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Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)

Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)
Literature review current through: Jan 2024.
This topic last updated: Jun 21, 2023.

INTRODUCTION — Vulvar squamous intraepithelial lesions (SIL), previously referred to as vulvar intraepithelial neoplasia (VIN), are a group of premalignant conditions of the vulva. There are no routine screening methods for vulvar SIL or vulvar carcinoma.

In this topic, we will discuss the classification, manifestations, diagnosis, and treatment of vulvar SIL, with a focus on high-grade lesions.

Vulvar low-grade SIL lesions are discussed in more detail elsewhere. (See "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis" and "Condylomata acuminata (anogenital warts): Treatment of vulvar and vaginal warts".)

The diagnosis and treatment of vulvar cancer are also discussed separately. (See "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment" and "Squamous cell carcinoma of the vulva: Staging and surgical treatment" and "Squamous cell carcinoma of the vulva: Medical therapy and prognosis".)

TERMINOLOGY AND EPIDEMIOLOGY

Terminology — The terminology and classification systems for vulvar SIL have changed significantly over time (table 1). The most current and widely accepted classification system was published in 2015 by the International Society for the Study of Vulvovaginal Disease (ISSVD) [1]. This topic review will utilize the 2015 ISSVD nomenclature. However, it is recognized that the supporting studies cited in this topic may have used previous editions of this classification system, which will be documented where appropriate. We recognize that this is a limitation of the existing data.

The 2015 ISSVD terminology for vulvar SILs is:

Low-grade squamous intraepithelial lesion (LSIL) of the vulva (vulvar LSIL, flat condyloma, or human papillomavirus [HPV] effect).

This entity was previously referred to as vulvar intraepithelial neoplasia [VIN] 1.

High-grade squamous intraepithelial lesion (HSIL) of the vulva (vulvar HSIL, VIN usual type [uVIN]).

This entity was previously referred to as VIN 2 and VIN 3.

Differentiated VIN (dVIN) – dVIN includes lesions that are not associated with HPV but are associated with vulvar dermatoses, mainly lichen sclerosus.

This entity was previously referred to as VIN simplex type.

Histopathologic features of these entities are described below. (See 'Diagnosis and histopathology' below.)

Epidemiology — In a study based on data from a United States national cancer database, the incidence of VIN 3 was 2.86 per 100,000 females in the year 2000 [2]; however, incidence may be increasing. In one database from the Netherlands, the incidence of vulvar HSIL (VIN 2,3) increased from 2.39 to 3.26 per 100,000 females between the years 1991 and 2011 [3]. dVIN is rare, with the same database reporting an incidence of 0.08 per 100,000 females between the years 2006 and 2011 [3].

The prevalence of vulvar SIL is higher in premenopausal than in postmenopausal patients. The average age at diagnosis is 46 years based on data from a systematic review of 97 studies including over 3300 females with VIN 3 [4]. Females younger than 50 years old account for 75 percent of cases [2,5].

RISK FACTORS AND PREVENTION

Risk factors for vulvar high-grade SIL (vHSIL; VIN 2,3) include:

Human papillomavirus (HPV) – The majority of cases of vulvar SIL are associated with HPV infection. Risk factors for exposure include sexual contact, including genital, anal, or oral contact to the vulva. Vaginal intercourse is not required to transmit HPV.

HPV testing of the vulva is not typically performed in clinical settings, but in research studies, the majority of vulvar SIL lesions test positive for HPV [6].

High-grade SIL is most often associated with high-risk HPV subtypes [7]. In a meta-analysis including 48 studies, the prevalence of HPV in high-grade SIL was 83 percent; the most common HPV genotypes were HPV 16 (80 percent) followed by HPV 33 (6 percent) [8].

Low-grade SIL is most often associated with low-risk HPV subtypes (6 and 11); however, in a minority of lesions, high-risk types (16, 18, 31) can be found [9]. In the meta-analysis discussed above, the prevalence of HPV in low-grade SIL was 63 percent [8].

HPV-associated squamous neoplasia at other lower genital tract sites is also associated with vulvar SIL/intraepithelial neoplasm. Approximately 60 percent of patients with vaginal intraepithelial neoplasia (VaIN) 3 or VIN have preexisting or synchronous cervical intraepithelial neoplasia (CIN), and close to 10 percent of patients with CIN 3 have concomitant squamous intraepithelial neoplasm at other sites (eg, 3 percent have VaIN 3 and 7 percent have VIN) [10-12].

The quadrivalent and 9-valent HPV vaccines, which are active against HPV subtypes 6, 11, 16, 18 (quadrivalent) and additionally for 31, 33, 45, 52, 58 (9-valent), decrease the risk of vulvar SIL [13-16]. In the United States, only the 9-valent vaccine is available. Based on immunogenicity and efficacy studies, it is expected that HPV vaccination, particularly with the 9-valent HPV vaccine, has the potential to prevent up to 90 percent of HPV-associated vulvar carcinomas [17]. (See "Human papillomavirus vaccination".)

