Abstract
Background
Signet-ring cell carcinoma (SRCC) of the bile duct is a rare malignancy with poorly characterized clinical features and prognosis. Given its rarity and the critical need to differentiate its behavior from common cholangiocarcinoma (CCA), this population-based study aimed to characterize SRCC and compare survival outcomes with CCA, while developing prognostic nomograms for individualized prediction.
Methods
We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database [2000–2021], identifying 98 SRCC and 18,979 CCA cases. Propensity score matching (PSM) analysis (1:5 ratio) was conducted to balance baseline characteristics between groups (98 SRCC vs. 490 CCA). Independent prognostic factors for overall survival (OS) and cancer-specific survival (CSS) were identified using multivariable Cox regression. These factors were incorporated into nomograms for OS and CSS prediction. Model performance was evaluated using the concordance index (C-index), calibration curves, receiver operating characteristic (ROC) curve analysis, and decision curve analysis (DCA).
Results
SRCC predominantly involved the extrahepatic bile duct (86.7%) and exhibited poor survival [median OS (mOS) 7.0 months, 95% confidence interval (CI): 4.0–10.0; median CSS (mCSS) 8.0 months, 95% CI: 5.0–12.0]. After PSM, no significant survival difference was observed between SRCC and CCA (P>0.05). Older age and distant metastasis were independent factors associated with poor survival, whereas surgery and chemotherapy were independently associated with better survival. The nomograms demonstrated moderate predictive accuracy (C-index: OS 0.78, 95% CI: 0.71–0.84; CSS 0.78, 95% CI: 0.70–0.85). Calibration curves showed excellent agreement between predicted and observed survival, ROC analysis confirmed discriminative ability, and DCA indicated strong clinical utility.
Conclusions
SRCC of the bile duct is a rare, aggressive malignancy with a prognosis similar to CCA. The developed nomograms, integrating readily available clinical factors, provide clinically applicable tools for individualized prognosis prediction.
Keywords: Signet-ring cell carcinoma (SRCC); bile duct; cholangiocarcinoma (CCA); Surveillance, Epidemiology, and End Results database (SEER database); prognosis
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Key findings
• Bile duct signet-ring cell carcinoma (SRCC) is rare, predominantly affects the extrahepatic duct (86.7%), and exhibits poor survival (median overall survival 7.0 months).
• After propensity score matching, SRCC survival outcomes were not significantly different from common cholangiocarcinoma (CCA).
• Older age and distant metastasis were independent predictors of worse survival, while surgery and chemotherapy predicted better survival.
• Prognostic nomograms for overall survival and cancer-specific survival demonstrated moderate accuracy (concordance index: 0.78) and strong clinical utility.
What is known and what is new?
• SRCC of the bile duct is a rare malignancy with poorly characterized clinical features and prognosis compared to CCA.
• This study provides a robust population-based comparison, revealing that SRCC has a similar prognosis to CCA after adjusting for baseline differences. It identifies specific independent prognostic factors and, crucially, develops and validates the first clinically applicable nomograms for individualized prediction of survival in this rare disease.
What is the implication, and what should change now?
• SRCC is confirmed as an aggressive but prognostically similar entity to CCA. The nomograms provide a practical tool for personalized outcome prediction using readily available clinical factors.
• Clinicians should recognize SRCC’s aggressive nature but similar prognosis to CCA. The validated nomograms would be integrated into clinical practice to aid individualized prognostic assessment and treatment decision-making for patients with this rare cancer. Further validation in external cohorts is warranted.
Introduction
Signet-ring cell carcinoma (SRCC) is a distinct subtype of adenocarcinoma that is notable for its abundant production of intracellular mucin (1). This accumulation of mucin displaces the nucleus to the periphery of the cancer cell, developing the characteristic “signet-ring” appearance. Once an SRCC invades beyond the submucosal layer, it demonstrates a propensity for extensive dissemination and metastasis development (2). Although SRCC can originate in various anatomical sites, including the gastrointestinal tract, breast, lung, pancreas, gallbladder, and bladder, approximately 63.4% of SRCC occur in the stomach (3). Similarly, SRCC can also originate from the biliary system, and most SRCC of the biliary system have been reported in the gallbladder (4). In contrast, SRCC in the bile duct is relatively rare.
