Rare case of primary HPV negative vaginal cancer presenting in a young woman with normal cervix

Background: Primary vaginal cancer is defined as malignancy of the vaginal wall without coexisting cervical or vulvar pathology or history of such in the past 5 years. It is a rare diagnosis, and makes up only 1-3% of all gynecologic cancer globally. Major risk factors historically have included older age, history of high-risk HPV infection, diethylstilbestrol (DES) exposure, immunocompromise, history of tobacco smoking (Adams et al., 2025, Di Donato et al., 2012). Case presentation: A healthy 32-year-old women, with well documented history of normal Pap smears presented with primary, HPV negative, invasive squamous cell carcinoma of the vagina. The patient was diagnosed via tissue biopsy and treated successfully according to standard chemoradiation protocol for primary vaginal cancer, despite rare presentation. The patient remains disease free at 22 months and avoided vaginectomy to preserve sexual function. Conclusions: This case emphasizes the importance of tissue biopsy for suspicious vaginal lesions, even in the absence of major risk factors for malignancy, as well as the potential broad application of standard chemoradiation in atypical presentations of primary invasive squamous cell vaginal cancer.