Premalignant disease of the vulva

Introduction

Squamous carcinoma of the vulva is the most common vulval ma­lignancy, though overall it is a rare tumour, accounting for only 4% of gynaecological malignancies (18).

Vulval high grade intra-epithelial lesion (vHSIL) is caused by per­sistent infection with oncogenic strains of the human papillomavirus (HPV), particularly HPV 16 and 18 (19). The incidence of vHSIL is increasing in young women worldwide due to the increase in HPV infection which has mirrored the HIV pandemic, and may be asso­ciated with intraepithelial neoplasia in other areas of the anogenital tract (18). Differentiated VIN (dVIN) occurs in postmenopausal women, and is independent of HPV infection, but may be associ­ated with chronic inflammatory vulval skin disorders such as lichen sclerosus and squamous hyperplasia (18). While vHSIL accounts for 90% of cases of VIN (18), dVIN is significantly more likely to be associated with progression to squamous carcinoma (5.7% vs 33% respectively) (20-22). Besides the role VIN plays in the aetiology of vulval squamous carcinoma, it also causes significant morbidity in terms of symptoms, such as pain, pruritus, and dyspareunia.

Vulval extramammary Paget's disease is a rare intraepithelial adenocarcinoma which accounts for less than 2% of primary vulval tumours (23). It is currently thought that most cases of vulval Paget's disease are a primary intraepidermal neoplasm, with a few being as­sociated with cutaneous sweat gland tumours. It has also been de­scribed in association with an underlying adenocarcinoma, such as of the endometrium, endocervix, vagina, Bartholin's gland, urethra, or bladder. It has similar clinical and histological features to other skin neoplasms, such as malignant melanoma and atypical squa­mous disease (23).

Classification of premalignant vulval lesions

Premalignant vulval lesions have been recognized for nearly 100 years, though the pathological and clinical characteristics of these lesions have been the subject of continuous debate (Table 65.2) (24).

Two different types of VIN were introduced in the 1986 International Society for the Study of Vulval Disease (ISSVD) ter­minology, and confirmed in 2004, when the ISSVD introduced a two-t ier classification of VIN (25). HPV-associated vulval high grade intra-epithelial lesion was made up of high-grade lesions VIN 2-3; lesions which were previously called VIN 1 were categorized under condylomata accuminata. HPV-independent or differenti­ated VIN is always considered to be a high-grade lesion (25).

In 2012, the ISSVD participated in the introduction of the Lower Anogenital Squamous Terminology (LAST) (Table 65.3) by the American Society for Colposcopy and Cervical Pathology and the College of American Pathologists (26). This terminology is not con­fined to vulval lesions, but aims to classify all HPV-related lesions of the lower genital tract.

In relation to premalignant vulval lesions, two concerns have been raised about the LAST terminology. Firstly, that as LAST deals only with HPV-related lesions, it does not include dVIN, which accounts for 80% of the burden of invasive cancer, and this omission could lead to dVIN being overlooked by healthcare workers (20, 24). And sec­ondly, that by including vulval low-grade squamous intraepithelial lesion, there is potential for overdiagnosis and overtreatment of be­nign and occasionally self-limiting lesions (24).

Table 65.2 ISSVD classification of premalignant conditions of the vulva

Table 65.3 Comparison of ISSVD terminologies and Lower Anogenital Squamous Terminology of VIN

Source Bornstein J, Bogliatto F, Haefner H, et al.

Paget's disease may be mammary or extramammary, as well as primary (intraepithelial infiltration by neoplastic cells showing glandular differentiation) or secondary (spread from an underlying adenocarcinoma in a dermal adnexal gland or local organ with con­tiguous epithelium) (23).

Vulval melanosis is an uncommon, asymptomatic, and benign condition, and has no association with vulval melanoma, though it can be clinically indistinguishable from superficial spreading mel­anoma. When in doubt, all melanocytic naevi of the vulva require biopsy or excision to exclude malignancy (27).

Epidemiology of premalignant vulval lesions

vHSIL is mainly a condition of younger women, quoted as between 40 and 50 years in the literature (18), though in HIV-infected women, is frequently seen as young as 20-30 years. As it is caused by onco­genic HPV infection, the risk factors for vHSIL include those related to HPV acquisition, such as multiple sexual partners and young age of first intercourse, as well as impaired immunity and cigarette smoking (18).

dVIN is usually found in postmenopausal women, with a mean age of 68 years, and often develops in those with chronic skin con­ditions such as squamous hyperplasia, lichen sclerosus, and lichen simplex chronicus (18). Vulval Paget's disease is most commonly seen in postmenopausal women (23).

Aetiology of premalignant vulval lesions

vHSIL is caused by integration of high-risk oncogenic HPV DNA into the host genome (18). This leads to thickening of the epidermis, with parakeratosis and hyperkeratosis, loss of cell maturation, increased mitotic figures, pleomorphism, and high nuclear-to- cytoplasmic ratios (28).

