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

Sawyer, Elinor J.; Hanby, Andrew M.; Rowan, Andrew; Gillett, Cheryl; Thomas, Rachel; Poulsom, Richard; Lakhani, Sunil R.; Ellis, Ian O.; Ellis, Paul; Tomlinson, Ian

doi:10.1002/path.1067

Cited by 108 publications

(96 citation statements)

References 28 publications

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“…20 The Wnt pathway (bcatenin overexpression) and the IGF pathway could play a role in the development of these neoplasms. 21,22 Increased expression of KIT has been described in phyllodes tumors, [23][24][25] but KIT and PDGFRA activating mutations have not been identified so far. 23,24 Epidermal growth factor receptor (EGFR) overexpression and amplifications are common in phyllodes tumors.…”

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confidence: 99%

Phyllodes tumors of the breast segregate in two groups according to genetic criteria

et al. 2007

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Phyllodes tumors are rare fibroepithelial tumors of the breast. The pathologic grading of phyllodes tumors based on the aspect of the stromal component, is divided into 2 or 3 grades according to the system used. To determine whether genetic markers could be of use for improving the classification of phyllodes tumors and to provide a better knowledge of the genetic alterations in these tumors, we analyzed chromosomal changes detected by comparative genomic hybridization (CGH) in comparison with histological data, in a series of 30 cases. Recurrent chromosome imbalances were observed in 55, 91 and 100% of benign, borderline and malignant phyllodes tumors, respectively. The mean number of chromosome changes was one in benign, six in borderline, and six in malignant phyllodes tumors. Most frequent genetic imbalances were þ 1q (12/30), À13q (7/30), À6q (9/30), þ 5 (9/30) and À10p (8/30). Gains of 1q, present in only one of nine benign tumors, were found in 11/21 (51%) borderline or malignant tumors. Losses of 13q have 13q14.2 as smallest region of overlap, suggesting that the RB1 gene could be the target of deletions. Amplifications of 12q14, involving the MDM2 locus, and of 8p24, involving the MYC gene, were observed in one case each. Borderline and malignant phyllodes tumors could not be differentiated on the basis of their genomic imbalances (presence and number of chromosomal changes, presence of 1q gain and/or 13q loss). Conversely, benign tumors could be significantly differentiated from the group composed of borderline and malignant tumors (Po0.01). This study reveals two distinct patterns of genomic imbalance in phyllodes tumors: benign, with none or a few chromosome changes and malignant, with numerous recurrent chromosomal changes, in particular 1q gain and 13q loss. Helpful additional pathological criteria for differentiating the two genetic groups of phyllodes tumors are the nuclear size and the mitotic rate. Modern Pathology (2007) 20, 435-444.

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Phyllodes tumors of the breast segregate in two groups according to genetic criteria

et al. 2007

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“…8,9 Several studies have investigated b-catenin expression in spindle cell lesions of the breast, including fibromatoses, phyllodes tumours and metaplastic carcinomas. 7,[10][11][12][13] Aberrant b-catenin expression, that is, cytoplasmic and/or nuclear, is typically found in fibromatosis, 11 however, it has also been described in metaplastic breast carcinomas 10 and phyllodes tumours. [12][13][14][15] Aberrant b-catenin expression, and particularly the nuclear localization, which can be detected by immunohistochemistry, constitutes a good surrogate marker of Wnt canonical pathway activation.…”

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confidence: 99%

“…7,[10][11][12][13] Aberrant b-catenin expression, that is, cytoplasmic and/or nuclear, is typically found in fibromatosis, 11 however, it has also been described in metaplastic breast carcinomas 10 and phyllodes tumours. [12][13][14][15] Aberrant b-catenin expression, and particularly the nuclear localization, which can be detected by immunohistochemistry, constitutes a good surrogate marker of Wnt canonical pathway activation. 1,3,10 Therefore, and on the basis of its pattern of expression and cellular localization, b-catenin has been proposed as a useful immunohistochemical marker for the differential diagnosis of spindle cell lesions; [16][17][18] however, its use has not been addressed specifically in breast tumours.…”

