닫기

Ex) Article Title, Author, Keywords

Review Article

Split Viewer

Journal of Digestive Cancer Research 2024; 12(1): 1-5

Published online April 20, 2024

https://doi.org/10.52927/jdcr.2024.12.1.1

© Korean Society of Gastrointestinal Cancer Research

Factors Associated with Gastric and Duodenal Neuroendocrine Tumor Development


Kwangwoo Nam1 , Su Youn Nam2



1Department of Gastroenterology, Dankook University Hospital, Dankook University College of Medicine, Cheonan, 2Department of Internal Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea

Correspondence to :
Su Youn Nam
E-mail: nam20131114@gmail.com
https://orcid.org/0000-0002-5568-7714

Received: February 26, 2024; Revised: March 23, 2024; Accepted: March 23, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0). which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The incidence and prevalence of upper gastrointestinal neuroendocrine tumors (NETs), including gastric NETs (GNETs) and duodenal NETs (DNETs), have been gradually increasing. These trends may be associated with the increased use of health checkups, which includes upper endoscopy, in conjunction with better disease recognition. However, the clinical factors associated with GNETs and DNETs remain unknown; previous studies revealed discrepancies. Recently, metabolic disorders have been indicated as potential factors that are associated with GNETs and DNETs. This review summarizes the results of previous studies and briefly introduces the results of a recent Korean multicenter study on the factors associated with GNETs and DNETs.

KeywordsNeuroendocrine tumors Stomach Duodenum Associated factors

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) originate from enterochromaffin-like cells of the gut or islets of Langerhans of the pancreas. GEP-NETs are heterogeneous in nature based on their primary site [1]. The incidence and prevalence of GEP-NETs has gradually increased over the last three decades. According to recent Surveillance, Epidemiology, and End Result (SEER) data, the annual age-adjusted incidence rate in the United States has increased from 1.09 per 100,000 people (1973) to 6.98 per 100,000 people (2012) [2]. In addition, the prevalence of GEP-NETs has increased from 0.006% (1993) to 0.048% (2012) [3]. The small intestine is the most commonly affected sites, followed by the rectum, pancreas, stomach, and appendix. These recent increases in the number of GEP-NETs may be related to the increased use of endoscopic screening, developments in nuclear medicine, and improved recognition [4,5].

Although the proportion of upper gastrointestinal NET, including gastric and duodenal NETs (GNETs and DNETs, respectively), is relatively low in GEP-NETs, they can be detected in endoscopic screening, and endoscopic resection is a favorable treatment option for small and superficial GNETs and DNETs [6-9]. However, in contrast to many previous studies focusing on the treatment outcome and prognosis of GNETs and DNETs, epidemiologic and clinical factors associated with GNETs and DNETs have rarely been investigated, and there have been some discrepancies between studies [10-14].

Recent studies have shown differences in the natural history and clinical characteristics of GNETs and DNETs [15,16]. However, GNETs and DNETs commonly originate from foregut organs and may share common associated factors, in addition to their site-specific risk factors. In contrast, esophageal NETs are extremely rare compared to GNETs and DNETs, and show relatively aggressive behavior among upper gastrointestinal NETs [17,18]; thus, they will not be covered in this review. Here, we summarize the results of previous studies on factors associated with GNETs and DNETs and introduce a recent Korean multicenter study on the factors associated with development of GNETs and DNETs.

Previous studies on the factors associated with GEP-NETs

To date, no definite environmental risk factors have been described for GEP-NETs, and previous studies have reported inconsistent and discrepant results [19]. Potential clinical risk factors include a family history of cancer, smoking, alcohol consumption, high body mass index, diabetes mellitus, and medical treatment [20]. In a previous study conducted in the United States, diabetes and a family history of cancer were found to increase the risk of GNETs in women. These findings suggest that the genetic susceptibility of GNETs varies based on sex [10]. Another study from Portugal reported an association between GEP-NETs and obesity with metabolic syndrome components (increased waist circumference, high blood pressure, low high-density lipoprotein [HDL] level, high triglyceride level, and high fasting plasma glucose level) [11]. Another study from Israel reported the risk factors for GEP-NETs by case-control analysis, and GNETs were associated with obesity (high body mass index) and height, whereas small bowel NETs were associated with male sex [12]. A recent study suggested that metabolic syndrome is associated with aggressive behavior in GEP-NETs [21]. These studies show that metabolic disorder-associated systemic inflammation could affect the development of GEP-NETs. However, most studies included various types of GEP-NETs, and were performed at a single center in Western countries. In addition, only a small number of GNETs and DNETs were included in these studies, making it difficult to apply these findings to patients with GNETs and DNETs, especially in Korea.