In one cohort study including over 500,000 female patients ages 17 to 26 years, HPV-vaccinated compared with HPV-unvaccinated patients had lower rates of vulvar HSIL (55 versus 72 patients; hazard ratio [HR] 0.48, 95% CI 0.34-0.68) during the 6.4-year (average) study period [16]. While patients receiving HPV vaccination prior to age 16 years had the lowest rates of disease, the cumulative incidence of disease was low.

Cigarette smoking – Cigarette smoking has been consistently associated with development of vulvar SIL [18-20] and disease recurrence [21].

One series reported 27 of 40 patients with VIN were cigarette smokers compared with 5 of 40 age-matched patients with non-neoplastic vulvar disease (68 versus 13 percent) [22]. The mechanism for the association is unknown.

Patients should be encouraged to stop using tobacco to reduce the risk of vulvar SIL.

Immunodeficiency – Vulvar SILs are more common in patients infected with HIV than in uninfected controls [23,24]. (See "Vulvar and vaginal intraepithelial neoplasia in patients with HIV infection".)

Premenopausal patients are more likely to have HPV-associated vulvar HSIL, while postmenopausal patients are more likely to have non-HPV associated vulvar SIL.

The major risk factor for differentiated VIN (dVIN) is having an associated vulvar dermatosis, such as lichen sclerosus.

The cumulative incidence of vulvar squamous carcinoma in patients with lichen sclerosus is 6.7 percent; the risk is higher in patients with lichen sclerosus and VIN compared with those with lichen sclerosus only (18.8 versus 2.8 percent 10-year cumulative incidence, respectively) [25].

There is prospective evidence that earlier detection and proactive management of lichen sclerosus may lead to a reduction in risk of the development of squamous cell carcinoma [26]. (See "Vulvar lichen sclerosus: Clinical manifestations and diagnosis", section on 'Association with malignancy'.)

PATHOGENESIS — The anogenital epithelium is derived from the embryonic cloaca and includes the cervix, vagina, vulva, anus, and lower three centimeters of rectal mucosa up to the dentate line. Since the entire region shares the same embryologic origin and is susceptible to similar exogenous agents (eg, human papillomavirus [HPV] infection), SILs in this area are often both multifocal (ie, multiple foci of disease within the same organ) and multicentric (ie, foci of disease involving more than one organ). Thus, patients with vulvar SIL may have synchronous or metachronous squamous neoplasia of other lower genital tract sites (cervix, vagina, anus).

As detailed above, vulvar low-grade SIL (LSIL) is often associated with low-oncogenic HPV subtypes and is not considered a premalignant lesion. By contrast, high-grade SIL (HSIL) is associated with high-oncogenic HPV subtypes and is a premalignant lesion (ie, intraepithelial neoplasm). (See 'Risk factors and prevention' above.)

The pathogenesis of differentiated VIN (dVIN) is less well understood than vulvar HSIL and LSIL, and the diagnosis of solitary dVIN is very challenging. dVIN is usually unifocal and unicentric and is often associated with lichen sclerosus but not with HPV infection. While it is less common than HSIL (dVIN accounts for 2 to 29 percent of premalignant vulvar lesions) [9], dVIN is found adjacent to the majority of vulvar squamous cell carcinomas (SCC) and is associated with more rapid progression to SCC (see 'Natural history' below). Patients with lichen sclerosus with dyskeratosis and parakeratosis, hyperplasia, and/or basal cellular atypia tend to have the highest risk of progression to SCC. There are no known biomarkers to reliably identify the patients at highest risk [27,28]. (See "Vulvar lichen sclerosus: Clinical manifestations and diagnosis".)

NATURAL HISTORY — If left untreated, vulvar SIL may persist, progress, or resolve [4,29].

Vulvar low-grade SILs are benign manifestations of the skin's reaction to a human papillomavirus infection; they are often self-limited and will usually resolve within one to two years. These lesions should not be considered as potentially neoplastic, except in rare cases. This is discussed in more detail elsewhere. (See "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Association with malignancy'.)

Vulvar high-grade SILs (HSIL), on the other hand, are intraepithelial neoplasms and are estimated to be associated with approximately 20 percent of squamous cell carcinomas (SCC) of the vulva [9]. A systematic review of patients with VIN 3 included 10 studies involving 61 untreated patients and 27 patients in whom macroscopic VIN was left behind after treatment [4]. Eight of the 88 patients (9 percent) progressed to invasive vulvar carcinoma over one to eight years; four of these patients had had previous radiation therapy to the lower genital tract, and one was immunosuppressed. In addition, 13 studies reported complete spontaneous regression in 1.2 percent of patients (41/3322). All of these patients were under the age of 35 (mean age 20 years old); regression was related to pregnancy in 17 of 41 cases. A similar progression rate was noted in the European database discussed above (see 'Epidemiology' above); the 10-year cumulative risk of developing vulvar SCC with HSIL was 9.7 percent (95% CI 8-12 percent) [3].

