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Abstract

Objectives

Signet ring cell carcinoma (SRCC) of the urinary bladder is a rare and highly aggressive form of bladder cancer, with no widely agreed-upon treatment strategy. The aim of this study was to identify important factors influencing patient prognosis and to assess how various treatment approaches affect survival outcomes.

Methods

A retrospective study was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) Program, including patients with bladder primary SRCC who were presented between 2000 and 2017. Univariate and multivariate Cox regression models were used to examine the impact of various factors on cancer-specific survival (CSS) and overall survival (OS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were applied to homogenize both groups. The impact of different treatment regimens on patient CSS and OS was analyzed using the Kaplan-Meier method.

Results

A total of 33 cases of non-muscular invasive SRCC and 210 cases of muscular invasive SRCC were included in this study. Multivariate analysis identified race, TNM stage, and surgical method as independent variables influencing both OS and CSS. In non-muscle invasive bladder SRCC patients, radical cystectomy showed no CSS benefit compared to transurethral resection of bladder tumors (P = 0.304). For muscle invasive SRCC, patients who underwent partial cystectomy had better OS and CSS compared to those who underwent radical cystectomy (P = 0.019, P = 0.024). However, after conducting a PSM analysis, the differences between the two surgical outcomes were not statistically significant (P = 0.504, P = 0.335). Lymphadenectomy, chemotherapy, and radiation did not show any benefit to the prognosis of patients.

Conclusion

This study identified race, TNM stage, and surgical approach as significant independent predictors for SRCC outcomes. Simple radical cystectomy and partial cystectomy proved to be effective treatments for SRCC. The optimal treatment option still needs to be supported by a number of prospective research trials.

Keywords

signet ring cell carcinoma bladder cancer radical cystectomy

Introduction

Bladder cancer is one of the most common malignant tumors in urology. According to the latest 2023 cancer statistics in the United States, it is the fourth most common cancer in terms of incidence and the eighth in terms of mortality among men in the U.S.¹ The predominant pathological type is urothelial carcinoma, whereas primary signet ring cell carcinoma (SRCC) is relatively rare. First identified in 1955, over 300 cases of bladder SRCC have been reported previously in scientific literature. SRCC accounts for 0.12%–0.6% of all bladder malignancies, and is considered to be the subtype with the worst prognosis.^2,3

Bladder SRCC is an extremely malignant tumor typically characterized by high-grade pathology and a poor prognosis. Due to its rarity, there is no consensus on guidelines for managing SRCC.⁴ Currently, surgery remains the primary treatment approach.^5,6 Surgical methods including such as transurethral resection of bladder tumors (TURBT), partial cystectomy (PC), and radical cystectomy (RC), with RC being the preferred surgical method.^7,8 However, PC and TURBT have also been reported to be effective for localized tumors.^9,10 Regarding adjuvant treatment, SRCC is generally resistant to the standard chemotherapy regimens and radiotherapy used for advanced urothelial carcinoma. However, a few studies have also reported the effectiveness of chemotherapy, but most of the reports are case reports and summaries, with a lack of comprehensive data research and analysis.^11,12

To identify the optimal treatment regimen for patients with SRCC of the bladder, we analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database, focusing on cases from 2000 to 2017. Initially, we examined the clinicopathological characteristics of these patients. Subsequently, we investigated the factors affecting their prognosis and the effects of various treatment options on patient outcomes. Our findings offer a crucial reference for the precision treatment of patients with SRCC.

Materials and Methods

Study Design and Data Sources

This is a retrospective cohort study. This study utilized data from the Surveillance, Epidemiology, and End Results (SEER) database, specifically drawing from 17 registries. Our analysis included only patients diagnosed with their first primary signet ring cell carcinoma of the urinary bladder (International Classification of Diseases for Oncology, third edition (ICD-O-3) site code: C67.0-67.9; histological code: ICD-O-3 code: 8490/3) between 2000 and 2017. Data retrieval was performed using SEER*-Stat software version 8.4.0.1. The flowchart of case selection is shown in Figure S1. The reporting of this study conforms to RECORD guidelines.¹³ The study received ethical approval from the institutional review board of Beijing Tongren Hospital, Capital Medical University, and the requirement for written informed consent was waived due to the use of publicly available data (approval number: TREC2024-KY070, Beijing, 2024.04.06).

