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Cell proliferation in normal human breast ducts, fibroadenomas, and other ductal hyperplasias measured by nuclear labeling with tritiated thymidine. Effects of menstrual phase, age, and oral contraceptive hormones.

The proliferative rates of terminal duct cells were studied by tritiated thymidine labeling in vitro in 104 specimens of benign breast tissue from 92 women, The tritiated thymidine labeling index showed a cyclic pattern consistent with regulation by female sex hormones. It was low during the segment of the menstrual cycle encompassing days 2 through 15 (early cycle) and often was elevated during the segment encompassing days 16 through 1 (late cycle). The early cycle geometric mean index for morphologically normal terminal ducts was 0.19,and for ducts of fibroadenomas it was 0.77. The geomitric means for latecycle were 1.03 and 1.67 respectively. The difference for normal ducts between early and late cycles was highly significant (p less than 0.001). For both normal ducts and fibroadenomas the tritiated thymidine labeling index correlated negatively with the age of the patient, and the higher index value of fibroadenoma ducts relative to normal ducts was entirely accounted for by the younger mean age of the fibroadenoma patients. Oral use of contraceptive hormones could not be shown to change the index in either normal ducts or fibroadenoma ducts. Based on a postulated duration of DNA synthesis of 12 hours, the mean turnover time of the cells of normal terminal ducts would be approximately 22 days for 20 year old women with regular menstrual cycles, and would increase to 147 day at age 40. The mean potential doubling times of fibroadenomas would be approximately 33 days. The index values of other benign ductal proliferative lesions of the breast were similar to those of fibroadenomas and normal terminal ducts.

Adenofibroma↗

Nuclear feulgen DNA content and nuclear size in human breast carcinoma.

Biopsy specimens from 29 patients with operable breast carcinomas were examined by Feulgen-DNA microspectrophotometry. A diploid DNA stemline was found in ten tumors, seven of which were stage I carcinomas. In 19 tumors, ten of which were stage II cancers, a non-diploid DNA stemline was observed. The diploid tumors were most often estrogen receptor-positive (nine of nine examined carcinomas), whereas 13 of 19 non-diploid tumors studied did not contain estrogen receptors. The mean nuclear size of the non-diploid tumor cells was increased compared with that of the diploid malignant cells. Three grade I carcinomas were diploid, whereas three grade III tumors were non-diploid. Of the 23 grade II carcinomas, seven were diploid and 16 non-diploid. Hum Pathol 13:626-630, 1982.

Adenofibroma↗

Argyrophilic cells in mammary carcinoma.

Breast tumor tissues were treated by the Grimelius procedure and examined for the presence of argyrophilic cells. Carcinomas found to contain argyrophilic cells did not include classic carcinoid tumors; the group was, in fact, heterogeneous, comprising poorly differentiated ductal carcinomas, lobular carcinomas, carcinomas of uncertain origin, and colloid carcinomas. Colloid tumors were the most frequently encountered. The prominence of argyrophilic cells in colloid carcinomas raises the possibility that development into mucin-producing cells is propitious for endocrine differentiation.

Adenofibroma↗

Sclerosing lobular hyperplasia manifesting as a palpable mass of the breast in young black women.

Sclerosing lobular hyperplasia is defined as a lesion of the breast characterized solely by prominent hyperplasia of the lobules and sclerosis of the intralobular stroma. The extra-lobular connective tissue may or may not be fibrosed. To ascertain the frequency of this condition, the histologic sections of all benign breast lesions diagnosed at Howard University Hospital between January 1, 1980, and June 30, 1982, were reviewed. The patient population of the hospital is almost entirely black. Among a total of 590 benign breast lesions, 18 cases of sclerosing lobular hyperplasia were found. The mean age of the patients was 28.3 years. The patients generally complained of a painless or slightly tender lump in the breast, of one or two month's duration. The masses appeared finely nodular and varied in size from 0.8 X 1.2 cm to 3.5 X 5.0 cm. Some microscopic sections from patients with sclerosing lobular hyperplasia revealed incipient (lobule-sized) fibroadenoma. On re-examination of the available sections of 101 fibroadenomas, 47 (46.5 per cent) were found to be surrounded by breast tissue exhibiting focal sclerosing lobular hyperplasia. Apparently, sclerosing lobular hyperplasia is often overgrown by fibroadenoma, and the presenting symptoms are those of the dominant tumor rather than those of the preceding condition.

