M.V. LYSANYUK¹, P.N. ROMASHCHENKO¹, N.A. MAISTRENKO¹, R.V. ORLOVA², A.K. IVANOVA²

¹Military Medical Academy named after S.M. Kirov, Saint-Petersburg

²City Clinical Oncology Center, Saint-Petersburg

 Contact details:

Lysanyuk M.V. ― PhD (medicine), Associate Professor of the Department of Faculty Surgery named after S.P. Fedorov

Address: 6G Acad. Lebedev Str., Saint Petersburg, Russian Federation, 194044, e-mail: lysanjuk-maksim@rambler.ru

 Objective ― to assess the possibility of diagnosis and to determine the ways to improve the results of treatment of patients with gastroenteropancreatic neuroendocrine tumors.

Material and methods. The results of treatment of 283 patients with neuroendocrine tumors (NET) of the gastrointestinal tract and pancreas were studied.

Results. NET of the digestive tract were detected in 165 (58.3%) patients, of the pancreas ― in 108 (38.2%) patients, the localization of the primary NET was not defined in 10 (3.8%) patients. NET was asymptomatic in 24% cases, characterized by nonspecific symptoms ― in 58.4%, manifested by carcinoid syndrome ― in 10.2% cases. The sensitivity of chromogranin-A in the diagnosis of localized NET was 23.4%, locally distributed ― 33.4%, generalized ― 62.8%. The sensitivity of serotonin and 5-HIAA in the detection of NET with carcinoid syndrome was 91.3% and 79%, respectively. In the diagnosis of non-functioning pancreatic NET, the greatest sensitivity was shown by CT (88.0%) and MRI (87.5%), insulinomas ― EUS (100%). A reliable radiation sign of the small intestine NET is a tumor conglomerate of the mesentery, in the detection of which CT has the greatest sensitivity (96.4%). Surgical treatment was performed in 233 (82.3%) patients. Complex treatment provided an increase in the median survival rate of patients with generalized NET by 2 times (from 29.9 months up to 60 months), NEC ― 2.9 times (from 10.1 months up to 28.5 months).

Conclusion. Diagnosis of NET is difficult due to the peculiarities of clinical manifestations of the disease. The sensitivity of tumor neuroendocrine markers depends on the degree, localization, and clinical manifestations of NET. Modern instrumental methods of diagnosis in most cases allow determining the location of NET and assessing the degree of neoplastic process. The surgical method is the main in the treatment of NET, while complex treatment has a significant advantage in the treatment of patients with generalized tumors.

Key words: neuroendocrine tumor, carcinoid syndrome, laboratory diagnostics, chromogranin-A, instrumental diagnostics, surgical tactics, complex treatment.

(For citation: Lysanyuk M.V., Maistrenko N.A., Romashchenko P.N., Orlova R.V., Ivanova A.K. Results of diagnosis and treatment of gastroenteropancreatic neuroendocrine tumors. Practical medicine. 2019. Vol. 17, № 4, P. 123-132)

