Risk-benefit analysis of preoperative breast MRI in patients with primary breast cancer.

AIM: To analyse and compare the risks and benefits of preoperative breast MRI (BMRI) in patients with primary breast cancer (PBC), and to determine the influence of mammographic breast density (BD) and histological tumour type (TT). MATERIALS AND METHODS: One hundred and nineteen patients who underwent preoperative bilateral breast MRI for staging of PBC during a 1-year period from July 2005 to August 2006 were prospectively evaluated. Changes in clinical management due to BMRI findings were recorded. MRI-detected lesions were correlated with histology. Additional MRI-detected malignant lesions and spared additional biopsies because of negative MRI in case of unclear ultrasound findings were determined as beneficial for the patient. Biopsies of benign MRI detected lesions were defined as disadvantageous. The influence of BD (ACR 1-4) and TT on the change in clinical management and patient benefit was evaluated. RESULTS: The findings of the BMRI examinations changed the clinical management in 48 patients (40.3%). Seventeen women underwent mastectomy instead of breast conservation, eight patients underwent extended excision, 21 additional lesions were clarified by MRI intervention, and two ultrasound-detected lesions were not biopsied because of negative MRI. Histologically malignant additional or extended biopsies (n=34) and two cases of spared biopsies resulted in 36 (30.3%) women who benefited from preoperative BMRI. Twelve patients (10.1%) had additional biopsies of MRI-detected benign lesions, and therefore, had an unfavourable outcome due to BMRI. The change in clinical management and patient benefit were independent of BD and TT (p>0.05). CONCLUSION: Preoperative BMRI was beneficial for 30.3% of 119 patients with PBC. The percentage of additional biopsies of benign lesions (10.1%) seems acceptable.

Cell blocks of breast FNAs frequently allow diagnosis of invasion or histological classification of proliferative changes.

Two major limitations of breast fine needle aspiration (FNA) compared with core needle biopsies (CNB) are the inability to determine whether a cancer is invasive and to classify proliferative lesions. We studied 40 consecutive "rapid cell blocks" from breast FNAs with surgical pathology follow-up to test whether cell blocks can overcome these limitations. Of 25 carcinomas, invasion could be identified in the cell block sections in 11 (44%). One cystosarcoma phyllodes was suspected based on the cell block sections. Cell blocks from 12 of 14 benign breast FNAs showed sufficient cells to assign a histologic diagnosis of no hyperplasia (1 case, confirmed on follow-up) and usual hyperplasia (11 cases; confirmed in eight of 11 on follow-up). Specific histologic diagnoses included intraductal papilloma (2 cases), and in situ lobular neoplasia (2 cases). Cell blocks complement smears and monolayers and appear to overcome major limitations of breast FNA.

Id-1 overexpression in invasive ductal carcinoma cells is significantly associated with intratumoral microvessel density in ER-negative/node-positive breast cancer.

The aim of this study is to investigate the possible role of inhibitor of DNA binding (Id-1) overexpression in human breast cancer. We examined Id-1 expression by immunohistochemistry in 263 human breast cancers, 15 in situ lesions and 248 invasive cancers to investigate the relationship between its expression and various clinicopathological factors. Id-1 expression was significantly higher in invasive ductal carcinoma than in in situ ductal carcinoma or other invasive cancer subtypes (P=0.029 and 0.006, respectively). We also examined the association between Id-1 expression and tumor angiogenesis by measuring microvessel densities (MVD). Regarding the endothelial cells of microvessels showed negative or very weak Id-1 expression, Id-1 overexpression was found to be significantly related to MVD (P=0.014). Furthermore, Id-1 overexpression was found to be significantly associated with higher MVD in the ER-negative and node-involved subgroups of breast cancer (P=0.040 and 0.046, respectively). These data indicate that Id-1 overexpression is significantly associated with tumor angiogenesis, especially in the ER-negative and node-positive subtypes of invasive breast cancer. Thus, Id-1 presents a possible therapeutic antitumor target molecule in ER-negative and node-positive breast cancer.

