Mixed neuroendocrine-non-neuroendocrine neoplasms, amphicrine-like carcinoma and related lesions: a review of changes in classification and current concepts.

Abstract

To trace the historical evolution of gastrointestinal mixed epithelial-neuroendocrine tumour terminology, clarify current diagnostic criteria, histological features and approach to reporting these lesions in accordance with the latest classification of gastrointestinal tumours, a narrative overview was undertaken on mixed neuroendocrine-non-neuroendocrine neoplasia (MiNEN). The review traces terminology from early descriptions and successive World Health Organization (WHO) classifications culminating in the 2026 WHO classification and recommendations. Definitions, histological grading, immunohistochemistry, molecular evidence and morphological mimics are reviewed. In the 2026 classification, MiNEN remains a mixed tumour composed of two morphologically recognizable components; each component constituting ≥30% of the neoplasm, with clear neuroendocrine marker expression in the neuroendocrine component. It is clarified that neoplasms with a non-neuroendocrine component that is solely a precursor or intramucosal lesion are not MiNEN. For example, appropriate terminology would be a 'neuroendocrine carcinoma arising from an adenoma' rather than a 'MiNEN (mixed adenoma-neuroendocrine carcinoma)' or even a MANET ('mixed adenoma neuroendocrine tumour'). In the WHO 6th edition, to capture another class of tumours with mixed differentiation, the concept of 'amphicrine-like carcinoma' (ALC) is introduced. ALC refers to a tumour where the neuroendocrine and non-neuroendocrine differentiation is intimately intermixed (either in the same cells or morphologically similar cells) rather than forming distinct zones as in MiNEN. Both ALC and MiNEN represent a family of tumours rather than a distinct diagnosis and invariably require confirmation with immunohistochemistry. Molecular data support a clonal origin from a common precursor rather than collision.