Management of squamous cell carcinoma of unknown primary in the head and neck: current evidence-based diagnostic and treatment strategies

Summary Purpose Cancer of unknown primary (CUP) in the head and neck region accounts for around 5% of malignancies, predominantly presenting as squamous cell carcinoma (SCCUP). Despite improved diagnostic modalities that have resulted in a decreasing incidence, therapeutic management of SCCUP remains challenging due to conflicting retrospective evidence. Materials and methods A comprehensive literature search was performed using the keywords “cancer,” “unknown,” “primary,” “cervical,” “head,” “neck,” “squamous,” “cell,” “carcinoma,” “treatment,” and “diagnosis” across the PubMed database and OpenEvidence platform. Current guidelines, including those from the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO), were analyzed to summarize state-of-the-art diagnostic and therapeutic strategies. Results A standardized diagnostic workup is essential and comprises medical history, comprehensive ENT examination, ultrasound-guided core needle biopsy, positron-emission tomography (PET/CT) imaging, and panendoscopy with palatine and lingual tonsillectomy. This approach enables identification of the primary tumor in up to 78% of cases. If a primary tumor is detected, treatment follows site-specific protocols. All SCCUP cases should be reviewed in a multidisciplinary tumor board, taking into account factors such as disease burden, immunohistochemistry (IHC), performance status, comorbidities, potential treatment-related toxicities, patient compliance, and expected functional recovery. Treatment strategies are neck dissection (ND) with adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) if necessary or definitive RT or CRT. Due to inconsistent retrospective studies, it is unclear which treatment modality is currently superior. Conclusion Management of SCCUP remains complex and requires individualized multidisciplinary decision-making. Prospective trials are essential to optimize treatment strategies.