Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region

Head and neck squamous cell carcinomas (HNSCCs) frequently disseminate to regional lymph nodes. To investigate the possible mechanisms involved, we studied the expression of cancer cell adhesion molecules together with lymphatic vascular and blood vascular markers in a panel of 97 primary HNSCC tumors and correlated expression levels with conventional clinicopathological parameters and with long-term prognosis. In particular, we measured the density of intratumoral and peritumoral lymph vessels as assessed with the marker lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and the density of tumor CD44, a receptor up-regulated in many metastatic cancers. Intratumoral LYVE-1(+) lymphatic vessels were clearly associated with a higher risk for local relapse as well as with poor disease-specific prognosis (P = 0.02 and 0.0009, respectively). In contrast, a high density of peritumoral LYVE-1(+) vessels was a sign of favorable survival (P = 0.05). Strong primary tumor CD44 expression was associated with a poor prognosis, an increased risk of local recurrence (P = 0.03 and 0.02, respectively), and an increase in resistance to radiation therapy (P = 0.03). CD44 was the only factor with an independent prognostic value for the disease-specific overall survival (P = 0.04). Our results suggest that intratumoral lymphatics play a greater role than peritumoral lymphatics in nodal metastasis of HNSCC and that tumor CD44 levels can predict sensitivity to radiation therapy. These parameters may be useful predictive and prognostic tools in the clinical management of HNSCC.