MTDH Expression in Invasive Micropapillary Carcinoma of the Breast

OBJECTIVE To clarify the expression of MTDH in invasive micropapillary carcinoma of the breast （IMPC） and analyze the relationship between MTDH expression and clinicalpathologic parameters of the IMPC patietns.

Relationship between Lymphatic Vessel Density and Lymph Node Metastasis of Invasive Micropapillary Carcinoma of the Breast

OBJECTIVE To investigate the relationship between lymphatic vessel density and lymph node metastasis of invasive micropapillary carcinoma (IMPC) of the breast. METHODS The immunohistochemical study for vascular endothelial growth factor-c (VEGF-C), VEGF Receptor-3 (VEGFR-3) and lymphatic vessel density of 51 cases of IMPC were performed, and lymph node metastases were examined by microscopic analysis of these cases. RESULTS In IMPC, VEGF-C was expressed in the cytoplasm and/or on the membrane of the tumor cells, and the expression of VEGF-C showed a positive correlation with lymph node metastasis (P<0.01). Lymphatic vessel density was determined by the number of micro-lymphatic vessels with VEGFR-3 positive staining. Lymphatic vessel density was positively correlated with VEGF-C expression (P<0.01) and lymph node metastasis (P<0.01). The percentage of IMPC in the tumor was not associated with the incidence of lymph node metastasis. The metastatic foci in lymph nodes were either pure or predominant micropapillary carcinoma. CONCLUSION The results suggested that VEGF-C overexpression stimulated tumor lymphangiogenesis, and the increased lymphatic vessel density may be the key factor that influenced lymph node metastasis of IMPC.

Inverted Apical CD24 and Weak EZH2 Expressions Are Phenotypic Characteristics of Pure Invasive Micropapillary Carcinoma of the Breast

Invasive micropapillary carcinomas (IMPC) of the breast account for less than 2% of all breast cancers and have been recently described as luminal B carcinomas. CD24, CD44, ALDH1 and EZH2 are commonly used as stem-cell markers that display differential expression as a function of stage and molecular type, but their pattern of expression according to this rare histological type remains poorly defined and unknown for EZH2. We assessed expression of these markers in a series of 28 micropapillary breast carcinomas and compared the results with those obtained in a series of luminal A (27 cases) and B (34 cases) invasive carcinomas not otherwise specified (IC-NST). CD24 and CD44 were expressed in most cases. However, CD24 was expressed at the inverted apical membrane in 85% of invasive micropapillary carcinoma and at the apical pole of gland-forming cells in 45% of luminal A (p-val = 6.8 × 10-4) and 13% of luminal B cases (p-val = 1.1 × 10-7). ALDH1 was expressed in the stroma in most tumors, but in only 25%, 11% and 15% in epithelial cells of IMPC, luminal A and B IC-NST, respectively. Nuclear expression of EZH2 was not observed in luminal A tumors, and was detected in 35% (12/34) of luminal B carcinomas (p-val = 6.1 × 10-3) and only 4% (1/28) of invasive micropapillary carcinomas. This series shows that invasive micropapillary carcinomas harbor a CD24-positive inverted apical pole associated with weak EZH2 expression, phenotypical characteristics that distinguish this entity from other luminal carcinomas.

Polo-like kinase 1 as a biomarker predicts the prognosis and immunotherapy of breast invasive carcinoma patients

Invasive breast carcinoma(BRCA)is associated with poor prognosis and high risk of mortality.Therefore,it is critical to identify novel biomarkers for the prognostic assessment of BRCA.Methods:The expression data of polo-like kinase 1(PLK1)in BRCA and the corresponding clinical information were extracted from TCGA and GEO databases.PLK1 expression was validated in diverse breast cancer cell lines by quantitative real-time polymerase chain reaction(qRT-PCR)and western blotting.Single sample gene set enrichment analysis(ssGSEA)was performed to evaluate immune infiltration in the BRCA microenvironment,and the random forest(RF)and support vector machine(SVM)algorithms were used to screen for the hub infiltrating cells and calculate the immunophenoscore(IPS).The RF algorithm and COX regression model were applied to calculate survival risk scores based on the PLK1 expression and immune cell infiltration.Finally,a prognostic nomogram was constructed with the risk score and pathological stage,and its clinical potential was evaluated by plotting calibration charts and DCA curves.The application of the nomogram was further validated in an immunotherapy cohort.Results:PLK1 expression was significantly higher in the tumor samples in TCGA-BRCA cohort.Furthermore,PLK1 expression level,age and stage were identified as independent prognostic factors of BRCA.While the IPS was unaffected by PLK1 expression,the TMB and MATH scores were higher in the PLK1-high group,and the TIDE scores were higher for the PLK1-low patients.We also identified 6 immune cell types with high infiltration,along with 11 immune cell types with low infiltration in the PLK1-high tumors.A risk score was devised using PLK1 expression and hub immune cells,which predicted the prognosis of BRCA patients.In addition,a nomogram was constructed based on the risk score and pathological staging,and showed good predictive performance.Conclusions:PLK1 expression and immune cell infiltration can predict post-immunotherapy prognosis of BRCA patients.