The inclusion criteria are as follows: (1) age ≥18 years; (2) the primary site is limited to the bladder; (3) histological: signet ring cell carcinoma; (4) confirmed by histological positivity and the first positive indicator of malignancy; (5) staging was performed according to the United States Joint Committee on Cancer (AJCC) Staging Manual, 6th edition. The exclusion criteria are as follows: (1) no histological diagnosis; (2) no survival data; (3) histological grading or AJCC staging information is unknown.

The variables collected from the SEER database included race, year of diagnosis, age at diagnosis, sex, stage at diagnosis, tumor grade, status of cancer-directed surgery, radiotherapy status, and chemotherapy status.

Outcomes

The primary measure of this study was to determine the potential effect of different treatment regimens on cancer specific survival (CSS) and overall survival (OS) of bladder SRCC. Treatment information included: no surgery, transurethral resection of bladder tumors (TURBT), partial cystectomy (PC), radical cystectomy (RC), lymphadenectomy, radiotherapy, and chemotherapy. Prognostic factors analyzed comprise age at diagnosis, year of diagnosis, race, gender, cancer grade, TNM stage, type of surgery, and details on radiotherapy, chemotherapy, and lymph node removal. The study timeframe extends until the most recent update of the SEER database.

Statistical Analysis

All data was analyzed using R software. Chi-square was employed to compare the demographics and tumor characteristics of the two groups of patients. Propensity score matching (PSM) was applied to homogenize both groups.¹⁴ If two groups cannot use PSM, use propensity score inverse treatment weighted probability (IPTW) to reduce confusion.¹⁵ SMD is calculated after weighting the data with IPTW, and an SMD value of less than 0.2 indicates a low level of covariate imbalance. OS and CSS curves were plotted according to the Kaplan-Meier method, and compared using the log-rank test. To identify independent risk factors for SRCC, both univariate and multivariate Cox regression analyses were employed. A P-value of less than 0.05 was deemed to be statistically significant.

Results

Demographics and Tumor Characteristics

A total of 33 cases (13.58%) of non-muscle-invasive SRCC and 210 cases (86.42%) of muscle-invasive SRCC were included in this study. The male-to-female ratio was approximately 3:1. Patients with muscle-invasive SRCC were significantly younger than those with non-muscle-invasive SRCC (P < 0.043). Patients with muscle-invasive SRCC also had a higher rate of undergoing surgery, radiotherapy, and chemotherapy compared to those with non-muscle-invasive SRCC. Among the non-muscle-invasive SRCC patients, 21.21% underwent radical cystectomy, significantly less than the 54.76% of muscle-invasive SRCC patients who underwent this procedure (Table 1).

Table 1.

Demographic Characteristics of Non-muscular Invasive and Muscular Invasive Bladder SRCC Based on SEER Database.

	NMI-SRCC	MI- SRCC	P value
	(N = 33)	(N = 210)	P value
Age at diagnosis (years)
<60	7 (21.21%)	87 (41.42%)
≥60	26 (78.79%)	123 (58.58%)	0.043
Sex
Female	7 (21.21%)	61 (29.09%)	0.469
Male	26 (78.79%)	149 (70.95%)
Diagnosis year
2000-2004	8 (24.24%)	39 (18.57%)	0.592
2005-2010	14 (42.42%)	75 (35.71%)
2011-2015	8 (24.24%)	65 (31.95%)
2016-2017	3 (9.10%)	31 (14.76%)
Survival months
Median (IQR)	33 (20, 83)	15 (13, 21)	0.048
Race
AI/AN	1 (3.03%)	1 (0.48%)	0.366
API	2 (6.06%)	12 (5.71%)
Black	2 (6.06%)	25 (11.90%)
White	28 (84.85%)	172 (81.90%)
T Stage
T1	31 (93.97%)	0 (0.00%)	<0.001
T2	0 (0%)	55 (26.19%)
T3	0 (0%)	63 (30.00%)
T4	0 (0%)	92 (43.81%)
Tis	2 (6.06%)	0 (0.00%)
N stage
N0	33 (100.00%)	125 (59.52%)	<0.001
N1	0 (0.00%)	30 (14.29%)
N2	0 (0.00%)	50 (23.81%)
N3	0 (0.00%)	5 (2.38%)
M Stage
M0	32 (96.97%)	171 (81.43%)	0.047
M1	1 (3.03%)	39 (18.57%)
Grade
G2	0 (0.00%)	7 (3.33%)	0.215
G3	16 (48.48 %)	119 (56.67%)
G4	8 (24.24%)	54 (25.71%)
Gx	9 (27.27%)	30 (14.29%)
Type of surgery
No	5 (15.15%)	15 (7.14%)	0.001
TURBT	20 (60.61%)	57 (27.14%)
PC	1 (3.03%)	23 (10.95%)
RC	7 (21.21%)	115 (54.76%)
Lymph node removal
Yes	4 (12.12%)	107 (50.95%)	<0.001
No/unknown	29 (87.88%)	103 (49.05%)
Radiation
Beam radiation	4 (12.12%)	43 (20.48%)	0.372
None/Unknown	29 (87.88%)	167 (79.52%)
Chemotherapy
Yes	7 (21.21%)	111 (52.86%)	0.048
No/Unknown	26 (78.79%)	99 (47.14%)