REFERENCES

1. Fraenkel M., Kim M., Faggiano A. et al. Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocrine-Related Cancer, 2014, vol. 21 (3), pp. 153-163, doi: 10.1530/ERC-13-0125.
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, vol. 3 (10), pp. 1335-1342, doi: 10.1001/jamaoncol.2017.0589.
3. Lawrence B., Gustafsson B.I., Chan A. et al. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol. Metab. Clin. N. Am, 2011, vol. 40, pp. 1-18, doi: 10.1016/j.ecl.2010.12.005.
4. Niederle B., Pape U.F., Costa F. et al. ENETS Consensus Guidelines Update for Neuroendocrine Neoplasms of the Jejunum and Ileum. Neuroendocrinology, 2016, vol. 103 (2), pp. 125-138, doi: 10.1159/000443170.
5. Vinik A.I., Silva M.P., Woltering E.A. et al. Biochemical testing for neuroendocrine tumors. Pancreas, 2009, vol. 38 (8), pp. 876-889, doi: 10.1097/MPA.0b013e3181bc0e77.
6. Partelli S., Maurizi A., Tamburrino D. et al. GEP-NETS update: a review on surgery of gastro-entero-pancreatic neuroendocrine tumors. Eur. J. Endocrinol, 2014, vol. 171 (4), pp. 153-162, doi: 10.1530/EJE-14-0173.
7. Pusceddu S., De Braud F., Festinese F. et al. Evolution in the treatment of gastroenteropancreatic neuroendocrine neoplasms, focus on systemic therapeutic options: a systematic review. Future Oncol, 2015, vol. 11 (13), pp. 1947-1959, doi: 10.2217/fon.15.86.
8. Maystrenko N.A., Romashchenko P.N., Lysanyuk M.V. Diagnosis and surgical treatment of neuroendocrine tumors of the pancreas and gastrointestinal tract. Annaly khirurgicheskoy gepatologii, 2016, vol. 2 (1), pp. 13-20 (in Russ.), doi.org/10.16931/1995-5464.2016113-20.
9. Klimstra D.S. Pathologic Classification of Neuroendocrine Neoplasms. Hematol. Oncol. Clin. North. Am, 2016, vol. 30 (1), pp. 1-19, doi: 10.1016/j.hoc.2015.08.005.
10. Mocellin S., Nitti D. Gastrointestinal carcinoid: epidemiological and survival evidence from a large population-based study (n=25 531). Ann. Oncol, 2013, vol. 24 (12), pp. 3040-3044, doi: 10.1093/annonc/mdt377.
11. Kasumova G.G., Tabatabaie O., Eskander M.F., et al. National Rise of Primary Pancreatic Carcinoid Tumors: Comparison to Functional and Nonfunctional Pancreatic Neuroendocrine Tumors. J. Am. Coll. Surg, 2017, vol. 224 (6), pp. 1057-1064, doi: 10.1016/j.jamcollsurg.2016.11.014.
12. Siegel R.L., Miller K.D., Jemal A. Cancer Statistics, 2018. CA Cancer J. Clin, 2018, vol. 68 (1), pp. 7-30, doi: 10.3322/caac.21442.
13. Singh S., Granberg D., Wolin E., et al. Patient-Reported Burden of a Neuroendocrine Tumor (NET) Diagnosis: Results From the First Global Survey of Patients With NETs. J. Glob. Oncol, 2016, vol. 3 (1), pp. 43-53, doi: 10.1200/JGO.2015.002980.
14. Marotta V., Zatelli M.C., Sciammarella C., et al. Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: more flaws than fame. Endocr. Relat. Cancer, 2018, vol. 25 (1), pp. 11-29, doi: 10.1530/ERC-17-0269.
15. Oberg K., Modlin I.M., De Herder W., et al. Consensus on biomarkers for neuroendocrine tumour disease. Lancet Oncol, 2015, vol. 16 (9), pp. 435-446, doi: 10.1016/S1470-2045(15)00186-2.
16. Zandee W.T., Kamp K., van Adrichem R.C., et al. Limited value for urinary 5-HIAA excretion as prognostic marker in gastrointestinal neuroendocrine tumours. Eur. J. Endocrinol, 2016, vol. 175 (5), pp. 361-366, doi: 10.1530/EJE-16-0392.
17. Bodei L., Sundin A., Kidd M., et al. The status of neuroendocrine tumor imaging: from darkness to light? Neuroendocrinology, 2015, vol. 101 (1), pp. 1-17, doi: 10.1159/000367850.