Clinical Value Analysis of Ultrasonography and MRI in Diagnosis of Invasive Micropapillary Carcinoma of Breast

Objective:To investigate the diagnostic value of invasive micropapillary carcinoma(IMPC)by ultrasonography and MRI.Method:63 female patients with IMPC were selected,all of which were confirmed by pathological examination,and were assigned to the IMPC group.In the same period,40 patients with invasive ductal carcinoma(IDC group)were selected for diagnostic efficacy control.The efficacy indexes of accuracy,sensitivity,specificity,positive prediction rate and negative prediction rate were 73.0%,65.9%,89.5%,93.5%,46.9%,respectively.The efficiency indexes of accuracy,sensitivity,specificity,positive prediction rate and negative prediction rate of ultrasound combined with breast MRI were 93.6%,93.2%,94.7%,97.6%,85.7%.Ultrasonography combined with MRI has more application value in the diagnosis of IMPC.

Invasive micropapillary carcinoma:A distinct type of adenocarcinomas in the gastrointestinal tract

Invasive micropapillary carcinoma (IMPC) is a rare histological type of tumor, first described in invasive ductal breast cancer, than in malignancies in other organs such as lungs, urinary bladder, ovaries or salivary glands. Recent literature data shows that this histological lesion has also been found in cancers of the gastrointestinal system. The micropapillary components are clusters of neoplastic cells that closely adhere to each other and are located in distinct empty spaces. Moreover, clusters of neoplastic cells do not have a fibrous-vascular core. The IMPC cells show reverse polarity resulting in typical &#x02018;&#x02019;inside-out&#x02019;&#x02019; structures that determines secretary properties, disturbs adhesion and conditions grade of malignancy in gastrointestinal (GI) tract. Invasive micropapillary carcinoma in this location is associated with metastases to local lymph nodes and lymphovascular invasion. IMPC can be a prognostic factor for patients with cancers of the stomach, pancreas and with colorectal cancer since it is related with disease-free and overall survival. The purpose of this review is to present the characterization of invasive micropapillary carcinoma in colon, rectum, stomach and others site of GI tract, and to determine the immunohistological indentification of IMPC in those localization.

Vascular Endothelial Growth Factor Expression in Invasive Ductal Carcinoma of Breast

Objective： To detect the expression of VEGF and MVD count in invasive ductal carcinoma of breast to clarify the association of VEGF expression and MVD count with the clinicopathologic features. Methods： The expressions of VEGF, ER, PR, C-erbB-2 and MVD count in 88 cases of invasive ductal carcinoma of breast were examined by immunohistochemistry staining （SP-method）. Results： Sixty-two out of the eighty-eight specimens of breast carcinoma （70.45%） showed positive expression of VEGF. The positive rate of VEGF in cases with lymph node metastasis was higher than that without lymph node metastasis （P〈0.05）. The positive rate of VEGF in stage IIb-Ⅲ was higher than that in stage Ⅰ-Ⅱa （P〈0.05）. The positive rate of VEGF in C-erbB-2 positive group was higher than that in C-erbB-2 negative group （P〈0.05）. Higher expression of VEGF was observed in cases with higher tissue differentiation degree （P〈0.05）. Also, significant higher MVD count was observed in cases with higher tissue differentiation degree （P〈0.01）. The MVD count increased significantly with the increase of the expression of VEGF （P〈0.01）. Conclusion： The result of this study suggested that in invasive ductal carcinoma of breast, angiogenesis and metastasis were mediated mainly by VEGF. The expression of VEGF and MVD might be reference predictors for the biological behavior of breast carcinoma. The antiangiogenic therapy which used VEGF as a target would become a new method to treat patients who were C-erbB-2 positive in the future.

