Vascular endothelial growth factor (VEGF) expression is not associated with prognosis in patients with radically resected ampullary carcinoma

Vascular endothelial growth factor (VEGF) is known to be a potent angiogenic mitogen that plays an important role in tumor angiogenesis [1Go]. The correlation between the expression of VEGF and either metastasis or a poor prognosis has been reported for several cancers [2Go]. Kurahara and colleagues demonstrated that VEGF expression in patients with pancreatic head cancer is significantly associated with lymphatic metastasis and prognosis [3Go]. Khan and colleagues [4Go] analysed the micro vessel density (MVD) as a prognostic factor in a sample of resected ampullary cancer patients. They demonstrated that MVD expression was higher in patients with lymph node metastasis, but failed to show a significant correlation with survival.

In order to investigate the potential prognostic role of VEGF expression in ampullary carcinoma we included in the present report 39 consecutive radically resected ampullary cancer patients. Pathologic findings (tumor size and spread, and lymph node status) were obtained from the pathologists' original reports and were re-assessed by our pathologists. Survival was defined as from the date of initial surgery to the date of death or the last contact. Follow-up data were available for all included patients. The most representative blocks of each patient were selected to be cut into new 5 µm-thick sections for immunohistochemical studies. Immunohistochemical staining (ICH) was performed by the streptoavidin-biotin method. The antibodies used were a polyclonal antibody against VEGF protein (A-20 Santa Cruz Biotechnology) in a 1:200 dilution at room temperature for 2 h. Immunohistochemical staining of tumors with this antibody showed primarily a cytoplasmatic localization of VEGF protein. The expression of VEGF was assessed according to the percentage of immunoreactive cells in a total of 1000 neoplastic cells (quantitative analysis). Immunoreactivity was graded as follows: positive, more than 10% of carcinoma cells stained and negative. No detectable staining or less than 10% of carcinoma cells stained [5Go]. Furthermore, the qualitative intensity of staining for VEGF was assessed using a scale of 0–3+, with 0 representing no detectable stain, and 3+ representing the strongest stain [6Go]. The univariate survival analysis for the prognostic variable on overall survival was estimated by the Kaplan–Meier method. The statistical significance of the differences in survival distribution among the prognostic groups was evaluated by the log-rank test. P values <0.05 were regarded as statistical significant in two-tailed tests. SPSS software (version 10.00, SPSS, Chicago) was used for statistical analysis.

The cohort consisted of 39 patients with pathological diagnosis of ampullary cancer (20 men and 19 women) undergoing pancreatic-duodenectomy with radical intent. The median age at diagnosis was 62.3 years (range 38–78). Fourteen patients were node-positive and 25 patients were node-negative. The median duration of follow-up after surgery was 51 months (range 13–102). The median overall survival was 46 months (range 6–100). Adjuvant radiotherapy and/or chemotherapy for ampullary cancer was not routinely offered in the hospitals involved in the study.

The expression analysis of VEGF revealed that in 35 out of 39 (89.74%) specimens VEGF staining was positive. The VEGF staining was always cytoplasmatic. To determine the prognostic impact of VEGF protein expression by univariate survival analysis, patients were stratified according to the dichotomized variables (criteria as stated above) in VEGF 0–1+ versus VEGF 2–3+. By univariate analysis, overall survival was not influenced by VEGF expression (P = 0.651). In particular, the median survival time in patients with low VEGF expression was 65 months (95% confidence interval 20.76–109.24 months) versus 65 months (95% CI 45.22–84.78 months) in patients with high VEGF expression.

There are few substantial data reporting significant prognostic markers for ampullary cancer patients. An increasing interest in oncology research is now focused on molecular markers of angiogenesis in order to select patients with better prognosis, and who are therefore in need of more targeted specific treatments. For these reasons, for the first time in the literature, we have attempted to characterize the expression examining the possible prognostic significance of an angiogenesis marker as VEGF in a homogeneous cohort of patients with radically resected cancer of the ampulla of Vater. The present study reports the absence of a prognostic role of angiogenesis in this type of cancer.

D. Santini1,*, B. Vincenzi1, G. Perrone2, C. Rabitti2, D. Borzomati3, S. Valeri3, R. Coppola3, P. Magistrelli4 and G. Tonini1

1 Department of Medical Oncology, 2 Department of Pathology 3 Department of Surgery, University Campus Bio-Medico, Rome; 4 Department of Surgery, Catholic University of Rome, Italy

* E-mail: d.santini{at}unicampus.it

References

1. Leung DW, Cathians G, Kuang WJ et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246: 1305–1309.

2. Pepper MS. Lymphangiogenesis and tumor metastasis: myth or reality? Clin Cancer Res 2001; 7: 462–468.[Abstract/Free Full Text]

3. Kurahara H, Takao S, Maemura K et al. Impact of vascular endothelial growth factor-C and -D expression in human pancreatic cancer. Clin Cancer Res 2004; 10: 8413–8420.[Abstract/Free Full Text]

4. Khan AW, Dhillon AP, Hutchins R et al. Prognostic significance of intratumoural microvessel density (IMD) in resected pancreatic and ampullary cancers to standard histopathological variables and survival. Eur J Surg Oncol 2002; 28: 637–644.[CrossRef][ISI][Medline]

5. Saito H, Tsujitani S, Ikeguchi M et al. Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue. Br J Cancer 1998; 78: 1573–1577.[ISI][Medline]

6. Takahashi Y, Tucker SL, Kitadai Y et al. Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg 1997; 132: 541–546.[Abstract]





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