Abstract
Background
Updated epidemiological data of neuroendocrine tumors are currently lacking. Thus, we performed epidemiological and survival analyses on a large cohort of patients with neuroendocrine tumors and developed a new nomogram to predict survival.
Methods
This population-based study examined 112,256 patients with neuroendocrine tumors between 2000 and 2018 using data from the Surveillance, Epidemiology, and End Results program.
Results
The age-adjusted incidence per 100,000 persons of neuroendocrine tumors increased from 4.90 in 2000 to 8.19 in 2018 (annual percentage change, 3.40; 95% confidence interval, 3.13–3.67), with the most significant increases in grade 1, localized stage, and appendix neuroendocrine tumors. The age-adjusted mortality rate increased 3.1-fold from 2000 to 2018 (annual percentage change, 4.14; 95% confidence interval, 3.14–5.15). The 1-, 5-, and 10-year relative survival rates for all neuroendocrine tumors were 80.5%, 68.4%, and 63.5%, respectively. Multivariate analyses showed that male sex; older age; Black, American Indian, and Alaska Native populations; earlier year of diagnosis; lung neuroendocrine tumors; higher grades; and later stage were associated with a worse prognosis and that disease stage and grade were the most important risk factors for prognosis. Furthermore, we established a nomogram to predict the 3-, 5-, and 10-year survival rates, and its discrimination ability was better than that of the TNM classification.
Conclusions
The incidence, prevalence, and mortality rate of neuroendocrine tumors continued to increase over the last two decades. Additionally, the nomogram could accurately quantify the risk of death in patients with neuroendocrine tumors and had good clinical practicability.
Background
Neuroendocrine tumors (NETs) are a rare group of tumors that develop from neuroendocrine cells and peptidergic neurons with endocrine functions and express neuroendocrine markers. NETs can occur in any body part, but they occur most commonly in the lung, gastrointestinal tract, and pancreas (1, 2, 3). NETs are highly heterogeneous tumors. Most NETs are relatively indolent; however, some are highly aggressive and metastatic (4, 5, 6). The incidence of NETs has significantly increased from 1.09/100,000 to 6.98/100,000 between 1973 and 2012 in the USA (1); however, updated epidemiologic data are currently lacking.
With improvements in diagnostic techniques (7, 8), stage migration due to updated staging and grading classifications (9, 10, 11), and more effective administered therapies, the prognosis of most patients with NETs has improved significantly. Although NETs have traditionally been considered rare and indolent neoplasms, their biological behavior varies greatly depending on the primary tumor location, histological differentiation and proliferation rate, ability to secrete various peptides/amines, and the extent of the disease. Given the high heterogeneity of clinical presentations and a rapidly increasing trend of the incidence of NETs, large-scale population-based registry investigations are warranted.
To date, the prognosis of NETs remains largely based on the American Joint Committee on Cancer (AJCC) TNM staging; however, other clinicopathological features, including sex, age, grade, and the primary tumor site may also significantly influence the prognosis (12). To the best of our knowledge, only a few studies have used nomograms to predict the prognosis of all patients with NETs (13, 14, 15).
Methods
Data source and case selection
This study used the Surveillance, Epidemiology, and End Results (SEER) 18 registry program (2000–2018) for epidemiological and survival analyses. We used histology codes from the International Classification of Diseases for Oncology, Third Edition, as described in a previous publication (4), to identify patients with NETs from January 1, 2000, to December 31, 2018 (Supplementary Table 1, see section on supplementary materials given at the end of this article). The institutional review board deemed that this study could be exempted from review and informed consent because the data used in the study were freely available. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines.
