
==== Front
Medicine (Baltimore)
Medicine (Baltimore)
MD
Medicine
0025-7974
1536-5964
Lippincott Williams & Wilkins Hagerstown, MD

MD-D-24-04156
00014
10.1097/MD.0000000000039616
3
3700
Research Article
Observational Study
Incidence, survival, and prognostic nomogram of patients with small intestinal neuroendocrine tumors: A SEER population-based study
https://orcid.org/0009-0007-9373-1951
Peng Yao MM py190607@163.com
a
Xu Boqi MM xuboqisz@126.com
a
Zhang Fan MM 1396691020@qq.com
a
Wu Runda MM z1396691029@163.com
a
Tong Shan MM tongs9d@163.com
a
https://orcid.org/0000-0002-5634-2822
Mao Zhongqi MD a*
a Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
* Correspondence: Zhongqi Mao, Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China (e-mail: maozq31@hotmail.com).
13 9 2024
13 9 2024
103 37 e3961616 4 2024
25 5 2024
16 8 2024
Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Small intestinal neuroendocrine tumors (SI-NETs) are a group of rare and significantly heterogeneous tumors with limited research currently available. This study aimed to investigate the incidence, survival, and prognostic factors of SI-NETs. We selected data from the surveillance, epidemiology, and end results (SEER) database between 2000 and 2019 and evaluated the incidence trend of SI-NETs during this period. We utilized the Kaplan–Meier method to examine the association between clinical variables and survival rates. Based on the multivariable Cox regression analysis results, we developed a nomogram to predict the 1-, 2-, and 3-year cancer-specific survival (CSS) of SI-NETs patients. We evaluated the consistency, accuracy, and clinical utility of the nomogram by drawing calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) curves. The incidence of SI-NETs showed an upward trend in recent years. Age, grade, T stage, M stage, and primary tumor surgery were independent risk factors for CSS in SI-NETs patients. The nomogram model based on these risk factors showed high accuracy and clinical benefit. SI-NETs are rare tumors with an increasing incidence rate. The nomogram model is expected to be an effective tool for personalized prognosis prediction in SI-NETs patients, which may benefit clinical decision-making.

incidence
neuroendocrine tumors
nomogram
prognostic factors
survival
OPEN-ACCESSTRUE
==== Body
pmc1. Introduction

Small intestinal neuroendocrine tumors (SI-NETs) represent a rare and heterogeneous group of enterochromaffin-originating tumors in the small intestine, with an increasing incidence in recent years.[1]

Compared to other gastrointestinal malignancies, SI-NETs are typically characterized by an indolent clinical course.[2] The rarity, heterogeneity, nonspecific clinical manifestations, and unique indolent clinical presentation of tumors often contribute to delayed diagnosis, with over 30% of patients already having distant metastases at the time of confirmation.[3]

Due to the secretion of 5-hydroxytryptamine and histamine by the tumor, many patients with delayed diagnosis may exhibit a carcinoid syndrome characterized by facial flushing and diarrhea.[4,5] Another prominent feature of advanced SI-NETs is mesenteric fibrosis, a desmoplastic response from the tumor-infiltrated mesentery and lymph nodes. This condition could potentially give rise to severe complications, including intestinal ischemia, obstruction, or perforation.[6,7] These clinical manifestations of advanced tumors often result in a decrease in patients’ quality of life and survival rate, as well as a significant consumption of social healthcare resources.[3]

The objective of this study was to comprehensively investigate the epidemiological characteristics of SI-NETs using the surveillance, epidemiology, and end results (SEER) database. This study also aimed to predict the survival time of SI-NETs, analyze potential prognostic factors that may affect cancer-specific survival (CSS), and establish a nomogram model based on these independent factors.

2. Methods and materials

2.1. Data source

Data for the analysis in this study were derived from retrospective data in the SEER database. The SEER database, derived from cancer registries in 18 regions of the United States, encompasses approximately 30% of the population.[8] For our analysis, we used the SEER database version available on April 2022 (November 2021 Submission).

