Journal of Pathology and Translational Medicine

Original Articles

High Expression of Galectin-1, VEGF and Increased Microvessel Density Are Associated with MELF Pattern in Stage I-III Endometrioid Endometrial Adenocarcinoma: Dmitry Aleksandrovich Zinovkin, Sergey Leonidovich Achinovich, Mikhail Grigoryevich Zubritskiy, Jacqueline Linda Whatmore, Md Zahidul Islam Pranjol; J Pathol Transl Med. 2019;53(5):280-288. Published online June 27, 2019; DOI: https://doi.org/10.4132/jptm.2019.05.13

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Background
In this study, we investigate the expression of markers of angiogenesis and microvessel density (MVD) in cases of microcystic, elongated and fragmented (MELF) pattern, with its prognostic role in the survival of endometrioid endometrial adenocarcinomas (EA) patients.
Methods
In this study, 100 cases of EA, 49 cases with MELF pattern and 51 without, were immunohistochemically stained for galectin-1, vascular endothelial growth factor (VEGF), and MVD. Morphometry and statistical (univariate and multivariate) analyses were performed to assess overall survival (OS) and disease-free survival.
Results
The expression of VEGF (p<.001) and galectin-1 (p<.001), as well as MVD area (p<.001) and number of vessels/mm2 (p<.050), were significantly higher in the +MELF pattern group compared to the –MELF group. A low negative correlation between MELFpattern and the number of days of survival (p<.001, r=–0.47) was also found. A low positive correlation of MELF-pattern with galectin-1 expression (p<.001, r=0.39), area of vessels/mm2 (p<.001, r=0.36), outcome of EA (p<.001, r=0.42) and VEGF expression (p<.001, r=0.39) suggests potential pathological relevance of these factors in the prognosis of EA. A univariate survival analysis indicated a role for all parameters of survival. Multivariate Cox proportional hazard regression analysis revealed that only area of vessels/mm2 (hazard ratio [HR], 1.018; 95% confidence interval [CI], 1.002 to 1.033), galectin-1 (HR, 1.049; 95% CI, 1.025 to 1.074) and VEGF (HR, 1.049; 95% CI, 1.022 to 1.077) play key roles in OS.
Conclusions
This study reports an increase in MVD, VEGF and galectin-1 expression in EA with MELF pattern and suggests that MELF pattern, along with the angiogenic profile, may be a prognostic factor in EA.

Citations

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Correlation between Tumor Angiogenesis and Metastasis in Invasive Breast Carcinoma.: Nam Hoon Kim, Moon Hyang Park; Korean J Pathol. 1995;29(6):740-745.

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Abstract PDF: Tumor angiogenesis(TA) refers to the growth of new vessels toward and within a tumor. TA is necessary both at the beginning and at the end of the metastatic cascade of events. Recently, experimental evidence suggests that the growth of a tumor beyond a certain size requires angiogenesis. To investigate how tumor angiogenesis correlates with metastases in breast carcinoma, the microvessels were counted (per 200 / field) in the most active areas of neovas-cularization by two investigators. The microvessels within breast carcinoma were highlighted by in imunohistochemical staining for factor VIII-related antigen. Microvessel count(MVC) in node-positive carcinoma(59.66=35) was significantly higher than in node-negative carcinoma(44.76=17)(p=0.009). MVC was also statistically correlated with tumor size and stage, but not with histologic grading, DNA ploidy, or hormonal receptors(estro-gen and progesterone). MVC in invasive breast carcinoma may be one of many prognostic predictors of node-positive breast carcinoma. Assessment of tumor angiogenesis may therefore be valuable in selecting patients with early breast carcinoma for aggressive therapy.

Microvessel Quantification, Expression of p53 Protein and MIB-1 in Colorectal Adenoma and Carcinoma.: Tae Jung Jang, Jung Ran Kim, Han Ik Bae; Korean J Pathol. 1997;31(1):40-50.

