Human Papilloma Virus-independent Adenocarcinoma of the Cervix: A Narrative Review of the Rare Histology

Across the world, cervical cancer is the fourth most prevalent malignancy among women, accounting for approximately 350,000 annual deaths. But an overwhelming 94% proportion of the global burden of mortality is disproportionately borne by low- and middle-income countries, with India accounting for the highest number of deaths. While the majority originate due to the persistence of human papillomavirus (HPV) infection, emerging evidence highlights a distinct subset of tumors, independent of HPV infection, comprising approximately 5% of cervical cancer cases. The WHO 2020 classification now stratifies cervical carcinoma into HPV-associated (HPVA) and HPV-independent (HPVI) categories, reflecting critical differences in pathogenesis and prognosis in the disease spectrum. HPVI tumors exhibit unique molecular profiles characterized by frequent mutations in TP53 , ARID1A , PTEN , KRAS, and CTNNB1, along with decreased expression of cell cycle regulators, such as p16 and p27. These tumors demonstrate higher genomic instability, affecting older women, with advanced FIGO stages at presentation and atypical metastatic patterns. Survival outcomes are markedly poorer in these cases, with resistance to conventional chemoradiation. Diagnostic challenges stem from morphological overlap with HPVA lesions and other gynecological malignancies, necessitating rigorous histopathological testing and immune profiling. Current therapeutic strategies remain non-specific, although preclinical studies show promising targets in PI3K/AKT pathways and WNT/β -catenin signaling. This review encompasses etiopathogenesis, diagnostic algorithms, and therapeutic innovations, emphasizing on individualized treatment strategies for this aggressive entity. A literature search was conducted using PubMed, MEDLINE, EMBASE, Scopus, and Google Scholar focusing on articles addressing HPVI adenocarcinoma of the cervix.