Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:

1. Identify patients with abnormal vulvar symptoms or lesions for biopsy.

2. Provide tailored advice and treatment options for patients with vulvar intraepithelial neoplasia.

3. Describe appropriate patient surveillance for vulvar intraepithelial neoplasia.

Epidemiology and Terminology

Vulvar intraepithelial neoplasia (VIN) is a widespread condition that is increasing in incidence, estimated to affect 5 out of every 100,000 women between 1997 and 2004 according to data from the Surveillance, Epidemiology, and End Results database.1,2 VIN is more commonly encountered in White women than in Black, Asian, or Hispanic women, and the mean age at diagnosis is decreasing.2 If untreated, up to 10% of patients may progress to invasive carcinoma; the risk of progression is even higher in some types of VIN. Prominent risk factors for developing VIN include increasing age, smoking, immunosuppression, human papilloma virus (HPV) infection, cervical dysplasia, and vulvar dermatosis such as lichen sclerosus.3

The classification of VIN has undergone numerous changes in the past 2 decades. In 2004, the International Society for the Vulvovaginal Disease (ISSVD) reclassified VIN into usual type VIN (HPV-related) and differentiated VIN (HPV-independent). The current terminology, and the classification system that will be used in the remainder of this review, arose from several reclassifications by the Lower Anogenital Squamous Terminology (LAST) project in 2012, the World Health Organization in 2014, and the ISSVD in 2015 in an effort to standardize disparate terminology for vulvar dysplasia.4,5 The current classification is as follows:

* Vulvar low-grade squamous intraepithelial lesion (vLSIL)-condyloma effect secondary to HPV infection (previously VIN1);

* Vulvar high-grade squamous intraepithelial lesion (vHSIL)-vulvar squamous dysplasia requiring treatment (previously VIN2-3); and

* Differentiated vulvar intraepithelial neoplasia (dVIN)-HPV-independent intraepithelial neoplasia, often found in the context of other vulvar skin disorders such as lichen sclerosus.

Like cervical dysplasia, the majority of VIN is associated with HPV infection, which is thought to induce disordered cellular proliferation via the production of viral oncoproteins.2 In one histologic case series of 587 VIN tissue samples, HPV was detected in 86.7% of samples, with HPV 16, 33, and 18 being the most prevalent genotypes.6 For this reason, the Centers for Disease Control and Prevention recommends routine vaccination with the 9-valent (Gardasil) HPV vaccine, which covers against HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58. Two dosing schedules are recommended: 2 doses at 0 and 6 to 12 months for those initiating vaccination between ages 9 and 14 years or 3 doses at 0, 1 to 2, and 6 months for those initiating vaccination between ages 15 and 45 years or immunocompromised individuals initiating vaccination between ages 9 and 26 years.7

Diagnosis

The American College of Obstetricians and Gynecologists (ACOG) does not recommend a particular screening algorithm for vulvar dysplasia.1 Rather, screening occurs via visual examination at the time of routine gynecologic examination. Evaluation can be prompted by symptomatic lesions, followed by biopsy of any abnormal lesions. Thorough history taking is a key component of diagnosis. A history of HPV infection and related cervical or anal dysplasia is a risk factor for vHSIL and a history of lichen sclerosus should prompt an increased suspicion for dVIN. Patients may describe symptoms of pruritus, irritation, pain, dyspareunia, and bleeding; 70% of patients with vHSIL will be symptomatic.3 Physical examination should include visual assessment of the pubis, lymph nodes, vulva, and perianal region.