Differentiated VIN (dVIN) has the highest risk of progression to SCC, which in some studies is estimated at 33 percent, and is the putative precursor lesion of approximately 80 percent of keratinizing vulvar SCC [9,30]. In the European database discussed above, the 10-year cumulative risk of developing vulvar SCC with dVIN was 50 percent (95% CI 22-78 percent) [3]. (See "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment", section on 'Squamous cell carcinoma'.)

CLINICAL PRESENTATION — Vulvar SIL can be asymptomatic or present with the following:

Vulvar pruritus – Vulvar pruritus is the most common complaint among symptomatic patients. Other potential symptoms are vulvar pain, burning, or dysuria [31]. Dysuria may occur if there is a periurethral lesion or if urine comes into contact with a lesion at another site. A systematic review of 97 studies including over 3300 patients with VIN 3 reported that 64 percent presented with pruritus or pain [4].

Vulvar lesion – Approximately 40 percent of patients with vulvar SIL are asymptomatic and are diagnosed when a lesion is noted by the patient, detected during a routine gynecologic examination, or at colposcopy for abnormal cervical cytology [4]. A visible lesion or a palpable abnormality may be noted. (See 'Physical examination' below.)

Persistent abnormal cervical cytology with no abnormality identified on cervical biopsy – Given SILs in this region are often multicentric, vulvar SIL can initially present with an abnormal cervical cytology result, which is actually representative of disease in other nearby genital tract sites (such as the vulva, vagina, and anus). (See 'Pathogenesis' above.)

DIAGNOSTIC EVALUATION

History — The medical history should include questions about symptoms and risk factors associated with vulvar SIL (see 'Clinical presentation' above and 'Risk factors and prevention' above). Patients should be asked about a prior history of vulvar SIL, genital warts, or vulvar cancer, and about other human papillomavirus (HPV)-associated lower genital tract neoplasia, most commonly cervical neoplasia. The history should include questions about smoking, conditions associated with immunosuppression, and HPV vaccination status.

Physical examination — A gynecologic examination should be performed, with thorough inspection and palpation of the vulva and groin for lesions, color changes, masses, or ulceration.

Most vulvar SILs are multifocal (49 percent in one systematic review [4]) and are located in the nonhairy part of the vulva [32]. The lesions are often raised or verrucous and white (picture 1), but the color may be red (picture 2), pink, gray, or brown (picture 3). Macular lesions mostly occur on adjacent mucosal surfaces. There is no pathognomonic clinical appearance, and more than one of these patterns may be seen in the same patient.

Condylomata acuminata (genital warts) may be difficult to differentiate on examination from vulvar low-grade SIL. It may also be difficult to distinguish between high-grade SIL, differentiated VIN, and invasive vulvar squamous carcinoma, which can present as a plaque, ulcer, or mass (fleshy, nodular, or warty), and both may coexist in a patient. Other vulvar lesions may mimic VIN, including lichen sclerosus or lichen planus and condyloma latum. (See "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations' and "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment", section on 'Clinical presentation'.)

Colposcopy — In our practice, we perform colposcopy in patients with any of the following characteristics:

Visible vulvar lesion – The visible lesion should be biopsied, but because of the high prevalence of multicentric synchronous intraepithelial lesions, colposcopic evaluation of the entire lower genital tract and perianal area may detect additional lesions in patients with vulvar SIL.

Persistent symptoms consistent with vulvar SIL but no visible lesions – Patients who present with persistent focal vulvar pruritus or pain, have no grossly visible lesion, and who remain symptomatic despite treatment for other conditions (eg, candidiasis, dermatitis, vulvodynia) should be evaluated with colposcopy.

Persistent abnormal cervical cytology with no cervical intraepithelial neoplasia on biopsy. (See 'Clinical presentation' above.)

Colposcopy of the vulva can identify subclinical lesions not appreciated on gross visual examination and helps to define the extent of disease and guide biopsy. If colposcopy is not available, a hand lens provides similar magnification and is easy to use. (See "Colposcopy", section on 'Vulvar colposcopy'.)

Biopsy — Any vulvar lesion found on examination and/or colposcopy that is not known to be benign/non-neoplastic warrants a biopsy. A vulva with multiple areas of abnormalities warrants multiple biopsies. If a lesion is treated without biopsy and does not completely resolve or is refractory to a defined course of empiric therapy, it should be biopsied to obtain a definitive diagnosis.

Infrequently, a biopsy is appropriate in the absence of a visible lesion. If no lesion is found at colposcopy and the symptoms cannot be explained by another diagnosis, a biopsy from the symptomatic area of the vulva should be performed. (See 'Differential diagnosis' below and "Vulvar lesions: Differential diagnosis of vesicles, bullae, erosions, and ulcers".)

The procedure for a vulvar biopsy is discussed separately. (See "Vulvar lesions: Diagnostic evaluation", section on 'Procedure'.)

DIAGNOSIS AND HISTOPATHOLOGY — Diagnosis of vulvar SIL is based on histologic findings observed in a biopsy specimen. Appropriate sites for biopsy are identified by physical examination and colposcopy. (See 'Physical examination' above and 'Colposcopy' above.)

Based on pathology evaluation, the histologic classification is determined, according to the terminology discussed above. (See 'Terminology and epidemiology' above.)