Disease characteristics of GNETs

GNETs are classified according to the WHO classification based on Ki-67 expression and mitotic index [19]. In addition, the treatment and prognosis of GNETs varies according to the different subtypes, based on serum gastrin and gastric pH levels [6]. Classification of GNET has not been well established, but usually type 1 GNETs account for 70–80% of cases and are associated with chronic atrophic gastritis (CAG). The absence of gastric acid is associated with autoimmune CAG, which destroys gastric parietal cells and stimulates antral G cells, thereby causing hypergastrinemia. Type 1 GNETs usually present as small, multiple tumors; therefore, endoscopic resection is a feasible treatment option for small, superficial GNETs. The overall prognosis is favorable, with an excellent 5-year survival rate (90–95%) [3]. Type 2 GNETs are the rarest subtype and are associated with hyperchlorhydria, hypergastrinemia, gastrinoma, and multiple endocrine neoplasia. They are commonly associated with peptic ulcer disease and Zollinger-Ellison syndrome, and their overall prognosis shows favorable 5-year survival rate (70–90%) [3]. Type 3 GNETs occur sporadically and are not usually accompanied by hypergastrinemia or CAG. They show high malignant potential and early lymph node metastasis. Thus, in contrast to type 1 GNETs, surgical resection is primarily considered, even at an early stage. Type 4 GNETs refer to poorly differentiated neuroendocrine carcinoma (NEC) showing very aggressive behavior, and frequent lymph node and liver metastases which are associated with a poor prognosis. Recent 2019 WHO classification specified poor differentiated NEC as small-cell type NEC and large-cell NEC, respectively, and introduced mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) as a new category (Table 1) [6,22,23].

Table 1 . Characteristics of Subtypes and Classification of Grading for Gastric Neuroendocrine Tumors

Gastric NETsGastric NECsOthers



Type 1Type 2Type 3Type 4 (Small-cell type NEC, Large-cell type NEC)MiNEN
Relative frequency70–80%5–6%14–25%6–8%
FeaturesMostly small (< 1–2 cm) and multipleMostly small (< 1–2 cm) and multipleSolitary, often > 2 cmSolitary mostly exulcerated, 2 cm
Associated conditionCAGMEN1/ZESNoNo
HistologyWell differentiated, G1–3Well differentiated, G1–3Well differentiated, G1–3Poorly differentiated, G3Well or poorly differentiated, G1–3
Serum gastrin(Very) high(Very) highNormal(Mostly) normal
Gastric pHAnacidicHyperacidicNormal(Mostly) normal
Metastases< 10%10–30%50–100%80–100%
Tumor-related deathsNo< 10%25–30%≥ 50%

CAG, chronic atrophic gastritis; G1, low grade (mitotic rate < 2, Ki-67 index < 3%); G2, intermediate grade (mitotic rate 2–20, Ki-67 index 3–20%); G3, high grade (mitotic rate > 20, Ki-67 index > 20%); MEN1, multiple endocrine neoplasia type 1; MiNEN, mixed neuroendocrine-non-neuroendocrine neoplasm; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; ZES, Zollinger-Ellison syndrome.



Disease characteristics of DNETs

DNETs frequently arises in the bulb (58%) and second portion (33%), whereas NETs in the ampulla of Vater (20%) are considered separate disease entities. From a histopathological perspective, in addition to the WHO classification, four subtypes have been suggested: gangliocytic paragangliomas, gastrinomas, ampullary-type somatostatin-producing tumors, and ordinary non-functioning NETs [9]. Unlike that surgical resection is generally recommended for ampullary NETs regardless of tumor size, endoscopic resection is recommended for small, superficial DNETs that have a low tendency to metastasize and show favorable outcomes [8].

Recent Korean studies on the factors associated with development of GNETs and DNETs

Considering the paucity of related studies, this multicenter case-control study was conducted to evaluate the factors associated with development of GNETs and DNETs [24]. A total of 396 patients with GNETs and 193 patients with DNETs were included in the case group. Clinical and laboratory characteristics were compared and evaluated in a control group of 1,725 healthy controls. Multivariate analyses showed that age, diabetes, hypertension, low serum HDL levels, and past/present H. pylori infection were associated with GNETs, whereas diabetes, hypertension, low serum HDL levels, and past/present H. pylori infection were associated with DNETs. In addition, sex-specific differences were observed in both GNETs and DNETs. This study showed that several metabolic factors could affect the development of GNETs and DNETs and suggested the necessity of personalized and sex-specific approaches for patients with GNETs and DNETs.

