Immunohistochemical and Molecular Features Distinguishing Metaplastic Breast Carcinoma With Squamous Differentiation From Cutaneous Squamous Cell Carcinoma.

Metaplastic breast carcinoma (MBC) with squamous differentiation can often be diagnosed by routine histopathologic evaluation, but cutaneous squamous cell carcinoma (cSCC) may enter the differential diagnosis in selected pure squamous carcinomas involving the breast/chest, particularly in limited samples or cases lacking definitive epidermal connection, ductal carcinoma in situ, or complete clinical information. Determining the site of origin is clinically important because management strategies for breast and cutaneous carcinomas differ substantially. We sought to identify immunohistochemical and genetic features that could distinguish MBC with squamous differentiation from cSCC arising in breast/chest skin in cases of uncertain origin. To this end, we comprehensively characterized 15 MBC with pure to mixed squamous differentiation and 18 invasive/in situ cSCC arising in breast/chest skin. Comparisons between these cohorts and 48 SCC of other anatomic sites identified significant immunohistochemical differences, with CK7, SOX10, and TRPS1 expression more frequent in MBC than cSCC (P=0.0005, 0.0227, and 0.0290, respectively). HER2 overexpression was identified only in breast and esophageal carcinomas. Next-generation sequencing of the breast/chest tumors demonstrated more frequent PIK3CA/PIK3R1 alterations in MBC than cSCC (P=0.0040), whereas NOTCH1 mutations were exclusive to cSCC (P=0.0407). cSCC showed higher tumor mutational burden and percentage of ultraviolet-associated mutations than MBC (P=0.0002 and <0.0001, respectively). These distinguishing features were then applied to 9 additional breast cases of uncertain origin, demonstrating the added value of molecular data in diagnostically challenging cases. Overall, these findings support a stepwise diagnostic approach integrating immunohistochemistry, selected molecular features, and clinicopathologic context to aid in this distinction.