Low-Grade and High-Grade Invasive Ductal Carcinomas of the Breast Follow Divergent routes of Progression

Low-grade invasive ductal carcinoma is almost diploid, and has frequent losses of chromosome 16q, which is shared by other precancerous lesions of the mammary gland such as flat epithelial atypia （FEA）, atypical ductal hyperplasia （ADH）, and lownuclear grade ductal carcinoma in situ （DCIS）. The genetic alterations accumulate in a stepwise fashion as the precancerous lesions progress to invasve ductal carcinoma. This supports the linear progression model of breast cancer from FEA, through ADH, to low- nuclear grade DCIS as non-obligate early events in low-grade IDC evolution. In contrast, high-grade carcinoma tends to aneuploidy with complex genetic alterations--most importantly, frequent gains at chromosome 16q. Frequent losses at chromosome 16q in low-grade IDC and gains in the same arm of the same chromosome in high-grade IDC imply that these lesions are two end outcomes of different disease processes and that they do not lie in the same continuum of a process. Therefore, low-grade and high-grade IDC are two distinct diseases with a divergent route of progression.

Gastrointestinal metastasis secondary to invasive lobular carcinoma of the breast:A case report

BACKGROUND Gastrointestinal metastasis of breast cancer is rare,and clinicians may not have previously encountered this disease in clinical practice.CASE SUMMARY We report a patient with invasive lobular carcinoma of the breast who developed gastrointestinal metastasis two years after modified radical surgery.Mild elevation of carbohydrate antigen 15-3 was observed in the patient at an early stage;however,diagnosis and treatment were delayed due to non-specific clinical manifestations and no identifiable metastasis observed on imaging.CONCLUSION Clinicians should pay attention to gastrointestinal metastasis of breast cancer,especially invasive lobular carcinoma of the breast.

sLe^(x) expression in invasive micropapillary breast carcinoma is associated with poor prognosis and can be combined with MUC1/EMA as a supplementary diagnostic indicator

Objective: Mucin 1(MUC1/EMA) and sialyl Lewis X(sLe^(x)) indicate polarity reversal in invasive micropapillary carcinoma(IMPC). The purpose of this study was to evaluate the expression of MUC1/EMA and sLe^(x) and to assess their diagnostic and prognostic value in patients with IMPC.Methods: The expression of sLe^(x) and MUC1/EMA in 100 patients with IMPC and a control group of 89 patients with invasive ductal carcinoma not otherwise specified(IDC-NOS) were analyzed with IHC. Fresh tumor tissues were collected from patients with IMPC or IDC-NOS for primary culture and immunofluorescence analysis.Results: The rate of nodal metastasis was higher in patients with IMPC than those with IDC-NOS, and IMPC cells tended to express more sLe^(x) and MUC1/EMA in the cytomembranes(the stroma-facing surfaces of the micropapillary clusters) than IDC-NOS cells. In IMPC, high cytomembrane expression of sLe^(x), but not MUC1/EMA, indicated poor prognosis. In addition, among the 100 patients with IMPC, 10 patients had sLe^(x)+/EMA-expression patterns, and 8 patients had sLe^(x)-/EMA+ expression patterns. The primary IMPC cells were suspended, non-adherent tumor cell clusters, whereas the primary IDC cells were adherent tumor cells. Immunofluorescence analysis showed that MUC1/EMA and sLe^(x) were co-expressed on the cytomembranes in IMPC cell clusters and in the cytoplasm in IDC-NOS cells.Conclusions: sLe^(x) can be used as a prognostic indicator and can be combined with MUC1/EMA as a complementary diagnostic indicator to avoid missed IMPC diagnosis.

Vascular endothelial growth factor and microvessel density for detection and prognostic evaluation of invasive breast cancer

