Current state of diagnosis and treatment of functional neuroendocrine pancreatic tumors: Literature review

Neuroendocrine tumors (NETs) occur at a frequency of 2 to 5 new cases per 100,000 people per year. Among the NETs of the gastrointestinal tract, about 70–80 % are pancreatic neoplasms. In 40–50 % of cases, NETs are functional tumors of the pancreas most often represented by insulinomas and gastrinomas, less common are VIPomas, glucagonomas and somatostatinomas.

The incidence of multiple endocrine neoplasia type 1 (MEN-1) is approximately 1–10 cases per 100,000 population. MEN-1 is an autosomal dominant disorder characterized by combined occurrence of pancreatic NETs with tumors of the parathyroid glands and pituitary gland. In patients with MEN-1 syndrome, pancreatic lesions occur in 30–80 % of cases.

The main tasks in diagnostics of NETs are establishment of syndromic and topographic diagnosis, exclusion of MEN-1 syndrome. To establish topographic diagnosis, the following are methods are used: ultrasound, including endoscopic, computed tomography, magnetic resonance imaging, angiography and arterial blood sampling with hormone measurement, scintigraphy of somatostatin receptors with octreotide, Ga-68 positron emission tomography, single-photon emission tomography with Tс-99m combined with computed tomography.

The next task for doctors is the choice of therapy for NET. Currently, the following types of treatment are used: radical surgeries, including extensive resections, organ-sparing interventions, minimally invasive interventions (microwave and radiofrequency ablation), cytoreductive surgeries (including minimally invasive), treatment of liver metastases of pancreatic NETs, as well as therapy within the framework of MEN-1 such as radio-, chemo-, bio- and immunotherapy. It should be noted that more than half of the patients require more than one therapy, i. e. combination therapy.

1. Artamonova E.V., Gorbunova V.A., Delektorskaya V.V. et al. Neuroendocrine neoplasia of the gastrointestinal tract and pancreas. RUSSCO Guidelines, v. 1.1. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2):427–44. (In Russ.)

2. Das S., Dasari A. Epidemiology, incidence, and prevalence of neuroendocrine neoplasms: Are there global differences? Curr Oncol Rep 2021;23(4):43. DOI: 10.1007/s11912-021-01029-7

3. Hallet J., Law C.H., Cukier M. et al. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 2015;121(4):589–97. DOI: 10.1002/cncr.29099

4. Frost M., Lines K.E., Thakker R.V. Current and emerging therapies for PNETs in patients with or without MEN1. Nat Rev Endocrinol 2018;14(4):216–27. DOI: 10.1038/nrendo.2018.3

5. Parbhu S.K., Adler D.G. Pancreatic neuroendocrine tumors: contemporary diagnosis and management. Hosp Pract (1995) 2016;44(3):109–19. DOI: 10.1080/21548331.2016.1210474

6. Modlin I.M., Oberg K., Chung D.C. et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008;9(1):61–72. DOI: 10.1016/S1470-2045(07)70410-2

7. Klöppel G., Rindi G., Perren A. et al. The ENETS and AJCC/ UICC TNM classifications of the neuroendocrine tumors of the gastrointestinal tract and the pancreas: a statement. Virchows Arch 2010;456(6):595–7. DOI: 10.1007/s00428-010-0924-6

8. WHO Classification of Tumours Editorial Board. Endocrine and Neuroendocrine tumours. Lyon (France): International Agency for Research on Cancer; 2022. Vol. 8.

9. Gurevich L.E., Kazantseva I.A. Current approaches to the morphological diagnosis of pancreatic neuroendocrine tumors and prediction of their clinical course based on the analysis of our own database. Almanakh klinicheskoy meditsiny = Almanac of Clinical Medicine 2018;46(4):298–313. DOI: 10.18786/2072-0505-2018-46-4-298-313 (In Russ.)

10. Delektorskaya V.V. Neuroendocrine tumors of the digestive system: pathologic and molecular characteristics. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2018;46(4):298–313. DOI: 10.18786/2072-0505-2018-46-4-298-313 (In Russ.)

