Introduction

Vulvar squamous intraepithelial lesions (SIL) refer to vulvar lesions that have a spectrum of clinical and histopathological presentations ranging from benign to premalignant lesions with different risks of progression to invasive cancer.

Terminology

Over the years, terminology has changed concomitant with knowledge. The following table outlines the changes in Terminology over the years.

The first description of vulvar epithelial neoplasia was reported in 1922 as dyskeratose erythroplasiforme de la muquese.⁸ Over the years, terminology has changed concomitant with knowledge. The use of the terms vulvar carcinoma in situ and vulvar intraepithelial carcinoma in 1943 led to the concept that every intraepithelial lesion carried a high neoplastic potential and should be removed by extensive surgery with adequate margins.⁹ In 1982 the introduction of the term vulvar intraepithelial neoplasia (VIN)¹⁰ clarified that the low-grade lesions of the vulva may be treated expectantly. In 1986 two different types of squamous VIN were introduced in the ISSVD (International Society for the Study of Vulvovaginal Disease) terminology, and confirmed in 2005:¹¹ usual VIN (uVIN), HPV-associated, with approximately 20% of the burden of invasive cancer, and differentiated VIN (dViN), not HPV associated, with approximately 80% of the burden of invasive cancer.  In 2012 the Lower Anogenital Squamous Terminology (LAST) classification separated low and high-grade lesions, underlining the difference between the low malignant potential of LSIL (low-grade squamous intraepithelial lesion) that may be observed, versus the high malignant potential of HSIL.¹² There was concern that LAST terminology, not unique to the vulva but aimed to unify the nomenclature of HPV, did not include the term differentiated VIN. There was equal concern that, with the inclusion of LSIL, LAST had recreated the potential for over-diagnosis and over-treatment for benign and sometimes self-limiting lesions.¹³

The 2015 ISSVD terminology made clear that LSIL replaces the term VIN 1; it is not a precancerous lesion but rather a condyloma or HPV change. The word neoplasia is not used. Treatment is not indicated to prevent progression to cancer. dVIN represents high-grade squamous epithelial lesions and replaces the VIN 2 and VIN 3 categories. Treatment is indicated to prevent progression to cancer.

2015 Nomenclature

The 2015 International Society for the Study of Vulvovaginal Disease Terminology of Vulvar Squamous Intraepithelial Lesions¹⁴reclassifies SIL into three main groups:

(1) Low-grade SIL of the vulva (vulvar LSIL, flat condyloma, or HPV effect)

(2) High-grade SIL of the vulva (vulvar HSIL, VIN usual type)

(3) Vulvar intraepithelial neoplasia, differentiated type, dVIN

Epidemiology

HSIL, referred to as uVIN, formerly VIN2/VIN3 in the medical literature, is the most commonly diagnosed type of vulvar squamous dysplasia and has increased in incidence over the last 2 decades, although the incidence of invasive vulvar squamous cell carcinoma (SCC) has not increased¹⁵

dVIN accounts for 5% of vulvar dysplasia diagnoses. Despite being underdiagnosed, dVIN is recognized in 38% of women who subsequently develop SCC.¹⁶

Etiology

LSIL is strongly related to human papillomavirus (HPV) and represents condyloma effect or reactive atypia. It does not represent true squamous dysplasia,¹⁷ and does not need to be treated as a potentially neoplastic lesion.¹⁸

HSIL or uVIN is strongly associated with HPV, usually type 16, and is found in 80% of all HSIL lesions, whereas 90% of LSIL, condyloma effect, is caused by HPV 6 and 11.¹⁹ HSIL occurs most commonly in young women who smoke or have a history of multiple sexual partners.²⁰ Immunodeficiency of HIV is associated with HSIL.²¹

There is no strong link between dVIN and HPV.²² A germline mutation in the p53 gene is thought to be associated with ~90% of dVIN cases, and to date, no infectious agent has been identified in association with dVIN.²³ In contrast to uVIN, dVIN is not a frequent diagnosis as an isolated lesion, but is usually observed around invasive squamous cell carcinoma and lichen sclerosus in vulvectomy specimens. Immunohistochemical staining for the tumor suppressor p53 gene has been reported as above. However, a number of dVINs do not show mutations of p53 or are associated with deletions of p53, suggesting that other causes, potentially infectious, may play a role in at least a subset of dVIN cases.²⁴

Several reports show a clear relationship between dVIN and lichen sclerosus (LS) in adjacent skin of vulvar squamous cell carcinoma.²⁵²⁶²⁷ On the other hand, HSIL associated with LS without coexisting vulvar carcinoma is more likely to be uVIN.²⁸

Lifelong monitoring is recommended for all patients with LS because the risk of SCC increases with the duration of LS: 1% at two years and 37% after 25 years of disease.²⁹ Other studies found that the rate of progression of LS ranged from 2% to 5%, but duration of disease was not studied.³⁰ Recently, Lee and colleagues³¹ found that the only risk factor for progression from LS to vulvar SCC was noncompliance with LS treatment.

