Reduced E-cadherin expression correlates with disease progression in Paget's disease of the vulva but not Paget's disease of the breast

Ellis, Patricia; Cano, Salvador Diaz; Fear, Mark W.; Kelsell, David P.; Ghali, Lucy; Crow, Julie; Perrett, CW; MacLean, Allan

doi:10.1038/modpathol.2008.50

Cited by 21 publications

(9 citation statements)

References 25 publications

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“…We have demonstrated that the cell adhesion molecule E-cadherin is significantly reduced ( P = 0.039) in Paget's disease of the vulva cases with invasive disease when compared with Paget's disease of the vulva cases without invasive disease. E-cadherin expression was normal in PDB and there was no difference between those cases of PDB with or without DCIS or invasive disease [44]. These findings and the results from this current study demonstrate the critical steps involved in the pathogenesis of PDB and PDV may occur by different mechanisms.…”

Section: Discussionsupporting

confidence: 61%

Angiogenesis in Paget's Disease of the Vulva and the Breast: Correlation with Microvessel Density

Ellis

MacLean

Fong

et al. 2012

Journal of Oncology

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Our understanding of the pathogenesis of Paget's disease of the vulva and the breast remains limited. Current evidence supports the fact that angiogenesis plays an important role in the pathogenesis of several diseases. Therefore, we sought to define its role, as correlated with microvessel density, in Paget's disease of the vulva and the breast. Microvessels were analysed using anti-von Willebrand factor antibody in 105 cases of Paget's disease of the vulva and the breast comprising 71 cases of Paget's disease of the vulva, including 8 cases with invasive disease, and 34 cases of Paget's disease of the breast. The latter included 12 cases with DCIS, 5 cases with both DCIS and invasive carcinoma, and 6 with carcinoma alone. Eleven cases had no underlying tumour identified. Increased microvessel density was demonstrated in Paget's disease of the breast with DCIS and with carcinoma alone compared to Paget's disease of the breast alone, P < 0.08 and P < 0.013, respectively. There were no significant differences in microvessel density in the vulval cases. Neovascularisation is an important process in the development of Paget's disease of the breast. Other biological and molecular processes are more involved in the pathogenesis of Paget's disease of the vulva.

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Section: Discussionsupporting

confidence: 61%

Angiogenesis in Paget's Disease of the Vulva and the Breast: Correlation with Microvessel Density

Ellis

MacLean

Fong

et al. 2012

Journal of Oncology

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“…Loss of E‐cadherin and increased cyclin D1 expression have also been described in invasive adenocarcinoma associated with vulval Paget's disease, although these changes were not correlated specifically with EMT‐like features . We have noted similar immunophenotypic changes at the invasive margin of some vulval squamous carcinomas, particularly within small infiltrative groups of cells and at the border of larger tumour nests (Figure ).…”

Section: Emt In Gynaecological Malignancysupporting

confidence: 69%

Epithelial–mesenchymal transition in carcinomas of the female genital tract

Stewart

McCluggage

2012

Histopathology

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Invasion is a defining feature of malignancy, but the mechanisms of invasion in many common cancers, including gynaecological malignancies, remain unclear. However, it has been proposed that malignant cells may usurp a normal embryological process, epithelial-mesenchymal transition (EMT), as a means of acquiring migratory capacity. The synergistic role of the tumour microenvironment in EMT induction has also been explored and helps to explain the spatially restricted distribution of EMT at the deep tumour margin (invasive front). Furthermore, tumour cells undergoing EMT may acquire cancer stem cell characteristics, and this may be relevant to the entire metastatic process and to tumour recurrence and treatment failure. Nevertheless, doubts persist regarding the role of EMT in malignant progression in vivo, partly because few studies have correlated molecular and histological alterations in clinical pathology specimens. In the current review we summarize the evidence for EMT in the common gynaecological epithelial malignancies, and discuss the morphological and immunohistochemical changes occurring at the invasive tumour front that may represent EMT-like processes. The possibility that carcinosarcomas represent a variant type of EMT with 'fixed' mesenchymal differentiation is also considered. Diagnostic histopathologists are ideally placed to critically evaluate the role of EMT in gynaecological and other types of malignancy.

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“…As the majority of studies to date have focused on IHC detection of one or several proteins, 32,33 our knowledge of the genetic and epigenetic features of extramammary Paget's disease remain largely unknown. In this study, we collected extramammary Paget's disease tumor samples from 132 unrelated Figure 2 The normalized methylation-sensitive, high-resolution melting analysis standard curve used to evaluate methylation levels of extramammary Paget's disease cases.…”

Section: Discussionmentioning

confidence: 99%

Correlation of DLC1 gene methylation with oncogenic PIK3CA mutations in extramammary Paget's disease

Kang

Zhang

et al. 2012

Modern Pathology

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Extramammary Paget's disease is a rare cutaneous malignant neoplasm. The genetic and epigenetic mechanisms underlying its pathology remain unknown. In this study, we investigated the expression levels, and mutation and methylation status of a common tumor suppressor gene, deleted in liver cancer 1 (DLC1), and an oncogene, PIK3CA, in tumor (n ¼ 132) and normal tissues (n ¼ 20) from unrelated patients. The presence of epigenetic and genetic lesions was then correlated to the patient pathology data to determine the potential role of these genes in extramammary Paget's disease etiology and progression. The DLC1 gene was found to be downregulated in 43 (33%) tumors, as compared with immunohistochemistry results from normal tissues. Methylation-sensitive, high-resolution melting analysis indicated that the DLC1 promoter was hypermethylated in 51 (39%) extramammary Paget's disease tumors. This hypermethylation was associated with significantly decreased DLC1 levels (P ¼ 0.011), and had a strong positive correlation with advanced age (P ¼ 0.002). PIK3CA mutations were detected by direct sequencing in 32 (24%) tumors, the majority of which were invasive. Furthermore, PIK3CA mutations significantly correlated with DLC1 hypermethylation. Thus, aberrant DLC1 methylation and PIK3CA mutations may have important roles in extramammary Paget's disease pathogenesis, and may represent potential molecular targets for therapy.

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Reduced E-cadherin expression correlates with disease progression in Paget's disease of the vulva but not Paget's disease of the breast

Cited by 21 publications

References 25 publications

Angiogenesis in Paget's Disease of the Vulva and the Breast: Correlation with Microvessel Density

Angiogenesis in Paget's Disease of the Vulva and the Breast: Correlation with Microvessel Density

Epithelial–mesenchymal transition in carcinomas of the female genital tract

Correlation of DLC1 gene methylation with oncogenic PIK3CA mutations in extramammary Paget's disease

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