Expression and signaling activity of Wnt-5a/discoidin domain receptor-1 and Syk plays distinct but decisive roles in breast cancer patient survival.

PURPOSE: The loss of Wnt-5a, a G-protein-coupled receptor ligand, or Syk, an intracellular kinase, has in separate studies been associated with poor prognosis of breast cancer patients. Both proteins are involved in cell adhesion, a key event in epithelial cancer metastasis. Here, we have investigated whether Syk is part of the Wnt-5a/discoidin domain receptor-1 (DDR1) signaling pathway and if a signaling interaction of these proteins is important for breast cancer-specific survival. EXPERIMENTAL DESIGN: The signaling interactions between Wnt-5a/DDR1 and Syk were addressed in mammary cell lines. Their mRNA and protein levels and the respective clinical correlates were investigated in 94 cases of primary breast cancer. RESULTS: The expression of Wnt-5a and Syk correlated in four of five tumor cell lines. However, despite a constitutive association between Syk and the Wnt-5a-dependent adhesion receptor DDR1, we found no evidence of a Wnt-5a/DDR1-mediated activation of Syk. Instead, beta(1) integrins initiate the adhesion-induced activation of Syk. In tumors from breast cancer patients, the protein expression of Wnt-5a and Syk were differently regulated at the translational and transcriptional level, respectively. Analysis of breast cancer-specific survival revealed that the presence of Wnt-5a and Syk in primary tumors has good predictive value for a favorable outcome. Intriguingly, a simultaneous loss of both proteins did not reduce survival more than loss of either. CONCLUSIONS: Despite the difference in regulation of Wnt-5a and Syk protein expression and their lack of signaling interaction, our clinical data indicate that a favorable prognosis in breast cancer requires the expression and signaling activity of both.

Carcinogenesis and translational controls: TACC1 is down-regulated in human cancers and associates with mRNA regulators.

The three human TACC genes encode a family of proteins that are suspected to play a role in carcinogenesis. Their function is not precisely known; a Xenopus TACC protein called Maskin is involved in translational control, while the Drosophila D-TACC associates with microtubules and centrosomes. We have characterized the human TACC1 gene and its products. The TACC1 gene is located in region p12 of chromosome 8; its mRNA is ubiquitously expressed and encodes a protein with an apparent molecular mass of 125 kDa, which is cytoplasmic and mainly perinuclear. We show that TACC1 mRNA gene expression is down-regulated in various types of tumors. Using immunohistochemistry of tumor tissue-microarrays and sections, we confirm that the level of TACC1 protein is down-regulated in breast cancer. Finally, using the two-hybrid screen in yeast, GST pull-downs and co-immunoprecipitations, we identified two potential binding partners for TACC1, LSM7 and SmG. They constitute a conserved subfamily of Sm-like small proteins that associate with U6 snRNPs and play a role in several aspects of mRNA processing. We speculate that down-regulation of TACC1 may alter the control of mRNA homeostasis in polarized cells and participates in the oncogenic processes.

Minichromosome maintenance protein 2 is a strong independent prognostic marker in breast cancer.

PURPOSE: To test the hypothesis that prognostic information in breast cancer may be derived from an accurate assessment of epithelial cell cycle entry, as indicated by expression of minichromosome maintenance (MCM) proteins. MATERIALS AND METHODS: We used immunohistochemistry to examine the distribution of Mcm-2 in breast tissue. Power calculations based on a pilot study of 67 whole tissue sections led to selection of an independent 347-core breast carcinoma tissue microarray validation set. We tested for associations between Mcm-2 (and Ki-67) labeling index (LI) and various clinicopathologic parameters. RESULTS: Mcm-2 was expressed more frequently than the standard proliferation marker Ki-67 in whole tissue sections of normal breast (P =.0003) and breast carcinoma (P <.0001). In 221 assessable cores of invasive carcinoma, the Mcm-2 LI showed a positive association with tumor size (P =.002), mitotic index (P <.0001), histologic grade (P <.0001), and the Nottingham Prognostic Index (NPI) score (P <.0001). Using a cutoff value of 50%, Mcm-2 LI was associated with overall survival (P =.0007), disease-free interval (P =.0002), and with the development of regional recurrence (P =.011) and distant metastases (P =.0016). Cox regression analysis suggested that the Mcm-2 LI is a strong prognostic factor in breast cancer that is independent and superior to histologic grade, lymph node stage, and Ki-67 LI, but not the NPI score. CONCLUSION: Mcm-2 may be of utility as a prognostic marker to refine the prediction of outcome in breast cancer, for example when combined with parameters currently used in the NPI.