2.2. Patient selection

Patient data of SI-NETs from 2000 to 2019 were obtained from the SEER database according to the International Classification of Diseases for Oncology, the Third Edition (ICD-O-3).

The following inclusion criteria were used: tumor located in small intestine (the site code: C17.0–17.9); tumor histological type: neuroendocrine tumor (SEER histology codes: 8013/3, 8041/3, 8152/3, 8153/3, 8156/3, 8240/3, 8241/3, 8242/3, 8243/3,8246/3, 8249/3)[9]; confirmation of SI-NETs diagnosis histologically or microscopically. The following were the exclusion criteria: survival time was unknown or less than 1 month; incomplete clinical and pathological data.

Patient clinical and pathological variables included age, gender, race, marital status, tumor site, tumor grade, tumor size, TNM staging, regional nodes examined, and therapies employed.

2.3. Statistical analysis

The R version 4.2.2 was employed for all statistical analyses. Categorical variables were presented using percentages. Kaplan–Meier curves and log-rank tests were used to generate overall survival (OS) and CSS curves for different subgroups of patients. Using the US population per 1,000,000 person-years as the denominator, the standardized incidence rates of SI-NETs were calculated. The annual percent change (APC) and 95% confidence interval (CI) were used to describe the trend in incidence rates.

After excluding patients who did not die from cancer-specific causes, the remaining SI-NETs patients were randomly divided into a training set and a validation set in a 7:3 ratio. In the training set, univariable and multivariable Cox regression analyses were performed to identify independent risk factors for CSS in SI-NETs patients. A nomogram was constructed to predict the 1-, 2-, and 3-year CSS of patients with SI-NETs based on the independent risk factors. The accuracy and clinical utility of the nomogram were validated by drawing calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) curves.

3. Results

3.1. Incidence and trend of SI-NETs

After selection (Fig. 1), 1727 patients with SI-NETs were included in the study (Table 1). As shown in Figure 2A, the incidence rates of SI-NETs increased from 2000 to 2019 (APC = 7.093, 95% CI: 5.597–8.609, P < .05), reaching its peak in 2017 (6.608 cases per 1,000,000 person-years). Furthermore, we also calculated the incidence rate of SI-NETs by gender (Fig. 2B), age (Fig. 2C), and tumor sites (Fig. 2D). The results revealed a higher incidence rate of SI-NETs in males and individuals aged 60 or older. Compared to the duodenum, SI-NETs were more commonly found in the jejunum and ileum, with the highest incidence rate observed in 2017 (4.705 cases per 1000,000 person-years).

Table 1 Clinical and pathological characteristics of SI-NETs Patients.

Factors	N	Percentage	
Age	
 <60years	669	38.7	
 ≥60years	1058	61.3	
Sex	
 Female	828	47.9	
 Male	899	52.1	
Race	
 Non-Whites	288	16.7	
 White	1439	83.3	
Marital status	
 Married	1077	62.4	
 Single	650	37.6	
Primary tumor site	
 Duodenum	286	16.6	
 Jejunum and ileum	1441	83.4	
Grade	
 I	1304	75.5	
 II	310	18.0	
 III/IV	113	6.5	
Tumor size	
 ＞2cm	697	40.4	
 ≤2cm	1030	59.6	
T stage	
 T0 to 2	563	32.6	
 T3 to 4	1164	67.4	
N stage	
 N0	566	32.8	
 N1	1161	67.2	
M stage	
 M0	1238	71.7	
 M1	489	28.3	
Primary tumor surgery	
 No surgery	55	3.2	
 Local resection	1106	64.0	
 Radical resection	566	32.8	
Metastasectomy	
 No	1444	83.6	
 Yes	283	16.4	
Chemotherapy	
 No	1560	90.3	
 Yes	167	9.7	
Regional nodes examined	
 <4	602	34.9	
 ≥4	1125	65.1	
Abbreviations: SI‐NETs = small intestinal neuroendocrine tumors.

Figure 1. Inclusion and exclusion procedures for SI-NETs patients from SEER database. SEER = surveillance, epidemiology, and end results, SI-NETs = small intestinal neuroendocrine tumors.

