Abstract
Neuroendocrine neoplasms (NENs) are heterogeneous tumors with a common phenotype. There are two fundamentally different groups of NENs: well-differentiated, low-proliferating NENs, called neuroendocrine tumors (NETs) or carcinoids, and poorly differentiated, highly proliferating NENs, called small- or large-cell neuroendocrine carcinomas (NECs). This NEN dichotomy is probably due to an origin from different neuroendocrine progenitor cells. The current World Health Organization (WHO) classification of gastrointestinal NENs uses the Ki67 proliferation index to grade NETs as G1 or G2, and NECs as G3. In the pancreas, NETs and NECs may overlap in their proliferation index, making the distinction between them difficult and leading to therapeutic uncertainties. Therefore, the WHO classification of pancreatic NENs (PanNENs) from 2017 introduced a new NET G3 category. Helpful for the distinction of NETs G3 from NECs is the expression of p53 and rb1 that is usually negative in PanNETs. Comparison of the WHO classification of digestive system NENs with other NEN classifications reveals site-specific differences in terminology and a general lack of grading systems. However, all classifications recognize the existence of the two major NEN families and provide a general basis for their prognostic and therapeutic stratification. A development of a common NEN classification across organs is desirable.