HPV-independent squamous sell carcinoma of cervix: a clinicopathological, immunohistochemical, and molecular analysis of six cases

HPV-independent squamous cell carcinoma (SCC) of the cervix is a rare subtype associated with aggressive clinical behavior and poor prognosis, as reported in limited studies with small sample sizes. This study aims to investigate the clinicopathological, immunohistochemical, and molecular characteristics of six cases of HPV-independent SCC. Formalin-fixed, paraffin-embedded tissues from six patients were analyzed using immunohistochemistry and Next-Generation Sequencing (NGS). Human papillomavirus (HPV) testing was performed using the Aptima HPV assay, and immunohistochemical markers, including p16, p53, PD-L1, HER2 and CK5/6 were evaluated. The median age at diagnosis was 62 years. Key histopathological features included an infiltrative-destructive growth pattern, pronounced keratinization, and extensive necrosis in the majority of cases. All tumors were p16-negative and high-risk HPV-negative by the Aptima HPV assay, confirming their HPV-independent status. One case exhibited p53 overexpression and HER2 positivity (score 3 +). Five out of six patients succumbed to the disease. FIGO stages ranged from IIB to IVB. Molecular analysis identified mutations in TP53 and PIK3CA, as well as novel CTNNB1 and TERT promoter mutations, and HER2 amplification. In five of six patients PD-L1 expression with at least CPS score of 2,5 was observed. HPV-independent cervical SCC typically affects older patients and is associated with poor clinical outcomes. This study highlights TP53 and PIK3CA mutations and novel findings, including CTNNB1, TERT promoter mutations, and HER2 amplification. The observed PD-L1 expression patterns may suggest potential benefits from immunotherapy. Further research is warranted to better understand the clinicopathologic characteristics and molecular drivers of HPV-independent SCC and to explore novel therapeutic strategies.