Evolving Paradigms in Human Papillomavirus–Associated Vulvar Intraepithelial Neoplasia Management

Teresa K. L. Boitano MDCharles A. Leath III MDAlthough the cervix is the most frequent site of preinvasive as well as invasive lesions of the lower genital tract, increasing attention in terms of both knowledge and treatment is focused on the vulva. Vulvar intraepithelial neoplasia (VIN) represents a range of premalignant epithelial changes of the vulva, and its incidence has continued to rise over the past few decades.1 Two distinct pathogenic pathways are recognized: human papillomavirus–associated (usual-type VIN) and HPV-independent (differentiated VIN). Due to the risk of progression to invasive carcinoma, high-grade VIN traditionally has been treated surgically with wide local excision or, in more extensive cases, partial vulvectomy; laser ablation tends to be reserved for smaller lesions or when cancer is not a concern.2 Although effective, these procedures can result in chronic cosmetic and functional changes, along with lasting effects on sexual function.3 Recognizing that HPV-associated VIN is driven by viral and immune mechanisms, topical imiquimod has emerged as a promising nonsurgical alternative.4–6 Although early clinical results have been promising and it has received U.S. Food and Drug Administration approval for treatment of genital and perianal warts, imiquimod has not yet received approval for the treatment of VIN. There is a clear need for effective nonsurgical options in the management of HPV-associated VIN; however, direct comparative data on the long-term efficacy of imiquimod and surgical treatment remain limited. Evidence to date suggests comparable short-term outcomes between the two approaches, but most studies lack extended follow-up to assess durability of response and recurrence risk.7 Human papillomavirus–associated VIN is largely driven by the viral oncoproteins E6 and E7, which disrupt the normal function of the tumor suppressors p53 and Rb. Whether a lesion regresses, persists, or progresses often depends on how well the patient's immune system can recognize and clear the infection. Because imiquimod stimulates local immune activity, it can enhance immune surveillance and promote clearance of HPV-infected cells,8 offering a biologically sound, tissue-sparing alternative to surgery for select patients. Reid and colleagues9 sought to evaluate treatment options for VIN and compared surgical excision with topical imiquimod therapy. The authors used data from their tertiary care colposcopy clinic over a nearly 25-year period. Although the study was retrospective, the majority of the data appear to have been collected in a prospective fashion. Importantly, the authors excluded individuals treated with laser ablation (n=15, 4.5%) and limited the focus to those with HPV-dependent lesions; therefore, the findings do not apply to differentiated VIN (usually caused by chronic inflammatory dermatoses such as lichen sclerosis or planus). This study provides data demonstrating that topical imiquimod appears to be as effective as surgical management. The median follow-up time of 3 years likely allowed for adequate evaluation of recurrence rates in both populations of patients. Success rates for preventing recurrence were 60% for imiquimod and 65% for surgical excision. Moreover, the authors noted the effect of various clinical covariates as potential predictors for VIN recurrence based on treatment approach. Specifically, for the excision group, the authors noted that, in addition to surgical margin status (OR 4.68. 95% CI, 2.52–8.62), the presence of multifocal lesions (OR 2.27, 95% CI, 1.19–4.33) and an initial diagnosis of carcinoma in situ (OR 6.21, 95% CI, 1.45–26.6) were associated with recurrence of VIN, whereas age, lesion location, immunosuppression status, history of HPV, history of lichen sclerosis, other lower genital tract dysplasia, and current or prior tobacco use were not associated. Although there is no tissue or margin status in the imiquimod group, the only covariates associated with VIN recurrence were reported side effects with imiquimod therapy or barriers to obtaining the therapy or both (OR 2.46, 95% CI, 1.01–6.02). In general, the route of therapy depends on shared decision making between the patient and physician. As demonstrated in Table 1, there are pros and cons of each treatment modality. Topical imiquimod normally is applied 3–5 times/week for 12–20 weeks, and it sometimes can be challenging to get insurance coverage for VIN-treatment use.10 Surgical management requires an outpatient procedure along with recovery time, which can vary depending on the extent of the resection and healing speed. The presented data from Reid et al provide more information regarding the potential use and effectiveness of imiquimod therapy for HPV-associated VIN.Table 1.: Pros and Cons of Treatment Options for Vulvar Intraepithelial NeoplasiaRecent data demonstrate a steady rise in HPV-related VIN and HPV-associated vulvar cancers over the past few decades.11 Although both surgical excision and topical imiquimod remain effective treatment options, true disease control begins with prevention. This occurs through widespread HPV vaccination and patient education on vulvar health. Somewhat worrisome is the overall extremely low rate of known HPV vaccination in the study, which is well under 10%; however, vaccination may not have been commercially available considering the age and time period of the cohort. These trends highlight the continued importance of comprehensive pelvic examinations to assess the vulva, vagina, and cervix, rather than relying solely on Pap screening. The study by Reid et al provides evidence that, in properly selected patients, topical imiquimod therapy is a safe and effective method of treating HPV-associated VIN. If there is concern for occult cancer, surgical excision always should be performed to rule out microinvasive disease. It is important that adequate patient education and side-effect management are performed to increase compliance with imiquimod therapy. In the setting of HPV-associated VIN, treatment modality should be guided by lesion characteristics, disease extent, and patient-centered preferences. Considering the predictors of recurrence outlined, is it reasonable to consider that imiquimod should be considered as a first-line therapy for lesions without oncologic concerns, reserving surgery for patients with persistent lesions or those who are unable to tolerate therapy? The current data are unable to provide an answer to this question but can inform future research, perhaps designed with a crossover in mind, to determine optimal treatment sequencing for these patients.