18. Romashchenko P.N., Maystrenko N.A., Orlova R.V., Lysanyuk M.V. The rationale for treatment and diagnostic tactics in patients with neuroendocrine tumors of the small intestine. Vestnik khirurgii im. I.I. Grekova, 2018, vol. 177 (4), pp. 28-37 (in Russ.).
19. Mehrabi A., Fischer L., Hafezi M. et al. A systematic review of localization, surgical treatment options, and outcome of insulinoma. Pancreas, 2014, vol. 43 (5), pp. 675-686, doi: 10.1097/MPA.0000000000000110.
20. Öberg K., Sundin A. Imaging of Neuroendocrine Tumors. Front. Horm. Res, 2016, vol. 45, pp. 142-151, doi: 10.1159/000442331.
21. Lee L., Ito T., Jensen R.T. Imaging of pancreatic neuroendocrine tumors: recent advances, current status, and controversies. Expert. Rev. Anticancer Ther, 2018, vol. 18 (9), pp. 837-860, doi: 10.1080/14737140.2018.1496822.
22. Ito T., Jensen R.T. Molecular imaging in neuroendocrine tumors: recent advances, controversies, unresolved issues, and roles in management. Curr. Opin. Endocrinol. Diabetes Obes, 2017, vol. 24 (1), pp. 15-24, doi: 10.1097/MED.0000000000000300.
23. Yang Z., Klimstra D.S., Hruban R.H., Tang L.H. Immunohistochemical Characterization of the Origins of Metastatic Well-differentiated Neuroendocrine Tumors to the Liver. Am. J. Surg. Pathol, 2017, vol. 41 (7), pp. 915-922, doi: 10.1097/PAS.0000000000000876.
24. Maxwell J.E., Sherman S.K., Stashek K.M., et al. A practical method to determine the site of unknown primary in metastatic neuroendocrine tumors. Surgery, 2014, vol. 156 (6), pp. 1359-1365, doi: 10.1016/j.surg.2014.08.008.
25. Kyriakopoulos G., Mavroeidi V., Chatzellis E. et al. Histopathological, immunohistochemical, genetic and molecular markers of neuroendocrine neoplasms. Ann. Transl. Med, 2018, vol. 6 (12), p. 252, doi: 10.21037/atm.2018.06.27.
26. Eriksson J., Garmo J.E.H., Ihre-Lundgren C., Hellman P. Prognostic factors for death after surgery for small intestinal neuroendocrine tumours. BJS Open, 2018, vol. 2 (5), pp. 345-352, doi: 10.1002/bjs5.76.
27. Smith J.K., Ng S.C., Hill J.S. et al. Complications after pancreatectomy for neuroendocrine tumors: a national study. J. Surg. Res, 2010, vol. 163 (1), pp. 63-68, doi: 10.1016/j.jss.2010.04.017.
28. Jilesen A.P., van Eijck C.H., in’t Hof K.H. 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, vol. 40 (3), pp. 729-748, doi: 10.1007/s00268-015-3328-6.
29. Lysanyuk M.V., Romashchenko P.N., Orlova R.V. Lysanyuk M.V., Romashchenko P.N., Orlova R.V. The choice of tactics for the treatment of patients with neuroendocrine tumors. Tavricheskiy mediko-biologicheskiy vestnik, 2018, vol. 21 (1), pp. 84-97 (in Russ.).
30. Maxwell J.E., Sherman S.K., O’Dorisio T.M. et al. Liver-directed surgery of neuroendocrine metastases: What is the optimal strategy? Surgery, 2016, vol. 159 (1), pp. 320-333, doi: 10.1016/j.surg.2015.05.040.
31. Morgan R.E., Pommier S.J., Pommier R.F. Expanded criteria for debulking of liver metastasis also apply to pancreatic neuroendocrine tumors. Surgery, 2018, Vol. 163 (1), pp. 218-225, doi: 10.1016/j.surg.2017.05.030.
32. Ejaz A., Reames B.N., Maithel S. et al. The impact of extrahepatic disease among patients undergoing liver-directed therapy for neuroendocrine liver metastasis. J. Surg. Oncol, 2017, vol. 116 (7), pp. 841-847, doi: 10.1002/jso.24727.
33. Daskalakis K., Karakatsanis A., Hessman O. et al. Association of a Prophylactic Surgical Approach to Stage IV Small Intestinal Neuroendocrine Tumors With Survival. JAMA Oncol, 2018, vol. 4 (2), pp. 183-189, doi: 10.1001/jamaoncol.2017.3326.