11. Martin-Perez E., Capdevila J., Castellano D. et al. Prognostic factors and long-term outcome of pancreatic neuroendocrine neoplasms: Ki-67 index shows a greater impact on survival than disease stage. The large experience of the Spanish National Tumor Registry (RGETNE). Neuroendocrinology 2013;98(2):156–68. DOI: 10.1159/000355152

12. Dai M., Mullins C.S., Lu L. et al. Recent advances in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. World J Gastrointest Surg 2022;14(5):383–96. DOI: 10.4240/wjgs.v14.i5.383

13. Juchems M., Kläsner B. Neuroendocrine tumors of the pancreas. Radiologie (Heidelb) 2023;63(12):894–99. DOI: 10.1007/s00117-023-01231-7 (In German)

14. Gonzalez R.S. Diagnosis and management of gastrointestinal neuroendocrine neoplasms. Surg Pathol Clin 2020;13(3):377–97. DOI: 10.1016/j.path.2020.04.002

15. Geurts J.L. Inherited syndromes involving pancreatic neuroendocrine tumors. J Gastrointest Oncol 2020;11(3):559–66. DOI: 10.21037/jgo.2020.03.09

16. Egorov A.V., Musaev G.Kh., Kondrashin S.A. et al. Prognostic factors of the immediate results of surgical treatment of organic hyperinsulinism. Khirurgiya. Zhurnal im. N.I. Pirogova = Pirogov Russian Journal of Surgery 2011;6:60–5. (In Russ.)

17. Okabayashi T., Shima Y., Sumiyoshi T. et al. Diagnosis and management of insulinoma. World J Gastroenterol 2013;19(6):829–37. DOI: 10.3748/wjg.v19.i6.829

18. Chernousov A.F., Egorov A.V., Kondrashin S.A. et al. Diagnosis and treatment of gastrin–producing tumors and Zollinger-Ellison syndrome. Vestnik khirurgicheskoy gastroenterologii = Herald of Surgical Gastroenterology 2007;3:17–26 (In Russ.).

19. Norton J.A., Foster D.S., Ito T., Jensen R.T. Gastrinomas: Medical or surgical treatment. Endocrinol Metab Clin North Am 2018;47(3):577–601. DOI: 10.1016/j.ecl.2018.04.009

20. Pusceddu S., Rossi R.E., Torchio M. et al. Differential diagnosis and management of diarrhea in patients with neuroendocrine tumors. J Clin Med 2020;9(8):2468. DOI: 10.3390/jcm9082468

21. Modlin I.M., Gustafsson B.I., Moss S.F. et al. Chromogranin A – biological function and clinical utility in neuroendocrine tumor disease. Ann Surg Oncol 2010;17(9):2427–43. DOI: 10.1245/s10434-010-1006-3

22. Egorov A.V., Vasilyev I.A., Parnova V.A. et al. Diagnosis and management of hormon active pancreatic neuroendocrine tumours: State of the art. Vysokotekhnologicheskaya meditsina = High-Tech Medicine 2017;4(1):32–42. (In Russ.)

23. Egorov A.V., Musaev G.Kh., Fominykh E.V. et al. Evolution of topical diagnostic algorithm for pancreatic hormone-producing neuroendocrine tumors. Annaly khirurgicheskoy gepatologii = Annals of HPB Surgery 2016;21(1):21–7. (In Russ.)

24. Cives M., Strosberg J.R. Gastroenteropancreatic neuroendocrine tumors. CA Cancer J Clin 2018;68(6):471–87. DOI: 10.3322/caac.21493

25. Zilli A., Arcidiacono P.G., Conte D., Massironi S. Clinical impact of endoscopic ultrasonography on the management of neuroendocrine tumors: lights and shadows. Dig Liver Dis 2018;50(1):6–14. DOI: 10.1016/j.dld.2017.10.007

26. Vasilyev I.A., Egorov A.V., Kondrashin S.A. et al. Reoperated insulinomas. Tavrichesky mediko-biologichesky vestnik = Tavrichesky Medical and Biological Bulletin 2020;23(2):48–52. (In Russ.)

