Abstract
Mixed neuroendocrine and non-neuroendocrine neoplasms (MiNEN) represent a heterogeneous group of bidirectionally differentiated epithelial malignancies that are, in most cases, highly aggressive. They are defined by the presence of morphologically distinct, yet clonally related, neuroendocrine and non-neuroendocrine components, each comprising at least 30% of the tumor mass according to current guidelines. Tumors that fall within the differential diagnostic spectrum of MiNEN include amphicrine carcinomas-characterized by the co-expression of neuroendocrine and non-neuroendocrine features within the same tumor cell-as well as conventional carcinomas that lack neuroendocrine morphology but exhibit immunohistochemical expression of neuroendocrine markers. However, these entities do not fulfill the current diagnostic criteria for MiNEN. In this review, we aim to outline the current diagnostic framework for MiNEN and examine the conceptual and classification boundaries of amphicrine carcinomas and conventional carcinomas with aberrant neuroendocrine marker expression in relation to what is presently defined as a MiNEN. In addition, we highlight key unresolved questions that should be addressed in future guidelines to streamline the diagnostic process and improve consistency. Finally, we provide an outlook on emerging technologies and future perspectives that may further refine the classification and clinical management of these complex neoplasms.