Objective The purpose of this study was to evaluate the distribution of vascular endothelial growth factor （VEGF） and CD105-microvessel density （MVD）in invasive breast carcinomas. We also aimed to analyze the relationship between VEGF and MVD expression with other standard prognostic parameters associated with invasive breast cancer, such as size, grade, stage of the cancer, metastases, and tumor recurrence. Methods immunohistochemistry via the Ultra SensitiveTM S-P method was used to detect VEGF and MVD expression in 128 cases of invasive breast carcinoma. Specimens were evaluated for CD105 expression. Positively stained microvessels were counted in dense vascular loci under 400x magnification, MVD in the peripheral area adjacent to the lesion and in the central, area within the lesion in invasive breast carcinomas and benign leisions groups were also assessed. Fifty cases of benign breast disease tissue were selected as the control group. Results Results showed that 64.1% of invasive breast cancer samples were VEGF-positive, higher than in benign breast disease tissue （22.0%, P 〈 0.05）. There was a positive correlation between VEGF overexpression and histological grade, lymph node metastasis, and distant metastasis of invasive breast cancer. VEGF expression was not related to age or size of the tumor （P 〉 0.05）. MVD of the peripheral area adjacent to the lesion was significantly higher than those central area within the lesion in both invasive breast cancer and benignbreast disease groups （P 〈 0.01 for each group）. There were significant differences in the mean CD105-MVD, between invasive breast tumors with a histological grade of Ⅰ or Ⅱ and grade Ⅲ; between tumors with lymph node or distant metastasis; and between patients with or without recurrence （P 〈 0.05）. However, there was no difference in the mean MVD between the two age groups （≤ 50 years vs. 〉 50 years） or the two tumor diameter groups （〈 2 cm vs. 〉 2 cm）, P 〉 0.05. Conclusion Overexpression of VEGF and MVD may be important biological.markers for invasion and lymph node and distant metastases of invasive breast cancer. Combined detection of the two tumor markers could provide better prognostic monitoring for disease recurrence and metastasis, as well as aid with clinical staging of breast tumors. Prediction of the risk for metastasis and recurrence, as well as recurrence patterns based on VEGF and MVD post-surgery, could aid design of better follow-up regimens and appropriate treatment strategies for breast cancer patients.

Immunohistochemical analysis of 8 biomarkers on tissue microarray (TMA) of 46 Moroccan invasive breast carcinoma

Aim of the study: Immunohistochemical evaluation of hormone receptors, Her2/neu, CK5/6, E-cadherin, beta-catenin, p53 and PTEN on Tissue Micro Array (TMA) of 46 Moroccan invasive breast carcinomas. Materials and Methods: The cases comprised 40 invasive ductal carcinomas, 4 invasive lobular carcinomas, 1 mixed carcinoma and 1 invasive colloid carcinoma. TMA paraffin blocs were prepared with the Beecher manual arrayer and immunostaining was performed using standard immunoperoxidase techniques. Results: 58.69% of the cases were ER positive. 43.18% (19/44) were triple negative breast cancers (TNBC) of which 15.78% (3/19) were of the basal phenotype expressing CK5/6. On the other hand, 72.22% (13/18) of the TNBC cases were IDC grade 3. Of the 18 IDC grade 3, 22.22% (4/18) were CK5/6 positive. 41.30% and 10.86% of the cases showed reduced expression of E-cadherin and beta-catenin respectively. Beta-catenin nuclear and cytoplasmic staining was noted in 20% and 97.82% respectively. p53 was overexpressed in 10.86% of the cases whereas PTEN loss or reduced expression was noted in 86.95% of the cases. Conclusion: The aim of our study was to introduce TMA technique in our hospital which is considered a reference institution for cancer in Morocco. Although no statistical study was performed to look for any significance of the results obtained, we found good correlation with some of the data in the literature. To determine the molecular characteristics, if any, of the Moroccan patient, larger multidisciplinary and prospective studies would be interesting in the aim to personalize therapeutic decisions.

Metastatic Lobular Carcinoma of the Breast Presenting with Small Bowel Metastases:Case Report and Literature Review

