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Immunohistochemical Evaluation of 5-Hydroxymethylcytosine (5-hmC) in Breast Phyllodes Tumors

Jasmine Vickery, Lisa Han, Stephen Dzul, Wei Zhang, Zhou Zhang, Razvan Lapadat, Husain Sattar, Jeffrey Mueller, Thomas Krausz, Anna Biernacka

Phyllodes Tumors (PTs) pose a significant diagnostic challenge in breast pathology as histological criteria and cutoffs for grading are complex and arbitrary. Nevertheless, the clinical behavior of PTs varies widely and correlates, in part, with the histological grade. Methylation signatures have gained interest as diagnostic and prognostic tools in a variety of neoplasms. In particular, 5-hydroxymethylcytosine (5-hmC) has been found to be a useful biomarker. Herein, we assess 51 PTs of varying grades and 15 cellular fibroadenomas (cFAs) for stromal expression of 5-hmC by immunohistochemistry. We demonstrate that nuclear 5-hmC decreases as PT grade increases, correlating with histologic predictors of adverse behavior, while it shows comparable levels in benign PTs and cFAs. We identify thresholds at which reduced 5-hmC levels help to distinguish borderline and malignant PT from their benign counterparts. Our results indicate that 5-hmC may serve as a valuable adjunct in classifying PTs in diagnostically difficult cases.