Time‐intensity curve parameters in colorectal tumours measured using double contrast‐enhanced ultrasound: correlations with tumour angiogenesis

Aim The aim of the study was to assess the correlation between time‐intensity curve (TIC) parameters and colorectal tumour angiogenesis using double contrast‐enhanced ultrasound (DCEUS), in which an intraluminal contrast agent was used in combination with an intravascular contrast agent. Method Thirty nine patients with colorectal tumours were examined preoperatively. During hydrocolonal examination with the intraluminal contrast agent, an intravascular contrast agent, SonoVue, was used to perform the DCEUS. The parameter arrival time (AT), time to peak (TTP), peak intensity (PI) and area under the curve (AUC) were measured. Postoperative specimens were assessed for microvessel density (MVD) and vascular endothelial growth factor (VEGF). The correlation between TIC parameters and the expression of VEGF or MVD was studied. Results The mean values of AT, TTP, PI and AUC of the colorectal tumours were 14.32 ± 11.36 s, 30.61 ± 18.65 s, 20.38 ± 17.45 dB and 221.10 ± 156.09 dB.s, respectively. Both AUC and MVD were significantly higher in colorectal adenocarcinomas than in adenomas (all P < 0.05). A positive linear correlation was found between the AUC and MVD in colorectal tumours (r = 0.686, P = 0.0019). No correlation was found between VEGF and any TIC parameter. Conclusion DCEUS is a valuable method for evaluating angiogenesis in colorectal tumours in vivo. The AUC has a positive linear correlation with MVD and could form a new index for assessing angiogenesis and the biological behaviour of colorectal tumours.     

骨肉瘤肺转移与血管内皮生长因子和微血管密度的关系

目的 探讨骨肉瘤盱市转移与血管内皮生长因子(VEGF)和微血管密度(MVD)的关系.方法 用免疫组织化学法检测30例骨肉瘤组织中VEGF的表达和MVD.结果 VEGF在骨肉瘤中的阳性率表达分别为70.00%(21/30),其中有肺转移的病例阳性率为92.31%(12/13).无肺转移病例的阳性率为52.94%(9/17),差异有统计学意义(P<0:05).骨肉瘤组织中VEGF阳性表达与骨肉瘤的组织学分型无明显相关(P>0.05).骨肉瘤中VEGF表达强度与MVD呈正相关(r=0.799,P<0.01);有肺转移的骨肉瘤患者其瘤组织中MVD与无肺转移的骨肉瘤患者其瘤组织中MVD差异有统计学意义(P<0.05),有肺转移的明显高于无肺转移的病例.结论 VEGF是促进微血管生成的主要细胞因子,检测VEGF表达与MVD值可作为判断肿瘤预后的重要指标.     

Vascular endothelial growth factor expression and capillary architecture in high-grade PIN and prostate cancer in untreated and androgen-ablated patients

BACKGROUND: Recent studies have demonstrated that angiogenesis is a potent prognostic indicator for patients with prostate cancer (PCa) and have pointed out that the evaluation of vascular endothelial growth factor (VEGF) is useful in assessing the angiogenic phenotype in PCa. The aim of the study was to investigate immunohistochemically the expression of VEGF and its correlation with the pattern of capillary architecture in prostate cancer and high-grade prostatic intraepithelial neoplasia (PIN), in untreated and androgen-ablated patients. METHODS: Forty-five patients who underwent radical prostatectomy (RP) for localized prostate carcinoma were recruited for this study. The study population included two groups: 35 patients who did not receive chemo-, hormone, or radiation therapy before surgery, and 10 patients who were under complete androgen blockade (CAB) for 3 months at time of surgery. VEGF was examined by immunohistochemistry, and its tissue expression was compared with the pattern of capillary architecture evaluated by immunostaining the endothelial antigen CD34. The relationship of VEGF expression to chromogranin A-positive (e.g., neuroendocrine) cells was investigated. RESULTS: In normal tissue, the intensity of the VEGF immunoreactivity in the cytoplasm of secretory cells ranged from negative to low. Very few basal cells stained for VEGF. All prostate cancer specimens stained positively, the intensity of the immunoreaction ranging from low to strong and being correlated with the Gleason score. Strongly positive VEGF immunoreactivity was detected in vascular endothelial cells and in stromal cells surrounding blood vessels. Two discrete immunostaining patterns were observed in high-grade PIN. VEGF expression of low-to-moderate intensity was defined as pattern A. The other, characterized by a strong cytoplasmic immunoreaction similar to that of poorly differentiated tumors, was defined as pattern B. The capillary architecture in high-grade PIN with pattern A was similar to the orderly vascular network seen in normal prostates, whereas in the pattern B it had the characteristics of microvessels usually seen in PCa. The degree of vascularization in the stroma adjacent to intensely VEGF-stained cells (neuroendocrine phenotype) was higher than that noted in association with secretory cells. CAB before surgery downregulated the expression of VEGF and decreased the degree of vascularization, except in the cell areas with neuroendocrine (NE) features. CONCLUSIONS: Our immunohistochemical results indicate that significant levels of VEGF are present in prostate cancer and in a population of PIN lesions, expression being highest in association with NE cells. VEGF expression is downregulated by hormonal manipulation, except in the population of NE cells.     

