ENDOCRINE SOCIETY
OXFORD
Rising Incidence of Neuroendocrine Neoplasms in Northern Switzerland-Data From the Cancer Registry
Alessa Fischer,10 Miriam Wanner,20D Flurina Suter,2,3[D Dimitri Korol,2,3[D Constanze Hantel,1D Felix Beuschlein, 1,4,50D Sena Blümel, 60D Ralph Fritsch,70D Andreas Wicki,2,7 [D Sabine Rohrmann,2,3[D and Svenja Nolting 1.4D
1Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich CH-8091, Switzerland
2Cancer Registry of the Canton Zurich, Zug, Schaffhausen and Schwyz, University Hospital Zurich, Zurich CH-8091, Switzerland
3Division of Chronic Disease Epidemiology, Epidemiology, Biostatistics, and Prevention Institute, University of Zurich, Zurich CH-8091, Switzerland
4Department of Medicine IV, University Hospital, Ludwig-Maximilians-University Munich, Munich 80336, Germany
5The LOOP Zurich-Medical Research Center, Zurich 8044, Switzerland
6Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich CH-8091, Switzerland
7Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich CH-8091, Switzerland
Correspondence: Prof. Svenja Nölting, MD, Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich, Rämistrasse 100, Zurich CH-8091, Switzerland. Email: svenja.noelting@usz.ch.
Abstract
Context: Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors that arise in multiple organs and encompass pheochromocytomas/paragangliomas (PPGLs). Adrenocortical carcinoma (ACC), though distinct, is a rare endocrine malignancy with a poor prognosis. We analyzed incidence and survival trends across NENs and ACC over 4 decades.
Methods: We conducted a population-based study using cancer registry data from the Canton of Zurich (1980-2022). NENs were classified by site and histology. Age-standardized incidence rates (ASIRs) were calculated per 100,000 person-years (European standard population). Joinpoint regression estimated the annual percent change (APC) for each trend segment and the average APC (AAPC) for the period.
Results: A total of 2723 patients with a diagnosis of a NEN (n = 2647) or ACC (n = 76) between 1980 and 2022 were extracted from the database. ASIR of gastrointestinal NENs rose from 1.4 in 1980 to 11.3 per 100,000 in 2022 [AAPC +5.07%, 95% confidence interval (CI) 4.20-6.50%], with the most pronounced increases in rectal and appendiceal NENs, particularly since the early 2000s. Pancreatic NEN incidence also increased, especially from 2004 to 2022 (0.6-2.7 per 100,000; APC 5.36%, 95% CI 3.13-16.97%). ASIR of PPGLs rose from 0 in 1980 to 0.4 per 100,000 by 2022, while the ASIRs of ACC remained stable with ASIR of 0.2 per 100,000 in 2022.
Conclusion: The incidence of gastroenteropancreatic NENs and PPGLs continues to rise, with a pronounced acceleration since the early 2000s. These trends underscore the need for a deeper understanding of risk factors underlying NEN development.
Key Words: gastroenteropancreatic, pulmonary, NEN, PPGL, incidence, adrenocortical carcinoma
Neuroendocrine neoplasms (NENs) represent a diverse group of tumors originating from endocrine tissues located through- out the body. NENs can be found in the gastrointestinal sys- tem, the pancreas, the lung, the thymus, or the thyroid [medullary thyroid carcinomas (MTCs)]. Based on histology (morphology and proliferation), NENs are categorized in well-differentiated neuroendocrine tumors (NETs) G1, G2, or G3 depending on their proliferation (mitotic index, Ki-67 index) and poorly differentiated neuroendocrine carcinomas (NECs) [1]. NECs represent approximately 10% of all NENs depending on the organ they arise from [1].
Tumors arising from the sympathetic and parasympathetic paraganglia (paragangliomas) or from the adrenal medulla (pheochromocytomas; intra-adrenal paragangliomas) collect- ively known as pheochromocytomas/paragangliomas (PPGLs),
also belong to the family of NENs [2, 3]. Adrenocortical carcin- omas (ACCs), though not NENs, are very rare endocrine malig- nancies that arise from the cortex of the adrenal gland and generally have a poor prognosis [4].
Surgery is the only curative treatment option for most NENs, ACCs, and PPGLs [4, 5]. However, at the time of diag- nosis, approximately 40% to 45% of gastroenteropancreatic (GEP) NENs have already metastasized to other organs, ne- cessitating systemic treatment approaches [5].
Globally, an increase in NEN incidence has been reported since the early 2000s [6-11]. In Europe, Swiss cancer registry data from Vaud and Neuchâtel (1976-2016) reported an average annual rise in GEP-NEN incidence by 1.7% in men and 1.3% in women [12]. Data from Germany showed a doubling of GEP-NEN incidence from 2.2 to 4.8 per
100,000 between 2005 and 2019 [7]. In the United States, GEP- and pulmonary NEN incidence increased more than 5-fold between the 1970s and 2021, reaching up to 8.52 per 100,000 (2021), with prominent increases observed across al- most all sites and stages and a shift toward earlier-stage diag- noses [6, 13]. In the present study, we analyzed incidence trends and survival across a comprehensive range of neuroen- docrine neoplasms, including not only GEP-NENs but also pulmonary NENs, medullary thyroid carcinoma, and PPGLs and, in addition, reported separately on the non-NEN entity ACC using data from the cancer registry of the Canton of Zurich, the most populous region in Switzerland.
