ABSTRACT
G3 neuroendocrine tumors (G3 NET) have >20% Ki-67 index and >20 mitoses/10 high-power field but have well-differentiated tumor morphology compared to neuroendocrine carcinomas. They have poor prognosis compared to G2 tumors but have better prognosis than G3 carcinomas. In this review chracteristics and clinical approach to G3 NET is summarized.
Keywords:
Neuroendocrine tumor, grade 3, neuroendocrine carcinoma
References
1
Pellat A, Coriat R. Well Differentiated Grade 3 Neuroendocrine Tumors of the Digestive Tract: A Narrative Review. J Clin Med 2020;9:1677.
2
Sonbol MB, Halfdanarson TR. Management of Well-Differentiated High-Grade (G3) Neuroendocrine Tumors. Curr Treat Options Oncol 2019;20:74.
3
Rinke A, Gress TM. Neuroendocrine Cancer, Therapeutic Strategies in G3 Cancers. Digestion 2017;95:109-114.
4
Klöppel G. Neuroendocrine Neoplasms: Dichotomy, Origin and Classifications. Visc Med 2017;33:324-330.
5
Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009;27:4656-4563.
6
Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014;371:224-233.
7
Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992;326:519-523.
8
Bajetta E, Rimassa L, Carnaghi C, et al. 5-Fluorouracil, dacarbazine, and epirubicin in the treatment of patients with neuroendocrine tumors. Cancer 1998;83:372-378.
9
Ducreux M, Dahan L, Smith D, et al. Bevacizumab combined with 5-FU/streptozocin in patients with progressive metastatic well-differentiated pancreatic endocrine tumours (BETTER trial)--a phase II non-randomised trial. Eur J Cancer 2014;50:3098-3106.
10
Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 2011;117:268-275.
11
Kunz PL, Catalano PJ, Nimeiri H, et al. A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced tumors: A trial of the ECOG- pancreatic neuroendocrine ACRIN Cancer Research Group (E2211). JCO 2018;36:4004.
12
Rogowski W, Wachuła E, Gorzelak A, et al. Capecitabine and temozolomide combination for treatment of high-grade, well-differentiated neuroendocrine tumour and poorly-differentiated neuroendocrine carcinoma - retrospective analysis. Endokrynol Pol 2019;70:313-317.
13
Brixi-Benmansour H, Jouve JL, Mitry E, et al. Phase II study of first-line FOLFIRI for progressive metastatic well-differentiated pancreatic endocrine carcinoma. Dig Liver Dis 2011;43:912-916.
14
Bajetta E, Catena L, Procopio G, et al. Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours? Cancer Chemother Pharmacol 2007;59:637-642.
15
Dussol AS, Joly MO, Vercherat C, et al. Gemcitabine and oxaliplatin or alkylating agents for neuroendocrine tumors: Comparison of efficacy and search for predictive factors guiding treatment choice. Cancer 2015;121:3428-3434.
16
Sorbye H, Welin S, Langer SW, 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;24:152-160.
17
Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011;364:514-523.
18
Fonseca PJ, Uriol E, Galván JA, et al. Prolonged clinical benefit of everolimus therapy in the management of high-grade pancreatic neuroendocrine carcinoma. Case Rep Oncol 2013;6:441-449.
19
Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011;364:501-513.
20
Faivre S, Niccoli P, Castellano D, et al. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol 2017;28:339-343.
21
Pellat A, Dreyer C, Couffignal C, et al. Clinical and Biomarker Evaluations of Sunitinib in Patients with Grade 3 Digestive Neuroendocrine Neoplasms. Neuroendocrinology 2018;107:24-31.
22
Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med 2017;376:125-135.
23
Carlsen EA, Fazio N, Granberg D, et al. Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study. Endocr Relat Cancer 2019;26:227-239.
24
Nicolini S, Severi S, Ianniello A, et al. Investigation of receptor radionuclide therapy with 177Lu-DOTATATE in patients with GEP-NEN and a high Ki-67 proliferation index. Eur J Nucl Med Mol Imaging 2018;45:923-930.
25
Thang SP, Lung MS, Kong G, et al. Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis. Eur J Nucl Med Mol Imaging 2018;45:262-277.
26
Strosberg J, Mizuno N, Doi T, et al. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study. Clin Cancer Res 2020;26:2124-2130.
27
D’Angelo SP, Russell J, Lebbé C, et al. Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial. JAMA Oncol 2018;4:e180077.
28
Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med 2016;374:2542-2552.
29
Patel SP. A phase II basket trial of dual anti- CTLA-4 and anti-PD-1 blockade in rare tumors (DART) S1609: the neuroendocrine cohort. 2019. Presented at the 2019 Annual Conference of the American Associa- tion for Cancer Research (AACR) in Atlanta, Georgia, USA, 2019.