The predictive value of bcl-2, bax, bcl-xL, bag-1, fas, and fasL for chemotherapy response in advanced breast cancer.

PURPOSE: The purpose was to evaluate the utility of some bcl-2 family proteins fas and fasL as predictive indicators for chemotherapy response in advanced breast cancer. EXPERIMENTAL DESIGN: Between October 1994 and October 1997, 283 patients with advanced breast cancer were included in a multicenter randomized study comparing docetaxel (D) to sequential methotrexate and 5-fluorouracil (MF) after anthracycline failure. The response rates (complete response + partial response) were 42 and 21% in the D and MF arms, respectively (P < 0.001). In 126 patients, histological blocks of primary tumors were available for immunohistochemical analysis of bax, bcl-2, bcl-xL, bag-1, fas and fasL. RESULTS: Of the investigated factors, bag-1 correlated positively with bax, bcl-2, and fasL, and fasL correlated positively with fas and bax. None of these apoptosis-related factors was associated with a response to chemotherapy either in the whole patient population or in the D or MF arms. Interestingly, low bcl-2 expression was associated with shorter time to progression (P = 0.02) and shorter overall survival (OS; P = 0.001). High fasL expression showed a trend toward shorter OS. In multivariate backwards stepwise Cox analysis, in which histological grade and estrogen receptor status (ER) were also included, bcl-2 (P = 0.01) and fasL (P = 0.005) remained highly significantly associated with OS, whereas histological grade and ER lost their significance. CONCLUSIONS: None of the investigated apoptosis-related factors of primary tumor could predict the later response to either D or MF treatment. However, fasL and bcl-2 were strong prognostic factors. Patients who had tumors with high fasL and low bcl-2 expression had the shortest OS.

DNA hypomethylation is prevalent even in low-grade breast cancers.

Hypomethylation of some portions of the genome and hypermethylation of others are very frequent attributes of human cancer. We previously showed that cancer-associated DNA hypomethylation often involves satellite 2 (Sat2), the main DNA component of the large juxtacentromeric (centromere-adjacent) heterochromatin of chromosome 1. In this study, we compared methylation of Sat2 and centromeric satellite DNA (Satalpha) as well as overall genomic methylation in 41 breast adenocarcinomas of known tumor grade and stage, 16 non-neoplastic breast tissues (mostly fibroadenomas), and a variety of normal somatic tissue controls. The cancers were significantly hypomethylated at Sat2 relative to the fibroadenomas or normal somatic tissues and at Satalpha relative to the normal somatic tissues. However, unlike Sat2, Satalpha did not display significant differences in methylation between the cancers and the non-neoplastic breast tissues. Therefore, hypomethylation at Sat2 is a much better marker of breast cancer than is Satalpha hypomethylation. There was a significant association of Sat2 hypomethylation with global DNA hypomethylation in the cancers but not with tumor grade, stage, axillary lymph node involvement, or hormone receptor status. Extensive cancer-associated hypomethylation of juxtacentromeric satellite DNA and global DNA hypomethylation were common even in grade-1 or stage-1 carcinomas, which suggests that demethylation of the genome is an early event in breast carcinogenesis.

An evaluation of the prognostic significance of vascular endothelial growth factor in node positive primary breast carcinoma.

