Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis

We performed a meta-analysis of all 87 published studies linking intratumoral microvessel density (MVD), reflecting angiogenesis, to relapse-free survival (RFS) and overall survival (OS). With median MVD as cutoff, MVD impact was measured by risk ratio (RR) between the two survival distributions. Seventeen studies did not mention survival data or fit inclusion criteria. Twenty-two were multiple publications of the same series, leaving 43 independent studies (8936 patients). MVD was assessed by immunohistochemistry, using antibodies against factor VIII (27 studies; n = 5262), CD31 (10 studies; n = 2296), or CD34 (8 studies; n = 1726). MVD might be a better prognostic factor when assessed by CD31 or CD34 versus factor VIII (P = 0.11). For RFS, statistical calculations were performed in 25 studies (6501 patients). High MVD significantly predicted poor survival [RR = 1.54 for RFS and OS with the same 95% confidence interval (CI), 1.29-1.84]. Twenty-two studies analyzed separately lymph node-negative patients (n = 3580), for whom predictors of poor survival are requested. This latter meta-analysis included 15 studies for RFS (2727 patients) and 11 for OS (1926 patients). High MVD significantly predicted poor survival [RR = 1.99 for RFS (95% CI, 1.33-2.98) and RR = 1.54 for OS (95% CI, 1.01-2.33)]. Between-study variations could result from patient selection criteria, techniques to stain and count microvessels, and cutoff selection. MVD was a significant although weak prognostic factor in women with breast cancer. Standardization of MVD assessment is needed.     

Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature

We performed a meta-analysis of all published studies relating intratumoural microvessel density (MVD) (45 studies) or vascular endothelial growth factor (VEGF) expression (27 studies), both reflecting angiogenesis, to relapse free (RFS) and overall survival (OS) in colorectal cancer (CRC). For each study, MVD impact was measured by risk ratio between the two survival distributions with median MVD as cutoff. Eleven studies did not mention survival data or fit inclusion criteria, six were multiple publications of same series, leaving 32 independent studies for MVD (3496 patients) and 18 for VEGF (2050 patients). Microvessel density was assessed by immunohistochemistry, using antibodies against factor VIII (16 studies), CD31 (10 studies) or CD34 (seven studies). Vascular endothelial growth factor expression was mostly assessed by immunohistochemistry. Statistics were performed for MVD in 22 studies (the others lacking survival statistics) including nine studies (n = 957) for RFS and 18 for OS (n = 2383) and for VEGF in 17 studies, including nine studies for RFS (n = 1064) and 10 for OS (n = 1301). High MVD significantly predicted poor RFS (RR = 2.32 95% CI: 1.39-3.90; P < 0.001) and OS (RR = 1.44; 95% CI: 1.08-1.92; P = 0.01). Using CD31 or CD34, MVD was inversely related to survival, whereas it was not using factor VIII. Vascular endothelial growth factor expression significantly predicted poor RFS (RR = 2.84; 95% CI: 1.95-4.16) and OS (RR=1.65; 95% CI: 1.27-2.14). To strengthen our findings, future prospective studies should explore the relation between MVD or VEGF expression and survival or response to therapy (e.g. antiangiogenic therapy). Assessment of these angiogenic markers should be better standardised in future studies.     

Prognostic significance of tumor angiogenesis in primary fallopian tube cancer.

Tumor angiogenesis has been found to be prognostically significant in many types of malignant tumors. We assessed tumor vascularity in 43 cases of histologically proven primary fallopian tube cancer, FIGO stage I-IV, using the highly specific endothelial cell marker CD34. Microvessel count was determined by counting CD34-positive cells at 200 x magnification. The 5-year disease-free survival probability was 43.8% (+/- 11.5%) in 24 patients whose tumors had a microvessel count < or = 19 microvessels/field and 19.7% (+/- 9.5%) in the > 19 microvessels/field group (P = 0.046). Stage and microvessel count were statistically significant for disease-free survival in univariate analysis. Therefore, a larger sample size would be required to detect an independent and statistically significant prognostic effect of microvessel density in primary fallopian tube cancer in multivariate analysis.     