Adenofibroma↗

Adenomas of the breast and ectopic breast under lactational influences.

The tubular adenomas, lactating adenomas, and ectopic lactation- or gestation-associated benign lesions of the breast diagnosed during a 22-year period are reported. Forty-two breast adenomas (in 28 patients) that demonstrated lactational changes are reviewed, with special attention to classification and clinical presentation. Five ectopic lactating adenomas--three axillary or in the chest wall and two vulvar, the latter occurring in the same patient--were identified in three patients. The lesions in the remaining cases were fibroadenomas with lactational changes (16 patients) and lactating or tubular adenomas (nine patients). Striking histologic and clinical similarities between the tubular and lactating adenomas and the lesions identified as lactational changes within a fibroadenoma were observed, with foci of tubular adenomatous change present within otherwise typical fibroadenomas. The overlapping morphologic spectrum and the strong association with pregnancy or lactational influences blur the distinction between these entities and suggest a common pathogenesis. The cytologic features of lactational lesions of the breast and ectopic breast pose special problems in diagnosis by fine needle aspiration.

Adenofibroma↗

Stromal proliferations of the breast: an ultrastructural and immunohistochemical evaluation of cystosarcoma phyllodes, juvenile fibroadenoma, and fibroadenoma.

The stromal cells of three cystosarcoma phyllodes, five typical fibroadenomas, and one juvenile fibroadenoma were studied by light and electron microscopy. Immunohistochemical staining for the S-100 protein also was performed on tissues from each of the three categories. On ultrastructural examination, cells comprising the three varieties of lesions were similar. Cells with fibroblastic features predominated in all cases. Myoid differentiation was present in two cases, one of cystosarcoma and one of fibroadenoma. Junctional complexes were present in the cystosarcomas but not in the fibroadenomas. Basal lamina was focally present around stromal cells in the cystosarcoma phyllodes but was not evident around cells of the typical fibroadenomas or the juvenile fibroadenoma. Stromal cells of the fibroadenomas and the cystosarcoma phyllodes did not stain for S-100 protein. The results support the hypothesis that the proliferating cells in all three tumor categories are similar and have features of fibroblasts. The lack of staining for S-100 protein would suggest an origin different from the myoepithelia. The latter conclusion, however, must be interpreted with a degree of reservation as we have shown that not all myoepithelial cells stain with certain monoclonal antibodies directed against the alpha and beta chain of S-100 protein.

Adenofibroma↗

Differential diagnosis of benign epithelial proliferations and carcinomas of the breast using antibodies to cytokeratins.

The immunohistochemical reactivity on frozen sections of diverse benign and malignant epithelial proliferations of human breast tissue from 156 patients was examined using antibodies to different cytokeratins. Antibodies recognizing cytokeratins 18 and 19 reacted with luminal epithelial cells but not with myoepithelial cells of normal mammary gland, cystic disease, adenosis, papilloma, and fibroadenoma or with a subpopulation of proliferating cells in sclerosing adenosis and epitheliosis. These antibodies reacted with the tumor cells of all in situ and invasive carcinomas. KA1 antibody, which by one- and two-dimensional gel electrophoresis and immunoblotting was shown to bind preferentially to cytokeratin 14 in a complex with cytokeratin 5, reacted with the nonproliferating myoepithelium of normal gland, cystic disease, adenosis, papilloma, fibroadenoma, and in situ carcinoma; it also reacted with a subpopulation of proliferating cells in sclerosing adenosis and epitheliosis (papillomatosis) but was negative with the tumor cells of all preinvasive and most invasive carcinomas. In adenotic and epitheliotic proliferations, groups of cells were identified that reacted strongly with KA1 antibody in addition to antibodies to cytokeratins 18 and 19. The data are discussed with respect to epithelial cell heterogeneity in the breast. We show that by using such antibodies, benign epithelial proliferations are clearly distinguished from carcinomas.

Adenofibroma↗

MT1-MMP and MMP-2 mRNA expression in human ovarian tumors: possible implications for the role of desmoplastic fibroblasts.