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Abstract PDF: Angiogenesis is a crucial step in tumor growth and progression. Scarce data is available on angiogensis in gastrointestinal tumors. We studied 16 normal colon, 44 adenomas and 29 carcinomas to evaluate angiogenesis in colorectal tumors and to assess the correlation among p53 protein, proliferative activity and other clinical prognostic parameters. Endothelial cells were immunostained with an anti-Factor VIII mAb; in each case three microscopic fields(x 200) were counted: average number of the three fields was defined as microvessel density (MVD). p53 protein expression was 45.5%(20/44) in adenomas, and 79.3%(23/29) in carcinomas (p<0.01). p53 protein expression of carcinomas was 57.1%(4/7) in diploid tumors, 100%(8/8) in aneuploid tumors (p=0.07), 100%(8/8) in well differentiated tumors, and 50%(2/4) in poorly differentiated tumors (p=0.09). MIB-1 score was 2.3+/-0.7(38) in adenomas, 3.4+/-0.5(29) in carcinomas (p<0.01). There was no significant correlation between p53 protein and MIB-1 score. MVD was 10.4+/-4.1(16) in the normal mucosa, 21.5+/-7.9(39) in the adenomas, 35.3+/-9.7(26) in carcinomas (normal versus adenomas, p<0.01; adenomas versus carcinomas, p<0.01). MVD was 25.8+/-5.4(2) in carcinomas confined to mucosa, and 36.1+/-9.6(24) in carcinomas with transmural invasion. The higher MIB-1 score was in carcinomas the more MVD increased but there was no statistical significance (r=0.38, p=0.055). MVD of carcinomas was not associated with nodal metastasis, p53 expression, and DNA ploidy. p53 protein and MIB-1 expression are useful methods for the evaluation of malignancy, and tumor angiogenesis is an early event in a colorectal tumor but MVD does not correlate with prognostic parameters except for the tumor depth.

Microvessel Quantitation and Assessment of its Utility by CD34 Staining in Invasive Breast Carcinoma.: Hwa Sook Jeong, Ro Hyun Sung; Korean J Pathol. 1997;31(4):298-307.

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Abstract PDF: Tumor angiogenesis, the development of new blood vessels by tumor, is a widely observed phenomenon associated with the growth of human solid tumors. To investigate how tumor angiogenesis correlates with other prognostic features i.e. menopause status, tumor size, lymph node metastasis, mitosis, angioinvasion, estrogen receptor (ER), p53 protein expression, histologic grade and clinical stage, we counted microvessels by immunohistochemistry using antibody for CD34 antigen in 56 cases of invasive breast carcinoma (27 with and 29 without axillary lymph node metastases) and 20 cases of non-inflammatory benign breast lesion. CD34 antigen is expressed on the surface of hematopoietic progenitor cells and more sensitively expressed than factor VIII in vascular endothelial cells. Microvessel count (MVC) was performed at a single hot field of 200x magnification (0.74 mm2 per field). The results are summarized as follows; 1) The mean MVC of invasive carcinoma and benign breast lesion were 92.0+/-54.4 (range, 7-237) and 20.7+/-16.6 (range, 4-73), respectively (p<0.0001). 2) Although MVC had no correlation with all other prognostic factors i.e. menopause status, tumor size, lymph node metastasis, mitosis count, angioinvasion, ER, p53 protein expression, histologic grade, and clinical stage (p>0.05), MVC had a tendency to increase in tumors with axillary LN metastasis or without ER expression. 3) Without correlation with MVC, ER (+), angioinvasion (-) and higher histologic grade correlate to significantly higher mitosis count (p<0.0005). Also, angioinvasion correlate to a significantly higher histologic grade (p<0.05). In conclusion, angiogenesis is related to tumorigenesis, but MVC may not be related to other clinicopathologic factors.

Tumor Angiogenesis and Stage in Ovarian Carcinoma.: Eun Sook Chang, Hyun Chang Joo, Tae Sung Lee; Korean J Pathol. 1999;33(8):596-602.

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Abstract PDF: Tumor angiogenesis has been found to have prognostic significance in many tumor types for predicting an increased risk of metastasis. We assessed tumor vascularity in 28 cases of borderline malignancy and 71 cases of carcinoma of the ovary which had been resected and diagnosed, using the highly specific endothelial cell marker CD34. The numbers of microvessels were counted in 200 magnification in three highly vascularised areas. The numbers of microvessels in carcinomas were higher than that in the borderline malignancy of serous and mucinous tumors. The number of microvessels of mucinous carcinomas was significantly higher than that of serous carcinomas. There were neither significant differences in the number of microvessels according to histological tumor types (p=0.075) nor significant differences in the number of microvessels according to FIGO stages (p=0.072). But in serous carcinomas, the number of microvessels was higher in the FIGO III-IV stage than in the FIGO I-II stage (p=0.017). This study showed higher neovascularization in malignant tumor than borderline malignancy, and in the advanced stage (FIGO III-IV) than less advanced stage (FIGO I-II) of serous carcinomas.

Microvessel Density and Vascular Endothelial Growth Factor Expression in Invasive Breast Carcinomas.: Mi Yeong Jeon, Mee Young Sol, Kyung Sun Park, Hye Kyoung Yoon; Korean J Pathol. 2000;34(2):138-144.

