An update on the development of concepts, diagnostic criteria, and challenging issues for neuroendocrine neoplasms across different digestive organs.

Digestive neuroendocrine neoplasms (NENs) are a group of heterogeneous neoplasms found throughout the digestive tract, with different behaviour and genetic background. In the last few years, nomenclature and WHO/UICC classifications of digestive NENs have changed, and molecular classifications have emerged, especially in pancreatic locations. Increasing patho-molecular details are needed to diagnose the different categories of NEN, including the use of helpful immunohistochemical markers. In this review, we address these topics in three successive chapters. We first briefly review recent updates in classifications, discuss important grading and proliferating issues and advances in the molecular understanding of NEN. Then, we provide an update on diagnosis, including the most important differential diagnoses of NEN, with a focus on high-grade neoplasms and mixed tumours. Finally, we highlight a variety of currently used and next-generation predictive and prognostic biomarkers as well as biomarkers of tumour origin and describe some site specificities of gastrointestinal NEN. We specifically focus on biomarkers available to pathologists with the potential to change the way patients with NEN are diagnosed and treated.