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β-catenin/Wnt signalling pathway in fibromatosis, metaplastic carcinomas and phyllodes tumours of the breast

et al. 2010

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Wnt signalling pathway is known to have a critical role in carcinogenesis and in epithelial-to-mesenchymal transition. Upon Wnt activation, b-catenin is translocated from the membrane to the cytoplasm and nucleus, where it interacts with transcriptional activators. It has been suggested that various spindle cell lesions of the breast may harbour Wnt pathway activation. Given that b-catenin nuclear localization constitutes a good surrogate marker of Wnt canonical pathway activation, we have investigated the distribution of b-catenin in spindle cell lesions of the breast and whether it could be employed in the differential diagnosis of these lesions. A total of 52 metaplastic breast carcinomas, eight fibromatoses and 23 phyllodes tumours were retrieved from our institutions' archives. We performed immunohistochemistry using two anti-b-catenin antibodies. In all, three fibromatoses and 21 metaplastic breast carcinomas were subjected to CTNNB1 (b-catenin encoding gene) mutation analysis by direct gene sequencing. A good correlation between the two antibodies was observed (Spearman's r40.82, Po0.001). All fibromatoses and 23% of metaplastic breast carcinomas expressed nuclear b-catenin. In fibromatosis, b-catenin was more often diffusely expressed, whereas in metaplastic breast carcinomas, expression was more frequently focal. Membranous b-catenin expression was significantly lower in spindle cell carcinomas than in other subtypes of metaplastic breast carcinomas. In phyllodes tumours, stromal cells of benign and malignant subtypes displayed nuclear b-catenin expression in 94 and 57% of cases, respectively. No CTNNB1 mutation was identified in any of the 21 metaplastic carcinomas analysed, whereas the mutations 45S4S/P and 41T4T/A were found in samples of fibromatosis. In conclusion, b-catenin nuclear expression is a common feature in fibromatoses and in the stromal component of phyllodes tumours, but may also be observed in metaplastic breast carcinomas. b-catenin nuclear expression should not be used as a single marker to differentiate fibromatosis from other spindle cell tumours of the breast.

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“…Both the stroma and the epithelium in phyllodes tumor can show distinct molecular changes, suggesting that both are part of the neoplastic process (29). It has also been observed that there is an interdependence of growth between the stromal and the epithelial components that explains the complex morphology seen in these tumors (30,31). Stromal mitotic activity occurs in close proximity to the epithelial component, strengthening the role of stromal-epithelial interactions in progression of phyllodes tumor (30).…”

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confidence: 97%

Aggressive Giant Fibroepithelial Lesion with Unusual Vascular Stroma—A Case Report

2003

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The stroma of fibroadenoma and phyllodes tumor usually consists of fibroblastic proliferation. Rarely the stroma contains bundles of smooth muscle. Pseudoangiomatous hyperplasia of the mammary stroma has been described in fibroadenomas. However, true benign vascular stroma has not been reported. We report a case of a 34-year-old Chinese woman who presented with a large mass occupying the entire left breast. Left mastectomy was performed and showed a large, well-circumscribed, lobulated, rubbery-firm tumor measuring 13 ؋ 10 ؋ 6 cm. A 34-year-old Chinese woman presented with a large mass occupying the entire left breast. Left mastectomy was performed that showed a remarkable fibroepithelial lesion with stroma showing extensive vascular proliferation. The patient developed a local recurrence a year later, and the resection was diagnosed as malignant phyllodes tumor with ductal carcinoma in situ. The patient had had right mastectomy 5 years ago in China before coming to Canada. No information on the pathology could be obtained.

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

Cited by 108 publications

References 28 publications

Phyllodes tumors of the breast segregate in two groups according to genetic criteria

Phyllodes tumors of the breast segregate in two groups according to genetic criteria

β-catenin/Wnt signalling pathway in fibromatosis, metaplastic carcinomas and phyllodes tumours of the breast

Aggressive Giant Fibroepithelial Lesion with Unusual Vascular Stroma—A Case Report

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