Figure 2. Incidence of SI-NETs. (A) overall incidence, (B) sex-based incidence, (C) age-based incidence, and (D) tumor site-based incidence. SI-NETs = small intestinal neuroendocrine tumors.

3.2. Survival Analysis Between Different Pathological Subgroups

We generated the OS and CSS curves for patients with SI-NETs (Fig. 3). Based on our calculations, the 1-, 2-, and 3-year OS rates for SI-NETs patients were 0.937 (0.925–0.948), 0.893 (0.879–0.908), and 0.856 (0.840–0.873), respectively, while the 1-, 2-, and 3-year CSS were found to be 0.958 (0.948–0.969), 0.928 (0.915–0.942), and 0.901 (0.885–0.916), respectively.

Figure 3. Kaplan–Meier survival curves describing the OS (A) and CSS (B) of patients with SI-NETs. OS = overall survival, CSS = cancer-specific survival, SI-NETs = small intestinal neuroendocrine tumors.

Using the Kaplan–Meier method, we further analyzed the relationship between various clinical variables and survival rates in SI-NETs patients. As shown in Figure 4A and B, patients aged ≥ 60 years were significantly associated with poorer OS and CSS. No differences in OS and CSS were observed among patients of different genders (Fig. 4C and D) and tumor sites (Fig. 4E and F). In Figure 4G and H, it can be observed that surgical treatment significantly improved the survival rates of patients. However, we found no significant difference in survival rates between patients who received local resection and radical resection (Fig. 4I and J).

Figure 4. Kaplan–Meier survival curves describing the OS and CSS of SI-NETs patients in different subgroups. (A) age-based OS, (B) age-based CSS, (C) sex-based OS, (D) sex-based CSS, (E) site-based OS, (F) site-based CSS, (G) surgery-based OS, (H) surgery-based CSS, (I) surgical procedure-based OS, and (J) surgical procedure -based CSS. OS = overall survival, CSS = cancer-specific survival, SI-NETs = small intestinal neuroendocrine tumors.

3.3. Feature selection and nomogram construction

A total of 1441 patients with SI-NETs were randomly divided into a training group and a validation group in a ratio of 7:3. Their clinical and pathological characteristics were shown in Table 2, with no significant differences observed.

Table 2 Baseline clinical characteristics of SI-NETs patients in the training and validation sets.

	Training (N = 1008)	Validation (N = 433)	Overall (N = 1441)	χ²	P	
Age				0.11	.736	
 <60years	435 (43.2%)	182 (42.0%)	617 (42.8%)			
 ≥60years	573 (56.8%)	251 (58.0%)	824 (57.2%)			
Sex				2.12	.145	
 Female	473 (46.9%)	222 (51.3%)	695 (48.2%)			
 Male	535 (53.1%)	211 (48.7%)	746 (51.8%)			
Race				0.53	.465	
 Non-Whites	171 (17.0%)	66 (15.2%)	237 (16.4%)			
 White	837 (83.0%)	367 (84.8%)	1204 (83.6%)			
Marital status				1.62	.203	
 Married	654 (64.9%)	265 (61.2%)	919 (63.8%)			
 Single	354 (35.1%)	168 (38.8%)	522 (36.2%)			
Primary tumor site				0.62	.432	
 Duodenum	154 (15.3%)	74 (17.1%)	228 (15.8%)			
 Jejunum and ileum	854 (84.7%)	359 (82.9%)	1213 (84.2%)			
Grade				0.74	.691	
 I	768 (76.2%)	323 (74.6%)	1091 (75.7%)			
 II	172 (17.1%)	82 (18.9%)	254 (17.6%)			
 III/IV	68 (6.7%)	28 (6.5%)	96 (6.7%)			
Tumor size				0.03	.869	
 >2 cm	415 (41.2%)	181 (41.8%)	596 (41.4%)			
 ≤2 cm	593 (58.8%)	252 (58.2%)	845 (58.6%)			
T stage				0.26	.613	
 T0 to 2	332 (32.9%)	136 (31.4%)	468 (32.5%)			
 T3 to 4	676 (67.1%)	297 (68.6%)	973 (67.5%)			
N stage				1.62	.204	
 N0	310 (30.8%)	118 (27.3%)	428 (29.7%)			
 N1	698 (69.2%)	315 (72.7%)	1013 (70.3%)			
M stage				0.92	.337	
 M0	704 (69.8%)	314 (72.5%)	1018 (70.6%)			
 M1	304 (30.2%)	119 (27.5%)	423 (29.4%)			
Primary tumor surgery				0.12	.940	
 No surgery	30 (3.0%)	14 (3.2%)	44 (3.1%)			
 Local resection	639 (63.4%)	271 (62.6%)	910 (63.2%)			
 Radical resection	339 (33.6%)	148 (34.2%)	487 (33.8%)			
Metastasectomy				1.13	.288	
 No	842 (83.5%)	351 (81.1%)	1193 (82.8%)			
 Yes	166 (16.5%)	82 (18.9%)	248 (17.2%)			
Chemotherapy				0.00	.981	
 No	903 (89.6%)	387 (89.4%)	1290 (89.5%)			
 Yes	105 (10.4%)	46 (10.6%)	151 (10.5%)			
Regional nodes examined				2.76	.097	
 <4	340 (33.7%)	126 (29.1%)	466 (32.3%)			
 ≥4	668 (66.3%)	307 (70.9%)	975 (67.7%)			
Abbreviations: SI-NETs = small intestinal neuroendocrine tumors.

