Breast carcinoma is a prevalent form of cancer worldwide. Around 20% of women diagnosed with breast cancer eventually develop metastases to distant sites. These metastatic relapses can manifest in various forms and locations, resembling the primary breast tumors. The most commonly affected sites for metastasis are the bone (65.1%), followed by lungs (35.4%) and liver (26.0%).[1, 2]

Metastatic carcinoma cells originating from lobular carcinoma of the breast typically appear as single cells with occasional tissue fragments. They often display a uniform appearance with a high nuclear-to-cytoplasmic (n/c) ratio. Distinguishing these single cells in cytology specimens poses a diagnostic challenge, as they need to be differentiated from other cells such as benign or malignant lymphocytes (due to their high n/c ratio and relatively small cell size) and melanoma (due to their frequent eccentric nuclei and potential lack of cohesion).

In such cases, the patient's clinical history and immunohistochemistry (IHC) play a critical role in providing valuable information. GATA-3 is a sensitive marker commonly used in diagnosing metastatic breast cancer. However, GATA-3 alone lacks specificity, as it can also be positive in other tumor types such as urothelial carcinoma (84-100%), basal cell carcinoma (98%), skin squamous cell carcinoma (81%), malignant mesothelioma (58%), chromophobe renal cell carcinoma (51%), salivary gland ductal carcinoma (43%).[6]. Micropapillary variant of metastatic urothelial carcinoma, exhibits strong GATA-3 expression and frequent HER-2 expression, may be a diagnostic pitfall when presenting with scanty cellularity in small biopsy/cytopathology specimen. Tumor cells expressing GATA-3, along with other breast markers (e.g. mammaglobin, GCDFP-15) or breast biomarkers (ER, PR, and HER-2), typically supports the diagnosis of metastatic breast carcinoma. Whereas, immunoexpression of CK20, p40, uroplakin-3, GATA-3, and HER-2 favors a urothelial primary over a breast primary.[1]

Novel markers such as trichorhinophalangeal syndrome-1 (TRPS-1) show promise in diagnosing challenging subtypes of metastatic breast cancer with a high sensitivity, especially the triple negative breast carcinoma [3, 4], which is a challenging diagnosis using conventional breast markers. GCDFP-15 and mammaglobin have reported sensitivities of up to 18% and 23%, respectively, for the diagnosis of metastatic triple-negative breast carcinoma. [5] TRPS-1, SOX-10, and GATA-3 are recommended IHC markers for diagnosing metastatic triple-negative breast carcinoma.[4]. The only subtype of triple-negative breast carcinoma that was reported positive for GATA-3 and negative for TRPS-1 is the triple-negative apocrine carcinoma.[1]

The evaluation of a metastatic breast carcinoma, whether the primary tumor is known or unknown, should include breast-specific markers such as GATA-3, TRPS-1, mammaglobin, GCDFP-15, ER, PR, and HER-2. The panel should be expanded to include other common metastatic carcinomas such as TTF-1 (pulmonary, and thyroid), CK20 (urothelial, gastrointestinal and pancreatobiliary), PAX-8 (gynecological and ovarian), and CDX2 and SATB2 (gastrointestinal).