Vulvar squamous intraepithelial lesion refers to a group of lesions confined to the squamous epithelium of the vulva, which are associated with human papillomavirus (HPV) infection and have the potential to progress to invasive carcinoma. These lesions are most commonly observed in women around the age of 45, though there has been a rising trend in younger women. Approximately 50% of affected individuals present with squamous intraepithelial lesions in other anatomical regions, and around 38% of cases may resolve spontaneously. Only 2%–4% of cases progress to invasive carcinoma.
Vaginal squamous intraepithelial lesion refers to a squamous cell proliferative lesion of the vagina associated with HPV infection. The lesion is confined to the vaginal epithelium but carries a risk of progression to vaginal invasive carcinoma. The incidence is low, and the condition often coexists with squamous intraepithelial lesions of the cervix and vulva.
Etiological Factors
The precise causes remain unclear. Most vulvar and vaginal squamous intraepithelial lesions are associated with persistent infection with high-risk HPV types, primarily HPV types 16, 18, 31, and 33.
Nomenclature and Pathology
According to the 2020 WHO Classification of Tumors of Female Reproductive Organs, squamous intraepithelial lesions in the lower genital tract (including the cervix, vagina, and vulva) are categorized as HPV-associated and non-HPV-associated.
HPV-associated lesions include low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL).
Non-HPV-associated vaginal lesions have similarities with cervical lesions, while non-HPV-associated vulvar lesions are referred to as differentiated vulvar intraepithelial neoplasia.
The primary pathological features of squamous intraepithelial lesions include varying degrees of epithelial cell proliferation accompanied by nuclear atypia, increased mitotic activity, and disorganized cell arrangement.
Low-Grade Squamous Intraepithelial Lesions (LSIL)
This is previously referred to as vulvar intraepithelial neoplasia (VIN) grade I, vaginal intraepithelial neoplasia (VaIN) grade I (mild dysplasia), flat condyloma, or atypical koilocytosis. These lesions are associated with both low-risk and high-risk HPV infections, reflecting clinical and pathological changes caused by HPV. LSIL is more common in younger women, with over 30% of cases involving other squamous intraepithelial lesions of the lower genital tract, most frequently affecting the cervix. The lesions often regress spontaneously, and the risk of progression to invasive carcinoma is extremely low.
High-Grade Squamous Intraepithelial Lesions (HSIL)
This category includes what were previously referred to as VIN grade II and III, VaIN grade II and III (moderate to severe dysplasia), carcinoma in situ, Bowen’s disease, or Bowenoid dysplasia. These lesions are frequently observed in premenopausal women and are primarily caused by high-risk HPV infection. Without treatment, the risk of progression to invasive carcinoma is significant. For lesions that are completely excised, the recurrence rate is approximately 15%. However, if surgical margins are involved, the recurrence rate can reach 50%.
Differentiated Vulvar Intraepithelial Neoplasia (dVIN)
This type is unrelated to HPV infection and may arise due to TP53 mutations. It most commonly occurs in older women and is often associated with conditions such as lichen sclerosus or lichen planus, occasionally accompanied by keratinizing squamous cell carcinoma. dVIN carries a high risk of progression to invasive carcinoma within a short period.
Clinical Manifestations
The symptoms of vulvar squamous intraepithelial lesions are nonspecific, and some patients may remain asymptomatic. Symptomatic cases often present with vulvar itching, skin damage, or ulcers. Vulvar lesions may be variable in appearance, but key features include well-defined, raised, and asymmetric white or red plaques. Certain lesions may appear pigmented (brown/tan plaques) and are most commonly found on the labia majora, labia minora, and posterior commissure, with less frequent involvement of the clitoris, mons pubis, perineum, or perianal areas. Approximately 40% of cases are multifocal. Around half of dVIN cases are asymptomatic, while symptomatic cases typically present with vulvar itching, pain, or a burning sensation. dVIN lesions are usually solitary, presenting as thick keratotic plaques or erosive erythematous areas. Multiple lesions are often observed in skin or mucosa affected by lichen sclerosus or lichen planus.
Vaginal squamous intraepithelial lesions are typically asymptomatic, though some patients may experience dyspareunia or vaginal discharge. For asymptomatic cases, a meticulous and comprehensive clinical examination is essential. Lesions are often multicentric and may involve the mucosa of all vaginal walls, with a particular focus on the upper third and the vaginal vault during gynecological examination. The lesions may present as normal mucosa, warty growths, erosions, erythematous areas, or leukoplakic plaques.
