Abstract
HPV-independent cervical cancers represent a small proportion of these types of cancers, predominantly glandular lesions. It should be noted that some cases may depend on diagnostic problems that lead to false negative cases. However, the most recent classifications distinguish cervical tumors into HPV-associated and HPV-independent cancers. HPV-negative cervical carcinomas (5-11% of all cases) mainly include rare adenocarcinomas (gastric, mesonephric, clear, serous, and endometrioid) and present distinct clinical and molecular features. These tumors usually affect older women and are diagnosed at more advanced stages than HPV-positive tumors, with an overall worse prognosis. This concerning and notably worse prognosis highlights the need for further research and understanding. Unlike HPV-positive carcinomas (which depend on the viral oncogenes E6/E7), HPV-independent tumors accumulate genomic mutations that activate oncogenes and inactivate suppressor genes. Therefore, a comprehensive overview of these aspects can be the key to a better understanding and developing personalized treatments. In the present review, the main mutated genes, the signaling pathways involved, the differences from HPV-positive tumors, the distinctive immunohistochemical markers, and the diagnostic and therapeutic implications are explored in depth.