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Abstract PDF: Angiogenesis is essential for tumor growth and metastasis, however, the prognostic value of neovascularization is undetermined. The aim of this study is to evaluate the prognostic significance of microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression in breast carcinomas. An immunohistochemical stains for CD 31 (DAKO) to estimate MVD and VEGF (Santa Cruz) were done on 40 cases of invasive breast carcinoma. MVD was calculated as an average count of vessels per 200 power field in the most vascularized areas. VEGF expression was interpreted according to staining intensity and number of positive cells. Mean MVD was 35, and MVD was not correlated with lymph node metastasis or histologic grade, but high MVD (mean MVD>35) showed an increasing tendency in cases with larger size, negative ER/PR, and positive cathepsin D. All of the cases showed VEGF expression, but VEGF expression was not correlated with tumor size, histologic grade, lymph node metastasis, ER/PR status, and cathepsin D expression. These results suggest that MVD and VEGF expressions are not reliable prognostic factors.

VEGF Expression and Microvessel Density in Oral Squamous Cell Carcinomas.: Ji Jun Lim, Sam Pyo Hong, Jae Il Lee, Seong Doo Hong, Chang Yun Lim; Korean J Pathol. 2000;34(3):190-198.

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Abstract PDF: Angiogenesis is an essential process in tumor growth and metastasis. VEGF has been considered a leading candidate inducing tumor angiogenesis. VEGF expression was significantly correlated with clinical stage, lymph node matastasis, and prognosis of cancers of various parts of body. However, little has been known about the correlation between VEGF expression and clinicopathologic parameters in oral squamous cell carcinoma. The aim of this study was to correlate VEGF expression with the clinicopathological parameters and microvessel density. Forty six oral squamous cell carcinomas were analyzed using immunohistochemical method with primary antibodies to VEGF and CD31. VEGF expression was detected in 33 (71.7%) of the 46 cases. The microvessel density was significantly correlated with VEGF expression (P=0.002). There was no correlation between microvessel density and tumour size, clinical stage, and lymph node metastasis, respectively. VEGF expression did not correlate with the histological grade of tumour differentiation, tumour size, and clinical stages. The VEGF-positive rate seemed to be higher in patients with cervical lymph nodal metastasis than in those without it, but it was not statistically significant. In conclusion, the overexpression of VEGF in the oral squamous cell carcinoma seemed to be associated with a more aggressive course of the disease. Further study is necessary to define the role of VEGF in oral squamous cell carcinoma.

Expression of Matrix Metalloproteinase and Tissue Inhibitor of Metallproteinase in Breast Carcinoma Related to Angiogenesis and Invasion.: Yoon Jung Choi, Woo Hee Jung, Hy De Lee, Kwang Gil Lee; Korean J Pathol. 2000;34(9):652-664.

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Abstract PDF: Among the enzymes which are responsible for basement membrane breakdown, matrix metalloproteinases (MMP) form a family of neutral proteases that are regulated at the levels of gene transcription, proenzyme activation by the cleavage of protein, and the inhibition of the active enzyme by tissue inhibitors of matrix metalloproteinases (TIMP). Recent reports have demonstrated that the expression of these proteolytic enzymes are elevated in several solid tumors and that it can be associated with invasiveness and poor prognosis. We examined the expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 by immunohistochemistry in 160 cases of infiltrating ductal carcinoma. And we compared these data with the established prognostic parameters - tumor size, nodal status, clinical stage, hormonal receptor status, microvessel density, and TGF-beta1 expression in order to evaluate how MMP and TIMP expression are associated with breast cancer progression and prognosis. Microvessel density in invasive breast carcinoma was significantly correlated with tumor size and recurrence (p<0.05). The immunohistochemical expression of TGF-beta1 was significantly associated with tumor size, lymph node metastasis, and clinical stage (p<0.05). The microvessel density was significantly correlated with TGF-beta1 expression in more than 50% of tumor cells. The immunohistochemical expression of MMP-2 and MMP-9 were significantly correlated with nodal metastasis and absence of immunoreactivity for estrogen and progesterone receptors. The immunohistochemical expression of TIMP-1 was inversely correlated with clinical stage and microvessel density while that of TIMP-2 was inversely correlated with clinical stage (p<0.05). Small size of tumor, presence of progesterone receptor, highly differentiated histologic grade, and absence of immunoreactivity for MMP-9 were significantly associated with higher survival rate, but in multivariate analysis only tumor size and MMP-9 expression appeared to affect survival independently.

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