While there are limited data on the factors associated with GNETs and DNETs, conflicting results have been reported. Notably, common metabolic disorders such as diabetes, hypertension, and low serum HDL levels were significantly associated with both GNETs and DNETs. Furthermore, sex-specific associations in both GNETs and DNETs were suggested, highlighting the need for personalized and sex-specific approaches for the management of GNETs and DNETs. Further studies are required to understand better and validate these findings.

This study was supported by the Korean Society of Gastrointestinal Cancer Research (2021). The funding source did not play any role in the planning or implementation of this study, interpreting the results, or writing the manuscript. The views and opinions expressed are those of the authors and do not necessarily reflect those of the supporting institutions.

No potential conflict of interest relevant to this article was reported.

Conceptualization: Kwangwoo Nam, Su Youn Nam. Data acquisition: Kwangwoo Nam. Formal analysis: Kwangwoo Nam, Su Youn Nam. Funding: Su Youn Nam. Supervision: Su Youn Nam. Writing—original draft: Kwangwoo Nam. Writing—review & editing: Kwangwoo Nam, Su Youn Nam.

  1. Cives M, Strosberg JR. Gastroenteropancreatic neuroendocrine tumors. CA Cancer J Clin 2018;68:471-487. https://doi.org/10.3322/caac.21493.
    Pubmed CrossRef
  2. Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 2017;3:1335-1342. https://doi.org/10.1001/jamaoncol.2017.0589.
    Pubmed KoreaMed CrossRef
  3. Ahmed M. Gastrointestinal neuroendocrine tumors in 2020. World J Gastrointest Oncol 2020;12:791-807. https://doi.org/10.4251/wjgo.v12.i8.791.
    Pubmed KoreaMed CrossRef
  4. Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063-3072. https://doi.org/10.1200/JCO.2007.15.4377.
    Pubmed CrossRef
  5. Rossi RE, Massironi S. The increasing incidence of neuroendocrine neoplasms worldwide: current knowledge and open issues. J Clin Med 2022;11:3794. https://doi.org/10.3390/jcm11133794.
    Pubmed KoreaMed CrossRef
  6. Park MI. Endoscopic treatment for early foregut neuroendocrine tumors. Clin Endosc 2013;46:450-455. https://doi.org/10.5946/ce.2013.46.5.450.
    Pubmed KoreaMed CrossRef
  7. Kwon YH, Jeon SW, Kim GH, et al. Long-term follow up of endoscopic resection for type 3 gastric NET. World J Gastroenterol 2013;19:8703-8708. https://doi.org/10.3748/wjg.v19.i46.8703.
    Pubmed KoreaMed CrossRef
  8. Kim GH, Kim JI, Jeon SW, et al. Endoscopic resection for duodenal carcinoid tumors: a multicenter, retrospective study. J Gastroenterol Hepatol 2014;29:318-324. https://doi.org/10.1111/jgh.12390.
    Pubmed CrossRef
  9. Rossi RE, Rausa E, Cavalcoli F, Conte D, Massironi S. Duodenal neuroendocrine neoplasms: a still poorly recognized clinical entity. Scand J Gastroenterol 2018;53:835-842. https://doi.org/10.1080/00365521.2018.1468479.
    Pubmed CrossRef
  10. Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC. Risk factors associated with neuroendocrine tumors: a U.S.-based case-control study. Int J Cancer 2008;123:867-873. https://doi.org/10.1002/ijc.23529.
    Pubmed CrossRef
  11. Santos AP, Santos AC, Castro C, et al. Visceral obesity and metabolic syndrome are associated with well-differentiated gastroenteropancreatic neuroendocrine tumors. Cancers (Basel) 2018;10:293. https://doi.org/10.3390/cancers10090293.
    Pubmed KoreaMed CrossRef
  12. Katz LH, Levi Z, Twig G, et al. Risk factors associated with gastroenteropancreatic neuroendocrine tumors in a cohort of 2.3 million Israeli adolescents. Int J Cancer 2018;143:1876-1883. https://doi.org/10.1002/ijc.31589.
    Pubmed CrossRef
  13. Soto-Solís R, Romano-Munive AF, Santana de Anda K, Barreto-Zuñiga R. Factors related to gastric neuroendocrine tumors. Rev Gastroenterol Mex (Engl Ed) 2019;84:52-56. https://doi.org/10.1016/j.rgmxen.2018.06.007.
    CrossRef
  14. Campana D, Ravizza D, Ferolla P, et al. Risk factors of type 1 gastric neuroendocrine neoplasia in patients with chronic atrophic gastritis. A retrospective, multicentre study. Endocrine 2017;56:633-638. https://doi.org/10.1007/s12020-016-1099-y.
