Ellis, P.E.; (2007) The molecular pathology of Paget's disease of the vulva and the breast. Doctoral thesis , University of London.

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Abstract

Paget's disease of the vulva and breast are rare diseases. Unlike Paget's disease of the breast, where the consensus is that the great majority of cases are associated with an in-situ or invasive ductal carcinoma, only approximately 10-30% of cases of Paget's disease of the vulva have an invasive adenocarcinoma present. It is believed that the Paget cells in Paget's disease of the breast are derived from the underlying in-situ or invasive breast carcinoma, and these cells migrate up through the ducts onto the nipple epidermis. The histogenesis underlying vulval Paget's disease is unclear. Paget's disease of the vulva may become secondarily invasive even in the absence of an underlying malignancy. The aim of the study was to identify abnormalities present in Paget's diseases of the vulva and the breast and to investigate whether there are any differences in molecular markers in the Paget cells of those cases with invasive disease compared to those cases without invasive disease. Such an analysis may identify some of the molecular pathways underlying both vulval and breast Paget's disease, as well as generating potential markers for clinical prognosis. Archival paraffin wax-embedded sections of Paget's disease of the vulva or breast were used. Immunohistochemical analysis was performed to analyse markers involved in the cell cycle (p53, pRb, cyclin Dl, Ki67), in angiogenesis (e.g. VEGF, PD-ECGF/TP, MVD) and cell adhesion molecules (e.g. plakoglobin, E-cadherin, (3-catenin). Sections that were immunopositive for the tumour marker p53 were microdissected, the DNA extracted, amplified and sequenced. In situ hybridisation was also used to determine the presence of mRNA of the adhesion molecules in the tissue sections. A national register for Paget's disease of the vulva was established requesting that clinicians who have patients with Paget' s disease of the vulva should enrol them. Results suggest E-cadherin, plakoglobin and pRb and p53 may have a role to play in the pathogenesis of Paget's disease of the vulva and pRb, plakoglobin, VEGF and PD-ECGF/TP in Paget's disease of the breast. Wide local excison was the preferred treatment option for patients registered in the PDV database. The information from the Paget's register and the results obtained from the thesis may increase the understanding of Paget's disease of the vulva and breast.

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