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Breast cancer metastases are commonly encountered in clinical practice owing to the high prevalence of this disease
☆ Competing interest: The authors declare that there is no conflict of inter-est regarding the publication of this article.
Corresponding author at: Division of Breast Pathology, Department of Pathology, Wexner Medical Center at The Ohio State University, 410 W.
E-mail address: [email protected] (G. H. Tozbikian).
and the high frequency that these lesions are surgically biopsied. Breast cancer is one of the most common cancers in the United States. Based on National Cancer Institute/ Surveillance, Epidemiology, and End Results reporting, in 2016 new breast cancer diagnoses exceeded 266 000, with more than 40 000 breast cancer deaths reported . The most significant cause of breast cancer mortality is due to metastatic progression. Risks for the development of metastases are re-lated to several factors including primary tumor size, histo-logic grade, lymph node involvement, and tumor biology/ biomarker status [2,3]. Breast cancer patients have a high
likelihood of developing metastases, especially if diagnosed at an early age . Accurate diagnosis of breast cancer metasta-ses is critically important to facilitate clinical therapeutic deci-sion making. Per current guidelines, those patients with clinically suspected breast cancer metastases who are surgi-cally appropriate and have accessible lesions should be offered biopsy for confirmation of disease process, and for the reas-sessment of breast biomarkers BQ-788 sodium salt receptor (ER), proges-terone receptor (PR), and human epidermal growth factor receptor 2 (HER2) . The diagnostic distinction of a sus-pected metastatic breast cancer (MBC) from a nonbreast ma-lignancy is a very relevant clinical consideration. Published studies indicate that women who are diagnosed as having a pri-mary breast cancer (PBC) have a relatively higher risk of de-veloping a second nonbreast malignancy compared with women from the general population. This risk is highest within the first 10 years after the PBC diagnosis and in younger pre-menopausal patients .
The confirmation of a breast primary site of origin of a met-astatic lesion is generally straightforward if (1) the patient has an established history of breast cancer, (2) histologic slides from the prior PBC are available to re-review for morphologic comparison to metastasis, (3) the metastasis shows stable ex-pression of both breast lineage markers and biomarkers (ER/ PR/HER2). However, in clinical practice, these favorable diagnostic conditions may not be present. It can be difficult to establish the origin of a putative breast metastasis if the pri-mary tumor is either triple negative for breast biomarkers (ER/ PR/HER2) or if there is a loss of biomarker expression in the metastasis. Likewise, the histologic slides from the prior PBC may not be practically available for re-review. In addi-tion, a metastasis may represent the initial clinical presentation from an occult PBC.
It is important to note that the sensitivity of standard breast lineage markers is dependent on tumor subtype, with the low-est sensitivity observed in grade 3, ER-negative, and metaplas-tic breast cancers . High-grade and triple-negative breast cancer (TNBC) can pose a diagnostic challenge because they may display both nonspecific histomorphologic features and immunophenotypic staining profiles. TNBC and basal-like breast cancers often do not show positivity for established standard breast lineage markers such as mammaglobin (17%-24%) and GCDFP-15 (0-5%) . The reduced sensitivity of most breast lineage markers including GATA3 in TNBC can complicate the diagnosis of MBC . In addition, the potential for loss of biomarker expression in MBC imposes a further di-agnostic challenge, as ER/PR/HER2 status is not infrequently discordant between the primary and metastatic lesion .