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

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.

Norepinephrine/β2-Adrenergic Receptor Pathway Promotes the Cell Proliferation and Nerve Growth Factor Production in Triple-Negative Breast Cancer

“…Breast cancer patients have severe depression and anxiety resulting from the fact that the SNS is in a state of excessive stress, which promotes sympathetic nerve fiber in the breast tissue, releasing large amounts of NE [ 6 7 8 ]. To study the effect of sympathetic adrenergic neurotransmitter NE on TNBC cells, we stimulated several breast cancer cell lines, such as the normal breast epithelial cell line (MCF10A), TNBC cell lines (MDA-MB-231, MDA-MB-468, BT-549, and HS-578T), and non-TNBC cell line (MCF7) with different NE concentrations.…”

“…Most patients with breast cancer experience distress such as severe depression and anxiety, which increases the density of sympathetic nerve fiber in the breast tissue releasing a large amount of norepinephrine (NE) [ 6 7 ]. NE primarily binds to the β 2 -adrenergic receptor (β 2 -AR) on the surface of tumor cells in the tumor microenvironment [ 8 ]. β 2 -ARs are associated with heterotrimeric guanine nucleotide-binding proteins (G proteins) and initiate various signaling pathways such as adenylyl cyclase and mitogen-activated protein kinases (MAPKs) [ 9 10 ].…”

Clinicopathological Characteristics and Prognostic Profiles of Breast Carcinoma with Neuroendocrine Features

“…Functional NEN produces excessive hormones, leading to clinical symptoms such as diarrhea and facial flushing. Non-functional NENs do not produce enough hormones to cause these symptoms [ 17 ]. Paraneoplastic endocrine syndrome may occur in breast cancer with or without neuroendocrine differentiation [ 18 ].…”

Primary neuroendocrine breast cancer—an unusual occurrence

“…This type is called luminal type A breast cancer. Luminal B type may also be present [ 11 ]. Krawczyk et al [ 12 ] found the most common immunohistochemical subtype to be ER, PR+ and HER2/neu negative.…”