Vulvar intraepithelial neoplasia (VIN) is a non-invasive precursor lesion usually found in 50–70% of patients affected by vulvar squamous cell carcinoma (VSCC) . Squamous precursor lesions of the vulva were first identified about a century ago, and are characterized by cytological and architectural features of dysplasia, but without any sign of stromal invasion. Moreover, it is widely known that these intraepithelial lesions could precede the development of VSCC by a variable period .
There are two different pathogenetic pathways leading to VSCC, through the development of two distinct vulvar pre-cancerous lesions: (i) VIN of usual type (uVIN), also referred as classic or bowenoid VIN, that is associated to Human Papillomavirus (HPV) infection; and (ii) VIN of differentiated type (dVIN), also known as simplex VIN, that is HPV-independent [2,3].
Over time, various terms and many classification schemes have been proposed. The term “intraepithelial neoplasia” was first proposed by Richart in 1967 for lesions of the cervix, and only later for the vulva. In 1986, the International Society for the Study of Vulvo-Vaginal Disease (ISSVD) introduced the term VIN and identified three grades (VIN 1, 2, 3) according to the depth of dysplastic epithelial involvement [1,4]. An additional category, “VIN 3, differentiated type”, was defined . Nevertheless, emerging evidence argued that there was not a biological continuum, as suggested by this classification. VIN 1 was usually represented by flat condylomatous lesions and associated with low-risk (LR) HPV genotypes, especially 6 and 11. On the contrary, VIN 2 and 3 were usually related to risk of progression to VSCC and associated with high-risk (HR) HPV genotypes . Due to the negligible progression risk of VIN 1, in 2004, the ISSVD proposed a new classification, including (i) uVIN that comprehended lesions previously classified as VIN 2 and VIN 3; and (ii) dVIN .
More recently, a new consensus was reached by multiple committees, all supporting the terminology “squamous intraepithelial lesion”. In 2012, the Lower Anogenital Squamous Terminology (LAST) was proposed by the College of American Pathologists (CAP) and the American Society for Colposcopy and Cervical Pathology (ASCCP) in order to unify the terminology applied to HPV lesions affecting the cervix, vagina, vulva, perineum, anus and penis, under two categories: (i) low-grade squamous intraepithelial lesion (L-SIL); and (ii) high-grade squamous intraepithelial lesion (H-SIL) . The 2014 World Health Organization (WHO) and the 2015 ISSVD classifications accepted the LAST, but included dVIN as an additional category .
The incidence of both uVIN, nowadays named vulvar H-SIL (vH-SIL), and dVIN has risen over the last three decades, even if the incidence of VSCC has remained relatively stable. Indeed, the incidence of vH-SIL almost doubled from 1.2/100,000 in 1992 to 2.1/100,000 women in 2005, whereas the incidence of dVIN even increased nine-fold from 0.013/100,000 to 0.121/100,000 women [10,11]. The rising number of VINs may reflect a real increased incidence related to the growing age of the population or a better recognition and more effective treatment of these precursor lesions before the development of VSCC .
Regarding aetiology, many agents, like herpes simplex virus (HSV), arsenic and granulomas, have been suggested as being responsible, before HPVs role was showed for the majority of anogenital squamous carcinomas, including VSCC . HPV infection is strongly associated with vH-SIL, accounting for more than 80% of vH-SIL. HPV 16 is the most common genotype identified in vH-SIL and HPV-dependent VSCC, followed by other genotypes, such as 18, 31, 33 and 45 .
Lichen sclerosus (LS) has been suggested as a precursor of dVIN and HPV-independent VSCC, but the carcinogenic mechanism has not been established yet. The association was probably supposed because LS is a frequent finding in the skin adjacent to dVIN and VSCC, and because women with LS have a significantly higher risk of developing VSCC. Nevertheless, most of the women with LS do not develop dVIN or VSCC .
vH-SIL usually occurs in young women, in the third to the fifth decades, with the same risk factors as cervical lesions, such as number of sexual partners, smoking and immunosuppression . vH-SIL appears as white, erythematous or pigmented macules or papules, that can coalesce to create plaques. Most patients report pruritus or pain, but almost 20% of women are asymptomatic . Over half of patients have multifocal lesions of the vulva and present with multicentric lesions of the ano-genital tract, therefore a thorough examination is strongly recommended .
dVIN typically affects post-menopausal women in the sixth to the eight decades, and is often associated with LS or other chronic inflammatory dermatoses, such as lichen simplex chronicus. As opposed to vH-SIL, dVIN tends to be a single lesion and may appear as a grey-white stain, a thick plaque or a nodule. A long history of itching, burning and vulvar pain is reported by 60% of patients. However, many dVINs are asymptomatic and represent a large clinical challenge .
