Metachronous Metastatic Invasive Breast Carcinoma and Metastatic Small Cell Carcinoma Clinically and Radiologically Favoured to Be of Pulmonary Origin: A Case Report

Background: In patients with metastatic breast carcinoma, newly identified visceral or pulmonary lesions may represent progression of the known malignancy or, less commonly, a distinct second primary tumor. Histopathological and immunohistochemical evaluation is therefore essential for establishing tumor lineage and guiding treatment. Case Presentation: We report the case of a 46-year-old woman diagnosed in 2021 with metastatic hormone receptor-positive/HER2-negative breast carcinoma, presenting with a left breast mass and multiple osteolytic bone metastases. Histopathological examination demonstrated invasive breast carcinoma of no special type, with 98% estrogen receptor expression, 98% progesterone receptor expression, a Ki-67 proliferation index of 15%, and negative HER2 status. She received palliative radiotherapy for painful bone metastases and systemic treatment with letrozole and ribociclib. Five years later, she was evaluated for newly detected liver lesions. Positron emission tomography-computed tomography also demonstrated a metabolically active right centrohilar pulmonary lesion, although a primary lung tumor could not be definitively distinguished radiologically from nodal disease. Liver biopsy revealed a high-grade small-cell neuroendocrine carcinoma with positivity for TTF-1, chromogranin, synaptophysin, and CD56, a Ki-67 proliferation index of 85%, and negative GATA3 expression. These findings, together with the clinical and radiological features, favored a pulmonary origin. The patient was subsequently treated with cisplatin, etoposide, and atezolizumab. Discussion: This case illustrates the difficulty of distinguishing progression of metastatic breast carcinoma from a metachronous second malignancy. The markedly different morphology with a discordant neuroendocrine immunophenotypic profile together with the radiological and serological findings, favored a distinct second malignancy rather than progression of the known breast carcinoma. Conclusions: New metastatic-appearing lesions in patients with a known malignancy should not automatically be attributed to progression of the original cancer. Re-biopsy and integrated histopathological, immunohistochemical, clinical, and radiological assessment may identify a distinct second malignancy and substantially alter systemic treatment and clinical management.