Expression of thymidine phosphorylase as an indicator of poor prognosis for patients with transitional cell carcinoma of the bladder

BACKGROUND: Thymidine phosphorylase (TP), which is identical to platelet-derived endothelial cell growth factor (PD-ECGF), stimulates chemotaxis of endothelial cells and is involved in the angiogenesis of human solid tumors. METHODS: The activity and expression of TP were examined in human transitional cell carcinomas (TCCs) of the bladder, and their association with clinicopathologic findings was determined. The activity of the enzyme in 37 TCCs and 12 adjacent nonneoplastic tissues was measured spectrophotometrically. The expression of TP was also examined by immunoblotting. Immunohistochemical analysis was performed on 108 TCCs. RESULTS: TP activity in the carcinomas was higher than that in adjacent normal tissues (P = 0.002). TP activity in Grade 3 tumors or those classified as pT2-4 was higher than in Grade 1 and 2 tumors (P = 0.017) or those classified as pT1 (P = 0.007). The level of expression of TP detected by immunoblotting correlated well with TP activity. Immunohistochemical analyses showed that 62 of 108 cases (57.4%) were TP positive. There was a significant correlation between TP expression and histologic grade, infiltration pattern, local invasion, and lymph node metastasis. TP expression as a prognostic variable was studied using the Cox proportional hazards model. TP overexpression was an independent prognostic factor, as were lymph node metastasis and local invasion. CONCLUSIONS: These findings suggest that TP activity and its level of expression influence the progression of TCC and the prognoses of patients with this disease.     

环氧化酶-2 在膀胱癌组织及尿脱落细胞中的表达和意义

 目的 探讨COX-2在膀胱癌组织中的表达，了解尿脱落细胞COX-2表达在膀胱癌早期诊断中的价值。方法 应用免疫组化技术检测48例膀胱移行细胞癌组织、免疫细胞化学技术检测40例膀胱移行细胞癌患者和30例非肿瘤患者尿脱落细胞COX-2的表达。结果 膀胱移行细胞癌组织COX-2阳性表达率为72．9％，对照组正常膀胱黏膜无表达。COX-2的表达与膀胱癌临床分期显著相关(P<0．05)，不同病理分级膀胱癌的表达差别无显著性意义。非肿瘤患者尿脱落细胞无COx-2表达，膀胱癌尿脱落细胞COX-2免疫细胞化学检测阳性率为67．5％，明显高于常规尿细胞学的37．5％(P<0．05)，尤其对于G1级和Ta～T1期的低级、早期肿瘤，尿脱落细胞COX-2免疫细胞化学检测与常规尿细胞学检查相比，具有显著性意义(P<0．05)。结论 COX-2在膀胱移行细胞癌的发生发展中起重要作用，与肿瘤的浸润、转移相关。尿脱落细胞COX-2表达检测特异性高，可作为早期诊断膀胱癌的一种标志物。     

Expression of inducible nitric oxide synthase and cyclooxygenase-2 in angiogenesis and clinical outcome of human gastric cancer

BACKGROUND AND OBJECTIVES: It has been recognized that inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) produce important endogenous factors of human tumors such as nitric oxide (NO) and prostaglandins, which is involved in the process of carcinogenesis and tumor progression. This study aimed to evaluate the association of clinicopathologic factors, microvessel density, and patient survival with the expression of iNOS and COX-2 in patients with gastric adenocarcinoma. MATERIALS AND METHODS: Seventy-nine specimens, resected from patients with gastric adenocarcinoma, were investigated by immunohistochemical stain against iNOS and COX-2. Microvessels were stained using anti-CD34 antibody and counted as microvessel density. RESULTS: Positive iNOS and COX-2 expressions were significantly correlated with microvessel density by multivariate analysis, respectively (P = 0.0127 vs. P = 0.0214). There was significant difference among the four groups (both iNOS and COX-2 positive, iNOS positive only, COX-2 positive only, and both negative) in serosal invasion (P = 0.038), lymph node metastasis (P = 0.038), Helicobacter pylori infection (P = 0.025), vascular invasion (P = 0.035), and microvessel density (P = 0.019). In patients with gastric cancer that co-expressed iNOS and COX-2, prognosis was significantly poorer than in those that expressed either iNOS or COX-2, or did not express both of them (P = 0.01738). The Cox proportional hazard regression analysis indicated that iNOS expression, vascular invasion, serosal invasion, and microvessel density are independent prognostic factors for patients with gastric cancer. CONCLUSIONS: iNOS and COX-2 expression of gastric cancer are related to tumor angiogenesis, tumor progression, and patient survival in human gastric cancer.     

Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma

BACKGROUND: Cyclooxygenases regulate the production of prostaglandins and play a role in tumor development and progression. The authors investigated the prognostic impact of expression of the cyclooxygenase (COX) isoforms, COX-1 and COX-2, on disease-free survival and progression-free survival in patients with primary breast carcinoma as well as the association between COX expression and other clinicopathologic parameters. METHODS: In this study COX isoform expression was determined by immunohistochemistry in a cohort of 221 patients with primary breast carcinoma. RESULTS: Expression of COX-2 was detected in 36% of breast carcinoma samples and was associated significantly with several clinicopathologic parameters, including positive lymph node status (P < 0.0005), larger tumor size (P < 0.0005), poor differentiation (P < 0.0005), vascular invasion (P = 0.03), and negative estrogen receptor status (P = 0.04). In contrast, COX-1 was expressed in 45% of tumors and was associated with smaller tumor size (P = 0.02) and with negative lymph node status (P = 0.01). In a univariate survival analysis, a significant association was observed between elevated COX-2 expression and decreases in disease-free survival (P = 0.0007) and overall survival (P = 0.02). In a multivariate analysis, expression of COX-2 was of borderline significance for disease-free survival (relative risk, 1.90; 95% confidence interval, 1.00-3.59), adjusting for tumor size, histologic grade, number of positive lymph nodes, and patient age. Elevated expression of COX-1 in tumor tissue had no statistically significant influence on patient prognosis. CONCLUSIONS: The current data suggest that increased expression of COX-2 may play a role in the progression of primary breast carcinoma. It remains to be investigated whether treatment with selective inhibitors of COX-2 may be an additional therapeutic option for patients with breast carcinoma.     

Expression of cyclooxygenase-2 in renal cell carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, expression of matrix metalloproteinase-2, and survival.

PURPOSE: Cyclooxygenase (COX)-2 plays an important role in tumor cell proliferation, resistance to apoptosis, angiogenesis, and invasion in various malignant tumors. However, the relationships between COX-2 expression and these biological processes, clinicopathological features, and survival rate in patients with renal cell carcinoma are not clear. EXPERIMENTAL DESIGN: Tumor sections surgically removed from 131 patients were examined for COX-2 expression by immunohistochemistry. We also examined Ki-67 labeling index, apoptotic index, microvessel density, and matrix metalloproteinase (MMP)-2 expression, and correlated COX-2 expression with various clinicopathological features and survival. RESULTS: Of 131 sections, 70 (53.4%) were positive for COX-2 expression. COX-2 expression was associated significantly with various clinicopathological features, and correlated with the Ki-67 labeling index, microvessel density, and MMP-2 expression (P < 0.01), but not with the apoptotic index (P = 0.054). COX-2 expression was also identified as an independent risk factor for large tumor size (>7 cm) in multivariate logistic regression model. COX proportional hazards analysis showed that distant metastasis and high T stage were independent prognostic factors [odds ratio (OR), 9.41; 95% confidence interval (CI), 2.16-41.11; P < 0.01 and OR, 5.19; 95% CI, 1.02-26.54; P = 0.048, respectively), whereas COX-2 expression was not (OR, 1.46; 95% CI, 0.24-9.00; P = 0.68). CONCLUSION: COX-2 expression in patients with renal cell carcinoma is associated with several clinicopathological factors, and appeared to play an important role in tumor cell proliferation and MMP-2 expression, but is not a significant prognostic factor.     

Expressions of COX-2 and VEGF-C in gastric cancer: correlations with lymphangiogenesis and prognostic implications

Background

Cyclooxygenase-2 (COX-2) has recently been considered to promote lymphangiogenesis by up-regulating vascular endothelial growth factor-C (VEGF-C) in breast and lung cancer. However, the impact of COX-2 on lymphangiogenesis of gastric cancer remains unclear. This study aims to test the expression of COX-2 and VEGF-C in human gastric cancer, and to analyze the correlation with lymphatic vessel density (LVD), clinicopathologic features and survival prognosis.

Methods

Using immunohistochemistry, COX-2, VEGF-C and level of LVD were analyzed in 56 R0-resected primary gastric adenocarcinomas, while paracancerous normal mucosal tissues were also collected as control from 25 concurrent patients. The relationships among COX-2 and VEGF-C expression, LVD, and clinicopathologic parameters were analyzed. The correlations of COX-2, VEGF-C and level of LVD with patient prognosis were also evaluated by univariate tests and multivariate Cox regression.

