By Rebecca H. Allen, MD, MPH
Assistant Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Providence, RI
Dr. Allen reports she is a Nexplanon trainer for Merck and a Liletta trainer for Actavis, and she has served on advisory boards for Bayer and Pharmanest.
In 2012, the American Society for Colposcopy and Cervical Pathology and the College of American Pathologists introduced the Lower Anogenital Squamous Terminology (LAST).1 The goal of LAST was to unify the diagnosis of human papilloma virus (HPV)-related diseases of the entire lower anogenital tract for both females and males. The LAST system divided HPV-associated squamous lesions into low-grade and high-grade including vulvar lesions. Low-grade squamous intraepithelial lesion (LSIL) of the vulva represented the old term vulvar intraepithelial lesion 1 (VIN 1) and high-grade squamous intraepithelial lesion (HSIL) of the vulva represented VIN 2-3. However, there were a couple of issues with this classification according to the International Society for the Study of Vulvovaginal Disease (ISSVD).2 First, albeit focusing on HPV only, LAST did not include the entity known as differentiated VIN (DVIN), which has a higher risk of progression to cancer than HPV-associated VIN. DVIN usually is not associated with HPV, and it is important to note that the vulva has no transformation zone like the cervix and anus. DVIN is often related to preexisting lichen planus or lichen sclerosus of the vulva. In a recent worldwide review of 2000 cases of VIN and vulvar cancer, HPV DNA was found in 86.7% of VIN and 28.6% of vulvar cancer.3 In a smaller U.S. review, HPV DNA was found in 97.1% of VIN 3 and 69% of invasive vulvar cancer.4 Second, by including vulvar LSIL, there was concern that the LAST system would lead to overdiagnosis and treatment of an essentially benign lesion with no risk of progression to HSIL or cancer. Vulvar LSIL or VIN 1 is not considered a precancerous lesion, but rather “the reaction of the skin to HPV infection.”2 To resolve these two concerns, the ISSVD adapted LAST to the specifics of the vulva and released the new 2015 ISSVD terminology (see Table 1). Vulvar LSIL is benign and includes HPV effect and flat condyloma. Vulvar HSIL is the usual HPV-associated type of high-grade vulvar intraepithelial neoplasia and the non-HPV-associated type is labeled differentiated-type vulvar intraepithelial neoplasia.
Now that the classification is clear, what about diagnosis and treatment? The most common presenting symptom of vulvar HSIL/DVIN is pruritis.5 However, lesions may be asymptomatic; therefore, a careful vulvar exam at each annual gynecologic visit is important. For those groups who advocate abandoning the yearly pelvic exam, I would argue that an external vulvar exam should not be omitted, regardless of whether a speculum or bimanual exam is being performed. A vulvar biopsy should be performed for lesions of uncertain etiology, lesions that do not respond to therapy as expected, and lesions for which dysplasia or malignancy cannot be excluded. It is important to remember that vulvar HSIL/DVIN may be found concomitantly with vulvar carcinoma, so the threshold for vulvar biopsy should be low.
Vulvar LSIL does not require any treatment unless the patient is symptomatic or desires removal for cosmetic reasons.2 Vulvar HSIL and DVIN should be treated, as it is impossible to predict progression to vulvar carcinoma. Treatment choices include wide local excision (WLE), laser ablation, and medical therapy. It is important to counsel patients that, for all treatments, there is a high incidence of recurrence (30-50%) and a risk of progression to cancer.5 One retrospective study of 303 patients with VIN 2-3 found that 87 patients (28.7%) developed recurrent disease, which was associated with smoking, larger lesion size, and positive margins. Seven women (2.3%) developed invasive disease a median of 109 months (range 12-327 months) from initial diagnosis.6 For surgical modalities, an excisional margin of at least 5 mm is recommended.5 Candidates for laser ablation should be selected carefully, as occult squamous cancer was found in 22% of patients in one review of 73 cases.7 Additionally, in one study of 50 women, those undergoing WLE were more likely to be free of recurrences at 5 years compared to those who underwent laser vaporization (91% for surgery vs. 51.3% for ablation).8
Medical therapy most commonly uses 5% imiquimod cream, an immune response modifier that triggers a local immune response. A recent review examined imiquimod therapy for vulvar HSIL.9 The authors identified 14 studies encompassing 780 women, of which 354 were treated with imiquimod. All the patients had histologically confirmed VIN 2-3 and there were two randomized, controlled trials, eight prospective uncontrolled studies, and four retrospective cohort studies. The most common regimen used was escalating doses of cream application, starting once a week and then increasing to three times a week for 12-20 weeks, depending on response and side effects. Overall, complete clinical response ranged from 16% to 76%, depending on the study.9 Looking at just the randomized, controlled trials that compared imiquimod to placebo, one study of 52 women showed a complete response of 35% compared to 0% for placebo, and the other study of 32 women showed an 81% response rate compared to 0% for placebo. The difference in response rate was not explained by dosing regimen, smoking, or lesion grade. Adverse effects of treatment included vulvar burning, pruritis, and pain that required dose reductions or pauses in treatment among 8% to 85% of patients, depending on the study.9 Other topical agents such as cidofovir are being studied. There are no quality trials comparing medical and surgical treatment. The most recent Cochrane review on the subject concluded that “topical treatment (imiquimod or cidofovir) may effectively treat about half of vulvar HSIL cases after a 16-week course of treatment, but the evidence on whether this effect is sustained is limited.”10 Ultimately, the decision to proceed with topical therapy rather than surgery will have to be individualized, taking into account the number of lesions, lesion size, and whether occult cancer is suspected.