Assessment of vulvar lesions should include anatomic site, size, focality (single or multifocal), shape, border regularity, color, thickness, and abnormal vasculature. Vulvar colposcopy after application of acetic acid may be used to aid in diagnosis, especially in patients who are symptomatic but do not have visually apparent lesions.1,3 The presentation of vHSIL is variable, and can present as opaline or pigmented macules, papules, or plaques located near the introitus.3 On the other hand, dVIN typically presents in the background of lichen sclerosus (diagnosis and treatment of lichen sclerosus is beyond the scope of this review). Patients with dVIN lesions may present with maculopapular plaques with irregular warty or leukoplakic appearance.3 Both vHSIL and dVIN lesions may involve some degree of erythema. Clinical judgment guides decision to biopsy. The ACOG specifically recommends biopsy of lesions unresponsive to topical therapy, atypical vascular patterns, and dynamic lesions changing in color or size and all warty lesions in postmenopausal patients.1 Ultimately, we recommend biopsy of any new or unusual lesion and of any skin changes on the vulva before initiating treatment.

Management

There is no known oncogenic potential for vLSIL. Therefore, these lesions may only need treatment in patients with symptoms of pain, bleeding, urinary or vaginal obstruction, disfigurement, or psychosocial concerns. Given the high risk of progression to carcinoma, the diagnosis of vHSIL or dVIN necessitates treatment. Approximately 10% of untreated patients with vHSIL will progress to invasive carcinoma and this risk can be reduced to 3% to 5% with treatment.8 Differentiated VIN carries a significantly higher risk of progression to invasive carcinoma of at least 33%.9 Management is guided by several factors, including ability to completely remove the lesion(s), patient symptoms, preservation of vulvar anatomy and function, and avoiding psychosexual impairment. Selection of an appropriate treatment depends on several factors including the suspicion for occult malignancy, size and location of lesion(s), comorbidities, reliability of follow-up, medical resources, and provider experience.

Surgical Excision

Surgical excision is the preferred first-line treatment for vulvar dysplasia, as it yields a pathologic specimen that can be evaluated for invasive cancer.1 Wide local excision is the most appropriate and commonly performed surgery for vulvar dysplasia. Complete skinning vulvectomy is rarely performed. Surgical management is always recommended for dVIN, given the high risk of progression to invasive carcinoma.

Visually abnormal tissue should be excised in its entirety. There is no definitive consensus on what the minimum margin of excision should be. However, a lateral margin of at least 5 mm and up to 10 mm is recommended to decrease the rate of recurrence.1-3 In terms of the depth of the excision, removal of the epidermis is sufficient for treatment of vHSIL and removing a small amount of underlying dermis serves to ensure the absence of early invasive carcinoma. This may involve the removal of any involved hair follicles.2,3 Margins and depth of excision should be adjusted to avoid disrupting critical structures such as the urethra, clitoris, or anus. Negative margins are associated with a reduced risk of recurrence, though the absolute risk remains high. Grossly visible residual lesions require treatment, but microscopically positive margins can be clinically observed. In one case series of 405 patients with dysplasia treated with surgical excision, Jones et al10 found a 50% risk of retreatment within 5 years for patients with positive margins, but only a 15% risk for those with negative margins. As vHSIL is often multifocal, a negative margin will only reduce the recurrence risk at that site and not the lifelong risk of the development of vHSIL at other sites on the vulva. Risk of recurrence is also higher for multifocal lesions.11

Surgical Ablation

CO₂ laser ablation represents an alternative to surgical excision in patients who carry a low risk of malignancy, or in whom biopsies have excluded malignancy. The advantages of laser ablation include favorable cosmetic and functional outcomes. However, ablative techniques will not yield a specimen for pathologic evaluation and may be associated with greater postoperative pain and wound care requirements as compared with surgery.3 Laser ablation can be particularly useful for patients with multifocal disease or those who have lesions involving the clitoris, urethra, or anus. Laser ablation is contraindicated in dVIN, given the high risk of concurrent malignancy. The evidence comparing recurrence rates between patients treated with laser ablation versus surgical excision is poor, but the data we do have do not seem to show any meaningful difference in recurrence.12

Recommended ablative margins are the same as with surgical excision. Lateral margins of 5 to 10 mm are ideal when possible.1 Laser ablation must similarly target hair follicles, which can contain vHSIL cells and extend to depths of 3 mm or greater. In regions without hair follicles, ablation to the level of the dermis (2 mm in depth) is appropriate.1,3 Care must be taken to avoid deep coagulation injury, which can result in poor cosmetic and functional outcomes.2 Use of appropriate power density and intraoperative colposcopy can help to reduce these risks. Given the treatment requirements, patients with large lesions involving many hair follicles may be more appropriate excisional candidates. Conversely, patients with small, multifocal lesions in areas without hair may be excellent candidates for laser ablation.