The relationship between angiogenesis and cyclooxygenase-2 expression in prostate cancer

OBJECTIVE: To test the hypothesis that angiogenesis in prostate cancer is associated with tumour invasion and metastasis, and that this is mediated through increased cyclooxygenase-2 (COX-2) expression. PATIENTS AND METHODS: Angiogenesis was assessed in 105 patients with either prostate cancer (79) or benign prostatic hyperplasia (BPH, 26) and these data correlated with levels of COX-2 expression in the same dataset. The mean microvessel density (MVD) was analysed as a marker of angiogenesis, using the endothelial antigen CD34 stained by immunohistochemistry. RESULTS: There was no difference in MVD in progressive tumour stages compared with BPH. There was a negative correlation between MVD and COX-2 expression, but the effect of increased COX-2 expression on MVD was not marked. CONCLUSION: These data suggest that COX-2 drives tumour spread in prostate cancer by means other than the promotion of angiogenesis.     

骨肉瘤肺转移与血管内皮生长因子和微血管密度的关系

目的 探讨骨肉瘤盱市转移与血管内皮生长因子(VEGF)和微血管密度(MVD)的关系.方法 用免疫组织化学法检测30例骨肉瘤组织中VEGF的表达和MVD.结果 VEGF在骨肉瘤中的阳性率表达分别为70.00%(21/30),其中有肺转移的病例阳性率为92.31%(12/13).无肺转移病例的阳性率为52.94%(9/17),差异有统计学意义(P<0:05).骨肉瘤组织中VEGF阳性表达与骨肉瘤的组织学分型无明显相关(P>0.05).骨肉瘤中VEGF表达强度与MVD呈正相关(r=0.799,P<0.01);有肺转移的骨肉瘤患者其瘤组织中MVD与无肺转移的骨肉瘤患者其瘤组织中MVD差异有统计学意义(P<0.05),有肺转移的明显高于无肺转移的病例.结论 VEGF是促进微血管生成的主要细胞因子,检测VEGF表达与MVD值可作为判断肿瘤预后的重要指标.     

The role of colour Doppler ultrasonography in detecting prostate cancer

OBJECTIVE: To determine the usefulness of colour Doppler ultrasonography (CDUS) in detecting prostate cancer, by comparing CDUS with grey-scale transrectal ultrasonography (TRUS) and magnetic resonance imaging (MRI). PATIENTS AND METHODS: In all, 278 patients who underwent prostate biopsies because of an abnormal digital rectal examination, elevated prostate specific antigen levels, and/or abnormal TRUS between May 1998 and November 1999 were evaluated. The diagnostic accuracies of TRUS, CDUS, MRI and combinations of these imaging techniques in detecting prostate cancer were compared, based on the biopsy results. RESULTS: Carcinoma was detected in 233 of 1696 specimens, and 87 patients were diagnosed with prostate cancer. For each detected cancer site, the sensitivity of CDUS was lower than those of other imaging techniques, but CDUS had high a specificity and positive predictive value. The combination of grey-scale TRUS and CDUS or MRI improved the sensitivity and negative predictive value. The specificity and positive predictive value of the combination of grey-scale TRUS and MRI were less than those for grey-scale TRUS alone, while those for the combination of grey-scale TRUS and CDUS were higher than those for grey-scale TRUS alone. Five tumours were isoechoic but seen as hypervascular lesions with CDUS. CONCLUSION: CDUS provides information useful for detecting prostate cancer when used in combination with grey-scale TRUS, and should be included in the routine examination for prostate cancer.     