The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis

The proto-oncogene RAS, coding for a 21 kDa protein (p21), is mutated in 20% of lung cancer. However, the literature remains controversial on its prognostic significance for survival in lung cancer. We performed a systematic review of the literature with meta-analysis to assess its possible prognostic value on survival. Published studies on lung cancer assessing prognostic value of RAS mutation or p21 overexpression on survival were identified by an electronic search. After a methodological assessment, we estimated individual hazard ratios (HR) estimating RAS protein alteration or RAS mutation effect on survival and combined them using meta-analytic methods. In total, 53 studies were found eligible, with 10 concerning the same cohorts of patients. Among the 43 remaining studies, the revelation method was immunohistochemistry (IHC) in nine and polymerase chain reaction (PCR) in 34. Results in terms of survival were significantly pejorative, significantly favourable, not significant and not conclusive in 9, 1, 31, 2, respectively. In total, 29 studies were evaluable for meta-analysis but we aggregated only the 28 dealing with non-small-cell lung cancer (NSCLC) and not the only one dealing with small-cell-lung cancer (SCLC). The quality scores were not statistically significantly different between studies with or without significant results in terms of survival, allowing us to perform a quantitative aggregation. The combined HR was 1.35 (95% CI: 1.16-1.56), showing a worse survival for NSCLC with KRAS2 mutations or p21 overexpression and, particularly, in adenocarcinomas (ADC) (HR 1.59; 95% CI 1.26-2.02) and in studies using PCR (HR 1.40; 95% CI 1.18-1.65) but not in studies using IHC (HR 1.08; 95% CI 0.86-1.34). RAS appears to be a pejorative prognostic factor in terms of survival in NSCLC globally, in ADC and when it is studied by PCR.     

Microvessel density as a prognostic factor in non-small-cell lung carcinoma: a meta-analysis of individual patient data

BACKGROUND: Angiogenesis is a potential prognostic factor that has been investigated in patients with non-small-cell lung carcinoma. However, published studies of the role of angiogenesis as a prognostic factor are inconclusive. We aimed to collect individual patient data to assess microvessel-density counts (ie, a measure of angiogenesis) as a prognostic factor in non-small-cell lung carcinoma. METHODS: We obtained published and unpublished datasets and extracted appropriate data, taking particular care to ensure data quality. Detailed information was obtained for the laboratory methods used by every research centre that generated the data. The outcome of interest was overall survival. We did a meta-analysis to estimate the prognostic role of microvessel density by combining separately estimated hazard ratios (HR) from every study, which were adjusted for tumour stage and age. Analyses were done separately for studies that used the Chalkley method or for those that counted all microvessels. FINDINGS: 17 centres provided data for 3200 patients, 2719 of which were included in the analysis. All but three centres (datasets 9, 10, and 13-367 cases) had already published their findings, and six had updated follow-up information (datasets 1, 2, 3, 6, 7, and 8-1273 cases). For all but three centres (datasets 4, 11, and 13) some data corrections were necessary. For microvessel density counts obtained by the Chalkley method, the HR for death per extra microvessel was 1.05 (95% CI 1.01-1.09, p=0.03) when analysed as a continuous variable. For microvessel density counts obtained by the all vessels method, the HR for death per ten extra microvessels was 1.03 (0.97-1.09, p=0.3) when analysed as a continuous variable. INTERPRETATION: Microvessel density does not seem to be a prognostic factor in patients with non-metastatic surgically treated non-small-cell lung carcinoma. This conclusion contradicts the results of a meta-analysis of published data only. Therefore, the methodology used to assess prognostic factors should be assessed carefully.     

Microvessel Density as a Prognostic Factor in Ovarian Cancer: a Systematic Review and Meta-analysis

Background: The prognostic value of microvessel density (MVD), reflecting angiogenesis, detected in ovariancancer is currently controversial. Here we performed a meta-analysis of all relevant eligible studies. Materials andMethods: A comprehensive search of online PubMed, Medline, EMBASE and Sciencedirect was performed toidentify all related articles. The search strategy was designed as ‘microvessel density’, ‘ovarian cancer’, ‘ovarianneoplasm’, ‘CD34’ and ‘angiogenesis’. Results: The studies were categorized by author/year, number of patients,FIGO stage, histology, cutoff value for microvessel density, types of survival analysis, methods of hazard rations(HR) estimation, HR and its 95% confidence interval (CI). Combined hazard ratios suggested that high MVDwas associated with poor overall survival (OS) and progression-free survival (PFS), with HR and 95% CIs of1.84 (1.33-2.35) and 1.36 (1.06-1.66), respectively. Subgroup analysis showed that high MVD detected by CD34was relevant for OS [HR=1.67 (1.36-2.35)], but not MVD detected with other antibodies [HR=2.11 (0.90-3.31)].Another subgroup analysis indicated that high MVD in patients without pre-chemotherapy, but not with prechemotherapy,was associated with OS [HR=1.88(1.59-2.18 and HR=1.70 (-0.18-3.59)]. Conclusions: The OSand PFS with high MVD were significant poorer than with low MVD in ovarian cancer patients. However, highMVD detected by CD34 seems to be more associated with survival for patients without pre-chemotherapy.     

