Efficacy of Multimodal Work-Up of Head and Neck Squamous Cell Carcinoma Lymph Node Metastasis of Unknown Primary

Background: Head and neck squamous cell carcinoma (HNSCC) often presents with cervical lymph node metastasis, with 1%–4% of cases presenting as cancer of unknown primary (CUP). CUP poses diagnostic and therapeutic challenges and is linked to poorer survival outcomes. Its incidence is expected to rise with the increasing prevalence of HPV-positive HNSCC. This study evaluated the use of MRI, 18F-FDG PET, examination under anesthesia (EUA), and TORS-assisted tonsillectomy and tongue base mucosectomy (TORS-TE/TBM) in the work-up of CUP. Methods: This single-center retrospective study included 79 patients with cytologically confirmed CUP (years 2019–2024). HPV-positive (n = 51) and HPV-negative (n = 28) cases were evaluated separately. Primary tumor detection rates for MRI, 18F-FDG PET and EUA were calculated. For HPV-positive tumors TORS-TE/TBM was additionally evaluated for primary tumor detection. Results: In HPV-positive cases MRI and 18F-FDG PET had detection rates of 45% individually (respectively) and 53% combined. Of detected cases, 37% were identified by a single modality. Post-hoc image review increased the detection rate to 63%. Subsequent imaging-guided EUA had a detection rate of 68%. When TORS-TE/TBM was performed after negative EUA, tumor detection occurred in 50% of cases. Multimodal work-up resulted in an over-all detection rate of 75%. In contrast, HPV-negative cases had a lower over-all multimodal detection rate of 39%. Conclusion: MRI and 18F-FDG PET each play a pivotal and complimentary role for the detection of primary tumors in HNSCC CUP. Image-guided EUA and, in selected cases, TORS-TE/TBM further improve detection. A multimodal approach including expert imaging interpretation is recommended for optimal tumor identification and treatment planning.