Background
Head and neck carcinomas with lymphatic metastasis usually require radical therapeutic management and are associated with poor prognosis. This is particularly true for squamous cell carcinoma of the larynx (LSCC). In addition, patients with lymph node (LN) involvement have a worse prognosis compared to patients without LN metastasis [
1]. The identification of early stage LSCC patients at high risk therefore could help improving prognosis and treatment selection and preventing recurrence [
2,
3]. Although clinically of high importance, the mechanisms which drive metastasis to the lymph nodes in LSCC are still largely unknown. It has been suggested that a pro-angiogenic tumor microenvironment may promote lymphatic metastasis [
4‐
6]. The presence of neovascularization around neoplastic tissue is a typical finding in many solid tumors. Angiogenesis seems to be an important biological parameter implicated in tumor growth, metastasis and progression [
4,
5]. However, in LSCC controversial data with respect to the impact of angiogenesis on metastasis have been reported. Some studies suggested angiogenesis as a precursor for regional lymph node metastasis [
6] and implicated microvessel density in local tumor progression [
7]. In contrast, other studies did not show any prognostic relation between angiogenesis and prognosis, especially in patients with LSCC [
8‐
11].
Well defined markers of angiogenesis are CD31 and vascular endothelial growth factor (VEGF). CD31 is highly expressed on the surface of endothelial cells and well established for the monitoring of vessel density in malignant tissue. It is a member of the Immunoglobulin-superfamily PECAM-1 [
12] and it was reported that CD31 is involved in angiogenesis for example in early breast cancer [
13]. CD31 was even used as a prognostic marker for nasopharyngeal cancer [
14]. Sion-Vaardy et al. found a significantly increased number of vessels in head and neck tumors with deeper invasion [
15]. Kyzas et al., however, have questioned the role of CD31 for the prognosis of LSCC in their study on 69 patients with LSCC and oral cancer. They rather suggested that the expression of VEGF might have prognostic significance in these patients [
16].
VEGF is an important growth factor and signaling molecule involved in vasculogenesis and angiogenesis [
17]. VEGF was reported to influence the pathogenesis of LSCC as a parameter of angiogenesis [
16,
18‐
21]. In addition, a gene polymorphism of VEGF was suspected to be a risk factor for LSCC [
22]. Chen et al. found as well that VEGF influenced the pathogenesis of head and neck cancer and supposed an important role of VEGF as a serological biomarker [
23]. In contrast, Burian et al. were not able to demonstrate a relevant impact of elevated VEGF in the prognostic relevance of LSCC [
8].
The controversial results regarding the role of these angiogenic factors may be due to the heterogeneity of the patient cohorts with regard to early or late stage disease. The aim of this study therefore was to investigate a possible relation between markers of angiogenesis, N-stage, T-stage, overall survival and recurrence rates in a cohort of 97 patients with LSCC with a special emphasis on tumor stage.
Conclusion
Patients with low T-stage and negative N-stage are generally known to have a good five-year survival rate. However, our study identified a subgroup of patients with strong VEGF expression and high CD31-positive vessel number, which was linked to poor prognosis and increased risk for relapse. Thus, our study provides further evidence that quantification of angiogenesis in a subgroup of patients with laryngeal cancer could help to predict patient outcome and to better guide therapeutic decisions in this cancer entity.
Acknowledgements
The authors wish to thank Petra Altenhoff (Department of Otorhinolaryngology, University Hospital Essen) for excellent technical support and Ulrike Krahn (University Hospital Essen, IMIBE = Institute of medical informatics, biometry and epidemiology) for support with the statistical analyses.
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