Angiogenesis is intimately related to the growth and progression of tumours and must be induced to facilitate growth beyond a minimum size. It has been implicated in the development of metastases and survival in breast carcinoma. VEGF is a cytokine that plays an important role in angiogenesis. Its expression is increased in solid tumours during induction of angiogenesis and it has been implicated as a prognostic marker in patients with node negative breast carcinoma. We studied VEGF expression, in a series of patients with node positive breast carcinoma and examined histopathological parameters of the tumour and the prognostic value of VEGF expression. Specimens from 108 cases of node positive breast cancer were stained for VEGF using an antibody suitable for use on formalin fixed tissue. VEGF staining was cytoplasmic and was scored by intensity and the percent positive cells. Patients with positive VEGF staining (n=48) were compared with patients with negative VEGF staining (n=60). Demographic criteria were similar in both groups. Only one (12%) patient with lobular carcinoma and one (14%) patient with medullary carcinoma expressed VEGF compared with 46 (49%) patients with ductal carcinoma (NOS). DCIS was present in 60 tumours. There was a strong correlation between staining in DCIS and the adjacent invasive tumours. There was no significant association between VEGF staining and T stage, tumour size or the number of positive lymph nodes. VEGF expression had no prognostic significance either for disease-free or overall survival in patients with node positive disease. This study failed to support a role for VEGF as a prognostic marker in patients with node positive breast carcinoma.

Antioxidative response for nitric oxide production in breast carcinoma.

Our aim was to study the role of oxidant and nitric oxide (NO)-derived damage in human breast carcinomas by studying the expression of nitrotyrosine in tumor tissue. To elucidate whether nitrotyrosine levels associate with NO synthesis and have an effect on antioxidative enzyme response or angiogenesis, we also studied the expression of all three nitric oxide synthases (NOS), manganese superoxide dismutase (MnSOD), catalase and vascular endothelial growth factor (VEGF) in the tumors. A large set of breast cancer samples in microarray blocks were stained with antibodies to nitrotyrosine, iNOS, eNOS, nNOS, MnSOD, catalase and VEGF. Nitrotyrosine expression was seen in 56% of the cases. There was a close relationship between the expression of nitrotyrosine and all three NOS isoforms (for all p<0.0005), catalase (p<0.0005) and MnSOD (p=0.043), in addition enlarged tumor size was in association with high nitrotyrosine (p=0.046), eNOS (p=0.005) and VEGF (p=0.046) levels. Our findings suggest that NO-derived oxidative damage takes place and its level associates to NOS synthesis in human breast cancer. The current results also imply the attempt of cells to hedge against effects of NO by increasing their MnSOD and catalase expression.

Breast tumour growth inhibition in vitro through the combination of cyclophosphamide/metotrexate/5-fluorouracil, epirubicin/cyclophosphamide, epirubicin/paclitaxel, and epirubicin/docetaxel with the bisphosphonates ibandronate and zoledronic acid.

Breast cancer has a significant capacity to metastasize to bone. Bisphosphonates are the standard treatment for hypocalcaemia of malignancy (HCM), which is a common complication of bone metastasis. The combination of bisphosphonates with standard anticancer drugs such as paclitaxel or tamoxifen results in a synergistic apoptotic effect greater than that produced by either single agent alone. Potential antitumour effects in vitro of the two bisphosphonates zoledronic acid (Zol) and ibandronate (Ib) (each at 30 microM) combined with different anticancer drug combinations: cyclophosphamide/metotrexate/5-fluorouracil (CMF), epirubicin/cyclophosphamide (EC), epirubicin/paclitaxel (ET), and epirubicin/docetaxel (EDoc) were investigated using ATP-cell viability assay (ATP-CVA). Twenty cases of female primary, invasive breast cancer were assessed. Ibandronate and zoledronic acid alone showed an inhibitory effect on breast cancer tumour cells in vitro. The breast tumour growth inhibition effect for those two drugs amounted to 22 and 25% respectively. Inhibitory effects were clearly visible for all four combinations of anticancer drugs together with both bisphosphonates. Combinations of anticancer drugs with zoledronic acid seem to be more effective with respect to tumour growth inhibition than combinations with ibandronate.

