PURPOSE: Breast Cancer is an inter-tumoral and intra-tumoral heterogeneous disease. It remains unclear whether this heterogeneity results from different target cells or from different subsets of genetic abnormalities, otherwise from both. We postulated that in addition to genetic cloning, a variety of cells that exist during the defined developmental stages of the human mammary gland could give rise to the heterogeneity of breast cancer. To verify this postulation, we have analyzed pure ductal carcinoma in situ (DCIS) for the expression of the biomarkers that represent the mammary stem cell, the early progenitor cells, and the glandular and myoepithelial cells of the mammary gland. METHODS: We investigated the relationship between the immnuohistochemical expression of the mammary development-associated biomarkers {cytokeratin-18 (CK18), cytokeratin-6 (CK6), alpha-smooth muscle actin (SMA), Wnt-1, Notch 3} and some other factors {the menopausal status, the estrogen receptor (ER) status, the progesterone receptor (PR) status, c-erbB-2, and the number of tumor foci} in 26 cases of DCIS. RESULTS: All 26 cases included in this study showed the positive expressions of CK18 and SMA. The expression of all the markers was not correlated with the menopausal status. The positive expression of CK6 had a statistically significant relationship with a negative estrogen receptor (p=0.014), positive c-erbB-2 (p=0.048), high nuclear grade (p=0.001), and single focus of DCIS (p=0.017). The expression of Wnt-1 and Notch 3 did not have significant correlation with any factors. However, the positive expression of Wnt-1 showed a tendency of a negative ER (p=0.061) and the positive expression of Notch 3 also showed a tendency of a negative ER (p=0.086) and a high nuclear grade (p=0.086). CONCLUSION: The CK6 positive tumor is thought to originate from the more primitive cells compared to the CK6 negative tumor. Unifocality of the CK positive tumor might result from the arrest of differentiation of the original cell after disease affection. DCISs could be categorized into the CK6 positive and negative groups.
Actins ; Biomarkers ; Breast Neoplasms ; Carcinoma, Ductal* ; Carcinoma, Intraductal, Noninfiltrating* ; Clone Cells ; Cloning, Organism ; Estrogens ; Keratin-6 ; Mammary Glands, Human* ; Population Characteristics ; Receptors, Progesterone ; Stem Cells*

INTRODUCTION: Cathepsin D (CD) is a lysosomal protease that can be used as an important prognostic cytosolic factor for breast cancer. Its over-expression in breast cancer cells and in the host stromal cells in the tumor has been proposed as being a poor prognostic indicator. However, its prognostic value is still being debated. Therefore, CD expression needs to be examined in more relevant subsets of tissue in order to refine its prognostic significance and the clinical applications. METHODS: Regardless of the lymph node status, 110 T1 invasive ductal carcinomas of the breast were immunohistochemically evaluated for the CD expression using rabbit anti-cathepsin D monoclonal antibody. This study separately assessed the expression of CD in the invasive component (IDC), in the in situ component (DCIS), and in the juxtatumoral stromal cells (JTSC). The CD expression level in these three kinds of tissues were correlated with the nuclear grade, ER, PR, c-erb-B2, p53, the N stage, the T stage, and the 5 year metastasis-free survival. RESULTS: Positive CD expression in the JTSC was associated with the T stage (p = 0.001) and the N stage (p = 0.029), whereas positive CD expression in the DCIS and IDC was not. In addition, strong CD expression in the JTSC correlated with the nuclear grade of the invasive component (p = 0.024). In all three components, no statistically significant correlation was found between the biomarker (ER, PR, cerb-B2, p53) and the CD expression. On univariate analysis, positive expression in the JTSC was correlated with a poor 5 year- metastasis free survival (p = 0.007), but the positive expression in the IDC and DCIS was not. CONCLUSION: CD expression of the JTSC could represent the N stage, the T stage, and the nuclear grade of T1 IDC. Whether or not it would have an independent influence on the prognosis of T1 IDC, CD expression in the JTSC is probably an indicator of the tumor virulence. CD expression in the JTSC will provide an important clue for the development of new CD targeted therapies, and it will serve as an important criterion for selecting the appropriate candidates for these future targeted therapies.
Breast ; Breast Neoplasms ; Carcinoma, Ductal* ; Carcinoma, Intraductal, Noninfiltrating ; Cathepsin D* ; Cathepsins* ; Cytosol ; Lymph Nodes ; Neoplasm Metastasis ; Prognosis ; Stromal Cells* ; Virulence

PURPOSE: We analyzed the histopathologic findings of the patients with ultrasongraphic Breast Imaging Reporting and Data System (BI-RADS) Category 4a breast lesions to determine which patient can be excluded from any invasive, diagnostic procedure in the future. METHODS: Of the 180 cases of BI-RADS Category 4a breast lesions that were diagnosed with ultrasonography during a 6 month-period, 132 cases were pathologically confirmed and these were analyzed retrospectively. Four benign cases that did not undergo any further procedure after fine needle biopsy and 6 malignant cases (4.5%) were excluded from this study. RESULTS: Of the 122 cases, 77 cases (63.1%) showed homogeneous benign finding, and 45 cases (36.9%) showed heterogeneous finding that was made up of two or more different pathologic lesions. Fibroadenoma (55.8%) was the most frequent pathologic finding in the cases with homogeneous finding, followed by fibrocystic change (14.3%), and fibrosis (7.8%). The cases with heterogeneous finding presented fibrocystic change (55.5%), microcalcification (48.8%), ductal hyperplasia (42.2%), and fibroadenoma (31.1%) in the order of frequency. CONCLUSION: Lesion with heterogeneous histopathologic nature was the most frequent finding defined as category 4a in breast ultrasonography, followed by fibrodenoma, fibrocystic change, microcalcification, and ductal hyperplasia. Refining more specific ultrasonographic findings of these lesions would guarantee that radiologists exclude more benign lesions from category 4a.
Biopsy, Fine-Needle ; Breast ; Fibroadenoma ; Fibrosis ; Humans ; Hyperplasia ; Information Systems ; Retrospective Studies ; Ultrasonography, Mammary