Finally, in terms of prevention, the HPV vaccine holds the most promise to reduce the incidence of vulvar HSIL. In a review of 244 cases of VIN 3 and invasive vulvar cancer in the United States before HPV vaccine introduction, HPV 16 was present in 48.6% of invasive vulvar cancer cases and 80.9% of VIN 3 cases; other high-risk HPV was present in 19.2% of invasive vulvar cancer cases and 13.2% of VIN 3 cases.4 The new 9-valent HPV vaccine, which includes HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58, was found to reduce the risk of high-grade cervical, vulvar, and vaginal disease by 96.7% in the per protocol efficacy population.11 It is anticipated that the HPV vaccine will play a large role in reducing the incidence of vulvar HSIL in the future. For prevention of differentiated type-VIN, a recent study demonstrated that women with vulvar lichen sclerosus who were compliant with preventive topical corticosteroids were significantly less likely to develop VIN and squamous cell carcinoma.12
- Darragh TM, Colgan TJ, Thomas Cox J, et al. The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: Background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Int J Gynecol Pathol 2013;32:76-115.
- Bornstein J, Bogliatto F, Haefner HK, et al. The 2015 International Society for the Study of Vulvovaginal Disease terminology of vulvar squamous intraepithelial lesions. Obstet Gynecol 2016;127:264-268.
- de Sanjose S, Alemany L, Ordi J, et al. Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva. Eur J Cancer 2013;49:3450-3461.
- Gargano JW, Wilkinson EJ, Unger ER, et al. Prevalence of human papillomavirus types in invasive vulvar cancers and VIN 3 in the United States before vaccine introduction. J Low Genit Tract Dis 2012;16:471-479.
- Nelson EL, Bogliatto F, Stockdale CK. Vulvar intraepithelial neoplasia and condylomata. Clin Obstet Gynecol 2015;58:512-525.
- Wallbillich JJ, Rhodes HE, Milbourne AM, et al. Vulvar intraepithelial neoplasia (VIN 2/3): Comparing clinical outcomes and evaluating risk factors for recurrence. Gynecol Oncol 2012;127:312-315.
- Modesitt SC, Waters AB, Walton L, et al. Vulvar intraepithelial neoplasia III: Occult cancer and the impact of margin status on recurrence. Obstet Gynecol 1998;92:962-966.
- Leufflen L, Baermann P Jr, Rauch P, et al. Treatment of vulvar intraepithelial neoplasia with CO(2) laser vaporization and excision surgery. J Low Genit Tract Dis 2013;17:446-451.
- De Witte CJ, van de Sande AJ, van Beekhuizen HJ, et al. Imiquimod in cervical, vaginal, and vulvar intraepithelial neoplasia: A review. Gynecol Oncol 2015;139:377-384.
- Lawrie TA, Nordin A, Chakrabarti M, et al. Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia. Cochrane Database Syst Rev 2016 Jan 5;1:CD011837.
- Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med 2015;372:711-723.
- Lee A, Bradford J, Fischer G. Long-term management of adult vulvar lichen sclerosus: A prospective cohort study of 507 women. JAMA Dermatol 2015;151:1061-1067.