Baseline clinicopathological characteristics for all neuroendocrine tumors in the training set and testing set.
| Variables | All patients (n = 29,285) (%) | Training set (n = 20,499) (%) | Validation set (n = 8786) (%) | P |
|---|---|---|---|---|
| Sex | 0.671 | |||
| Male | 13,798 (47.1) | 9675 (47.2) | 4123 (46.9) | |
| Female | 15,487 (52.9) | 10,824 (52.8) | 4663 (53.1) | |
| Age, years | 0.699 | |||
| <30 | 1476 (5.0) | 1035 (5.1) | 441 (5.0) | |
| 30–59 | 13,696 (46.8) | 9554 (46.6) | 4142 (47.2) | |
| ≥60 | 14,113 (48.2) | 9910 (48.3) | 4203 (47.8) | |
| Race | 0.053 | |||
| White | 23,046 (78.7) | 16,114 (78.6) | 6932 (78.9) | |
| Black | 4112 (14.0) | 2848 (13.9) | 1264 (14.4) | |
| AI/ANa | 167 (0.6) | 114 (0.6) | 53 (0.6) | |
| A/PIb | 1960 (6.7) | 1423 (6.9) | 537 (6.1) | |
| Year of diagnosis | 0.379 | |||
| 2000–2004 | 2435 (8.3) | 1739 (8.5) | 696 (7.9) | |
| 2005–2009 | 4527 (15.5) | 3178 (15.5) | 1349 (15.4) | |
| 2010–2014 | 11,414 (39.0) | 7950 (38.8) | 3464 (39.4) | |
| 2015–2018 | 10,909 (37.2) | 7632 (37.2) | 3277 (37.3) | |
| Grade | 0.657 | |||
| I | 19,064 (65.1) | 13,314 (64.9) | 5750 (65.4) | |
| II | 4853 (16.6) | 3389 (16.5) | 1464 (16.7) | |
| III | 4017 (13.7) | 2841 (13.9) | 1176 (13.4) | |
| IV | 1351 (4.6) | 955 (4.7) | 396 (4.5) | |
| Stage | 0.693 | |||
| Localized | 15,604 (53.3) | 10,889 (53.1) | 4715 (53.7) | |
| Regional | 7039 (24.0) | 4944 (24.1) | 2095 (23.8) | |
| Distant | 6642 (22.7) | 4666 (22.8) | 1976 (22.5) | |
| Site | 0.555 | |||
| Lung | 6879 (23.5) | 4785 (23.4) | 2094 (23.8) | |
| Appendix | 3003 (10.3) | 2109 (10.3) | 894 (10.2) | |
| Cecum | 918 (3.1) | 661 (3.2) | 257 (2.9) | |
| Colon | 1009 (3.5) | 722 (3.5) | 287 (3.3) | |
| Pancreas | 4370 (14.9) | 3093 (15.1) | 1277 (14.5) | |
| Rectum | 4793 (16.4) | 3327 (16.2) | 1466 (16.7) | |
| Small intestine | 6337 (21.6) | 4426 (21.6) | 1911 (21.8) | |
| Stomach | 1976 (6.7) | 1376 (6.7) | 600 (6.8) |
aAI/AN: American Indian and Alaska Native; bA/PI: Asian and Pacific Islander.
Stage and grade classification
In the study, the SEER staging system was used according to SEER records and previous reports (4). The tumors were classified as localized, regional, or distant. For tumor classification, the SEER classification scheme was used to systematically categorize cases into four grades, namely, G1, G2, G3, and G4 (4).
Nomogram construction and validation
The research design is presented as a flowchart (Fig. 1). The factors associated with overall survival (OS) were assessed using multivariate Cox proportional hazard regression models. Verification of the nomogram was mainly based on internal (training cohort) and external (validation cohort) discrimination and calibration measurements (16). The consistency index (C-Index) was used to evaluate the discriminative ability of the nomogram. A calibration curve was used to compare the predicted survival according to the nomogram and actual survival. The ability of the nomogram and TNM staging system to predict 3-, 5-, and 10-year survival rates was compared using the area under the curve (AUC) value of the receiver operating characteristic curve.
Flowchart of patient selection and study design. NETs, neuroendocrine tumors.
