The Wnt pathway, epithelial–stromal interactions, and malignant progression in phyllodes tumours

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Abstract
In a previous study of phyllodes tumours, it has been shown that both the stroma and the epithelium can exhibit distinct molecular changes, suggesting that both are part of the neoplastic process. In view of this finding, it was decided to study stromal–epithelial interactions in these tumours by examining the Wnt–APC–β‐catenin pathway. β‐catenin and cyclin D1 immunohistochemistry was performed on 119 phyllodes tumours. Eighty‐six (72%) showed stromal nuclear β‐catenin localization and in 57% the staining was moderate or strong; however, of the eight malignant tumours in the series, seven showed absent or weak nuclear staining (ppAPC mutation, but only one (benign) tumour showed LOH. Wnt2 and Wnt5a mRNA was localized by in situ hybridization in 13 cases (three malignant) chosen to reflect the different β‐catenin staining patterns. There was an association between strong nuclear β‐catenin staining of stromal cells and epithelial Wnt5a expression (p<0.0015). These data suggest that stromal proliferation in benign phyllodes tumours relies on abnormalities in the Wnt pathway which result not from mutation, but from Wnt5a expression in the epithelium. In the progression to malignancy, the stromal proliferation appears to become independent of the Wnt pathway and, presumably, of the epithelial component of these tumours. Copyright © 2002 John Wiley & Sons, Ltd.