Vulval intraepithelial neoplasia

What is vulval intraepithelial neoplasia?

Vulval (or vulvar) intraepithelial neoplasia is a pre-cancerous skin lesion (a type of squamous cell carcinoma in situ) that can affect any part of the vulva. The term vulval intraepithelial neoplasia describes two conditions with different biological behaviour: usual type and differentiated type.

Usual type vulval intraepithelial neoplasia

Usual-type VIN is associated with human papillomavirus (HPV) infection, and is also called uVIN and vulval high-grade squamous intraepithelial lesion (HSIL). In this article, we abbreviate the condition as uVIN/HSIL.

• uVIN/HSIL is an intraepithelial form of squamous cell carcinoma
• uVIN/HSIL was previously known as Bowen disease of the vulva, but this term is no longer used.
• About 12% of uVIN/HSIL resolves spontaneously within a year. This is usually multifocal disease occurring in young women.
• uVIN/HSIL is not invasive cancer, but vulval cancer (squamous cell carcinoma, SCC) may develop in many cases after an average of 7 years if uVIN/HSIL is left untreated.
• The term uVIN/HSIL excludes vulval extramammary Paget disease and vulval in-situ melanoma.

Differentiated vulval intraepithelial neoplasia

Differentiated VIN (dVIN) is associated with inflammatory diseases of the vulva, lichen sclerosus and erosive lichen planus (and not with HPV). It is much less common than uVIN/HSILand accounts for 5% of VIN. Up to 85% of dVIN will progress to SCC if untreated.

How do uVIN/HSIL and dVIN present?

Although some women do not have symptoms, uVIN/HSIL and dVIN often present with:

• Mild to severe vulval itching
• Mild to severe vulval burning
• One or more flat or slightly raised well-defined skin lesions
• These may be pink, red, brown and/or white in colour.

The lesions can occur on any part of the vulva, but are most frequently diagnosed on hair-bearing labia majora, and non-hair–bearing labia minora and posterior fourchette. Most cases of dVIN occur on non-hair bearing skin.

See images of VIN/HSIL and dVIN ...

Why do VIN/HSIL and dVIN occur and who is at risk?

uVIN/HSIL

uVIN/HSIL may occur in women of all ages, although an increased number of younger women (even teenagers) are presenting; the average age at diagnosis is about 40 years.

The following factors have been associated with uVIN/HSIL.

• HPV causes most cases of uVIN/HSIL. HPV also causes genital warts and other genital cancers and precancers (cervical cancer, vaginal cancer and anal cancer). Only oncogenic types of HPV (especially types 16, 18 and 33) are associated with uVIN/HSIL. (Visible genital warts are mostly caused by types 6 and 11). About half of women with uVIN/HSIL also have a history of abnormal cervical smears or cervical cancer.
• Smoking: it is thought that the cancer promoting agents in cigarettes are concentrated in the skin of the lower genital tract and smokers have a higher risk of uVIN/HSIL than non-smokers.
• Immunosuppression by disease, such as human immunodeficiency virus (HIV) infection, or medications, such as those taken by organ transplant recipients.

dVIN

dVIN is associated with chronic vulval inflammatory skin disease, particularly lichen sclerosus or erosive lichen planus. The average age of presentation with dVIN is 60 years.

How are uVIN/HSIL and dVIN diagnosed?

One or more flat or thickened, irregular red, white or pigmented plaques on the vulva may suggest a diagnosis of uVIN/HSIL or dVIN. Colposcopy (examination using magnification and a special light) may be used to examine the appearance and extent of the condition. A skin biopsy is required to confirm abnormal epithelial cells within the epithelium, and to identify any invasive cancer.

• The epithelium may be hyperkeratotic (scaly) and acanthotic (thickened).
• uVIN/HSIL reveals vacuolated and dysplastic cells with mitoses throughout the epithelium, which can include follicular epithelium.
• dVIN reveals dysplastic cells and mitoses confined to the basal layer.
• Immunohistochemistry stains: uVIN/HSIL is p16 positive, and dVIN is p53 positive.

Warty lesions in postmenopausal women should undergo biopsy, particularly if they do not resolve with simple treatment.

Women with vulval lichen sclerosus and erosive lichen planus should be followed up carefully. Any areas failing to respond to high-potency topical corticosteroids, particularly if hyperkeratotic, should have a biopsy taken to exclude dVIN.