    Pubmed CrossRef
  15. Massironi S, Campana D, Partelli S, et al. Heterogeneity of duodenal neuroendocrine tumors: an Italian multi-center experience. Ann Surg Oncol 2018;25:3200-3206. https://doi.org/10.1245/s10434-018-6673-5.
    Pubmed CrossRef
  16. Rossi RE, Milanetto AC, Andreasi V, et al. Risk of preoperative understaging of duodenal neuroendocrine neoplasms: a plea for caution in the treatment strategy. J Endocrinol Invest 2021;44:2227-2234. https://doi.org/10.1007/s40618-021-01528-1.
    Pubmed CrossRef
  17. Giannetta E, Guarnotta V, Rota F, et al. A rare rarity: neuroendocrine tumor of the esophagus. Crit Rev Oncol Hematol 2019;137:92-107. https://doi.org/10.1016/j.critrevonc.2019.02.012.
    Pubmed CrossRef
  18. Wu IC, Chu YY, Wang YK, et al. Clinicopathological features and outcome of esophageal neuroendocrine tumor: a retrospective multicenter survey by the digestive endoscopy society of Taiwan. J Formos Med Assoc 2021;120:508-514. https://doi.org/10.1016/j.jfma.2020.06.024.
    Pubmed CrossRef
  19. Chun HJ, Park SJ, Lim YJ, Song SY. Gastrointestinal cancer: a comprehensive guide to diagnosis and management. Gastrointestinal cancer: a comprehensive guide to diagnosis and management. Singapore: Springer, 2023:437-446.
    CrossRef
  20. Feola T, Puliani G, Sesti F, et al. Risk factors for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a three-centric case-control study. J Endocrinol Invest 2022;45:849-857. https://doi.org/10.1007/s40618-021-01715-0.
    Pubmed CrossRef
  21. Barrea L, Muscogiuri G, Modica R, et al. Cardio-metabolic indices and metabolic syndrome as predictors of clinical severity of gastroenteropancreatic neuroendocrine tumors. Front Endocrinol (Lausanne) 2021;12:649496. https://doi.org/10.3389/fendo.2021.649496.
    Pubmed KoreaMed CrossRef
  22. Scherübl H, Jensen RT, Cadiot G, Stölzel U, Klöppel G. Management of early gastrointestinal neuroendocrine neoplasms. World J Gastrointest Endosc 2011;3:133-139. https://doi.org/10.4253/wjge.v3.i7.133.
    Pubmed KoreaMed CrossRef
  23. Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology 2020;76:182-188. https://doi.org/10.1111/his.13975.
    Pubmed KoreaMed CrossRef
  24. Nam K, Nam SY, Park JC, et al. Factors associated with gastric and duodenal neuroendocrine tumors: a multicenter case-control study. Dig Liver Dis. https://doi.org/10.1016/j.dld.2024.01.210.
    Pubmed CrossRef

Article

Review Article

Journal of Digestive Cancer Research 2024; 12(1): 1-5

Published online April 20, 2024 https://doi.org/10.52927/jdcr.2024.12.1.1

Copyright © Korean Society of Gastrointestinal Cancer Research.

Factors Associated with Gastric and Duodenal Neuroendocrine Tumor Development

Kwangwoo Nam1 , Su Youn Nam2

1Department of Gastroenterology, Dankook University Hospital, Dankook University College of Medicine, Cheonan, 2Department of Internal Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea

Correspondence to:Su Youn Nam
E-mail: nam20131114@gmail.com
https://orcid.org/0000-0002-5568-7714

Received: February 26, 2024; Revised: March 23, 2024; Accepted: March 23, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0). which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The incidence and prevalence of upper gastrointestinal neuroendocrine tumors (NETs), including gastric NETs (GNETs) and duodenal NETs (DNETs), have been gradually increasing. These trends may be associated with the increased use of health checkups, which includes upper endoscopy, in conjunction with better disease recognition. However, the clinical factors associated with GNETs and DNETs remain unknown; previous studies revealed discrepancies. Recently, metabolic disorders have been indicated as potential factors that are associated with GNETs and DNETs. This review summarizes the results of previous studies and briefly introduces the results of a recent Korean multicenter study on the factors associated with GNETs and DNETs.

