Background: Regional lymph node (LN) metastases is a poor prognostic factor in oral squamous cell carcinoma (OSCC), reducing survival by 50%. Tumor pathologic features are imprecise at predicting metastatic disease, therefore, novel biomarkers are needed to identify OSCC at risk for LN metastases. Vascular endothelial growth factor (VEGF) and associated angiogenesis mediators have been implicated in metastatic head and neck cancer.
Objective: To determine if serum angiogenic factors are predictive of tumor histology features, metastases, recurrence, and survival.
Materials/Methods: Serum collected from patients with OSCC prior to surgery was analyzed for HGF, VEGF-A, VEGF-C, VEGF-D, IL-6, IL-8, and IL-17 (human-specific Milliplex® multi-analyte Luminex panel kit) using a MagPix® instrument platform and related xPONENT® software (Luminex Corporation, Austin, TX, USA). Histologic grade, perineural invasion (PNI), lymphovascular invasion (LVI), depth of invasion (DOI), and extranodal extension (ENE) was collected from the pathology record, and a head and neck pathologist performed additional scoring based on Brandwein criteria (worst pattern of invasion (WPOI), lymphocyte infiltration, and PNI). Outcomes were followed prospectively for 3 years. The study population was characterized using descriptive univariate statistics. T test and chi square test were used to compare the study population based on regional metastatic disease and 3-year recurrence and survival.
Results: Ninety-nine patients were included with a mean age of 61 (std 13.4, min 26, max 83), 66% male (N=65) and 91% white (N=90). Most tumors were moderately-poorly differentiated (N=77, 81.1%) with 49% (N=48) with PNI and 27.6% (N=27) with LVI. The rate of regional metastatic disease was 37.1% (N=33), rate of 3-year recurrence was 19.2% (N=19), and overall survival at 3 years was 80.8% (N=80). Patients with regional metastatic disease had higher rate of moderately-poorly differentiated tumors (p=0.001), PNI (p=0.0001), LVI (p=0.0001), greater DOI (p=0.0001), and higher Brandwein scores (4.6 vs 3.1; p=0.008). Patients with recurrence were older (67.5 vs 59.5 years; p=0.019) and tumors had higher rate of PNI (p=0.004), ENE (p=0.001), greater DOI (p=0.030), augmented Brandwein scores (4.8 vs 3.3; p=0.017), and higher combined positive score (CPS) (5 vs 56.3; p=0.035). Patients alive at 3 years were younger (59.4 vs 67.9 years; p=0.012) and tumors had a lower rate of PNI (p=0.0001), ENE (p=0.031), less DOI (p=0.0166), and lower Brandwein scores (3.2 vs 4.9; p=0.002). Patients with regional metastatic disease had higher levels of preoperative HGF (232 vs 202pg/mL; p=0.046) and VEGFC (617.1 vs 433.7pg/mL; p=0.007) in their serum. On bivariate logistic regression, VEGFC was predictive of positive LN status (OR 1.002, 95% CI 1.001-1.004, p=0.012). Patients dead at 3 years had higher levels of preoperative HGF (239.9 vs 205.1pg/mL; p=0.05) and lower levels of IL17 (5.2 vs 6.7pg/mL; p=0.035). On multivariate logistic regression, HGF (OR 1.008, 95% CI 1.00-1.016; p=0.045) and IL17 (OR 0.744, 95% CI 0.551-0.946, p=0.030) were predictive of survival. Preoperative angiogenic serum markers were not associated with recurrence or tumor histologic features.
Conclusion: Select serum angiogenic factors correlate with metastasis and mortality in OSCC. These factors could be incorporated into effective risk stratification algorithms for management of OSCC.