Primary bilateral mucosa-associated lymphoid tissue lymphoma of the breast with atypical ductal hyperplasia and localized amyloidosis. A case report and review of the literature.

Primary non-Hodgkin lymphoma of the breast is a rare disease. Primary mucosa-associated lymphoid tissue lymphoma is even rarer, and bilateral involvement is exceptional. We describe a case of primary bilateral breast mucosa-associated lymphoid tissue lymphoma with bilateral atypical ductal hyperplasia and bilateral localized amyloidosis in a 64-year-old woman with a history of arthritis and systemic lupus erythematosus and its clinical, histologic, and immunohistochemical features. Microscopic examination of the breast lesion showed dense periductal and perilobular small and plasmacytoid lymphocytes with eosinophilic amyloid in the vessels and the stroma. Bilateral single foci of atypical ductal hyperplasia were also noted. Fine needle aspiration showed small and large lymphocytes and plasma cells. Molecular analysis demonstrated a heavy chain immunoglobulin H gene rearrangement. Flow cytometry studies showed an abnormal B-cell population. The combined histologic, paraffin immunohistochemistry, flow cytometry, and molecular results were considered diagnostic for low-grade mucosa-associated lymphoid tissue lymphoma. The patient underwent bilateral local breast radiation without other organ or site involvement.

Uptake and washout of 99mTcV-dimercaptosuccinic acid and 99mTc-sestamibi in the assessment of histological type and grade in breast cancer.

This study was performed to investigate the relationship between histological type and grade, with the uptake and washout of 99mTc-hexakis-2-methoxyisobutylisonitrile (99mTc-sestamibi, 99mTc-MIBI) and 99mTcV-dimercaptosuccinic acid (99mTcV-DMSA) in breast cancer. Forty-five patients with histologically proven breast cancer had previously been referred for 99mTcV-DMSA and/or 99mTc-MIBI scintimammography. Twenty-five of them underwent both 99mTcV-DMSA and 99mTc-MIBI scintigraphy in a double phase study. Lateral prone and anterior supine images were acquired at 15 and 60 min after administration of 740-925 MBq of each radiotracer. Uptake ratios and retention index were calculated and correlated with histology and grade of malignancy. Histology showed eight different histotypes: 77.7% were infiltrating ductal or lobular carcinomas. Mammography was definitely positive in 32/45, indeterminate in 10 and negative in three cases (sensitivity 71%). 99mTcV-DMSA was true positive in 37/40 (sensitivity 92.5%) and 99mTc-MIBI in 28/30 (sensitivity 93.3%) breast cancers. Uptake ratios were significantly higher in ductal than in lobular carcinomas on 99mTcV-DMSA and 99mTc-MIBI scintigrams at early and delayed phases. Grade II carcinomas had significantly lower values of retention index (rapid washout) than grade III carcinomas. This finding was statistically significant only on 99mTc-MIBI scans and was observed in ductal and lobular carcinomas. The retention index did not show any significant difference between ductal and lobular carcinomas. Uptake ratios were also not statistically different between grade II and III cancers. It is concluded that 99mTc-MIBI and 99mTcV-DMSA uptake in breast cancer is probably related to histological type and may distinguish ductal from lobular carcinomas. To a certain degree, the washout rate may reflect the histological grade, but since grade is not the only factor influencing this phenomenon it should be explored further in conjunction with other parameters by multivariate analysis in order to clarify eventual indirect correlations.

Breast cancer: diagnosis, treatment and prognosis.

This article reviews staging of breast cancer and treatment protocols for the disease, then examines several different types of breast cancer. Each type is described in terms of its mammographic, sonographic and histologic appearance, along with its treatment and prognosis. The author concludes with a discussion of magnetic resonance imaging's role in breast cancer detection and treatment planning.

