Gastroenteropancreatic Well-Differentiated Grade 3 Neuroendocrine Tumors: Review and Position Statement

Abstract

: In 2010, the World Health Organization (WHO) classification of neuroendocrine neoplasms was reviewed and validated the crucial role of the proliferative rate. According to the WHO classification 2010, gastroenteropancreatic neuroendocrine neoplasms are classified as well-differentiated neuroendocrine tumors (NETs) of grade 1 or 2 in up to 84%, or poorly differentiated neuroendocrine carcinomas in 6%-8%. Neuroendocrine carcinomas are of grade G. Recently, a proportion of neuroendocrine tumors presenting a number of mitoses or a Ki-67 index higher than 20% and a well-differentiated morphology have been identified, calling for a new category, well-differentiated grade 3 NET (NET G-3). Studies that have reported the characteristics of neuroendocrine neoplasms have identified more well-differentiated NET G-3 than neuroendocrine carcinomas. The main localizations of NET G-3 are the pancreas, stomach, and colon. Treatment for NET G-3 is not standardized and is balanced between G-1/2 neuroendocrine tumor and neuroendocrine carcinoma treatments. In nonmetastatic neuroendocrine tumors, the European and American guidelines recommended a surgical resection for localized neuroendocrine neoplasm, irrespective of the tumor grading. In NET G-3, chemotherapy is the benchmark if the main treatment goal is reduction of the tumor mass, particularly if it would allow a secondary surgery. In the present work, we review the epidemiology and make recommendations for the management of NET G-3.

Implications for practice: Neuroendocrine tumors presenting a number of mitoses or a Ki-67 index higher than 20% and a well-differentiated morphology have been identified and named well-differentiated grade 3 neuroendocrine tumors (NET G-3). The main localizations of NET G-3 are the pancreas, stomach, and colon. The prognosis is worse than that for NET G-2. In nonmetastatic NET G-3, surgery appeared to be the first option. The chemotherapy regimen in pancreatic NET G-3 should be in line with that implemented in NET G-1/2 when the Ki-67 index is below 55% and should be in line with that implemented for neuroendocrine carcinoma when Ki-67 is above 55%.

Keywords: Chemotherapy; Grade 3; Neuroendocrine tumor; Targeted therapy; WHO classification; Well-differentiated.

Figure 1.

Neuroendocrine neoplasms showing different histologic grades based on 2010 WHO criteria. (A, B): Two cases illustrate low-grade (G-1) NETs with regular nuclei (A) and marked nuclear pleomorphism (B), which can lead to misdiagnosis as a high-grade malignancy. (C, D): Pancreatic NET of high-grade (G-3) showing a Ki-67 index at 45%. (E, F): Pancreatic small-cell NEC showing small atypical cells with necrosis foci and a Ki-67>70%. (A–C, E): H&E staining; original magnification, ×200. (D, F): Immunohistochemical staining for Ki-67; original magnification, ×200. Abbreviations: NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor.

Figure 2.

Proposed algorithm for patients with advanced neuroendocrine tumors regarding the tumor grade. ∗,Cutoff score proposed based on experts’ considerations and from the NORDIC NEC study (Ki-67 with a cutoff for response found at 55%) as the minimum level that should be considered satisfactory to propose platinum-based chemotherapy. Abbreviations: 5-FU, 5-fluorouracil; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; PRRT, peptide receptor radionuclide therapy.