Katsumi Ikeda

Androgen receptor expression in breast cancer: relationship with clinicopathological factors and biomarkers

BackgroundBreast cancer is a hormone-dependent tumor. Most breast cancer cells have an androgen receptor (AR), but the clinical value of AR expression is unclear.MethodsAR expression was evaluated in 227 primary breast cancers using immunohistochemistry. The relation of AR expression to clinicopathological factors and biomarkers was analyzed. AR expression was assessed semiquantitatively, and tumors with more than 10% of stained cells were regarded as positive.ResultsThe AR-positive rate was higher in smaller tumors (P = 0.045), tumors with negative lymph node metastasis (P = 0.045), scirrhous-type tumors (P < 0.0001), tumors of low histological grade (P = 0.0001), and p53-negative tumors (P = 0.0097). Although AR had no relation to menopausal status, 79% of cases of high AR expression (>50% stained cells) were in postmenopausal women. AR was related to estrogen receptor (ER; P = 0.027) and progesterone receptor (PR; P = 0.016) expression, but showed no relation to human epidermal growth factor receptor type 2 (Her2) expression. Regarding the coexpression of these receptors, 18 of the 42 cases of triple-negative (ER/ PR/ Her2-negative) tumors (43%) were AR-positive.ConclusionAR expression is related to low malignancy in breast cancer. The assessment of AR expression may lead to new treatment strategies for breast cancer, especially in postmenopausal women and in women with tumors that show triple negativity for hormone receptors.

The Value of Ultrasound-Guided Fine-Needle Aspiration Cytology for Thyroid Nodules: An Assessment of Its Diagnostic Potential and Pitfalls

Abstract This study was conducted to assess the diagnostic potential and pitfalls of performing fine-needle aspiration cytology (FNAC) for thyroid nodules. We retrospectively analyzed 1012 aspirated samples obtained from 806 thyroid nodules by the ultrasound (US)-guided method. Of these 806 nodules, 226 (31%) had been surgically treated, 152 (67%) of which were histologically diagnosed as malignant. The rate of sufficient aspirate was 82%, being lower in nodules with a diameter of less than 5 mm (73%, P = 0.10); either calcified (77%, P = 0.043) or benign (72%, P = 0.0002). The accuracy of FNAC was 75%, the rate of indeterminate diagnosis was 16%, the false negative rate was 13%, and the positive malignancy rate was 99%. The rate of indeterminate diagnosis was higher in adenomatous goiter, follicular carcinoma, and malignant lymphoma, at P = 0.015, P = 0.0008, and P = 0.035, respectively. The accuracy was lower in follicular carcinoma and malignant lymphoma (both at P = 0.013). Sufficient aspirate was finally obtained from 701 (87%) of the 806 nodules by repeated aspiration. Of 152 malignant nodules, 28 (18%) were diagnosed after two or more aspirations, and the accuracy was improved to 81% by repeating the procedure. These findings indicated that repeated aspiration may be a simple and effective method of improving the diagnostic potential of FNAC.

Immunohistochemical Assessment for Estrogen Receptor and Progesterone Receptor Status in Breast Cancer : Analysis for a Cut-off Point as the Predictor for Endocrine Therapy

BackgroundAn immunohistochemical (IHC) method is commonly used for determining estrogen receptor (ER) and progesterone receptor (PR) status in breast cancer. However, the proper cut-off points of IHC have not been established. Cut-off points for ER and PR status as predictive factors for endocrine therapy are needed.MethodsA total of 249 cases of female breast cancer were enrolled. ER and PR status by IHC were analyzed using the proportion of stained cells and staining intensity by Allred’s score.ResultsProportion score (PS) and intensity score (IS) were related to enzyme immunoassay (EIA) titers, for both in ER and PR(p < 0.0001, all). PS correlated with IS in both ER and PR (R=0.47 and 0.41,respectively). ER status by IHC was related to tumor size and lymph node status, while PR was related to tumor size and menopausal status. In 152 patients who received endocrine therapy with a median follow-up term of 38 months, differences in disease-free survival were most significant using a cut-off point of PS 3 which indicated more than 10% of cells stained positively for both ER and PR(p = 0.0007 and 0.0087, respectively). In addition, combination analysis of ER and PR using this cut-off point revealed a notable prognostic difference.ConclusionA 10% staining proportion may be an acceptable cut-off point for both ER and PR status by IHC, in terms of predicting response to endocrine therapy in breast cancer.