Effects of androgen suppression and radiation on prostate cancer suggest a role for angiogenesis blockade

Antiandrogen therapy is an important modality in the treatment of prostate cancer. Recent research into the role of angiogenesis in tumour growth and metastasis has uncovered links between antiandrogen therapy, radiation therapy and angiogenesis, which have exciting implications for the treatment of prostate cancer. Angiogenic cytokines such as vascular endothelial growth factor (VEGF) have been identified in prostate cancer cells and tumours, and androgens appear to stimulate VEGF. This article assesses the antiangiogenic effects of hormonal therapy and assesses the role that angiogenesis may play in the observed cooperation between hormonal and radiation therapies for prostate cancer.     

骨肉瘤肺转移与血管内皮生长因子和微血管密度的关系

目的 探讨骨肉瘤盱市转移与血管内皮生长因子(VEGF)和微血管密度(MVD)的关系.方法 用免疫组织化学法检测30例骨肉瘤组织中VEGF的表达和MVD.结果 VEGF在骨肉瘤中的阳性率表达分别为70.00%(21/30),其中有肺转移的病例阳性率为92.31%(12/13).无肺转移病例的阳性率为52.94%(9/17),差异有统计学意义(P<0:05).骨肉瘤组织中VEGF阳性表达与骨肉瘤的组织学分型无明显相关(P>0.05).骨肉瘤中VEGF表达强度与MVD呈正相关(r=0.799,P<0.01);有肺转移的骨肉瘤患者其瘤组织中MVD与无肺转移的骨肉瘤患者其瘤组织中MVD差异有统计学意义(P<0.05),有肺转移的明显高于无肺转移的病例.结论 VEGF是促进微血管生成的主要细胞因子,检测VEGF表达与MVD值可作为判断肿瘤预后的重要指标.     

Thrombospondin-1, vascular endothelial growth factor expression and their relationship with p53 status in prostate cancer and benign prostatic hyperplasia

OBJECTIVE: To evaluate the expression of thrombospondin-1 (TSP-1, a potent inhibitor of angiogenesis) and vascular endothelial growth factor (VEGF, an important angiogenic factor in solid tumours) in prostate cancer, and their relationship with p53 status. PATIENTS AND METHODS: Using immunohistochemistry, the expression of VEGF, TSP-1 and p53 was assessed in 82 archival tissue specimens from 23 patients with benign prostatic hyperplasia (BPH), 22 with localized prostate cancer and 37 with metastatic prostate cancer. Seven of the last group had received androgen deprivation therapy. The relationship between the expression of VEGF, TSP-1 and p53 status was also evaluated with tumour grade and stage in patients with prostate cancer. RESULTS: The seven patients receiving hormonal treatment were excluded from the analysis because androgen deprivation significantly increased TSP-1 and decreased VEGF expression (both P < 0.01). Immunohistochemical analysis showed significantly higher VEGF and significantly lower TSP-1 expression (both P < 0.01) in prostate cancer than in BPH tissues. There was also significantly higher VEGF and significantly lower TSP-1 expression (both P < 0.05) in tissues from metastatic than localized prostate cancer. There was no significant correlation between VEGF or TSP-1 expression and Gleason score, but a significant inverse correlation between TSP-1 and VEGF expression. There was a significant association between VEGF expression and p53 status (P < 0.05), but TSP-1 expression was not associated with p53 status. CONCLUSIONS: Angiogenic factors, including VEGF and TSP-1, might be important in the development and progression of prostate cancer. These changes seem to be influenced by p53 status. Identifying the angiogenic factors involved in prostate cancer might lead to the development of diagnostic or therapeutic strategies based on anti-angiogenesis.     