Results

The expression rates of COX-2 and VEGF-C were 69.64% and 55.36%, respectively, in gastric carcinoma. Peritumoral LVD was significantly higher than that in both normal and intratumoral tissue (P < 0.05). It was significantly correlated with lymph node metastasis and invasion depth (P = 0.003, P = 0.05). VEGF-C was significantly associated with peritumoral LVD (r = 0.308, P = 0.021). However, COX-2 was not correlated with VEGF-C (r = 0.110, P = 0.419) or LVD (r = 0.042, P = 0.758). Univariate analysis showed that survival time was impaired by higher COX-2 expression and higher peritumoral LVD. Multivariate survival analysis showed that age, COX-2 expression and peritumoral LVD were independent prognostic factors.

Conclusions

Although COX-2 expression was associated with survival time, it was not correlated with VEGF-C and peritumoral LVD. Our data did not show that overexpression of COX-2 promotes tumor lymphangiogenesis through an up-regulation of VEGF-C expression in gastric carcinoma. Age, COX-2 and peritumoral LVD were independent prognostic factors for human gastric carcinoma.     

Cyclooxygenase-2 and p53 expressions in endometrial cancer.

Cyclooxygenase-2 (COX-2) has been known to be related with various types of carcinoma, but we have insufficient knowledge about the association between COX-2 and endometrial cancer. Many have reported a close relationship between p53 expression and a poor prognosis in endometrial cancer, but it is unclear whether p53 is an independent prognostic factor. To clarify these uncertainties, we examined the expressions of COX-2 and p53 in endometrial cancer tissues. The study was carried on 152 endometrial cancer patients who had operation at Seoul National University Hospital. Paraffin-embedded tissue blocks were sectioned and immunostained using monoclonal anti-COX-2 and anti-p53 antibodies. Twenty-seven (17.8%) specimens stained as COX-2 positive. COX-2 positivity was more frequently observed in postmenopausal patients than in premenopausal patients (8.8% versus 25.0%; P = 0.009). However, COX-2 positivity did not show a statistically significant association with any other clinicopathologic characteristic (parity, body mass index, histotype, International Federation of Gynecology and Obstetrics stage, grade, lymph node metastasis, deep myometrial invasion, or p53 overexpression). Thirty-one (20.4%) specimens showed p53 overexpression and this was significantly correlated with an advanced stage (P = 0.001), poor differentiation (P < 0.001), lymph node metastasis (P = 0.012), and deep myometrial invasion (P < 0.001). Multivariate Cox regression analysis showed that advanced stage was an independent prognostic factor of survival, but p53 overexpression was not. COX-2 may be associated with endometrial cancer carcinogenesis during the postmenopausal period but not with tumor aggressiveness and p53 overexpression. The p53 overexpression was found to be strongly associated with endometrial cancer aggressiveness.     

Increased cyclooxygenase-2 expression is associated with chemotherapy resistance and poor survival in cervical cancer patients.

PURPOSE: To investigate the expression of cyclooxygenase (COX-2) and its association with clinicopathologic parameters and clinical outcome in patients with cervical cancer. PATIENTS AND METHODS: The study included 84 patients with stage IB to IVA cervical cancer. Patients with early-stage cases (n = 21) underwent radical surgery, whereas patients with locally advanced cervical cancer (LACC) (n = 63) were first administered neoadjuvant cisplatin-based treatment and subjected to surgery in case of response. Immunohistochemical analysis was performed on paraffin-embedded sections with rabbit antiserum against COX-2. RESULTS: COX-2--integrated density values in the overall population ranged from 1.2 to 82.3, with mean plus minus SE values of 27.4 plus minus 2.4. According to the chosen cutoff value, 36 (42.9%) of 84 patients were scored as COX-2 positive. COX-2 levels were shown to be highly associated with tumor susceptibility to neoadjuvant treatment. COX-2 showed a progressive increase from mean plus minus SE values of 19.9 plus minus 8.0 in complete responders through 31.5 plus minus 3.5 in partial responses to 44.8 plus minus 3.9 in patients who were not responsive (P =.0054). When logistic regression was applied, only advanced stage and COX-2 positivity retained independent roles in predicting a poor chance of response to treatment. COX-2--positive patients had a shorter overall survival (OS) rate than COX-2--negative patients. In patients with LACC, the 2-year OS rate was 38% in COX-2--positive versus 85% in COX-2--negative patients (P =.0001). In the multivariate analysis, only advanced stage and COX-2 positivity retained independent negative prognostic roles for OS. CONCLUSION: The assessment of COX-2 status could provide additional information to identify patients with cervical cancer with a poor chance of response to neoadjuvant treatment and unfavorable prognosis.     