Citation: Endocrine Connections 12, 12; 10.1530/EC-23-0331
Statistical analysis
The age-adjusted incidence, limited-duration prevalence rates, incidence-based mortality rate (17, 18), and relative survival (RS) (19, 20) were calculated using SEER*Stat software, version 8.4.0 (Surveillance Research Program, National Cancer Institute). We calculated the annual percentage change (APC) by fitting a simple linear model, performing regression on the logarithm of the yearly age-adjusted rates, and thereafter, using slope transformation to calculate the APC (21). The RS trends, including APC and average annual percent change (AAPC), were quantified using the Joinpoint Regression Program (version 4.9.0.1) (22). Statistical analyses were performed using the R software (version 4.0.5; http://www.r-project.org/). All tests of statistical significance were two-sided, and a P < 0.05 was considered to be statistically significant.
Results
Patient characteristics
Between 2000 and 2018, 112,256 patients diagnosed with NETs were identified from the SEER 18 registry database. Among them, 59,195 (52.7%) were women, and more than half of the patients with NETs (64,240, 57.2%) were individuals ≥60 years old (Supplementary Table 2 ). The percentages of White, Black, Asian and Pacific Islander (A/PI), and American Indian and Alaska Native (AI/AN) patients were 77.3% (86,736), 14.4% (16,142), 6.0% (6787), and 0.6% (680), respectively. The number of patients diagnosed gradually increased over the decades from 19,565 in 2000–2004 to 33,593 in 2015–2018. Of the 50,112 NETs with a known grade, 30,289 (27.0%), 8220 (7.3%), 8429 (7.5%), and 3174 (2.8%) were G1, G2, G3, and G4, respectively. Among the 95,853 NETs with a known stage, 51,974 (46.3%), 19,181 (17.1%), and 24,698 (22.0%) had localized, regional, and distant disease, respectively, at the time of diagnosis. Regarding the primary tumor sites of NETs, the lung was most commonly involved (25,455 (22.7%)), followed by the small intestine (19,585 (17.4%)) and rectum (17,956 (16.0%)).
Annual incidence
The annual age-adjusted incidence rate per 100,000 persons of NETs was 4.90 in 2000, which increased to 8.19 in 2018, with an APC of 3.40 (95% confidence interval (CI), 3.13–3.67) as shown in Fig. 2A (and contrasted with an annual age-adjusted incidence of all malignant neoplasms). The detailed incidence data are presented in Supplementary Table 3. The age-adjusted incidence rates significantly increased in male and female patients with an APC of 2.84 (95% CI, 2.53–3.15) and 3.89 (95% CI, 3.61–4.17), respectively. Regarding different races and ethnicities, the age-adjusted incidence rates increased significantly (Fig. 2B).
Incidence of neuroendocrine tumors from 2000 to 2018. (A) All neuroendocrine tumors and all malignant neoplasms, (B) by sex and race, (C) by stage and grade, (D) by site. NETs, neuroendocrine tumors.
Citation: Endocrine Connections 12, 12; 10.1530/EC-23-0331
The incidence rates of NETs per 100,000 persons continued to increase during the period of analysis, which is widely reflected in the stages, grades, and primary sites. Among stage groups from 2000 to 2015, the incidence of localized NETs increased the most from 1.94 to 4.18 (APC, 4.97, 95% CI, 4.24–5.71), followed by regional NETs from 0.86 to 1.36 (APC, 3.39, 95% CI, 3.00–3.78) in compared with distant NETs, which increased from 1.23 to 1.59 (APC, 2.64, 95% CI, 2.04–3.23) (Fig. 2C). Regarding different grades from 2000 to 2017, the incidence increased the most for G1 NETs, from 0.25 to 4.33 (APC, 18.93, 95% CI, 17.42–20.46), followed by G2 NETs, from 0.14 to 0.91 (APC, 11.45, 95% CI, 6.91–16.18) and G3 NETs, from 0.57 to 0.59 (APC, 1.57, 95% CI, 0.80–2.35) as compared to G4 NETs, which increased from 0.26 to 0.26 (APC, 0.81, 95% CI, −1.54–3.21) (Fig. 2C). Among different NETs sites, the incidence increased the most in appendix (from 0.12 to 1.12, APC, 16.35, 95% CI, 13.54–19.23) compared to the lung (from 1.55 to 1.54, APC, 1.01, 95% CI, 0.47–1.55), and only declined in the cecum (from 0.15 to 0.13, APC, −1.73, 95% CI, −2.72 to −0.72) (Fig. 2D). Overall, the highest incidences were 1.57 in the lung, and 4.18 in gastroenteropancreatic sites (including the appendix, 0.45; colon, 0.22; rectum, 1.11; small intestine, 1.21; stomach, 0.46; pancreas, 0.73) in SEER 18 (2000–2018) (Fig. 2D).