Characteristics of the three histopathologic entities are described below (table 2) [1]:

Vulvar low-grade SIL (LSIL) – LSIL is characterized by cytologic atypia, most prominent in the upper keratinocytes, increased mitotic activity in the basal or parabasal epithelium, and squamous maturation in the upper two-thirds of the epithelium.

Vulvar high-grade SIL (HSIL) – HSIL is characterized by loss of maturation of the middle (formerly VIN 2) and upper third to full thickness (formerly VIN 3) of the squamous epithelium. HSILs can be subdivided based on their morphologic and histologic features (picture 4). Although each of these types exists in pure form, mixtures of warty and basaloid HSIL are common and are classified together as vulvar HSIL.

The basaloid subtype has a thickened epithelium with a relatively flat, smooth surface. Histologically, it consists of atypical, immature parabasal-type cells with numerous mitotic figures and enlarged hyperchromatic nuclei.

The warty (condylomatous) subtype is characterized by a surface that is undulating or spiking, giving it a condylomatous appearance. Histologically, it consists of marked cellular proliferation with numerous mitotic figures and abnormal maturation, but it may have some maturation (not all basaloid cells).

Vulvar HSILs are often multifocal. The interlabial grooves, posterior fourchette, and perineum are most frequently affected by multifocal lesions; more extensive disease is often confluent, involving the labia majora, minora, and perianal skin. Confluent or multifocal lesions exist in up to two-thirds of patients with HSIL [33].

Differentiated VIN (dVIN) – dVIN is commonly found adjacent to keratinizing squamous cell carcinoma or in patients with a history of vulvar cancer. The differentiated (simplex) type refers to lesions in which the epithelium is thickened and parakeratotic with elongated and anastomosing rete ridges. The abnormal cells are confined to the parabasal and basal portion of the rete pegs with little or no atypia above the basal or parabasal layers [34]; p53 is frequently abnormally expressed (ie, overexpression in all of the epithelium, no expression at all, or cytoplasmic expression). dVIN is the putative precursor of human papillomavirus-negative vulvar cancer [9,35,36]. Distinguishing dVIN from reactive squamous proliferations can be quite difficult.

DIFFERENTIAL DIAGNOSIS — Vulvar SILs are typically multifocal, and the lesions vary in appearance. Thus, many other vulvar lesions can mimic vulvar SIL, including vulvar cancer, condyloma acuminatum, lichen sclerosus, lichen planus, or condyloma latum. Although physical examination findings may be similar, these lesions can be differentiated with vulvar biopsy. (See 'Physical examination' above.)

Many vulvar lesions, like vulvar SILs, are also associated with vulvar pruritus and pain; examples include candidiasis, dermatitis, molluscum contagiosum, lichen sclerosus, lichen planus, lichen simplex chronicus, psoriasis, and herpes simplex virus. Further discussion on the differential diagnosis of vulvar lesions is found elsewhere. (See "Vulvar lesions: Differential diagnosis of vesicles, bullae, erosions, and ulcers".)

TREATMENT

Low-grade squamous intraepithelial lesions — Vulvar low-grade SIL (LSIL) are equivalent to condylomata acuminata (anogenital warts), are not precancerous lesions, should not be considered as potentially neoplastic lesions, and do not need to be treated unless symptomatic. Treatment of symptomatic LSIL is discussed in detail separately. (See "Condylomata acuminata (anogenital warts): Treatment of vulvar and vaginal warts".)

High-grade squamous intraepithelial lesions

Deciding between options — The goals for treatment of vulvar high-grade SIL (HSIL) are to prevent development of vulvar squamous carcinoma and to relieve symptoms while preserving normal vulvar anatomy and function [13]. Management options for vulvar HSIL include excision, ablative therapy, and topical treatment.

Our approach to treatment depends on the level of concern for invasive disease based on examination and biopsy results, prior treatment history, and the location and focality of the lesion(s). Guiding principles are as follows (algorithm 1):

Excision is generally indicated for those patients with vulvar HSIL who have the following:

A lesion that is worrisome for possible invasive disease (eg, raised, ulcerative, or with irregular borders), irrespective of results from colposcopy/biopsy.

A lesion in the setting of clinically significant risk factors for invasive disease (eg, previous vulvar HSIL, differentiated VIN [dVIN], or vulvar carcinoma; immunosuppression; or lichen sclerosus).

If excision of the lesion would risk significant negative functional or anatomic sequelae (ie, because of its proximity to the urethra, anus, or clitoris), the patient should be referred to a gynecologic oncologist.

For patients lacking any of the features listed above, our approach at initial presentation is the following:

For patients with single lesions, we treat with excision, provided that complete removal with satisfactory cosmetic and functional results is expected.

By contrast, for patients with any of the following characteristics, we suggest ablative therapy with CO2 laser or argon beam coagulator rather than excision:

-Multifocal disease.

-Lesions that involve the clitoris, urethra, anus, or vaginal introitus (as excision may impair function or cause dyspareunia).