Diagnosis
Definitive diagnosis requires pathological examination. Any suspicious lesion warrants a biopsy at multiple sites. Targeted biopsies under colposcopic guidance can also be performed. To ensure adequate sampling, the depth of biopsy should be sufficient, and the application of 3%–5% acetic acid or 1% toluidine blue solution to the lesion may improve diagnostic accuracy.
Differential Diagnosis
Vulvar squamous intraepithelial lesions need to be differentiated from conditions such as vulvar eczema, hypopigmented disorders of the vulva, nevi, melanoma, and acanthoma. Vaginal squamous intraepithelial lesions should be differentiated from conditions such as vaginal epithelial atrophy, vaginal adenosis, and vaginal endometriosis.
Management
The primary goals of treatment are to eliminate lesions, alleviate symptoms, and prevent the progression to invasive carcinoma. Treatment decisions should consider factors such as the patient's age, symptoms, lesion location, extent of the lesion, pathological type and grade, and the impact of the treatment method on the structure and function of the vulva and vagina. An individualized treatment plan is recommended based on these considerations.
Management of LSIL
In asymptomatic cases, periodic follow-up without immediate treatment may be sufficient. Symptomatic patients may benefit from topical medications, including imiquimod cream, fluorouracil ointment, or 1% cidofovir. Laser therapy may be an option for younger patients with extensive lesions.
Management of HSIL
Recent approaches to vulvar and vaginal HSIL have trended toward more conservative, individualized, and targeted therapies. For localized, recurrent, or suspected invasive lesions, local excision may be performed. Excision margins should extend at least 5 mm beyond the visible lesion and to a depth of at least 4 mm. For younger women or multifocal lesions, CO₂ laser, electrocautery, cryotherapy, or other physical treatments are recommended due to their minimal invasiveness and simplicity. Vaginal lesions may also be treated using ultrasound emulsification and aspiration, though total vaginectomy is rarely performed. Intracavitary radiation therapy is an option for recurrent vaginal HSIL, cases resistant to other treatments, or patients with contraindications to surgery. While effective, radiation therapy requires consideration of long-term side effects, including post-radiation vaginal sequelae and damage to surrounding organs.
Management of Differentiated Vulvar Intraepithelial Neoplasia (dVIN)
Given the high risk of progression to invasive carcinoma within a short time, rapid and complete lesion excision is necessary. Elderly patients or those with extensive lesions may undergo simple vulvectomy, which involves excising vulvar skin and a portion of the subcutaneous tissue without removing the perineal fascia. If invasive carcinoma is detected in conjunction with dVIN, treatment should follow protocols for vulvar cancer.
Prognosis
The prognosis varies according to the lesion type. Approximately 32.8% of dVIN cases progress to vulvar squamous cell carcinoma, with a median time to progression of 22.8 months. For vulvar HSIL, the probability of progression to vulvar cancer after treatment ranges from 3.3% to 5.7%, with a median progression time of 41.4 months. In untreated cases, the risk of progression is higher, at 9%–15.8%, occurring over a period of 1–8 years.
For vaginal HSIL, the progression rate to invasive carcinoma following surgery, radiotherapy, and treatment with fluorouracil is 5.3%–8.3%, 7.1%, and 6.7%, respectively. High-risk factors for recurrence include positive surgical margins, multifocal lesions, persistent high-risk HPV infection, and advanced age.
Follow-Up
Close follow-up is essential during the first 2–3 years after treatment for vulvar and vaginal squamous intraepithelial lesions. Post-treatment follow-up every 6 months is recommended, with examinations including cytology, HPV testing, and colposcopy. If no abnormalities are detected after 2 years of follow-up, the interval may be extended to annual follow-ups.
Prevention
Similar to cervical cancer, persistent HPV infection, especially HPV16, is strongly associated with vulvar and vaginal HSIL. Data from regions with HPV vaccination programs suggest that HPV-associated vulvar and vaginal cancer rates are likely to decline following widespread vaccination. Currently, there is no evidence supporting routine screening for vulvar or vaginal cancer. For symptomatic individuals and those who have undergone hysterectomy due to cervical lesions, cytological examination, HPV testing, and colposcopy are recommended to detect vulvar or vaginal lesions early. Timely treatment of high-grade vulvar and vaginal lesions is crucial to preventing progression to invasive carcinoma.