The relation of p53 protein nuclear accumulation and angiogenesis in human prostatic carcinoma

All neoplasms require angiogenesis and resulting neovascularity for growth beyond 1 mm(2). Quantitative microvessel density (MVD) has been shown to provide staging and prognostic significance in human prostate cancer (CaP). recently, it has been demonstrated that loss of the wild-type allele of the p53 tumour suppressor gene results in reduced expression of thrombospondin-1 (TSP-1), a potent inhibitor of angiogenesis. There is also an increased expression of vascular endothelial growth factor which promotes neovascularization. p53 gene mutation and MVD were investigated in men with prostate cancer. Sections from 103 radical prostatectomy cases were evaluated with immunohistochemistry to detect mutant p53 proteins. Quantitative MVD was performed on the cases exhibiting p53 positive staining and compared with negative fields of similar Gleason grade on the same histologic sections. Twenty of the 103 cases (19.4%) revealed positive p53 staining nuclei. In 19 of these 20 cases, the MVD in p53 positive areas was greater than corresponding control regions (overall P<0.0001). Extent of p53 abnormality, as well as MVD, correlated with pathologic stage. These data suggest that mutations of the p53 tumour suppressor gene may be associated with increased angiogenesis in CaP. In addition to providing staging and prognostic information, this relationship potentially has therapeutic implications.     

Prognostic significance of angiogenesis in superficial bladder cancer

OBJECTIVE: To assess the prognostic significance of angiogenesis parameters such as microvessel density (MVD) and vascular endothelial growth factor (VEGF) in superficial bladder cancer. PATIENTS AND METHODS: We studied 127 superficial bladder cancer samples immunohistochemically for the above factors. We compared them with standard clinicopathological features (grade, stage, concurrent in situ, multifocality, primary or recurrent status) as well as with p53 expression, recurrence and progression to muscle infiltrating disease. RESULTS: During a 36 months median follow up of 109 patients with superficial primary tumors (min. 3, max. 69 months), 80 of them recurred (73.4%), while 8 patients (7.3%) progressed to muscle invading disease. A significant correlation was noted between MVD and VEGF in all 127 samples (p = 0.019). No association was noted between MVD or VEGF with the other clinicopathological features, recurrence or progression. Although progression free survival rates of categorized microvessel density (up to and higher than median value) differed significantly only in grade 3 patients, no independent prognostic significance could be attributed to MVD. No correlation was observed between MVD or VEGF with p53 protein. CONCLUSIONS: Based on our data we suggest that VEGF is not useful for predicting recurrence or progression in superficial bladder cancer. Microvessel density determination may help to predict progression of grade 3 patients to muscle invasive disease but not as an independent prognostic factor.     

Angiogenesis and lymphangiogenesis in stage 1 germ cell tumours of the testis

OBJECTIVE: To determine whether angiogenesis can be used as an additional prognostic indicator in patients with stage 1 germ cell tumours of the testis. PATIENTS AND METHODS: Paraffin sections were assessed immunohistochemically from 51 patients with clinical stage 1 germ cell tumours of the testis (28 seminoma, 23 teratoma) treated by orchidectomy and surveillance only. Sections were analysed for microvascular density (MVD), and expression of the angiogenic factors vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). In addition, in the seminoma cases the presence of mRNA for the lymphangiogenic factor VEGF-C was examined by in situ hybridization, and its corresponding receptor VEGFR-3 by immunohistochemistry. RESULTS: Teratoma specimens had a significantly higher mean (range) MVD (85, 26-163; P < 0.01) than both seminoma (37, 16-91) and four normal specimens (26, 18-30). Teratoma specimens also had significantly higher VEGF expression than both seminoma and normal specimens (P < 0.01). Despite these differences between groups, and indeed individual tumours, there was no significant correlation between MVD and VEGF, or between either MVD or VEGF and relapse-free survival. TP expression was significantly greater in tumours than in normal specimens (P < 0.02) but with very little inter-tumour variation. VEGF-C mRNA and VEGFR-3 protein were detected in a third to a half of cases, with expression mostly around endothelial vessels. CONCLUSIONS: The marked differences between normal testis and tumours implicate angiogenesis in the biology of germ cell tumours of the testis. In addition, the detection of factors involved in lymphangiogenesis in some seminomas, tumours which initially metastasize primarily to lymph nodes, indicate that although not prognostic in this study, further studies are warranted in both these areas in the search for further prognostic indicators and therapeutic targets.     

