Pelvic HPV-associated squamous cell carcinoma of unknown primary origin: a case report

Background Cancer of unknown primary (CUP) is a rare subtype of malignant tumor. When it presents as pelvic squamous cell carcinoma (SCC), the difficulty of clinical diagnosis and treatment increases significantly. Notably, some such pelvic SCC cases are confirmed to be associated with human papillomavirus (HPV) infection, yet the primary tumor remains unidentified despite systematic imaging evaluation, endoscopy, and pathological biopsy. Currently, there is no unified consensus on the diagnostic criteria, therapeutic strategies, and prognostic assessment of this specific clinical entity, which has become one of the urgent problems to be solved in oncology. Case presentation A 55-year-old postmenopausal woman was admitted with urinary discomfort and lower abdominal distension for 15 days. Physical examination revealed a fixed, non-tender solid pelvic mass in the left lower abdomen. Laboratory testing showed an elevated serum squamous cell carcinoma antigen (SCC-Ag) level of 9.11 ng/mL, while other tumor markers, including carcinoembryonic antigen and carbohydrate antigen 125, were within normal ranges. Transvaginal ultrasonography and 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) demonstrated a hypermetabolic mass in the left pelvis. To investigate the primary site, comprehensive evaluation including cervical HPV testing and cytology, colonoscopy, and cystoscopy was performed, but no definite primary malignant lesion was identified. Ultrasound-guided percutaneous biopsy of the pelvic mass showed well-differentiated squamous cell carcinoma. Exploratory laparotomy was subsequently performed, and postoperative histopathological examination confirmed moderately to well-differentiated invasive squamous cell carcinoma. Diffuse strong p16 expression together with positive tumor HPV E6/E7 mRNA in situ hybridization supported an HPV-associated tumor phenotype. Although lymph node metastasis was suspected intraoperatively, no definite lymph node metastasis was confirmed by pathological examination. Conclusion This case describes a rare HPV-associated pelvic squamous cell carcinoma of unknown primary origin in which no definite primary malignancy was identified in the cervix, other lower genital tract sites, gastrointestinal tract, or urinary tract after comprehensive evaluation. The case highlights the diagnostic value of integrating imaging, endoscopic assessment, histopathology, immunohistochemistry, and tumor-based HPV testing in patients with pelvic SCC of uncertain origin. Importantly, the absence of a detectable mucosal primary site should not be interpreted as evidence of a primary pelvic origin. Instead, occult mucosal disease and other potential primary sites should remain diagnostic considerations. Further accumulation of similar cases and longer follow-up are needed to clarify the biological origin and optimal management of this rare clinical presentation.