Keywords: Neuroendocrine tumors, Stomach, Duodenum, Associated factors

INTRODUCTION

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) originate from enterochromaffin-like cells of the gut or islets of Langerhans of the pancreas. GEP-NETs are heterogeneous in nature based on their primary site [1]. The incidence and prevalence of GEP-NETs has gradually increased over the last three decades. According to recent Surveillance, Epidemiology, and End Result (SEER) data, the annual age-adjusted incidence rate in the United States has increased from 1.09 per 100,000 people (1973) to 6.98 per 100,000 people (2012) [2]. In addition, the prevalence of GEP-NETs has increased from 0.006% (1993) to 0.048% (2012) [3]. The small intestine is the most commonly affected sites, followed by the rectum, pancreas, stomach, and appendix. These recent increases in the number of GEP-NETs may be related to the increased use of endoscopic screening, developments in nuclear medicine, and improved recognition [4,5].

Although the proportion of upper gastrointestinal NET, including gastric and duodenal NETs (GNETs and DNETs, respectively), is relatively low in GEP-NETs, they can be detected in endoscopic screening, and endoscopic resection is a favorable treatment option for small and superficial GNETs and DNETs [6-9]. However, in contrast to many previous studies focusing on the treatment outcome and prognosis of GNETs and DNETs, epidemiologic and clinical factors associated with GNETs and DNETs have rarely been investigated, and there have been some discrepancies between studies [10-14].

Recent studies have shown differences in the natural history and clinical characteristics of GNETs and DNETs [15,16]. However, GNETs and DNETs commonly originate from foregut organs and may share common associated factors, in addition to their site-specific risk factors. In contrast, esophageal NETs are extremely rare compared to GNETs and DNETs, and show relatively aggressive behavior among upper gastrointestinal NETs [17,18]; thus, they will not be covered in this review. Here, we summarize the results of previous studies on factors associated with GNETs and DNETs and introduce a recent Korean multicenter study on the factors associated with development of GNETs and DNETs.

MAIN SUBJECTS

Previous studies on the factors associated with GEP-NETs

To date, no definite environmental risk factors have been described for GEP-NETs, and previous studies have reported inconsistent and discrepant results [19]. Potential clinical risk factors include a family history of cancer, smoking, alcohol consumption, high body mass index, diabetes mellitus, and medical treatment [20]. In a previous study conducted in the United States, diabetes and a family history of cancer were found to increase the risk of GNETs in women. These findings suggest that the genetic susceptibility of GNETs varies based on sex [10]. Another study from Portugal reported an association between GEP-NETs and obesity with metabolic syndrome components (increased waist circumference, high blood pressure, low high-density lipoprotein [HDL] level, high triglyceride level, and high fasting plasma glucose level) [11]. Another study from Israel reported the risk factors for GEP-NETs by case-control analysis, and GNETs were associated with obesity (high body mass index) and height, whereas small bowel NETs were associated with male sex [12]. A recent study suggested that metabolic syndrome is associated with aggressive behavior in GEP-NETs [21]. These studies show that metabolic disorder-associated systemic inflammation could affect the development of GEP-NETs. However, most studies included various types of GEP-NETs, and were performed at a single center in Western countries. In addition, only a small number of GNETs and DNETs were included in these studies, making it difficult to apply these findings to patients with GNETs and DNETs, especially in Korea.

