Challenges in High-grade Neuroendocrine Neoplasms and Mixed Neuroendocrine/Non-neuroendocrine Neoplasms

The growth in knowledge of the pathogenesis, molecular background, and immunohistochemical profile of neuroendocrine neoplasms (NENs) has led not only to an increased awareness of these diseases but also to several changes of the nomenclature. In particular, the concept and terminology of high-grade (grade 3) NENs and mixed neoplasms have changed considerably over the last 20 years, creating some confusion among pathologists and clinicians. The aim of this review is to elucidate the diagnostic criteria, including the most important differential diagnoses of high-grade NENs and mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs). The role of the Ki67 labelling index and morphology, used to define grade 3 NENs of the digestive system and lungs, is also discussed. The evolution of the concepts and terminology of MiNENs is revised, including the most important differential diagnoses.

Automated summary

The increasing knowledge of neuroendocrine neoplasms has led to changes in nomenclature, particularly concerning high-grade NENs and MiNENs, causing confusion among pathologists and clinicians. The review aims to clarify diagnostic criteria and discuss the role of Ki67 labelling index in defining grade 3 NENs, as well as review the evolution of concepts and terminology of MiNENs.