Because of its rarity, previous investigations on primary SRCC of the bile duct are sparse, with only a limited number of cases documented in the literature (5-10). These investigations reported that this disease often occurs in the extrahepatic bile duct and in individuals aged 31 to 73 years. SRCC of the bile duct was also reported more common in women than in men (5). Meanwhile, these observations revealed that primary SRCC of the extrahepatic bile duct predominantly exhibits wall-invasive growth and is frequently associated with lymph node metastasis, whereas distant organ metastasis remains uncommon (6,8-11). Given the limited number of reported cases, these characteristics require further investigation in a larger cohort. In addition, there is currently a lack of standardized protocols and guidelines for treating this disease. Although surgical intervention remains the cornerstone for patients without distant metastasis, combinations of surgery, radiotherapy, and chemotherapy have been applied in previous case reports or case series. Furthermore, follow-up studies providing detailed prognostic information are sparse, leaving prognostic factors for patients with SRCC of the bile duct inadequately understood. In addition, it remains unclear whether this rare disease exhibits distinct clinicopathological characteristics and survival outcomes compared with cholangiocarcinoma (CCA) owing to its unique histologic features. Thus, comprehensive studies are essential to better understand the specific features and clinical behavior of this rare disease.
In the present study, we performed a population-based study on patients with SRCC of the bile duct registered in the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2021. SEER program, initiated in 1973, is one of the world’s most comprehensive and authoritative population-based cancer registries. Its longitudinal framework and standardized reporting protocols yield high-quality data on rare oncologic events. The purposes of this population-based study were as follows: (I) to describe the clinicopathological features of this rare disease; (II) to perform a comparative analysis of the characteristics and survival between SRCC and CCA located in the bile duct from SEER database; (III) to identify potential prognostic factors specific to SRCC of the bile duct; and (IV) to develop prognostic nomograms for predicting individual survival. We present this article in accordance with the TRIPOD reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2662/rc).
Methods
Data source
The SEER database, maintained by the National Cancer Institute, covers approximately 34.6% of the US population across diverse regions (12). The SEER database used a standardized reporting framework to systematically capture population-based cancer data, including cancer incidence, clinicopathological features, therapeutic methods, and survival outcomes. The database of “incidence-SEER Research data, 17 Registries, Nov 2023 sub (2000-2021)” was utilized to identify the participants of this study. Since the SEER database is publicly available, institutional review board approval for this study was exempted. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Participant
All patients diagnosed with SRCC and CCA located in the intra-/extrahepatic region between 2000 and 2021 were identified based on the International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) primary site-labeled (C22.1-intrahepatic bile duct, C24.0-extrahepatic bile duct), as well as the histological codes (8160/3 CCA, 8490/3 SRCC). To participate in this study, the participant must meet the following criteria: (I) SRCC and CCA in the bile duct as the only primary cancer diagnoses for eligible patients; and (II) patients must have known information on survival time and survival status.
Characteristics
Demographic and clinicopathological characteristics of each patient were collected using SEER*Stat 8.4.4, including age, sex, race, marital status, primary site, American Joint Committee on Cancer tumor-node-metastasis (AJCC-TNM) staging, tumor stage (T stage), lymph node metastasis, distant metastasis, surgery, radiotherapy, chemotherapy, survival time, vital status, and the cause of death classification. The study endpoints included overall survival (OS) and cancer-specific survival (CSS). OS refers to the interval from diagnosis until death from any cause, while CSS refers to the interval from diagnosis until death, specifically caused by SRCC or CCA of the intra-/extrahepatic bile duct.
