Primary breast large-cell neuroendocrine carcinoma (LCNEC)/squamous cell carcinoma (SCC), also referred to as mixed neuroendocrine/non-neuroendocrine neoplasms of the breast (Br-MiNENs), represents an exceedingly rare malignancy. We report the first case of primary breast LCNEC/SCC diagnosed via ultrasound-guided fine-needle aspiration (FNA) biopsy of the left supraclavicular and left internal mammary lymph nodes. The patient, a 40-year-old female, underwent a lumpectomy followed by breast-conserving surgery and was diagnosed with primary breast LCNEC. Notably, within merely four months following the breast-conserving surgery, PET-CT revealed lymph node enlargement, prompting the performance of FNA. FNA cytology of metastatic lymph nodes revealed two distinct tumor components, allowing for clear differentiation between LCNEC and SCC in the smear. The diagnosis was further corroborated by immunocytochemical (ICC) staining of the cell blocks. Subsequently, histopathological re-examination of the breast mass revealed occult SCC components comprising less than 1% of the tumor cells. Additionally, the case exhibited triple-negative breast cancer, with PIK3CA, TP53, RB1, and BCL2L11 mutations identified through next-generation sequencing (NGS). Br-MiNEN is exceedingly rare, and its cytological diagnosis poses significant challenges. It is recommended that a detailed and objective description of each tumor component and its proportion be provided. This report provides the first detailed description of the FNA cytology of LCNEC/SCC, thereby enhancing cytopathologists' comprehension of this tumor. Auxiliary studies, including ICC staining and molecular biology assays, are crucial for accurate diagnosis, therapy, and prognosis.
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