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Fibroadenomas and mammary phyllodes tumour arise by proliferation of mammary stroma and epithelial elements. However, it is the stromal element that determines the biology of these biphasic tumours. Normal mammary stroma, like most collagenous connective tissue, contains resident populations of CD34+ dendritic interstitial cells and scattered factor XIIIa+ collagen-associated dendrophages. Actin+myofibroblasts are usually absent from mammary stroma in non-disease states. To determine whether CD34+ and factor XIIIa+ cells proliferate in fibroadenomas and phyllodes tumours, and to study myofibroblastic differentiation in these lesions, we examined 19 fibroadenomas in 14 patients along with five low grade and two high grade phyllodes tumours. We employed antibodies against the human progenitor cell antigen CD34, coagulation factor XIIIa and HHF-35 actin. In three fibroadenomas and two phyllodes tumours, we used Ki-67 antigen to study cell proliferation and oestrogen and progesterone receptors to study possible hormonal influence on stromal cells. In all fibroadenomas, CD34 strongly stained interlobular, pericanalicular and intracanalicular fibroblasts with collagenous and/or myxoid features. Four low grade phyllodes tumours also had CD34+ fibroblasts as did one high grade tumour. Actin reactivity varied and was most pronounced in six fibroadenomas resembling the so-called cellular variant, while seven regular fibroadenomas had no actin+stromal cells and six had only focal and weak actin+stromal cells. Factor XIIIa+ cells were prominently admixed in the stroma of all tumours studied comprising from 5% to 20% in fibroadenomas and, focally, up to 50% in phyllodes tumours. Oestrogen and progesterone receptors were expressed only in glandular elements. Ki-67 index in stromal cells was 1% to 3% in fibroadenoma, 10% to 20% in low grade, and 20% to 40% in high grade phyllodes tumour. We conclude that fibroadenomas and some phyllodes tumours are composed of CD34+ fibroblasts that show varying myxoid, collagenous or myofibroblastic differentiation. The fibroblasts are accompanied by a subset of dendritic histiocytes that express factor XIIIa. Fibroadenoma variants show prominent collagenous actin+myofibroblastic differentiation of CD34+ stromal cells, sometimes with a gradient of CD34 down-regulation. Fine-needle or limited stereotactic core biopsy of these biphasic tumours, if they yield only stromal cells, must be distinguished from other CD34+ stromal tumours. Increased factor XIIIa+ dendrophage populations were seen in phyllodes tumours, especially in two high grade tumours that had malignant fibrous histiocytoma-like features, suggesting clonal evolution toward the fibrohistiocytic final pathway. Further study of CD34 and factor XIIIa+ mammary stromal cells in larger numbers of phyllodes tumours might ascertain whether increasing factor XIIIa reactivity correlates with differentiation and increased tumour aggressiveness.
Fibroadenomas and mammary phyllodes tumour arise by proliferation of mammary stroma and epithelial elements. However, it is the stromal element that determines the biology of these biphasic tumours. Normal mammary stroma, like most collagenous connective tissue, contains resident populations of CD34+ dendritic interstitial cells and scattered factor XIIIa+ collagen-associated dendrophages. Actin+myofibroblasts are usually absent from mammary stroma in non-disease states. To determine whether CD34+ and factor XIIIa+ cells proliferate in fibroadenomas and phyllodes tumours, and to study myofibroblastic differentiation in these lesions, we examined 19 fibroadenomas in 14 patients along with five low grade and two high grade phyllodes tumours. We employed antibodies against the human progenitor cell antigen CD34, coagulation factor XIIIa and HHF-35 actin. In three fibroadenomas and two phyllodes tumours, we used Ki-67 antigen to study cell proliferation and oestrogen and progesterone receptors to study possible hormonal influence on stromal cells. In all fibroadenomas, CD34 strongly stained interlobular, pericanalicular and intracanalicular fibroblasts with collagenous and/or myxoid features. Four low grade phyllodes tumours also had CD34+ fibroblasts as did one high grade tumour. Actin reactivity varied and was