Disease characteristics of GNETs

GNETs are classified according to the WHO classification based on Ki-67 expression and mitotic index [19]. In addition, the treatment and prognosis of GNETs varies according to the different subtypes, based on serum gastrin and gastric pH levels [6]. Classification of GNET has not been well established, but usually type 1 GNETs account for 70–80% of cases and are associated with chronic atrophic gastritis (CAG). The absence of gastric acid is associated with autoimmune CAG, which destroys gastric parietal cells and stimulates antral G cells, thereby causing hypergastrinemia. Type 1 GNETs usually present as small, multiple tumors; therefore, endoscopic resection is a feasible treatment option for small, superficial GNETs. The overall prognosis is favorable, with an excellent 5-year survival rate (90–95%) [3]. Type 2 GNETs are the rarest subtype and are associated with hyperchlorhydria, hypergastrinemia, gastrinoma, and multiple endocrine neoplasia. They are commonly associated with peptic ulcer disease and Zollinger-Ellison syndrome, and their overall prognosis shows favorable 5-year survival rate (70–90%) [3]. Type 3 GNETs occur sporadically and are not usually accompanied by hypergastrinemia or CAG. They show high malignant potential and early lymph node metastasis. Thus, in contrast to type 1 GNETs, surgical resection is primarily considered, even at an early stage. Type 4 GNETs refer to poorly differentiated neuroendocrine carcinoma (NEC) showing very aggressive behavior, and frequent lymph node and liver metastases which are associated with a poor prognosis. Recent 2019 WHO classification specified poor differentiated NEC as small-cell type NEC and large-cell NEC, respectively, and introduced mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) as a new category (Table 1) [6,22,23].

Table 1 . Characteristics of Subtypes and Classification of Grading for Gastric Neuroendocrine Tumors.

Gastric NETsGastric NECsOthers



Type 1Type 2Type 3Type 4 (Small-cell type NEC, Large-cell type NEC)MiNEN
Relative frequency70–80%5–6%14–25%6–8%
FeaturesMostly small (< 1–2 cm) and multipleMostly small (< 1–2 cm) and multipleSolitary, often > 2 cmSolitary mostly exulcerated, 2 cm
Associated conditionCAGMEN1/ZESNoNo
HistologyWell differentiated, G1–3Well differentiated, G1–3Well differentiated, G1–3Poorly differentiated, G3Well or poorly differentiated, G1–3
Serum gastrin(Very) high(Very) highNormal(Mostly) normal
Gastric pHAnacidicHyperacidicNormal(Mostly) normal
Metastases< 10%10–30%50–100%80–100%
Tumor-related deathsNo< 10%25–30%≥ 50%

CAG, chronic atrophic gastritis; G1, low grade (mitotic rate < 2, Ki-67 index < 3%); G2, intermediate grade (mitotic rate 2–20, Ki-67 index 3–20%); G3, high grade (mitotic rate > 20, Ki-67 index > 20%); MEN1, multiple endocrine neoplasia type 1; MiNEN, mixed neuroendocrine-non-neuroendocrine neoplasm; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; ZES, Zollinger-Ellison syndrome..



Disease characteristics of DNETs

DNETs frequently arises in the bulb (58%) and second portion (33%), whereas NETs in the ampulla of Vater (20%) are considered separate disease entities. From a histopathological perspective, in addition to the WHO classification, four subtypes have been suggested: gangliocytic paragangliomas, gastrinomas, ampullary-type somatostatin-producing tumors, and ordinary non-functioning NETs [9]. Unlike that surgical resection is generally recommended for ampullary NETs regardless of tumor size, endoscopic resection is recommended for small, superficial DNETs that have a low tendency to metastasize and show favorable outcomes [8].

Recent Korean studies on the factors associated with development of GNETs and DNETs

Considering the paucity of related studies, this multicenter case-control study was conducted to evaluate the factors associated with development of GNETs and DNETs [24]. A total of 396 patients with GNETs and 193 patients with DNETs were included in the case group. Clinical and laboratory characteristics were compared and evaluated in a control group of 1,725 healthy controls. Multivariate analyses showed that age, diabetes, hypertension, low serum HDL levels, and past/present H. pylori infection were associated with GNETs, whereas diabetes, hypertension, low serum HDL levels, and past/present H. pylori infection were associated with DNETs. In addition, sex-specific differences were observed in both GNETs and DNETs. This study showed that several metabolic factors could affect the development of GNETs and DNETs and suggested the necessity of personalized and sex-specific approaches for patients with GNETs and DNETs.

CONCLUSION

While there are limited data on the factors associated with GNETs and DNETs, conflicting results have been reported. Notably, common metabolic disorders such as diabetes, hypertension, and low serum HDL levels were significantly associated with both GNETs and DNETs. Furthermore, sex-specific associations in both GNETs and DNETs were suggested, highlighting the need for personalized and sex-specific approaches for the management of GNETs and DNETs. Further studies are required to understand better and validate these findings.