Advantages of adjuvant chemotherapy for patients with triple-negative breast cancer at Stage II: usefulness of prognostic markers E-cadherin and Ki67

IntroductionTriple-negative breast cancer (TNBC), which is characterized by negativity for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2), is a high risk breast cancer that lacks specific targets for treatment selection. Chemotherapy is, therefore, the primary systemic modality used in the treatment of this disease, but reliable parameters to predict the chemosensitivity of TNBC have not been clinically available.MethodsA total of 190 TNBC patients who had undergone a curative resection of a primary breast cancer were enrolled. The adjuvant chemotherapy was performed for 138 (73%) of 190 TNBC cases; 60 cases had an anthracyclin-based regimen and 78 a 5-fluorouracil-based regimen. The prognostic value of E-cadherin, Ki67 and p53 expression in the outcome of TNBC patients with adjuvant chemotherapy was evaluated by immunohistochemistry.ResultsThe adjuvant therapy group, especially those with Stage II TNBC, had a more favorable prognosis than the surgery only group (P = 0.0043), while there was no significant difference in prognosis between the anthracyclin-based regimen and 5-fluorouracil-based regimen. Patients with E-cadherin-negative and Ki67-positive expression showed significantly worse overall survival time than those with either E-cadherin-positive or Ki67-negative expression (P < 0.001). Multivariate analysis showed that the combination of E-cadherin-negative and Ki67-positive expression was strongly predictive of poor overall survival (P = 0.004) in TNBC patients receiving adjuvant chemotherapy. In contrast, p53 status was not a specific prognostic factor.ConclusionsAdjuvant therapy is beneficial for Stage II TNBC patients. The combination of E-cadherin and Ki67 status might be a useful prognostic marker indicating the need for adjuvant chemotherapy in Stage II TNBC patients.

Effect of organ-specific fibroblasts on proliferation and differentiation of breast cancer cells.

SummaryBreast carcinomas contain both tumor cells and stromal cells, including fibroblasts, endothelial cells, and lymphocytes. Proliferation of breast cancer cells may be controlled partly by mesenchymal cells, especially fibroblasts. We studied effects of fibroblasts on tumorigenicity and histologic features of breast cancer cells vivo, and analyzed fibroblast-produced growth-promoting factors in vitro. Breast carcinoma cells from four lines, and fibroblasts from lines obtained from skin and breast tissue of four patients with breast cancer were used. A suitable number of breast tumor cells and fibroblasts were inoculated subcutaneously into nude mice; resulting tumors were examined. Then conditioned medium from fibroblasts was added to cultures of breast cancer cells to study growth effects, and growth-promoting factors from breast fibroblasts were analyzed. Co-inoculation of breast cancer cells with breast fibroblasts into mice significantly increased tumorigenicity and tumor size beyond those obtained with breast cancer cells alone. Histologically, tumors resulting from co-inoculation with breast fibroblasts showed a scirrhous pattern with extensive fibrosis, while those formed by breast cancer cells injected alone or co-inoculation with skin fibroblasts showed a solid pattern. Medium from breast fibroblasts significantly increased breast cancer cell growth in vitro, while the various skin fibroblasts did not all show this effect. Structural and functional interactions between organ-specific fibroblasts and breast cancer cells may importantly regulate breast cancer growth and progression.

Evaluation of the metastatic status of lymph nodes identified using axillary reverse mapping in breast cancer patients

BackgroundAxillary reverse mapping (ARM) is a new technique to preserve upper extremity lymphatic pathways during axillary lymph node dissection (ALND), thereby preventing lymphedema patients with breast cancer. However, the oncologic safety of sparing the nodes identified by ARM (ARM nodes), some of which are positive, has not been verified. We evaluated the metastatic status of ARM nodes and the efficacy of fine needle aspiration cytology (FNAC) in assessing ARM node metastasis.MethodsSixty patients with breast cancer who underwent ARM during ALND between January 2010 and July 2012 were included in this study. Twenty-five patients were clinically node-positive and underwent ALND without sentinel lymph node biopsy (SLNB). Thirty-five patients were clinically node-negative but sentinel node-positive on the SLND. The lymphatic pathway was visualized using fluorescence imaging with indocyanine green. ARM nodes in ALND field, whose status was diagnosed using FNAC, were removed and processed for histology. We evaluated the correlation between the cytological findings of FNAC and the histological analysis of excised ARM nodes.ResultsThe mean number of ARM nodes identified per patient was 1.6 ±0.9 in both groups. In most patients without (88%) and with (79%) SLNB, the ARM nodes were located between the axillary vein and the second intercostobrachial nerve. FNAC was performed for 45 ARM nodes, 10 of which could not be diagnosed. Six of the patients without SLNB (24%) and onewith SLNB (3%) had positive ARM nodes. Of these sevenpatients, four had >3 positive ARM nodes. There was no discordance between the cytological and histological diagnosis of ARM nodes status.ConclusionsPositive ARM nodes were observed in the patients not only with extensive nodal metastasis but also in those with a few positive nodes. FNAC for ARM nodes was helpful in assessing ARM nodes metastasis, which can be beneficial in sparing nodes essential for lymphatic drainage, thereby potentially reducing the incidence of lymphedema. However, the success of sampling rates needs to be improved.