Leading specific tumor sites by race, sex, and grade
As shown in Fig. 3, among different races and ethnicities, the lung, small intestine, and rectum were the three most common sites. In the A/PI populations, the rectum, pancreas and lung ranked as the top three sites. The lung, small intestine, and rectum also were the three most common sites among different sexes. Among most sites, including the appendix, pancreas, rectum, small intestine, and stomach, G1 and G2 were the most common, while in the lung, cecum, and colon, G1 and G3 were the most common.
Leading specific tumor sites by race, sex, and grade. (A) by race, (B) by sex, (C) by grade.
Citation: Endocrine Connections 12, 12; 10.1530/EC-23-0331
Prevalence according to tumor grade and site
The detailed 20- and 10-year limited-duration prevalence and absolute counts are presented in Supplementary Table 4. The 20-year limited-duration prevalence increased significantly, from 0.00380% in 1998 to 0.05997% in 2017. Among the grade groups, the prevalence increased the most in G1 NETs (from 0.00017% to 0.02490%), followed by G2 disease (from 0.00013% to 0.00594%) and G3/G4 disease (from 0.00052% to 0.00208%) (Fig. 4A). The prevalence of different primary tumor sites was the highest in the rectum (0.01581%), followed by the small intestine (0.01120%) and the lungs (0.01041%) (Fig. 4B).
Twenty-year limited-duration prevalence of neuroendocrine tumors: (A) by grade and (B) by site.
Citation: Endocrine Connections 12, 12; 10.1530/EC-23-0331
Annual mortality rate
The annual age-adjusted mortality rate per 100,000 persons of NETs was 0.74 in 2000, which increased to 2.31 in 2018, with an APC of 4.14 (95% CI, 3.14–5.15), as shown in Fig. 5A. The age-adjusted mortality rates significantly increased both in male patients from 0.90 to 2.47 with an APC of 3.69 (95% CI, 2.67–4.72) and for female from 0.61 to 2.17 with an APC of 4.55 (95% CI, 3.51–5.61) (Fig. 5B). In different races and ethnicities, the age-adjusted mortality rates also increased significantly (Fig. 5B).
The incidence-based mortality of neuroendocrine tumors from 2000 to 2018. (A) All neuroendocrine tumors, (B) by sex and race, (C) by stage and grade, and (D) by site.
Citation: Endocrine Connections 12, 12; 10.1530/EC-23-0331
Incidence-based mortality rates per 100,000 persons of NETs also increased among stages, grades, and primary sites. The mortality rates increased in all the stage groups from 2000 to 2015, among which localized diseases increased the most from 0.06 to 0.46 (APC, 12.53; 95% CI, 9.19–15.97), followed by the regional diseases (from 0.09 to 0.36 (APC, 8.23; 95% CI, 3.27–13.43)), and distant diseases with an APC of 4.87 (95% CI, 3.43–6.34) (Fig. 5C). Regarding different grades between 2000 and 2017, the mortality rate of G1 NETs rapidly increased from 0.01 to 0.41 (APC, 20.87; 95% CI, 15.95–26.00). The mortality rate of G3 NETs increased rapidly until 2003 and subsequently slowed down, and that of G2 and G4 NETs grew at a uniform rate (Fig. 5C). Among different sites of NETs, the APCs for various sites ranged from 10.01 (95% CI, 7.57–12.51) in the appendix to 1.91 (95% CI, 0.88–2.96) in the lungs. The highest mortality rates per 100,000 persons were 0.57 in the lungs and 0.77 in gastroenteropancreatic sites (including appendix, 0.04; colon, 0.07; rectum, 0.10; small intestine, 0.24; stomach, 0.09; pancreas, 0.23) (Fig. 5D).
