Woo Hee Jung

Radiologic and Clinical Features of Idiopathic Granulomatous Lobular Mastitis Mimicking Advanced Breast Cancer

Idiopathic granulomatous lobular mastitis (IGLM), also known as idiopathic granulomatous mastitis, is a rare chronic inflammatory lesion of the breast that can clinically and radiographically mimic breast carcinoma. The aim of this study was to describe the radiological imaging and clinical features of IGLM in order to better differentiate this disorder from breast cancer. We performed a retrospective analysis of the clinical and radiographic features of 11 women with a total of 12 IGLM lesions. The ages of these women ranged between 29 and 42 years, with a mean age of 34.8 years. Ten patients were examined by both mammography and sonography and one by sonography alone. The sites that were the most frequently involved were the peripheral (6/12), diffuse, (3/12), and subareolar (3/12) regions of the breast. The patient mammograms showed irregular ill-defined masses (7/11), diffuse increased densities (3/11), and one oval obscured mass. In addition, patient sonograms showed irregular tubular lesions (7/12) or lobulated masses with minimal parenchymal distortion (2/12), parenchymal distortion without definite mass lesions (2/12), and one oval mass. Subcutaneous fat obliteration (12/12) and skin thickening (11/12) were also observed in these patients. Contrary to previous reports, skin changes and subareolar involvement were not rare occurrences in IGLM. In conclusion, the sonographic features of IGLM show irregular or tubular hypoechoic masses with minimal parenchymal distortion. Both clinical information and the description of radiographic features of IGLM may aid in the differentiation between IGLM and breast cancer, however histological confirmation is still required for the proper diagnosis and treatment of the disorder.

Metabolic interaction between cancer cells and stromal cells according to breast cancer molecular subtype

IntroductionThe aim of this study was to investigate the differential expression of markers related to metabolic, mitochondrial and autophagy status in different molecular subtypes of breast cancer.MethodsUsing tissue microarray sections generated from 740 cases of breast cancer, we performed immunohistochemical staining for Glut-1, CAIX, MCT4, ATP synthase, glutaminase, BNIP3, Beclin-1, LC3A, LC3B and p62. Based on the immunohistochemical expression of estrogen receptor (ER), progesterone (PR), HER2, and Ki-67 labeling index, the cases were classified into luminal A, luminal B, HER2 and triple-negative breast cancer (TNBC). We further classified metabolic phenotypes of tumors according to glycolytic status by assessing Glut-1 and CAIX expression as follows: Warburg type: tumor (glycolysis type), stroma (nonglycolysis type); reverse Warburg type: tumor (nonglycolysis type), stroma (glycolysis type); mixed type: tumor (glycolysis type), stroma (glycolysis type); and null type: tumor (nonglycolysis type), stroma (nonglycolysis type).ResultsExpression of Glut-1, MCT4 and LC3A was highest in TNBC and lowest in luminal A type (P < 0.001). Tumors were classified into 298 Warburg type (40.3%), 54 reverse Warburg type (7.3%), 62 mixed type (8.4%) and 326 null type (44.0%). The mixed type had a higher histologic grade, ER negativity, PR negativity and Ki-67 index, whereas the null type showed lower histologic grade, ER positivity, PR positivity and Ki-67 index (P < 0.001). TNBC constituted the major portion of Warburg and mixed types, and luminal A consisted mainly of reverse Warburg and null types (P < 0.001).ConclusionBreast cancer is heterogeneous in its metabolic status, and therefore it can be classified into various metabolic phenotypes. Specifically, the Warburg and mixed types had strong associations with TNBC, whereas reverse the Warburg and null types had associations with the luminal type, suggesting a correlation between metabolic phenotype and the biology of breast cancer.

Metabolism-related proteins are differentially expressed according to the molecular subtype of invasive breast cancer defined by surrogate immunohistochemistry.