Angiogenesis in non-small cell lung cancer: the prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood

BACKGROUND: Due to a dismal prognosis of advanced lung cancer, novel screening tools and more effective treatments are clearly needed. Lately, an increasing number of tumour-released angiogenic cytokines which affect vessel formation, tumour growth, invasion, and metastasis have been identified. Vascular endothelial growth factors (VEGFs) and basic fibroblast growth factor (bFGF) are among the most important angiogenic factors. Based on available literature, we have explored the mechanisms of angiogenesis and its prognostic significance in non-small cell lung cancer, estimated by microvessel density (MVD) and the presence of VEGF and bFGF in the tumour and blood from NSCLC patients. METHODS: Several comprehensive Pubmed searches for the period January 1993 to May 2005 were performed using strategic combinations of the terms non-small cell lung cancer, angiogenesis, vascular endothelial growth factor, basic fibroblast growth factor, tumour expression, microvessel density, circulating, and serum. RESULTS: NSCLC neoangiogenesis, as measured by MVD, and tumour expression of VEGF are poor prognostic factors for survival (MVD, HR 1.8-2.0; VEGF, HR 1.5). bFGF tumour expression is also associated with poor survival and more aggressive disease. When evaluating the prognostic impact of elevated VEGF levels in blood, 10 of 16 studies (63%) indicated a negative prognostic impact. Of five studies on the prognostic value of circulating bFGF, three studies reported a negative prognostic impact, while one indicated bFGF as a good prognostic factor and one was inconclusive. CONCLUSION: Angiogenic factors are poor prognostic indicators for tumour aggressiveness and survival in NSCLC. Assessments of circulating levels of VEGF and possibly bFGF may be valuable future tools for treatment planning and monitoring of treatment effect and relapse. First, however, these blood tests need to be standardised and validated in large-scale prospective clinical trials.     

The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic and macrophage infiltration, microvessel density and survival in patients with primary operable breast cancer

The significance of the inter-relationship between tumour and host local/systemic inflammatory responses in primary operable invasive breast cancer is limited. The inter-relationship between the systemic inflammatory response (pre-operative white cell count, C-reactive protein and albumin concentrations), standard clinicopathological factors, tumour T-lymphocytic (CD4+ and CD8+) and macrophage (CD68+) infiltration, proliferative (Ki-67) index and microvessel density (CD34+) was examined using immunohistochemistry and slide-counting techniques, and their prognostic values were examined in 168 patients with potentially curative resection of early-stage invasive breast cancer. Increased tumour grade and proliferative activity were associated with greater tumour T-lymphocyte (P<0.05) and macrophage (P<0.05) infiltration and microvessel density (P<0.01). The median follow-up of survivors was 72 months. During this period, 31 patients died; 18 died of their cancer. On univariate analysis, increased lymph-node involvement (P<0.01), negative hormonal receptor (P<0.10), lower albumin concentrations (P<0.01), increased tumour proliferation (P<0.05), increased tumour microvessel density (P<0.05), the extent of locoregional control (P<0.0001) and limited systemic treatment (P相似文献   

Prognostic significance of platelet and microvessel counts in operable non-small cell lung cancer

BACKGROUND: Microvessel density, an indirect measure of angiogenesis, has been shown to be an independent prognostic marker in many solid tumours including non-small cell lung cancer (NSCLC). Platelets transport and release angiogenic growth factors. Platelets are increasingly likely to adhere to tumour microvessels due to raised expression of platelet-binding proteins and stasis in blood-flow. Increased vascular permeability in tumour microvessels facilitates platelet extravasation into the extracellular matrix. Adherence and extravasation both lead to platelet activation and release of growth factors capable of instigating the angiogenic process. METHODS: A total of 181 patients were identified who underwent resection of stage I-IIIa NSCLC with a post-operative survival >60 days. Patients were followed-up for a minimum of 24 months. Sections from the tumour periphery were stained for the endothelial marker CD34 (Novocastra NCL-END) using standard ABC immunohistochemistry. Chalkley counting was used to assess microvessel density. RESULTS: A pre-operative platelet count greater than the median and above the normal range (>400) was associated with a poor outcome (P=0.01 and P=0.04, respectively). Tumours with an above median and high Chalkley count (upper tertile) had a worse prognosis (P=0.007 and P=0.0006, respectively). There was no association between platelet count and Chalkley count. CONCLUSIONS: Platelet and microvessel counts are both potential prognostic markers for NSCLC. The role of platelets in the angiogenic process needs to be further investigated.     

