HIGH-GRADE GASTROENTEROPANCREATIC NEUROENDOCRINE NEOPLASMS. MODERN CLASSIFICATION, DIAGNOSTICS AND TREATMENT

Poorly differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are rare malignancies, most of which are characterized by aggressiveness, a tendency to rapid metastasis and an unfavorable prognosis even when localized. In 2017 World Health Organization (WHO) updated classification of GEP NENs and recognized the category of well-differentiated pancreatic NET G3, associated with Ki‑67 index usually over 20%. The upper level of Ki‑67 is not defined. Usually it is 55%. Highgrade poorly differentiated pancreatic NENs are defined as pancreatic neuroendocrine carcinomas (panNECs). Although the NET G3 category is recognized for pancreatic neuroendocrine neoplasms only, many specialists consider it reasonable to apply this term to all well-differentiated GEP NETs with Ki‑67 index in the 20 to 55 percent range. Clinical behavior and therapeutic approaches for advanced GEP NECs and NETs G3 are different. Standard palliative chemotherapy for GEP NECs consists of cisplatin or carboplatin combined with etoposide. The second-line regimens include irinotecan-, oxaliplatin, fluoropyrimidine- and temozolomide-based regimens. Temozolomide-based chemotherapy regimens, as well as targeted therapy are more preferable as first line therapy for patients with NETs G3. The platinum-based chemotherapy regimens are considered at the time of disease progression. Further clinical studies with the inclusion of much more patients will determine the optimal treatment strategy for this category of patients.

neuroendocrine neoplasms, neuroendocrine tumors G3, neuroendocrine carcinoma, proliferative index Ki67

1. Korse C. M., Taal B. G., van Velthuysen M. L., 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. Vol. 49. P. 1975.

2. Kang H., O’Connell J.B., Leonardi M. J. et al. Rare tumors of the colon and rectum: a national review. Int. J. Colorectal. Dis. 2007. Vol. 22. P. 183.

3. Нейроэндокринные опухоли. Общие принципы диагностики и лечения / Под ред. проф. В. А. Горбуновой. Москва, 2015. 34 с. [Neiroendokrinnye opukholi. Obshchie printsipy diagnostiki i lecheniya. (Neuroendocrine tumors. General principles of diagnosis and treatment). ed. V. A. Gorbunova. Moscow, 2015. 34 p. (In Russ.)].

4. Jann H., Roll S., Couvelard A. et al. Neuroendocrine tumors of midgut and hindgut origin: tumor-node-metastasis classification determines clinical outcome. Cancer. 2011. Vol. 117. P. 3332–3341.

5. La Rosa S., Inzani F., Vanoli A. et al. Histologic characterization and improved prognostic evaluation of 209 gastric neuroendocrine neoplasms. Hum. Pathol. 2011. Vol. 42. P. 1373.

6. Strosberg J. R., Cheema A., Weber J. et al. Prognostic validity of a novel American Joint Committee on Cancer Staging Classification for pancreatic neuroendocrine tumors. J. Clin. Oncol. 2011. Vol. 29. P. 3044.

7. Dolcetta-Capuzzo A., Villa V., Albarello L. et al. Gastroenteric neuroendocrine neoplasms classification: comparison of prognostic models. Cancer. 2013. Vol. 119. P. 36.

8. Strosberg J. R., Weber J. M., Feldman M. et al. Prognostic validity of the American Joint Committee on Cancer staging classification for midgut neuroendocrine tumors. J. Clin. Oncol. 2013. Vol. 31. P. 420

9. La Rosa S., Sessa F., Uccella S. Mixed Neuroendocrine-Nonneuroendocrine Neoplasms (MiNENs): Unifying the Concept of a Heterogeneous Group of Neoplasms. Endocr. Pathol. 2016. Vol. 27. P. 284.

10. Rindi G., Arnold R., Bosman F. T. et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: WHO Classification Tumours of the Digestive System, 4th ed, Bosman T. F., Carneiro F., Hruban R. H., Theise N. D. (Eds). Lyon, International Agency for Reseach on Cancer (IARC), 2010. P. 13.

11. Scoazec J. Y., Couvelard A., Monges G. et al. Well-differentiated grade 3 digestive neuroendocrine tumors: myth or reality? The PRONET Study Group (abstract). J. Clin. Oncol. 2012. Vol. 30. P. 4129. Available at: http://meetinglibrary.asco.org/content/100442–114.

12. Heetfeld M., Chougnet C. N., Olsen I. H. et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr. Relat. Cancer. 2015. Vol. 22. P. 657.

