Concept of neuroendocrine neoplasms of all organs with a focus on grading, subtyping

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms encompassing both well differentiate neuroendocrine tumors (NETs), and poorly differentiated neuroendocrine carcinomas (NECs). This classification is supported by distinct histological, clinical, and molecular profiles. NETs are typically slow-growing and hormone-producing, with organoid architecture and frequent associations with hereditary syndromes such as multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) disease. In contrast, NECs are highly malignant, rapidly proliferating tumors characterized by mutations in adenocarcinoma-driver genes and in addition to TP53 mutations and RB1 inactivation, without hereditary links to endocrine tumor syndomes. Recent WHO classifications introduced site-specific grading systems, including NET G3 in the digestive, urogenital, gynecological and head and neck organs. There is growing evidence of progression from NET G1 to G3 with occasionally NEC-like features via acquired TP53 mutations. Advances in transcription factor profiling related to hormonal expression, molecular alterations resulted in further subtyping especially in pancreatic, pulmonary, and pituitary NETs. These tools support more precise treatment strategies. Genomic studies focusing on pancreatic NETs highlighted mutations in MEN1, DAXX, ATRX, and targets in mTOR pathway. NECs display higher tumor mutation burdens and harbor various actionable alterations. Approximately 5-10% of NETs are associated with hereditary syndromes, though recent findings suggest germline pathogenic variants, which were present in additional 5% of apparently sporadic NETs and NECs, requiring further study. An integrated histological, molecular, and clinical approach is essential to improve the classification, prognostication, and management of NENs, while recognizing the distinct biology of individual subtypes.