FUNDING

This study was supported by the Korean Society of Gastrointestinal Cancer Research (2021). The funding source did not play any role in the planning or implementation of this study, interpreting the results, or writing the manuscript. The views and opinions expressed are those of the authors and do not necessarily reflect those of the supporting institutions.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR’S CONTRIBUTIONS

Conceptualization: Kwangwoo Nam, Su Youn Nam. Data acquisition: Kwangwoo Nam. Formal analysis: Kwangwoo Nam, Su Youn Nam. Funding: Su Youn Nam. Supervision: Su Youn Nam. Writing—original draft: Kwangwoo Nam. Writing—review & editing: Kwangwoo Nam, Su Youn Nam.

Table 1 . Characteristics of Subtypes and Classification of Grading for Gastric Neuroendocrine Tumors.

Gastric NETsGastric NECsOthers



Type 1Type 2Type 3Type 4 (Small-cell type NEC, Large-cell type NEC)MiNEN
Relative frequency70–80%5–6%14–25%6–8%
FeaturesMostly small (< 1–2 cm) and multipleMostly small (< 1–2 cm) and multipleSolitary, often > 2 cmSolitary mostly exulcerated, 2 cm
Associated conditionCAGMEN1/ZESNoNo
HistologyWell differentiated, G1–3Well differentiated, G1–3Well differentiated, G1–3Poorly differentiated, G3Well or poorly differentiated, G1–3
Serum gastrin(Very) high(Very) highNormal(Mostly) normal
Gastric pHAnacidicHyperacidicNormal(Mostly) normal
Metastases< 10%10–30%50–100%80–100%
Tumor-related deathsNo< 10%25–30%≥ 50%

CAG, chronic atrophic gastritis; G1, low grade (mitotic rate < 2, Ki-67 index < 3%); G2, intermediate grade (mitotic rate 2–20, Ki-67 index 3–20%); G3, high grade (mitotic rate > 20, Ki-67 index > 20%); MEN1, multiple endocrine neoplasia type 1; MiNEN, mixed neuroendocrine-non-neuroendocrine neoplasm; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; ZES, Zollinger-Ellison syndrome..