Topical therapy with imiquimod can be used for carefully selected patients (eg, patients with clitoral lesions) who prefer to avoid excision and ablation, provided that they are able to comply with a long treatment course (four to six months). (See 'Topical therapies' below.)

For such patients, treatment with imiquimod or excision appear to have similar outcomes, but data are limited. In a randomized phase 3 noninferiority trial including 98 patients with vulvar HSIL (the majority with unifocal disease) and completing the study protocol, treatment with imiquimod (5% cream up to three times weekly for up to 24 weeks) was noninferior to excision or ablation in terms of clinical response (imiquimod: 80 percent; surgery: 79 percent), HPV clearance, and treatment satisfaction at six months [37]. The overall rate of adverse events was also noninferior, but the types of events were different (eg, imiquimod group: local pruritus; excision group: intense pain).

For patients with recurrent lesions without evidence of invasion, we generally suggest ablative or topical therapy to avoid multiple excisional procedures that may distort anatomy or result in impairment of function or chronic pain. This is especially relevant in patients with risk factors for recurrent disease (eg, heavy smokers, immunocompromised patients). The choice between ablative and topical therapy (or combined modality treatment) is based on many patient-specific factors, including prior treatment history, location and focality of the lesion(s), and coexisting vulvar dermatoses. Careful colposcopic examination with biopsies to exclude invasive disease is mandatory prior to beginning treatment. (See 'Alternatives and later-line treatments' below.)

In terms of efficacy, there are few high-quality data to guide the choice of treatment of vulvar HSIL, but based on the available evidence, the major surgical interventions appear to be similarly effective [4]. In a literature review of 1905 surgically treated patients, the frequency of recurrence after vulvectomy, partial vulvectomy, local excision, and laser ablation was 19, 18, 22, and 23 percent, respectively, during a mean follow-up of 39 months [4]. However, a large single-institution study of 303 patients treated for VIN found a higher risk of recurrence after laser ablation compared with excision (41.9 versus 26.4 percent) [38].

Preferred initial options

Excision — Excision provides both treatment and a diagnostic specimen, which is valuable given the risk of occult invasive disease [39,40]. Appropriate candidates for excision are discussed elsewhere. (See 'Deciding between options' above and 'Risk of occult carcinoma' below.)

The excision technique is described in detail separately. (See "Vulvar wide local excision and simple vulvectomy", section on 'Operative technique'.)

Choosing the type of excision – Wide local excision is generally performed for patients with focal or small lesions, while simple vulvectomy is reserved for lesions that are extensive or multifocal and highly symptomatic, particularly when prior treatments (eg, topical treatments, laser ablation, smaller excisions) have failed to control the disease. Skinning vulvectomy is rarely indicated. Further details on each of these methods are discussed below.

Wide local excision – Wide local excision, defined as excision of an individual lesion with a 1 cm margin, generally provides satisfactory cosmetic results. (See "Vulvar wide local excision and simple vulvectomy", section on 'One or two focal lesions: Wide local excision'.)

While the gross surgical margin after vulvar resection is reduced by 15 percent when measured in the final fixed specimen, a grossly negative 1 cm margin will rarely harbor significant disease [41]. However, a 1 cm margin is often hard to accomplish as the surgeon has to balance the desire for complete excision with preservation of vulvar anatomy and function. In terms of depth of excision, removal of the epidermis provides sufficient depth for treatment of HSIL, provided the margins are clear. Removing a small amount of underlying dermis helps to ensure the absence of early invasive disease.

Positive epithelial margins are common and a risk factor for recurrent disease. If there is a grossly visible residual lesion, it should be treated. If a margin is positive microscopically, but there is no visible residual disease, the patient may be followed by close clinical observation and colposcopy. Retreatment is provided if another visible lesion occurs. It is also important to note that, because HSILs are often multifocal in nature, a negative margin will only reduce the recurrence risk at that site, not the lifelong risk of recurrence of HSIL elsewhere on the vulva.

Simple, or total, vulvectomy – Simple, or total, vulvectomy refers to removal of the entire vulva together with perineal tissues, as indicated, and usually includes some subcutaneous tissue [21]. (See "Vulvar wide local excision and simple vulvectomy", section on 'Extensive or multifocal lesions: Simple vulvectomy'.)

Skinning vulvectomy – Skinning vulvectomy is rarely performed and requires removing the vulvar skin along a relatively avascular plane beneath the epidermis while preserving the subcutaneous tissue [42,43]. Primary closure is often achieved by using a split thickness skin graft.

Ablative therapy — For patients with vulvar HSIL in whom there is no concern for invasive disease and who have multifocal disease or have lesions involving the clitoris, urethra, anus, and/or vaginal introitus, ablative therapy may be the best option to preserve vulvar anatomy. (See 'Deciding between options' above.)

The major limitations of laser ablation are that special training is required and this equipment may not be readily available at all institutions. Additionally, since tissue is ablated rather than excised, the coexistence of invasive cancer must be carefully excluded by liberal use of colposcopically directed biopsies prior to the procedure.