Statistical analysis
Descriptive statistics were described as percentages for categorical variables. Age was categorized as ≤68 and >68 years according to the median age of all patients. The Chi-squared test was used to compare the differences in clinicopathological characteristics between SRCC and CCA of the bile duct. To assess the differences in OS and CSS between these two groups, Kaplan-Meier plots were drawn, and a log-rank test was conducted. To eliminate the influence of unbalanced baseline clinicopathological characteristics on the survival of SRCC and CCA patients, a propensity score matching (PSM) analysis with a 1:5 ratio was performed to balance the potential confounding factors between these two groups. Univariate Cox analysis was conducted to identify the potential factors related to OS and CSS among patients with SRCC of the bile duct, and the significant factors from the univariate Cox analysis were further incorporated into the multivariate Cox analysis to determine independent prognostic factors. Moreover, a nomogram was constructed to predict the OS and CSS of patients with SRCC of the bile duct using independent prognostic factors. To assess the predictive accuracy and discriminability of established OS-/CSS-specific nomograms, the concordance index (C-index) was calculated, and further area under the curve (AUC) analysis and calibration plots were performed. An AUC value between 0.6 and 0.8 indicates moderate diagnostic accuracy, while an AUC between 0.8 and 0.9 demonstrates good diagnostic accuracy (13). In addition, the decision curve analysis (DCA) was performed to describe the clinical effectiveness of the established nomograms. Statistical analyses were performed using GraphPad Prism (version 10.0, Boston, MA, USA) and R statistical software (version 4.2.2; http://www.R-project.org/) with the packages “MatchIt”, “pROC”, “rms”, “ggDCA”, “ggplot2”, “survival”, “survminer”, etc. Statistical significance was set at P<0.05.
Results
Description of demographic and clinicopathological characteristics
A total of 98 patients diagnosed with SRCC of the bile duct and 18,979 cases with CCA who were registered in the SEER database between 2000 and 2021 were identified. The demographic features and clinicopathological characteristics of the patients are shown in Table 1. Compared with CCA, SRCC of the bile duct occurred more frequently in the extrahepatic bile duct (86.7% vs. 34.9%, P<0.001). In addition, no significant differences in the other characteristics were observed between the two groups.
Table 1. Baseline characteristics of patients with SRCC of the bile duct and CCA in unmatched cohort.
| Characteristics | SRCC (n=98) | CCA (n=18,979) | P value |
|---|---|---|---|
| Age (years) | 0.56 | ||
| <68 | 53 (54.1) | 9,613 (50.7) | |
| ≥68 | 45 (45.9) | 9,366 (49.3) | |
| Sex | 0.47 | ||
| Female | 44 (95.2) | 9,286 (48.9) | |
| Male | 54 (4.8) | 9,693 (51.1) | |
| Race | 0.23 | ||
| White | 77 (78.6) | 14,377 (75.7) | |
| Black | 11 (11.2) | 1,570 (8.3) | |
| Other | 10 (10.2) | 2,958 (15.6) | |
| Unknown | 0 | 74 (0.4) | |
| Primary site | <0.001 | ||
| Intrahepatic bile duct | 13 (13.3) | 12,364 (65.1) | |
| Extrahepatic bile duct | 85 (86.7) | 6,615 (34.9) | |
| Stage | 0.28 | ||
| I | 10 (10.2) | 1,389 (7.3) | |
| II | 12 (12.2) | 1,036 (5.5) | |
| III | 11 (11.2) | 1,395 (7.4) | |
| IV | 19 (19.4) | 3,349 (17.6) | |
| Unknown | 46 (46.9) | 11,810 (62.2) | |
| T stage | 0.46 | ||
| T1 | 15 (15.3) | 2,195 (11.6) | |
| T2 | 4 (4.1) | 904 (4.7) | |
| T3 | 14 (14.3) | 2,104 (11.1) | |
| T4 | 12 (12.2) | 1,174 (6.2) | |
| Unknown | 53 (54.1) | 12,602 (66.4) | |
| N stage | 0.95 | ||
| N0 | 33 (33.7) | 5,001 (26.3) | |
| N1 | 15 (15.3) | 2,122 (11.2) | |
| Unknown | 50 (51.0) | 11,856 (62.5) | |
| M stage | 0.40 | ||
| M0 | 35 (35.7) | 4,602 (24.2) | |
| M1 | 19 (19.4) | 3,349 (17.7) | |
| Unknown | 44 (44.9) | 11,028 (58.1) | |
| Surgery | 0.06 | ||
| No | 71 (72.4) | 15,212 (80.2) | |
| Yes | 26 (26.5) | 3,507 (18.4) | |
| Unknown | 1 (1.0) | 260 (1.4) | |
| Radiation | 0.007 | ||
| No/unknown | 75 (76.5) | 16,318 (86.0) | |
| Yes | 23 (23.5) | 2,661 (14.0) | |
| Chemotherapy | 0.86 | ||
| No/unknown | 52 (53.1) | 10,331 (54.4) | |
| Yes | 46 (46.9) | 8,648 (45.6) |
Data are presented as n (%). CCA, cholangiocarcinoma; M, metastasis; N, node; SRCC, signet-ring cell carcinoma; T, tumor.