Abbreviations: NMI-SRCC, non-muscle invasive signet ring cell carcinoma; MI- SRCC, muscle invasive signet ring cell carcinoma; API, Asian or Pacific Islander; AI/AN, American Indian/Alaska Native; TURBT, transurethral resection of bladder tumors; PC, partial cystectomy; RC, radical cystectomy.

Prognostic Factors

In all patients, univariate analysis identified year of diagnosis, race, TNM stage, surgical method, and radiotherapy as affecting OS. Multivariate analysis revealed that race, T stage, M stage, and surgical method were independent factors affecting OS (Table 2). For CSS, univariate analysis indicated that TNM stage and surgical method influenced CSS, while multivariate analysis determined that T stage and M stage and surgical method were independent factors affecting CSS (Table 3).

Table 2.

Univariate and Multivariate Analyses of Overall Survival (OS) for Patients With Bladder SRCC.

	Univariate COX Regression		Multivariate Cox Regression
	HR (95% CI)	P value	HR (95% CI)	P value
Age at diagnosis (years)
<60	Reference
≥60	1.18 (0.89-1.58)	0.249
Sex
Female	Reference
Male	1.06 (0.78-1.45)	0.697
Diagnosis year
2000-2004	Reference		Reference
2005-2010	1.60 (1.07-2.40)	0.021	1.14 (0.75-1.75)	0.540
2011-2015	1.66 (1.08-2.55)	0.020	1.15 (0.71-1.87)	0.560
2016-2017	1.51 (0.88-2.59)	0.133	0.72 (0.38-1.37)	0.322
Race
White	Reference		Reference
Black	1.67 (1.10-2.54)	0.016	1.68 (1.09-2.60)	0.020
API	0.73 (0.40-1.35)	0.321	0.64 (0.32-1.28)	0.206
AI/AN	1.90 (0.47-7.69)	0.369	3.07 (0.73-13.00)	0.128
T Stage
T1	Reference		Reference
T2	1.19 (0.72-1.94)	0.497	1.53 (0.90-2.59)	0.114
T3	1.26 (0.78-2.03)	0.348	2.79 (1.55-5.02)	0.001
T4	1.88 (1.19-2.97)	0.007	2.36 (1.31-4.25)	0.004
Tis	0.68 (0.09-5.04)	0.707	1.19 (0.15-9.19)	0.866
N stage
N0	Reference		Reference
N1	1.30 (0.86-1.98)	0.213	0.89 (0.55-1.45)	0.646
N2	1.67 (1.18-2.37)	0.004	1.47 (0.99-2.17)	0.056
N3	1.58 (0.58-4.28)	0.372	1.77 (0.59-5.29)	0.304
M Stage
M0	Reference		Reference
M1	2.99 (2.09-4.29)	<0.001	2.44 (1.58-3.78)	<0.001
Grade
G2	Reference
G3	2.87 (0.91-9.02)	0.072
G4	2.67 (0.83-8.58)	0.098
Gx	1.96 (0.60-6.41)	0.268
Type of surgery
TURBT	Reference		Reference
No	2.69 (1.60-4.52)	<0.001	1.67 (0.92-3.04)	0.094
PC	0.29 (0.16-0.52)	<0.001	0.20 (0.10-0.39)	<0.001
RC	0.56 (0.41-0.76)	<0.001	0.35 (0.23-0.52)	<0.001
Lymph node removal
No/unknown	Reference
Yes	0.77 (0.58-1.02)	0.070
Radiation
Beam radiation	Reference		Reference
None/Unknown	0.66 (0.47-0.94)	0.021	0.86 (0.57-1.30)	0.479
Chemotherapy
No/Unknown	Reference
Yes	1.13 (0.85-1.49)	0.402

Abbreviations: API, Asian or Pacific Islander; AI/AN, American Indian/Alaska Native; TURBT, transurethral resection of bladder tumors; PC, partial cystectomy; RC, radical cystectomy.

Table 3.