Cyclooxygenase-2 Expression in Urinary Bladder Transitional Cell Carcinoma and its Association with Clinicopathological Characteristics

Background: Transitional cell carcinoma (TCC) is the most predominant type of urinary bladder tumor. Ascyclooxygenase (COX)-2 is recently introduced as an attractive target molecule in bladder TCC, we evaluated theimmunohistochemical expression of this marker and its association with several clinicopathological characteristics.Materials and Methods: This cross-sectional study was performed in the Pathology department of Sina Hospitalin Tehran, Iran during 2006-2011. Ninety-two paraffin embedded blocks were selected from patients withurinary bladder TCC who underwent cystectomy or transurethral resection (TUR). Then, we assessed COX-2expression by immunohistochemical staining using antibody against COX-2. Staining in more than 5% of tumorcells was considered as positive expression. Results: COX-2 was expressed in 50 % of our patients. This markerwas markedly expressed in high grade bladder TCC (62.1%) versus other grades and there was statisticallya significant difference in COX-2 expression between various grades (p=0.008). In addition, patients’ age,lymphatic and perineurial invasion were associated with the expression of COX-2 (p=0.001, 0.015 and 0.039,respectively). However, other parameters such as stage, tumor size, venous invasion and lymph node metastasisdid not show any significant relationship with this marker (all, p>0.05). Conclusions: COX-2 was expressed inurinary bladder TCC especially in high grade forms, advocating its probable role in the differentiation of thistumor. Accordingly, COX-2 could be a valuable biological target molecule in the evaluation and treatment ofpatients with bladder TCC.     

COX-2 Expression in Renal Cell Carcinoma and Correlations with Tumor Grade,Stage and Patient Prognosis

Background: Cyclooxygenase 2 (COX-2) is important as an enzyme in the pathway leading to the production of prostaglandin E2 (PGE2) and arachidonic acid. This pathway is known to play a role in inflammation, tumor growth, invasiveness and metastasis, inhibition of apoptosis and angiogenesis. Inhibition of COX-2 has been shown to be a promising antitumor and antiangiogenic strategy in several tumor types, including renal cell carcinoma (RCC). Therefore, we decided to evaluate the immunohistochemical expression of this marker and its association with several clinicopathological characteristics in a series of cases. Materials and Methods: COX-2 expression was examined immunohistochemically in tumor tissues obtained from 96 patients who underwent radical (94 cases) or partial (2 cases) nephrectomy. Correlations between COX-2 expression and clinicopathologic findings including pathologic stage, nuclear grade and other indicator of prognosis were examined. Results: Of 96 tumors, 20.9% were positive for COX-2 expression. A correlation was found between COX-2 expression and tumor histological subtype (P=0.03).The papillary subtype showed maximum expression of this marker (43.8%) and the clear subtype minimum (14.7%). There were also possible links between COX-2 expression and pathologic stage, nuclear grade and nodal involvement but the results were not statistically significant (P=0.8, P= 0.14 and P=0.06, respectively). No correlation was found between COX2 expression and patient age, gender, tumor size, metastasis or survival. Conclusions: In our study, COX-2 expression was correlated with the histological subtype of RCC. Additional research is required to determine the link between COX-2 expression and prognosis and also evaluation of probable effectiveness of COX-2 inhibitor drugs in treatment of RCC patients.     

基质金属蛋白酶与膀胱癌分化和浸润的关系

目的 探讨基质金属蛋白酶2（MMP－2）在膀胱移行细胞癌（TCC）中的表达与肿瘤分化和浸润,以及与p53和ki-67表达的关系。方法 采用免疫组化DAKO En Vision System方法,测定MMP－2,p53和ki-67在83例膀胱TCC中的表达。结果 MMP－2在TCC中的性率为63．9％,表达显著高于癌旁粘膜（P＜0．01）;MMP－2表达强度与TCC癌细胞的分化高低和浸润深度呈明显正相关（P＜0．05）,并与ki-67表达有显著意义的关联（P＜0．01）,但与p53表达无明显相关（P＞0．05）。结论 MMP－2在TCCR的发展和浸润过程中发挥重要作用,可能成为预测TCC预后的参考指标。     