13. Coriat R., Walter T., Terris B. et al. Gastroenteropancreatic Well-Differentiated Grade 3 Neuroendocrine Tumors: Review and Position Statement. Oncologist. 2016. Vol. 21. P. 1191.

14. Делекторская В. В. Нэйроэндокриные новообразования поджелудочной железы: новые аспекты морфологической классификации (всемирная организация здравоохранения, 2017) // Успехи молекулярной онкологии. 2017. № 3(4). С. 104–108. [Delektorskaya V. V. Pancreatic neuroendocrine tumors: new aspects of morphological classification (World Health Organization, 2017). Advances in molecular oncology. 2017. Vol. 3(4). P. 104–108 (In Russ.).

15. Scoazec J. Y., Couvelard A., Monges G. et al. Professional Practices and Diagnostic Issues in Neuroendocrine Tumour Pathology: Results of a Prospective One-Year Survey Among French Pathologists (the PRONET Study). Neuroendocrinology. 2017. Vol. 105(1). P. 67–76. Epub 2016 Jul 21.

16. Korse C. M., Taal B. G., van Velthuysen M. L., 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. Vol. 49. P. 1975.

17. Walenkamp A. M., Sonke G. S., Sleijfer D. T. Clinical and therapeutic aspects of extrapulmonary small cell carcinoma. Cancer Treat. Rev. 2009. Vol. 35. P. 228.

18. Brennan S. M., Gregory D. L., Stillie A. et al. Should extrapulmonary small cell cancer be managed like small cell lung cancer? Cancer. 2010. Vol. 116. P. 888.

19. Terashima T., Morizane C., Hiraoka N. et al. Comparison of chemotherapeutic treatment outcomes of advanced extrapulmonary neuroendocrine carcinomas and advanced small-cell lung carcinoma. Neuroendocrinology. 2012. Vol. 96(4). P. 324–332. Epub 2012 Aug 28.

20. Conte B., George B., Overman M. et al. High-Grade Neuroendocrine Colorectal Carcinomas: A Retrospective Study of 100 Patients. Clin. Colorectal Cancer. 2016. Vol. 15(2). P. e1-e7. Epub 2015 Dec 29.

21. Dasari A., Mehta K., Byers L. A. et al. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: A SEER database analysis of 162,983 cases. Cancer. 2018. Vol. 124. P. 807.

22. Sorbye H., Welin S., Langer S. W. et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann. Oncol. 2013. Vol. 24. P. 152.

23. Brenner B., Tang L. H., Shia J. et al. Small cell carcinomas of the gastrointestinal tract: clinicopathological features and treatment approach. Semin. Oncol. 2007. Vol. 34. P. 43.

24. Coriat R., Walter T., Terris B. et al. Gastroenteropancreatic Well-Differentiated Grade 3 Neuroendocrine Tumors: Review and Position Statement. Oncologist. 2016. Vol. 21. P. 1191.

25. Walter T., Tougeron D., Baudin E. et al. Poorly differentiated gastro-entero-pancreatic neuroendocrine carcinomas: Are they really heterogeneous? Insights from the FFCD-GTE national cohort. Eur. J. Cancer. 2017. Vol. 79. P. 158.

26. SEER Stat Database: Incidence — SEER9 Regs Research Data, November 2011 submission (1973–2010). Bethesda, MD: National Cancer Institute, Cancer Statistics Branch, 2013. http://www.seer.cancer.gov.

27. Klimstra D. S., Modlin I. R., Coppola D. et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010. Vol. 39. P. 707.

28. Vélayoudom-Céphise F.L., Duvillard P., Foucan L. et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr. Relat. Cancer. 2013. Vol. 20. P. 649.

29. Maru D. M., Khurana H., Rashid A. et al. Retrospective study of clinicopathologic features and prognosis of highgrade neuroendocrine carcinoma of the esophagus. Am. J. Surg. Pathol. 2008. Vol. 32. P. 1404.

30. Делекторская В. В. Морфологическая классификация нэйроэндокринных новообразований пищеварительной системы: современное состояние проблемы и нерешенные вопросы // Успехи молекулярной онкологии. 2016. № 3(3). C. 56–66. [Delektorskaya V. V. Morphological classification of digestive neuroendocrine neoplasms: the current concepts and controversies. Advances in molecular oncology. 2016. Vol. 3(3). P. 56–66 (In Russ.)].