Regarding treatment options, the proportion of patients who were administered chemotherapy was similar between the two groups, but patients with SRCC of the bile duct were more likely to receive radiotherapy (23.5% vs. 14.0%, P=0.007) and undergoing surgery (26.5% vs. 18.4%, P=0.06) than patients with CCA.
Survival between SRCC of the bile duct and CCA
The median OS (mOS) and median CSS (mCSS) of patients diagnosed with SRCC of the bile duct were 7.0 months [95% confidence interval (CI): 4.0–10.0] and 8.0 months (95% CI: 5.0–12.0), respectively (Figure 1). The 6-, 12-, and 24-month OS rate among patients with SRCC of the bile duct were 50.0%, 32.9%, and 22.3%, respectively, with a 5-year OS rate of 7.9%. As for CSS, the 6-, 12-, and 24-month OS rate among patients with SRCC of the bile duct were 54.8%, 39.5%, and 26.8%, respectively, with a 5-year CSS rate of 11.0%.
Figure 1.
The survival analysis for OS and CSS between SRCC and CCA of the bile duct in the unmatched cohort (A,B) and the matched cohort (C,D). CCA, cholangiocarcinoma; CI, confidence interval; CSS, cancer-specific survival; HR, hazard ratio; OS, overall survival; SRCC, signet-ring cell carcinoma.
As shown in Figure 1, patients with SRCC of the bile duct had similar OS and CSS to those with CCA. We performed a 1:5 PSM analysis to balance the baseline characteristics of patients with SRCC and CCA. Eventually, 490 patients with CCA were matched with 98 patients with SRCC of the bile duct. As shown in Table 2, no significant differences were observed in the demographic and clinicopathological characteristics of the two groups in the matched cohort after PSM analysis. Consistent with the unmatched cohort, the survival analysis in the matched cohort also demonstrated that patients with SRCC of the bile duct had no significant difference in OS and CSS when compared with CCA patients (Figure 1C,1D).
Table 2. Baseline characteristics of patients with SRCC of the bile duct and CCA in 1:5 matched cohort.
