Introduction

Vulvar cancer comprises approximately 5% of all cancers in women, with 90% of those presenting as vulvar squamous cell carcinoma (VSCC).¹

Development of primary VSCC takes place as a result of two separate pathways, one related to HPV infection, the other not related to HPV, but both forming precursor lesions that may lead to invasive disease.

Terminology and classification

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

Epidemiology

Vulvar LSILs are related to infections with a low-risk HPV type (e.g. 6 or 11) and do not progress to invasive cancer. The prevalence has been reported as 107-229 per 100, 000 women.^{9 10}

Vulvar HSIL (uVIN) is the most commonly diagnosed type of VIN (approximately 90%) and has increased in incidence over the last 2 decades, contributing to a higher incidence of vulvar cancer seen in higher income countries, mostly in women younger than age 60.¹¹

Vulvar HSIL (uVIN) is found primarily in premenopausal women, with an average age at diagnosis of 46. A 2021 study showed that HPV vaccine given to those younger than 17 years can significantly reduce the risk of developing vulvar and vaginal cancer.¹²

Analysis of data from the Dutch Pathology Registry revealed that the incidence of HSIL (uVIN) was 2.39 per 100,000 woman-years (European standardized incidence rate (ESR)) between 1991-1995, and rose to 3.26 between 2006-2011, while the ESR for dVIN increased only from 0.02 to 0.08. The 10 year cumulative risk for VSCC was 10.3%: 9.7% for HSIL and 50.0% for dVIN.¹³

Differentiated type VIN (dVIN) accounts for 2-10% of all VIN diagnoses and is seen mostly in postmenopausal women, usually associated with vulvar dermatoses such as lichen sclerosus and, less frequently, lichen planus. Despite being diagnosed less frequently, dVIN is recognized in 36-79% of women who subsequently develop VSCC.¹⁴

Etiology and risk factors

VSCC develops through two separate and distinct etiologic pathways via VIN precursor lesions. One pathway is driven by human papillomavirus (HPV) infection, the other by inflammatory vulvar skin conditions.

Vulvar LSIL, although strongly related to human papillomavirus (HPV), (usually low risk types 6 and 11), is not a VIN precursor. It represents condyloma effect or reactive atypia and is a benign lesion.^{15 16}

Vulvar HSIL or usual type VIN (uVIN)

The HPV-associated precursor lesion is vulvar HSIL (uVIN). Infection with a high-risk HPV type (16 and/or 18) is found in 80% of all HSIL lesions. This pathway accounts for approximately 30% of invasive vulvar squamous cell carcinoma (warty, basaloid type).^{17 18} Usual type VIN (uVIN) occurs most commonly in young women who smoke or have a history of multiple sexual partners.¹⁹ Women with a history of cervical intraepithelial neoplasia are also at higher risk for HSIL of the vagina and vulva, as are those who are immunocompromised. ²⁰ Immunodeficiency of HIV is also associated with uVIN.²¹ The risk of progression to invasive cancer is 3-9%. The time to progression to VSCC by the precursor has been estimated as 41-43 months. 

Differentiated VIN (dVIN)

The other pathway to the development of invasive VSCC occurs independent of HPV. The precursor lesion is differentiated VIN (dVIN). This pathway accounts for approximately 80% of invasive vulvar cancers. These cancers develop in older women (>65 years of age). Differentiated VIN is not a frequent diagnosis as an isolated lesion. It is usually observed associated with lichen sclerosus. 

Although accounting for only 5% of vulvar dysplasia diagnoses, dVIN has a higher rate of progression to squamous cell carcinoma, shorter interval to progression, and higher recurrence rate than HSIL.²² The progression to cancer has been estimated to be 33%. The time to progression to VSCC by precursor is 6-22 months.

The mechanism for the development of HPV independent VSCC is unknown. To date, no infectious agent has been identified in association with dVIN.²³ A germline mutation in the p53 gene is thought to be associated with ~90% of dVIN cases. Mutations in p53 and PTEN are often seen in these cancers.²⁴ More recently recognized are two new HPV-independent precursor lesions that are TP53 wildtype, termed DE-VIL (differentiated exophytic vulvar intraepithelial lesion) and VAAD (vulvar acanthosis with altered differentiation).²⁵ These are hypothesized to represent a possible third pathway to development of VSCC.

Several reports show a clear relationship between dVIN and lichen sclerosus (LS) in adjacent skin of VSCC.^{26 27 28} On the other hand, HSIL associated with LS without coexisting vulvar carcinoma is more likely to be uVIN.²⁹

The true overall risk of women with vulvar lichen sclerosus developing cancer is unknown. (The risk has been estimated as 3-5% (pre-steroid era studies) and <3% (post-steroid era).^{30 31} A recent review showed the following risks: the incidence of VSCC ranged from 1.16 (95% CI 0.03-6.44) to 13.67 (95% CI 5.50–28.17) per 1000 person-years for LS. The absolute risk of developing VSCC in patients ranged from 0.0% (95% CI 0.0–5.52) to 21.88% (95% CI 9.28–39.97) with LS and was 1.16% (95% CI 0.1–4.1) with lichen planus (LP).³²

Age increases risk. Women greater than 70 years of age with dVIN have an estimated 5.9% risk of developing VSCC. Whereas those under 50 have a 1.8% risk.³³ The risk of VSCC increases with the duration of LS. One study estimated the risk of developing cancer: 1% at two years and 37% after 25 years of disease.³⁴

Symptoms and clinical features

There are no screening strategies for the prevention of vulvar cancer through early detection of vulvar HSIL (uVIN).³⁸ HPV-related HSIL is often subtle and asymptomatic. Symptoms such as pruritus or pain are observed in about 60% of patients.³⁹ Lack of symptoms in the remaining 40% makes accurate anogenital inspection during routine gynecologic examination important.

