It is not a secret that breast pathology has gray areas that are subject to interobserver variability. Efforts by the breast pathology community and years of research have led to the establishment of precise diagnostic criteria and classification of most lesions. However, there are still difficult areas, such as the evaluation of atypia in proliferative breast lesions, the classification of low-grade intraductal proliferations, and the diagnosis of metastatic disease to and from the breast, particularly when dealing with triple-negative breast carcinoma (TNBC). The use of immunohistochemistry (IHC) is an essential addition to the daily practice of breast pathology. The increasing repertoire of available markers facilitates accurate interpretation and results in proper patient management and stratification. As such, it is important to stay abreast regarding the discovery and evaluation of new markers as well as being familiar with staining patterns and possible diagnostic pitfalls. The article by Rammal et al comprehensively explores the utility of SOX10 in the diagnosis of the problematic breast lesions mentioned above. SOX10 (SRY-related HMG-box 10 protein), a transcription factor expressed in melanocytic and Schwann cell lineages, is being increasingly used in breast pathology as an aid in the diagnosis of metastatic TNBC and, to a lesser degree, as a myoepithelial cell marker.[3,4]
The diagnosis of metastatic TNBC can be difficult to establish. Traditional markers such as mammaglobin and gross cystic disease fluid protein 15 can be negative in a significant number of metastatic TNBCs, as their sensitivity decreases with the lack of estrogen receptor (ER) expression. GATA-3, a highly sensitive maker for breast carcinoma, also loses sensitivity in TNBC. In addition, it has been demonstrated that GATA-3 lacks specificity for breast carcinoma.[3–5] The use of SOX10, as shown by Rammal et al, has proven to be of significant utility, especially when all other breast markers are negative, as often seen in basal-like breast carcinomas. In this study, SOX10 was found particularly useful in the distinction between TNBC and gynecologic malignancies because all tested gynecologic carcinomas were negative for SOX10. In addition, they demonstrated that androgen receptor–positive TNBC was less likely to be positive for SOX10.
The distinction between usual ductal hyperplasia (UDH) and atypical ductal hyperplasia (ADH) and their separation from low-grade ductal carcinoma in situ (LG-DCIS) is crucial because the diagnosis of ADH and LG-DCIS triggers excision in most clinical settings, whereas the diagnosis of UDH and other proliferative lesions without atypia does not require surgical management. Immunohistochemical markers most commonly used to distinguish UDH, ADH, and LG-DCIS include ER and antibodies containing CK5. UDH usually displays a patchy nuclear staining pattern with ER, whereas ADH and LG-DCIS are usually strongly and diffusely positive. On the other hand, UDH usually reveals a mosaic staining pattern with CK5 and other CK5-containing antibodies, while ADH and LG-DCIS are usually negative. ER and CK5 are not useful in the diagnosis of high-grade basal-like DCIS, as these are usually ER negative and express basal cytokeratins such as CK5. In their study, Rammal et al found that SOX10 shows a similar staining pattern to CK5 in this setting, making it an alternative or a complement to CK5. SOX10 stains myoepithelial cells in a variety of lesions, including normal breast tissue. However, it has been shown that there can be attenuation of SOX10 in DCIS; therefore, it is clear that SOX10 does not outperform other well-established myoepithelial cell markers, and its use in this setting is limited.[2,8]
The main diagnostic pitfall with the use of SOX10 as a breast marker is metastatic melanoma. Melanoma is a well-known morphologic mimicker and a common metastatic tumor to the breast. Therefore, as recommended in this article, when dealing with a poorly differentiated, triple-negative tumor, using an IHC panel is always preferred.
In summary, Rammal et al confirm the usefulness of SOX10 in the practice of breast pathology, mainly its utility as a marker for TNBC, its role in cases in which gynecologic malignancies are in the differential, and its value in the diagnosis of atypia. The addition of new markers such as SOX10 to the pathologist's armamentarium to evaluate breast lesions is important because no marker by itself is entirely sensitive or specific in this setting.
Am J Clin Pathol. 2022;158(5):557-558. © 2022 American Society for Clinical Pathology