27. Egorov A.V., Musaev G.H., Kondrashin S.A. et al. Diagnosis and management of patients with neuroendocrine tumors of pancreas in type 1 multiple endocrine neoplasia. Annaly khirurgicheskoy gepatologii = Annals of HPB Surgery 2010;15(3):25–30. (In Russ.)

28. Faggiano A., Mansueto G., Ferolla P. et al. Diagnostic and prognostic implications of the World Health Organization classification of neuroendocrine tumors. J Endocrinol Invest 2008;31(3):216–23. DOI: 10.1007/BF03345593

29. Kondrashin S.A., Egorov A.V., Pashkova I.L., Mayorova E.M. Angiography and intra-arterial calcium stimulation test in localizing the source of organic hyperinsulinism. Diagnosticheskaya interventsionnaya radiologiya = Diagnostic and Interventional Radiology 2008;2(1):13–28. (In Russ.)

30. Pauwels E., Cleeren F., Bormans G., Deroose C.M. Somatostatin receptor PET ligands – the next generation for clinical practice. Am J Nucl Med Mol Imaging 2018;8(5):311–31

31. Abgral R., Leboulleux S., Deandreis D. et al. Performance of (18) fluorodeoxyglucose-positron emission tomography and somatostatin receptor scintigraphy for high Ki67 (>10 %) well-differentiated endocrine carcinoma staging. J Clin Endocrinol Metab 2011;96(3):665–71.

32. Scott A.T., Howe J.R. Evaluation and management of neuroendocrine tumors pancreas. Surg Clin North Am 2019;99(4):793–814. DOI: 10.1016/j.suc.2019.04.014

33. Giovannini E., Giovacchini G., Borso E. et al. 68Ga-Dota peptide PET/CT in neuroendocrine tumors: Main clinical applications. Curr Radiopharm 2019;12(1):11–22. DOI: 10.2174/1874471012666181212101244

34. Horiguchi S., Kato H., Shiraha H. et al. Dynamic computed tomography is useful for prediction of pathological grade in pancreatic neuroendocrine neoplasm. J Gastroenterol Hepatol 2017;32(4):925–31. DOI: 10.1111/jgh.13594

35. Yukina M.Yu., Troshina E.A., Nuralieva N.F. et al. SPECT/CT with 99mTc-Tectrotide in the diagnosis of insulinoma. Ozhirenie i metabolism = Obesity and Metabolism 2023;20(1):43–8. DOI: 10.14341/omet12977. (In Russ.)

36. Egorov A.V., Zhemerikin G.A., Vetshev F.P. et al. Ultrasound study as the primary method of intraoperative topical diagnosis in pancreatic neuroendocrine tumor surgery. Annaly khirurgicheskoy gepatologii = Annals of HPB Surgery 2025;30(2):33–41. (In Russ.)

37. Ramamoorthy B., Nilubol N. Multiple endocrine neoplasia type 1 syndrome pancreatic neuroendocrine tumor genotype/phenotype: is there any advance on predicting or preventing? Surg Oncol Clin N Am 2023;32(2):315–25. DOI: 10.1016/j.soc.2022.10.008

38. Sipos B. Multiple neuroendocrine tumors of the pancreas. Pathologie (Heidelb) 2024;45(1):28–34. DOI: 10.1007/s00292-023-01289-z

39. Vasiliev I., Egorov A., Kondrashin S. et al. Managements of patients with multiple pancreatic tumors. In: Abstracts of the 8th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease. Lisbon, 2011.

40. Jensen R.T., Norton J.A. Treatment of pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: Some clarity but continued controversy. Pancreas 2017;46(5):589–94. DOI: 10.1097/MPA.0000000000000825

41. Egorov A.V., Vetshev F.P., Zhemerikin G.A. et al. Modern approaches to surgical treatment of neuroendocrine pancreatic tumors. In: XXIX Russian Cancer Congress, December 11–13, 2025. Moscow, 2025. (In Russ.)