Objective: The purpose of this study was to investigate the expression of metabolism-related proteins such as Glut-1 and carbonic anhydrase IX (CAIX) according to breast cancer molecular subtype. Methods: We generated a tissue microarray of 276 breast cancer patients and performed immunohistochemical staining for known metabolism-related proteins, which were evaluated according to the molecular subtype. Results: The expression of IGF-1, MIF, and HIF-1α was correlated with the HER-2 type (p < 0.05). Glut-1 overexpression and CAIX expression were associated with TNBC type, especially with basal-like type, high histologic grade, estrogen receptor negativity, and progesterone receptor negativity (p < 0.05). The expression of Glut-1 and CAIX was correlated with statistical significance (p < 0.001). Conclusion: We identified different patterns of expression of metabolism-related proteins according to the molecular subtypes of breast cancer defined by surrogate immunohistochemistry. Increased expression of HIF-1α, IGF-1, and MIF was noted in HER-2 type breast cancer and increased expression of Glut-1 and CAIX was noted in TNBC type breast cancer, especially in the basal-like subtype, which exhibited a glycolytic and acid-resistant tumor phenotype.

Expression of MT-1 MMP, MMP2, MMP9 and TIMP2 mRNAs in Ductal Carcinoma in Situ and Invasive Ductal Carcinoma of the Breast

We investigated the expression of membrane type-1 (MT1)-MMP, MMP2, MMP9 and TIMP2 mRNAs and their roles in ductal carcinoma in situ (DCIS) and T1 and T2 invasive ductal carcinoma of the breast. We further compared these two types of carcinomas for differences in microvessel density, and expression of angiogenic factors and CD44std. MT1-MMP, MMP2, MMP9 and TIMP2 mRNA were expressed in both DCIS and invasive ductal carcinomas. Expression rates of MT1-MMP, MMP2, MMP9 and TIMP2 mRNAs were not statistically different between DCIS and invasive ductal carcinomas, nor did they differ statistically when grouped by tumor size, histologic grade or nuclear grade of invasive ductal carcinoma. Microvessel density and expression of VEGF and TGF-β1 were not statistically different between DCIS and invasive ductal carcinoma. CD44std expression was significantly increased in DCIS compared to invasive ductal carcinoma (p < 0.05) and it was also significantly increased in lower clinical stage, histologic grade and nuclear grade of invasive ductal carcinoma (p < 0.05). Axillary node metastasis was significantly correlated with MT1-MMP mRNA, VEGF and TGF-β1 expression (p < 0.05) and MT1-MMP mRNA was positively correlated with VEGF expression and TIMP2 mRNA (p < 0.05). In summary, patterns of MMP mRNA expression in DCIS and invasive ductal carcinoma suggest that the invasive potential of breast carcinoma is already achieved before morphologically overt invasive growth is observed. As MT1-MMP mRNA expression is significantly correlated with axillary nodal metastasis, it may be useful as a prognostic indicator of invasive ductal carcinoma. Considering the positive correlation of MT1-MMP mRNA and TIMP2mRNA expression, our finding supports a role for TIMP2 in tumor growth, as well as the utility of CD44std as a prognostic indicator of breast cancer.

Microwave detection of metastasized breast cancer cells in the lymph node; potential application for sentinel lymphadenectomy.

Metastasis is the leading cause of death in breast cancer patients and an appropriate detection of metastasis can provide better prognosis and quality treatments. Microwaves can reveal the unique electromagnetic properties of materials, and this study aims to unleash the electromagnetic properties of breast cancer cells, especially, metastasized cancer cells in the lymph nodes, using broad-band microwaves in attempts to detect metastases. To distinguish the cancer-specific patterns of cancer tissues, three primary microwave parameters were assessed, i.e., permittivity in mid-band frequency (3–5 GHz), conductivity in high-band frequencies (25–30 GHz) and slope changes of permittivity at high-band frequencies (15–30 GHz). An additional parameter, Cancer Metastasis Index (CMI), was developed to effectively represent all parameters. Broadband microwave scanning can reveal cancer specific electromagnetic behaviors in all three parameters, and these were reliably reflected by CMI. CMI effectively magnified the difference of the electromagnetic properties between normal nodal tissues and cancer tissues. immunohistochemistries were performed to verify the origin of electromagnetic changes represented by CMI values.