The effect of cyclooxygenase-2 expression on tumor vascularity in advanced stage ovarian serous carcinoma

BACKGROUND: Cyclooxygenase-2 (COX-2) seems to be involved at various steps in the processes of malignant transformation and tumor progression. Investigations have shown that COX-2 overexpression is associated with increased proliferation, reduced apoptosis, and angiogenesis. METHODS: Specimens from 125 patients with high-grade, advanced-stage (Stage III-IV) serous ovarian carcinoma were evaluated by immunohistochemistry for COX-2, p53, bcl-2, epidermal growth factor receptor (EGFR), and Her-2/neu expression and for CD34-stained microvessel density (MVD). Statistical analysis was performed to investigate the correlations between COX-2 expression and 1) clinicopathologic characteristics, 2) tumor MVD, and 3) expression of other molecular markers. The effect of COX-2 expression on survival was determined using survival analysis. RESULTS: Increased COX-2 expression was significantly correlated with tumor MVD (Spearman rank correlation test: r = 0.41; P < 0.001). There was no association observed between COX-2 expression and expression levels of EGFR, Her-2/neu, bcl-2, or p53. Patients who had tumors that showed high COX-2 expression had a worse prognosis compared with patients who had tumors with low expression (death hazard ratio, 2.0; 95% confidence interval, 1.2-3.5; P < 0.001). A multivariate analysis revealed that COX-2 expression was the strongest predictor of survival among the different prognostic factors analyzed. CONCLUSIONS: The current study demonstrated that COX-2 expression was correlated significantly with survival in patients with high-grade, high-stage serous ovarian carcinoma. Expression of COX-2 also was correlated with tumor angiogenesis but not with EGFR, Her-2/neu, or p53 expression. In addition to their prognostic significance, a better understanding of the biology of these molecular changes may help identify new targets for therapy in patients with ovarian carcinoma.     

COX-2和Survivin在食管癌组织芯片的表达及临床意义

目的：检测食管癌组织中COX-2和Survivin蛋白的表达情况及其与食管癌患者临床病理特征的关系。方法：采用免疫组化EnVision法和组织芯片技术，检测手术切除的56例食管癌患者肿瘤组织中COX-2和Survivin蛋白的表达状况，分析其与临床病理特征之间的关系及COX-2和Survivin表达的相关性。结果：COX-2在食管癌组织表达主要分布于细胞质，少数位于细胞膜，而Survivin则分布于细胞核。COX-2和Survivin在食管癌组织阳性表达率分别为69．6％和71．4％，而在食管癌旁组织则无表达。COX-2表达与性别（P=0．543）、年龄（P=0．561）和肿瘤分化程度（P=0．216）尤关，但与肿瘤浸润深度（P=0．046）、淋巴结转移（P=0．001）及TNM分期（P=0．001）密切相关。Survivin表达与性别（P=1．000）、年龄（P=1．000）和肿瘤分化程度（P=0．333）亦无关，与肿瘤浸润深度（P=0．020）、淋巴结转移（P=0．003）及TNM分期（P=0．002）具有相关性。COX-2和Survivin均为阳性表达35例（62．5％），呈正相关（P=0．000，r=0．614）。结论：COX-2和Survivin在食管癌中呈过度表达，并与肿瘤浸润深度、淋巴结转移和临床分期密切相关，两者表达呈正相关，提示COX-2和Survivin在肿瘤进展中可能有协同作用。     

survivin和COX-2在非小细胞肺癌中的表达及意义

背景与目的 应用组织芯片技术可以方便快捷地进行免疫组化染色。本研究的目的是探讨survivin和COX-2与非小细胞肺癌（NSCLC）患者临床病理特征和长期预后之间的关系。方法 将88例NSCLC及5例正常肺组织标本制作成组织芯片，应用免疫组织化学SP法检测survivin和COX-2的表达。结果 survivin胞质和胞核阳性表达率分别为94．3％和79．5％，COX-2阳性表达率为71.6％，而正常肺组织均为阴性，NSCLC中的survivin和COX-2表达明显高于正常肺组织（P〈0．005）。survivin胞核阳性表达率在吸烟者中明显升高（P=0．002）。COX-2在女性、不吸烟者、腺癌和淋巴结转移阳性者中表达明显升高（P〈0．05）。单因素分析显示COX-2表达与患者生存有密切关系（P=0．014），而survivin表达与生存未见明显关系。多因素分析显示survivin和COX-2均不是影响预后的独立危险因素。结论 survivin检测可能有助于NSCLC的诊断；COX-2阳性表达者预后差，可能在预后判定中有重要作用。     

Cell proliferation of transitional cell bladder tumours determined by PCNA/cyclin immunostaining and its prognostic value.