Introduction: Invasive lobular carcinoma (ILC) is the second most common histologic type of breast cancer, representing 5% to 15% of invasive tumors. ILC tends to spread to bones, lungs, central nervous system, reproductive organs, and the gastrointestinal tract (GI tract). The most commonly affected organs in the GI tract are the stomach, small intestine, followed by colon and rectum. Case presentation: A 78-year-old woman who was referred to our institution after having a bowel obstruction that required a diagnostic laparoscopy where they identified an obstructing ulcerative lesion in the distal ileum that was managed with a segmental bowel resection. Pathology report showed an invasive lobular breast carcinoma that occluded 90% of the bowel lumen. A PET/CT scan revealed a left breast tumor with increased metabolism. The patient was staged as a clinical cT4b, cN0, cM1 left breast invasive lobular carcinoma (ER/PgR positive, HER-2 negative). She was managed with endocrine therapy with Letrozole (an eight-week course). A follow-up PET/CT showed a peritoneal hypermetabolic nodule adjacent to the previous ileal anastomosis. The lesion decreased in size and metabolic activity. In a multidisciplinary fashion, the endocrine therapy was extended for another three months. Another follow-up PET/CT scan was performed three months after the identification of the peritoneal implant that showed that the nodule increased in size and in metabolism. The lesion continued to decrease significantly in size and became metabolically inactivity. Due to the good breast response and the possibility that the ileal nodule could be a granuloma, she underwent an exploratory laparoscopy with excision of the peritoneal nodule, and a modified left radical mastectomy with immediate breast reconstruction (complex wound closure). The final pathology report of the nodule was negative for malignancy. She continued on endocrine therapy and underwent whole breast irradiation four weeks after the operation. Currently, she is free of disease with no evidence of local, regional, or distant recurrence, and she is still on endocrine therapy. Discussion: The time interval between primary breast cancer and gastrointestinal involvement may range from synchronous presentation to as long as 30 years. The clinical manifestations in GI lobular breast cancer metastasis may range from non-specific complaints to acute GI symptoms, such as a bowel obstruction. There are multiple controversies in the management of ILC. Systemic treatment should be initiated as soon as possible. Indications for postmastectomy radiotherapy are also controversial, given the propensity for multifocal/multicentric tumors and late recurrences, sometimes in atypical locations. Five years of postoperative adjuvant hormonal therapy is an option for women with poor prognosis. Remissions are observed in 32% to 53% of patients. Conclusion: Metastatic lobular carcinoma of the breast has a wide range of clinical presentations. Patients with a history of breast cancer who present with new GI tumors should have these lesions evaluated for evidence of metastasis through histopathologic and immunohistochemical analysis, this will allow for appropriate management. Currently, breast cancer management involves a multidisciplinary approach including surgery, radiotherapy, and systemic medical therapy, and the treatment must be tailored to the patient’s needs.

Clinical and pathological characteristics of intraductal proliferative lesions and coexist with invasive ductal carcinomas

Objective： The purpose of this study was to study the clinical and pathological characteristics of breast intraductal proliferative lesions （IDPLs） and associated with invasive breast cancer. Methods： We reviewed 327 cases of breast intra- ductal proliferative lesions including 53 cases of usual ductal hyperplasia, 57 cases of atypical ductal hyperplasia, 89 cases of ductal carcinoma in situ, and 128 cases coexist with invasive ductal carcinomas. Cases of pure invasive cancer without intraductal proliferative lesions were excluded. The mult IDPLs biological parameters including the express of ER, PR, HER2, HIF-lo and Ki-67 detected by immunohistochemistry S-P method （n = 327） and the levels of CA153, TSGF, CA125 and CEA both in nipple discharge and serum （n = 179） measured with Electrochemiluminescence method and their relationship were studied, and 30 cases of normal pregnant women were compared with. Results： A single histologic subtype was present in 49.85% （163/327） of the cases, two subtypes in 33.03% （108/327）, and three in 17.13% （56/327）. The most common subtypes present were cribriform （43.12%, 141/327） and solid （38.53%, 126/327）, while the comedo （16.35%, 54/327）, and micropapillary （12.84%, 42/327） subtypes were less common. Comedo and solid were frequently found together for coexpres- sion as were micropapillary and papillary subtypes. However, Comedo subtype was much less likely to be found with papillary, cribriform or micropapillary subtypes. Additionally, comedo subtypes tend to be hormone receptor negative, Her2 positive and high-grade while the cribriform and solid subtype tends to be hormone receptor positive, Her2 negative and low grade. Papil- lary subtype was least likely to be associated with an invasive cancer. Furthermore, the nipple discharge and serum levels of CA153, TSGF, CA125 and CEA in coexist with invasive ductal carcinomas patients were significantly higher than those in the benign breast disease （pure intraductal proliferative lesions） and normal pregnant women （P 〈 0.01）. Additionally, the levels of CA153, TSGF, CA125 and CEA in nipple discharge were significantly higher than in the serum （P 〈 0.01）, and had a positive correlation with the Ki-67, grade, clinical stage, lymph node metastasis and tumor recurrence （P 〈 0.05）, and negative correla- tion with the level of ER and PR （P 〈 0.05）. The sensitivity of the four serum tumor markers in combination was only 69.77%, in contrast, the combined detection both in discharge and serum was 97.67%, and the negative predictive value was 99.03%. The sensitivity of combined detection both in nipple discharge and serum were significantly higher than other detection （P 〈 0.05）. Conclusion： IDPLs often present more than one histologic subtype and the most common subtypes are cribriform and solid, while comedo and micropapillary subtypes are less common. Our results suggest that the levels of CA153, TSGF, CA125 and CEA in nipple discharge were significantly higher than those in the serum, and is associated with HIF-le. The aberration of HIF-la may play a key role during oncogenesis and promote breast cellular transformation into malignancy, a finding useful for further understanding of tumorigenesis. Nipple discharge can be the earliest presenting symptom of breast cancer. The dynamic combined detection of the four tumor markers both in nipple discharge and serum are helpful to the stratification of preoperative patients and benefit to better prewarning markers for monitoring their recurrence and metastasis and clinical staging of tumors in clinic, but cannot increase the sensitivity of judging the patients with early breast cancer.