The thoracoscopic approach for internal mammary nodes in breast cancer

AbstractBackground: This pilot study was conducted to estimate the use of the thoracoscopic surgery as a new approach for the internal mammary nodes (IMN) in breast cancer. Patients and methods: For this study, 21 women with breast cancer who underwent the approach for nodes IMN were enrolled. All the women had suspicious IMN metastasis and no distant metastasis. Results: Thoracoscopic IMN dissection was performed safely for 20 of the women, with an average operative time of 44 min. One woman was excluded from the procedure because of pleural adhesion. The patients were restricted from walking for 1.3 days because of chest drainage, but no patients had severe complication or chest wall deformity after the operation. Six patients had positive IMN outcomes. After surgery, 10 of the 20 patients had a lower tumor node metastases (TNM) staging. Two patients who tested positive for IMN and three who tested negative experienced a relapse, but none had pleural dissemination in a median follow-up period of 24 months. Conclusion: Thoracoscopic surgery may be useful in managing patients with IMN.

MR 77 KDA factor derived from fibroblasts stimulates the invasion ability of breast‐cancer cells

Breast‐cancer cells frequently invade into the skin. However, few reports have described the mechanisms responsible for this invasion. In this study, we investigated the effects of skin fibroblasts on the invasion ability of breast‐cancer cells, using a modification of Boydens chamber method, and purified an invasion‐stimulating factor from fibroblasts. Conditioned medium of skin fibroblasts, DF‐1, significantly stimulated the invasion ability of breast‐cancer cells, OCUB‐1. The invasion‐stimulating factor produced from skin fibroblasts was then partially purified and characterized. The soluble invasion‐stimulating factor of fibroblasts was a protein of 77 kDa, as calculated by SDS‐PAGE. Although TGF‐α and bFGF stimulated the invasion of OCUB‐1, no inhibition of the 77 kDa factor was achieved with neutralizing antibodies against TGF‐α and bFGF. These findings suggest that the 77 kDa factor derived from skin fibroblasts might be unique, might play an important role in invasion to the skin and might explain the frequent skin invasion in breast carcinoma.

Ultrasonic Screening of the Thyroid in Patients with Breast Complaints

From 1994 until 2002, we performed 6956 ultrasonic screenings of the thyroid for all patients who received breast examination by ultrasonography. We discovered 14 thyroid cancers (0.32%) from 4327 cases with breast complaints. The incidence of thyroid cancer with breast cancer (0.25%) was three times higher than that of thyroid cancer without breast cancer (0.73%). It was concluded that ultrasonic screening of the thyroid was useful in patients with breast complaints.

Estrogen receptor status is the most important prognostic factor in breast cancer with ten or more positive lymph nodes

AbstractBackground. In breast cancer, the prognosis worsens with increasing lymph node involvement, and aggressive therapies may prolong survival in patients with advanced breast cancer. However, there are sub-populations of patients with advanced breast cancer with ten or more diseased nodes who have long survival. Implementing appropriate treatment depends on having a realistic and well-founded view of the prognosis. Methods. Sixty-nine patients (mean follow-up, 46 months) were enrolled. All patients underwent adjuvant therapy following radical mastectomy. Thirty-seven patients relapsed after curative surgery and 40 died of their cancer. Clinicopathologic factors, tumor estrogen receptor (ER) status, progesterone receptor status, and p53 protein expression were analyzed for prognostic significance. Results. Lower lymph node stage and positive ER status reflected longer relapse-free survival (P = 0.001 and P = 0.0001, respectively). Lower tumor stage (P = 0.039), lower lymph node stage (P = 0.006), absence of distant metastasis (P = 0.006), positive ER status (P = 0.0002), and negative p53 status (P = 0.02) reflected longer overall survival. ER status was the only independent significant prognostic factor for both relapse-free and overall survival. Conclusion. ER status, an indicator of response to endocrine therapy, was the most significant factor predicting prognosis in patients with breast cancer with ten or more positive lymph nodes.