Symptoms and clinical features

There are no screening strategies for the prevention of vulvar cancer through early detection of vulvar HSIL (VIN usual type).³² HPV-related HSIL is often subtle and asymptomatic, but some patients present with chronic itching, burning, dyspareunia, erythema, edema, and pain. Symptoms such as pruritus or pain are observed in about 60% of patients.³³ Lack of symptoms in the remaining 40% makes accurate vulvar inspection during routine gynecologic examination important.

Lesions are diverse in color and architecture and are often multifocal. They may be red, white, or pigmented, flat or raised, erosions or ulcers.³⁴ Usual, undifferentiated VIN may present as well-demarcated, multifocal, white, red, or skin-colored flat-topped papules and plaques.³⁵

Any area of anogenital skin can be affected.³⁶

The most common sites are labia majora and minora and the fourchette.³⁷  The lesions can measure 2 to 3 cm. They can look much like condylomata.

dVIN is often a solitary lesion appearing as a single, pink or reddish, sharply marginated patch or plaque. It can be skin-colored or red, shiny, and almost velvety looking on the surface.

HPV-related VIN is often subtle and asymptomatic, but some patients present with chronic itching, burning, dyspareunia, erythema, edema, and pain. Symptoms such as pruritus or pain are observed in about 60% of patients.³⁸ Lack of symptoms in the remaining 40% makes accurate vulvar inspection during routine gynecologic examination important.

DVIN is often a solitary lesions appearing as a single, pink or reddish, sharply marginated patch or plaque. It can be skin-colored or red, shiny, and almost velvety looking on the surface.

Diagnosis

uVIN may present as well-demarcated white, red, or skin-colored flat-topped papules and plaques. Biopsy makes the diagnosis. In uVIN multicentric disease involving the cervix, vagina, or anus, is common and is age-related. It decreases from 59% in women aged 20-34 to 10% in women over 50 years.³⁹  A careful examination includes the lower anogenital tract: the vulvar, perineum and perianal areas, as well as vaginal examination, Pap smear, cervical colposcopy and biopsy if indicated.

dVIN is often missed clinically and histologically.⁴⁰ Diagnosis is clinical and by biopsy, and can be improved with the use of a colposcope and/or aceto-whitening. Biopsy of the most suspicious part of the lesion(s) should be performed under local anesthesia.⁴¹ [LINK to Annotation G: Biopsy] It is important to assess extent: multiple biopsies are needed in multifocal disease to rule out invasion. Red lesions and areas with hyperkeratosis, ulceration, or a rough and irregular surface are suspicious for dVIN.⁴² Patients are often symptomatic with a long history of lichen sclerosus or lichen planus and related vulvar itching and burning.⁴³ Biopsy in these patients is essential. dVIN is almost always seen in areas of lichen sclerosus or lichen planus; there is only one case report of dVIN as a solitary lesion in a patient without a history of lichen sclerosus or lichen planus.⁴⁴

Pathology/Laboratory Findings

uVIN

In HSIL, the epidermis is thickened and accompanied by hyperkeratosis and/or parakeratosis. There is loss of cell maturation with associated nuclear hyperchromasia, pleomorphism and mitotic figures at all levels.⁴⁵ Underlying skin appendages may be involved.⁴⁶

In warty HSIL, there are wide and deep rete ridges, similar to a condyloma. Cellular polymorphism and abnormal cell maturation are present. It is common to see acanthosis, abnormal mitotic figures, koilocytosis, multinucleation, and corps rounds.⁴⁷

In basaloid HSIL there is thickened epithelium with a flat and non-papillomatous surface. In the epidermis there are large numbers of undifferentiated cells with a basaloid appearance. Numerous mitotic figures are present; koilocytic cells and corps rounds are not as frequent as in warty HSIL.⁴⁸

DVIN

Because of the high degree of cellular differentiation and the lack of architectural disarray, dVIN can be confused with a benign dermatosis.⁴⁹ Typically, the epithelium is thickened with parakeratosis, elongated and anastomizing rete ridges, and enlarged abnormal keratinocytes with premature eosinophilic cytoplasmic differentiation. Keratin pearl formation is commonly observed.⁵⁰

Although accounting for only 5% of vulvar dysplasia diagnoses, dVIN has a higher rate of progression to squamous cell carcinoma, shorter tie interval to progression, and higher recurrence rate than HSIL.⁵¹

Differential Diagnosis

Other vulvar malignancies (adenocarcinoma, melanoma, basal cell carcinoma, undifferentiated carcinomas, soft tissue sarcomas, metastatic cancers), benign neoplasms (condyloma, seborrheic keratoses), and inflammatory dermatoses (lichen sclerosus, lichen planus, lichen simplex chronicus).⁵² Paget disease is also a consideration.