Univariate and Multivariate Analyses of Cancer Special Survival (CSS) for Patients With Bladder SRCC.

	Univariate COX Regression		Multivariate Cox Regression
	HR (95% CI)	P value	HR (95% CI)	P value
Age at diagnosis (years)
<60	Reference
≥60	0.99 (0.71-1.39)	0.970
Sex
Female	Reference
Male	1.30 (0.91-1.85)	0.154
Diagnosis year
2000-2004	Reference
2005-2010	1.36 (0.86-2.16)	0.185
2011-2015	1.23 (0.75-2.023)	0.413
2016-2017	1.09 (0.58-2.06)	0.795
Race
White	Reference
Black	1.34 (0.80-2.27)	0.269
API	0.55 (0.24-1.26)	0.159
AI/AN	1.20 (0.17-8.62)	0.855
T Stage
T1	Reference		Reference
T2	1.81 (0.91-3.61)	0.092	2.49 (1.23-5.04)	0.011
T3	1.91 (0.97-3.76)	0.062	4.79 (2.22-10.32)	<0.001
T4	2.92 (1.53-5.58)	0.001	4.39 (2.08-9.23)	<0.004
Tis	1.54 (0.20-11.97)	0.678	3.07 (0.38-24.66)	0.292
N stage
N0	Reference		Reference
N1	1.30 (0.79-2.14)	0.304	0.80 (0.47-1.36)	0.415
N2	1.67 (1.11-2.53)	0.015	1.26 (0.81-1.98)	0.305
N3	1.62 (0.51-5.13)	0.415	1.49 (0.45-4.89)	0.513
M Stage
M0	Reference		Reference
M1	3.35 (2.24-5.02)	<0.001	2.28 (1.45-3.57)	<0.001
Grade
G2	Reference
G3	3.03 (0.75-12.34)	0.121
G4	2.57 (0.62-10.71)	0.196
Gx	1.92 (0.45-8.26)	0.379
Type of surgery
TURBT	Reference		Reference
No	2.38 (1.28-4.44)	0.006	1.05 (0.53-2.09)	0.887
PC	0.27 (0.13-0.58)	<0.001	0.16 (0.07-0.37)	<0.001
RC	0.59 (0.41-0.85)	0.005	0.33 (0.21-0.52)	<0.001
Lymph node removal
No/unknown	Reference
Yes	0.80 (0.57-1.12)	0.202
Radiation
Beam radiation	Reference
None/Unknown	0.69 (0.46-1.05)	0.083
Chemotherapy
No/Unknown	Reference
Yes	1.23 (0.88-1.72)	0.232

Abbreviations: API, Asian or Pacific Islander; AI/AN, American Indian/Alaska Native; TURBT, transurethral resection of bladder tumors; PC, partial cystectomy; RC, radical cystectomy.

Group analysis indicated that race, TNM stage, surgical method, and lymphadenectomy were factors affecting OS in patients with muscle-invasive SRCC. Multivariate analysis confirmed that race, TNM stage, and surgical method were independent prognostic factors (Table 4). Regarding cancer-specific survival (CSS), univariate analysis identified T stage, M stage, surgical method, and lymphadenectomy as influencing factors. Subsequent multivariate analysis established that T stage, M stage, and surgical method were independent factors affecting CSS (Table 5).

Table 4.

Univariate and Multivariate Analyses of Overall Survival (OS) for Patients With Muscle Invasive Signet Ring Cell Carcinoma.

