A Rare Case of Metastatic Urethral Squamous Cell Carcinoma Presenting with Paraneoplastic Sweet Syndrome and Treated with Pembrolizumab

Primary urethral cancer is an extremely rare malignancy, accounting for less than 1% of all cancers. Due to its rarity, evidence-based treatment recommendations are lacking. We report the case of a 44-year-old woman with metastatic squamous cell urethral carcinoma and paraneoplastic Sweet syndrome. The tumor was p16-positive with strong PD-L1 expression (CPS > 50%). Following surgery and adjuvant chemoradiotherapy, the patient developed hepatic and lymph node metastases. Pembrolizumab was initiated as first-line systemic therapy because of prior hematologic toxicity with cisplatin. After four cycles, complete radiologic remission of metastases and full resolution of the Sweet syndrome were achieved. This case highlights the potential benefit of immune checkpoint inhibitors in metastatic urethral SCC, particularly in p16-positive and PD-L1-high tumors, suggesting an inflamed and immunogenic microenvironment. To our knowledge, this is the first reported case of paraneoplastic Sweet syndrome successfully treated with pembrolizumab. These findings underscore the need for further investigation of immunotherapy in this rare and challenging malignancy.