References

  1. Cives M, Strosberg JR. Gastroenteropancreatic neuroendocrine tumors. CA Cancer J Clin 2018;68:471-487. https://doi.org/10.3322/caac.21493.
    Pubmed CrossRef
  2. Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 2017;3:1335-1342. https://doi.org/10.1001/jamaoncol.2017.0589.
    Pubmed KoreaMed CrossRef
  3. Ahmed M. Gastrointestinal neuroendocrine tumors in 2020. World J Gastrointest Oncol 2020;12:791-807. https://doi.org/10.4251/wjgo.v12.i8.791.
    Pubmed KoreaMed CrossRef
  4. Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063-3072. https://doi.org/10.1200/JCO.2007.15.4377.
    Pubmed CrossRef
  5. Rossi RE, Massironi S. The increasing incidence of neuroendocrine neoplasms worldwide: current knowledge and open issues. J Clin Med 2022;11:3794. https://doi.org/10.3390/jcm11133794.
    Pubmed KoreaMed CrossRef
  6. Park MI. Endoscopic treatment for early foregut neuroendocrine tumors. Clin Endosc 2013;46:450-455. https://doi.org/10.5946/ce.2013.46.5.450.
    Pubmed KoreaMed CrossRef
  7. Kwon YH, Jeon SW, Kim GH, et al. Long-term follow up of endoscopic resection for type 3 gastric NET. World J Gastroenterol 2013;19:8703-8708. https://doi.org/10.3748/wjg.v19.i46.8703.
    Pubmed KoreaMed CrossRef
  8. Kim GH, Kim JI, Jeon SW, et al. Endoscopic resection for duodenal carcinoid tumors: a multicenter, retrospective study. J Gastroenterol Hepatol 2014;29:318-324. https://doi.org/10.1111/jgh.12390.
    Pubmed CrossRef
  9. Rossi RE, Rausa E, Cavalcoli F, Conte D, Massironi S. Duodenal neuroendocrine neoplasms: a still poorly recognized clinical entity. Scand J Gastroenterol 2018;53:835-842. https://doi.org/10.1080/00365521.2018.1468479.
    Pubmed CrossRef
  10. Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC. Risk factors associated with neuroendocrine tumors: a U.S.-based case-control study. Int J Cancer 2008;123:867-873. https://doi.org/10.1002/ijc.23529.
    Pubmed CrossRef
  11. Santos AP, Santos AC, Castro C, et al. Visceral obesity and metabolic syndrome are associated with well-differentiated gastroenteropancreatic neuroendocrine tumors. Cancers (Basel) 2018;10:293. https://doi.org/10.3390/cancers10090293.
    Pubmed KoreaMed CrossRef
  12. Katz LH, Levi Z, Twig G, et al. Risk factors associated with gastroenteropancreatic neuroendocrine tumors in a cohort of 2.3 million Israeli adolescents. Int J Cancer 2018;143:1876-1883. https://doi.org/10.1002/ijc.31589.
    Pubmed CrossRef
  13. Soto-Solís R, Romano-Munive AF, Santana de Anda K, Barreto-Zuñiga R. Factors related to gastric neuroendocrine tumors. Rev Gastroenterol Mex (Engl Ed) 2019;84:52-56. https://doi.org/10.1016/j.rgmxen.2018.06.007.
    CrossRef
  14. Campana D, Ravizza D, Ferolla P, et al. Risk factors of type 1 gastric neuroendocrine neoplasia in patients with chronic atrophic gastritis. A retrospective, multicentre study. Endocrine 2017;56:633-638. https://doi.org/10.1007/s12020-016-1099-y.
    Pubmed CrossRef
  15. Massironi S, Campana D, Partelli S, et al. Heterogeneity of duodenal neuroendocrine tumors: an Italian multi-center experience. Ann Surg Oncol 2018;25:3200-3206. https://doi.org/10.1245/s10434-018-6673-5.
    Pubmed CrossRef
  16. Rossi RE, Milanetto AC, Andreasi V, et al. Risk of preoperative understaging of duodenal neuroendocrine neoplasms: a plea for caution in the treatment strategy. J Endocrinol Invest 2021;44:2227-2234. https://doi.org/10.1007/s40618-021-01528-1.
    Pubmed CrossRef
  17. Giannetta E, Guarnotta V, Rota F, et al. A rare rarity: neuroendocrine tumor of the esophagus. Crit Rev Oncol Hematol 2019;137:92-107. https://doi.org/10.1016/j.critrevonc.2019.02.012.
    Pubmed CrossRef
  18. Wu IC, Chu YY, Wang YK, et al. Clinicopathological features and outcome of esophageal neuroendocrine tumor: a retrospective multicenter survey by the digestive endoscopy society of Taiwan. J Formos Med Assoc 2021;120:508-514. https://doi.org/10.1016/j.jfma.2020.06.024.
    Pubmed CrossRef
  19. Chun HJ, Park SJ, Lim YJ, Song SY. Gastrointestinal cancer: a comprehensive guide to diagnosis and management. Gastrointestinal cancer: a comprehensive guide to diagnosis and management. Singapore: Springer, 2023:437-446.
    CrossRef
  20. Feola T, Puliani G, Sesti F, et al. Risk factors for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a three-centric case-control study. J Endocrinol Invest 2022;45:849-857. https://doi.org/10.1007/s40618-021-01715-0.
    Pubmed CrossRef
  21. Barrea L, Muscogiuri G, Modica R, et al. Cardio-metabolic indices and metabolic syndrome as predictors of clinical severity of gastroenteropancreatic neuroendocrine tumors. Front Endocrinol (Lausanne) 2021;12:649496. https://doi.org/10.3389/fendo.2021.649496.
    Pubmed KoreaMed CrossRef
  22. Scherübl H, Jensen RT, Cadiot G, Stölzel U, Klöppel G. Management of early gastrointestinal neuroendocrine neoplasms. World J Gastrointest Endosc 2011;3:133-139. https://doi.org/10.4253/wjge.v3.i7.133.
    Pubmed KoreaMed CrossRef
  23. Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology 2020;76:182-188. https://doi.org/10.1111/his.13975.
    Pubmed KoreaMed CrossRef
  24. Nam K, Nam SY, Park JC, et al. Factors associated with gastric and duodenal neuroendocrine tumors: a multicenter case-control study. Dig Liver Dis. https://doi.org/10.1016/j.dld.2024.01.210.
    Pubmed CrossRef

Journal Info

JDCR
Vol.12 No.1
April 20, 2024
eISSN : 2950-9505
pISSN : 2950-9394
Frequency: Triannual

open access

Article Tools

Stats or Metrics

Share this article on

  • line

Journal of Digestive Cancer Research

eISSN 2950-9505
pISSN 2950-9394

  • 2021
  • 2022
  • 2023
  • 2024