Head and neck squamous cell carcinoma (SCCa) is primarily managed by surgical resection. Recurrence rates after surgery can be as high as 55% if residual cancer is present. In this study, hyperspectral imaging (HSI) is evaluated for detection of SCCa in ex-vivo surgical specimens. Several methods are investigated, including convolutional neural networks (CNNs) and a spectral-spatial variant of support vector machines. Quantitative results demonstrate that additional processing and unsupervised filtering can improve CNN results to achieve optimal performance. Classifying regions that include specular glare, the average AUC is increased from 0.73 [0.71, 0.75 (95% confidence interval)] to 0.81 [0.80, 0.83] through an unsupervised filtering and majority voting method described. The wavelengths of light used in HSI can penetrate different depths into biological tissue, while the cancer margin may change with depth and create uncertainty in the ground-truth. Through serial histological sectioning, the variance in cancer-margin with depth is also investigated and paired with qualitative classification heat maps using the methods proposed for the testing group SCC patients.