A marker panel comprising EGFR, EPCAM, and MUC1 differentiated HNSCC from SQCCL in this limited subgroup (n = 11) with 96.97% sensitivity, 45.45% specificity, 92.75% positive predictive value and 75.00% negative predictive value.<h4>Conclusion</h4>Flow-cytometric profiling of circulating large EV provides a feasible liquid biopsy approach for tumor characterization in HNSCC. Here, EPCAM is linked to head and neck squamous cell carcinoma.