Classification of VIN/SIL

The classification of uVIN/SIL has evolved over a number of years. The terminology adopted by the International Society for the Study of Vulvovaginal Diseases (ISSVD) in 2015 is:

1. Low grade squamous intraepithelial lesion (flat condyloma or HPV effect) (LSIL)
2. High grade squamous intraepithelial lesion (VIN usual type) (HSIL), previously called VIN 2 and VIN3
3. Intraepithelial neoplasia, differentiated-type (dVIN)

HSIL and dVIN have potential to progress to invasive vulval cancer, whereas LSIL lesions are low risk and are not neoplastic. HSIL-associated cancers tend to be warty in appearance.

Does uVIN/HSIL need to be treated?

LSIL does not always require treatment, but follow-up should be arranged until the lesions resolve, as they sometimes progress to uVIN/HSIL.

There is also a group of younger women with multifocal uVIN/HSIL whose disease resolves spontaneously within a year. Their lesions are usually papular and pigmented. If they persist for longer, treatment should be performed.

uVIN/HSIL and d-VIN are treated to reduce the risk of developing invasive cancer and to alleviate symptoms.

What treatments are available for uVIN/HSIL?

The aim is to remove all affected tissue with a margin of apparently unaffected tissue. This may be done by surgical excision. Sometimes a complete vulvectomy (removal of the vulva) is undertaken because of the extent of disease or because of multifocal uVIN/HSIL. Excision is also undertaken for dVIN, which is rarely multifocal but can be more aggressive than uVIN/HSIL.

If invasive cancer is not suspected, laser ablation may be used in some centres. Like surgical excision, it is performed under general anaesthetic.

Medical therapy is reported to be effective in at least some cases of uVIN/HSIL, and is useful for treating a field area prone to multifocal disease. Options include:

• Imiquimod cream, applied 3 times weekly for 12 to 20 weeks. This results in red, inflamed, and eroded tissue and is often accompanied by considerable discomfort.
• 5-fluorouracil cream, applied twice daily for several weeks. This causes quite severe inflammation for several weeks, and will not be tolerated by all women. It is less effective than imiquimod cream and thus is used less frequently than in the past.
• Photodynamic therapy (PDT) requires specialised equipment and can also be very painful.
• Therapeutic HPV vaccination.
• Cidovir has been described to be useful in some patients.

None of these medical treatments are officially approved for uVIN/HSIL and they are rarely recommended for dVIN.

Unfortunately uVIN/HSIL recurs in up to half of of patients after treatment. This is more likely if:

• The patient is immunosuppressed
• The lesion was incompletely removed (positive margins may have been reported by the pathologist)
• Disease is multifocal.

Lichen sclerosus associated with dVIN is also a risk factor for recurrence.

Prevention of uVIN/HSIL and dVIN

Immunisation with HPV vaccine has been shown to decrease the development of uVIN/HSIL as well as cervical cancer and genital warts. Theoretically, nine–valent HPV vaccine could reduce the risk by 80–90%. It does not reduce the risk of dVIN.

Women that have had genital warts or previous uVIN/HSIL should be strongly encouraged to stop smoking.

Effective treatment of vulval skin disorders such as lichen sclerosus may reduce the risk of uVIN/HSIL, dVIN, and vulval cancer.

What is the outcome for women with uVIN/HSIL and dVIN?

If left untreated:

• LSIL usually resolves within a year or two.
• uVIN/HSIL may develop into an invasive cancer. On average it takes 6–7 years for untreated HPV-associated uVIN/HSIL to progress to cancer.
• Untreated dVIN results in vulval cancer in most cases within 2–4 years. Cancer develops more rapidly in dVIN than in uVIN/HSIL, and the likelihood of this increases with age.

Careful follow-up after treatment is essential long term.

• uVIN/HSIL and dVIN may recur in up to 50% of cases after treatment, particularly if excision margins are inadequate.
• Follow-up every 6–12 months is recommended for at least 5 years after surgery for uVIN/HSIL and indefinitely for dVIN.

Up to 50% of women with uVIN/HSIL develop cervical intraepithelial neoplasia (CIN), anal intraepithelial neoplasia (AIN), vaginal intraepeithelial neoplasia (VAIN) or invasive cancer of the genital tract or anus.

• It is particularly important to have regular cervical smears.
• Immunosuppressed patients, especially those with HIV infection, should also undergo cytology of the anus.