HPV-Associated Field Cancerization: Molecular Alterations in Histologically Normal Tissues and Implications for Early Detection and Cancer Prevention

Human papillomavirus (HPV)-associated cancers have traditionally been viewed as focal diseases arising from localized malignant transformation. However, growing molecular evidence suggests that HPV-associated molecular alterations may extend beyond visible lesions into histologically normal epithelium, raising the possibility of a virus-associated field effect. In this review, HPV-induced field cancerization is distinguished from HPV infection alone and is used to describe spatially extended molecular abnormalities demonstrated in histologically normal HPV-positive or tumor-adjacent tissue, whereas findings from premalignant lesions, established tumors, and experimental models are considered supportive evidence of progression or mechanism. This emerging concept challenges conventional models of HPV-driven carcinogenesis and carries important implications for early detection and cancer prevention. Evidence relevant to HPV-associated field effects includes spatially distributed viral, epigenetic, transcriptomic, and immune alterations in selected histologically normal tissues, while findings related to viral integration, metabolic reprogramming, premalignant lesions, tumors, and experimental models provide complementary progression or mechanistic evidence. Such molecular abnormalities have been reported most consistently in cervical disease, with supportive but more limited evidence in the oropharynx and anal canal, whereas the relevance of HPV-associated field effects in the urinary bladder remains controversial. In this review, we aim to synthesize current molecular evidence supporting HPV-induced field cancerization, discuss potential underlying mechanisms, and evaluate emerging methodological approaches for detecting field effects in normal tissues. We further highlight the translational relevance of this phenomenon for molecular-based screening, risk stratification, and preventive strategies aimed at intercepting HPV-associated cancers at their earliest stages.