Mixed neuroendocrine-non-neuroendocrine neoplasms of the digestive system: A mini-review

Abstract

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are rare mixed tumors containing both neuroendocrine (NE) and non-NE components. Each component must occupy at least 30% of the tumor volume by definition. Recent molecular evidence suggests MiNENs are clonal neoplasms and potentially harbor targetable mutations similar to conventional carcinomas. There have been multiple changes in the nomenclature and classification of MiNENs which has created some confusion among pathologists on how to integrate the contributions of each component in a MiNEN, an issue which in turn has resulted in confusion in communication with front-line treating oncologists. This mini review summarizes our current understanding of MiNENs and outline diagnosis, prognosis, and management of these neoplasms. The authors emphasize the importance of treating the most aggressive component of the tumor regardless of its percentage volume.

Keywords: Mixed adenoneuorendocrine carcinoma; Mixed neuroendocrine neoplasms; Mixed neuroendocrine non-neuroendocrine neoplasms; Neuroendocrine; Non-neuroendocrine.

Figure 1

Classification of mixed neuroendocrine neoplasms. Mixed neuroendocrine-non-neuroendocrine neoplasms are specific mixed neuroendocrine tumors, which show an intimate mixture of neuroendocrine and non-neuroendocrine cells and are both derived from a common precursor cell. MiNEN: Mixed neuroendocrine-non-neuroendocrine neoplasms.

Figure 2

Conceptual framework for mixed neuroendocrine-non-neuroendocrine neoplasm of the digestive system. The tumor must include one neuroendocrine component and one non-neuroendocrine component. In the digestive system both components must have metastatic potential, excluding benign non-neuroendocrine neoplasms such as adenomas or squamous papillomas. NET: Neuroendocrine tumors; NEC: Neuroendocrine carcinomas.

Figure 3

Evolution of the terminology of mixed neuroendocrine-non-neuroendocrine neoplasm. The terminology has been broadened to include other non-neuroendocrine epithelial components beyond adenocarcinoma as well as including indolent or benign tumors such as neuroendocrine tumors. NE: Neuroendocrine; NEC: Neuroendocrine carcinoma; NET: Neuroendocrine tumor; MEEC: Mixed exocrine-endocrine carcinoma; MANEC: Mixed adenoneuroendocrine carcinoma; MiNEN: Mixed neuroendocrine-non-neuroendocrine neoplasm.

Figure 4

Histopathology of a mixed neuroendocrine-non-neuroendocrine neoplasm of colon. A: Hematoxylin and eosin (H&E) stain of mixed neuroendocrine-non-neuroendocrine neoplasm. On the right side is a well-differentiated invasive adenocarcinoma. On the left side is a poorly differentiated neuroendocrine carcinoma (20 ×, H&E); B: The adenocarcinoma component is positive for cytokeratin 20, but the neuroendocrine component is negative (20 ×); C: Positive synaptophysin staining in the neuroendocrine component but negative staining in the adenocarcinoma component (20 ×); D: Positive CDX2 staining in both adenocarcinoma and neuroendocrine carcinoma components (20 ×); E: Merging area of adenocarcinoma and neuroendocrine carcinoma components (20 ×); F: Positive synaptophysin staining of neuroendocrine cells in the merged area (20 ×).

Figure 5

Sample pathology report. MiNEN: Mixed neuroendocrine-non-neuroendocrine neoplasm.