	Univariate COX Regression		Multivariate Cox Regression
	HR (95% CI)	P value	HR (95% CI)	P value
Age at diagnosis (years)
<60	Reference
≥60	1.37 (1.01-1.86)	0.041	1.73 (1.25-2.40)	0.001
Sex
Female	Reference
Male	1.05 (0.76-1.45, P = .783)	0.783
Diagnosis year
2000-2004	Reference		Reference
2005-2010	1.54 (1.00-2.38)	0.051
2011-2015	1.50 (0.95-2.36)	0.080
2016-2017	1.42 (0.81-2.52)	0.224
Race
White	Reference		Reference
Black	1.56 (1.01-2.41)	0.046	1.57 (1.01-2.46)	0.047
API	0.68 (0.34-1.33)	0.258	0.57 (0.28-1.19)	0.138
AI/AN	4.18 (0.58-30.36)	0.157	3.93 (0.51-30.21)	0.189
T Stage
T2	Reference		Reference
T3	1.07 (0.71-1.61)	0.741	2.11 (1.31-3.40)	0.002
T4	1.56 (1.07-2.28)	0.019	1.74 (1.11-2.72)	0.016
N stage
N0	Reference		Reference
N1	1.21 (0.79-1.86)	0.373	1.04 (0.65-1.68)	0.862
N2	1.57 (1.09-2.25)	0.014	1.62 (1.08-2.43)	0.021
N3	1.47 (0.54-4.01)	0.449	1.34 (0.46-3.93)	0.592
M Stage
M0	Reference		Reference
M1	2.89 (2.00-4.18)	<0.001	2.59 (1.70-3.94)	<0.001
Grade
G2	Reference
G3	2.91 (0.92-9.19)	0.068
G4	2.97 (0.92-9.60)	0.068
Gx	2.33 (0.70-7.75)	0.167
Type of surgery
TURBT	Reference		Reference
No	0.62 (0.34-1.12)	0.110	0.81 (0.41-1.59)	0.542
PC	0.13 (0.06-0.28)	<0.001	0.14 (0.06-0.35)	<0.001
RC	0.25 (0.14-0.45)	<0.001	0.22 (0.11-0.47)	<0.001
Lymph node removal
No/unknown	Reference
Yes	0.72 (0.53-0.97)	0.029	1.17 (0.71-1.93)	0.531
Radiation
Beam radiation	Reference
None/Unknown	0.75 (0.52-1.08)	0.119
Chemotherapy
No/Unknown	Reference
Yes	1.01 (0.75-1.37)	0.939

Abbreviations: API, Asian or Pacific Islander; AI/AN, American Indian/Alaska Native; TURBT, transurethral resection of bladder tumors; PC, partial cystectomy; RC, radical cystectomy.

Table 5.

Univariate and Multivariate Analyses of Cancer Special Survival (CSS) for Patients With Muscle Invasive Signet Ring Cell Carcinoma.

	Univariate COX Regression		Multivariate Cox Regression
	HR (95% CI)	P value	HR (95% CI)	P value
Age at diagnosis (years)
<60	Reference
≥60	1.25 (0.88-1.78)	0.219
Sex
Female	Reference
Male	1.21 (0.83-1.75)	0.325
Diagnosis year
2000-2004	Reference
2005-2010	1.45 (0.88-2.37)	0.143
2011-2015	1.23 (0.73-2.08)	0.434
2016-2017	1.12 (0.57-2.19)	0.744
Race
White	Reference
Black	1.15 (0.66-2.02)	0.619
API	0.49 (0.20-1.21)	0.121
AI/AN	4.95 (0.68-36.14)	0.115
T Stage
T2	Reference		Reference
T3	1.06 (0.65-1.72)	0.821	1.95 (1.13-3.35)	0.016
T4	1.62 (1.04-2.53)	0.031	1.92 (1.16-3.18)	0.011
N stage
N0	Reference
N1	1.15 (0.69-1.91)	0.592
N2	1.48 (0.97-2.26)	0.068
N3	1.45 (0.46-4.61)	0.530
M Stage
M0	Reference		Reference
M1	3.14 (2.08-4.74)	<0.001	2.29 (1.48-3.56)	<0.001
Grade
G2	Reference
G3	3.13 (0.77-12.75)	0.111
G4	3.07 (0.73-12.87)	0.124
Gx	2.47 (0.57-10.71)	0.226
Type of surgery
TURBT	Reference		Reference
No	0.70 (0.35-1.40)	0.314	1.22 (0.58-2.55)	0.605
PC	0.13 (0.05-0.33)	<0.001	0.17 (0.06-0.50)	0.001
RC	0.28 (0.14-0.55)	<0.001	0.31 (0.14-0.71)	0.006
Lymph node removal
No/unknown	Reference
Yes	0.69 (0.49-0.99)	0.042	1.34 (0.79-2.28)	0.276
Radiation
Beam radiation	Reference
None/Unknown	0.81 (0.53-1.25)	0.341
Chemotherapy
No/Unknown	Reference
Yes	1.02 (0.72-1.45)	0.910

Abbreviations: API, Asian or Pacific Islander; AI/AN, American Indian/Alaska Native; TURBT, transurethral resection of bladder tumors; PC, partial cystectomy; RC, radical cystectomy.

