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

1. Identify patients to screen for vaginal intraepithelial neoplasia.

2. Explain treatment options and their adverse effects for patients with vaginal intraepithelial neoplasia.

3. Describe appropriate patient surveillance for patients with vaginal intraepithelial neoplasia.

Vaginal intraepithelial neoplasia (VaIN) is an uncommon lower genital tract dysplasia with malignant potential. Due to its rarity, there is a paucity of high-quality clinical research guiding management. Observational studies have demonstrated that there is a long latency period between the diagnosis of VaIN and the development of invasive carcinoma. Thus, the lengthy burden of surveillance is tasked to women's health providers including gynecologists and primary care physicians.

We review much of the available research on VaIN to help guide clinicians with surveillance and management decisions and provide some of the clinical reasoning behind this guidance. We also discuss special populations and give recommendations on when to refer to subspecialty care. As VaIN is a relatively uncommon condition, large-scale data are limited, and recommendations presented here are based primarily on the results of retrospective studies and expert opinion.

Background and Epidemiology

VaIN is rare, affecting 0.2 per 100,000 women and representing just 0.4% of all lower genital tract dysplasia in women.1 However, several recent studies indicate that the frequency of diagnosis is increasing, although it is difficult to determine whether this is due to enhanced screening or increasing incidence.2 Most patients with VaIN either have or have had other lower genital tract dysplasia or carcinoma of the cervix, vulva, or anus.3

Similar to other lower genital tract dysplasia, VaIN is classified according to the depth of epithelial involvement. VaIN 1 involves the lower one-third of the epithelium, VaIN 2 involves the lower two-thirds of the epithelium, and VaIN 3 involves more than two-thirds of the epithelium but does not have any evidence of invasion.

The median age of diagnosis ranges from 43 to 50 years in the general population. However, in special populations, age of diagnosis can be older or younger based on clinical history and risk factors. For example, a case-control study by Liao et al4 demonstrated a median age of diagnosis of VaIN after radiation for a prior pelvic malignancy to be 55. Conversely, a series on lower genital tract dysplasia in solid organ transplant recipients by Thimm et al5 demonstrated a younger median age of diagnosis.

Risk factors for the development of VaIN include human papilloma virus (HPV) infection, immunosuppression or immunodeficiency, history of pelvic radiation therapy, in utero diethylstilbesterol (DES) exposure, and prior hysterectomy for benign, premalignant, and malignant conditions. Risk of persistence is increased by some of these factors such as HPV infection and chronic immunosuppression or immunodeficiency, along with cigarette smoking. This necessitates long-term surveillance due to the increased risk of developing invasive cancer. Fortunately, persistence and progression are both relatively infrequent. One of the highest risk groups is patients who have undergone a hysterectomy for cervical intraepithelial neoplasia (CIN). This group has a risk of developing VaIN 2+ that is as high as 7.4%.6

The most common risk factor for VaIN is persistent HPV infection, and this is the main factor associated with persistence, recurrence, and progression. The distribution of HPV subtypes varies, but HPV 16 is the subtype implicated in the majority of high-grade dysplasia.3 Additional suggested risk factors for progression to carcinoma are a history of hysterectomy for cervical dysplasia/carcinoma and a history of pelvic radiation therapy.4,7 Overall, the rate of progression to invasive cancer has been found to be somewhere between 2% and 8% in several retrospective studies.8-13

The incidence of VaIN is much lower than the incidence of CIN in patients with HPV infection. It is thought that this could be because the metaplastic transformation zone of the cervix is more susceptible to oncogenic transformation, whereas the more mature vaginal squamous epithelium is less vulnerable. Interestingly, patients who were exposed to DES in utero can have squamous metaplasia of the vagina, which could explain the increased incidence of VaIN in these patients.14,15

The largest series exploring the course of VaIN was published by Kim et al,16 and reviewed 576 cases of VaIN from 2000 to 2016 with a median follow-up time of 44.6 months. This series demonstrated the rate of persistence and progression to be 18.3% and 4.7%, respectively. Additionally, 16.9% of those who initially regressed had a recurrence during the study period. Notably, the grade of dysplasia was not significantly associated with regression and recurrence rates, although high-grade dysplasia had an increased risk of progression.16

Diagnosis

VaIN is most commonly asymptomatic although it can be associated with vaginal discharge or postcoital spotting. Diagnosis of vaginal dysplasia can be made by cytology alone or by cotesting (cytology plus HPV testing), then colposcopy with biopsy. The histologic findings are that of squamous dysplasia without invasion. Gunderson et al9 found that high-grade cytology is predictive of VaIN 2 and Van 3 in 89% of cases; low-grade cytology is not as predictive, but is still associated with VaIN 2 and Van 3 in 53% of cases.9 This highlights the need to thoroughly follow up all abnormal vaginal Pap testing including low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and atypical glandular cells of undetermined significance (AGUS) with vaginoscopy and/or colposcopy. Nearly all VaIN lesions are located in the epithelial recesses of the upper third of the vagina; therefore, it is important to fully visualize this area and biopsy all suspicious lesions. In contrast to cervical dysplasia, there are no data to support random biopsies after an abnormal vaginal pap.

