Project Summary The current standard of care for evaluation and surveillance of regional and metastatic disease in advanced stage head and neck squamous cell carcinoma (HNSCC) is 18F-FDG-PET/CT scan, which is highly sensitive but not specific and as a result identifies a significant number of indeterminate lesions. Interrogation of these lesions leads to unnecessary procedures, overdiagnosis/upstaging, patient anxiety, increased cost, and possible treatment delays due to the need for repeat imaging. To address this, we will investigate whether PET imaging using a radiolabeled anti-EGFR antibody (89Zr-panitumumab) can be used to detect cancer with high specificity. We will use 89Zr-panitumumab PET/CT to assess HNSCC patients with indeterminate findings on 18F-FDG PET/CT and determine the positive predictive value of 89Zr- pan PET/CT for detection of metastatic disease. The nonspecific nature of 18F-FDG-PET/CT also limits its usefulness in detecting small primary tumors in patients with oropharyngeal cancer. This study will assess the effectiveness of 89Zr-pan PET/CT imaging for detecting unknown primary tumors in patients presenting with an enlarged neck node without identification of the primary tumor on exam or conventional imaging. Successful detection of the primary tumor using 89Zr-pan PET/CT would avoid the invasive biopsies typically required to locate the primary tumor in these patients. The novel imaging modality developed in this study could overcome the limitations of metabolic 18F-FDG PET/CT imaging, thereby reducing the number of invasive procedures and avoiding delays in treatment due to indeterminate findings.