Methods
This study retrospectively analyzed data from the population- based cancer registry of the Canton of Zurich. The Canton of Zurich represents approximately 18% of the total population of Switzerland (end of 2022: Zurich 1.578 million, Switzerland 8.815 million inhabitants) [14]. Within the cancer registry, data of every patient diagnosed with cancer whose reg- istered residence was in the Canton of Zurich at the time of diag- nosis have been collected since 1980 [15]. Patient and tumor information is derived from pathology laboratories, treating physicians, and hospitals. Cancer cases in the Canton of Zurich have been registered under a presumed consent frame- work, based on a 1980 decision by the Zurich Government Council and a general approval granted in 1995 by the Federal Commission of Experts for Professional Secrecy in Medical Research. All data used for this study were anonymized.
For this study, we analyzed patients diagnosed with NENs based on histology and registered in the cancer registry of Zurich between 1980 and 2022. Primary tumor site topog- raphy and morphology according to the International Classification of Diseases for Oncology (ICD-O), age at diag- nosis, sex, and survival data were extracted from the registry in April 2025. The ICD-O topography code defines the tu- mor’s anatomical site of origin, while the morphology code specifies its histological type and behavior.
NENs were categorized based on topography and morph- ology codes as follows (Table S1 [16]): esophageal NEN (C15), gastric NEN (C16), small intestinal NEN (C17), colonic NEN (C18, excluding C18.1; C19; C26), rectal NEN (C20), appendiceal NEN (C18.1), pancreatic NEN (C25), pulmonary carcinoid (C34), PPGL (C74.1; morphology code 8700 and C75.5; morphology code 8680), ACC (C74.0; morphology code 8370), MTC (C73.9; morphology codes 8345-8347), thymic carcinoid (C37.9; morphology codes 8240 and 8249), and mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs) of any site (morphology codes 8244 and 8245). Based on morphology independent of site, NETs were further differentiated into NETs G1 (morphology codes 8240) and G2/3 (8249; the distinction between grades 2 and 3 was not feasible due to the absence of proliferative indices); poorly differentiated NECs including small-cell NECs (code 8041), large-cell NECs (codes 8013 and 8243), and NECs not other- wise specified (code 8246); and MiNENs including codes 8154 (of the pancreas) and 8244/45. The group “other pancre- atic NETs” comprised functioning pancreatic NETs such as in- sulinoma (code 8151), glucagonoma (code 8152), gastrinoma (code 8153), vipoma (code 8155), and nonfunctioning pancre- atic endocrine tumor, well-differentiated, with grade not fur- ther specified (code 8150).
Statistics
Annual incidence rates were calculated per 100,000 person- years and age-standardized to the European standard popula- tion using the direct method [17]. Population data from the Canton of Zurich (1981-2022) were used for standardization [14]. For 1980, population data of the Canton of Zurich were not available; therefore, the population from 1981 was used. Rates were stratified by tumor site and sex. Temporal trends were assessed using Joinpoint regression software [18], applying a grid search algorithm with constraints on minimum segment length and number of joinpoints [18, 19]. Heteroscedasticity was adjusted for by using standard errors. Average annual per- cent change (AAPC) with 95% confidence intervals (CIs) was estimated as a summary measure for the entire observation pe- riod (1980-2022). Annual percentage changes (APC) were esti- mated for each trend segment between two joinpoints.
The Kaplan-Meier method was used to estimate median overall survival (OS) stratified by tumor site with follow-up time defined as the time between diagnosis and death, loss of follow-up, or last follow-up, whichever occurred first. A log-rank test was performed to compare the survival distribu- tion of subgroups. Statistical significance was determined at a 2-sided a of .05. Statistical analyses were conducted using the open-source statistics software R (version 4.3.2, R Foundation for Statistical Computing, Vienna, Austria) [20].
Results
A total of 2723 patients with a diagnosis of a NEN or ACC between 1980 and 2022 were extracted from the database of the Cancer Registry of the Canton of Zurich. Thereof, 1363 (50.1%) were female. Gastrointestinal NENs were pre- sent in 1581 patients, with small-intestinal NENs being the most frequent (n = 626) within this group. Pancreatic NENs were present in 397 patients; 486 patients had a pulmonary car- cinoid, 51 patients a PPGL, 76 patients an ACC, 64 patients an MTC, and 5 patients a thymic carcinoid. Sixty-three patients had mixed carcinomas at different sites and were therefore not included in further site-specific calculations. Characteristics of the study cohort are presented in Table 1.
Trends in Incidence of GEP-NENs
Overall, a significant increase in age-standardized incidence rates (ASIR) of gastrointestinal NENs was observed during the study period from 1.4 in 1980 to 11.3 per 100,000 person- years in 2022, corresponding to a significant AAPC of +5.07% (95% CI 4.20-6.50%). The APC increased most dra- matically after 2005 from 3 to 11.5 per 100,000 in 2018 (APC 11.22%, 95% CI 8.99-21.80%), followed by a decline until 2022. The significant increase in ASIR of gastrointestinal NENs was observed for both sexes (Fig. 1A, Table 2).