Expression of HIF-1α in breast cancer and precancerous lesions and the relationship to clinicopathological features

Objective： The aim of this study was to observe the expressions and clinical significance of HIF-1a in breast cancer and precancerous lesions, and analyze the relationship between the expressions and clinicopathological features in breast cancer. Methods： We analyzed the HIF-1a expression in 128 cases of invasive ductal carcinomas, 146 precancerous lesions patients including 89 cases of ductal carcinoma in situ and 57 cases of atypical ductal hyperplasia. 53 cases of usual ductal hyperplasia breast tissues were selected as a control group. The specimens were evaluated for HIF-1a, estrogen receptor （ER） ＆ progesterone receptor （PR）, epidermal growth factor receptor type 2 （HER2/neu） and Ki-67. Immunoreactivity was semi-quantitatively evaluated in at least 1000 cells examined under the microscope at 40 x magnification and recorded as the percentage of positive tumor cells over the total number of cells examined in the same area. The percentage scores were subsequently categorized. The express of HIF-1a and their relationship with multiple biological parameters including ER ＆ PR, HER2/neu and Ki-67, the biomarkers levels of CA153, CA125 TSGF, and CEA in blood serum and nipple discharge, histological grade, region lymph node metastasis, distant metastasis and recurrence on files were also assessed. Results： Compared with usual ductal hyperplasia, the positive expression rate of HIF-1a in atypical ductal hyperplasia, ductal carcinoma in situ and invasive ductal carcinomas group was significantly increased （P 〈 0.01）. The positive rates of HIF-1a in invasive ductal carcinomas were 68.75%, which were significantly higher than that in ductal carcinoma in situ （43.8%）, atypical ductal hyperplasia （31.6%）, usual ductal hyperplasia （9.4%; X2 = 13.44, 22.27, 52.79, respectively, P 〈 0.01）. Statistical analysis showed that difference of abnormal expression rate of HIF-1a between ductal carcinoma in situ and usual ductal hyperplasia （X2 = 18.37, P = 0.00）, atypical ductal hyperplasia and usual ductal hyperplasia （x2 = 8.14, P = 0.00） was significant （P = 0.00）. However, no significant difference in the positive expression rate of HIF-1a was found between atypical ductal hyperplasia and ductal carcinoma in situ tissue （X2 = 2.19, P = 0.14）. There was a significantly difference in the mean HIF-1a frequency between ER ＆ PR positive invasive ductal carcinomas group and negative group, epidermal growth factor receptor type 2 （HER2/neu） positive and negative groups, Ki-67 proliferation index 〈 14% and 〉 14% groups, histological grade （I ＋ II） and grade III invasive ductal carcinomas groups, with lymph node metastasis, distant metastasis and recurrence groups （P 〈 0.05） and without groups （P 〈 0.05）. However, there was not difference in the mean HIF-1a between age （〈 50 years vs 〉 50 years）, tumor diameter （〈 2 cm vs 〉 2 cm; P 〉 0.05）. The nipple discharge and serum levels of CA153, TSGF, CA125 and CEA in invasive ductal carcinomas HIF-1a positive patients were significantly higher than those in the negative patients （P 〈 0.05）. Conclusion： In breast cancer, HIF-1a expressibn was abnormally increased. The aberration of HIF-1a may play a key role during oncogenesis （atypical ductal hyperplasia or ductal carcinoma in situ） and promote breast cellular transformation into malignancy, a finding useful for further understanding of tumorigenesis. The abnormal expression of HIF-1a may be as an early event in the development of breast tumor. The over-expression of HIF-1a might be important biological markers for invasion, metastasis and recurrence of breast cancer.