UVIN lesions are diverse in color and architecture and are often multifocal, ranging in size from 0.5 to 3 cm but sometimes coalescing to larger sizes.  They often present as well-demarcated, skin colored, white, red, pink, brown, or black flat-topped papules and plaques.⁴⁰ Any area of anogenital skin can be affected.

Patients with lichen sclerosus or lichen planus require life-time surveillance and treatment.⁴¹ There is no such thing as a cure for either disorder. DVIN is more likely to present with symptoms of itching, burning, or pain. It appears as a solitary red, brown, or pink sharply marginated plaque or nodule, from 2 to 5 cm in size, often with scale, crusting, or erosion, especially within the setting of lichen sclerosus or lichen planus in any anogenital area.⁴²

Diagnosis

A careful examination includes the entire lower anogenital tract: the vulvar, perineal and perianal areas, as well as vaginal examination, cervical cytology and HPV screening, cervical colposcopy and biopsy if indicated. Digital anal/rectal exam is indicated in women over the age of 50.

Clinical suspicion can be aided by colposcopy or use of a hand-help magnifying glass and leads to biopsy. (Aceto-whitening has a high false positive rate and should be avoided by most clinicians). Biopsy of the most suspicious part of the lesion(s) should be performed under local anesthesia.⁴³ [See Annotation G: Biopsy] Multiple biopsies are needed in multifocal disease to rule out invasion and not miss significant lesions. Red lesions and areas with hyperkeratosis, ulceration, or a rough and irregular surface are suspicious for dVIN⁴⁴ which is often missed clinically and histologically.⁴⁵ Patients are often symptomatic with a long history of lichen sclerosus or lichen planus and related vulvar itching and burning⁴⁶ and the index of suspicion may be low for advancing disease.

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.⁴⁷ Underlying skin appendages may be involved.⁴⁸

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.⁴⁹

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.⁵⁰

DVIN

Because of the high degree of cellular differentiation and the lack of architectural disarray, dVIN can be confused with a benign dermatosis.⁵¹ 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.⁵²

Immunohistochemistry and genetic mutation analysis

Given the difficulties inherent in diagnosing VIN, several studies have recommended the use of p16 and p53 immunostaining for increased accuracy, with positivity for p16 supporting diagnosis of HSIL (uVIN) and a finding of p53 common in dVIN.^{53 54 55}

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).⁵⁶ Paget disease is also a consideration.

Treatment/management

Two recent articles^{57 58} point out the importance of three steps in prevention of VSCC: 1) Primary prevention utilizing HPV vaccination, 2) Secondary prevention encouraging heightened awareness amongst clinicians for careful inspection of the anogenital tract, especially for those with possibly related signs and symptoms, a low index of suspicion for performing biopsy, and routine follow up of HPV positive cervical pathology with careful vulvar and vaginal exams. In addition, the authors recommend teaching self-examination to patients with chronic inflammatory vulvar skin conditions. 3) Their third preventive recommendation is treatment of high grade VIN lesions.

DVIN

Effective and compliant treatment of lichen sclerosus has been shown, in small studies, to reduce the risk of developing VSCC,⁵⁹ the most common treatment being the ongoing use of topical corticosteroid ointments and strict surveillance. Excision with 0.5-1cm margins is the treatment of choice.^{60 61} And, because of frequent recurrence, these patients need to be followed by a specialist who has had training in managing vulvar disease.⁶²

LSIL

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  in 1.2% of women (usually <35 years old and pregnant women),⁶³ uVIN should be considered a premalignant condition. Individualized treatment is recommended for all women with uVIN.

SURGERY AND CO2 LASER

Preserving normal anatomy and function of the vulva and preventing development of VSCC are essential treatment goals, and limited surgery, consisting of removal of all visible lesions, has become the accepted approach.^{64 65}  Cold knife local excision with a 5 mm margin and 4 mm depth may be all that is needed in the case of focal lesions.  UVIN, however is often multifocal, or may occur in the delicate clitoral, urethral, or anal areas, in which case CO2 laser vaporization to a depth of 1 mm is also an effective modality 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.⁶⁶ There is little difference in the risk of VIN recurrence between surgical excision and laser vaporization.⁶⁷ The advantage of excision includes the presence of a histopathology specimen to rule out microinvasion. 

MEDICAL THERAPY

Medical therapy has become a possibility 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.⁶⁸

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.⁶⁹

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.⁷⁰ 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.⁷¹

Imiquimod is applied to the individual lesions three times weekly for 16 weeks; it is used most commonly when there are clitoral lesions. 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.⁷²

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.⁷³ It has the advantages of minimal tissue destruction, short healing time, and minimal side effects.⁷⁴

Several nonrandomized and uncontrolled studies have shown response rates to PDT of 0-71%,^{75 76 77} with small unifocal lesions showing better response.⁷⁸ A recurrence rate of 48% is comparable to that of surgery or laser therapy.⁷⁹

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.⁸⁰

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.⁸¹

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.⁸² Specifics can be found on the CDC website: https://www.cdc.gov/vaccinesafety/vaccines/hpv-vaccine.html

Commercially-available vaccines are recommended to prevent HPV in healthy women, but do not elicit the cellular immune response necessary for HSIL treatment.⁸³

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.^{84 85 86}

One study showed equal efficacy in each of the major treatment methods (excision, CO2 laser ablation, or Imiquimod) but worse recurrence rates in those treated with a combination of excision and laser.⁸⁷ Recurrence rates were also worse for smokers, those with larger lesion size or positive margins.

Follow up is long term and frequent for both uVIN and dVIN patients, with close surveillance of the entire anogenital area and a low threshold for performing colposcopy and biopsy.

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