Current Issues and Clinical Evidence in Tumor-Infiltrating Lymphocytes in Breast Cancer

With the advance in personalized therapeutic strategies in patients with breast cancer, there is an increasing need for biomarker-guided therapy. Although the immunogenicity of breast cancer has not been strongly considered in research or practice, tumor-infiltrating lymphocytes (TILs) are emerging as biomarkers mediating tumor response to treatments. Earlier studies have provided evidence that the level of TILs has prognostic value and the potential for predictive value, particularly in triple-negative and human epidermal growth factor receptor 2–positive breast cancer. Moreover, the level of TILs has been associated with treatment outcome in patients undergoing neoadjuvant chemotherapy. To date, no standardized methodology for measuring TILs has been established. In this article, we review current issues and clinical evidence for the use of TILs in breast cancer.

Adipocytes can induce epithelial-mesenchymal transition in breast cancer cells

Adipocytes are known to be involved in epithelial-mesenchymal transition (EMT) in several cancers. However, the role of adipocytes in the EMT of breast cancer cells is poorly understood. The purpose of this study was to investigate the involvement of adipocytes in the EMT in breast cancer. Breast cancer cell lines MCF-7, MDA-MB-453, MDA-MB-435S, MDA-MB-231, and MDA-MB-468 were co-cultured with adipocytes and analyzed for morphological changes, proliferation activity, EMT markers, migration, and invasion. In addition, 296 human breast cancer specimens were classified according to the presence of the fibrous or adipose stroma and analyzed by immunohistochemistry for the expression of estrogen and progesterone receptors, human epidermal growth factor receptor 2, antigen Ki-67, N-cadherin, Twist-related protein 1 (TWIST1), high-mobility group AT-hook 2, TGFβ, and S100 calcium-binding protein A4 using tissue microarray. After co-culture with adipocytes, MCF-7, MDA-MB-435S, and MDA-MB-231 cells exhibited elongated spindle-like morphology and increased proliferation; MDA-MB-435S and MDA-MB-231 cells also showed increased dispersion. In all tested breast cancer cells, adipocytes induced migration and invasion. The EMT-like phenotypic changes and increased cell migration and invasion were accompanied by the upregulation of matrix metallopeptidase 9 and TWIST1. Consistently, breast cancer tumors with the adipose stroma showed higher TWIST1 expression than those with the adipose stroma; however, no difference was observed in the levels of other EMT-related proteins. Adipocytes stimulate breast cancer cells to acquire aggressive tumor phenotype by inducing EMT-associated traits, and breast cancer with the adipose stroma expresses EMT markers as breast cancer with the fibrous stroma.

Positive Expression of Insulin-Like Growth Factor-1 Receptor Is Associated with a Positive Hormone Receptor Status and a Favorable Prognosis in Breast Cancer

Purpose Insulin-like growth factor 1 receptor (IGF-1R) is commonly expressed in primary breast cancers. Understanding the role of IGF-1R signaling in the different subtypes of breast cancer is important because each subtype has a different outcome and requires different treatment modalities. However, the precise biological significance of IGF-1R expression in cancer cells is still unclear. In this study, we examined the expression of IGF-1R in the different molecular subtypes of breast cancer. The effects of IGF-1R expression on the survival rates and outcomes of breast cancer were also examined. Methods IGF-1R expression was evaluated immunohistochemically in tissue microarray blocks constructed from 1,198 invasive breast cancer samples collected from six medical institutions. IGF-1R expression was interpreted according to the human epidermal growth factor receptor 2 (HER2)/neu immunohistochemistry scoring system. Scores of 2+ and 3+ were considered positive. Results Positive IGF-1R expression was observed in 65.4% of invasive breast cancer samples. IGF-1R expression was detected in all cancer subtypes (luminal A, 84.4%; luminal B, 75.9%; HER2, 21.2%; triple-negative, 46.6%) and was found to be associated with a positive hormone receptor status and the absence of HER2 amplification (p<0.001). Positive IGF-1R expression was significantly associated with high survival rates (p=0.014). However, a multivariate analysis revealed that the expression levels of IGF-1R did not achieve statistical significance. In the triple-negative cancer subtype, IGF-1R expression was found to be associated with a lower disease-free survival rate (p=0.031). Conclusion Positive IGF-1R expression is associated with a favorable prognosis in breast cancer. IGF-1R is frequently expressed in the luminal A/B subtypes of breast cancer, and its expression is related to the hormone receptor status.