42. Salvia R., Lionetto G., Perri G. et al. Total pancreatectomy and pancreatic fistula: friend or foe? Updates Surg 2021;73(4):1231–6. DOI: 10.1007/s13304-021-01130-3

43. Xu Q., Xie Q., Ge C. et al. Risk factors and prevention of postoperative pancreatic fistula after insulinoma enucleation: a retrospective study from a high-volume center. Pancreatology 2021;21(6):1208–15. DOI: 10.1016/j.pan.2021.06.001

44. Souche R., Hobeika C., Hain E., Gaujoux S. Surgical management of neuroendocrine tumours of the pancreas. J Clin Med 2020;9(9):2993. DOI: 10.3390/jcm9092993

45. Egorov A.V., Vasilyev I.A., Musayev G.H., Mironova A.V. The role of microwave ablation in management of functioning pancreatic neuroendocrine tumors. Gland Surg 2019;8(6):766–72. DOI: 10.21037/gs.2019.12.07

46. Chernousov A.F., Egorov A.V., Musaev G.Kh. et al. First experience of ultrasound-assisted percutaneous microwave ablation of insulin-producing pancreatic tumor. Khirurgiya. Zhurnal im. N.I. Pirogova = Pirogov Russian Journal of Surgery 2015;(12):107–110. DOI: 10.17116/hirurgia201512107-110 (In Russ.)

47. Egorov A.V., Zhemerikin G.A., Alekseev K.I. et al. Complications after minimally invasive surgery for neuroendocrine pancreatic tumors: prevention and treatment. In: VIII International Forum of Oncology and Radiotherapy “For Life”, September 15–19, 2025. Moscow, 2025. (In Russ.)

48. Crinò S.F., Napoleon B., Facciorusso A. et al. Endoscopic ultrasound-guided radiofrequency ablation versus surgical resection for treatment of pancreatic insulinoma. Clin Gastroenterol Hepatol 2023;21(11):2834–43.e2. DOI: 10.1016/j.cgh.2023.02.022

49. Popov S.A., Zhemerikin G.A., Pavlovsky A.V., Egorov A.V. Possibilities of combined treatment of patients with metastatic and locally advanced neuroendocrine tumors of the pancreas. In: XXXV Russian Symposium on Surgical Endocrinology “Kalinin Readings” with the participation of endocrinologists, September 26–27, 2025. Moscow, 2025. (In Russ.)

50. Tarazov P.G., Polikarpov A.A., Granov D.A. Arterial chemoembolization in the treatment of carcinoid liver metastases patients. Annaly khirurgicheskoy gepatologii = Annals of HPB Surgery 2010;15(3):19–24. (In Russ.)

51. Chan M.Y., Ma K.W., Chan A. Surgical management of neuroendocrine tumor-associated liver metastases: a review. Gland Surg 2018;7(1):28–35. DOI: 10.21037/gs.2017.11.16

52. Partelli S., Inama M., Rinke A. et al. Long-term outcomes of surgical management of pancreatic neuroendocrine tumors with synchronous liver metastases. Neuroendocrinology 2015;102(1–2):68–76. DOI: 10.1159/000431379

53. Cloyd J.M., Wiseman J.T., Pawlik T.M. Surgical management of pancreatic neuroendocrine liver metastases. J Gastrointest Oncol 2020;11(3):590–600. DOI: 10.21037/jgo.2019.11.02

54. Marini F., Giusti F., Tonelli F., Brandi M.L. Pancreatic neuroendocrine neoplasms in multiple endocrine neoplasia type 1. Int J Mol Sci 2021;22(8):4041. DOI: 10.3390/ijms22084041

55. Simon R. Complications after pancreaticoduodenectomy. Surg Clin North Am 2021;101(5):865–74. DOI: 10.1016/j.suc.2021.06.011

56. Birnbaum D.J., Turrini O., Vigano L. et al. Surgical management of advanced pancreatic neuroendocrine tumors: short-term and long-term results from an international multi-institutional study. Ann Surg Oncol 2015;22(3):1000–7. DOI: 10.1245/s10434-014-4016-8

57. Orel N.F., Artamonova E.V., Gorbunova V.A. et al. Practical recommendations for the drug treatment of neuroendocrine tumors of the gastrointestinal tract, pancreas and other localizations. Zlokachestvennye opukholi = Malignant Tumors 2020;10(3s2-1): 519–32. (In Russ.)