Prognostic value of vascular density and cell proliferation in breast cancer patients (original) (raw)
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IP Innovative Publication Pvt. Ltd., 2018
Introduction: Microvessel density is used in assessment of the angiogenesis, a prognostic factor for many malignancies. While it has extensively been studied in cancers of lung, brain, colon, prostate as well as in melanoma, but, there are scanty reports for the study of microvessel density of breast carcinoma. Aim: Present study was aimed to find the correlation of microvessel density with tumor type, tumor size, histological grade and lymph node status. Study Design: The biopsy specimens, from 38 women diagnosed for carcinoma breast who underwent modified radical mastectomy and subsequently were examined with routine H&E stain and immunoperoxidase for CD-31 marker. Micro vessel density was measured as micro vessel count/mm2 on all the specimens of breast carcinoma. Micro vessel density correlated well with tumor size, tumor type, histological grade and lymph node status. Results: micro vessel density had significant positive correlation with tumor type, histological grade, and lymph node status (p<0.05). Conclusion: Estimation of micro vessel density could be used as the prognostic marker for breast carcinoma. Keywords: Carcinoma of breast, Micro-vessel density (MVD), Histological grade, Lymph node status, Tumor type and tumor stage.
Histopathology, 2004
Microvessel density compared with the Chalkley count in a prognostic study of angiogenesis in breast cancer patients Aims: Evaluation of angiogenesis by intratumoral vessel profiles can be performed by different methods. The aim of this study was to investigate the prognostic value of estimates obtained by the intratumoral microvessel density (MVD) method and then to compare with corresponding estimates obtained by the Chalkley method. Methods and results: A total of 330 patients treated for primary, unilateral, invasive breast carcinoma were included. The median follow-up time was 14 years and 4 months. The microvessels were immunohistochemically stained by antibodies to CD34. MVD was not significantly correlated with any clinicopathological variables. By univariate analysis, MVD showed no prognostic value with regard to recurrence-free survival (RFS) or overall survival (OS), while the Chalkley count had significant prognostic value (P < 0.0001; RFS and OS). In the Cox multivariate analysis, MVD had no prognostic impact {median HR [confidence interval (CI)] was 0.93 [0.66, 1.32] for RFS; and HR [CI] was 0.86 [0.62, 1.19] for OS}, while the Chalkley count [median HR (CI) was 2.12 (1.48, 3.06) for RFS; and HR (CI) was 1.71 (1.23, 2.37) for OS] provided independent prognostic value when adjusted for age, menopausal status, axillary lymph node status, tumour size, histological grade, adjuvant systemic treatment and radiation therapy. In comparing the results obtained by MVD in our study with those from other published studies we find good agreement. Conclusions: The Chalkley count technique seems to be preferable for estimating angiogenesis with regard to the prognostic stratification of breast cancer patients, based on its strong prognostic impact, and acceptable reproducibility.
Breast Cancer Research and Treatment, 1995
In the present study we update previous results on the prognostic value of intratumoral microvessel density (IMD), determined immunocytochemically using the monoclonal antibody CD-31 and a standard streptavidin-immunoperoxidase technique, published in theJ Clin Oncol 12:454–466, 1994. This study was undertaken in those 211 node-negative breast cancer (NNBC) cases of that series of which we had pathological material available to determine all the prognostic indicators. The median period of follow-up has been extended to 78 and 80 months for relapse-free survival (RFS) and overall survival (OS), respectively, and new biological indicators (i.e. Ki-67 labeling and 67 kDa laminin receptor expression) were included in the analysis. The main results obtained are:i) a confirmation that IMD is not associated with the other biological markers studied, i.e. expression of p53 protein, c-erbB-2 protein, 67 kDa laminin receptor, and cell kinetics; IMD was weakly associated only with histological grade (p=0.053);ii) IMD remains a highly significant prognostic factor for RFS and OS (p<0.0001 and p=0.018, respectively) in univariate analysis;iii) in multivariate analysis on RFS, IMD (likelihood ratio test (LRT)=30.16; p<0.0001), 67 kDa laminin receptor (LRT=9.80; p=0.0017), the IMD/67 kDa laminin receptor interaction (LRT=8.62; p=0.0033), tumor size (LRT=8.56; p=0.0034), and p53 protein (LRT=4.96; p=0.025) are significant and independent prognostic indicators. For OS, only tumor size (LRT=8.34; p=0.0038), menopausal status (LRT=5.16; p=0.023), p53 protein (LRT=4.37; p=0.036), and IMD (LRT=4.05; p=0.044) retain a significant and independent prognostic value. The results of this study confirm the prognostic importance on RFS of the variables previously tested, but not of peritumoral lymphatic vessel invasion. A novel finding is that 67 kDa laminin receptor and the IMD/67 kDa laminin receptor interaction are also significant and independent variables. For OS, the results confirm that both IMD and tumor size are significant and independent variables. With prolonged follow-up the novel finding that emerges is the prognostic importance of menopausal status and p53 protein. This new information could be useful for a more accurate selection of high-risk NNBC patients who require careful follow-up and may benefit from adjuvant therapy.