Prognostic Effect of Treatment Regimens

In patients with non-muscle-invasive SRCC, the KM analysis showed no significant differences in OS and CSS between those who underwent RC compared to those who underwent TURBT (Figure 1). After two groups of patients underwent IPTW, and the results showed that there was no statistical difference in CSS between patients who received RC and those who received TURBT, but it was significantly better than that of patients receiving TURBT in OS (Table S1-2, Figure S2A). In patients with muscle-invasive SRCC, the patients who received PC has the lower T stage, N stage and Grades than those of patients received RC (Table S3). The results of KM analysis showed that the OS and CSS of patients who received PC were significantly better than those of patients who received RC (Figure 2A and B). After PSM, the results of KM analysis showed that there was no significant difference in OS and CSS between patients who received PC and those who received RC (Table S3, Figure S2B, Figure 2C and D).

Figure 1.

Kaplan-Meier survival curves of patients with NMI-SRCC who underwent TURBT and radical cystectomy. (A)The OS in patients stratified by surgery. (B) The CSS in patients stratified by surgery. Abbreviations: NMI-SRCC, non-muscle invasive signet ring cell carcinoma; OS, overall survival; CSS, cancer specific survival; TURBT, transurethral resection of bladder tumors; RC, radical cystectomy.

Figure 2.

Kaplan-Meier survival curves of patients with MI-SRCC who underwent partial cystectomy and radical cystectomy. (A) The OS in patients stratified by surgery before PSM. (B) The CSS in patients stratified by surgery before PSM. (C) The OS in patients stratified by surgery after PSM. (D) The CSS in patients stratified by surgery after PSM. Abbreviations: MI-SRCC, muscle invasive signet ring cell carcinoma; PSM, Propensity score matching; OS, overall survival; CSS, cancer specific survival; RC, radical cystectomy; PC, partial cystectomy.

The muscle-invasive SRCC patients were divided into two groups based on whether they received lymphadenectomy or not (Table S4), and the KM analysis showed no difference in OS and CSS between the two groups (Figure 3A and B).

Figure 3.

Kaplan-Meier survival curves of patients with MI-SRCC who underwent radical cystectomy and radical cystectomy with lymphadenectomy. (A)The OS in patients stratified by lymphadenectomy. (B) The CSS in patients stratified by lymphadenectomy. Abbreviations: MI-SRCC, muscle invasive signet ring cell carcinoma; PSM, Propensity score matching; OS, overall survival; CSS, cancer specific survival; RC, radical cystectomy; LN, lymphadenectomy.

The patients of muscle-invasive bladder SRCC were divided into two groups based on whether they received chemotherapy or not (Table S5), and the KM analysis showed that there was no significant difference in OS and CSS between the two groups (Figure 4A and B). After PSM analysis, the KM results showed that there were still no significant differences in OS and CSS between the two groups (Table S5, Figure S2C, Figure 4C and D).

Figure 4.

Kaplan-Meier survival curves of patients with MI-SRCC who underwent chemotherapy. (A) The OS in patients stratified by chemotherapy before PSM. (B) The CSS in patients stratified by chemotherapy before PSM. (C) The OS in patients stratified by chemotherapy after PSM. (D) The CSS in patients stratified by chemotherapy after PSM. Abbreviations: MI-SRCC, muscle invasive signet ring cell carcinoma; PSM, Propensity score matching; OS, overall survival; CSS, cancer specific survival.

In muscle-invasive bladder SRCC, the patients were divided into two groups based on whether they received radiation or not (Table S6), and the KM analysis showed that there was no significant difference in OS and CSS between the two groups (Figure 5A and B). After PSM analysis, the KM results showed that there were still no significant differences in OS and CSS between the two groups (Table S6, Figure S2D, Figure 5C and D).

Figure 5.

Kaplan-Meier survival curves of patients with MI-SRCC who underwent radiation. (A) The OS in patients stratified by radiation before PSM. (B) The CSS in patients stratified by radiation before PSM. (C) The OS in patients stratified by radiation after PSM. (D) The CSS in patients stratified by radiation after PSM. Abbreviations: MI-SRCC, muscle invasive signet ring cell carcinoma; PSM, Propensity score matching; OS, overall survival; CSS, cancer specific survival.

Discussion

SRCC is an exceptionally rare type of bladder cancer, making large randomized controlled trials challenging to conduct and resulting in a lack of consensus on treatment protocols.⁴ This study is the first to utilize the SEER database to compare the effectiveness of various treatment regimens for patients with SRCC. For non-muscle-invasive SRCC, our findings show that patients undergoing RC did not experience improved CSS compared to those receiving TURBT, although they did exhibit a trend toward better OS. RC proved to be an effective treatment for muscle-invasive SRCC, with PC also demonstrating favorable OS and CSS outcomes in some cases. Additionally, this study highlights several prognostic factors in addition to TNM staging, including race, and surgical approach, which are critical in influencing patient outcomes. Our findings are expected to provide recommendations for personalized treatment and precision treatment for patients with SRCC.