Then, a subgroup analysis of gastrointestinal NENs based on the anatomical site of the tumor was performed (Table S2 [16]). From 1980 to 2022, no significant changes in AAPC in esophageal and gastric NENs were observed with an ASIR of 0.2 and 0.9 per 100,000 in 2022, respectively. However, a significant increase in ASIR from 1980 to 2022 was observed for small intestinal NEN (from 0.9 to 3 per 100,000, AAPC 2.14%, 95% CI 1.55-2.99%), colon NEN (from 0 to 0.7 per 100,000, AAPC 2.21%, 95% CI 0.82-4.69%), rectal NEN (from 0 to 2.5 per 100,000, AAPC 5.28%, 95% CI 3.33-8.11%), and appendiceal NEN
| Esophageal NEN | Gastric NEN | Small intestinal NEN | Colonic NEN | Rectal NEN | Appendiceal NEN | Pancreatic NEN | Pulmonary Carcinoid | PPGL | ACC | MTC | Thymic Carcinoid | Mixed Carcinoid | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n, patients (%) 15 (0.6) | 144 (5.3) | 626 (23) | 147 (5.4) | 235 (8.6) | 414 (15.2) | 397 (14.6) | 486 (17.8) | 51 (1.9) | 76 (2.8) | 64 (2.4) | 5 (0.2) | 63 (2.3) | 2723 (100) |
| n, female 7 | 65 | 261 | 68 | 109 | 250 | 164 | 284 | 24 | 51 | 40 | 1 | 39 | 1363 |
| n, male 8 | 79 | 365 | 79 | 126 | 164 | 233 | 202 | 27 | 25 | 24 | 4 | 24 | 1360 |
| Age, median (min-max) 76 (58-87) | 67 (25-90) | 68 (25-96) | 65 (21-97) | 54 (18-90) | 51.5 (9-94) | 63 (13-90) | 65.5 (20-99) | 54 (20-81) | 57.5 (1-83) | 55 (6-82) | 53 (26-82) | 64 (37-87) | |
| No. of patients per age groups (years) | |||||||||||||
| <20 — | — | — | — | 1 | 33 | 4 | — | — | 2 | 2 | — | — | 42 |
| 20-34 — | 2 | 10 | 7 | 21 | 63 | 15 | 32 | 6 | 9 | 9 | 1 | — | 175 |
| 35-49 — | 24 | 44 | 19 | 46 | 102 | 63 | 53 | 16 | 12 | 10 | 1 | 9 | 399 |
| 50-64 2 | 38 | 186 | 47 | 107 | 109 | 137 | 144 | 15 | 23 | 28 | 1 | 23 | 860 |
| 65-74 5 | 39 | 197 | 38 | 38 | 59 | 86 | 128 | 8 | 18 | 8 | 1 | 16 | 641 |
| 75-84 6 | 32 | 146 | 29 | 16 | 37 | 76 | 103 | 6 | 12 | 7 | 1 | 14 | 485 |
| >84 2 | 9 | 43 | 7 | 6 | 11 | 16 | 26 | — | — | — | — | 1 | 121 |
Abbreviations: ACC, adrenocortical carcinoma; MTC, medullary thyroid carcinoma; NEN, neuroendocrine neoplasm; PPGL, pheochromocytoma/paraganglioma.
(from 0.3 to 4 per 100,000, AAPC 5.87%, 95% CI 4.78-7.41%) (Table 2). For rectal NENs, the increase in ASIR was most pronounced after 2006, whereas the increase in ASIR was strongest for appendiceal NEN after 2009, repre- senting the highest ASIR of all gastrointestinal NENs with a maximum incidence rate of 4.4 per 100,000 in 2019 (Fig. 1B). In pancreatic NENs, an increasing trend in ASIR was ob- served during the study period. However, Jointpoint regres- sion analysis revealed a significant rise in pancreatic NENs mainly from 2004 to 2022, from 0.6 to 2.7 per 100,000 (APC 5.36%, 95% CI 3.13-16.97%) (Fig. 1C). The rise in pancreatic NENs was more pronounced for males (AAPC 4.25%, 95% CI 2.79-5.60%) than for females (AAPC 2.59%; 95% CI 1.65-4.0%).
Other NENs and Other Endocrine Tumors
In pulmonary carcinoid, a significant increase of the incidence rate from 0.6 in 1980 to 2.3 per 100,000 in 2022 (AAPC 2.31%; 95% CI 1.71-3.22%) was observed, with a more pro- nounced AAPC in females (2.82%; 95% CI: 1.98-4.20%) than in males (1.32%; 95% CI: 0.45-2.65%) (Fig. 1D). In PPGLs, ASIR significantly increased with an AAPC of 2.61% (95% CI 0.17-5.31%) from 0 in 1980 to 0.4 per 100,000 in 2022. The increase was most pronounced after 2015. In contrast, ASIR of MTC (AAPC 0.85%, 95% CI -0.27-2.49%) and ACC (AAPC 0.06%, 95% CI -1.96-2.27%) did not increase significantly between 1980 and 2022 (Fig. 1E).
ASIR based on Histologic Subtypes
Over the observation period, the ASIR of NET G1 increased markedly from 1.8 per 100,000 in 1980 to 11.4 per 100,000 in 2022, representing the primary contributor to the overall rise in incidence. The ASIR of NECs also increased, although more modestly, and started to decline after 2010. Sites of NECs are presented in Table S3 [16]. In contrast, the incidence of MiNENs remained stable across the entire ob- servation period. Notably, the ASIR of other NENs, including functional pancreatic NETs, decreased over the study period (Table 3, Fig. 1F).
Survival Analyses
Kaplan-Meier survival analysis was performed for the sub- groups of NENs based on tumor entity and site. Evidence of a statistically significant difference in median OS between tu- mor subtypes was found (log-rank test, P <. 001). Median OS was 12.6 years (95% CI 11.2-14.3) for gastrointestinal NENs, 4.8 years (95% CI 3.9-6.4) for pancreatic NENs, 7.1 years (95% CI 5.6-10.3) for pulmonary carcinoids, 19.2 years [95% CI 6.9-not reached (NR)] for PPGLs, 2.2 years (95% CI 1.43-3.7) for ACCs, 31.1 years (95% CI 21.9-NR) for MTCs, and 0.6 years (95% CI 0.6-NR) for thymic carcinoids (Fig. 2A, Table S4 [16]).