The risk of progression of vH-SIL to VSCC is 9–16% in untreated patients and about 3% in treated patients, respectively. Advanced age, previous radiotherapy and immunosuppression have been recognized as potential risk factors for malignant progression. Recurrence occurs in approximately 30% of patients, but the role of margin status and of new HPV acquisition have not been well defined . Spontaneous regression has been reported in less than 1.5% of women, especially in patients younger than 35 years, pregnant women and those with multifocal lesions  (Table 1).
dVIN has higher risk of progression (32.8%) over a shortened time-period (22.8 versus 41.4 months) than vH-SIL .
However, since dVIN is an uncommon lesion, it should be assumed that dVIN is often underdiagnosed and probably represents a transient lesion that rapidly progresses to VSCC . Furthermore, the diagnosis of isolated dVIN is rather rare due to an application problem of the diagnostic criteria by many pathologists
In the past, extended vulvectomy was usually considered as the standard treatment for VIN. Considering the risk of the malignant progression of VIN and the important psychological and physical morbidities related to radical surgery, several less aggressive therapies have arisen since the late 1970s. Nowadays, therapeutic options for vH-SIL include local excision, laser ablation, topical imiquimod, cidofovir or 5-fluorouracil and photodynamic therapy .
Current prophylactic HPV vaccines represent a promising tool for the prevention of HPV pre-neoplastic and neoplastic ano-genital lesions. The broad diffusion of HPV vaccination is widely expected to result in a significant reduction of incidence of vH-SIL, especially in young women [22,23]. Furthermore, there are great expectations for the clinical response of patients affected by vH-SIL through therapeutic synthetic long-peptide vaccines against the HPV-16 oncoproteins E6 and E7 .
HPV-related malignancies are associated with a persistent HPV infection. The host immune response plays a crucial role in determining the clearance or persistence of both HPV infections and HPV-related VIN. In immune-compromised patients, i.e., renal transplant recipients, the malignant potential of vH-SIL is 50 times higher compared to the general population . HPV produces several proteins among which the oncoproteins E6 and E7. E6 and E7 oncoproteins can interfere with crucial cell-cycle checkpoints. For instance, HPV E6 can lead to the dysfunction of the tumour suppressor gene p53 , while E7 can inactivate the retinoblastoma tumour suppressor gene (pRb), leading to the overexpression of p16ink4a and p14arf and proliferation of infected cells . In most vH-SIL lesions immunohistochemistry is positive to p16ink4a and p14arf, but negative to p53 . The knowledge of the role of the oncoproteins E6 and E7 may lead to the development of new strategies to increase the immune response to prevent HPV-related malignancies.
Screening tests for the diagnosis of VIN are not available. VIN is diagnosed during the visual assessment of the vulva. A tissue specimen can be obtained in order to have a pathologic confirmation. Recently, digital dermoscopy features of small case series of VIN lesions have been reported, suggesting that digital dermoscopy may become a useful diagnostic tool in the near future [29,30] (Figure 1).
2. Treatment of Vulvar Intraepithelial Neoplasia
VIN treatment is usually dictated by both the characteristics of the lesions and of patients. Lesion size, location, and the presence of a multifocal disease should be carefully considered together with patient’ age, comorbidities, psychological distress, symptoms and reliability for post-treatment follow-up. The availability of adequate medical resources and equipment is another key point which should be considered when planning VIN treatment . The ideal treatment should completely ensure the absence of stromal invasion, improve subjective symptoms, reduce the risk of recurrence, and preserve vulvar function and morphology. To date, available treatments are not able to ensure these ideal results and the high morbidity associated with surgery makes it necessary to explore less harmful but effective approaches for VIN treatment .
dVIN is strongly associated with invasive squamous cell carcinoma (SCC) and surgical excision represents the treatment of choice for this condition. Full thickness tissue specimens obtained by surgery are appropriate for a complete and careful histological evaluation to evaluate the degree of stromal invasion. Medical therapies must be avoided in dVIN treatment .
Due to the increasing incidence of vH-SIL in younger women and the lower progression rate in this population a conservative and individualized management is indicated for vH-SIL, since extensive surgery may affect the body image and produce psychosexual distress.
Local excision, consisting of the removal of all visible lesions, can be performed with different techniques—scalpel, electrosurgery, or CO2 laser excision—with all techniques showing a similar efficacy. Several medical treatments have been used to avoid or limit surgery in vH-SIL patients. However, most of the studies lack of enough evidence because of the low number of subjects accrued, different inclusion criteria, comparison groups or limited follow-up . Therefore, no medications are approved by the FDA for vH-SIL.
