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CLINICAL REVIEW

Vulvar Intraepithelial Neoplasia: A Growing Concern

Kathryn Martin, PharmD

Vulvar intraepithelial neoplasia (VIN) is a premalignant squamous-cell dysplastic lesion of the vulva that can be differentiated from squamous cell carcinoma of the vulva in that it has not penetrated the epithelial basement membrane. While cancer of the vulva is uncommon, with approximately 3,400 new cases each year and an estimated 870 deaths in 2008, the incidence of VIN appears to be increasing, particularly among young women.1,2

The malignant potential of VIN has not been defined, with estimates ranging from 9% to as high as 87%.3,4 Regardless of the level of risk, high-grade VIN is routinely treated due to the potential for malignant transformation. VIN may also result in symptoms (itching, burning, chronic vulvar discomfort) that can adversely affect both quality of life and sexuality.5

A majority of cases of VIN can be attributed to infection with the human papillomavirus (HPV) subtypes 16 and 18.2,3 In a randomized trial of topical imiquimod, 96% of subjects with grade 2 or 3 VIN tested positive for HPV DNA at baseline. The hypothesis that high-grade VIN lesions may represent a failure of the immune system to clear HPV is supported by the higher incidence of VIN in immunosuppressed patients such as transplant recipients.2

Historically, treatment of VIN was limited to surgery, laser treatment, or photodynamic therapy.5 Although surgical removal of individual lesions may be successful, it may be associated with disfigurement and psychosexual stress, and does not address the underlying HPV infection that causes most cases.3.6

Imiquimod is an immune response modifier approved for the treatment of actinic keratosis, superficial basal cell carcinoma, and external genital warts.7 Given imiquimod’s activity in disease associated with HPV and the strong association of HPV with VIN, it was a logical extension to evaluate the safety and efficacy of imiquimod 5% cream in the management of VIN (Table).

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TABLE. Selected Published Clinical Trials of Imiquimod in Vulvar Intraepithelial Neoplasia*

Although it is not FDA-approved for this indication, positive long-term clinical outcomes for VIN have been reported with topical imiquimod. In a randomized study, complete response and partial response (76% to 99% reduction in lesion size) were seen at one year in 35% and 46% of subjects, respectively, and all subjects with complete response at 20 weeks remained free of disease at 12 months. Only 2 of 12 (17%) of those with a partial response following treatment had enlargement of lesions.6 In a phase 2 study, patients treated with imiquimod had a significantly lower rate of recurrence and longer time to recurrence compared to surgically treated patients.5

In a placebo-controlled study of 52 subjects with grade 2 or 3 VIN, viral clearance of HPV was strongly associated with histologic regression of lesions.6 In a phase 2 study, there was a significant association between the need for dose reduction and observed complete response to treatment that has been observed in patients with actinic keratoses treated with imiquimod.5

Use of imiquimod has also been associated with relief of pruritis and pain both immediately following treatment and long term (12 months).2,6

Reported side effects with imiquimod for VIN were generally local and included erythema, erosion, vesiculation, edema, burning, discomfort, dyspareunia, dysuria, and ulceration, which were most often mild to moderate.5,6 The side effects occasionally necessitated interruption of treatment.2 A published report has linked prolonged use of imiquimod with vulva pemphigus.5

In summary, imiquimod has shown good efficacy and acceptable toxicity in multiple clinical trials. Although initial data have been positive, many of the studies have had small patient populations and limited long-term follow-up. While further investigation in larger, controlled studies comparing it to surgical intervention will provide a more clear definition of its role, imiquimod potentially represents an efficacious and safe alternative for the treatment of VIN, particularly in women who prefer to avoid invasive treatments.

The author reports no actual or potential conflicts of interest in relation to this article.

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Kathryn Martin, PharmD, is a clinical writer and consultant, Montibello, New York.

References

1. American Cancer Society. Cancer Facts & Figures 2008. Atlanta GA. www.cancer.org/downloads/STT/2008CAFFfinalsecured.pdf. Accessed February 24, 2009.
2. Winters U, Daayana S, Lear JT, et al. Clinical and immunologic results of a phase II trial of sequential imiquimod and photodynamic therapy for vulvar intraepithelial neoplasia. Clin Cancer Res. 2008;14(16):5292–5299.
3. Mathiesen O, Buus SK, Cramers M. Topical imiquimod can reverse vulvar intraepithelial neoplasia: a randomised, double-blind study. Gynecol Oncol. 2007;107(2): 219–222.
4. Canavan TP, Cohen D. Vulvar cancer. Am Fam Physician. 2002;66(7):1269–1274.
5. Le T, Menard C, Hicks-Boucher W, Hopkins L, Weberpals J, Fung-Kee-Fung M. Final results of a phase 2 study using continuous 5% Imiquimod cream application in the primary treatment of high-grade vulva intraepithelial neoplasia. Gynecol Oncol. 2007;106(3):579–584.
6. Van Seters M, van Buerden M, ten Kate FJ, et al. Treatment of vulvar intraepithelial neoplasia with topical imiquimod. N Engl J Med. 2008;358(14):1465–1473.
7. ALDARA? Cream 5% (imiquimod) Prescribing Infor-mation. Graceway Pharmaceuticals. Revised 11/07. www.aldara.com/pdfs/carcinoma_professional_pi.pdf. Accessed February 24, 2009.

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