The grey zone between pure (neuro)endocrine and non-(neuro)endocrine tumours: a comment on concepts and classification of mixed exocrine-endocrine neoplasms

Terms such as mixed endocrine-exocrine carcinoma (MEEC) and adenocarcinoma with neuroendocrine (NE) differentiation (ADC-NE) identify tumours belonging to the spectrum of neoplasms with divergent exocrine and (neuro)endocrine differentiation. These tumours display variable quantitative extent of the two components, potentially ranging from 1 to 99%, and variable structural patterns, ranging from single scattered NE cells to a well-defined NE tumour cell population organized in organoid, trabecular or solid growth patterns. In the present report, the grey zone of tumours/carcinomas with mixed NE and non-NE features is explored for various organs. From a practical point of view, MEECs differ from carcinomas with focal NE differentiation by (1) the extension of each component (more than 30%) and (2) the structural pattern of the NE component, either organoid for well-differentiated or solid/diffuse for poorly differentiated cases. In MEECs, the most aggressive cell population drives the clinical behaviour. Conversely, ADC-NE generally do not show a different clinical outcome, compared to the corresponding conventional forms, except for prostatic adenocarcinoma, in which NE cells are a negative prognostic factor. The recognition of MEECs may be of relevance for a targeted therapeutic strategy, foreseeing the use of biotherapies similar to those proposed for pure NE tumours.