most pronounced in six fibroadenomas resembling the so-called cellular variant, while seven regular fibroadenomas had no actin+stromal cells and six had only focal and weak actin+stromal cells. Factor XIIIa+ cells were prominently admixed in the stroma of all tumours studied comprising from 5% to 20% in fibroadenomas and, focally, up to 50% in phyllodes tumours. Oestrogen and progesterone receptors were expressed only in glandular elements. Ki-67 index in stromal cells was 1% to 3% in fibroadenoma, 10% to 20% in low grade, and 20% to 40% in high grade phyllodes tumour. We conclude that fibroadenomas and some phyllodes tumours are composed of CD34+ fibroblasts that show varying myxoid, collagenous or myofibroblastic differentiation. The fibroblasts are accompanied by a subset of dendritic histiocytes that express factor XIIIa. Fibroadenoma variants show prominent collagenous actin+myofibroblastic differentiation of CD34+ stromal cells, sometimes with a gradient of CD34 down-regulation. Fine-needle or limited stereotactic core biopsy of these biphasic tumours, if they yield only stromal cells, must be distinguished from other CD34+ stromal tumours. Increased factor XIIIa+ dendrophage populations were seen in phyllodes tumours, especially in two high grade tumours that had malignant fibrous histiocytoma-like features, suggesting clonal evolution toward the fibrohistiocytic final pathway. Further study of CD34 and factor XIIIa+ mammary stromal cells in larger numbers of phyllodes tumours might ascertain whether increasing factor XIIIa reactivity correlates with differentiation and increased tumour aggressiveness.
Previously we demonstrated the expression of Factor XIIIA (FXIIIA), a coagulatioli traasglutaminase, in avian embryonic growth plate. To explore whether FXIIIA is also expressed by chondrocytes of the iiiamliialian cartilage anlagen of bones, we analyzed tlie iiiouse embryonic growth plate by iiiiinuiiostainilig using anti-FXIIIA antibodies developed against human zind chicken proteins. We revealed the expression of FXIIIA in the epipliyseal growth plate, where FXIIIA appears first intracellularly in the zone of proliferation/iiiaturatioii, and remains intra-and extracellularly throughout the hypertrophic zone. Externalizatioii of FXIIIA O C C L I~S before mineralization. Transglutaminase activity was assayed in organ cultures using rliodamine-labeled synthetic substrate Pro-Val-Lys-Gly. Enzyiiiatic activity shows a restricted distribution in cartilage and correlates with FXIIIA expression pattern, suggesting that cartilagenous transglutaminase activity is due, at least partially, to the FXIIIA isoform. We conclude, that coagulation factor FXIIIA is expressed by chondrocytes of embryonic mouse long bone cartilages in a strictly regulated pattern.which correlates with chondrocyte differentiation and matrix mineralization.
Cardiac myxoma is an enigmatic tumour thought to arise from primitive cardiac mesenchymal cells. Factor XIIIa+ dendrophages are tissue histiocytes that are active in tissue repair and thrombosis. To explore whether factor XIIIa+ dendrophages play a role in cardiac myxoma morphogenesis, we stained four cases with an antiserum against coagulation factor XIIIa (FXIIIa). We also used antibodies recognizing CD34, CD31, and S-100 protein. Samples of valvular endocardium from 12 and 16 week fetuses and two adult autopsies were compared with the four myxomas. All cardiac myxomas had rounded and dendritic FXIIIa+ cells admixed with more numerous CD34+ spindle and stellate myxoma cells. The CD34+ cells formed multicellular syncytia and capillary sprouts. Many of these syncytial structures also expressed CD31 and, to a lesser extent, S-100 protein, strongly in two cases and more focally in two. Fetal subendocardium was composed of CD34+ stellate fibroblast-like cells invested with scattered FXIIIa+ histiocytes; no S-100+ cells were detected. Our findings confirm that cardiac myxomas are composed of CD34+ primitive subendocardial cells. These cells show a capacity for CD31+ endothelial differentiation. In cardiac myxoma, the CD34+ myxoma cells are accompanied by numerous FXIIIa+ dendrophages, the presence of which suggests abnormal organizing thrombus-like differentiation in cardiac myxoma morphogenesis.
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