Vascular endothelial growth factor and its correlation with angiogenesis and p53 expression in prostate cancer

BACKGROUND: Previously it was demonstrated that in prostate tumors, angiogenesis measured as microvessel density (MVD) is associated with tumor stage as well as WHO grade and is an independent predictor of clinical outcome. Vascular endothelial growth factor (VEGF) is a major inducer of angiogenesis. There is some evidence that P53 mutations cause overexpression of VEGF. We studied VEGF expression, p53 overexpression, and P53 mutations in prostate cancer (PCA) to investigate the role of VEGF as an angiogenic marker and the possible deregulation of VEGF as a result of P53 mutations in PCA. METHODS: Immunohistochemical staining with a polyclonal VEGF antibody was performed in 55 paraffin-embedded PCA, in which MVD had previously been determined, as well as in 5 prostatic adenomas (PA) and 20 adjacent normal prostate tissues. In addition, 37 PCA and 5 PAs were examined for p53 expression by immunohistochemistry. Temperature gradient gel electrophoresis (TGGE) was performed in 13 of these PCA to screen for P53 mutations. VEGF expression, p53 expression, and mutations were then correlated with tumor stage, grade, MVD, and clinical outcome. RESULTS: While PA and normal prostate tissue generally showed no or only low VEGF expression, there was a significant increase in VEGF expression with tumor stage, grade, and MVD in PCA. During clinical follow-up (mean, 31.9 months), 9 of 55 patients had tumor progression. Significant differences in VEGF expression were found between patients with tumor progression and those without (P = 0.0004). Of the 37 PCA evaluated for p53 expression, 12 exhibited p53 overexpression. TGGE revealed P53 mutations in 3 of 13 PCA. However, there was no correlation between VEGF expression, p53 overexpression, and P53 mutation, respectively. CONCLUSIONS: VEGF seems to be an important, clinically relevant inducer of angiogenesis in PCA. VEGF expression was shown to correlate positively with tumor stage, grade, MVD, and clinical outcome. However, regulation of VEGF in PCA appears to be independent of p53 expression.     

膀胱癌组织中血管内皮生长因子的表达及与血管生成的关系

目的 探讨血管内皮生长因子（ＶＥＧＦ）在原发性膀胱移行细胞癌中的表达及其与膀胱癌血管生成之间的关系。方法 免疫组织化学技术检测６８例原发性膀胱移行细胞癌和７例正常膀胱组织中血管内皮生长因子的表达,测定４０例浸润性膀胱癌的微血管密度,并分析ＶＥＧＦ和ＭＶＤ间以及它们与膀胱癌病理分级和临床分期间的关系。结果 ＶＥＧＦ在正常膀胱中不表达或低表达,而在膀胱表达较强;ＶＥＧＦ表达及ＭＶＤ值均与肿瘤的病理分级     

经尿道前列腺电切术中出血与前列腺增生组织MVD、VEGF的关系

目的通过检测经尿道前列腺电切（TURP）术后前列腺增生组织血管内皮生长因子（VEGF）的蛋白表达、微血管密度（MVD）,对照术中出血量,探讨其间的相关性。方珐采用免疫组化方法,对徐州市第二人民医院2005年2月～2007年6月的100例TuRP组织按前列腺体积进行分组,按病理学类型分别进行血管标记和染色检测MVD及VEGF的表达。采用氰化高铁血红蛋白比色计算术中出血量,并与病理学分类及MVD、VEGF进行比较。结果1。0例患者中,同体积前列腺术中出血量与MVD、VEGF呈明显相关性。MVD、VEGF高表达者术中出血多（P〈0．05）。随体积增大（〉60mL）,前列腺增生病理类型发生变化,但术中出血量与前列腺体积大小不一致,而与MVD、VEGF表达呈正相关。结论TURP术中出血量与前列腺病理学类型相关,组织MVD、VEGF表达高者,术中出血量多。     

Microvessel density and regulators of angiogenesis in malignant and nonmalignant prostate tissue

