19 Vulval intraepithelial neoplasia (VIN) is a squamous precancerous condition. The nonsquamous types of VIN are extramammary Paget’s disease (see Chapter 20) and melanoma in situ (see below). Squamous VIN can be divided into undifferentiated or usual VIN (uVIN) and differentiated VIN (dVIN). Undifferentiated VIN can be further classified into different subtypes – warty and basaloid (Table 19.1). The classification and terminology is evolving and a recent change has been accepted by the International Society for the Study of Vulvovaginal Disease (ISSVD). The purpose of this latest classification is to differentiate between the various types of intraepithelial lesions of the vulva, according to their etiologies (i.e. HPV or non‐HPV related). Low‐grade squamous intraepithelial lesions (LSIL) are not premalignant and therefore do not need to be treated to prevent progression. The previously used term ‘VIN’ is now reserved for premalignant lesions, which should be treated to prevent progression to cancer. Premalignant HPV related lesions are termed ‘high‐grade squamous intraepithelial lesions’ (HSIL) and non‐HPV related lesions are termed ‘differentiated type’. Table 19.1 Squamous vulval intraepithelial neoplasia (VIN) terminology. Undifferentiated VIN mainly affects young women, is caused by human papilloma virus (HPV) infection and therefore usually presents as a multifocal disease on the vulva and is often associated with other intraepithelial neoplasia in the lower genital tract. Recurrences after treatment occur in up to 50% of women and are associated with smoking, immunosuppression, multifocality, positive surgical margins and large lesion size. Since the 1970s, the incidence of uVIN has been estimated as 5 per 100 000 but it is increasing, particularly in the younger age group. This is most likely to be due to a rise in the incidence of HPV infection. Any age group is affected, but it is most common in women under 50. Most patients with uVIN are heavy smokers. Immunosuppression, such as HIV infection, or the use of immunosuppressant drugs, increases the risk of developing uVIN. Spontaneous regression of uVIN seldom occurs but when it does it is usually in women under 35 years, with multifocal pigmented lesions, and is often related to pregnancy. Differentiated VIN is less common, although pathologists do recognize dVIN more often in recent years. Less than 2–5% of all VIN lesions are of the dVIN type. They are not related to HPV and are usually found in older women, observed in association with lichen sclerosus (LS). Differentiated VIN does not regress spontaneously. The lifetime risk of becoming infected with HPV in Western societies is around 80% and approximately 40% of all sexually active, female adolescents are infected with high‐risk HPV (hrHPV) at least once. In less than 10% of cases, hrHPV persists and premalignant disorders of the lower anogenital tract, such as uVIN, can develop. The reported prevalence of HPV in VIN ranges from 72–100% and, in most cases, HPV16 is detected. HPV‐DNA is found more commonly in multifocal VIN than in unifocal VIN and in VIN coexisting with other multicentric intraepithelial lesions in the lower genital tract. In contrast to uVIN, the presence of HPV in dVIN is very rare and the exact cause of dVIN is still unclear. Differentiated VIN is related to LS and there is a clear relationship between dVIN and LS in skin adjacent to a vulval squamous cell carcinoma (SCC). Differentiated VIN is often HPV‐negative and p53 positive. Undifferentiated VIN can be prevented by the use of the prophylactic quadrivalent HPV vaccine in girls, which provides sustained protection against uVIN. In the HPV‐naïve population the vaccine efficacy against HPV16‐18 related uVIN is nearly 95%. It is anticipated that a reduction in the precursor lesions of vulval cancer would reduce the rates of invasive vulval SCC. It is assumed that prevention of dVIN and vulval SCC in patients with LS is best achieved by the use of ultrapotent corticosteroids. Histopathologically, uVIN can be classified into different subtypes – warty and basaloid Both can be easily recognized. Typically, the epidermis is thickened and is accompanied by a surface reaction of hyperkeratosis and / or parakeratosis. There is loss of cell maturation with associated nuclear hyperchromasia, pleomorphism and numerous mitotic figures at all levels of the epidermis. The intraepithelial process may also involve the underlying skin appendages. The epidermis of warty VIN has wide and deep rete ridges, often reaching close to the surface, which gives a characteristic condylomatous appearance. There is striking cellular polymorphism and evidence for abnormal cell maturation. Koilocytosis, corps rounds, multinucleation, (abnormal) mitotic figures and acanthosis are common. Basaloid uVIN is characterized by a thickened epithelium with a relatively flat and nonpapillomatous surface. Large numbers of relative uniform undifferentiated cells with a basaloid appearance are seen in the epidermis. Mitotic figures are numerous but koilocytic cells and corps rounds are less frequently seen than in warty uVIN. Patterns of warty and basaloid uVIN are often found in the same lesion, which is referred to as mixed uVIN (Figure 19.1). Figure 19.1 Undifferentiated VIN with, on the left, the warty type with the condylomatous appearance and the basaloid type with large numbers of relative uniform undifferentiated cells, on the right, often coexisting in one lesion. The histopathological diagnosis of dVIN is difficult and can be mistaken easily for a benign dermatosis because of the high degree of cellular differentiation and absence of widespread architectural disarray. Histopathological features are atypical mitoses in the basal layer, basal cellular atypia, dyskeratosis, prominent nucleoli and elongation and anastomosis of the rete ridges (Figure 19.2). Staining with MIB1 and p53 can be helpful in distinguishing dVIN from normal vulvar epithelium. Figure 19.2 Differentiated VIN with atypical mitosis in the basal layer, basal cellular atypia, dyskeratosis, prominent nucleoli and elongation and anastomosis of the rete ridges. Undifferentiated VIN causes many severe and long‐lasting symptoms such as pruritus, vulvodynia and psychosexual dysfunction. Many patients experience episodes of anxiety and depression. However, a large proportion of women are without any vulval symptoms. As patients can be asymptomatic, accurate inspection of the vulva during routine gynaecological examination is important. Undifferentiated VIN has a variety of clinical appearances. Lesions are often multifocal, raised, well demarcated and asymmetrical. Lesions might be white, red or pigmented (Figure 19.3). The commonest affected sites are the labia majora and minora and the fourchette, but all sites of the vulva might be affected (Figure 19.4). Lesions may be subtle (Figure 19.5) or they can form large confluent plaques (Figure 19.6). Sometimes only pigmented papules can be seen in young women – they can regress spontaneously (Figure 19.7
Vulval Intraepithelial Neoplasia
Introduction
ISSVD, 1986
ISSVD, 2005
ISSVD, 2015
Low‐grade SIL (flat condyloma and HPV effect)
VIN 1, mild atypia
VIN, usual type (warty, basaloid, mixed)
High‐grade SIL
VIN 2, moderate dysplasi
VIN 3, severe dysplasia, CIS
VIN 3, differentiated type
VIN, differentiated type
VIN, differentiated type
Epidemiology
Aetiology
Prevention
Histological features
Symptoms
Clinical features
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