Paraneoplastic Florid Oral Papillomatosis and Malignant Acanthosis Nigricans Associated With HPV‐Related Squamous Cell Carcinoma of Unknown Primary

ABSTRACT We present the case of a 76‐year‐old man with paraneoplastic florid oral papillomatosis (FOP) and malignant acanthosis nigricans (MAN) associated with an HPV‐16‐positive keratinizing squamous cell carcinoma of unknown primary. The patient initially presented with a painless left cervical mass and was diagnosed through cytology and PET‐CT. Following radiotherapy and surgical resection of a subsequent pulmonary lesion, the disease progressed, and pembrolizumab was initiated. Shortly thereafter, the patient developed sudden‐onset viral warts on the hands and forearms, with HPV genotyping confirming types 6, 16, 53, and 58. As the disease advanced, papillomatous lesions emerged in the oral cavity, pharynx, and lips. Histopathological examination revealed benign epithelial hyperplasia. While all oral and pharyngeal lesions tested negative for HPV, the lip lesion was positive for HPV‐6, possibly due to autoinoculation from viral warts on the hands. Additional findings included perianal warts and hyperpigmented, velvety thickening in the intergluteal fold, consistent with MAN. Acitretin led to partial clinical improvement but was discontinued due to xerostomia. The disease progressed despite a second pembrolizumab cycle, and the patient eventually died. This case highlights the uncommon coexistence of HPV‐related verrucosis and HPV‐negative mucocutaneous paraneoplastic phenomena following immune checkpoint inhibitor therapy. The presentation raises intriguing questions regarding the role of HPV in paraneoplastic dermatoses and the paradoxical emergence of viral infections in the setting of immunotherapy. It underscores the need for vigilance in monitoring cutaneous signs that may reflect internal malignancy progression, especially in patients with cancer of unknown primary.