| Characteristics | SRCC (n=98) | CCA (n=490) | P value |
|---|---|---|---|
| Age (years) | >0.99 | ||
| <68 | 53 (54.1) | 264 (53.9) | |
| ≥68 | 45 (45.9) | 226 (46.1) | |
| Sex | >0.99 | ||
| Female | 44 (44.9) | 222 (45.3) | |
| Male | 54 (55.1) | 268 (54.7) | |
| Race | 0.76 | ||
| White | 77 (78.6) | 395 (80.6) | |
| Black | 11 (11.2) | 56 (11.4) | |
| Other | 10 (10.2) | 39 (8.0) | |
| Primary site | >0.99 | ||
| Intrahepatic bile duct | 13 (13.3) | 65 (13.3) | |
| Extrahepatic bile duct | 85 (86.7) | 425 (86.7) | |
| Stage | 0.96 | ||
| I | 10 (10.2) | 42 (8.6) | |
| II | 12 (12.2) | 73 (14.9) | |
| III | 11 (11.2) | 53 (10.8) | |
| IV | 19 (19.4) | 92 (18.8) | |
| Unknown | 46 (46.9) | 230 (46.9) | |
| T stage | 0.64 | ||
| T1 | 15 (15.3) | 54 (11.0) | |
| T2 | 4 (4.1) | 39 (8.0) | |
| T3 | 14 (14.3) | 82 (16.7) | |
| T4 | 12 (12.2) | 60 (12.2) | |
| Unknown | 53 (54.1) | 255 (52.0) | |
| N stage | 0.49 | ||
| N0 | 33 (33.7) | 149 (30.4) | |
| N1 | 15 (15.3) | 100 (20.4) | |
| Unknown | 50 (51.0) | 241 (49.2) | |
| M stage | >0.99 | ||
| M0 | 35 (35.7) | 177 (36.1) | |
| M1 | 19 (19.4) | 92 (18.8) | |
| Unknown | 44 (44.9) | 221 (45.1) | |
| Surgery | 0.74 | ||
| No | 71 (72.4) | 364 (74.3) | |
| Yes | 26 (26.5) | 117 (23.9) | |
| Unknown | 1 (1.0) | 9 (1.8) | |
| Radiation | 0.55 | ||
| No/unknown | 75 (76.5) | 391 (79.8) | |
| Yes | 23 (23.5) | 99 (20.2) | |
| Chemotherapy | 0.80 | ||
| No/unknown | 52 (53.1) | 250 (51.0) | |
| Yes | 46 (46.9) | 240 (49.0) |
Data are presented as n (%). CCA, cholangiocarcinoma; M, metastasis; N, node; SRCC, signet-ring cell carcinoma; T, tumor.
Effect of different treatment modalities on survival
Next, the effects of the treatment modalities on survival among patients with SRCC of the bile duct were evaluated. Survival analysis showed that surgery, radiotherapy, and chemotherapy significantly prolonged the OS and CSS among these patients (P<0.001). Patients receiving surgery have a mOS and mCSS of 35.0 months (95% CI: 18.0–49.0) and 35.0 months (95% CI: 18.0–62.0), much longer than those without surgery (mOS: 4.0 months, mCSS: 5.0 months), respectively (Figure 2A,2B).
Figure 2.
The effect of different treatment modalities on OS and CSS among patients with SRCC of the bile duct. (A) OS analysis stratified by surgery; (B) CSS analysis stratified by surgery; (C) OS analysis stratified by different treatment modalities; (D) CSS analysis stratified by different treatment modalities. CSS, cancer-specific survival; OS, overall survival; S, surgery; SC, surgery plus chemotherapy; SR, surgery plus radiotherapy; SRC, surgery, radiotherapy plus chemotherapy; SRCC, signet-ring cell carcinoma.
Of the 26 patients who underwent surgery, 12 were treated with a combination of surgery, radiotherapy, and chemotherapy, five received surgery and chemotherapy, three received surgery and radiotherapy, and six underwent surgery only. Survival analysis showed that multimodality treatment regimens did not yield more benefit in OS and CSS than patients who received surgery alone (Figure 2C,2D).
Identifying prognostic factors
To identify potential factors related to OS and CSS among patients with RSCC of the bile duct, both univariate and multivariate Cox regression analyses were performed. As shown in Tables 3,4, univariate Cox analysis indicated that age, metastasis stage (M stage), surgery, radiotherapy, and chemotherapy were significantly associated with survival, including OS and CSS. These factors were then incorporated into the multivariate Cox regression analysis to adjust for confounding factors. The results suggested that older age and distant metastasis were independent prognostic factors for poor OS and CSS, whereas the use of surgery or chemotherapy was independently associated with favorable OS and CSS.
