Untold story of human cervical cancers: HPV-negative cervical cancer

Cervical cancer is the fourth most common malignancy in women worldwide. Although infection from human papillomavirus (HPV) has been the leading cause of cervical cancer, HPV-negative cervical cancer accounts for approximately 3-8% of all cases. Previous research studies on cervical cancer have focused on HPV-positive cervical cancer due to its prevalence, resulting in HPV-negative cervical cancer receiving considerably less attention. As a result, HPV-negative cervical cancer is poorly understood. Its etiology remains elusive mainly due to limitations in research methodology such as lack of defined markers and model systems. Moreover, false HPV negativity can arise from inaccurate diagnostic methods, which also hinders the progress of research on HPV-negative cervical cancer. Since HPV-negative cervical cancer is associated with worse clinical features, greater attention is required to understand HPV-negative carcinoma. In this review, we provide a summary of knowledge gaps and current limitations of HPV-negative cervical cancer research based on current clinical statistics. We also discuss future directions for understanding the pathogenesis of HPV-independent cervical cancer.