British Journal of Cancer, 2007
In contrast to early breast cancer, the prognostic effect of tumour angiogenesis in tumours with advanced axillary spread has been less studied. We retrospectively analysed the effect of microvessel density (MVD) and vascular endothelial growth factor (VEGF) by immunohistochemistry on the outcome of 215 patients treated uniformly within prospective trials of high-dose chemotherapy for 4-9 and X10 positive nodes, and followed for a median of 9 (range 3 -13) years. Microvessel density was associated with epidermal growth factor receptor (EGFR) expression (Po0.001) and tumour size (P ¼ 0.001). Vascular endothelial growth factor overexpression (51% of patients) was associated with overexpression of EGFR (P ¼ 0.01) and HER2 (Po0.05), but not with MVD (P ¼ 0.3). High MVD was associated with worse relapse-free survival (74 vs 44%, Po0.001) and overall survival (76 vs 44%, Po0.001). Vascular endothelial growth factor overexpression had no effect on outcome. Multivariate analyses showed a prognostic effect of MVD independently of other known prognostic factors in this patient population. In conclusion, tumour angiogenesis, expressed as MVD, is a major independent prognostic factor in breast cancer patients with extensive axillary involvement. ER ¼ oestrogen receptors; nodal ratio ¼ number of involved nodes/number of dissected nodes; PR ¼ progesterone receptors. a ER/PR ¼ '1' if positive and ¼ '0' if negative. b Predictive score ¼ (nodal ratio  3.05)+(tumour size  0.15)ÀER/PR  1.15.
The Journal of Pathology, 1995
In some studies of breast cancer, quantitation of immunohistochemically highlighted microvessel 'hot spots' has been shown to be a powerful prognostic tool. However, the antibody used, the number and size of the 'hot spots' assessed, and the stratification of patients into high and low vascular groups vary between studies. Furthermore, little is known about the relationship between microvessel density and other vascular parameters. These uncertainties and the laborious nature of the technique make it unsuitable for diagnostic practice. Both manual and computerized image analysis techniques were used in this study to examine the relationship between microvessel density and the vascular parameters in different sized microscopic fields in a pilot series of 30 invasive breast carcinomas. Automated pixel analysis of immunohistochemical staining, Chalkley point counting, and observer subjective vascular grading were also assessed as more rapid methods of measuring tumour vascularity. A Chalkley count was also performed on a further 2 1 1 invasive breast carcinomas. Significant correlations were observed between manual microvessel density and luminal perimeter (r=0.6, P=0.0004), luminal area (~0 . 5 6 , P=0.002), and microvessel number ( r z 0 . 5 7 , P=0.0009) by computerized analysis. There were also significant correlations between the microscopic hot spots of 0.1 55 mm2 and 0.848 rqm2 for microvessel number (rz0.81, P<0.00005), luminal perimeter (r=0.78, P<0.00005), and luminal area (rx0.65, P=O.OOOl). In addition, a significant correlation was observed between microvessel density and both subjective vascular grade (P=0.002) and Chalkley count (P=O.OOOl). A significant reduction in overall survival was observed between patients stratified by Chalkley count in both a univariate (P=0.02) and a multivariate (P=0.05) analysis in the 21 1 invasive breast carcinomas. These findings show that Chalkley counting is a rapid method of quantifying tumour angiogenesis and gives independent prognostic information which might be useful in diagnostic practice.
