Molecules involved in epithelial-mesenchymal transition and epithelial-stromal interaction in phyllodes tumors: implications for histologic grade and prognosis.

The aim of this study was to investigate the expression of molecules associated with epithelial-mesenchymal transition (EMT) and epithelial-stromal interactions (ESI) and to evaluate their roles in phyllodes tumors (PTs). Tissue microarrays (TMAs) were constructed from 207 PT specimens (157 benign, 34 borderline and 16 malignant). The presence of EMT-related markers including N-cadherin, Twist, TGF-beta, HMGA2, S100A4 and Ezrin as well as ESI-related molecules such as SDF1 and CXCR4 among the TMAs was assessed immunohistochemically. Immunohistochemical results were analyzed in terms of clinicopathologic parameters. For higher grade PTs, expressions of Twist (p < 0.001), HMGA2 (p = 0.005), S100A4 (p < 0.001), CXCR4 (p < 0.001) and TGF-beta (p < 0.001) were higher. As PTs showed higher stromal cellularity, higher stromal mitosis, stromal overgrowth and infiltrative tumor margin, the expressions of Twist, HMGA2 and CXCR4 in the stromal component thereof were increased (p < 0.05). High Twist expression in the stromal component was associated with shorter disease-free survival (DFS) and overall survival (OS) (p < 0.001) as well as shorter OS in multivariate COX analysis (p = 0.031, odds ratio: 24.6). In conclusion, the expressions of Twist, HMGA2, TGF-beta and S100A4, which are EMT-associated molecules, and CXCR4, an ESI-associated molecule, were increased in the stromal component of advanced grade PTs. Further, high expression of Twist in the stromal component was correlated with poorer prognoses.