Pancreatic resections or observation in management of sporadic non-functioning stage T1 neuroendocrine tumors of the pancreas (PNET) (literature review)

The availability of modern high-precision diagnostic methods increased the detection rate of pancreatic neuroendocrine neoplasia (pNEN). There is no doubt concerning the necessity of surgical treatment for localized functioning tumors, whilecurrently there is no objective way to choose the tactic for non-functioning asymptomatic neuroendocrine tumors of the pancreas (pNET) with the exception of the tumor size.

Treatment tactics for non-functioning asymptomatic T1 neuroendocrine tumors (less 2 cm in size) are debatable. According to literature surgical treatment for lesions less than 2 cm does not always increase survival. In the same time even in high-volume centers pancreatic surgery shows high morbidity and mortality rate. Prospective randomized trials comparing surveillance and operative treatment are not published yet, as far as authors concerned. International guidelines answer the question of treatment such neoplasms ambiguously, while national Russian recommendations do not cover the topic. Guidelines are based on heterogeneous retrospective studies; therefore, the aim of scientific research is to determine reliable criteria for patient selection for dynamic observation or surgical treatment.

This article provides an overview of 60 scientific publications covering the problem.

1. Gorbunova VA. Neuroendocrine Tumors. General Principles of Diagnosis and Treatment: Practical Guide. Moscow: GEOTAR-Media; 2021. (In Russ.)]. doi: https://doi.org/10.33029/9704-5997-3-neu-2021-1-600

2. Kochatkov AV, Kovalenko ZA. Epidemiology of neuroendocrine neoplasms. Pirogov Russian Journal of Surgery. 2016;(9):94-100. (In Russ.)]. doi: https://doi.org/10.17116/hirurgia2016994-100

3. Kuo EJ, Salem RR. Population-level analysis of pancreatic neuroendocrine tumors 2 cm or less in size. Ann Surg Oncol. 2013;20(9):2815-2821. doi: https://doi.org/10.1245/s10434-013-3005-7

4. Sonbol MB, Mazza GL, Mi L, et al. Survival and incidence patterns of pancreatic neuroendocrine tumors over the last 2 decades: A SEER database analysis. Oncologist. 2022;27(7):573-578. doi: https://doi.org/10.1093/oncolo/oyac049

5. Xu Z, Wang L, Dai S, et al. Epidemiologic trends of and factors associated with overall survival for patients with gastroenteropancreatic neuroendocrine tumors in the United States. JAMA Netw Open. 2021;4(9):e2124750. doi: https://doi.org/10.1001/jamanetworkopen.2021.24750

6. Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76(2):182-188. doi: https://doi.org/10.1111/his.13975

7. Jensen RT, Berna MJ, Bingham DB, Norton JA. Inherited pancreatic endocrine tumor syndromes: Advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer. 2008;113(S7):1807-1843. doi: https://doi.org/10.1002/cncr.23648

8. Da Silva Xavier G. The cells of the islets of langerhans. J Clin Med. 2018;7(3):54. doi: https://doi.org/10.3390/jcm7030054

9. Gorelik M, Ahmad M, Grossman D, Grossman M, Cooperman AM. Nonfunctioning Incidental Pancreatic Neuroendocrine Tumors. Surg Clin North Am. 2018;98(1):157-167. doi: https://doi.org/10.1016/j.suc.2017.09.014

10. Mehrabi A, Fischer L, Hafezi M, et al. A Systematic review of localization, surgical treatment options, and outcome of insulinoma. Pancreas. 2014;43(5):675-686. doi: https://doi.org/10.1097/MPA.0000000000000110

11. Burghardt L, Meier JJ, Uhl W, et al. Importance of localization of insulinomas: a systematic analysis. J Hepatobiliary Pancreat Sci. 2019;26(9):383-392. doi: https://doi.org/10.1002/jhbp.642

