Lymph node metastasis is a frequent reason for adverse clinical outcome in many epithelial neoplasms, including head and neck squamous cell carcinoma. The mechanisms underlying the capability of epithelial neoplasms to metastasize via lymphatic vessels have not yet been fully elucidated. There is great debate about whether cancer cells can metastasize by expansion and invasion of pre-existing peritumoral lymphatics or by the formation and invasion of new lymphatics within tumours (lymphangiogenesis). In order to investigate this issue, we examined 81 tissue specimens from patients with head and neck squamous cell carcinoma, using immunostaining for the specific lymphatic endothelium marker podoplanin, and assessed intratumoral and peritumoral lymphatic density. We also quantified lymphatic invasion and examined the possible associations of all the above parameters with clinicopathological features and outcome. Finally, we used double staining with podoplanin and the cell proliferation marker Ki-67 in order to evaluate lymphangiogenesis. High intratumoral and peritumoral lymphatic density were both significantly associated with the presence of lymph node metastasis at the time of diagnosis (chi2 test, p < 0.001 and p = 0.007, respectively) and there was a significant correlation between high intratumoral lymphatic density and lymphatic invasion. Patients with higher intratumoral lymphatic density exhibited shorter overall survival (log rank p < 0.001) and this correlation remained significant after multivariate analysis (Cox p = 0.04), indicating that intratumoral lymphatic density is an independent prognostic factor for mortality. Peritumoral lymphatic density had no influence on outcome. Double staining revealed the existence of proliferating intratumoral lymphatics, in which tumour emboli were occasionally observed. These results indicate that lymphangiogenesis indeed occurs in head and neck squamous cell carcinoma; that newly formed vessels are targets of invasion by cancer cells; and that intratumoral lymphatic density might be used as a criterion to separate patients at higher risk of an adverse clinical outcome.

Recent observations suggest an implication of the cyclooxygenase-2 (COX-2) in tumor lymphangiogenesis through an upregulation of vascular endothelial growth factor-C expression. It is unknown whether this mechanism also acts in squamous cell carcinoma of the head and neck region. We performed a retrospective study of 70 patients with head and neck squamous cell carcinoma in order to investigate whether COX-2 immunohistochemical expression correlates with vascular endothelial growth factor-C expression. We also examined the association of the expression of these molecules with clinicopathologic parameters (especially lymph node status) and outcome for these patients. We performed immunostaining on formalin-fixed, paraffinembedded tissue sections by the routine streptavidin-biotin peroxidase labeled procedure. Increased cyclooxygenase-2 expression was observed in 30 of the 68 tumor samples (44%), while high vascular endothelial growth factor-C expression occurred in 26 of the 68 tumor samples (38%). High expression of the two proteins was correlated with the presence of lymph node metastasis at the time of diagnosis, and the observed association was even stronger when there was overexpression for both the antibodies (Po0.001). High expression of vascular endothelial growth factor-C, but not of COX-2 was correlated with increased mortality in patients with oral-larynx squamous cell carcinoma. When multivariate Cox regression model was applied, the presence of lymph node metastasis at the time of diagnosis, combined with overexpression of both the antibodies, was the only independent prognostic factor for mortality of these patients. Our results suggest that a lymphangiogenic pathway, in which COX-2 overexpression stimulates vascular endothelial growth factor-C upregulation, probably exists in head and neck squamous cell carcinoma. Also, the predictive ability for mortality of regional lymph node metastasis can be improved with the combined evaluation of the immunohistochemical expression of these two proteins. Keywords: cyclooxygenase-2; head and neck cancer; lymphangiogenesis; metastasis; survival; vascular endothelial growth factor-C Clinical and pathological observations have shown that lymph node metastases at the time of diagnosis, is the most reliable prognostic factor for mortality or recurrence in patients with head and neck squamous cell carcinoma.

Vascular endothelial growth factor expression may have prognostic significance for patients with HNSCC.

Our study shows that MRI provides a credible preoperative differentiation of seminomatous from nonseminomatous testicular tumors, with excellent interobserver agreement.

In as much as ERbeta is possibly the only ER expressed in astrocytes, its decreased expression may play an important role in astrocytic tumor initiation and in the potential response of glial neoplasms to tamoxifen.