Cell proliferation of transitional cell bladder cancer (TCC) was determined by PCNA (proliferating cell nuclear antigen)/cyclin immunostaining in 178 TCCs and the results were related to established prognostic factors, progression and survival during a mean follow-up period of 10 years. The fraction of PCNA/cyclin positive nuclei was related to T-category (P = 0.008), papillary status, WHO grade, DNA ploidy, S phase fraction, M/V index (volume corrected mitotic index) and AgNORs (silver stained nucleolar organiser regions) (for all P less than 0.001). TCCs presenting with pelvic lymph node metastasis at diagnosis had a significantly higher growth fraction than the tumours confined to the bladder wall (P less than 0.001). The fraction of PCNA/cyclin positive nuclei predicted progression in T-, N- and M-categories (P less than 0.001). In Ta-T1 tumours high fraction of PCNA/cyclin positive nuclei predicted metastasis (P = 0.019). In survival analysis the fraction of PCNA/cyclin positive nuclei predicted survival in the entire cohort (P less than 0.001) and in Ta-T1 tumours (P = 0.0005). In a multivariate survival analysis the fraction of PCNA/cyclin positive nuclei showed independent predictive value in the entire cohort (P = 0.046), in papillary tumours (P = 0.006) and in Ta-T1 tumours (P = 0.015). The results show that the growth fraction as determined by PCNA/cyclin immunostaining is a significant prognostic variable in TCC.     

食管癌组织芯片COX-2和survivin表达及其 与预后的关系

 目的研究食管癌组织中COX-2和survivin蛋白的表达,及其预后意义。方法采用免疫组化EnVision法和组织芯片技术,检测手术切除的56例食管癌组织中COX-2和survivin蛋白的表达状况,通过Cox比例风险模型进行多因素分析,探讨与食管癌患者预后的关系。结果COX-2和survivin在食管癌组织阳性表达率分别为69.6％和71.4％。COX-2和survivin表达呈正相关（r=0.614,P=0.002）,且与肿瘤浸润深度、淋巴结转移及TNM分期密切相关。COX-2表达阳性患者的中位生存时间明显短于阴性患者（25.13月 vs.69.33月,P=0.0001）,survivin表达阳性患者的中位生存时间明显短于阴性患者（25.23月vs. 69.32月,P=0.0000）。Cox多因素分析表明,COX-2和survivin蛋白阳性表达为影响食管癌患者预后的独立因素。结论COX-2和survivin在食管癌中呈过度表达,且呈正相关,二者在肿瘤中可能发挥协调作用。COX-2和survivin高表达预示食管癌的不良预后,可以作为影响食管癌患者预后的独立因素。     

High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma

BACKGROUND: Vascular endothelial growth factor (VEGF), a recently identified growth factor with significant angiogenic properties, is a multifunctional angiogenic cytokine that is expressed in many tumors. High VEGF expression has been shown to correlate with the incidence of metastasis and poor prognosis in various cancers. In this study, the authors investigated VEGF expression and microvessel density (MVD) in ductal pancreatic adenocarcinoma and examined the correlations among VEGF expression, clinicopathologic factors, and clinical outcome. The authors especially focused on the correlation between VEGF expression and liver metastasis. METHODS: Paraffin embedded tumor specimens of 142 surgically resected pancreas carcinoma were immunohistochemically stained for VEGF and MVD. The correlations among VEGF expression and MVD, clinicopathologic factors, and clinical outcome were then statistically analyzed. RESULTS: One hundred thirty-two (93%) of 142 ductal pancreatic adenocarcinomas were positive for VEGF protein by immunohistochemistry. A significant correlation was observed between VEGF positivity and MVD (P < 0.0001). Multivariate logistic regression analysis indicated a significant association between high VEGF expression and liver metastasis (P = 0.010) but no other factors, such as age, tumor size, histologic type, lymph node metastasis, venous invasion, neural invasion, peritoneal metastasis, or local recurrence. Patients with tumors that showed moderate or high VEGF expression had significantly shorter survival than patients with low VEGF expression or none at all in their tumors (P < 0.05). CONCLUSIONS: These results indicate that VEGF expression is closely correlated with MVD and seems to be an important predictor for both liver metastasis and poor prognosis in ductal pancreatic adenocarcinoma.