Abstract
Simple SummaryBreast 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.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.
Highlights
Neuroendocrine neoplasms (NENs) comprise a rare heterogeneous group of tumors defined as epithelial neoplasms composed of cells showing predominant neuroendocrinal (NE) differentiation and the characteristics of hormone-producing endocrine cells and nerve cells
Since most Br-NENs, regardless of the malignancy grade, show an admixture of elements of both neuroendocrine tumors and invasive cancer, the following recommendations have been made: invasive carcinoma with more than 90% of cells exhibiting NE morphology be classified as NET or neuroendocrine carcinoma (NEC), those with 10–90% of cells exhibiting NE morphology be classified as mixed invasive NST and NET/NEC, and those with less than 10% of cells exhibiting NE differentiation be classified as invasive carcinoma of NST, with an option for comment on the focal NE pattern [12] (Figure 2)
It is reported that the efficacy of neoadjuvant chemotherapy and adjuvant chemotherapy are equivalent in the aspect of distant recurrence and breast cancer mortality in invasive breast cancer of no special type (IBC-NST) [25], and neoadjuvant therapy is administered as a standard treatment
Summary
Neuroendocrine neoplasms (NENs) comprise a rare heterogeneous group of tumors defined as epithelial neoplasms composed of cells showing predominant neuroendocrinal (NE) differentiation and the characteristics of hormone-producing endocrine cells and nerve cells. NENs which possess neurosecretory granules in the tumor cells produce higher amounts of hormones than normal cells, which may cause clinical symptoms. These tumors can arise in any organ, including the intestine, pancreas, lung, and breast. Their clinical behaviors vary widely depending on the degree of NE differentiation of the tumor. Functional NENs produce excessive amounts of hormones that cause clinical symptoms such as diarrhea and facial flushing. Non-functional NENs do not produce hormones in sufficient amounts to cause these symptoms; the majority of NENs are non-functional. We review the literature on Br-NENs, including mixed-type tumors, and the historical transition of the WHO classifications
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