Role of sentinel lymph node biopsy in early breast cancer.

Current literature has suggested that sentinel lymph node biopsy may replace axillary dissection as the nodal staging procedure of choice in early breast cancer. The aim of this study is to evaluate the effectiveness and accuracy of sentinel lymph node biopsy using methylene blue dye in predicting axillary nodal status in early breast cancer with clinically impalpable axillary lymph nodes. In the period between June 2005 and May 2009, 50 patients with early breast cancer and clinically impalpable axillary lymph nodes, underwent sentinel lymph node biopsy using methylene blue dye followed by completion of axillary dissection in the same setting after taking a written consent from the patients. Of the included 50 patients, sentinel lymph node biopsy was successful in 48 patients (96.0%). Accuracy of sentinel lymph node biopsy was 95.8%, sensitivity was 90.0%, false negative rate was 6.7%, negative predictive value was 93.3%.

Pathology of invasive breast disease.

Invasive breast cancers constitute a heterogeneous group of lesions. Although the most common types are ductal and lobular, this distinction is not meant to indicate the site of origin within the mammary ductal system. The main purpose of the identification of specific types of invasive breast carcinoma is to refine the prediction of likely behavior and response to treatment also offered by the other major prognostic factors, including lymph node stage, histologic grade, tumor size, and lymphovascular invasion.

Decreasing trend of tumor size and downstaging in breast cancer in Iran: results of a 15-year study.

The aim of this cross-sectional study was to show the characteristics of breast cancer across a period of 15 years according to pathological records in Tehran, Iran. In the year 1985, a 20-year study was designed and developed in five major hospitals in Tehran to study the burden and characteristics of breast cancer in Iran. This study is based on the data collected from 1986 through 2000. SPSS version 13 was used for statistical analysis. In this study, 1612 female breast cancer records were reviewed. The mean age of patients was 47.95+/-12.42 years with a median of 47 years. Over the study period, the proportion of tumors diagnosed at T2 increased with a decline in the proportion of T3 cases. Similarly, the percentage of stage II cases at diagnosis increased, whereas stage III decreased. We detected a decrease in tumor size and downstaging of female breast cancer in Tehran, Iran. This can be attributed to the overall improvement in the level of health in Iran and also educational activities that teach women how to perform breast self-exam and when and why to ask for breast examination.

The adjacent vessel sign on breast MRI: new data and a subgroup analysis for 1,084 histologically verified cases.

OBJECTIVE: The adjacent vessel sign (AVS) is a descriptor for differentiating malignant from benign breast lesions on breast MRI (bMRI). This investigation was designed to verify the previous reports on the diagnostic accuracy of AVS and to assess correlation between AVS, histopathological diagnosis, lesion size and lesion grade. MATERIALS AND METHODS: This study was approved by the local ethical committee. Experienced radiologists evaluated 1,084 lesions. The exclusion criteria were no histological verification after bMRI and breast interventions that were done up to one year before bMRI (surgery, core biopsy, chemo- or radiation therapy). The native and dynamic contrast-enhanced T1-weighted series were acquired using standardized protocols. The AVS was rated positive if a vessel leading to a lesion could be visualized. Prevalence of an AVS was correlated with the lesions' size, grade and histology using Chi-square-tests. RESULTS: The AVS was significantly associated with malignancy (p < 0.001; sensitivity: 47%, specificity: 88%, positive-predictive-value [PPV]: 85%). Malignant lesions > 2 cm more often presented with an AVS than did those malignant lesions < 2 cm (p < 0.0001; sensitivity: 65%, PPV: 90%). There was no correlation of the AVS with the tumor grade. The prevalence of an AVS didn't significantly differ between invasive lobular carcinomas versus ductal carcinomas. In situ cancers were less frequently associated with an AVS (p < 0.001). CONCLUSION: The adjacent vessel sign was significantly associated with malignancy. Thus, it can be used to accurately assess breast lesions on bMRI. In this study, the AVS was particularly associated with advanced and invasive carcinomas.