Next, the median OS of gastrointestinal NENs stratified by site was analyzed. Again, median OS differed significantly be- tween NEN subtypes with esophageal NENs having the short- est OS (median 0.7 years; 95% CI 0.4-1.6) followed by NENs of the colon (median OS 3.6 years; 95% CI 1.8-6.6). Patients with NENs of the small intestine had a median OS of 6.7 years (95% CI 5.6-8.6) and those with gastric NENs of 13 years (95% CI 6.8-21.4). The longest median OS was observed in
A
Gastrointestinal NENs
B
Gastrointestinal NENs - Subgroups
12.0
. overall - 3 Joinpoints
11.5
1980-1989 APC = 11.90*
5.0
* Ga NEN - 2 Joinpoints
1980-2009 APC =- 1.24
11.0
-1989-2005 APC =- 1.41
4.5
2009-2013 APC = 41.17*
10.5
2005-2018 APC = 11.22*
2018-2022 APC =- 2.25
2013-2022 APC =- 4.25
10.0
+ female - 3 Joinpoints
* SI NEN - 0 Joinpoints
9.5
1980-1995 APC = 8.79*
4.0
1980-2022 APC = 2.14*
9.0
- 1995-2006 APC = - 5.36
Age-standardized rates (per 100,000)
Age-standardized rates (per 100,000)
* Colon NEN - 0 Joinpoints
8.5
2006-2013 APC =23.27
1981-2022 APC = 2.21*
8.0
2013-2022 APC = 3.98
3.5
* Rect NEN - 1 Joinpoint
+ male - 3 Joinpoints
1982-2006 APC = 0.73
7.5
7.0
1980-1989 APC = 15.45*
3.0
2006-2022 APC = 12.51*
· App NEN - 2 Joinpoints
6.5
- 1989-1999 APC = - 7.24
1999-2020 APC = 7.47
1980-2009 APC = 2.58
6.0
2020-2022 APC =- 13.05
2.5
2009-2012 APC = 48.32*
5.5
2012-2022 APC = 4.86*
5.0
2.0
4.5
4.0
3.5
1.5
3.0
2.5
1.0
2.0
1.5
0.5
1.0
0.5
0.0
0.0
1980
1985
1990
1995
2000
2005
2010
2015
2020
1980
1984
1988
1992
1996
2000
2004
2008
2012
2016
2020
Year
Year
C
D
Pancreatic NENs
Pulmonary Carcinoid
3.0
. overall - 1 Joinpoint
3
* overall - 0 Joinpoints
1980-2004 APC = 0.97
1980-2022 APC = 2.31*
2004-2022 APC = 5.36*
* female - 0 Joinpoints
* female - 0 Joinpoints
1980-2022 APC = 2.82’
* male - 0 Joinpoints
2.5
1980-2022 APC = 2.59*
* male - 1 Joinpoint
- 1980-2022 APC = 1.32*
1980-2020 APC = 2.63
Age-standardized rates (per 100,000)
2020-2022 APC = 42.55*
Age-standardized rates (per 100,000)
2.0
2
1.5
1.0
1
0.5
0
0.0
1980
1985
1990
1995
2000
2005
2010
2015
2020
1980
1985
1990
1995
2000
2005
2010
2015
2020
Year
Year
E
F
Other endocrine tumors
NENs by grade / functionality
1.2
* PPGL - 1 Joinpoint
12
· MINEN - 2 Joinpoints
1981-2016 APC =- 1,45
1989-2009 APC = - 2.78
2016-2022 APC = 29.85*
* ACC - 0 Joinpoints
11
2009-2018 APC = 21.35’
- 2018-2021 APC = - 39.88*
1.0
1980-2022 APC = 0.06
* NEC - 3 Joinpoints
* MTC - 0 Joinpoints
10
1980-1995 APC = 21.06*
1980-2022 APC = 0.85
Age-standardized incidence rates (per 100,000)
1995-2010 APC = 0.71
9
2010-2014 APC = - 23.71*
Age-standardized rates (per 100,000)
2014-2022 APC = 5.20
0.8
8
. NET G1 - 4 Joinpoints
1980-1993 APC = 5.09*
7
1993-1997 APC =- 29.46
1997-2009 APC = 5.64
6
2009-2013 APC = 37.71*
0.6
2013-2022 APC = 4.65*
* NET G2/G3 - 1 Joinpoint
5
2003-2013 APC = 39.41*
-2013-2022 APC = 2.36
0.4
4
* Other NET - 2 Joinpoints
1980-2010 APC = - 4.74*
3
2010-2018 APC = 31.00*
2018-2022 APC =- 53.90*
0.2
2
1
0.0
0
1980
1985
1990
1995
2000
2005
2010
2015
2020
1980
1983
1986
1989
1992
1995
1998
2001
2004
2007
2010
2013
2016
2019
2022
Year
Year
patients with rectal (median OS 27.3 years; 95% CI 2.9-NR) and appendiceal NENs (median OS 30.4 years; 95% CI 26.5-NR) (Fig. 2B).
The median OS in patients with NET G1 was significantly longer with 17.9 years (95% CI 14.6-21.8) compared to the median OS of patients with NET G2/G3 (median OS 10.8 years; 95% CI 10.1-NR) and patients with NECs (median OS 2.7 years; 95% CI 2-3.4) (Fig. S1 [16]).
Discussion
Here we report the ASIRs and survival of patients with NENs stratified by subgroups over 4 decades based on data from the cancer registry of the Canton of Zurich, representing approxi- mately 18% of the total population of Switzerland [14].