Medical Treatment

Imiquimod is a toll-like receptor 7 agonist that stimulates dendritic cells to increase expression of interferon-[alpha] and tumor necrosis factor-[alpha]. These cytokines enhance the cytotoxic ability of innate immune cells to destroy HPV-infected or dysplastic cells.13 Imiquimod has been approved by the FDA for treatment of HPV-related genital warts (vulvar LSIL or condyloma), but not for vHSIL. However, 2 randomized controlled trials by van Seters et al14 and Mathiesen et al15 have demonstrated the efficacy of topical imiquimod 5% in vulvar HSIL, leading to its off-label use. Reported complete histologic response rates vary widely between 31% and 81%. Recurrence rates are poorly reported.14,15

Imiquimod is applied topically to individual lesions and should not be applied to the entire vulva. Treatment involves applying a thin layer of cream 3 to 5 times per week on alternate days for 16 weeks.14,15

Topical imiquimod is associated with several adverse effects, including application site pain, irritation, erythema, erosion or edema, vaginal discharge, or fevers. These adverse effects are usually mild to moderate, and the drug is generally well-tolerated.13 Temporary dose reductions to one application per week or a 1-week break from treatment may be necessary if patients experience severe adverse effects, but treatment pauses of greater than 1 week are not recommended.15

Fluorouracil can be used when other therapies have failed. Fluorouracil causes chemical desquamation of vHSIL, and although response rates are high, it is rarely used because it is poorly tolerated by patients due to burning, pain, inflammation, edema, and ulcerations.

Cidofovir is under investigation as a potential agent to treat vHSIL. Cidofovir is a nucleoside analogue that competitively inhibits viral DNA polymerases. Hurt et al16 examined the efficacy of cidofovir versus imiquimod in 180 patients in a phase II multicenter trial, the only randomized controlled trial to compare these 2 therapies. The published regimen consisted of topical cidofovir 1% applied 3 times a week for 24 weeks.17 Rates of complete response were similar in both arms; however, the cidofovir arm showed significantly greater maintenance of complete response at 18-month follow-up (94% vs 71.6%).16 These results suggest that cidofovir may be just as efficacious as imiquimod in initial disease control with the added advantage of increased time to recurrence. However, given the scarcity of data, cidofovir is not yet routinely used.

Surveillance

The elevated lifetime risk of vulvar cancer and recurrent dysplasia in this population highlights the need for close surveillance after complete response to treatment for vulvar dysplasia. The ACOG recommends follow-up examination at 6 and 12 months after complete response followed by visual inspection annually.1 Patients may be instructed to perform visual self-inspection and to monitor for symptoms, but this does not replace clinical surveillance by a provider. European surveillance guidelines published by the European Academy of Dermatology and Venereology recommend lifetime surveillance every 6 to 12 months for patients with vHSIL, in addition to annual cervical dysplasia screening.18 Anal dysplasia screening may also be indicated in certain populations (see the Risk of Associated Anogenital Dysplasia subsection). Overall, gynecologic examination with visual inspection of the vulva every 6 months for 5 years followed by annual examinations thereafter is a reasonable approach to surveillance for vHSIL. For patients with dVIN, surveillance every 6 months at a minimum is indicated. There are no associated recommendations for other lower genital tract dysplasia, given its HPV-independent pathophysiology.18