In the training set, univariate and multivariate Cox regression analyses were conducted to identify independent risk factors for CSS in SI-NETs patients. The results were presented in Table 3, indicating that local resection (HR = 0.28, 95% CI: 0.18–0.46, P < .001) and radical resection (HR = 0.32, 95% CI: 0.19–0.52, P < .001) were protective prognostic factors, while age ≥ 60 years (HR = 2.81, 95% CI: 2.14–3.67, P < .001), moderately differentiated (HR = 1.68, 95% CI: 1.25–2.25, P = .004), poorly differentiated or undifferentiated (HR = 4.30, 95% CI: 3.14–5.89, P < .001), T3-4 stage (HR = 1.83, 95% CI: 1.31–2.55, P = .003), and M1 stage (HR = 2.45, 95% CI: 1.91–3.14, P < .001) were adverse prognostic factors.

Table 3 Univariate and multivariate analyses of factors associated with CSS in training set.

Characteristics	Univariable	Multivariable	
HR	95% CI	P	HR	95% CI	P	
Age	
 <60 yr	Reference			Reference			
 ≥60 yr	2.56	1.97 to 3.33	<.001	2.81	2.14 to 3.67	<.001	
Sex	
 Female	Reference						
 Male	1.05	0.83 to 1.32	.740				
Race	
 Non-Whites	Reference						
 White	0.98	0.72 to 1.33	.916				
Marital status	
 Married	Reference			Reference			
 Single	1.63	1.30 to 2.06	<.001	1.20	0.94 to 1.52	.222	
Primary tumor site	
 Duodenum	Reference						
 Jejunum and ileum	1.08	0.78 to 1.50	.701				
Grade	
 I	Reference			Reference			
 II	1.79	1.34 to 2.40	.001	1.68	1.25 to 2.25	.004	
 III/IV	6.02	4.48 to 8.08	<.001	4.30	3.14 to 5.89	<.001	
Tumor size	
 >2 cm	Reference			Reference			
 ≤2 cm	0.56	0.44 to 0.70	<.001	0.79	0.62 to 1.01	.116	
T stage	
 T0 to 2	Reference			Reference			
 T3 to 4	2.60	1.92 to 3.53	<.001	1.83	1.31 to 2.55	.003	
N stage	
 N0	Reference						
 N1	0.91	0.71 to 1.16	.517				
M stage	
 M0	Reference			Reference			
 M1	3.13	2.49 to 3.94	<.001	2.45	1.91 to 3.14	<.001	
Primary tumor surgery	
 No surgery	Reference			Reference			
 Local resection	0.24	0.15 to 0.37	<.001	0.28	0.18 to 0.46	<.001	
 Radical resection	0.30	0.19 to 0.48	<.001	0.32	0.19 to 0.52	<.001	
Metastasectomy	
 No	Reference						
 Yes	1.04	0.77 to 1.40	.838				
Chemotherapy	
 No	Reference			Reference			
 Yes	3.17	2.41 to 4.16	<.001	1.42	1.05 to 1.93	.059	
Regional nodes examined	
 <4	Reference						
 ≥4	0.77	0.61 to 0.97	.063				
Abbreviations: CI = confidence interval, CSS = cancer-specific survival, HR = Hazard ratio.