Our data shows a significant increase in ASIR over the study period for gastrointestinal, pancreatic, and pulmonary NENs, with the most pronounced increase in ASIR after 2005. For
| Tumor type | Group | Number of cases | ASIR 1980 (per 100,000) | ASIR 2022 (per 100,000) | AAPC (%) | 95% CI (%) |
|---|---|---|---|---|---|---|
| GI NEN | Overall | 1581 | 1.4 | 11.3 | 5.07ª | 4.20-6.50 |
| Female | 760 | 0.9 | 6.4 | 6.07ª | 4.96-8.01 | |
| Male | 821 | 0.5 | 4.9 | 4.31ª | 3.33-6.13 | |
| Pancreatic NEN | Overall | 397 | 1.2 | 2.7 | 2.83ª | 1.72-4.26 |
| Female | 164 | 0.5 | 0.5 | 2.59ª | 1.65-4.00 | |
| Male | 233 | 0.7 | 2.2 | 4.25ª | 2.79-5.60 | |
| Pulmonary carcinoid | Overall | 486 | 0.6 | 2.3 | 2.31ª | 1.71-3.22 |
| Female | 284 | 0.3 | 1.6 | 2.82ª | 1.98-4.20 | |
| Male | 202 | 0.4 | 0.7 | 1.32ª | 0.45-2.65 | |
| PPGL | Overall | 51 | 0 | 0.4 | 2.61ª | 0.17-5.31 |
| ACC | Overall | 76 | 0.2 | 0.2 | 0.06 | -1.96-2.27 |
| MTC | Overall | 64 | 0.3 | 0.5 | 0.85 | -0.27-2.49 |
| GI NEN by site | ||||||
| Esophageal NEN | Overall | 15 | 0 | 0.2 | 0.19 | -1.12-1.55 |
| Gastric NEN | Overall | 144 | 0.2 | 0.9 | 1.50 | -0.24-3.25 |
| Small intestinal NEN | Overall | 626 | 0.9 | 3.0 | 2.14ª | 1.55-2.99 |
| Colon NEN | Overall | 147 | 0 | 0.7 | 2.21ª | 0.82-4.69 |
| Rectal NEN | Overall | 235 | 0 | 2.5 | 5.28ª | 3.33-8.11 |
| Appendiceal NEN | Overall | 414 | 0.3 | 4.0 | 5.87ª | 4.78-7.41 |
Abbreviations: AAPC, average annual percent change; ACC, adrenocortical carcinoma; ASIR, age-standardized incidence rates; CI, confidence interval; GI, gastrointestinal; MTC, medullary thyroid carcinoma; NEN, neuroendocrine neoplasm; PPGL, pheochromocytoma/paraganglioma. “Indicates statistically significant.
| Tumor type | Group | ASIR 1980 (per 100,000) | ASIR 2022 (per 100,000) | AAPC (%) | 95% CI (%) |
|---|---|---|---|---|---|
| NET G1 | Overall | 1.8 | 11.4 | 3.87ª | 3.16-4.87 |
| NET G2/3 | Overall | 0.1 | 2.5 | 20.43ª | 14.17-43.84 |
| NEC | Overall | 0.5 | 2.2 | 5.61ª | 3.96-9.36 |
| Other NEN | Overall | 0.9 | 0.1 | -5.54 | -10.5 -- 3.66 |
| MiNEN | Overall | 0.1 | 0.2 | -1.08 | -5.68-2.94 |
Abbreviations: AAPC, average annual percent change; ASIR, age-standardized incidence rates; CI, confidence interval; MiNEN, mixed neuroendocrine- nonneuroendocrine neoplasms; NEC, neuroendocrine carcinoma; NEN, neuroendocrine neoplasm; NET, neuroendocrine tumors. “Indicates statistically significant.
gastrointestinal NENs, the ASIR increased almost 4-fold since 2005. This increase was mainly driven by rising ASIR of rectal and appendiceal NENs after 2006. The incidence of appendi- ceal NENs increased from 0.3 in 1980 to 4.0 per 100,000 in 2022, corresponding to an astonishing 13.3-fold increase, whereas the incidence of rectal NENs increased 2.5-fold over the study period. Small intestinal NENs represented the most frequent site of gastrointestinal NENs in our cohort. Within this group, the rise in incidence has been steady since 1980, with an AAPC of 2.14% and a 3-fold increase in inci- dence from 1980 to 2022. A rise in the incidence of pancreatic NENs was again most pronounced after 2004, with an APC of 5.36% mainly driven by an increase in ASIR in male patients.
Globally, an increase in NEN incidence has been reported since the early 2000s [6-10]. Data from the Bavarian cancer registry in Germany showed a doubling of GEP-NEN inci- dence from 2.2 to 4.8 per 100,000 between 2005 and 2019 with the most pronounced increase for NENs of the stomach, followed by those of the appendix, pancreas, and rectum [7].
In contrast, we only observed a statistically significant in- crease in ASIR in gastric NENs between 2009 and 2013 but not over the total study period. A study from western Switzerland, using data from cancer registries of the Cantons of Vaud and Neuchâtel (1976-2016), reported a lower average annual increase in GEP-NEN incidence (1.7% in men and 1.3% in women) compared to our data from the more populous Zurich region [12].
In the Netherlands and Norway, NEN incidence more than doubled over 2 decades, reaching 4.9 (2010) and 9.97 (2021) per 100,000, respectively [8, 21]. In contrast, data from Iceland indicate a stable and, in comparison to our data, lower incidence of both small intestinal NENs (0.78 per 100,000) and GEP-NENs (3.65 per 100,000) over a 30-year period [22, 23].
