Digestive Well-Differentiated Grade 3 Neuroendocrine Tumors: Current Management and Future Directions

SIMPLE SUMMARY: We herein present the latest data on characteristics and therapeutic management of gastro-entero-pancreatic well-differentiated neuroendocrine grade 3 tumors (GEP-NET G-3). Although neuroendocrine neoplasms (NEN) of the digestive tract are rare tumors, progress in diagnosis has allowed their better identification. Since 2017, a new category of NEN showing well-differentiated morphology and high Ki-67 index has been defined, the NET G-3. These tumors show differences not only in morphology but also in genotype, clinical features, and treatment response, compared with classical high-grade NEN. Therefore, they should be managed differently but suffer from lack of data. We find our work important, underlying the need to conduct new rigorous clinical studies in this population. ABSTRACT: Digestive well-differentiated grade 3 neuroendocrine tumors (NET G-3) have been clearly defined since the 2017 World Health Organization classification. They are still a rare category lacking specific data and standardized management. Their distinction from other types of neuroendocrine neoplasms (NEN) not only lies in morphology but also in genotype, aggressiveness, functional imaging uptake, and treatment response. Most of the available data comes from pancreatic series, which is the most frequent tumor site for this entity. In the non-metastatic setting, surgical resection is recommended, irrespective of grade and tumor site. For metastatic NET G-3, chemotherapy is the main first-line treatment with temozolomide-based regimen showing more efficacy than platinum-based regimen, especially when Ki-67 index <55%. Targeted therapies, such as sunitinib and everolimus, have also shown some positive therapeutic efficacy in small samples of patients. Functional imaging plays a key role for detection but also treatment selection. In the second or further-line setting, peptide receptor radionuclide therapy has shown promising response rates in high-grade NEN. Finally, immunotherapy is currently investigated as a new therapeutic approach with trials still ongoing. More data will come with future work now focusing on this specific subgroup. The aim of this review is to summarize the current data on digestive NET G-3 and explore future directions for their management.