Detection of human papillomavirus in warty carcinoma of the uterine cervix: comparison of immunohistochemistry, in situ hybridization and in situ polymerase chain reaction methods.

Warty carcinoma of the uterine cervix is a very rare specific variant of invasive squamous cell carcinoma, usually described as a hybrid feature of condyloma with invasive squamous cell carcinoma. Besides having the koilocytes and maturation of squamous epithelium, there is unequivocal stromal invasion. The feathery surface seems to be characteristic of warty carcinoma, differentiating it from condylomata acuminata or verrucous carcinoma. Using in situ polymerase chain reaction (IS-PCR) and in situ hybridization (ISH) as well as an immunohistochemical technique (IHC), we determined the amplification and expression of several human papilloma virus (HPV) types (6, 11, 33, 16 and 18) in nine warty carcinomas of the uterine cervix. We found amplified HPV predominantly in the nuclei of the feathery surface in all cases only when IS-PCR was applied, while it was detected only in five (55.6%) or six cases (66.7%) by conventional IHC or ISH, respectively. We found multiple types in the same lesion in six cases (66.7%) by IS-PCR, in comparison with ISH which detected a lower incidence (22.2%). This finding of coinfection is more consistent with that seen in low-grade squamous intraepithelial lesions (LSILs) of the uterine cervix than in high SIL. It is important to be aware of these distinct lesions in postmenopausal women with their characteristic feathery and thin surface, as well as a hybrid form of exophytic condyloma and stromal invasion, and frequent coinfection of multiple different HPVs as a type of LSILs.

Breast conserving therapy in stage I & II breast cancer in Korea

A randomized clinical study of 187 patients with T1, T2 breast cancer was performed, in order to compare the effects of modified radical mastectomy (MRM) and breast conserving therapy (BCT) on breast recurrence, overall survival, and disease-free survival. One hundred eighty seven patients with T1, T2 breast cancer, admitted at Yongdong Severance Hospital from April 1991 to August 1994, were randomized into two different treatment groups. Of the 187 patients, 111 patients had received MRM and 76 had received BCT. In any of the variables considered with the exceptions of age and menopausal status, patient characteristics such as tumor size, incidence of axillary lymph node metastasis, histologic grading, and estrogen and progesterone receptor positive rate were not significantly different between the two groups (p > 0.05). Using the Kaplan-Meier Product-limit method and log-rank test, the difference of locoregional recurrence, and overall and disease-free survival, between these comparable groups was analyzed. Average follow-up period was 37.6 months. Two out of 111 MRM patients and two out of 76 BCT patients had locoregional recurrence. Only one patient who had MRM was found to have a recurrence in her opposite breast. The overall survival rates in MRM and BCT patients were, respectively, 93.7% and 94.1%. Furthermore, the disease-free survival rates were, respectively, 89.2% and 93.9%. This result indicates that there were no significant differences between two groups in locoregional recurrence, and overall and disease-free survival. Having gained a better cosmetic appearance, the conservative treatment group was satisfied with the BCT. In this study, we conclude that BCT is a good alternative surgical treatment modality for T1, T2 Korean breast cancer patients, which could substitute for the more traditional MRM. However, further follow-up will be needed for long-term results.