Favorable Reproducibility of Ki-67-Labeling Index between Core Needle Biopsy and Surgical Materials in Mammary Carcinoma: Reproducibility Influenced by Hot Spots, a High Ki-67 Labeling Index, and the Total Length of Biopsy Material

Aims: The reproducibility of Ki-67 between core-needle biopsies and surgical materials has not been well documented in the literature, although the concordance affects the utility of the Ki-67 labeling index based on the core-needle biopsy materials, which indicates the need for preoperative chemotherapy. The aim of this study was to reveal the reproducibility of Ki-67 between both materials and the cause of discrepancies. Methods and Results: We analyzed 137 cases of invasive carcinoma of the breast and the compared Ki-67-labeling index between core-needle biopsy and surgical materials. The Ki-67-labeling index of biopsy and surgical specimens ranged from 1% to 85% (median: 13%) and 1% to 80% (median: 12%), respectively. The discrepancy of Ki-67-labeling ranged from 0% to 55% (median: 4%) and could be calculated by the tumor size, hot spots of surgical materials, a high Ki-67-labeling index based on the core-needle biopsy materials, and the total length of core needles, respectively. Conclusions: The concordance rate of the Ki-67-labeling index between core-needle biopsies and surgical materials was favorable, so we can use each Ki-67-labeling index of core-needle biopsies as a marker for preoperative chemotherapy. Factors affecting the index discrepancy were hot spots, a high Ki-67-labeling index, and the total length of biopsy material. Judgements on the subtypes and clinical procedures of invasive breast carcinoma could be made comprehensively based on not only the Ki-67-labeling index but also the existence of hot spots and histological grade.

Prognosis of lymphotropic invasive micropapillary breast carcinoma analyzed by using data from the National Cancer Database

Background:Invasive micropapillary carcinoma(IMPC)is an uncommon subtype of breast cancer.Previous studies of this subtype demonstrated a higher propensity for lymph node metastases as compared with invasive ductal carci-noma(IDC).The purpose of the present study was to determine the clinical characteristics,outcomes,and propensity for lymph node metastasis of patients with IMPC of the breast recorded in the National Cancer Database(NCDB).Methods:Records of patients with IMPC diagnosed between 2004 and 2014 were retrieved from the NCDB.Log-rank test was performed to evaluate associations of clinical characteristics with overall survival(OS).Cox proportional hazards model was used to determine variables associated with OS.Results:Overall,2660 patients with IMPC met the selection criteria;the 5-year OS rate was 87.5%and 24.9%of patients had nodal involvement at presentation.Patients with≥4 positive lymph nodes had shorter OS than node-negative patients,whereas patients with 1-3 positive nodes had similar OS to node-negative patients.Age<65 years,receipt of radiotherapy,and estrogen receptor positivity were also associated with prolonged OS.The benefit of radiotherapy was limited to IMPC patients undergoing lumpectomy;there was no benefit for the patients undergoing mastectomy(regardless of nodal positivity/negativity).Conclusions:Favorable prognostic factors of IMPC patients included age<65 years,<4 positive lymph nodes,receipt of radiotherapy,and estrogen receptor positivity.The results presented herein suggest a survival benefit asso-ciated with radiotherapy in IMPC treatment,though this may be limited to the patients treated with lumpectomy.

Roles of micro RNA-140 in stem cell-associated early stage breast cancer

An increasing body of evidence supports a stepwise model for progression of breast cancer from ductal carcinoma in situ(DCIS) to invasive ductal carcinoma(IDC). Due to the high level of DCIS heterogeneity, we cannot currently predict which patients are at highest risk for disease recurrence or progression. The mechanisms of progression are still largely unknown, however cancer stem cell populations in DCIS lesions may serve as malignant precursor cells intimately involved in progression. While genetic and epigenetic alterations found in DCIS are often shared by IDC, m RNA and mi RNA expression profiles are significantly altered. Therapeutic targeting of cancer stem cell pathways and differentially expressed mi RNA could have significant clinical benefit. As tumor grade increases, mi RNA-140 is progressively downregulated. mi R-140 plays an important tumor suppressive role in the Wnt, SOX2 and SOX9 stem cell regulator pathways. Downregulation of mi R-140 removes inhibition of these pathways, leading to higher cancer stem cell populations and breast cancer progression. mi R-140 downregulation is mediated through both an estrogen response element in the mi R-140 promoter region and differential methylation of Cp G islands. These mechanisms are novel targets for epigenetic therapy to activate tumor suppressor signaling via mi R-140. Additionally, we briefly explored the emerging role of exosomes in mediating intercellular mi R-140 signaling. The purpose of this review is to examine the cancer stem cell signaling pathways involved in breast cancer progression, and the role of dysregulation of mi R-140 in regulating DCIS to IDC transition.