12. Bartsch DK, Waldmann J, Fendrich V, et al. Impact of lymphadenectomy on survival after surgery for sporadic gastrinoma. Br J Surg. 2012;99(9):1234-1240. doi: https://doi.org/10.1002/bjs.8843

13. Zhang J, Kulkarni HR, Baum RP. 225Ac-DOTATOC–targeted somatostatin receptor α-therapy in a patient with metastatic neuroendocrine tumor of the thymus, refractory to β-radiation. Clin Nucl Med. 2021;46(12):1030-1031. doi: https://doi.org/10.1097/RLU.0000000000003792

14. Marchese U, Gaillard M, Pellat A, et al. Multimodal management of grade 1 and 2 pancreatic neuroendocrine tumors. Cancers (Basel). 2022;14(2):433. doi: https://doi.org/10.3390/cancers14020433

15. Inzani F, Petrone G, Rindi G. The new World Health Organization Classification for pancreatic neuroendocrine neoplasia. Endocrinol Metab Clin North Am. 2018;47(3):463-470. doi: https://doi.org/10.1016/j.ecl.2018.04.008

16. Maystrenko NA, Romashchenko PN, Lysanyuk MV. Diagnosis and surgical treatment of neuroendocrine tumors of the pancreas and gastrointestinal tract. Annaly khirurgicheskoy gepatologii. 2018;21(1):13-20. (In Russ.)]. doi: https://doi.org/10.16931/1995-5464.2016113-20

17. Regenet N, Carrere N, Boulanger G, et al. Is the 2-cm size cutoff relevant for small nonfunctioning pancreatic neuroendocrine tumors: a French multicenter study. Surgery. 2016;159(3):901-907. doi: https://doi.org/10.1016/j.surg.2015.10.003

18. Bettini R, Partelli S, Boninsegna L, et al. Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Surgery. 2011;150(1):75-82. doi: https://doi.org/10.1016/j.surg.2011.02.022

19. Sallinen VJ, Le Large TYS, Tieftrunk E, et al. Prognosis of sporadic resected small (≤2 cm) nonfunctional pancreatic neuroendocrine tumors – a multi-institutional study. HPB. 2018;20(3):251-259. doi: https://doi.org/10.1016/j.hpb.2017.08.034

20. Partelli S, Bartsch DK, Capdevila J, et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumours: surgery for small intestinal and pancreatic neuroendocrine tumours. Neuroendocrinology. 2017;105(3):255-265. doi: https://doi.org/10.1159/000464292

21. Partelli S, Cirocchi R, Crippa S, et al. Systematic review of active surveillance versus surgical management of asymptomatic small non-functioning pancreatic neuroendocrine neoplasms. Br J Surg. 2016;104(1):34-41. doi: https://doi.org/10.1002/bjs.10312

22. Hue J, Sugumar K, Ammori J, et al. Facility type and size-stratified analysis of management patterns and outcomes of patients with localized non-functional pancreatic neuroendocrine tumors. HPB. 2022;24(1):S356. doi: https://doi.org/10.1016/j.hpb.2022.05.754

23. Assi HA, Mukherjee S, Kunz PL, et al. Surgery versus surveillance for well-differentiated, nonfunctional pancreatic neuroendocrine tumors: An 11-year analysis of the National Cancer Database. Oncologist. 2020;25(2):e276-e283. doi: https://doi.org/10.1634/theoncologist.2019-0466

24. Sarfati D, Blakely T, Pearce N. Measuring cancer survival in populations: relative survival vs cancer-specific survival. Int J Epidemiol. 2010;39(2):598-610. doi: https://doi.org/10.1093/ije/dyp392

25. Zhu J, Fu C, Zhang Y, et al. Observation Versus Resection for Small, Localized, and Nonfunctional Pancreatic Neuroendocrine Tumors. Pancreas. 2022;51(1):56-62. doi: https://doi.org/10.1097/MPA.0000000000001959