Table 3. Prognostic factors for OS among patients with SRCC of the bile duct by univariate and multivariate Cox analysis.
| Characteristics | Univariate Cox | Multivariate Cox | |||
|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | ||
| Age (years) | |||||
| <68 | Reference | Reference | |||
| ≥68 | 1.83 (1.20–2.82) | 0.006 | 1.78 (1.11–2.87) | 0.02 | |
| Sex | |||||
| Female | Reference | ||||
| Male | 0.82 (0.53–1.26) | 0.82 | |||
| Race | |||||
| White | Reference | ||||
| Black | 1.19 (0.59–2.40) | 0.63 | |||
| Other | 0.64 (0.30–1.33) | 0.23 | |||
| Primary site | |||||
| Intrahepatic bile duct | Reference | ||||
| Extrahepatic bile duct | 0.80 (0.43–1.49) | 0.68 | |||
| T stage | |||||
| T1/T2 | Reference | ||||
| T3/T4 | 1.44 (0.77–2.70) | 0.25 | |||
| N stage | |||||
| N0 | Reference | ||||
| N1 | 1.17 (0.62–2.20) | 0.62 | |||
| Unknown | 1.09 (0.68–1.77) | 0.71 | |||
| M stage | |||||
| M0 | Reference | Reference | |||
| M1 | 2.33 (1.28–4.25) | 0.006 | 2.65 (1.37–5.14) | 0.003 | |
| Unknown | 1.09 (0.67–1.78) | 0.72 | |||
| Surgery | |||||
| No | Reference | Reference | |||
| Yes | 0.21 (0.12–0.38) | <0.001 | 0.25 (0.13–0.48) | <0.001 | |
| Unknown | 0.41 (0.06–3.00) | 0.38 | |||
| Radiation | |||||
| Yes | Reference | Reference | |||
| No/unknown | 0.36 (0.21–0.62) | <0.001 | 1.03 (0.53–1.98) | 0.94 | |
| Chemotherapy | |||||
| No/unknown | Reference | Reference | |||
| Yes | 0.38 (0.25–0.60) | <0.001 | 0.37 (0.22–0.62) | <0.001 | |
CI, confidence interval; HR, hazard ratio; M, metastasis; N, node; OS, overall survival; SRCC, signet-ring cell carcinoma; T, tumor.
Table 4. Prognostic factors for CSS among patients with SRCC of the bile duct by univariate and multivariate Cox analysis.
| Characteristics | Univariate Cox | Multivariate Cox | |||
|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | ||
| Age (years) | |||||
| <68 | Reference | Reference | |||
| ≥68 | 1.74 (1.10–2.75) | 0.02 | 1.78 (1.08–2.93) | 0.02 | |
| Sex | |||||
| Female | Reference | ||||
| Male | 0.99 (0.62–1.58) | 0.97 | |||
| Race | |||||
| White | Reference | ||||
| Black | 1.20 (0.57–2.52) | 0.63 | |||
| Other | 0.63 (0.28–1.38) | 0.25 | |||
| Primary site | |||||
| Intrahepatic bile duct | Reference | ||||
| Extrahepatic bile duct | 0.86 (0.44–1.69) | 0.67 | |||
| T stage | |||||
| T1/T2 | Reference | ||||
| T3/T4 | 1.64 (0.83–3.22) | 0.15 | |||
| Unknown | 1.30 (0.69–2.42) | 0.42 | |||
| N stage | |||||
| N0 | Reference | ||||
| N1 | 1.23 (0.64–2.39) | 0.53 | |||
| Unknown | 1.04 (0.62–1.74) | 0.87 | |||
| M stage | |||||
| M0 | Reference | Reference | |||
| M1 | 2.89 (1.54–5.42) | 0.001 | 3.14 (1.58–6.26) | 0.001 | |
| Unknown | 1.13 (0.66–1.91) | 0.66 | |||
| Surgery | |||||
| No | Reference | Reference | |||
| Yes | 0.23 (0.12–0.42) | <0.001 | 0.26 (0.13–0.53) | <0.001 | |
| Unknown | 0.47 (0.06–3.44) | 0.46 | |||
| Radiation | |||||
| Yes | Reference | Reference | |||
| No/unknown | 0.43 (0.25–0.74) | 0.30 | 1.13 (0.57–2.22) | 0.73 | |
| Chemotherapy | |||||
| No/unknown | Reference | Reference | |||
| Yes | 0.46 (0.29–0.74) | <0.001 | 0.42 (0.24–0.73) | <0.001 | |
CI, confidence interval; CSS, cancer-specific survival; HR, hazard ratio; M, metastasis; N, node; SRCC, signet-ring cell carcinoma; T, tumor.
