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Primary vaginal adenocarcinoma associated with human papillomavirus (HPV) infection is extremely rare. We report a case of primary adenocarcinoma of the vagina associated with human papilloma virus successfully treated with anterior pelvic exenteration and adjuvant concurrent chemoradiation therapy. A 51-year-old postmenopausal woman (gravida 1, para 1) presented with intermittent vaginal bleeding and pelvic pain. She was found to have a 5 x 5 cm necrotic tumor took up the vaginal. She had no previous history of antenatal exposure to diethylstilbestrol (DES). Pelvic magnetic resonance imaging (MRI) demonstrated a 4.8 x 6.0 cm mass in the vaginal canal, an 1.1 x 2.6 cm mass at the urinary bladder dome and a 1.1 cm irregular lymph node at the right external iliac chain with increased fluorodeoxyglucose (FDG) uptake from Fused wholebody positron emission tomography-computed tomography (PET-CT). Based on clinical investigations, the patient was diagnosed with a primary adenocarcinoma of vagina, staged International Fedestration of Gynecology and Obstetrics (FIGO) IVa. Anterior pelvic exenteration, simple vulvectomy, total vaginectomy, both pelvic lymph node dissection, and para-aortic lymph node dissection with ileal conduit urinary diversion (Bricker's operation) was done. Histologically primary vaginal HPV type 16-associated adenocarcinoma was confirmed. Both obturator lymph node was positive for metastasis. Postoperatively, the patient received weekly cisplatin regimen administered with a dose of 40 mg/m2 on day 1 of external radiation therapy (RT), 1 to 4 hours before RT initiation. External beam pelvic RT dose prescription to the whole pelvis was 59.4 Gy in 33 fractions at the isocenter. But, after total dose of 43.2 Gy, patient complained severe bowel habit change and discontinued further treatment. The patient remains free from recurrence 8 months after initial surgery. In the lack of information and comparative analysis of management options for the more unusual and rare varieties of primary vaginal neoplasms in the literature, this suggests the possibility that surgical treatment may be preferentially selected on a case-by-case basis. [ABSTRACT FROM AUTHOR]