26. Powers BD, Rothermel LD, Fleming JB, et al. A survival analysis of patients with localized, asymptomatic pancreatic neuroendocrine tumors: no surgical survival benefit when examining appropriately selected outcomes. J Gastrointest Surg. 2020;24(12):2773-2779. doi: https://doi.org/10.1007/s11605-019-04433-4

27. Partelli S, Ramage JK, Massironi S, et al. Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study protocol for a prospective observational study. Front Med. 2020;7(12):2773-2779. doi: https://doi.org/10.3389/fmed.2020.598438

28. Nussbaum DP, Penne K, Stinnett SS, et al. A standardized care plan is associated with shorter hospital length of stay in patients undergoing pancreaticoduodenectomy. J Surg Res. 2015;193(1):237-245. doi: https://doi.org/10.1016/j.jss.2014.06.036

29. Frey S, Mirallié E, Le Bras M, Regenet N. What are the place and modalities of surgical management for pancreatic neuroendocrine neoplasms? A narrative review. Cancers. 2021;13(23):5954. doi: https://doi.org/10.3390/cancers13235954

30. Bolm L, Petrova E, Woehrmann L, et al. The impact of preoperative biliary stenting in pancreatic cancer: A case-matched study from the German nationwide pancreatic surgery registry (DGAV StuDoQ|Pancreas). Pancreatology. 2019;19(7):985-993. doi: https://doi.org/10.1016/j.pan.2019.09.007

31. Lindner K, Binte D, Hoeppner J, et al. Resection of nonfunctional pancreatic neuroendocrine neoplasms—A SingleCenter Retrospective Outcome Analysis. Current Oncology. 2021;28(4):3071-3080. doi: https://doi.org/10.3390/curroncol28040268

32. Jilesen APJ, van Eijck CHJ, in’t Hof KH, et al. Postoperative complications, in-hospital mortality and 5-year survival after surgical resection for patients with a pancreatic neuroendocrine tumor: A systematic review. World J Surg. 2016;40(3):729-748. doi: https://doi.org/10.1007/s00268-015-3328-6

33. Paiella S, De Pastena M, Faustini F, et al. Central pancreatectomy for benign or low-grade malignant pancreatic lesions - A singlecenter retrospective analysis of 116 cases. Eur J Surg Oncol. 2019;45(5):788-792. doi: https://doi.org/10.1016/j.ejso.2018.11.021

34. Wakabayashi T, Felli E, Cherkaoui Z, et al. Robotic central pancreatectomy for well-differentiated neuroendocrine tumor: parenchymal-sparing procedure. Ann Surg Oncol. 2019;26(7):2121. doi: https://doi.org/10.1245/s10434-019-07387-8

35. Fernandez CJ, Agarwal M, Pottakkat B, et al. Gastroenteropancreatic neuroendocrine neoplasms: A clinical snapshot. World J Gastrointest Surg. 2021;13(3):231-255. doi: https://doi.org/10.4240/wjgs.v13.i3.231

36. Falconi M, Zerbi A, Crippa S, et al. Parenchyma-preserving resections for small nonfunctioning pancreatic endocrine tumors. Ann Surg Oncol. 2010;17(6):1621-1627. doi: https://doi.org/10.1245/s10434-010-0949-8

37. Cherif R, Gaujoux S, Couvelard A, et al. Parenchyma-sparing resections for pancreatic neuroendocrine tumors. J Gastrointest Surg. 2012;16(11):2045-2055. doi: https://doi.org/10.1007/s11605-012-2002-7

38. Finkelstein P, Sharma R, Picado O, et al. Pancreatic Neuroendocrine Tumors (panNETs): analysis of overall survival of nonsurgical management versus surgical resection. J Gastrointest Surg. 2017;21(5):855-866. doi: https://doi.org/10.1007/s11605-017-3365-6

39. Marchese U, Gaillard M, Pellat A, et al. Multimodal management of grade 1 and 2 pancreatic neuroendocrine tumors. Cancers. 2022;14(2):433. doi: https://doi.org/10.3390/cancers14020433