CO2 laser vaporization is the most commonly used ablative therapy, but argon beam ablation [44] and ultrasonic surgical aspiration [45,46] can also be used. Only one laser treatment is required in 75 to 80 percent of patients [47-49]. It is most advantageous when there are multiple small lesions [50,51]. The goal of ablative therapy is to treat the entire area of intraepithelial abnormality. Colposcopy is used to control the depth of tissue destruction to less than 1 mm (for hair-free epithelium), which will ablate the intraepithelial lesion and allow for rapid healing. Ablation to 3 mm of depth is required in hairy areas of the vulva because the hair root sheet tends to extend as deep as 2.5 mm and is at significant risk for harboring HSIL [52].

Superficial ablative therapy may offer cosmetic advantages over excisional procedures. By contrast, deep laser vaporization results in destruction of the skin appendage, which leads to hypertrophic scar formation, thus negating the cosmetic advantages. In addition, another method may be preferred for lesions in hair-bearing areas because laser treatment destroys the hair follicle [13].

Alternatives and later-line treatments

Topical therapies

Imiquimod – Imiquimod cream (Aldara) is a topical immune response modifier and is often the preferred initial treatment for recurrent vulvar HSIL. It can also be used as initial therapy for carefully selected patients (eg, patients with clitoral lesions) who prefer to avoid excision and ablation [37], provided that they are able to comply with a long treatment course (four to six months).

Imiquimod is applied topically to individual lesions, not to the entire vulva. A typical course involves applying a thin layer of cream three to five times per week (alternating days) for a total duration of 16 weeks. Side effects of imiquimod are common and consist mostly of inflammation at the application site, including mild to moderate erythema or erosions. Up to two-thirds of patients reduce the number of applications due to local side effects; therefore, some experts suggest an escalating dose regimen starting with an application once a week for two weeks, then twice a week for two weeks, then, if tolerated well, three times a week [37,53-55].

A systematic review of treatment of high-grade VIN with imiquimod cream that included two randomized trials and eight observational studies (total of 162 patients) reported a complete response rate of 51 percent, partial response rate of 25 percent, and a recurrence rate of 16 percent [56]. Similarly, a meta-analysis of three randomized trials including 104 patients found topical imiquimod cream to be superior to placebo for the treatment of vulvar HSIL after a 16-week course (58 percent cleared with imiquimod versus 0 percent with placebo) [57]. At 12 months after initiation of therapy, vulvar carcinoma had developed in 1 of 26 patients treated with imiquimod compared with 2 of 26 patients in the placebo group [53]. At seven-year follow-up, there were two additional vulvar cancers, both in patients with partial or no response to initial therapy. Long-term follow-up data were not reported for the placebo group [58].

Fluorouracil – We use topical fluorouracil only rarely and as a last resort when other therapies have failed. Application of fluorouracil cream causes a chemical desquamation of HSIL; response rates as high as 75 percent have been reported [59,60]. A disadvantage of this approach is that it is often poorly tolerated because of significant burning, pain, inflammation, edema, or painful ulcerations. For this reason, topical fluorouracil has a limited role in the primary therapy of HSIL.

Combined modality therapy — Data on combined modality therapy for both primary and recurrent disease are limited, and as such, we reserve this option for a very select group of patients whose disease distribution requires multimodality therapy to allow for organ preservation and to avoid significant disruption of normal vulvar anatomy.

A retrospective analysis of 303 patients with VIN treated at a single institution found individual treatment modalities (excision, laser, imiquimod) to be equally effective on multivariate analysis. However, the combination of excision and laser vaporization was associated with a significantly worse recurrence-free survival [38]. While this association may be more reflective of higher risk disease and less favorable disease distribution, it calls into question the elective use of first-line combination therapy, and we, therefore, use it only rarely in clinical practice.

Investigational therapies — Topical cidofovir, a potent antiviral agent, appears to have similar efficacy to imiquimod in clearing vulvar HSIL [60]. A randomized multicenter phase II trial comparing topical cidofovir gel with imiquimod for the treatment of VIN in 180 patients demonstrated complete response rates of 57 and 61 percent, respectively [61].

Other preliminary investigations include the use of vaccines designed to elicit a cellular immune response (commercially available vaccines elicit only a humoral response) [6,62-65], indole-3-carbinol [66], sinecatechins [67], photodynamic therapy [68], and the use of chemopreventive agents, such as retinyl acetate gel.

Differentiated VIN — For patients with dVIN, we recommend surgical excision rather than ablation or pharmacologic therapy since dVIN is associated with a high risk of developing invasive carcinoma. Decision making regarding the type of excision follows the same decision-making process as for HSIL. (See 'Excision' above.)

POSTTREATMENT SURVEILLANCE — After treatment has been completed, long-term surveillance of the entire genital tract is mandatory, given the possibility of late recurrences. In one study of almost 800 patients with high-grade VIN, a 26 percent recurrence rate was observed, with 8 percent of those recurrences progressing to cancer and 25 percent being late recurrences (44 to 196 months after initial treatment) [69].

We suggest follow-up with a gynecologic examination (including visual inspection of the vulva) every six months for five years and then annually. Further evaluation with colposcopy and biopsies is warranted if the patient exhibits symptoms and/or examination findings concerning for additional disease. (See 'History' above and 'Physical examination' above.)