According to the data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER)program in the United States, GEP- and pulmonary NEN incidence in- creased 5.2-fold between 1975 and 2021, reaching up to 8.52
A
+ Pulmonary Carcinoid + ACC + Thymic Carcinoid
B
GI NEN
Esophageal NEN
Small Intestinal NEN
Rectal NEN
Pancreatic NEN
Pancreatic NEN
PPGL
MTC
Gastric NEN
Colonic NEN
Appendiceal NEN
1.00 -
1.00-
0.75-
0.75-
Survival probability
Survival probability
0.50-
0.50-
0.25-
0.25-
0.00-
0.00-
0
5
10
15
20
25
30
35
40
0
5
10
15
20
25
30
35
40
Time [years]
Time [years]
GI NEN
1581
797
360
171
94
56
30
14
4
Eso NEN
15
0
0
0
0
0
0
0
0
Pan NEN
397
144
67
20
13
6
4
2
2
Gas NEN
144
73
30
15
10
5
3
1
1
Pul C
486
209
125
80
51
37
18
10
3
SI NEN
626
280
132
60
24
10
6
4
1
PPGL
51
20
13
8
5
4
2
1
0
Col NEN
147
58
21
11
7
6
5
4
2
ACC
76
23
14
6
5
3
2
0
0
Rec NEN
235
127
50
32
22
16
5
1
0
MTC
64
36
17
8
7
5
5
4
2
App NEN
414
259
127
53
31
19
11
4
0
Thy C
5
1
0
0
0
0
0
0
0
Pan NEN
397
144
67
20
13
6
4
2
2
0
5
10
15
20
25
30
35
Time [years]
40
0
5
10
15
20
25
30
35
Time [years]
40
per 100,000 (2021) with the prominent increases observed in appendiceal NENs, well-differentiated NENs, and a shift to- ward earlier-stage diagnoses [6, 11, 13]. In line with this, we also observed the strongest increase in the incidence of appen- diceal NENs. In contrast to the SEER database, we observed a higher ASIR for small intestinal NENs compared to pulmon- ary NENs at the end of the study period in the canton of Zurich. In Australia, NEN incidence tripled to 6.3 per 100,000 between 1986 and 2015 with stable mortality, while in Japan, the first national registry-based analysis reported an age-adjusted overall incidence of 3.53 per 100,000 in 2016, which predominantly occurred in the rectum and pancreas [9, 24]. Hence, in line with our results, epidemiological studies in Europe, America, and Asia found an increase in diagnosis of NENs of most organ systems [6-8, 10].
It remains unclear, however, whether the observed rise in NEN incidence reflects improved detection methods, includ- ing more incidental findings, shifts in risk factors such as a po- tential correlation with the rise of prevalence of metabolic diseases, or an increase in exposure to yet unknown risk fac- tors [25-29]. Based on our data, the most pronounced increase in ASIR occurred after 2005 and was primarily driven by a rise in NET G1, a subtype often asymptomatic and frequently de- tected incidentally on computed tomography or magnetic res- onance imaging performed for unrelated indications or during screening colonoscopy in the case of rectal and colonic NENs [30]. Moreover, functional imaging became available, and endoscopic ultrasound techniques have improved substantial- ly over the past decade [31, 32]. The hypothesis of early, inci- dental detection is further supported by the observation that symptomatic NENs, such as those of the esophagus, stomach, and functional pancreatic NETs, did not increase at a similar rate over the last decade. Similarly, ACC, in which patients typically present due to cortisol or androgen excess, also showed no significant increase in incidence in our study.
However, technical advancements do not fully explain the striking increase in appendiceal NENs, a trend also observed in Bavaria [7], as these tumors are typically not detected
through colonoscopy. Recent data from Switzerland indicated that appendectomies increased from 2013 to 2023 [33]. In the current study, the increase in appendiceal NENs was observed in both males and females, suggesting that the rise cannot be solely attributed to incidental findings during laparoscopic procedures, such as those performed for appendicitis or endo- metriosis. Prior to the introduction of ICD-O-3 at the cancer registry of the Canton of Zurich in 2003, certain NENs such as appendiceal NENs were sometimes classified as borderline or nonmalignant and were therefore not systematically cap- tured in the cancer registry. With the implementation of ICD-O-3, these entities began to be uniformly coded as malig- nant, leading to more consistent inclusion of cases in the regis- try. Consequently, at least part of the observed increase in incidence may reflect improved case ascertainment and changes in coding definitions rather than a true rise in disease occurrence. In line with this, the reclassification of appendi- ceal NENs as malignant has, according to a study from the United States, led to an artificial increase in reported colorec- tal cancers in children and young adults [34].
The more gradual increase in pancreatic and small intestinal NENs is, however, not fully explained by the factors discussed here. A potential association with the rising prevalence of metabolic disorders appears plausible, particularly given epi- demiological evidence linking obesity and diabetes to in- creased risk of several malignancies, including colorectal, breast, endometrial, and liver cancers and NENs [25-28, 35]. If insulin signaling plays a role in tumorigenesis, it is import- ant to consider that local insulin concentrations are higher in the pancreas and liver than in the systemic circulation. NENs arising in these regions, including those with liver me- tastases, may thus be especially vulnerable to the effects of hy- perinsulinemia due to their anatomical proximity to insulin-secreting ß cells. Several authors have proposed that type 2 diabetes and obesity may increase the risk of pancreatic and small intestinal NENs [26, 27, 36, 37]. In addition, the presence of metabolic syndrome, nonalcoholic fatty liver disease, and visceral adiposity has been associated with
more adverse clinicopathological features in patients with GEP-NENs [28].
Notably, our data also show an increase in the ASIR of PPGLs after 2015 from 0.2 to 0.4 per 100,000 in 2022. This rate remains lower than reported in studies from Denmark and Canada, which estimated an incidence of 0.66 cases per 100,000 person-years in the general population [38, 39]. The incidence of MTC (ASIR 2022 0.5 per 100,000) and ACC (ASIR 2022 0.2 per 100,000) did not change significant- ly over the last 4 decades in Zurich. ACC incidence was though higher compared to data from the Dutch Cancer and Danish health registries, both reporting an incidence rate from 0.1 to 0.14 per 100,000 [40, 41].
