Rare but distinct: A systematic review of primary neuroendocrine tumors of the breast according to WHO 2019 guidelines.

Primary breast neuroendocrine tumors (BNETs) are rare malignancies recently redefined by the World Health Organization (WHO) 2019 classification, which mandates neuroendocrine morphology in over 90% of tumor cells. This systematic review aims to provide the first comprehensive analysis of BNETs strictly adhering to these diagnostic criteria. A systematic search of PubMed and Embase was conducted for studies published between January 2019 and February 2025. Eligible studies included adult patients with primary BNETs diagnosed per WHO 2019 criteria, reporting clinical, pathological, or treatment data. Eight studies met inclusion criteria, encompassing 203 patients. BNETs predominantly affected postmenopausal women and typically presented as early-stage, hormone receptor-positive tumors. Estrogen receptor positivity was nearly universal (75.8%-100%), while HER2 overexpression was rare. Most tumors were grade 2 with low to moderate Ki-67 indices, and disease-free survival (DFS) rates were favorable (1-year DFS: 98.6%; 5-year DFS: 91.1%). Molecular studies suggested distinct genomic profiles compared to invasive breast carcinoma of no special type (IBC-NST), including lower TP53 and PIK3CA mutation rates and higher frequency of KMT2C and FOXA1 alterations. Somatostatin receptor 2 A (SSTR2A) expression was observed in up to 71% of cases in earlier studies, supporting potential for somatostatin analog therapy, although data were based on tumors not meeting current criteria. BNETs represent a biologically distinct subset of breast cancers with favorable prognostic features and a consistent luminal-like phenotype. However, evidence on optimal treatment remains limited. Further large-scale, prospective studies are needed to define clinical management and validate molecular findings.