Based on these independent risk factors, we constructed a nomogram to predict the 1-, 2-, and 3-year CSS rates of patients with SI-NETs (Fig. 5). The total predicted score was obtained by summing the scores of each variable.

Figure 5. A nomogram for predicting the 1-, 2-, and 3-yr CSS in patients with SI-NETs. CSS = cancer-specific survival, SI = small intestinal neuroendocrine tumors.

3.4. Performance and validation of the nomogram

The calibration curves of the nomogram demonstrated a high level of consistency between the predicted probabilities and the actual probabilities of CSS in both the training and validation sets (Fig. 6). In the training set, the AUC values of the nomogram for predicting 1-, 2-, 3- year CSS were 0.813 (95% CI: 0.739–0.887), 0.812 (95% CI: 0.753–0.870), and 0.810 (95% CI: 0.760–0.860), respectively (Fig. 7A). Similarly, in the validation set, the AUC values of the nomogram for predicting 1-, 2-, 3- year CSS were 0.838 (95% CI: 0.724–0.953), 0.881 (95% CI: 0.810–0.952), and 0.849 (95% CI: 0.788–0.909), respectively (Fig. 7B). Both the calibration curves and the ROC curves confirmed the accuracy and discriminative ability of the nomogram. Furthermore, the DCA curves indicated that the clinical value of the nomogram was higher than the TNM staging in both the training and validation sets (Fig. 8).

Figure 6. The calibration curves for predicting 1- (A), 2- (B), and 3-yr (C) CSS in the training set. The calibration curves for predicting 1- (D), 2- (E), and 3-yr (F) CSS in the validation set. CSS = cancer-specific survival.

Figure 7. ROC curves for the 1-, 2-, and 3-yr CSS in the training set (A) and validation set (B). ROC = receiver operating characteristic, CSS = cancer-specific survival.

Figure 8. The DCA curves of the nomogram and TNM staging system for predicting the 1- (A), 2- (B), and 3-yr (C) CSS in the training set. The DCA curves of the nomogram and TNM staging system for predicting the 1- (D), 2- (E), and 3-yr (F) CSS in the validation set. DCA = decision curve analysis, CSS = cancer-specific survival.

4. Discussion

SI-NETs are heterogeneous neoplasms with varying behaviors. Although some are relatively indolent, others may be more aggressive and fatal.[10] These relatively rare neoplasms can be studied effectively with large population-based registries. In this study, we analyzed data from 1727 patients with SI-NETs, sourced from the SEER database. We analyzed the incidence trend of SI-NETs over the past 20 years and identified the risk factors that impact prognosis. Subsequently, we developed a nomogram model and successfully validated its effectiveness.

SI-NETs have become increasingly prevalent over the last decades, making them 1 of the most frequently diagnosed small intestinal malignancies.[11] Our study revealed that the incidence rate of SI-NETs was only 0.964 cases per 1,000,000 person-years in 2000, but by 2019, it increased to 6.177 cases per 1,000,000 person-years, which was 6.4 times higher than before. While the development and availability of diagnostic techniques such as endoscopy, computed tomography, and magnetic resonance imaging might have been the primary reasons for the increased incidence, it remained unclear if other factors had also contributed to the rise in incidence.[12,13] Furthermore, our subgroup analysis revealed that SI-NETs had a higher incidence rate in males and individuals aged 60 or older, and they were more likely to occur in the ileum and jejunum. These findings were consistent with previous research studies.[3,14]

The prognosis for patients with SI-NETs was relatively favorable.[15,16] Koch et al discovered that the 3-year OS rate for SI-NETs patients was 0.843, which was very close to the 3-year OS rate of 0.856 we obtained from our research.[15] Wu et al discovered that surgical treatment can significantly enhance patient survival rates. However, there was no significant difference in survival rates between patients who received local resection and radical resection.[17] Our subgroup analysis also yielded the same conclusion.

