General Considerations
The vulvar skin is one component of the anogenital epithelium, extending from the distal vagina to the perineum and perianal skin. The lower genital tract epithelium is of common cloacogenic origin. Neoplasia of the vulvar skin is often associated with multiple foci of dysplasia in the lower genital tract. A strong association exists between sexually transmitted diseases and vulvar intraepithelial neoplasia (VIN), primarily human papillomavirus (HPV), but also gonorrhea, syphilis, Gardnerella vaginalis, trichomonas, and human immunodeficiency virus (HIV). Approximately 80% of VIN lesions are positive for high-risk HPV types, primarily HPV-16.

Other risk factors include smoking and other genital precancers or cancers. VIN can also be classified into viral and nonviral etiologies. Younger women are more commonly affected by viral VIN than older women and are also more likely to exhibit multifocal disease. Although the incidence of VIN and HPV has increased over the past decade, the incidence of vulvar carcinoma has remained relatively constant. The long-term risk of malignant transformation of treated VIN III has been estimated at 3.4-7% and the risk for progression of untreated VIN is thought to be higher.

Premalignant lesions of the vulva occur in both premenopausal and postmenopausal women, with the median age being approximately 40 years. The average age is shifting toward younger women, with 75% of lesions occurring during the premenopausal period. There is no racial predisposition to VIN and the disease process is often asymptomatic. The most common presenting symptom is pruritus, which is seen in more than 60% of patients with VIN. The diagnosis is made by careful inspection of the vulvar area followed by biopsy of suspicious lesions.

Pathology

In 1989, the International Congress of the International Society for the Study of Vulvar Disease (ISSVD) adopted a standard of reporting vulvar dysplastic lesions as VIN I, II, or III, depending on the degree of epithelial cellular maturation. The degree of loss of epithelial cellular maturation in a given lesion defines the grade of VIN. In VIN I, immature cells occur in the lower one-third of the epithelium. Complete loss of cellular maturation in the full thickness of epithelium is defined as VIN III, which is synonymous with carcinoma in situ of the vulva, or Bowen’s disease. VIN II is intermediate between VIN I and VIN III.

In contrast to intraepithelial carcinoma of the cervix, which seems to arise from a single point of origin, dysplasia of the vulva is often multicentric. These lesions may be discrete or diffuse, single or multiple, flat or raised. They even form papules and vary in color from the white appearance of hyperkeratotic tumors to a velvety red or black.

The microscopic appearance of dysplastic vulvar lesions is characterized by cellular disorganization and loss of stratification that involves essentially the full thickness of the epithelium. Cellular density is increased, and individual cells vary greatly in size, with giant and multinucleated cells, numerous mitotic figures, and hyperchromatism. HPV cytopathic changes, such as perinuclear halos with displacement of nuclei, are also common.

Diagnosis

Possibly 1-2% of young women with Cervical dysplasia have multifocal disease that tends to involve the upper third of the vagina and the vulva, perineum, and perianal areas—these surfaces arising from a common cloacogenic origin. A spectrum of disease may be found ranging from mild dysplasia to carcinoma in situ. Involvement may not be appreciated without careful inspection with and without the green colposcopy filter. Clinically, the appearance of VIN can be quite variable.

Lesions are typically white and hyperkeratotic, but may also appear gray, pink, or brown. Colposcopy and biopsy of any suspicious lesion should be performed and is considered the gold standard for diagnosis. In premenopausal women, lesions tend to be more multifocal, whereas in postmenopausal women, they are more often unifocal. An abnormal vascular pattern is most frequently associated with a severe degree of dysplasia, carcinoma in situ, or early invasive disease.

Treatment

Treatment options for VIN are individualized based on biopsy results and include wide local excision, laser ablation, topical application of 5-fluorouracil (5-FU) or imiquimod, or superficial vulvectomy with or without split-thickness skin grafting. Untreated VIN has the potential for progression to invasive carcinoma. This risk may be high for women older than age 40 years. In younger patients, spontaneous regression may occur.

Treatment modality depends on the extent of involvement of the vulva, perineum, and perianal skin, which is defined by colposcopy. Wide local excision of small foci of VIN is preferred. For unifocal lesions, a 1-cm margin of uninvolved skin is usually curative. Carbon dioxide laser may be used for multifocal disease. Disadvantages of the laser include painful recovery and lack of pathology specimens. The incidence of foci of microinvasion in VIN III has been reported to range from 10-22% in different series. Extensive disease may be best treated by superficial vulvectomy. The surgical goal is to preserve as much of the normal anatomy as possible. In the superficial “skinning” vulvectomy procedure, the excised vulvar skin can be closed with fine suture or may need to be replaced with a split-thickness skin graft if the defect is too large.

Topical application of 5-FU, cryotherapy, and photodynamic therapy have each historically been proven useful in the treatment of some lesions, but surgery remains the hallmark treatment modality for VIN. Promising future directions for treatment of VIN involve the development of a vaccine for HPV, which is currently in the experimental phase, and use of immunomodulating agents, such as topical imiquimod.

Follow-Up

Intraepithelial carcinoma of the vulva is often one manifestation of multifocal disease. For this reason, affected patients must be examined periodically for a number of years. Recommended follow-up includes thorough pelvic examinations with colposcopy every 3-4 months until the patient is disease-free for 2 years. If the patient is disease-free for a 2-year period, examinations can be done every 6 months.

Rowley KC, Gallion HH, Donalson ES, et al. Prognostic factors in early vulvar cancer. Gynecol Oncol 1988;31:43.