Relative survival analysis
The 1-, 5-, and 10-year relative survival rates (RSRs) for all the NETs, based on SEER 18 registry database from 2000 to 2018, were 80.5%, 68.4%, and 63.5%, respectively (Supplementary Table 5). For different grade groups, RSRs of G1 and G2 were close and better and those of G3 and G4 were significantly worse. For stage groups, RSRs were the highest for localized diseases, followed by regional, and were the worst for distant diseases. Among different sites, the rectum and appendix had the best RSRs, whereas lungs had the worst survival.
Supplementary Figs. 1 and 2 illustrate the survival trends of patients with NETs over the study period. The 5- and 10-year RSRs all marginally increased (5-year: AAPC = 0.97, 95% CI 0.94–1.00; 10-year: AAPC = 1.24, 95% CI 1.14–1.34). The 5- and 10-year RSR of the rectum were the highest, and the trends were stable. The RSR of the pancreas increased rapidly, the 5-year RSR increased from 37.00% in 2000 to 58.90% in 2013 (AAPC, 3.67; 95% CI, 3.55–3.79), and the 10-year RSR increased from 31.90% in 2000 to 45.90% in 2008 (AAPC, 4.32; 95% CI, 4.00–4.64). The 5- and 10-year RSR of regional disease increased the most (5-year: AAPC, 1.35; 95% CI, 1.10–1.60; 10-year: AAPC, 1.76; 95% CI, 1.63–1.89), followed by those of distant disease (5-year: AAPC, 0.79; 95% CI, 0.55–1.02; 10-year: AAPC, 1.29; 95% CI, 1.06–1.53), as compared with those of localized disease (5-year: AAPC, 0.26; 95% CI, 0.24–0.28; 10-year: AAPC, 0.37; 95% CI, 0.22–0.53). The 5- and 10-year RSR of G2 disease increased the most (5-year: AAPC, 2.56; 95% CI, 2.29–2.84; 10-year: AAPC, 3.15; 95% CI, 2.83–3.46), followed by those of G3 disease (5-year: AAPC, 1.38; 95% CI, 1.12–1.63; 10-year: AAPC, 1.96; 95% CI, 1.68–2.24) as compared with those of G4 disease (5-year: AAPC, 0.54; 95% CI, 0.14–0.94; 10-year: AAPC, 0.32; 95% CI, −0.62–1.28).
Multivariable analysis of OS
Next, we performed a multivariate analysis to further explore the independent prognostic risk factors (Fig. 6). Disease stage and grade were the most important risk factors for prognosis. Compared with localized disease, the risk of death for the distant disease increased by 4.46 times (hazard ratio (HR), 5.46; 95% CI, 5.13–5.82, P < 0.001). Compared with G1 disease, the risk of death for the G3 (HR, 5.30; 95% CI, 4.98–5.64, P < 0.001) and G4 (HR, 5.56; 95% CI, 5.14–6.02, P < 0.001) diseases significantly increased. Other parameters including sex, age, race, year of diagnosis, and tumor site were significantly associated with survival.
Multivariable regression analysis for neuroendocrine tumors. HR: hazard ratio; NR: not reached; y: year; OS: overall survival; NA: not applicable.
