Complications of Untreated HPV Infection

Both low-risk (subtypes 6 and 11) and high-risk (subtypes 16 and 18) HPV subtypes have also been associated with the very low-grade, well-differentiated squamous cell carcinoma known as verrucous carcinoma (VC). Verrucous carcinoma is divided into clinico-pathological types based on the anatomic area of involvement: oral florid papillomatosis (oral cavity), giant condyloma of Buschke and Löwenstein (anogenital area), and carcinoma cuniculatum (palmoplantar surface). These tumors tend to spread by local invasion and, therefore, rarely metastasize. While a direct causal relationship between HPV and VC has yet to be defined, it is hypothesized that HPV’s viral oncogene expression promotes the degradation of the p53 tumor suppression gene, thereby lowering the threshold for tumor formation. Histologically, VC can vary from benign-appearing pseudoepitheliomatous hyperplasia-like lesions to invasive SCC. Additionally, presence of vacuolation and prominent keratohyalin granules in the stratum granulosa cells, which are hallmark features of genital warts, was discovered to be variable in histological studies of VC. One can differentiate VC and SCC by comparing the immunoperoxidase staining pattern of expression of certain oncogenes. For instance, VC and SCC cells can stain positively for bcl-2, Ki-67, and p53. However, nuclei of VC stain positive for p53 and Ki-67 in the lower third of the epidermis, primarily in the basal proliferating cells. The nuclei of SCC stain positive throughout the full thickness of the epidermis for these markers.
Additionally, while most HPV infections clear spontaneously, in 10 to 20 percent of women these infections persist and these females are at risk for progression to grade 2/3 cervical intraepithelial neoplasm and, if left untreated, can eventually develop invasive cancer of the cervix. Penile cancer, which is 10 times less common than cervical cancer, also has a high correlation rate with high-risk HPV infection and history of EGW. A case-control study involving more than 100 men with penile cancer reported that the risk of penile cancer in men with a history of EGW was 5.9 times that of men with no such history (95% CI 2.1–17.6).

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