The aim of this study was to investigate the relationship between microvessel density (MVD), positive and negative angiogenic factors, and established prognostic factors in prostate cancer (PC), and, to clarify the effect of angiogenic factors to angiogenesis. The vascularization of neoplastic, non-neoplastic prostate tissue was determined by CD34 immunostaining. Angiogenetic mediators VEGF, bFGF, TSP-1, and p53 were studied by immunohistochemistry. Neovascularization and p53, VEGF, and TSP-1 expressions of tumorous tissue were higher than non-tumorous tissue.The bFGF expression in these tissues was not different.The p53 expression was not correlated with the expressions of VEGF, bFGF, and TSP-1 in PC. Our results demonstrate a significant increase in MVD, VEGF, TSP-1, and p53 expressions in prostate tumorigenesis. The pretreatment sPSA was the only parameter demonstrating significant correlation with tumor grade and may have a value in the prediction of aggressive tumor behavior in PC.     

Expression of the VEGF-receptor Flt-1 in benign, premalignant and malignant prostate tissues

PURPOSE: Vascular endothelial growth factor (VEGF) is one of the most potent regulators of angiogenesis and has been shown to act upon two tyrosine kinase family receptors: c-fms-like tyrosine kinase (Flt-1) and fetal liver kinase. Preliminary reports have emphasized that expression of VEGF receptors is endothelial cell-specific. In this study we verified the localization and distribution of Flt-1 protein and mRNA expression in prostatic adenocarcinoma (CaP) as well as prostate intraepithelial neoplasia (PIN) and benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: 30 selected surgical specimens exhibiting areas with CaP, PIN and BPH histology were evaluated for Flt-1 protein expression by immunohistochemistry. Results were compared with tumor differentiation (Gleason-Score), serum-PSA and clinical followup. Flt-1 synthesis by prostatic carcinoma cell lines, freshly isolated BPH epithelial cells (BPH-EC) and stromal cells was investigated using RT-PCR and intron spanning primer. RESULTS: VEGF receptor Flt-1 specific anti-sera revealed significant staining of prostatic endothelial cells, but the reactivity was not restricted to endothelial cells. BPH-epithelial cells of all specimens reacted significantly with anti-Flt-1. In contrast, tumor cells failed to react with anti-Flt-1 in 56% of the specimens. BPH-EC revealed a uniform anti-Flt-1 reactivity, which was less pronounced and weaker in PIN. Loss of anti-Flt-1 reactivity of prostatic tumor cells did not correlate with preoperative PSA serum levels but increased with tumor dedifferentiation. Interestingly, tumor cells of all CaP specimens with a Gleason score of >8 exhibit no anti-Flt-1 immunoreactivity. Accordingly while PC3, DU145 and LNCaP cells were negative when tested using RT-PCR all BPH tissue derived BPH-EC revealed Flt-1 coding mRNA expression.CONCLUSIONS: Widespread distribution of VEGF receptor Flt-1 in BPH, PIN and prostate cancer specimens suggests that VEGF function in prostate is not restricted to endothelial cells and angiogenesis. However, since the receptor is lost in CaP cells and with tumor dedifferentiation, these yet unknown effects of VEGF on epithelial cells are obviously suppressed with malignant transformation.     

Strong Immunohistochemical Expression of Vascular Endothelial Growth Factor Predicts Overall Survival in Head and Neck Squamous Cell Carcinoma

Background Head and neck squamous cell carcinoma (HNSCC) has high morbidity and mortality, and its relationship with tumor angiogenesis as measured by mircovessel density (MVD) or vascular endothelial growth factor (VEGF) expression has shown mixed results, with some, but not others, reporting correlation with outcome. Methods A retrospective study of 186 patients with HNSCC was performed. Patients were evaluated for MVD and VEGF and to correlate the levels with clinical parameters, including age at diagnosis, sex, site of tumor, stage, survival (disease free and overall), pathological tumor grade, and the presence of lymph node metastases. Results The 186 cancers included the following sites: oral tongue (n = 69), palate (n = 9), maxillary sinus (n = 8), floor of mouth (n = 13), oropharynx (n = 27), hypopharynx (n = 26) and larynx (n = 34). Over three-quarters of patients had advanced tumor (stage III/IV) and 58.6% had lymph node metastases. MVD and VEGF were assessed in 166 and 164 cases, respectively, but these were not correlated with site and grade. The 3-year overall and disease-free survival rates were 55.4% and 53.2%, respectively. Both univariate and multivariate survival analysis showed that advanced T stage, nodal metastasis, and strong VEGF intensity were independent adverse predictors for overall and disease-free survival. In stage IV disease, strong VEGF immunoreactivity was found to be the single adverse factor affecting the overall survival and a contributory factor for disease-free survival. Conclusions VEGF immunoreactivity is a strong predictor of adverse outcome, particularly in locoregionally advanced disease.     