Expression of activated MMP-2 (72 kDa type IV collagenase) is highly associated with the malignant phenotype in adenocarcinomas, but predominant expression of the mRNA appears to be in stromal cells. MT1-MMP (membrane type 1-matrix metalloproteinase) is implicated in tumor-epithelial cell surface activation of latent pro-MMP-2, indicating a mechanism for tumor-stromal interaction in invasion. We determined the relative mRNA distribution of these MMPs in human ovarian tumors with a view to analyzing potential variations in the epithelial-mesenchymal interactions dictating ovarian tumor cell spread. In situ hybridization using 35S-labeled riboprobes was used to analyze 33 human ovarian tumors and mouse xenografts of human ovarian (DOV 13, SKOV3) and breast (MCF 7) tumor cell lines known to express MT1-MMP and MMP-2. MMP-2 mRNA was expressed in 31 of 33 and MT1-MMP mRNA was expressed in 29 of 33 tumor cases. MMP-2 mRNA was predominantly expressed in desmoplastic fibroblasts and in the subepithelial stroma. MT1-MMP mRNA showed some colocalization with MMP-2 in stromal cells. Neoplastic epithelial cell labeling for MT1-MMP mRNA was present in borderline and malignant tumors but not in benign tumors, and was invariably less than stromal labeling. Xenografts of DOV 13, SKOV 3, and MCF 7 cells showed some stromal localization of MMP-2 mRNA and weak labeling of DOV 13 cells. There was variable labeling for MT1-MMP mRNA in the neoplastic cells only. The colocalization of MT1-MMP and MMP-2 mRNAs in ovarian carcinoma stroma supports the view that MT1-MMP is closely associated with MMP-2 expression and function. It suggests that either additional mechanisms are involved in regulating MMP-2 activation at the tumor cell surface, or more intriguingly, that desmoplastic fibroblasts may be the primary mediators of extracellular matrix remodeling with respect to this system.

Actins↗

Nonspecific alkaline phosphatase activity in normal and diseased human breast.

Nonspecific alkaline phosphatase activity was identified in human normal and diseased breasts with the use of the calcium-cobalt, the lead-nitrate, and the azo-dye methods. The results varied not only with the staining method, but also with the functional status of the breast structures. In normal, dysplastic, and fibroadenomatous tissues there was a strong parallelism between myoepithelial and capillary enzyme activities. The calcium-cobalt method was the only technique which allowed staining of carcinoma cells; cancer stromal enzyme activity was evidenced only with the use of the same method. Our findings suggest that nonspecific alkaline phosphatase activity probably reflects a functional status of the labelled structures; the enzyme activity of myoepithelial cells is variable and not really specific.

Adenofibroma↗

Metanephric stromal tumor: a rare benign pediatric renal mass.

We report a rare case and description of a benign pediatric renal mass. To our knowledge, this tumor has never been described in urologic published reports. It is possible that the identification of this renal tumor could spare a child the toxic adjuvant chemotherapy that would be administered if confused with histologically similar tumors such as clear cell sarcoma of the kidney.

Adenofibroma↗

Breast cancer and preceding clinical benign breast disorders. A chance association.

A review of 1059 patients seen in office consultation from 1970 to 1975 for breast disorders revealed that patients with clinically benign disorders were six times as numerous as those with breast cancer. Only 11% of patients with breast cancer had had a previous benign breast-biopsy specimen and on average they were 20 years older than the peak age for benign clinical disease. Of the 163 patients with a previous benign breast-biopsy specimen only 14 (9%) had breast cancer compared with 13% in women without such a history. It is concluded that clinical benign breast disorders do not predispose patients to cancer, and such women should not be singled out for special study.

Adenofibroma↗

Biochemical markers in human breast cancer.

Nineteen biochemical parameters, most of which have been individually advocated as tumour-index-substances for breast cancer, were measured in 51 patients with breast disease, 42 of whom had active breast cancer. Seven of these parameters were raised in more than half of the 17 patients of the series with overt metastases; these were serum ferritin (88%), C-reactive protein (87%), carcinoembryonic antigen (81%), acid glycoprotein (75%), total alkaline phosphatase (64%), sialyl transferase (56%), andthe urinary hydroxyproline/creatinine ratio (73%). The incidence of biochemical abnormalities in patients in this group compared favourably with the results of physical methods of detecting metastases. 7 of 16 further patients without evidence of distant metastases, but who had a poor prognosis as judged by histology of the primary tumour and axillary lymph-nodes, had abnormalities of at least one of the seven parameters. 3 of these patients have relapsed within a year of mastectomy. The results suggest that these biochemical tests could assist in monitoring metastatic disease and could indicate at the time of mastectomy, patients who might benefit from immediate systemic therapy in addition to local treatment of their breast carcinomas.

Adenofibroma↗