Metastasis to and from the breast: a guide to differential diagnosis and ancillary testing

Metastases can occur to the breast from extramammary sites and, more commonly, from the breast to a range of locations. In both situations, accurate diagnosis is critical to ensure appropriate management. Whilst metastatic lesions in the breast account for <2% of breast malignancies, identification of the primary source has implications for therapy. The most common lesions that metastasize to the breast include melanoma, haematological malignancies, lung, gastrointestinal and genitourinary malignancies. Careful morphological assessment can help flag features atypical for primary breast cancer, such as lack of an in-situ component or specific cellular morphology such as clear cell change, tall cells or high-grade discohesive cells. These features can guide selection of immunohistochemistry (IHC) to establish a diagnosis: panels of IHC to exclude primary breast carcinoma and confirm an alternate primary source are outlined, including the importance of the ‘ER+ trap’. Furthermore, a diagnostic approach to Carcinoma of Unknown Primary (CUP) is outlined. Metastases from the breast to distant sites are a major cause of mortality in breast cancer. The most common sites involved include bone, lung, liver and brain, though sites such as skin and peritoneum may be involved in ∼7% of cases. Different breast cancer subtypes display different propensity to metastasize to different organs: ER+ disease frequently metastasizes to bone with Triple Negative and Her2+ breast cancer more commonly spreading to lung and brain. Comprehensive IHC panels to distinguish between metastatic breast cancer and other metastatic lesions are outlined, emphasizing limitations of any given marker. For both metastatic lesions to the breast and identification of a breast origin in distant metastatic lesions, a multidisciplinary approach to diagnosis is essential, including provision of a detailed patient history. Using these approaches, it should be possible to avoid errors in diagnosis, even in challenging cases, and give the best treatment option to patients.