Previous studies have indicated a significant correlation between age, tumor grade, tumor infiltration depth, distant metastasis, and survival rate in SI-NETs patients.[18,19] In this study, we also identified the aforementioned clinical and pathological characteristics as independent risk factors for CSS in SI-NETs patients through univariate and multivariate Cox regression analysis. Despite the high survival rate, serious complications may still occur, due to the fibroproliferative response at the primary tumor site.[20] Surgical treatment served as the cornerstone of the multimodal therapy for SI-NETs, and may be curative when a complete R0 resection was obtained.[21] Our study found that surgical treatment significantly improved the survival rate of SI-NETs patients and was also an independent risk factor for CSS.

The SI-NETs are malignant tumors of the small intestine, which can be divided into 2 types: well-differentiated and poorly differentiated. This study established a nomogram to predict the CSS of patients with these 2 types of SI-NETs. Although we developed a nomogram model based on the independent risk factors identified from the training set data and validated it in both the training and validation sets, this study still had some limitations. Firstly, it was a retrospective study that utilized the SEER database, which might have introduced selection bias when including patients. Secondly, the SEER database lacked important information such as general patient condition, overall tumor burden, Ki-67 index, pathological differentiation, mitoses and immunohistochemical markers, which could also be related to the prognosis of SI-NETs patients.[22] Thirdly, detailed treatment information was lacking, such as chemotherapy regimens, immunotherapy, and targeted therapy.

5. Conclusion

In conclusion, SI-NETs are rare tumors with an increasing incidence rate and a relatively favorable prognosis. Age, grade, T stage, M stage, and primary tumor surgery are independent risk factors for CSS in SI-NETs patients. A nomogram model based on these risk factors has shown high accuracy and clinical benefit, enabling doctors to predict patient prognosis and make treatment decisions accurately.

Acknowledgments

We are grateful for all our colleagues in Department of General Surgery, The First Affiliated Hospital of Soochow University.

Author contributions

Conceptualization: Yao Peng.

Data curation: Yao Peng, Fan Zhang.

Formal analysis: Yao Peng, Zhongqi Mao.

Funding acquisition: Boqi Xu, Runda Wu, Shan Tong.

Investigation: Zhongqi Mao.

Methodology: Yao Peng, Runda Wu.

Project administration: Shan Tong.

Software: Yao Peng, Boqi Xu, Fan Zhang, Runda Wu, Zhongqi Mao.

Supervision: Shan Tong.

Visualization: Runda Wu.

Writing – original draft: Boqi Xu, Shan Tong, Zhongqi Mao.

Writing – review & editing: Boqi Xu.

Abbreviations:

APC annual percent change

CI confidence interval

CSS cancer-specific survivalcc

DCA decision curve analysis

HR hazard ratio

ICD-O-3 International Classification of Diseases for Oncology, the Third Edition

OS overall survival

ROC receiver operating characteristic

SEER surveillance, epidemiology, and end results

SI-NETs small intestinal neuroendocrine tumors

TNM tumor node metastasis

The authors declared that no funds, grants, or other support were received during the preparation of this manuscript.

Informed consent is waived as SEER is a de-identified, publicly available cancer database.

None of the authors involved in this article conducted any studies involving human participants or animals.

The authors have no affiliations with or involvement in any organization or entity with any financial interest or not-for-profit non-financial interest in the subject matter.

The datasets used are available from the corresponding author on reasonable request.

How to cite this article: Peng Y, Xu B, Zhang F, Wu R, Tong S, Mao Z. Incidence, survival, and prognostic nomogram of patients with small intestinal neuroendocrine tumors: A SEER population-based study. Medicine 2024;103:37(e39616).

YP and BX contributed equally to this work.
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