Citation: Endocrine Connections 12, 12; 10.1530/EC-23-0331
Nomogram
At a ratio of 7:3, patients were randomly assigned to the training (20,499) and testing sets (8786). Table 1 presents the baseline clinicopathological characteristics and no significant differences were observed between the two sets. A nomogram for predicting the 3-, 5-, and 10-year survival probabilities was constructed by including prognostic factors in the multivariate analysis based on the training set (Fig. 7A). In the training (internal validation) and validation (external validation) cohorts, the C indexes for OS prediction in the nomogram were 0.853 (95% CI, 0.850–0.856) and 0.857 (95% CI, 0.853–0.861), respectively. Finally, the calibration plots showed consistency between the nomogram outcomes predicting the 3-year (Fig. 7B), 5-year (Fig. 7C), and 10-year (Fig. 7D) OS rates and the actual outcomes in the internal and external validations.
Nomogram (A) to predict 3-, 5-, and 10-year survival probabilities of patients with neuroendocrine tumors and the calibration (B–D) of the nomogram in the training and testing sets, (B) Calibration plots of the nomogram for 3-year survival probabilities, (C) Calibration plots of the nomogram for 5-year survival probabilities, (D) Calibration plots of the nomogram for 10-year survival probabilities. AI/AN, American Indian and Alaska Native; A/PI, Asian and Pacific Islander; y, year; OS, overall survival.
Citation: Endocrine Connections 12, 12; 10.1530/EC-23-0331
Additionally, we compared the predictive ability of the nomogram and TNM staging using the AUC models of 3-, 5-, and 10-year OS rates (Fig. 8). For the SEER data sets, the AUCs of the nomogram predicting the 3-, 5-, and 10-year OS rates were 0.906 (95% CI, 0.899–0.913), 0.899 (95% CI, 0.892–0.906), and 0.858 (95% CI, 0.844–0.872), respectively, whereas for TNM staging, the AUCs were 0.790 (95% CI, 0.780–0.800), 0.786 (95% CI, 0.776–0.796), and 0.771 (95% CI, 0.751–0.790), respectively.
Areas under the curve (AUCs) of receiver operating characteristic (ROC) predicting the nomogram and TNM staging system.
Citation: Endocrine Connections 12, 12; 10.1530/EC-23-0331
Discussion
We conducted a population-based study that provided the largest comprehensive patients with NETs dataset with detailed information on the epidemiology and survival reported up to 2018. The overall incidence of NETs has continued to increase, from 4.90 in 2000 to 8.19 per 100,000 persons in 2018. The survival of patients with NETs has improved recently. Our findings provide a scientific basis for the prevention and control of NETs.
The global incidence of NETs varies significantly. The incidence in European and American countries is generally high, whereas that in Asian countries is low. The incidence rate of NETs in the USA, the UK, and Italy was 8.19/100,000, 8.6/100,000 (23), and 6.4/100,000 (24), respectively, while in China, it was 1.14/100,000 (25). The distribution of NETs differed significantly. The lung, small intestine, and rectal NETs are the most common sites in the USA. A comprehensive analysis from seven European countries concluded that the pancreas and small intestine were the most common sites for NETs (26), which is consistent with other studies (5, 16, 23, 27, 28, 29, 30, 31, 32). A nationwide investigation of 246 population-based cancer registries covering 272.5 million people in China showed that the most common primary sites were the lungs, pancreas, and stomach (25). These differences may be related to biological differences, regional environment, health-care patterns, and data captured by registries (1, 4, 33).