Constructing prognostic nomogram
The nomogram was developed to predict the survival outcomes (OS and CSS) of patients with SRCC of the bile duct using the independent prognostic factors identified in the multivariate Cox analysis (Figure 3). Among these two established nomograms, distant metastasis and surgery contributed greatly to the prediction of OS and CSS, followed by age and chemotherapy. The C-index of nomogram for predicting OS and CSS was 0.78 (95% CI: 0.71–0.84) and 0.78 (95% CI: 0.70–0.85), respectively. The calibration curve showed that the estimated value matched the observed value (Figure S1). The receiver operating characteristic (ROC) analysis of these nomograms demonstrated that the AUC of 6-, 12-, and 24-month OS reached 0.80, 0.88, and 0.92, respectively, while the AUC of 6-, 12-, and 24-month CSS reached 0.80, 0.86, and 0.91, respectively (Figure 4A,4B). Furthermore, DCA suggested that nomogram models showed a substantial positive net benefit in predicting the risk of death (Figure 4C,4D).
Figure 3.
Establishment of prognostic nomograms for predicting OS (A) and CSS (B) for patients with SRCC of the bile duct. CSS, cancer-specific survival; M, metastasis; OS, overall survival; SRCC, signet-ring cell carcinoma.
Figure 4.
ROC analysis (A,B) and DCA (C,D) of the established nomograms. AUC, area under the curve; CSS, cancer-specific survival; DCA, decision curve analysis; OS, overall survival; ROC, receiver operating characteristic.
Discussion
Primary SRCC of the bile duct is a rare malignancy, with the most relevant research consisting of case reports or case series. Due to its rarity, there is limited understanding of the clinicopathological features and prognosis of this rare disease, underscoring the need for population-based studies on this uncommon condition. The SEER database plays a crucial role in providing a large patient cohort, offering more reliable data and insights than single-center studies alone (14,15). This study involved the largest cohort of patients diagnosed with primary SRCC of the bile duct and aimed to describe the characteristics and prognosis of this disease.
This study indicated that SRCC of the bile duct is typically present in elderly patients, with an average age of 66.4 years, and shows a slight male predominance (1.23:1). These demographic features were not entirely consistent with the findings of previous studies. Xie et al. reported 12 cases with an average age of 58.5 years, ranging from 31 to 73 years (5). This case series reported a female predominance, with a female-to-male ratio of 3:1 (5). This study further confirms that population-based studies can provide a more comprehensive overview of rare diseases than case reports or case series. In addition, previous reports have indicated that primary SRCC of the extrahepatic bile duct predominantly exhibits wall-invasive growth and is more likely to develop lymph node metastases but not distant metastasis (6,8-11). Among the 48 cases with known information on lymph node metastasis in this population-based study, 31.3% had positive lymph node metastasis. Meanwhile, 19 of 54 (35.2%) patients with known information on distant metastasis had positive distant metastases. Survival analysis indicated that distant and lymph node metastases were significantly associated with both OS and CSS among these patients. These findings on the disease characteristics from population-based studies are crucial for understanding this rare disease.