Bladder SRCC typically occurs in the sixth decade of life and predominantly affects males, with a male-to-female ratio of about 3:1, consistent with our findings.^7,16 The most frequent clinical symptom is hematuria, occurring in 65% of cases, along with other symptoms like dysuria, urgency, and suprapubic pain.¹⁷ At diagnosis, about 25% of patients present with distant metastases.^7,16 In this study, the median survival of patients with non-muscle-invasive SRCC was 33 months, and the median survival of patients with muscle-invasive SRCC was 11 months, which was much lower than that of patients with bladder urothelial carcinoma.^18,19 In addition, in our study, we found that 40% of patients with muscle-invasive SRCC had metastases, contributing significantly to the poor prognosis of these patients.

Studies have reported that TNM stage, surgery, and lymphadenectomy are independent predictors of OS in bladder SRCC patients.^20,21 Similarly, in our study, we identified TNM stage and surgical approach as independent predictors of both OS and CSS in SRCC patients, underscoring the importance of early diagnosis and treatment in improving prognosis. Additionally, our findings indicated that race is also an independent prognostic factor. Racial disparities in health outcomes, including cancer survival rates, have been a significant concern in recent years.²² Our study revealed that the prognosis for Back patients with SRCC was significantly worse compared to White patients. These disparities in cancer outcomes have been well-documented. For instance, U.S. cancer statistics report lower survival rates for several cancers, including bladder cancer, among Black individuals compared to White individuals.¹ In bladder cancer, the proportion of patients with advanced diagnosis is significantly higher in Black patients than in White patients. ^23,24 Black patients being anywhere from 1.5-2 times less likely to receive an NCCN‐listed treatment in non‐metastatic disease compared to White patients.²³ This persistent gap can be attributed to various factors, such as differences in annual household income, ²⁵ social status,²⁶ and cultural factors,²⁷ all of which are ultimately linked to centuries of structural racism.^28,29 Overall, addressing these disparities remains a critical challenge that requires continued efforts and systemic change.

Due to the rarity of SRCC, the disease has often been neglected in research, with most previous studies being case reports. Consequently, there is no established consensus on the optimal treatment for SRCC. Surgery has been reported in 70% of cases.^5,6 In this study, we found that the type of surgery performed significantly impacts patient prognosis. Although RC is generally preferred over PC due to concerns that imaging may not fully capture local invasion, there have been reports of long-term survival following PC or TURBT for small, well-defined primary SRCC tumors.^7-10 In this study, we found that for non-muscle-invasive SRCC, patients who received RC had better OS than those who received TURBT, but there was no difference in CSS. For muscle-invasive SRCC, the prognosis of patients who underwent PC was better than that of patients who received RC, but there was no significant difference in prognosis between the two surgical modalities after PSM analysis. The potential cause of this situation may be selection bias, such as the staging and grading of patients with partial cystectomy is better than that of patients with radical cystectomy. This finding suggests that less invasive surgical options like TURBT and PC might be equally effective as more extensive procedures like RC for certain cases of SRCC, highlighting the need for further research to optimize treatment strategies for this rare and challenging cancer type.

SRCC of the bladder is generally considered resistant to the standard chemotherapy regimens typically used for advanced urothelial carcinoma, which is consistent with our research findings. However, a few studies have documented the efficacy of such treatment protocols. For instance, a case was reported where a patient with T2aN2M0 stage SRCC underwent RC followed by adjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin. Remarkably, this patient showed no signs of recurrence or metastasis six months post-surgery.¹¹ Another patient with primary SRCC at stage pT3bN1M0 received RC followed by systemic chemotherapy using cisplatin and gemcitabine. This treatment approach yielded a progression-free survival (PFS) of 18 months and OS of 22 months.¹² Furthermore, an additional case involving a patient with primary SRCC staged at pT4aN0M0 reported successful treatment with a preoperative chemotherapy regimen combining paclitaxel, cisplatin, and gemcitabine, followed by RC. This patient remained free of disease recurrence nine years after treatment.³⁰ Although many patients do not respond well to the conventional combination therapy of cisplatin and gemcitabine for bladder SRCC, alternative chemotherapeutic strategies are being explored. One such approach is the use of cisplatin combined with 5-fluorouracil (5-FU), a regimen inspired by treatments for gastrointestinal SRCC. For instance, a patient with primary SRCC (pT3bN0M0) who underwent RC followed by adjuvant chemotherapy with cisplatin and S-1—a drug used primarily in Japan for gastrointestinal cancers achieved a long-term survival of 90 months.³¹ Moreover, recent studies have highlighted the potential of new pharmacological treatments. A patient with metastatic SRCC initially received systemic induction chemotherapy with a combination of S-1 and cisplatin, followed by maintenance therapy with avelumab, an immune checkpoint inhibitor. After developing resistance to this treatment, the patient was administered enfortumab-vedotin, to which they showed a favorable response.³² This suggests the potential efficacy of novel drugs and immune therapies in treating bladder SRCC. The promising results from immune checkpoint inhibitors, which have proven highly effective in treating other types of bladder cancer, point to a critical area of future research.^33,34 The efficacy of these inhibitors in treating bladder SRCC warrants further exploration to better understand their role and optimize therapeutic outcomes for this challenging and rare cancer subtype.