Studies show that there is a high prevalence of oncogenic HPV types in the general population, with the lifetime incidence of HPV 16 infection estimated to be more than 50%.

Mutation of the TP53 gene appears to be implicated in the devel­opment of dVIN (30), and studies show identical TP53 mutations in lichen sclerosus and adjacent squamous carcinomas (31).

Presentation of premalignant vulval lesions

The commonest symptoms caused by premalignancies of the vulva are pruritus, pain, and sexual dysfunction. vHSIL may present as multifocal raised plaques that tend to coalesce, and which may be hyperpigmented (18). Patients may have multifocal lesions in the lower genital tract, particularly if they are immunocompromised. Women with dVIN are often asymptomatic, though may be known to have lichen sclerosus, squamous hyperplasia, or lichen simplex chronicus. They may present with discolouration of the vulval skin, white plaques, as well as red hyperkeratotic lesions (32). Pain and pruritus are present in up to 60% of women (33). Vulval pruritus is also the commonest symptom of women with vulval Paget's disease, and the clinical appearance is similar to mammary Paget's, with an erythematous weeping or crusted lesion with irregular borders (23). An associated tumour may be palpable.

Diagnosis of premalignant vulval lesions

While vulval cancer is uncommon and screening in the general population is not recommended, both patient and clinician delay in diagnosis have been reported more than in any other gynaecological malignancy (34). In one retrospective review of women with vulval cancer, 94% of women had chronic irritation of the vulva, and 85% had abnormal skin around the tumour (35). Inadequate knowledge and medical care contributes to development of these tumours, and appropriate examination of the vulva, referral, and full-thickness biopsy of the vulval skin are vital for identification of preinvasive lesions.

Cervical cytology screening programmes have had an enormous impact on the incidence of cervical cancer, and the use of vulval cy­tology as a screening test has been examined in a variety of studies. However, unlike in cervical disease, where the preinvasive lesion is not visible to the naked eye and is frequently asymptomatic, vulval cytology has been found to be unreliable when the vulva ap­pears normal, and does not replace the need for biopsy of visible lesions (34).

Similarly, vulvoscopy does not play as central a role in the diag­nosis of vulval preinvasive disease as colposcopy does in cervical disease. There is no evidence that it is effective as a screening tool, but it may be useful where early invasion is suspected, and in fol­lowing up women who have had multiple treatments in the past. It is also important in women who have multicentric disease, in order to examine the cervix and vagina (34).

vHSIL usually presents as a visible lesion, so is identified on exam­ination of the vulva, and during colposcopy for concurrent cervical disease. A biopsy should be taken of all atypical or suspicious areas, to confirm the diagnosis and exclude invasion, which is found in 19-22% of cases of VIN (36). Biopsies can be taken under local anaesthetic in an outpatient setting. The differential diagnosis of vHSIL includes reactive epithelial changes, vulval Paget's disease, and malignant melanoma, and a p16 immunostain is helpful in dif­ferentiating between these. In vHSIL lesions, there is a strong band­like pattern of staining with p16 (37). Histologically, vulval Paget's disease has large tumour cells with pale to eosinophilic cytoplasm within the epidermis. When immunohistochemistry is performed, these cells are positive for CK7, CEA, CAM 5.2, and GCDFP- 15 (38). Malignant melanoma is positive for melanocytic markers such as HMB-45, S-100, and Melan-A (18).

The histological features of dVIN are subtle, making it difficult to diagnose (18). Five histological criteria are useful in the diag­nosis of dVIN: atypical mitosis in the basal layer, basal cell atypia, dyskeratosis, prominent nucleoli, and elongation and anastomosis of the rete ridges (18).

Management of vulval intraepithelial neoplasia

Follow-up of women with VIN is a balancing act between the need for treatment and symptom control, and minimizing morbidity and the risk of developing squamous carcinoma. Untreated VIN pre­sents a far greater risk for malignant transformation than treated disease, with one study showing progression in 3.8% of women who had been treated, versus 87.5% in untreated women (39). VIN is treated in order to relieve symptoms, such as severe pruritus, to exclude invasive disease, and to decrease the risk of developing cancer. Local excision is adequate—it provides a histological spe­cimen, while having the same recurrence rate, but much less ef­fect on sexual function, as simple or radical vulvectomy. Excision also provides higher complete response rates than laser or medical treatments (36).

The consequences of not treating premalignant disease

Untreated, the progression of vHSIL to cancer is low, at about 10­12% (40, 41). The risk of progression is higher in women older than 45 years, and is up to 50- fold higher in immunocompromised women (42, 43). DVIN has a higher progression risk than uVIN (5.7% vs 33% respectively), and the time to progression is shorter (20-22).

Younger women may require more emphasis on the preservation of vulval anatomy and sexual function than older women. Specialist follow-up in multidisciplinary clinics, with access to conservative surgery and reconstruction, as well as psychosexual support, are important in the management of women with vulval premalignant disease (34).