Tumor angiogenesis is associated with progression after radical prostatectomy in pT2/pT3 prostate cancer

BACKGROUND: The clinical relevance of tumor angiogenesis has been investigated in several human tumor types. Angiogenesis (measured as microvessel density; MVD) was recently correlated with tumor stage, grade, and clinical course in prostate cancer (PC). However, considerable controversy remains concerning the prognostic value of angiogenesis in PC. METHODS: We examined MVD in primary PCs to further establish the prognostic relevance of angiogenesis in this tumor entity. In 98 paraffin-embedded PCs of various stages, 5 prostate adenomas, and 20 normal prostate tissues, MVD was determined immunohistochemically using a polyclonal antibody against factor VIII. The findings were correlated with the clinical data of the patients. RESULTS: Normal prostate tissue and prostate adenomas had a low MVD. In PC, MVD increased significantly with tumor stage and grade (P < 0.001). The Wilcoxon rank statistics showed significant differences for MVD (P < 0.0001), tumor stage (P < 0. 0027), and grade (P < 0.0001), but not for preoperative prostate-specific antigen values in PC patients with and without tumor progression subsequent to treatment, respectively. Importantly, multivariate survival analysis revealed that MVD and tumor grade were the only independent markers for progression in prostate carcinoma. CONCLUSIONS: In this study, tumor angiogenesis measured by MVD was associated with a dismal pathologic appearance and a negative clinical prognosis in PC after radical prostatectomy.     

Microvessel density and vascular endothelial growth factor expression in infiltrating lobular mammary carcinoma

Angiogenesis is an important prognostic factor in infiltrating ductal carcinoma (IDC). Vascular endothelial growth factor (VEGF) stimulates angiogenesis in vivo. VEGF expression has been correlated with high vascularity in IDC. However, little is known about the prognostic significance of microvessel density (MVD) and its correlation with the expression of VEGF in infiltrating lobular carcinoma (ILC). We analyzed tumor samples from 51 patients with primary classic ILC to determine the relationship between tumoral MVD and VEGF expression. Cases of pleomorphic lobular carcinoma and tubulolobular carcinoma were excluded. Five-micron thick sections obtained from formalin-fixed, paraffin-embedded tissue blocks were immunostained with antibodies to factor VIII-related antigen (Dako, Carpenteria, CA) and VEGF (Calbiochem, Boston, MA). The former was used for MVD analysis. The vessel counts from the three most vascular fields (x200 magnification) were recorded and the highest of the vessel counts of the three fields was designated as the MVD. The intensity of VEGF staining and the proportion of cells staining were scored. Both the vessel counts and the scoring of VEGF staining were evaluated by two independent pathologists. The Student's t-test and Wilcoxon rank sum test were used to compare mean MVD and VEGF scores according to various clinical and pathologic features. All significance tests were two-sided with an alpha-level of 0.05. There was good correlation between the MVD of each observer (correlation coefficient 0.775, p < 0.001). There was no correlation of MVD or VEGF score with the size or stage of the tumor. In addition, the MVD or VEGF score was not significantly different between axillary lymph node-positive cases and node-negative cases, between patients with recurrence and those without, and between patients who survived and those who died of disease. There was, however, a weak negative correlation between the MVD and VEGF expression (Spearman correlation coefficient -0.08). Neither MVD or VEGF immunoscore were associated with tumor recurrence or vital status in patients with ILC. The absence of a statistically significant positive correlation between MVD and VEGF expression suggests that other factors may play a more important role in the angiogenesis of ILC.