若干生物学指标对淋巴结阴性乳腺癌预后意义的评价

目的 综合评估（Ｃ－ｅｒｂＢ－２、ＣＤ４４Ｖ６、ｎｍ２３、组织蛋白酶Ｄ（ｅｒｔｈ－Ｄ）的表达,肿瘤微血管计数（ＭＶＣ）及常用临床病理指标对淋巴结阴性乳腺癌患者的预后意义。方法 对６２例单纯采用手术治疗并随访１０年以上的淋巴结阴性侵性乳腺癌石蜡包埋标本,用免疫组化Ｓ－Ｐ法检测Ｃ－ｅｒｂＢ－２、ＣＤ４４Ｖ６、ｎｍ２３、ｅｒｔｈ－Ｄ表达,肿瘤微血管计数及其他临床病理指标,并与患者１０年生存率关系进行单因     

Increased microvessel density in mucinous compared with malignant serous and benign tumours of the ovary.

Microvessel density of benign, borderline and malignant ovarian tumours was studied immunohistochemically using antibodies to the endothelial cell markers CD31, CD34 and factor VIII-related antigen. Microvessel density was compared in tumours of different histological subtype, stage and patient outcome. CD31-immunostained sections were examined and regions of high and average microvessel density were selected. Identical regions were located on CD34- and factor VIII-related antigen-immunostained serial sections and microvessel counts obtained and converted to vessels mm(-2). CD31 and CD34 immunostaining revealed increased microvessel density in both the high and average vessel density regions of mucinous (222.4 +/- 24.8; 79.9 +/- 8.5) compared with serous (105.4 +/- 20.7; 33.3 +/- 6.8) and benign (84.4 +/- 19.4; 20.4 +/- 4.4) tumours (P < 0.001). CD31 and CD34 immunostaining also revealed increased microvessel density in early-stage mucinous tumours (234.6 +/- 28.2; 87.8 +/- 9.2) compared with that observed in both early- (72.8 +/- 15; 12.9 +/- 2.4) and late- (115.6 +/- 26.5; 29.8 +/- 8.5) stage serous tumours (P < 0.001). No differences in microvessel density in samples from patients with differing outcomes were observed (P > 0.05). Reduced factor VIII-related antigen compared with CD31 and CD34 immunostaining was observed in both borderline and malignant mucinous and serous tumours (P < 0.02) but not in benign tumours (P > 0.05). Our results contradict the putative association between increased microvessel density and poor prognosis and suggest that the level and control of angiogenesis may differ between ovarian tumour types.     

Lack of association of microvessel density with prognosis of renal cell carcinoma: evidence from meta-analysis

To investigate microvessel density (MVD) and its association with prognosis of renal cell carcinoma (RCC) by means of a meta-analysis. We obtained published studies and extracted appropriate data, then did a meta-analysis to estimate the predictive role of MVD by combining estimated effect-size from individual studies. Analyses for overall survival (OS) and cancer-specific survival (CSS) were performed, separately. Subgroup analysis stratified by biomarkers were also performed for studies using CD34, factor VIII-related antigen (F VIII) and others, respectively. A total of 20 studies were included for meta-analyses including nine (four for F VIII, three for CD34, and two for others) for OS and 11 (two for F VIII, seven for CD34 and two for others) for CSS. There was no significance of MVD predicting OS or CSS of RCC. The pooled HR for OS was 0.910 (95 % CI 0.824–1.006; P?=?0.065) and CSS was 0.977 (95 % CI: 0.915–1.043; P?=?0.487). We failed to observe significant association between MVD and prognosis of RCC. Additional studies are needed to provide more precise evidences to support our results.     

Angiogenesis and platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in cervical cancer.