Tumor microvessel density and prognosis in node-negative breast cancer
International Journal of Cancer, 2000
Microvessel density (MVD) of breast cancer is widely regarded as a prognostic factor, but results from studies on the most important case series have produced conflicting results. The present study was performed with confirmatory intent to define the prognostic relevance of MVD on a series of 378 node-negative-breast-cancer patients, much larger than any other series previously analyzed. Microvessels were stained using Factor-VIII antibody and an immunoperoxidase reaction. MVD was determined independently by 2 observers according to Weidner's methods. In parallel, cell proliferation was evaluated as S-phase fraction and determined according to the 3H-thymidine-labeling index method (TLI). Estrogen and progesterone receptors were quantitatively assessed using the dextran-charcoal technique. Tumor MVD varied greatly from tumor to tumor (2 to 232 MV/mm 2 ) and was unrelated to patient age and menopausal status, or to tumor size, histology and steroid-receptor status. A significant (p ؍ 0.004) but weak inverse correlation (r s ؍ ؊0.188) was observed with cell proliferation. Univariate analysis using 40 MV/mm 2 as cut-off showed an inverse relation with 5-year relapse-free survival (82% vs. 71%, p ؍ 0.018). This finding was limited to very small tumors, slowly proliferating tumors and ER-negative tumors. Multivariate analysis identified tumor size and TLI, but not MVD, menopausal status or ER as independent prognostic factors.
Tumour microvessel density as predictor of chemotherapy response in breast cancer patients
British journal of cancer, 2002
The aim of this study was to evaluate the predictive value of intratumoural microvessel density in breast cancer. We studied immunohistochemically primary tumours of 104 patients with metastasised breast cancer who took part in a randomised multicentre trial comparing docetaxel to sequential methotrexate and 5-fluorouracil. Vessels were highlighted with factor VIII staining and counted microscopically. Microvessel density was compared with clinical response to chemotherapy and patient survival. The microvessel density of the primary tumour was not significantly associated with patient's response to chemotherapy, time to progression or overall survival in the whole patient population or in the docetaxel or methotrexate and 5-fluorouracil groups. However, disease-free survival was longer in patients with low microvessel density (P=0.01). These findings suggest that microvessel density of the primary tumour cannot be used as a predictive marker for chemotherapy response in advanced...
Evaluation of Vascular Proliferation in Molecular Subtypes of Breast Cancer
in Vivo, 2018
Background: Angiogenesis plays a pivotal role in tumor development. Although microvessel density (MVD) is the most common method used for evaluation of angiogenesis, it has several limitations. Our aim was to evaluate MVD and microvessel proliferation (MVP) in a series of invasive breast carcinomas and analyze whether angiogenesis is influenced by the molecular phenotype of each tumor. Materials and Methods: We examined vascular proliferation using double immunohistochemistry (CD34/Ki67) in a series of 54 invasive breast carcinomas and compared the results with standard MVD, molecular subtypes and other classical parameters. Results: Increased MVD and MVP values were recorded in basal-like subtype, but only the MVP value reached significance among this group of patients (p=0.0001). For all cases combined, increased MVP was significantly correlated with negative estrogen receptor (ER) status (p=0.010) and higher histological grade (p=0.002). Conclusion: MVP more accurately reflects the state of angiogenesis in breast cancer, compared with standard MVD. Vascular proliferation was associated with aggressive tumor features, indicating its contribution to tumor progression. The strong association between vascular proliferation and basal-like tumors suggests that this marker can be used for stratification of patients who might benefit from therapies targeting angiogenesis. Angiogenesis is considered a hallmark of cancer and a key requisite in their growth, invasion and progression (1). In 1971, Folkman suggested that tumors can be treated by inhibiting their vascularization (2). It is well known that tumors cannot exceed 2-3 mm without vascular support (2), thus, anti-angiogenic therapy is an attractive target for angiogenesis-dependent tumors such as breast cancer. Microvessel density (MVD) is the most widely method used for evaluation of angiogenesis, based on counting the vessels in the most vascularized areas of the tumors, namely 'hot spots'. This method was developed by Weidner and coworkers in 1991, who demonstrated that MVD influences the prognostic of patients with breast cancer (3, 4). Since then, many other researchers have investigated the role of MVD in breast tumors, but the results are contradictory. However, MVD has some limitations, as it cannot predict the response to therapy or the treatment efficacy (5). Recent studies showed that microvessel proliferation (MVP), defined as the average number of vessels exhibiting co-expression of an endothelial and a proliferation marker, is a better indicator of angiogenesis compared with MVD (5-7). In prostate and endometrial carcinomas, microvessel proliferation was found to be a more reliable prognostic marker compared with standard MVD (5-7). With this background, the aim of the present study was to evaluate vascular proliferation (CD34/Ki67 co-expression) and standard MVD in a series of invasive breast carcinomas, in accordance with the molecular classification. The results were compared by classical clincopathological parameters. Materials and Methods The present study included 54 female patients, aged between 39-85 years (mean=57.3 years), who underwent radical modified mastectomy and lymph node dissection between 2009-2013. Surgical specimens were fixed in buffer formalin and paraffin embedded and 5 μm-thick step sections were performed for each 79 This article is freely accessible online.