Treatment

Treatment of VaIN depends on grade. VaIN 1 is usually followed by close monitoring without active treatment. This recommendation is based on the observation that these lesions are often caused by nononcogenic HPV strains and will regress without treatment.17 Additionally, in postmenopausal women, these changes can be due in part to atrophy and treatment with topical estrogen therapy can be used.18

Current treatment options for VaIN 2 and VaIN 3 include topical medications, surgical excision, and laser ablation. Commonly used topical medications include imiquimod or 5-fluorouracil (5-FU) and topical chemotherapeutic agents, which act locally on rapidly proliferating cells. Surgical treatments include local excision or upper vaginectomy. Ablative therapy is typically done via carbon dioxide laser ablation, which requires specialized training and equipment. Treatment must be individualized to each patient.

Excision is recommended for patients in whom a larger specimen is needed for further evaluation or who have a lesion that is concerning for invasive disease. Wide local excision is the most frequently used surgical approach and can be performed transvaginally. This is very useful, particularly for patients with a single site of disease. Alternatively, for disease that is anatomically difficult to resect due to location in the upper vaginal folds or for more extensive disease distribution, upper vaginectomy or even total vaginectomy can be performed. These procedures are typically accomplished transabdominally either by a minimally invasive or open approach. Vaginal shortening and stenosis are the most common complications of surgery and vaginal dilator use after healing can help to minimize this.

Ablative procedures can be performed as long as the lesion is fully visualized and the possibility of invasion has been excluded. Kim et al16 demonstrated that laser ablation was significantly more effective in reducing persistence/recurrence/progression of multifocal lesions as compared with excision. Other authors have proposed primary laser treatment as a preferred treatment for multifocal disease.1 Other benefits to ablative therapy are that it preserves anatomy and vaginal length. Carbon dioxide laser and ultrasonic surgical aspiration are the 2 modalities used. Postoperative pain, bleeding, and the need for retreatment are the most common complications.

Nonsurgical management can be accomplished with the application of topical chemotherapeutic agents. Again, invasive disease must be excluded for topical treatments to be a safe option. Use of 5% imiquimod is overall well tolerated. It is commonly used 3 times a week for 8 weeks, and complete response rates can be as high as 77%.19 Fluorouracil can also be used; dosing is typically once a week for 10 weeks and then 2 weeks of daily vaginal estrogen to reduce irritation. This has been found to have similar success rates to imiquimod.20 Both topical methods have the advantage of being able to treat the entire vagina. Complications include pain and vaginal irritation or burning. Rates of recurrence and durability of response have not been well reported.

In rare patients who are unable to undergo surgery or do not respond to any other treatments, intracavitary radiation therapy has been used with good success. However, this can be associated with significant complications including stenosis, vaginal shortening, sexual dysfunction, poor wound healing, and inability to adequately assess the vaginal epithelium in the future. Therefore, this option should be reserved for very difficult or refractory cases.

Posttreatment Surveillance

Due to the risk of progression of VaIN 2 and VaIN 3 to invasive squamous cell carcinoma, long-term follow up is required. Risk of recurrence of VaIN can be as high as 18%.8,21 Grade 3 histology and prior hysterectomy for HPV-related disease are independent risk factors for progression. Most recurrences occur in the first 1 to 2 years. Therefore, clinical examination every 6 months for 2 years and annually thereafter with annual cotesting (cytology and HPV) is a reasonable surveillance strategy. Vaginal colposcopy should be performed for any HPV-positive test or cytologic abnormality.

Referral to a gynecologic oncologist is appropriate in several clinical scenarios. These include patients with a history of in utero DES exposure, immunosuppression due to solid organ transplant, or HIV/AIDS and history of persistent high-risk HPV infection. Additionally, patients who have had a hysterectomy for high-grade cervical dysplasia or cervical cancer and patients who have been treated for vulvar or anal cancer with surgery and/or radiation should be referred to a gynecologic oncologist for management.

Practice Pearls

* Include HPV testing with genotyping if available on vaginal Pap smears.

* Positive cytology on vaginal Pap smears should be followed up with thorough vaginoscopy with colposcopy and with careful attention paid to visualizing the recesses of the vaginal apex/cuff. Any suspicious lesion should be biopsied.

* High-risk patients combined with high-grade dysplasia necessitate treatment of VaIN, with excision being the preferred treatment modality.

* Provided that invasive disease has been ruled out, ablation or topical treatment with imiquimod or 5-FU can be considered for patients with high-grade dysplasia in certain circumstances, including multifocal or extensive distribution of disease in whom the maintenance of vaginal length and function is important.

* Surveillance every 6 months is ideal in the first 2 years after treatment for VaIN 2 and VaIN 3, then annual surveillance thereafter. Annual cytology and HPV testing with genotyping is an important strategy to guide more intensive surveillance with colposcopy when cytology is abnormal or HPV testing result is positive.

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