The object of this study was to clarify the association of platelet-derived endothelial cell growth factor (PD-ECGF)/thymidine phosphorylase (dThdPase), separately assessed in cancer cells and in stroma cells, with clinicopathological factors including tumor angiogenesis and prognosis in cervical cancer. The expression of PD-ECGF was evaluated by immunohistochemical staining in 92 patients with stage Ib-II cervical cancer. The microvessel count was assessed by immunostaining for factor VIII-related antigen in the most neovascularized area. Microvessel count was significantly higher in tumors with non-squamous cell carcinoma. PD-ECGF expression in cancer cells was significantly higher in tumors with pelvic node metastasis and squamous cell carcinoma. Immunopositivity for PD-ECGF in stroma cells was significantly higher in tumors with large size and deep stromal invasion. The microvessel counts in cases with positive PD-ECGF expression in stroma cells were significantly higher than those in cases with negative PD-ECGF expression in stroma cells (p=0.048). Disease-free survival and overall survival were significantly worse in patients with deep stromal invasion, parametrial involvement, vaginal involvement, lymph-vascular space involvement, pelvic lymph node metastasis and high microvessel count. A multivariate analysis using Cox's proportional hazard model showed that high microvessel count independently predicted disease-free and overall survival. The expression of PD-ECGF in stroma cells may play a crucial role in the promotion of angiogenesis and tumor angiogenesis can be used as a useful prognostic marker for cervical cancer.     

5个免疫组化指标预测胃癌预后的意义

 目的　探讨微血管数和cyclin E、p53、CD44s、CD44v6的表达分别预测胃癌预后的作用。方法　以免疫组化法检测了95例胃癌的上述5指标,并同时检测了临床病理特征,然后研究了各个因素分别与预后和淋巴、静脉侵润的关系。结果　微血管数和cyclin E表达显著影响胃癌的预后。p53、CD44s、CD44v6的表达不显著影响预后。微血管数是显著独立的预后因素。微血管每增1支,淋巴管浸润的相对危险度都为增前的1.0314倍(P<0.05)。p53阳性癌淋巴结转移的相对危险度是阴性者的2.2403倍(P<0.05)。5个指标的过度表达或增高未使胃癌浸润静脉的相对危险度显著增高。结论　在胃癌中,微血管数是预测预后的重要指标,cyclin E表达也有一定预测作用,而p53、CD44s、CD44v6的表达无预后判断意义。     

The prognostic significance of angiogenesis in epithelial ovarian carcinoma.

The molecular biology underlying the metastatic process in ovarian carcinoma remains poorly understood. For other neoplasms, the induction of angiogenesis by malignant cells has been shown to play a pivotal role in the process of tumor proliferation and metastasis. The purpose of this study was to characterize the degree of angiogenesis in epithelial ovarian malignancies and to determine whether the degree of neovascularization has prognostic significance for survival. Tissue sections obtained from 88 ovarian cancer patients were examined immunohistochemically for angiogenesis after staining with anti-human endothelial cell antibodies to von Willebrand factor and CD31. Light microscopy was performed, and individual microvessel counts were quantified at high power (x400). A chart review was completed, collating data regarding age, stage, grade, status of disease, and survival. Statistical exploratory methods were used to find potentially useful prognostic cutpoints for marker values of angiogenesis. Of the total 88 patients, tissue microvessel counts from 85 were evaluated via antibodies to von Willebrand factor and 87 for CD31. Overall, median survival was 2.7 years in women with cancers containing high microvessel counts versus 7.9 years in those with low microvessel counts (P = 0.03). A low microvessel count was associated with better 5-year survival in both early stage (I and II) and advanced stage (III and IV) disease. Our data suggest that the degree of neovascularization may have prognostic significance in epithelial ovarian carcinoma, especially for women with early-stage disease. In this group of women, the degree of angiogenesis may allow the selection of women at high risk for recurrence who may benefit from aggressive adjuvant therapy.     

Neovascularisation is a prognostic factor of early recurrence in T1/G2 urothelial bladder tumours.

BACKGROUND: Of patients with superficial bladder cancer, a group are still at risk of disease recurrence, progression and death from their cancer after curative treatment. Angiogenesis is a crucial pathogenic mechanism for this type of urothelial cell carcinoma (UCC), and is a potential therapeutic target. However, the selection of the appropriate patients remains a dilemma. PATIENTS AND METHODS: Vascular endothelial growth factor (VEGF) expression and the presence of angiogenesis and occurrence of CD31, CD34, endoglin and factor VIII immunoexpression, were evaluated in 66 superficial papillary UCCs of the bladder and were correlated with classical histopathological factors and disease outcome. RESULTS: VEGF immunoreactivity was observed in 100% of cases, and more intensely in the luminal surface. The presence of microvessel clusters independently of a fibrovascular core was observed in 22.7% of cases. Of these, the T1/G2 subgroup had an independent and significantly lower recurrence-free survival (P = 0.0002). CONCLUSIONS: These results indicate that the presence of angiogenesis in tumour urothelium is a potential prognostic factor in superficial UCC, particularly in T1/G2 tumours, and may be used to select patients for anti-angiogenic treatments.     