Examining the technique of angiogenesis assessment in invasive breast cancer
British Journal of Cancer, 1997
The intensity of angiogenesis as measured by the density of microvessels has been reported to be associated with a poor prognosis in invasive breast cancer in some, but not all, studies. The reasons for these discrepancies may be variations in the methodologies used. The monoclonal antibody used to identify the microvessels, the number of high-density areas or 'hotspots' counted and the type of value taken for statistical analysis (highest count or mean count) have varied between the different studies. We have assessed which of the three commonly used monoclonal antibodies provides the best visualization of microvessels in invasive breast cancer and have used methods that give reproducible data for the optimum number of 'hotspots' to count for each reagent. Thus, microvessels in formalin-fixed paraffin-embedded specimens from 174 primary breast cancers were immunohistochemically stained with monoclonal antibodies to FVIIIRAg, CD31 and CD34 and ten fields counted at 200 x magnification for each antibody. The highest count and the mean value of the highest of three, five and ten counts were used to examine the relationship between the density of microvessels and overall survival of patients with a median follow-up time of 7.1 years. Antibodies to CD31 and CD34 identified more vessels than antibodies to FVIIIRAg (median highest count per mm2: CD31 = 100, CD34 = 100, FVIIIRAg = 81). The monoclonal antibody to CD31, however, was the least reliable antibody, immunohistochemically staining only 87% of sections compared with 98% for the monoclonal to CD34 and 99% for the monoclonal to FVIIIRAg. There was a high degree of correlation between the number of vessels stained by the different antibodies, though there were some considerable differences in actual counts for serial sections of the same specimen stained by the different antibodies. Patients could be divided into two groups corresponding to those with high microvessel densities and those with low microvessel densities. Using Kaplan-Meier survival curves, there was a close association for all three antibodies between vessel density and survival whichever method of recording the highest vessel densities was used. Using log-rank tests and Cox's regression analysis, anti-CD34 gave the most significant results of the three antibodies, whereas a simple cutoff at the 75th percentile for the high and low groups produced the best association with patient survival. For anti-CD34 the highest microvessel density (P = 0.0014) and the mean value of the highest three microvessel densities (P= 0.004) showed a good correlation with patient death, whereas for anti-CD31 (P= 0.008) and anti-FVIIIRAg (P= 0.007) the highest count gave the best correlation using Cox's regression analysis.
Breast carcinoma: vascular density determined using CD105 antibody correlates with tumor prognosis
Cancer research, 1999
Angiogenesis is essential for tumor growth and metastasis. There are conflicting reports as to whether microvessel density (IMD) in breast cancers is associated with prognosis. This could be due to the use of different antibodies to endothelial cell markers, variation in tissue pretreatment protocols, and nonstandardized counting methods. We have assessed the IMD in 106 breast carcinomas using a pan-endothelial marker, CD34, and a recently described mAb to CD105, which preferentially reacts with endothelial cell in angiogenic tissues. IMD values (separated as above or below median) for CD105 expression showed a statistically significant correlation with overall (P = 0.0029) and disease-free survival (P = 0.0362). In contrast, blood vessel counts using a panendothelial marker CD34 did not correlate with overall or disease-free survival (P = 0.2912 and P = 03153, respectively). When IMD values were subdivided into quartiles and assessed for their prognostic values, there was a statist...