metastatic lesions with a high rate of undergoing invalid operations (21). In contrast, we found that surgical treatment still provided a survival benefit for SRCC patients. Compared with patients who received no treatment, surgery alone still showed an OS benefit (HR =0.147,9 5% CI: 0.110–0.196, P<0.001). A study including 1,675 patients with stage II/III colorectal SRCC showed that postoperative chemotherapy was an independent prognostic factor for better CSS and OS (CSS: HR =0.719, 95% CI: 0.612–0.844, P<0.001); (OS: HR =0.618, 95% CI: 0.537–0.713, P<0.001). It is consistent with our study: patients with SRCC can still derive survival benefit from chemotherapy even though they have a poor prognosis. Then, numerous studies have confirmed that SRCC patients with different molecular characteristics should be taken into account when being treated (19,22). Research on new drugs targeting different molecular characteristics is currently the most promising direction for the treatment of SRCC patients. Nevertheless, a key limitation of our study is the potential for selection bias, as patients in the combination therapy group inherently possessed better baseline health status, posing a challenge for interpreting the comparative outcomes.

Despite its ubiquitous role in prognosticating diverse malignancies, the AJCC staging system demonstrates a survival paradox in locally advanced colon cancer (9,10). SRCC patients have a greater proportion of advanced patients and a worse survival prognosis. Thus, the capabilities of AJCC staging system appear to be limited for SRCC patients. It is still necessary to develop a more comprehensive and accurate survival prediction system. Although many prognostic scoring systems have been developed, some still need improvement, including the optimization and simplification of scoring items and the improvement of prediction accuracy. Based on the above multivariate Cox regression analysis results, our research incorporated some new projects to develop the nomogram. As an optimized grouping of lymph node metastasis, LNR had more advantages in OS prognosis than AJCC N stage. In addition, we integrated different treatment strategies as the nomogram scoring project, which was second only to AJCC stage in its contribution. The nomogram model that we developed had high accuracy and consistency, and its ability was significantly better than AJCC TNM stage. Nevertheless, the findings presented here lack external validation, which limits the generalizability of our model. Consequently, performing such validation is a critical priority for our subsequent work.

Conclusions

In conclusion, as a rare but aggressive subtype of CRC, SRCC has distinct biological behavior, pathological features, and treatment responses. Compared with COAD, patients with SRCC exhibited advanced tumor stage, high tumor grade, high rate of lymph node involvement, abnormal distant metastasis, and a poorer survival prognosis. Comprehensive treatment including surgery, chemotherapy and radiotherapy is still the best treatment to improve the survival time of SRCC patients. Based on multivariate Cox regression analysis, absorbed LNR and treatment strategies, we developed a more advantageous nomogram model. This study provides a new reference for the diagnosis, treatment and prognosis of SRCC patients. Given the deficiencies in data and statistical methods, our conclusions require further corroboration. Future studies should therefore prioritize employing multi-faceted approaches to validate these results.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2429/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2429/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2429/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This investigation was conducted in full compliance with the ethical standards set forth by the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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