Expression and clinical significance of E-cadherin, β-catenin and E-cadherin-catenins complex in breast cancer and precancerous lesions

Objective： The aim of our study was to observe the expressions and clinical Significance of E-cadherin, β-catenin and E-cadherin-catenins complex in breast cancer and precancerous lesions, and analyze the relationship between the expressions and clinicopathological features in breast cancer. Methods： Immunhistochemical UltraSensitiveTM S-P method was employed to detect the expression of E-cadherin, β-catenin and E-cadherin-catenins complex in 128 cases of invasive ductal carcinomas, 89 cases of ductal carcinoma in situ and 57 cases of atypical ductal hyperplasia, 53 cases of usual ductal hyperplasia breast tissues were selected as a control group. The express of E-cadherin, β-catenin and their relationship with mult biological parameters including histological grade, region lymph node metastasis, distant metastasis and recurrence on files were also assessed. Results： （1） The staining patterns character of E-cadherin, β-catenin and E-cadherin-catenins complex： In UDH breast tissues, E-cadherin and a-catenin were expressed on cell membrane of ductal and acinic cells, showing cellular contour and border among cells. The abnormal expression of the three proteins occurred in breast invasive ductal carcinomas, ductal carcinoma in situ and atypical ductal hyperplasia tissues, showing cytoplasmic or nuclear staining, decrease and loss of cytomembrane staining. （2） The abnormal expression rates of E-cadherin, β-catenin and E-cadherin-catenins complex in invasive ductal carcinomas were 53.91%, 65.63% and 81.25%, which were significantly higher than that in ductal carcinoma in situ, atypical ductal hyperplasia, usual ductal hyperplasia tissues （P 〈 0.01）. Compared with usual ductal hyperplasia breast tissues group, the abnormal expression rates of E-cadherin, β-catenin and E-cadherin-catenins complex were significantly decreased （P 〈 0.01） in the breast cancer group. However, there was no significance of the abnormal expression rate between ductal carcinoma in situ and atypical ductal hyperplasia tissues groups （X2 = 0.76, P = 0.38; x2 = 0.14, P = 0.70; x2 = 0.81, P = 0.37; X2 = 2.19, P = 0.14） （P 〉 0.05）. （3） There was a significantly difference in the mean E-cadherin, β-catenin and E- cadherin-catenins complex frequency between estrogen receptor ＆ progesterone receptor positive IDC group and negative group, epidermal growth factor receptor type 2 （HER2/neu） positive and negative groups, Ki-67 proliferation index 〈 14% and 〉 14% groups, histological grade （I ＋ II） and grade III invasive ductal carcinomas groups, with lymph node metastasis, distant metastasis and recurrence groups （P 〈 0.05） and without groups （P 〈 0.05）. However, there was no difference in the mean E-cadherin, β-catenin and E-cadherin-catenins complex frequency between age （_〈 50 years vs 〉 50 years）, tumor diameter （〈 2 cm vs 〉 2 cm） （P 〉 0.05）. Conclusion： In breast cancer, the expressions of E-cadherin, β-catenin and E-cadherin-catenins complex are abnormally decreased and are correlated with pathology grade, differentiation disturbance and metastasis. E- cadherin and β-catenin may be as the predictors for prognosis. Combined detection may improve accuracy and sensitivity of predicting metastasis and prognosis of breast Cancer.

An AAS Dependent Method for Quantitative Analysis of Essential Trace Elements from Blood Samples of Pakistani Female Breast Cancer Patients

Breast cancer is the second leading cancer in the world. The long-term exposure of some metallic compounds induces different forms of cancer, including breast cancer. Trace elements are essential metals for the physiological functions of the cell on a molecular level and also contribute in treatment of many diseases. The aim of study was to compare the level of essential trace elements, sodium, potassium, calcium, iron, and zinc in breast cancer patients with normal healthy adult women. Total forty-five patients (age range from 25 - 73 years) were included in this study and divided into three groups according to three different stages of breast cancer including tumor-II, tumor-III and tumor-IV. Blood was collected from all participants after taking history, clinical data and taking consent. However, about fifteen non-cancer healthy women in age range from 26 - 69 years were subjected to this study. The elemental concentrations were determined through atomic absorption spectrophotometer subsequent to microwave-induced acid digestion. The results of Na, K, Zn, Fe, Ca, were observed to decrease in blood samples of breast cancer patients as compared to non-cancer subjects. The results are reliable with other numerous literature reported studies, the efficiency, and deficiency of these trace metals may contribute an important role in the progress of breast cancer.