HPV6-associated cervical squamous cell carcinoma: a case report and literature review

Low-risk human papillomavirus (HPV) types are traditionally regarded as non-oncogenic and are primarily associated with benign epithelial proliferations. Invasive cervical squamous cell carcinoma (CSCC) related to low-risk HPV infection is exceedingly rare. Here, we report a rare case of HPV6-associated CSCC in a postmenopausal woman and comprehensively characterize its clinicopathological, immunophenotypic, and molecular features, with a review of the relevant literature. The patient presented with irregular vaginal bleeding and an exophytic cervical mass. Histopathological examination revealed verrucous papillary squamous epithelial hyperplasia with prominent fibrovascular cores, surface koilocytosis, marked cytological atypia, and focal superficial stromal invasion (≤ 3 mm). Immunohistochemical analysis demonstrated negative p16 expression and a high Ki67 proliferation index. HPV genotyping detected isolated low-risk HPV type 6, with no evidence of high-risk HPV infection. Targeted next-generation sequencing identified multiple somatic alterations, including pathogenic mutations in TP53, CDKN2A, TERT promoter, and LATS1, suggesting a host-driven molecular carcinogenic process. The present study supports an indirect carcinogenic pathway for low-risk HPV-associated cervical squamous cell carcinoma, in which persistent viral-induced epithelial proliferation may facilitate the accumulation of oncogenic host mutations. Recognition of this rare entity expands the pathological spectrum of HPV-associated cervical cancer and underscores the importance of integrating morphology, immunohistochemistry, and molecular testing for accurate diagnosis and risk assessment.Awareness of this rare entity may help avoid underdiagnosis of malignant transformation in exophytic cervical lesions associated with low-risk HPV infection.