Our data showed that 86.7% of SRCC occurred in the extrahepatic bile duct, suggesting the extrahepatic bile ducts as the predominant disease site. All previously reported SRCC cases originated in the extrahepatic bile duct, and no case in the intrahepatic bile duct has been reported. In addition, previous case studies reported that eight out of 11 patients had primary SRCC in the extrahepatic bile duct located in the distal region, with the remaining three cases in the perihilar bile duct (5). Cumulative evidence from both current and prior studies showed that primary SRCC of the bile duct was more common in the extrahepatic bile duct than in the intrahepatic bile duct, with a higher occurrence in the distal bile duct than in the perihilar bile duct. SRCC of the bile duct, a rare form of bile duct adenocarcinoma, has uncertain origin. There are two theories about where it may come from, with one suggesting that it starts in the ectopic gastric mucosa and the other proposing that it stems from gastric-type epithelial metaplasia (5). Thus, the potential mechanism of occurrence in these specific sites is that the distal bile duct may be prone to the ectopic gastric mucosa and gastric-type epithelial metaplasia; however, these epidemiological data are required to be confirmed further (5,9).
Owing to the insidious onset of biliary system tumors, most patients are already ineligible for surgery at the time of initial diagnosis (16,17). However, surgery remains the most important treatment strategy to significantly improve patient survival. This phenomenon has also been observed in patients with SRCC of the bile duct. In this study, only 26.5% of patients underwent surgery after the diagnosis of SRCC of the bile duct, but surgery could reduce the risk of death from any cause and from this disease by 75% and 74%, respectively. Owing to the aggressive behavior and advanced stage at initial diagnosis, nearly half of the patients in this study received chemotherapy in the current cohort. Multivariate Cox regression analysis confirmed that chemotherapy is an independent prognostic factor associated with better survival. These results highlight the significant role of surgery and chemotherapy in patients with SRCC of the bile duct (18,19). In addition, 23.5% of the patients underwent radiotherapy; however, the role of radiotherapy remains ambiguous since multivariate Cox analysis after adjusting for confounding factors did not observe radiotherapy as an independent prognostic factor for both OS and CSS. However, these conclusions should be cautiously explained owing to the small sample size and limited information regarding chemotherapy and radiotherapy.
Survival analysis showed that patients with SRCC of the bile duct had relatively worse survival rates than those with CCA in both the unmatched and matched cohorts, but without significant statistical differences. This finding provides important new insights into the poor prognosis of this disease. For instance, the 5-year survival rate for this entire cohort was less than 10%, with a mOS of only four months among patients with distant metastasis. Based on the consistency between OS and CSS curves, we speculate that the primary cause of mortality in these patients may be directly related to the tumor itself rather than other non-cancer-related factors due to the malignant behavior of this rare disease. In addition, the independent prognostic factors for survival included age, distant metastasis, surgical intervention, and chemotherapy. These prognostic factors play an important role in the development of predictive nomograms for OS and CSS, which were evidenced by the C-index values and calibration plots. Despite these promising findings, external validation in independent patient cohorts is necessary to confirm the reliability and generalizability of nomograms.
There are several limitations in this study. First, the retrospective nature of the analysis based on the SEER database may introduce biases due to potential inaccuracies in data reporting and missing variables (e.g., detailed treatment responses, surgery margin status, performance status, etc.), and incomplete TNM staging information. The lack of molecular or genetic profiling limits understanding of SRCC’s biological mechanisms. Second, the small sample size of SRCC cases (n=98) may affect the precision of subgroup analyses, particularly for treatment modalities like radiotherapy. Third, an independent external cohort could not be set due to its rarity in real-world practice, raising questions about the generalizability of nomograms. This is required to further validate the predictive accuracy of these models in the future. Prospective studies integrating molecular data and external validation are needed to confirm these findings and improve clinical management.
Conclusions
In summary, this population-based study provides a new understanding of the clinicopathological characteristics and prognosis of patients with SRCC of the bile duct, utilizing data from the SEER database. The study demonstrated that this rare disease often occurs in the extrahepatic bile duct and is associated with poor survival. We constructed a prognostic nomogram that showed accuracy and reliability in predicting the survival of primary SRCC of the bile duct. Moreover, these models could enable physicians to predict the prognosis of individual with this disease.
Supplementary
The article’s supplementary files as
Acknowledgments
The authors would like to thank the SEER database for supplying clinical information.
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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Footnotes
Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2662/rc
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-2024-2662/coif). The authors have no conflicts of interest to declare.
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