Treatment/management

LSIL

The term VIN 1 has been discarded because it represents only benign HPV infection or reactive changes.⁵³ As discussed in etiology, LSIL does not require treatment as a neoplastic lesion.  It is treated as condyloma. Failure of irritative changes to improve may necessitate reevaluation for another dermatologic abnormality or re-biopsy.

UVIn

Although spontaneous regression has been reported, uVIN should be considered a premalignant condition. Treatment is recommended for all women with uVIN.⁵⁴

SURGERY

Individualization is more important than focusing on the premalignant nature and performing extensive surgery, especially since, regardless of the type of surgery performed, surgical margins are often positive and high recurrence rates are common.⁵⁵ Preserving normal anatomy and function of the vulva are essential treatment goals, and limited surgery, consisting of removal of all visible lesions, has become the accepted approach.⁵⁶ Cold knife wide local excision with a one centimeter margin and/or CO2 laser vaporization to a depth of one mm are highly effective modalities for biopsy-proven uVIN. While 1 mm depth is sufficient ablation for hair free epithelium, 3 mm 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.⁵⁷ There is little difference in the risk of VIN recurrence between surgical excision and laser vaporization.⁵⁸

MEDICAL THERAPY

Medical therapy has become a possibility recently for uVIN, provided that early invasive carcinoma has been ruled out by adequate biopsies. There is currently no evidence on how medical treatment compares with surgical treatment. Combined modalities may hold the key to optimal treatment of this complex disease.⁵⁹

Imiquimod: Imiquimod 5% cream produces a profound tumor-directed cellular immune response after binding on Toll-like receptors on the cell surface of dendritic cells, and stimulating secretion of pro-inflammatory cytokines.⁶⁰

A Cochrane Database Review reveals that topical treatment with imiquimod may effectively treat about half of uVIN cases after a 16-week course of treatment, but the evidence on whether this effect is sustained is limited.⁶¹ In three randomized controlled trials, a complete response occurred in 36/62 (58%) in the imiquimod group. Moderate-quality evidence suggested that the complete response was sustained at one year and beyond, particularly in women with smaller VIN lesions.⁶²

Imiquimod is applied to the individual lesions three times weekly for 16 weeks. Inflammation at the site of application can lead to erythema and erosion, often necessitating a reduction in application frequency to twice a week. 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, is recommended.⁶³

PHOTODYNAMIC THERAPY (PDT)

A tumor-localizing photo sensitizer, 5-aminnolevulinic acid, combined with non-thermal light, generates oxygen-induced cell death. PDT has been successful for non-melanoma skin cancer.⁶⁴ It has the advantages of minimal tissue destruction, short healing time, and minimal side effects.⁶⁵

Several nonrandomized and uncontrolled studies have shown response rates to PDT of 0-71%,⁶⁶⁶⁷⁶⁸ with small unifocal lesions showing better response.⁶⁹ A recurrence rate of 48% is comparable to that of surgery or laser therapy.⁷⁰

Fifteen patients received PDT after injection of photosensitizer hematoporphyrin derivative Photogem and 630-nm red laser light for VIN, vaginal intraepithelial neoplasia (VAIN), or vulvar Paget’s disease between January 2003 and December 2013.The complete response rate was 80% (12/15) at the 3-month follow-up and 72.4% (10/14) at the 1-year follow-up.⁷¹

Combination treatment of 20 uVIN patients with sequential imiquimod combined with PDT showed an overall response rate of 55%. At one year, 65% were asymptomatic, compared with 5% at baseline.⁷²

THERAPEUTIC VACCINES

Immunization with the quadrivalent or 9-valent human papillomavirus, which is effective against human papillomavirus genotypes 6,11,16 and 18, and 6,11,16,18,31,33,45,52, and 58 respectively, has been shown to decrease the risk of vulvar high grade squamous intraepithelial lesions (HSIL) (VIN usual type) and should be recommended for girls aged 11-12 years with catch-up through age 26 years if not vaccinated in the target age.⁷³

Commercially-available vaccines are recommended to prevent HPV in healthy women, but do not elicit the cellular immune response necessary for HSIL treatment.⁷⁴

OTHER TOPICAL TREATMENTS

5-fluorouracil, interferons, and indole-3-carbinaol have been used to treat uVIN with limited effectiveness or severe side effects that have eliminated them as standard therapy.⁷⁵⁷⁶⁷⁷

DVIN

In light of the association with invasive squamous cell carcinoma, radical surgical excision is the treatment of choice for dVIN.⁷⁸ And, because of the frequent recurrence, these patients need to be followed by a specialist who has had training in managing vulvar disease.⁷⁹

 

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