Premalignant disease of the vagina

Introduction

Vaginal intraepithelial neoplasia (VAIN) is a rare, premalignant condition of the vagina, which is caused by persistent infection with oncogenic strains of the human papillomavirus (HPV).

VAIN is much less common than cervical intraepithelial neoplasia (CIN). The incidence is approximately 0.2 per 100,000 women, and it makes up approximately 0.4% of all intraepithelial disease of the lower genital tract (2). It can be difficult to diagnose and treat, due to the proximity of surrounding structures such as the bladder and rectum, and the need to preserve sexual function.

The malignant potential of VAIN is not fully known (3, 4), though the risk of transformation of VAIN to invasive squamous carcinoma has been reported to be 9-10% (Table 65.1) (5).

Epidemiology of vaginal intraepithelial neoplasia

As VAIN is caused by oncogenic HPV infection, one of the com­monest sexually transmitted infections, its risk factors include those related to HPV acquisition, such as multiple sexual partners, as well as impaired immunity and cigarette smoking.

VAIN is usually diagnosed at colposcopy for coexisting cervical disease, and is quoted to be present in 1-6% of women with CIN as part of a multifocal field effect of HPV in the lower genital tract (1). Immunocompromised women are more likely to have multi­focal lower genital tract neoplasia, and to have VAIN or vulval intraepithelial neoplasia (VIN) without accompanying CIN (6).

VAIN may also be detected on cytology done during follow-up of women who have undergone hysterectomy for persistent CIN or early cervical cancer. The incidence of VAIN in women who have had a hysterectomy for CIN 3, who were followed up for 10 years, has been found to be 0.91% (7).

Women who have had pelvic irradiation are also at risk of devel­oping VAIN (1).

Aetiology of vaginal intraepithelial neoplasia

VAIN is caused by high-risk strains of HPV, particularly HPV 16. HPV is a double-stranded DNA virus which is sexually transmitted and infects the squamous epithelium of the lower genital tract. It can exist in a dormant state, undergo replication, or transform the host DNA, causing uncontrolled cell growth (6).

Presentation of vaginal intraepithelial neoplasia

VAIN is usually asymptomatic, though it may present with symp­toms of coexisting vulval or cervical disease, for example, pruritus from warts or VIN, or with postcoital bleeding.

Diagnosis of vaginal intraepithelial neoplasia

Colposcopy of the vagina and staining with Lugol's iodine are neces­sary in order to diagnose VAIN. Adequate visualization of the en­tire vagina is essential, as well as biopsy of colposcopically abnormal areas, in order to confirm the diagnosis and exclude invasion. This may need to be done in theatre under anaesthetic. Occult carcin­omas have been found in the vaginal vault in 28% of women with VAIN (8).

Management of vaginal intraepithelial neoplasia

There are no standardized guidelines for the treatment of VAIN, and management should be individualized. Treatment options in­clude surgery, radiotherapy (brachytherapy), and medical manage­ment. When deciding on a treatment modality, several factors need to be considered: age and comorbidities of the patient, site and ex­tent of disease, preservation of sexual function, patient preference, experience of the treating medical team, and previous treatment modalities (1).

Surgery

Excision

Wide local excision or partial colpectomy is an effective and safe treatment of high-grade VAIN, and has the benefit of providing histological assessment and margin status, though sexual function

Table 65.1 Classification of squamous intraepithelial neoplasia of the vagina

can be affected by shortening the vagina (1).

Vaginectomy

This can be partial or total, and refers to removal of the vaginal mu­cosa (1). Either a knife or electrocautery loop may be used, though when using diathermy, care must be taken not to injure the bladder or rectum. Upper vaginectomy is the treatment of choice for unifocal VAIN 3 of the vault after hysterectomy, but laser ablation is preferred for multifocal high-grade VAIN (10).

Total vaginectomy and split-thickness skin grafting is oc­casionally necessary to treat extensive lesions when more con­servative therapies have not been successful, though it can have severe complications, such as vesicovaginal and rectovaginal fistulae, and has a severe impact on the patient's psychosexual well-being (1).

Laser

A carbon dioxide laser may be used for both ablation and exci­sion of VAIN. Epithelial destruction to a depth of 1.5 mm is suf­ficient to destroy the dysplastic epithelium without damaging underlying structures (11). Laser excision has the benefit of pro­viding a specimen for histology, but laser ablation has a minimal impact on psychosexual function, as the anatomy of the vagina is preserved, and is therefore useful in the management of younger women, and for multifocal lesions. However, it cannot be used in the vaginal vault fornices due to the risk of damage to underlying structures (1).

Cavitational ultrasonic surgical aspiration

Where the equipment and expertise are available, this allows se­lective removal of dysplastic lesions, while preserving the sur­rounding normal tissue (1).

Brachytherapy

Brachytherapy is internal radiotherapy, where a radiation source is placed close to a lesion, and delivers the required amount of radiation (1). Radiotherapy is not recommended as a first-line treatment for VAIN, due to its early and late side effects, impact on sexual func­tion, and the risk of developing another vaginal malignancy, but can be considered where there has been failure of other treatment options (1).

Medical management

Trichloroacetic acid

This is known to be an effective treatment for HPV lesions of the vulva and cervix, and there has been one study which showed com­plete remission of all low-grade VAIN lesions following weekly ap­plication of 50% trichloroacetic acid (12). The main side effect is vaginal burning.

5-Fluorouracil

This may be used in a dosage of 2 g once weekly for 10-12 weeks (13). It is reported to have varying success rates in treating exten­sive or multifocal high-grade VAIN, and side effects such as va­ginal burning, dyspareunia, ulcers, and discharge are common, and limit its use. It can cause a severe tissue reaction, which may limit colposcopic follow-up for months after treatment (1).

Imiquimod

A topical immune modulator, this is an effective and well-tolerated treatment for low-grade VAIN, and has shown some activity in the treatment of high-grade VAIN (14). It causes a vaginal burning and discomfort, but the dose can be titrated against local side effects and tolerability.

Follow-up of vaginal intraepithelial neoplasia

VAIN has been estimated to progress to cancer in about 9-10% of identified cases (5). It is hoped that very much less of this disease will be seen following HPV vaccination.

The United Kingdom National Health Service Cervical Screening Programme guidelines state that women who have a hysterectomy, and have completely excised CIN, should have vaginal vault cytology at 6 and 18 months after their hysterectomy (15). However, HPV DNA testing may be more effective at detecting VAIN than conven­tional cytology. Whether vaginal vault smears need to be continued long term after hysterectomy for high-grade CIN or cervical cancer is the subject of ongoing debate (1).

There is no evidence to suggest that there is any benefit from con­tinuing with smears after hysterectomy for benign disease (16).

VAIN recurrence rates after partial vaginectomy, laser ablation, and topical 5-fluorouracil are quoted as 0%, 38% and 59% respect­ively, with multifocal disease being a major risk factor for recur­rence (17). There is no evidence to support a particular duration of follow-up for VAIN, and this may match the duration recommended for CIN.