DISEASE RECURRENCE — With prolonged follow-up, approximately one-third of patients develop recurrent vulvar SIL regardless of the treatment modality employed [4,10,38,39,42,50,51,70,71]. This is discussed in more detail above. (See 'Deciding between options' above.)

Risk factors for recurrent disease include:

Immunosuppression [69].

Presence of multifocal or multicentric disease (including metasynchronous vaginal intraepithelial neoplasia or cervical intraepithelial neoplasia) [10,50,69].

Large lesion size (eg, 3 cm [range 1 to 7 cm]) [38].

Age >50 years [69].

Positive margins on the excisional specimen – The risk of recurrent vulvar SIL is approximately threefold higher among patients with positive compared with negative margins on the excisional specimen [38,39,71].

Cigarette smoking [38]; smoking cessation should be encouraged.

Some studies report higher rates of recurrence associated with laser ablation than with excision (42 versus 26 percent) [64].

The risk of synchronous or subsequent vulvar carcinoma also differs by histologic type:

Vulvar high-grade SIL (HSIL) – The risk of subsequent locally invasive squamous carcinoma following initial treatment of VIN 3 has been reported to be 2 to 15 percent [4,10,50,51,57,71-74]. A meta-analysis of randomized trials including 975 patients with vulvar HSIL reported the development of vulvar cancer in 15 percent of patients at a median follow-up of 72 months independent of ablative or excisional therapy [57].

Differentiated VIN (dVIN) – The risk of invasive carcinoma is not well established since this is an uncommon histologic type and data are limited to a few small studies; however, the risk appears to be quite high [30]. This histologic type is often found adjacent to keratinizing squamous cell carcinoma or in patients with a history of vulvar carcinoma. Available data include one study of 67 patients with a diagnosis of solitary dVIN in which 33 percent had a subsequent diagnosis of vulvar carcinoma [72]. In another study, 86 percent of patients (n = 70) with dVIN also had invasive carcinoma [75]. This study contributes little information regarding the choice of treatment or prognosis for a patient with an initial diagnosis of dVIN because it included patients with vulvar carcinoma prior to, synchronous with, or following the diagnosis of VIN.

Low-grade SILs are benign lesions and, therefore, do not contribute to the development of vulvar carcinoma, except in rare cases. (See 'Natural history' above.)

SPECIAL CONSIDERATIONS

Risk of occult carcinoma

At initial diagnosis – Retrospective case series have reported the presence of occult squamous carcinoma in 10 to 22 percent of patients with a preoperative diagnosis of VIN who were treated with surgical excision [10,39,76-78]. A systematic review of 3322 patients treated for VIN found occult carcinoma in 3.2 percent of patients [4]. The latter may be an underestimate as not all patients underwent excisional therapy.

Data regarding risk factors for occult carcinoma are limited to small case series. In one series (n = 74), patients with versus without occult carcinoma were significantly less likely to have multifocal disease (12 versus 54 percent) [39]. Interestingly, patients with or without occult carcinoma did not differ significantly by age (the average age was 45 to 46 years in both groups) or recurrent VIN (occult carcinoma 35 percent versus no occult carcinoma 29 percent). The presence of invasive carcinoma was also not significantly associated with tobacco use, genital warts, or cervical neoplasia. Another series also found no increased risk of coexistent carcinoma in older patients [10]. (See "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment", section on 'Epidemiology'.)

At the time of recurrence – In the systematic review of data from 3322 patients treated for VIN, occult carcinoma was found in 3.3 percent of patients who were diagnosed with disease recurrence during follow-up [4]. There appear to be two distinct patterns of invasive vulvar carcinoma in these patients. One pattern is the development of invasive carcinoma at a prior site of incompletely treated SIL and reflects disease progression. In these cases, carcinoma is observed after a median of 2.4 years following treatment [71]. In the other pattern, an invasive carcinoma develops several years later at a site distinct from the previously treated SIL and represents a new neoplasm in the area at risk.

Management of vulvar SIL in pregnancy — Data regarding vulvar high-grade SIL (HSIL) and pregnancy are extremely limited. Approximately 15 percent of vulvar carcinomas have been reported to occur in patients under the age of 40 [79]. Thus, any vulvar lesion noted during pregnancy should be biopsied as outlined above for the nonpregnant patient (see 'Biopsy' above). Management options for the pregnant patient with vulvar SIL fall principally into two main categories:

Surgical therapy – Surgical treatment with either local excision or ablative therapy should follow the same general principles as for the nonpregnant patient (see 'Excision' above and 'Ablative therapy' above). These are the preferred treatment options for HSIL in pregnancy, especially for the patient remote from delivery.

Expectant management until after delivery – Once invasive carcinoma has been ruled out histologically, clinicians may consider deferring treatment of HSIL to the postpartum period, especially in patients who are diagnosed in the third trimester. Small series suggest a possibility for spontaneous regression, particularly in asymptomatic patients who are younger than 30 years of age and who present with multifocal pigmented HSIL [80]. While several of these spontaneous regressions were associated with pregnancy, there are no data regarding the incidence of regression in this patient population.