SRCC of the urinary bladder is not considered radiosensitive.⁵ In this study, we also found that radiotherapy had no significant effect on the patient’s OS and CSS. Radiotherapy for SRCC of the bladder has also been reported less relevantly. Two studies reported disease progression after radiotherapy in patients with bladder SRCC, suggesting a lack of response to radiotherapy in bladder SRCC.^17,35 Another study reported a sustained response of more than 16 months in a patient with metastatic SRCC using radiotherapy in combination with radio-sensitizing capecitabine and oxaliplatin.³⁶ Further research is still needed on the effectiveness of radiotherapy (including combination therapy).

Our study has several limitations: This is a database based retrospective analysis, which essentially contains selection bias, misclassification or missing data, and lacks the robustness of prospective randomized controlled trials. Therefore, it is difficult to measure the true effect of any single treatment modality. Moreover, critical data that could influence oncological outcomes such as details on lymphovascular invasion, adjuvant intravesical therapies, specific types of chemotherapy or radiotherapy, and the use of novel therapeutic agents were not available in this study. These can lead to biased survival analysis and outcomes, potentially overstating or understating the efficacy of certain treatments. Additionally, the small sample size in the subgroup analysis and the absence of post-match analysis introduced potential confounders that diminish the reliability of our findings. This may result in our findings not be generalizable to broader or more diverse populations outside of the study context.

Conclusion

Bladder SRCC is a rare disease with an extremely poor prognosis, and the optimal treatment for it has not been determined. Our findings revealed that factors such as TNM stage, ethnicity, and the type of surgical intervention significantly influence patient outcomes. Radical cystectomy has a survival advantage in patients with non-muscle-invasive bladder cancer and muscle-invasive bladder cancer. Partial cystectomy is also associated with a good prognosis in some selected patients. Therefore, further analysis is required to determine the most beneficial surgical procedures. In the future, collaborative multi-institutional clinical trials and international partnerships are essential to develop clearer treatment guidelines for primary bladder SRCC and enhance the survival rates of affected patients.

Supplemental Material

Supplemental Material - Treatment Options for Signet Ring Cell Carcinoma of the Urinary Bladder: A Population-Based Study

Supplemental Material for Treatment Options for Signet Ring Cell Carcinoma of the Urinary Bladder: A Population-Based Study by Yingwei Xie, Yishan Zhang, Zhen Du, Dan Liu, Wei Yan, Yuexin Liu, and Hao Ping in Cancer Control.

Footnotes

Acknowledgments

The authors would like to thank all the reviewers who participated in the review and MJEditor () for its linguistic assistance during the preparation of this manuscript.

Author Contributions

HP and YX contributed to the conception and design of the study. YZ, and DL did the literature search and construction of tables and figures. YZ, ZD and WY verified the underlying data. YL, and HP contributed to the administration and supervision. YX drafted the paper. YX and HP interpreted the results. YZ and YX contributed to the methodology. All authors contributed to data interpretation and rewriting of the paper. All authors reviewed and approved the final version. All authors had full access to all the data. The corresponding authors were responsible for the decision to submit the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (XMLX202134), the National Natural Science Foundation of China (No. 82072833, 82272864).

Ethical Statement

This study was approved by the Ethics Committee of Beijing Tongren Hospital, Capital Medical University (approval number: TREC2024-KY070). The requirement for consent to participate declarations was waived due to the use of publicly available data.

ORCID iD

Hao Ping

Data Availability statement

All supporting data were obtained from the SEER database. Data extraction rules, the detailed protocol, and the R program are available upon reasonable request to the corresponding author of Hao Ping (pinghaotrh@ccmu.edu.cn).*

Supplemental Material

Supplemental material for this article is available online.

Appendix

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