Risk Factors for Recurrence

Reported rates of recurrence for vulvar dysplasia are high, regardless of treatment modality. Approximately one-third of patients will develop recurrent vulvar squamous intraepithelial lesion. Recurrences can occur late (>5 years) and some of them will present as invasive cancer.1,19-21 Patient factors that increase recurrence risk include age more than 50 years, immunosuppression, concurrent vaginal intraepithelial neoplasia or cervical intraepithelial neoplasia, and smoking.19,21 Treatment and disease-related risk factors for recurrence include positive margins after excision, multifocal lesions, larger initial lesions, and presence of lichen sclerosus.19-21 The most significant of the aforementioned risk factors include presence of lichen sclerosus, positive surgical margins, and multifocal lesions, which were associated with 9.9-fold, 8.1-fold, and 3.3-fold odds of recurrence, respectively.19,21 Median times to recurrence range from 16.9 to 25 months, but can be as long as 15+ years. Overall, there were no observed differences in recurrence across initial treatment modalities.

Risk of Associated Anogenital Dysplasia

The pathophysiology of anal cancer is strongly associated with HPV coinfection (ranging from 30% to 80% in perianal cancer).22 Given the shared pathophysiology of HPV-induced cellular proliferation in both vulvar and anal dysplasia, concerns have been raised about the need for anal cancer screening in women with vulvar dysplasia. In a small pilot study of 57 women with a history of vHSIL, Proctor et al23 identified abnormal anal cotesting results in 56.1% and anal HSIL in 18.2% of patients. Anal cancer incidence rates are higher in patients with a diagnosis of vulvar cancer as well.24 In a study of 190 patients with cervical, vulvar, and vaginal dysplasia or malignancy, the prevalence of anal dysplasia was 41.2% and HPV was detected in 20.8% of anal pap smears. Anal dysplasia was found in 13.4% of these women who underwent anoscopy, with 4.2% having anal intraepithelial neoplasia grade 2 or more (AIN2+).25 Despite these associations, no major oncologic societies have made recommendations for routine anal cancer screening in the general population, much less patients with a history of vulvar dysplasia, as there is a paucity of evidence demonstrating benefit for routine screening.22

Practice Pearls

* All vulvar skin lesions that are new, changing, or do not respond to topical treatments should be biopsied.

* vHSIL and dVIN always require treatment due to the risk of progression to invasive cancer. Surgical excision is required in patients with dVIN and is the preferred treatment for vHSIL.

* Provided that invasive disease has been excluded, ablation or topical treatment with imiquimod can be considered for patients with vHSIL, particularly in those with multifocal disease or disease abutting the clitoris, urethra, or anus.

* Surveillance every 6 months is ideal in the first 2 years after treatment for vHSIL and dVIN, and then annual surveillance thereafter.

* Up-to-date cervical cancer screening and, in some cases, anal cancer screening is an important adjunct to vulvar surveillance in patients with a history of vHSIL.

Special Considerations

Patients With HIV Infection

Patients with HIV are at increased risk of developing lower genital dysplasia due to impaired ability to clear HPV infections.26 Bradbury et al26 conducted a retrospective cohort study of 107 women diagnosed with VIN and found that 84.8% of HIV-positive patients had multicentric dysplasia (concurrent cervical or vaginal dysplasia) compared with 43% of HIV-negative patients. In addition, HIV-positive patients were more likely to present with multifocal vulvar dysplasia (63.6% vs 22.2% in HIV-negative patients), an independent risk factor for recurrence. Unsurprisingly, HIV-positive status was associated with decreased recurrence-free survival and progression-free survival.26 There are currently few data on the utility of using CD4 counts in prognosticating the course of vulvar dysplasia, and similarly sparse data describing the impact of highly active antiretroviral therapy on VIN outcomes.2,26 Given the higher risk of dysplasia and progression to invasive cancer in this population, increased frequency of surveillance and lower threshold for repeat biopsies is appropriate.1 Ultimately, management of vulvar dysplasia in HIV-positive patients will be individualized to patient characteristics, clinical judgment of the provider, and available clinical resources.

REFERENCES