Medical therapy is generally not recommendedImiquimod's safety during pregnancy has not been clearly established [81,82], nor are there efficacy data on the use of imiquimod for the treatment of HSIL in pregnancy.

Management of vulvar SIL in HIV-infected patients — Individuals infected with HIV are at greater risk of human papillomavirus-related cancers. Vulvar SIL occurs commonly among patients infected with HIV. A full discussion regarding the diagnosis and treatment of vulvar SIL in patients with HIV is presented elsewhere. (See "Vulvar and vaginal intraepithelial neoplasia in patients with HIV infection".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vulvar cancer and vaginal cancer".)

SUMMARY AND RECOMMENDATIONS

Terminology – The International Society for the Study of Vulvovaginal Disease (ISSVD) 2015 terminology for vulvar squamous intraepithelial lesions (SIL) includes three categories (table 2) (see 'Terminology and epidemiology' above):

Vulvar low-grade squamous intraepithelial lesion (LSIL)

Vulvar high-grade squamous intraepithelial lesion (HSIL)

Differentiated vulvar intraepithelial neoplasia (dVIN)

Vulvar LSIL is a benign lesion and is not considered a premalignant lesion. By contrast, HSIL and dVIN are premalignant conditions (ie, intraepithelial neoplasms) and are associated with the development of squamous cell carcinomas of the vulva. (See 'Pathogenesis' above and 'Natural history' above.)

Risk factors – Risk factors for vulvar HSIL include human papillomavirus, cigarette smoking, and immunosuppression. The major risk factor for dVIN is having an associated vulvar dermatosis, such as lichen sclerosus. (See 'Risk factors and prevention' above.)

Pathogenesis – Vulvar SILs are usually multifocal (ie, multiple foci of disease within the same organ) and multicentric (ie, foci of disease involving more than one organ). Thus, having diseases in more than one location (vulva, vagina, cervix, or perianal area) is relatively common. By contrast, dVIN is usually unifocal and unicentric. (See 'Pathogenesis' above.)

Clinical presentation – Vulvar SIL can be asymptomatic and diagnosed when a visible lesion (picture 1 and picture 2 and picture 3) or palpable abnormality is incidentally found on pelvic examination. Among symptomatic patients, pruritus is the most common complaint. Other presentations include pain or dysuria. (See 'Clinical presentation' above.)

Diagnostic evaluation – Vulvar SIL can be difficult to distinguish clinically from lichen sclerosus or lichen planus, especially when they occur concurrently. Therefore, any lesion on the vulva that is not known to be benign warrants biopsy, as does any lesion that does not resolve with a defined course of medical therapy. Appropriate sites for biopsy are identified by physical examination and colposcopy. Tissue biopsy is necessary for a definitive diagnosis. (See 'Diagnostic evaluation' above.)

Treatment – The goals of treatment are to prevent development of invasive vulvar carcinoma and relieve symptoms while preserving normal vulvar anatomy and function. Treatment is individualized based on examination and biopsy results, prior treatment history, and the location and focality of the lesion(s). (See 'Treatment' above.)

LSIL – Vulvar LSILs are not precancerous lesions and do not need to be treated unless symptomatic. (See 'Low-grade squamous intraepithelial lesions' above.)

HSIL – For vulvar HSIL, our approach is as follows (algorithm 1):

-For lesions that have high-risk features (raised, ulcerative, or with irregular borders), or for patients with HSIL and significant risk factors for invasive disease (eg, previous vulvar HSIL, dVIN, or vulvar carcinoma; immunosuppression; or lichen sclerosus), we suggest initial treatment with surgical excision rather than ablation or medical therapy (Grade 2C). (See 'Deciding between options' above and 'Excision' above.)

-For patients with multifocal disease and/or lesions that involve the urethra, anus, clitoris, and/or vaginal introitus, we suggest initial treatment with ablation rather than excision (Grade 2C). Topical treatments may be an appropriate alternative in select patients. However, excision in these areas carries risk for impairment of anatomy or function and is not an appropriate option. (See 'Ablative therapy' above and 'Topical therapies' above.)

-Management of patients with recurrent vulvar HSIL needs to be individualized to ensure disease control while maintaining vulvar anatomy and function. For many of these patients, we suggest topical therapy with imiquimod rather than repeat excision if invasive disease is not suspected (Grade 2C). Careful colposcopic examination with biopsies to exclude invasive disease is mandatory prior to beginning treatment.

dVIN – For patients with dVIN, we suggest surgical excision rather than ablation or pharmacologic therapy given the high risk of developing invasive carcinoma (Grade 2C). (See 'Differentiated VIN' above.)

Surveillance – Despite treatment, approximately one-third of patients develop recurrent vulvar SIL. The risk of recurrence with progression to invasive carcinoma is approximately 8 percent. Therefore, long-term surveillance of the entire lower genital tract is mandatory. We suggest follow-up every six months for five years after the last treatment and then annually. (See 'Posttreatment surveillance' above.)

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References

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