34. Zhou B., Zhan C., Ding Y. et al. Role of palliative resection of the primary pancreatic neuroendocrine tumor in patients with unresectable metastatic liver disease: a systematic review and meta-analysis. Onco Targets Ther, 2018, vol. 11, pp. 975-982, doi: 10.2147/OTT.S158171.
35. Citterio D., Pusceddu S., Facciorusso A. et al. Primary tumour resection may improve survival in functional well-differentiated neuroendocrine tumours metastatic to the liver. Eur. J. Surg. Oncol, 2017, vol. 43 (2), pp. 380-387, doi: 10.1016/j.ejso.2016.10.031.
36. Kaçmaz E., Heidsma C.M., Besselink M.G.H. et al. Treatment of Liver Metastases from Midgut Neuroendocrine Tumours: A Systematic Review and Meta-Analysis. J. Clin. Med, 2019, vol. 8 (3), p. 403, doi: 10.3390/jcm8030403.
37. Gupta S. Intra-arterial liver-directed therapies for neuroendocrine hepatic metastases. Semin. Intervent. Radiol, 2013, vol. 30 (1), pp. 28-38, doi: 10.1055/s-0033-1333651.
38. Cavalcoli F., Rausa E., Conte D. et al. Is there still a role for the hepatic locoregional treatment of metastatic neuroendocrine tumors in the era of systemic targeted therapies? World J. Gastroenterol, 2017, vol. 23 (15), pp. 2640-2650, doi: 10.3748/wjg.v23.i15.2640.
39. Kennedy A.S. Hepatic-directed Therapies in Patients with Neuroendocrine Tumors. Hematol. Oncol. Clin. North Am, 2016, vol. 30 (1), pp. 193-207, doi: 10.1016/j.hoc.2015.09.010.
40. Pavel M., O’Toole D., Costa F. et al. ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site. Neuroendocrinology, 2016, vol. 103 (2), pp. 172-185, doi: 10.1159/000443167.
41. Singh S., Asa S.L., Dey C. et al. Diagnosis and management of gastrointestinal neuroendocrine tumors: An evidence-based Canadian consensus. Cancer Treat. Rev, 2016, vol. 47, pp. 32-45, doi: 10.1016/j.ctrv.2016.05.003.
42. Kolbeck K.J., Farsad K. Catheter-based treatments for hepatic metastases from neuroendocrine tumors. AJR Am. J. Roentgenol, 2014, vol. 203 (4), rr. 717-724, doi: 10.2214/AJR.14.12983.
43. Shamimi-Noori S., Gonsalves C.F., Shaw C.M. Metastatic Liver Disease: Indications for Locoregional Therapy and Supporting Data. Semin. Intervent. Radiol, 2017, vol. 34 (2), rr. 145-166, doi: 10.1055/s-0037-1602712.
44. Maystrenko N.A., Romashchenko P.N., Orlova R.V., Lysanyuk M.V. Treatment options for patients with generalized neuroendocrine tumors. Onkologiya. Zhurnal im. P.A. Gertsena, 2018, vol. 7 (2), pp. 16-25 (in Russ.), doi: 10.17116/onkolog20187216-25.
45. Garcia-Carbonero R., Sorbye H., Baudin E. et al. ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas. Neuroendocrinology, 2016, vol. 103 (2), pp. 186-194, doi: 10.1159/000443172.
46. Haugvik S.P., Janson E.T., Österlund P. et al. Surgical Treatment as a Principle for Patients with High-Grade Pancreatic Neuroendocrine Carcinoma: A Nordic Multicenter Comparative Study. Ann. Surg. Oncol, 2016, vol. 23 (5), pp. 1721-1728, doi: 10.1245/s10434-015-5013-2.
47. Du S., Ni J., Weng L. et al. Aggressive Locoregional Treatment Improves the Outcome of Liver Metastases from Grade 3 Gastroenteropancreatic Neuroendocrine Tumors. Medicine (Baltimore), 2015, vol. 94 (34), p. 1429, doi: 10.1097/MD.0000000000001429.
48. Galleberg R.B., Knigge U., Tiensuu Janson E. et al. Results after surgical treatment of liver metastases in patients with high-grade gastroenteropancreatic neuroendocrine carcinomas. Eur. J. Surg. Oncol, 2017, vol. 43 (9), pp. 1682-1689, doi: 10.1016/j.ejso.2017.04.010.