40. Duconseil P, Marchese U, Ewald J, et al. A pancreatic zone at higher risk of fistula after enucleation. World J Surg Oncol. 2018;16(1):177. doi: https://doi.org/10.1186/s12957-018-1476-5

41. Guerra F, Giuliani G, Bencini L, et al. Minimally invasive versus open pancreatic enucleation. Systematic review and meta-analysis of surgical outcomes. Journal of Surgical Oncology [Internet]. 2018;117(7):1509–16. doi: https://doi.org/10.1002/jso.25026

42. Solodkiy VA, Kriger AG, Akhaladze GG, et al. Enucleation of pancreatic tumors: a multiple-center study. Pirogov Russian Journal of Surgery. 2023;(2):13-20. (In Russ.)]. doi: https://doi.org/10.17116/hirurgia202302113

43. Altimari M, Abad J, Chawla A. The role of oncologic resection and enucleation for small pancreatic neuroendocrine tumors. HPB. 2021;23(10):1533-1540. doi: https://doi.org/10.1016/j.hpb.2021.03.005

44. Krampitz GW, Norton JA, Poultsides GA, et al. Lymph nodes and survival in pancreatic neuroendocrine tumors. Arch Surg. 2012;147(9):820. doi: https://doi.org/10.1001/archsurg.2012.1261

45. Roland CL, Bian A, Mansour JC, et al. Survival impact of malignant pancreatic neuroendocrine and islet cell neoplasm phenotypes. J Surg Oncol. 2012;105(6):595-600. doi: https://doi.org/10.1002/jso.22118

46. Ricci C, Casadei R, Taffurelli G, et al. The role of lymph node ratio in recurrence after curative surgery for pancreatic endocrine tumours. Pancreatology. 2013;13(6):589-593. doi: https://doi.org/10.1016/j.pan.2013.09.001

47. Boninsegna L, Panzuto F, Partelli S, et al. Malignant pancreatic neuroendocrine tumour: Lymph node ratio and Ki67 are predictors of recurrence after curative resections. Eur J Cancer. 2012;48(11):1608-1615. doi: https://doi.org/10.1016/j.ejca.2011.10.030

48. Haynes AB. Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors. Arch Surg. 2011;146(5):534. doi: https://doi.org/10.1001/archsurg.2011.102

49. Triponez F, Sadowski SM, Pattou F, et al. Long-term followup of MEN1 patients who do not have initial surgery for small ≤2 cm nonfunctioning pancreatic neuroendocrine tumors, an AFCE and GTE study. Ann Surg. 2018;268(1):158-164. doi: https://doi.org/10.1097/SLA.0000000000002191

50. Pavel M, de Herder WW. ENETS consensus guidelines for the standards of care in neuroendocrine tumors. Neuroendocrinology. 2017;105(3):193-195. doi: https://doi.org/10.1159/000457957

51. Pavel M, Öberg K, Falconi M, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(7):844-860. doi: https://doi.org/10.1016/j.annonc.2020.03.304

52. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Neuroendocrine and Adrenal Tumors, Version 2.2022. [cited 11.05.2023]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf

53. Mansour JC, Chavin K, Morris-Stiff G, et al. Management of asymptomatic, well-differentiated PNETs: results of the Delphi consensus process of the Americas Hepato-Pancreato-Biliary Association. HPB. 2019;21(5):515-523. doi: https://doi.org/10.1016/j.hpb.2018.09.020

54. The North American Neuroendocrine Tumor Society Guidelines [Internet]. 2022 Edition. [cited 11.05.2023]. Available from: https://nanets.net/images/guidelines/21513_NANETS_2022_Guidelines_Compendium.pdf

55. Howe JR, Merchant NB, Conrad C, et al. The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors. Pancreas. 2020;49(1):1-33. doi: https://doi.org/10.1097/mpa.0000000000001454

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