Neuroendocrine Neoplasms of the Breast: The Latest WHO Classification and Review of the Literature

SIMPLE SUMMARY: Breast tumors exhibiting neuroendocrine differentiation are a heterogeneous group of tumors that have been variously defined in previous World Health Organization (WHO) classifications. In the WHO Classification of Tumours, 5th edition, neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) of the breast, both of which are invasive cancers, are classified as neuroendocrine neoplasms (NENs) of the breast. However, the clinical significance of NE differentiation in breast cancers, especially in NETs of the breast, is not yet fully understood, and a large overlap appears to exist between breast cancers showing NE differentiation and invasive breast cancer of no special type (IBC-NST). While breast NECs show distinct clinical and morphological features, diagnosis of NETs based on the morphological characteristics alone can be challenging; one reason is that breast NETs do not necessarily have the same morphological characteristics as those of NENs arising in other organs. Thus, the heterogeneity of breast tumors with neuroendocrine differentiation and the changes in their classifications over the years have left many open issues that still need to be resolved. In this review, we shall summarize the history of breast “NENs,” including of mixed types of tumors and the characteristics of these tumors, and discuss their differences from NENs arising in other organs. ABSTRACT: Breast tumors with neuroendocrine (NE) differentiation comprise an uncommon and heterogeneous group of tumors, including invasive breast cancer of no special type (IBC-NST) with NE features, neuroendocrine tumors (NETs), and neuroendocrine carcinoma (NEC). The most recent World Health Organization (WHO) classification in 2019 defined neuroendocrine neoplasms (NENs) of the breast (Br-NENs) as tumors in which >90% of cells show histological evidence of NE differentiation, including NETs (low-grade tumors) and NEC (high-grade). Due to the low prevalence of these tumors and successive changes in their diagnostic criteria over the years, only limited evidence of these tumors exists, derived mainly from case reports and retrospective case series. Breast tumors with NE differentiation are usually treated like the more commonly occurring IBC-NSTs. Immunohistochemistry (IHC) of breast tumors with NE differentiation usually shows a hormone receptor (HR)-positive and human epidermal growth factor type 2 (HER2)-negative profile, so that hormonal therapy with cyclin-dependent kinase (CDK)4/6 inhibitors or other targeted agents would be reasonable treatment options. Herein, we present a review of the literature on breast tumors with NE differentiation as defined in the latest WHO 2019 classification, and discuss the clinical management of these tumors.