Has Cox-2 a prognostic role in non-small-cell lung cancer? A systematic review of the literature with meta-analysis of the survival results

Cyclooxygenase-2 (COX-2) is overexpressed in lung cancer, especially in adenocarcinoma (ADC). Our aim was to determine the prognostic value of COX-2 on survival in patients with lung cancer. Studies evaluating the survival impact of COX-2 in lung cancer, published until December 2005, were selected. Data for estimation of individual hazard ratios (HR) for survival were extracted from the publications and combined in a pooled HR. Among 14 eligible papers, all dealing with non-small-cell lung cancer, 10 provided results for meta-analysis of survival data (evaluable studies). Cyclooxygenase-2 positivity was associated with reduced survival, improved survival or no statistically significant impact in six, one and seven studies, respectively. Combined HR for the 10 evaluable studies (1236 patients) was 1.39 (95% confidence intervals (CI): 0.97-1.99). In stage I lung cancer (six evaluable studies, 554 patients), it was 1.64 (95% CI: 1.21-2.24). No significant impact was shown in ADC. A slight detrimental effect on survival in patients with lung cancer is associated with COX-2 expression, but the statistical significance is not reached. This effect is statistically significant in stage I, suggesting that COX-2 expression could be useful at early stages to distinguish those with a worse prognosis.     

Bcl-2 is an independent prognostic factor and adds to a biological model for predicting outcome in operable non-small cell lung cancer.

INTRODUCTION: The underlying biology of a tumour may hold the key to predicting the outcome for an individual patient as well as identifying potential therapeutic targets. Using epidermal growth factor receptor (EGFR) and matrix metalloproteinase (MMP)-9 immunoexpression combined with microvessel counts we have developed a prognostic model for operable non-small cell lung cancer (NSCLC) which predicts outcome independent of stage (Thorax, 56 (2001) 561-566). The aim of this study was to evaluate the impact of bcl-2 expression upon survival in this model. METHODS: This was a retrospective analysis of 167 patients with resected stage I-IIIa NSCLC and >60 days post-operative survival. Minimum follow-up was 2 years. Immunohistochemistry was performed on paraffin-embedded tissue sections for bcl-2, EGFR, MMP-9 and the microvessel marker CD34 to evaluate the relationships between, and impact on survival of these biological markers. RESULTS: Tumour cell MMP-9 (P=0.002), microvessel count > median (P=0.01), bcl-2 (P=0.02) and stage (P=0.02) were independent prognostic factors. Bcl-2 expression was associated with an improved survival in all sub-groups of our prognostic model. CONCLUSION: bcl-2, EGFR and MMP-9 expression and angiogenesis provide prognostic information independent of TNM stage. Prognostic models offer the potential of tailoring the therapeutic management for an individual patient.     

Immunohistochemical analysis of vascular density and area in colorectal carcinoma using different markers and comparison with clinicopathologic prognostic factors

Analysis of blood and lymphatic vessel in colorectal cancer is controversial in the literature, possibly due to variations in the methods of analysis. In this study, it was aimed to search for a reliable approach in the quantification of angio- and lymphangiovascular density and area as a prognostic factor and to compare such vessel counts in normal mucosa, adenomas and cancer. A retrospective study was performed on 60 sporadic colorectal cancer, 30 colorectal adenomas, and 10 colorectal non-neoplastic lesions. Archival tissues were submitted to immunohistochemical evaluation using antibodies to CD31, CD34, CD105, VEGF-A, VEGF-C, and D2-40. Microvessel density and total vascular area were determined by computer image analysis and values were compared in the three groups of lesions; the prognostic value of these parameters was evaluated in the group of colorectal cancer. Most markers showed progressive vessel counts from non-neoplastic tissue to carcinoma, both for microvessel density and total vascular area. Only microvessel density determined by CD34 in the central areas of the cancer correlated with recurrence/metastasis (p = 0.04) and survival (p = 0.02). Different methods of quantification (microvessel counting versus estimation of total vascular area), immunohistochemical markers (pan-endothelial marker versus neovessels and lymphatic markers), and areas of analysis (periphery versus inner portions of the lesion) were assessed using image analysis. The results corroborate the increase in vascularization of carcinoma and suggest that microvessel density determined by immunostaining for CD34 in the inner portion of the tumor might represent a prognostically relevant parameter in colorectal cancer.