Clinical Implication of Interleukin-6 and Angiogenesis in cN0 Oral Cancer Strictly Defined by Sentinel Node Biopsy

Despite advances in early detection, diagnosis, and treatment of oral squamous cell carcinoma (OSCC), the survival for patients with early stage OSCC remains at 80% for the past 30 years. Nodal status is still the most significant prognostic factor of OSCC. Therefore, early detection of the cervical lymph nodes metastasis is expected to further improve survival. We previously reported the clinical usefulness of sentinel node biopsy (SNB) diagnosed by histologic and genetic analysis. But the false negative cases remain at 10%. On the other hand, we previously examined several serum cytokines of OSCC patients by using a multiplexed measurement system. We showed that the serum interleukin (IL) -6 level tended to negatively correlate with favorable outcome in these patients. IL-6 has important roles in cancer progression via angiogenesis. This study aimed to determine the role of serum IL-6 concentration in early stage OSCC patients strictly defined as cN0 by SNB and we investigated whether serum IL-6 reflects the tumor angiogenesis and has prognostic value in patients with OSCC. Fifty-three patients with cT1-2N0 OSCC underwent SNB between 2006 and 2012. Sentinel lymph node was determined by radioisotope method, and was evaluated by histopathological examination and genetic analysis. We measured serum IL-6 taken from these patients by using ELISA. Expression of IL-6 and the infiltration of blood vessels (CD34) in surgical specimens were analyzed by an immunohistochemical staining of surgical specimens using immune reactive score. Results were correlated with disease-free survival (DFS) including second primary cancer. For statistical analysis, the Log-rank test was performed. The differences between the two groups of categorical data were analyzed by two-sided Fisher’s exact test. Values of P<0.05 were considered statistically significant. Cut-off of serum IL-6 value was set to 20 pg/ml based on ROC curve. In 53 cStage I/II patients before SNB, DFS of the patients with low IL-6 tended to be longer than that of the high IL-6 patients. (P=0.02). Thirteen patients showed lymph node metastasis by SNB or reclassified to pT4 from the surgically resected specimen. Thus, 40 patients were defined as early stage OSCC. In these 40 patients, DFS of the low serum IL-6 patients was statistically significantly longer than that of high IL-6 patients (P=0.047). Especially, in 19 patients who have SNB negative and serum low IL-6, the disease free rate was 100%. A significant correlation was observed between serum IL-6 levels and stromal IL-6 expression in the immunostaining (p<0.001). The DFS of the low IL-6 patients were significantly longer than those of the high IL-6 patients (p=0.003). Number of the blood vessels (CD34) in tumor tissues were also positively correlated with serum IL-6 levels (p<0.001). The DFS of the low CD34 patients were significantly longer than those of the high CD34 patients (p=0.023). These findings strongly suggest that the staging of SNB and preoperative serum IL-6 level have a high prognostic value in OSCC patients and IL-6 may be involved in poor clinical outcomes via angiogenesis. The relationship between IL-6 and angiogenesis offers new approaches to OSCC therapy.

References

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