Elsevier

Lung Cancer

Volume 34, Issue 2, November 2001, Pages 233-241
Lung Cancer

High vascularity in the peripheral region of non-small cell lung cancer tissue is associated with tumor progression

https://doi.org/10.1016/S0169-5002(01)00246-XGet rights and content

Abstract

Objectives: We attempted to determine if the degree of angiogenesis can serve as a prognostic factor in the case of completely resected non-small cell lung cancer patients, with special reference to the center and the periphery of the tumor tissue. Method: For 255 Japanese patients who underwent completely resected non-small cell lung cancer (NSCLC), micro vessel density (MVD) was assessed by visual quantification of microvessels immunostained with anti-CD34 monoclonal antibody in 5 m section. Vascular endothelial growth factor (VEGF) was also immunostained on the same paraffin block specimen. Results: MVD at the center (MVD-c) and that at the periphery (MVD-p) were frequently different in each individual although a weak positive correlation was observed (r=0.499, P<0.0001). One hundred and one patients with high MVD-p, but not the 107 patients with high MVD-c, showed a significantly higher proportion of advanced stage, larger tumor size and nodal metastasis as compared with MVD. The 5 year survival rate and median survival time for the high MVD-p group were significantly lower than that of low the MVD-p group (43.0%/31 months vs 48.6%/54 months, P=0.0256). As to the relationship among vascular endothelial growth factor (VEGF) and MVD, expression of VEGF was not associated with the degree of MVD. However, patients with high grade MVD-p showed an unfavorable prognosis in cases of high expression of VEGF. Conclusion: High MVD-p is associated with advancement of NSCLC, and it was particularly apparent in conjunction with high VEGF expression.

Introduction

In 1998 in Japan, lung cancer was found to be the leading cause of cancer-related mortality [1]. Despite improvements in surgical and medical management, the clinical behavior of lung cancer is unfavorable. Overall survival of patients with non-small cell lung cancer (NSCLC) continues to be less than 15% at 5 years. About 50% of the patients who underwent complete resection had a recurrence of the cancer [2], [3]. The TNM classification is the only predictor of the clinical outcome. Analysis of factors related to NSCLC resulted in identification of potentially important features [4], [5], [6], [7], [8], but an improvement in the prognosis was not produced. Identification of specific indicators for metastatic potential from primary tumors should prove beneficial for these patients.

Angiogenesis is a complex process that includes activation, proliferation and migration of endothelial cells, disruption of vascular basement membranes, formation of vascular tubes and networks, and linkage to the pre-existing vascular networks [9], [10], [11]. This process is vital for solid tumors to grow and metastasize and much evidences suggests that tumor angiogenesis closely correlates with prognosis or metastasis [12], [13], [14]. The first study of the impact of tumor angiogenesis on the prognosis of NSCLC was reported in 1992 [15]. There are clinical reports that angiogenesis correlates with metastasis or prognosis for patients with NSCLC [16], [17], [18], [19], [20]. Immunohistochemical methods involve assessing microvessel density, described as counting the number of microvessel entities within regions with an elevated vascular density (hot spots) [21]. However, there are reports on heterogeneity of vascularized areas in tumor tissue taken from a single specimen [22], [23]. The data suggested that neovasucularization in the periphery rather than the center is significant for tumor progression. Thus it seemed important to examine the relationship between the region of tumor angiogenesis and factors such as tumor size, stage and prognosis.

In this report, we quantified angiogenesis of the peripheral and central regions of tumor tissues to determine if the data could serve as an indicator of recurrence or prognosis, especially following complete resection of NSCLC.

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Patients

The subjects studied included 255 consecutively treated Japanese patients (154 men and 101 women) with NSCLC, who underwent surgery in the Department of Surgery II (Currently Department of Surgery and Science), Kyushu University from January 1990 through August 1997. Pre-operative diagnostic procedures included brain computed tomography, chest and upper abdomen computed tomography, and nuclear medicine bone scan. Lobectomy or pneumonectomy with complete mediastinal lymph node dissection was

Microvessel density in the center and the periphery of the lung tumor

Fig. 1 shows evidence of the immunostained microvessels. Mean MVD-c and MVD-p were 12.89±0.55 and 13.12±0.66, respectively, with no significant difference. As shown in Fig. 2, these two values were not identical in each tumor although they did show a positive correlation with a P value of less than 0.0001 and a r-value of 0.499. Histograms of MVD-c and MVD-p showed a similar pattern in that seen to a large population of tumors with fewer than 11 counts (Fig. 3a and b).

The level of MVD and clinicopathologic factors

The average MVD-p was

Discussion

Even in cases of complete resection of a lung tumor, cancer relapse and death can occur in stage I, II and III NSCLC at rates of about 30, 50 and 70% as determined at the 5 year-follow up [2], [3]. Recurrence may be related to the growth of occult micrometastasis established prior to the time of surgery. Identification of specific indicators for the metastatic potential of primary tumors will aid in selecting patients who are at high risk for a recurrence.

Angiogenesis is required for the growth

Acknowledgements

We thank Ms Mariko Ohara for critical comments on the manuscript. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture, Japan.

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