The survival rate of patients with NETs varies across different regions. In this study, the 5- and 10-year RSR for all NETs were 68.4% and 63.5%, respectively. Although a survival gap exists among regions, the overall 5-year RSR in China was 36.2% (25), and in Europe, the 5- and 10-year survival rate were 74.5% and 61%, respectively (26). The distribution of sex, stage, grade, and primary tumor site could partly explain the differences in survival prognosis among regions. Our study showed a higher proportion of women; localized disease; and G1 lung, small intestine, and rectal NETs in the USA. In China, a higher incidence was noted in males and in lung and pancreas sites, while in Europe, stage IV disease was found in approximately half of the patients. The management of NETs was also associated with survival outcomes. Recently, the treatment landscape for patients with NETs has dramatically changed (6). Treatment options for NETs are complex and varied, including endoscopic therapy, surgery, somatostatin analogs (SSA), chemotherapy, peptide receptor radionuclide therapy (34, 35), and targeted therapies (36, 37, 38). The SSA octreotide acetate was initially introduced in 1987. Subsequently, multiple studies (39, 40, 41, 42) have shown that SSAs are considered to be the cornerstone treatment for patients with well-differentiated NETs that relieve symptoms and control tumor growth (43). However, some clinical questions remain, including the optimal dose and administration frequency of SSAs.
We meticulously explored the risk factors for patients with NETs. Multivariate analysis showed that males, older age, Black and AI/AN populations, earlier year of diagnosis, lung NETs, higher grade, and later stage were associated with a worse prognosis. This is consistent with the results of previous studies (1, 13, 44). Possible explanations for the poorer prognosis in men are that estrogen and progesterone receptor expression is associated with the prognosis of patients with NETs and that those with receptor-negative tumors tend to have an inferior prognosis (45, 46); furthermore, men have a greater burden of comorbidities and a higher likelihood of noncancer death (47). We also found that older patients had poorer survival rates, which may be due to the greater number of comorbidities, later diagnosis, lower likelihood of receiving curative treatment, and socioeconomic inequalities in older patients (48). Poorer survival in the black populations may be explained by the general lack of access to medical resources for early diagnosis and treatment (49), and their incidence is likely to be underestimated. Consistent with other studies, we found that the patients with lung NETs had the worst survival, possibly because of a delay in diagnosis (50, 51). Based on these risk factors, we constructed a prognostic nomogram to accurately predict OS and compared its predictive power with that of the traditional TNM staging system. The results showed that the nomogram was superior to the traditional TNM staging system for predicting OS. This model is applicable to a wider population of patients with NETs, owing to the inclusion of the primary tumor site.
Limitations and strengths
There are limitations inherent to all retrospective population-based studies included in this study. First, only malignant NETs are reported in cancer registries, these smaller tumors may appear benign and may not be registered as malignant. Therefore, it is likely that the true incidence is underestimated. However, classifying NETs as benign or malignant may be difficult without obvious histopathological and/or clinical characteristics of malignancy (for instance, metastases). Second, the SEER database captures limited prognostic indicators, and some important information, including functional status, Ki-67, mitotic index (52), surgical status, and systemic therapy, is unavailable, which may affect decision-making and survival. However, this study is one of the largest and most recent studies available, and its size and long-term follow-up data largely compensate for these shortcomings by providing comprehensive epidemiological data, and prognostic information on survival in NETs.
Conclusions
In this study, NETs were noted to continue to increase over the last two decades, with the most significant increases in G1, localized stage, and appendix NETs. Future studies should investigate the reasons for the rise of NETs incidence and develop targeted prevention and control measures.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EC-23-0331.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding
None reported.
Ethics approval and consent to participate
The data analysed and used in this study was obtained from Surveillance, Epidemiology, and End Results (SEER) database in accordance with the SEER data use agreement. Therefore, this study did not require the approval of an ethical board.
Availability of data and materials
Publicly available datasets were analyzed in this study. These data are available at www.seer.cancer.gov.
Author contribution statement
All authors helped to perform the research; PW wrote the manuscript and performed procedures; DH contributed to writing the manuscript and performing data analysis; HC contributed to drafting conception and data analysis; XZ contributed to drafting conception, writing the manuscript and design. All authors approved the final manuscript.
Acknowledgements
We thank the Surveillance, Epidemiology, and End Results Program (National Cancer Institute) for developing the SEER database, and Editage (www.editage.com) for English language editing.
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