Pathogenesis and progression of fibroepithelial breast tumors

Abstract

Fibroadenoma and phyllodes tumor are fibroepithelial breast tumors. These tumors are biphasic, i.e. they are composed of stroma and epithelium. The behavior of fibroadenomas is benign, whereas phyllodes tumors can recur and even metastasize. Classification criteria for both tumors show considerable overlap, though. Further, morphological observations have suggested that fibroadenoma may progress to phyllodes tumor. The aim of this thesis can be summarized as a study of tumorigenesis and progression in fibroepithelial tumors, i.e. progression in fibroadenomas and progression in grade of phyllodes tumors.

By a comprehensive study of its histology, we identified several regions of phylloid-like stromal progression in fibroadenomas. We subjected these areas to clonality analysis and demonstrated that they are monoclonal. Further, monoclonal epithelial progression to carcinoma in situ was found in fibroadenomas as well. We therefore demonstrated that fibroadenoma may show both epithelial (to carcinoma) and stromal (to phyllodes tumor) progression. The molecular mechanisms underlying development of fibroepithelial tumors are largely unknown. We showed that, in phyllodes tumors, stromal progression is driven by cell cycle deregulation and EGFR overexpression. In addition, stromal p53 expression turned out to be the strongest single prognosticator in phyllodes tumors. In the epithelial component of phyllodes tumors and in fibroadenomas these carcinogenic changes were absent. Deregulation of the cell cycle machinery may lead to loss of genetic integrity. We obtained copy number profiles of fibroepithelial tumors and demonstrated genomic instability in phyllodes tumors, but not in fibroadenomas. Although not related to grade, it seems that genomic instability plays a role in development of phyllodes tumors. Little information is available on the cytokines involved in neovascularization of fibroepithelial tumors. We found that HIF-1α expression, a pivotal angiogenic factor, correlates with tumor grade and predicts prognosis in phyllodes tumors. Surprisingly, phyllodes tumor epithelium showed HIF-1α expression as well, which most likely reflects relatively distant microvasculature causing mild hypoxia. Although similar quantities of microvessels are found in fibroadenomas as compared to phyllodes tumors, HIF-1α does not seem to play a role here. Finally, we compared gene expression profiles of fibroadenomas and phyllodes tumors. We found many novel genes which may contribute to genesis and progression of fibroepithelial tumors. As compared to fibroadenomas, phyllodes tumors showed altered expression of factors involved in transcription, cell adhesion, apoptosis, Wnt signalling, cellular integrity and extracellular matrix degradation. CTAG1, a gene of unknown function, showed a nearly 50-fold upregulation in phyllodes tumors which suggests that it may aid diagnostics.

In this thesis we demonstrated that benign fibroadenoma may progress to the unpredictable phyllodes tumor. Further, we studied several major carcinogenic phenomena and found important roles for cell cycle deregulation, EGFR overexpression, angiogenic factors and genomic instability in phyllodes tumor genesis and progression. Although fibroadenoma and phyllodes tumor share morphological similarities, both tumors are different molecular entities. This thesis contains no data supportive of an active role of the epithelium in fibroepithelial tumors genesis., as had been suggested previously by some authors.