We also calculated the median OS of NEN patients. The shortest median OS was seen for thymic carcinoid (0.6 years) and ACC (2.2 years), as expected. Of note, the gastrointestinal NENs with the most pronounced increase in ASIR were also those with the longest median OS. Rectal NENs had a median OS of 27.3 years and appendiceal NENs a median OS of 30.4 years. This is in line with recent data from the SEER program, where patients with rectal and appendiceal NENs had the longest survival of over 30 years [11]. This finding supports the hypothesis that rising incidence reflects increased early de- tection, with tumors often identified at localized stages and ef- fectively treated by endoscopic or surgical resection, resulting in long-term remission.
A limitation of this study is the limited number of cases in certain subgroups. Small subgroup sizes and incomplete infor- mation on stage and treatment also precluded age-specific and subtype-specific analyses. An analysis of canton-specific can- cer registries only covers a part of Switzerland’s population, while a nationwide program would provide more comprehen- sive information. While we acknowledge the statistical con- straints associated with such analyses, particularly the potential for fluctuations in incidence trends due to single-case fluctuations, we choose to maintain separate reporting for rare entities like PPGL and ACC.
In conclusion, our study adds more population-based data on NEN incidence up to 2022 by incorporating more recent data over a very long observation period (>40 years) [6, 42]. We provide a comprehensive analysis of both common and rare NENs, including rare endocrine tumors such as PPGLs, MTC, and the non-NEN entity ACC, which are often under- represented in population-based studies. We confirm and ex- tend the previously observed trends of continuously rising incidence of NENs through 2022. This increase was evident across nearly all anatomical sites, with the most pronounced increase observed in rectal and appendiceal NENs, while the incidence of gastric and esophageal NENs remained stable or declined. Notably, the incidence of GEP-NENs and PPGLs continues to rise, whereas that of MTC and ACC re- mained stable over the 43-year observation period. These findings reinforce the ongoing shift in the epidemiology of NENs and underscore the importance of continued research into the underlying risk factors contributing to their development.
Funding
A.F. is supported by a research grant from the “Young Talents in Clinical Research” program of the Swiss Academy of Medical Sciences (SAMS) and of the G. & J. Bangerter-Rhyner Foundation, Switzerland.
Disclosures
The authors have nothing to disclose.
Data Availability
Restrictions apply to the availability of some or all data gen- erated or analyzed during this study to preserve patient confi- dentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.
References
1. Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classi- fication of tumours of the digestive system. Histopathology. 2020; 76(2):182-188.
2. Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classifi- cation framework for neuroendocrine neoplasms: an international agency for research on cancer (IARC) and world health organiza- tion (WHO) expert consensus proposal. Mod Pathol. 2018; 31(12):1770-1786.
3. Mete O, Asa SL, Gill AJ, Kimura N, de Krijger RR, Tischler A. Overview of the 2022 WHO classification of paragangliomas and pheochromocytomas. Endocr Pathol. 2022;33(1):90-114.
4. Fassnacht M, Puglisi S, Kimpel O, Terzolo M. Adrenocortical car- cinoma: a practical guide for clinicians. Lancet Diabetes Endocrinol. 2025;13(5):438-452.
5. Pavel M, Oberg K, Falconi M, et al. Gastroenteropancreatic neuro- endocrine neoplasms: ESMO clinical practice guidelines for diagno- sis, treatment and follow-up. Ann Oncol. 2020;31(7):844-860.
6. Dasari A, Shen C, Halperin D, et al. Trends in the incidence, preva- lence, and survival outcomes in patients with neuroendocrine tu- mors in the United States. JAMA Oncol. 2017;3(10):1335-1342.
7. Grundmann N, Voigtlander S, Hakimhashemi A, Pape UF, Meyer M, Muller-Nordhorn J. Site-specific trends in gastroenteropancre- atic neuroendocrine neoplasms in Bavaria, Germany. Cancer Med. 2023;12(19):19949-19958.
8. Korse CM, Taal BG, van Velthuysen ML, Visser O. Incidence and survival of neuroendocrine tumours in The Netherlands according to histological grade: experience of two decades of cancer registry. Eur J Cancer. 2013;49(8):1975-1983.
9. Wyld D, Wan MH, Moore J, Dunn N, Youl P. Epidemiological trends of neuroendocrine tumours over three decades in Queensland, Australia. Cancer Epidemiol. 2019;63:101598.
10. Ito T, Igarashi H, Nakamura K, et al. Epidemiological trends of pancreatic and gastrointestinal neuroendocrine tumors in Japan: a nationwide survey analysis. J Gastroenterol. 2015;50(1):58-64.
11. Dasari A, Wallace K, Halperin DM, et al. Epidemiology of neuro- endocrine neoplasms in the US. JAMA Netw Open. 2025;8(6): e2515798.
12. Alwan H, La Rosa S, Andreas Kopp P, et al. Incidence trends of lung and gastroenteropancreatic neuroendocrine neoplasms in Switzerland. Cancer Med. 2020;9(24):9454-9461.
13. Hallet J, Law CH, Cukier M, Saskin R, Liu N, Singh S. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer. 2015;121(4):589-597.
14. Federal Statistical Office. STAT-TAB-interactive tables (FSO). Accessed June, 2025. https://www.pxweb.bfs.admin.ch/pxweb/en/
15. Wanner M, Matthes KL, Korol D, Dehler S, Rohrmann S. Indicators of data quality at the cancer registry Zurich and Zug in Switzerland. Biomed Res Int. 2018;2018:7656197.