31. Tang L. H., Basturk O., Sue J. J., Klimstra D. S. A Practical Approach to the Classification of WHO Grade 3 (G3) Well-differentiated Neuroendocrine Tumor (WD-NET) and Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC) of the Pancreas. Am. J. Surg. Pathol. 2016. Vol. 40. P. 1192.

32. Raj N., Valentino E., Capanu M. et al. Treatment Response and Outcomes of Grade 3 Pancreatic Neuroendocrine Neoplasms Based on Morphology: Well Differentiated Versus Poorly Differentiated. Pancreas. 2017. Vol. 46. P. 296.

33. Strosberg J. R., Coppola D., Klimstra D. S. et al. The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas. 2010. Vol. 39. P. 799

34. Casas F., Ferrer F., Farrús B. et al. Primary small cell carcinoma of the esophagus: a review of the literature with emphasis on therapy and prognosis. Cancer. 1997. Vol. 80. P. 1366.

35. Meng M. B., Zaorsky N. G., Jiang C. et al. Radiotherapy and chemotherapy are associated with improved outcomes over surgery and chemotherapy in the management of limited-stage small cell esophageal carcinoma. Radiother. Oncol. 2013. Vol. 106. P. 317

36. Shafqat H., Ali S., Salhab M., Olszewski AJ.. Survival of patients with neuroendocrine carcinoma of the colon and rectum: a population-based analysis. Dis. Colon. Rectum. 2015. Vol. 58. P. 294.

37. Smith J. D., Reidy D. L., Goodman K. A. et al. A retrospective review of 126 high-grade neuroendocrine carcinomas of the colon and rectum. Ann. Surg. Oncol. 2014. Vol. 21. P. 2956.

38. Mitry E., Baudin E., Ducreux M. et al. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br. J. Cancer. 1999. Vol. 81. P. 1351.

39. Pavel M., O’Toole D., Costa F. et al. 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). P. 172–185

40. Fazio N., Spada F., Giovannini M. Chemotherapy in gastroenteropancreatic (GEP) neuroendocrine carcinomas (NEC): a critical view. Cancer Treat. Rev. 2013. Vol. 39. P. 270.

41. Sorbye H., Welin S., Langer S. W. et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann. Oncol. 2013. Vol. 24(1). P. 152–160.

42. Okita N. T., Kato K., Takahari D. et al. Neuroendocrine tumors of the stomach: chemotherapy with cisplatin plus irinotecan is effective for gastric poorly-differentiated neuroendocrine carcinoma. Gastric Cancer. 2011. Vol. 14. P. 161.

43. Yamaguchi T., Machida N., Morizane C. et al. Multicenter retrospective analysis of systemic chemotherapy for advanced neuroendocrine carcinoma of the digestive system. Cancer Sci. 2014. Vol. 105. P. 1176.

44. Irinotecan Plus Cisplatin Compared With Etoposide Plus Cisplatin for Extensive Stage Small-cell Lung Cancer. U.S. National Library of Medicine. http://www.clinicaltrials.gov.

45. Hentic O., Hammel P., Couvelard A. et al. FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3. Endocr. Relat. Cancer. 2012. Vol. 19. P. 751.

46. Walter T., Tougeron D., Baudin E. et al. Poorly differentiated gastro-entero-pancreatic neuroendocrine carcinomas: Are they really heterogeneous? Insights from the FFCD-GTE national cohort. Eur. J. Cancer. 2017. Vol. 79. P. 158.

47. Olsen I. H., Sоrensen J. B., Federspiel B. et al. Temozolomide as second or third line treatment of patients with neuroendocrine carcinomas. Scientific. World. J. 2012. Vol. 2012. 170496.

48. Hadoux J., Malka D., Planchard D. et al. Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma. Endocr. Relat. Cancer. 2015. Vol. 22. P. 289.

49. Sharpe S. M., In H., Winchester D. J. et al. Surgical resection provides an overall survival benefit for patients with small pancreatic neuroendocrine tumors. J. Gastrointest. Surg. 2015. Vol. 19. P. 117.

50. Haugvik S. P., Kaemmerer D., Gaujoux S. et al. Pathology and Surgical Treatment of High-Grade Pancreatic Neuroendocrine Carcinoma: an Evolving Landscape. Curr. Oncol. Rep. 2016. Vol. 18. P. 28.

51. Panzuto F., Rinzivillo M., Spada F. et al. Everolimus in Pancreatic Neuroendocrine Carcinomas G3. Pancreas. 2017. Vol. 46 (3). P. 302–305.