Two compounds with antiviral activity, the nucleoside analogue cidofovir, and the TLR7 agonist imiquimod, have been investigated as topical therapies in VIN patients.
Cidofovir may induce the apoptosis of HPV-infected cells. In a pilot study of Tristram, 4 of the 10 patients treated with cidofovir 1% showed a complete response (CR). The side effects included ulceration at the site of application . Cidofovir demonstrated response rates ranging from 40% to 79% in other small studies .
Imiquimod is a non-nucleoside heterocyclic amine, which acts as an immune-response modifier. Imiquimod induces the activity of interferon α (IFNα), tumor necrosis factor α (TNFα), and interleukin-6 via the stimulation of TLR7. Imiquimod demonstrated response rates ranging from 26% to 100% . In the largest prospective, randomized, double-blinded, and placebo-controlled study with 52 patients, a 35% CR and 46% partial response (PR) were observed. After a median follow-up of 7.2 years, VIN recurred in only one of the patients who had experienced a CR, suggesting that imiquimod is effective in the long term .
The CRUK-funded RT3 VIN clinical trial randomized VIN 3 patients to therapy with either cidofovir or imiquimod. Histologically-proven CRs were observed in 41 of 72 (57%) cidofovir patients and 42 of 69 (61%) imiquimod patients .
A predictive biomarker that could identify patients likely to respond to specific treatments would facilitate the optimal management of these patients.
The strategy of vaccination using E6 and E7 HPV oncoproteins to treat VIN is attractive. However, studies for the development and research of vaccines are very expensive and the focus is placed on the study of vaccines to prevent lower genital tract neoplasia, rather than to treat it.
3. Photodynamic Therapy in the Treatment of Vulvar Intraepithelial Neoplasia
Topical photodynamic therapy (PDT) is an effective and safe treatment for cutaneous non-melanoma skin cancer (NMSC) with favorable cosmetic outcomes. The PDT technique involves the topical application of a photosensitizer, 5-aminolevulinic acid (ALA) or its methyl ester-methyl aminolevulinate (MAL), and subsequent illumination of the skin area with light of the appropriate wavelength. PDT is a useful nonsurgical treatment option for actinic keratosis (AK), superficial basal cell carcinoma (BCC) and in situ squamous cell carcinoma (SCC), especially at sites that are cosmetically sensitive or prone to impaired wound healing . Besides NMSC, PDT is used to treat a wide range of medical conditions, including acne, skin aging, psoriasis, granuloma annulare, age-related macular degeneration and malignant neoplasms. The combination of photosensitizer, a light source and tissue oxygen leads to the chemical destruction of any tissues which have either selectively taken up the photosensitizer or have been locally exposed to light, with recruitment of inflammatory cells, increased immune response and vascular compromise.
Similarly to the classical PDT used for the treatment of skin cancer, in order to achieve a selective destruction of the target vulvar areas, the photosensitizer agent can be applied topically onto the affected areas and subsequently locally excited with the proper light source. In some studies and case series aimed at the evaluation of PDT treatment for VIN, photosensitizers have been administered intravenously before delivering the light to the selected vulvar areas using an appropriate light source.
The different studies of PDT for VIN treatment are characterized by a non-standardized methodology regarding the type of photosensitiser, route of administration of the photosensitiser, duration of photosensitiser application, type and wavelength of the light source and number of treatment cycles per patient. Furthermore, and most importantly, the definition of treatment response was different.
The first study on the PDT treatment of VIN was published by Martin–Hirsch and colleagues in 1998. The photosensitiser used was 5-aminolaevulinic acid (ALA) and the light source was a non-laser light at a wavelength of 630 nm. The first 10 VIN patients received a single dose of 50 J cm−2, and two patients showed a histological response. After this first phase, eight women received a single treatment dose of 100 J cm−2, following which three out of eight women demonstrated a complete histological response. Pre-treatment analgesia was administered due to poor tolerability of the treatment. Sixteen out of the 18 women who received PDT treatment reported symptom relief (89%). Ten women were followed up for one to two years and nine of them developed local recurrence at the treatment site .
In a subsequent study, six patients received PDT treatment with 20% 5-ALA cream and a single dose of broad band light source 580–740 nm (single dose, 150 J cm−2). Five out of six women showed persistent disease at a six-month follow-up evaluation. Treatment was associated with erythema and erosions in the majority of cases .
In another study, 25 women were treated with topical 20% 5-ALA and 57 cycles of laser light at 635 nm wavelength (100 J cm−2
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