16. Fischer A, Wanner M, Suter F, et al. Supplementary material for “Rising Incidence of Neuroendocrine Neoplasms in Northern Switzerland-Data From the Cancer Registry”. Open Science Framework (OSF). 2025. https://osf.io/9e5kj/overview?view_only= 11fad2b5f60e430b9dfb63fb66c03933
17. Boyle P, Parkin DM. Cancer registration: principles and methods. Statistical methods for registries. IARC Sci Publ. 1991;(95):126-158.
18. Surveillance Research Program, National Cancer Institute. Joinpoint Regression Software, Version 5.4.0. April 2025. https:// surveillance.cancer.gov/joinpoint
19. Kim HJ, Fay MP, Feuer EJ, Midthune DN. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med. 2000;19(3):335-351.
20. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; 2025. https://www.R- project.org
21. Thiis-Evensen E, Boyar Cetinkaya R. Incidence and prevalence of neuroendocrine neoplasms in Norway 1993-2021. J Neuroendocrinol. 2023;35(4):e13264.
22. Gudmundsdottir H, Moller PH, Jonasson JG, Bjornsson ES. Gastroenteropancreatic neuroendocrine tumors in Iceland: a population-based study. Scand J Gastroenterol. 2019;54(1):69-75.
23. Snorradottir S, Asgeirsdottir A, Rognvaldsson S, Jonasson JG, Bjornsson ES. Incidence and prognosis of patients with small intes- tinal neuroendocrine tumors in a population based nationwide study. Cancer Epidemiol. 2022;79:102197.
24. Masui T, Ito T, Komoto I, Uemoto S, Group JPS. Recent epidemi- ology of patients with gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NEN) in Japan: a population-based study. BMC Cancer. 2020;20(1):1104.
25. Pearson-Stuttard J, Zhou B, Kontis V, Bentham J, Gunter MJ, Ezzati M. Worldwide burden of cancer attributable to diabetes and high body-mass index: a comparative risk assessment. Lancet Diabetes Endocrinol. 2018;6(6):e6-e15.
26. Feola T, Puliani G, Sesti F, et al. Risk factors for gastroentero- pancreatic neuroendocrine neoplasms (GEP-NENs): a three-centric case-control study. J Endocrinol Invest. 2022;45(4):849-857.
27. Haugvik SP, Hedenstrom P, Korsaeth E, et al. Diabetes, smoking, alcohol use, and family history of cancer as risk factors for pancre- atic neuroendocrine tumors: a systematic review and meta-analysis. Neuroendocrinology. 2015;101(2):133-142.
28. Barrea L, Muscogiuri G, Modica R, et al. Cardio-metabolic indices and metabolic syndrome as predictors of clinical severity of gastro- enteropancreatic neuroendocrine tumors. Front Endocrinol (Lausanne). 2021;12:649496.
29. Leoncini E, Boffetta P, Shafir M, Aleksovska K, Boccia S, Rindi G. Increased incidence trend of low-grade and high-grade neuroendo- crine neoplasms. Endocrine. 2017;58(2):368-379.
30. Schneider R, Syrogiannouli L, Bissig S, et al. Ten-year changes in colorectal cancer screening in Switzerland: the Swiss health interview survey 2007, 2012 and 2017. Prev Med Rep. 2022;27:101815.
31. Anderson MA, Carpenter S, Thompson NW, Nostrant TT, Elta GH, Scheiman JM. Endoscopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pancreas. Am J Gastroenterol. 2000;95(9):2271-2277.
32. Geijer H, Breimer LH. Somatostatin receptor PET/CT in neuroen- docrine tumours: update on systematic review and meta-analysis. Eur J Nucl Med Mol Imaging. 2013;40(11):1770-1780.
33. Grossen H, Baechtold M, Antony P, et al. Future demand for vis- ceral surgeons in Switzerland: an empirical study. Langenbecks Arch Surg. 2025;410(1):248.
34. Bleyer A, Ries LAG, Cameron DB, Mansfield SA, Siegel SE, Barr RD. Colon, colorectal, and all cancer incidence increase in the young due to appendix reclassification. J Natl Cancer Inst. 2025; 117(7):1340-1349.
35. Tsilidis KK, Kasimis JC, Lopez DS, Ntzani EE, Ioannidis JP. Type 2 diabetes and cancer: umbrella review of meta-analyses of observa- tional studies. BMJ. 2015;350(jan02 1):g7607.
36. Osher E, Geva R, Wolf I, et al. Dysglycemia in non-functioning pan- creatic neuroendocrine tumors (NF-PNET): further insights into an under recognized entity. J Clin Transl Endocrinol. 2023;33:100322.
37. Zhang AMY, Magrill J, de Winter TJJ, et al. Endogenous hyperin- sulinemia contributes to pancreatic cancer development. Cell Metab. 2019;30(3):403-404.
38. Ebbehoj A, Stochholm K, Jacobsen SF, et al. Incidence and clinical presentation of pheochromocytoma and sympathetic paraganglio- ma: a population-based study. J Clin Endocrinol Metab. 2021; 106(5):e2251-e2261.
39. Leung AA, Pasieka JL, Hyrcza MD, et al. Epidemiology of pheo- chromocytoma and paraganglioma: population-based cohort study. Eur J Endocrinol. 2021;184(1):19-28.
40. Kerkhofs TM, Verhoeven RH, Van der Zwan JM, et al. Adrenocortical carcinoma: a population-based study on incidence and survival in The Netherlands since 1993. Eur J Cancer. 2013;49(11):2579-2586.
41. Pedersen J, Jarlov AE, Rasmussen AK, Stochholm K. Incidence, treatment, and survival of adrenocortical carcinoma in Denmark 2003-2019. J Endocr Soc. 2024;8(3):bvae012.
42. Huguet I, Grossman AB, O’Toole D. Changes in the epidemiology of neuroendocrine tumours. Neuroendocrinology. 2017;104(2): 105-111.