Human papillomavirus is a risk factor for vulvar cancer, whereas human papillomavirus-negative late onset vulvar carcinoma is associated with the dermatologic condition, lichen sclerosus. Human papillomavirus E6 protein targets TP53 for degradation and by inference it has been assumed that human papillomavirus-negative vulvar cancer is dependent upon the acquisition of p53 somatic mutations and subsequent allelic loss. To investigate this, TP53 expression, loss of heterozygosity, and p53 genomic sequence were examined in 29 cases of human papillomavirus-negative vulvar carcinoma with adjacent lichen sclerosus. We examined 37 cases of lichen sclerosus without vulvar carcinoma, 10 cases of nongenital lichen sclerosus, and 12 cases of normal vulvar epithelium served as controls. TP53 was evident in 72% of vulvar carcinoma, 48% in epithelium adjacent to vulvar carcinoma, but was minimal in normal samples. When lichen sclerosus cases were selected to exclude samples with absolutely no TP53 expression through probable failed antigen retrieval or homozygous p53 loss the number of epithelial cells expressing TP53 increased progressively from nongenital lichen sclerosus to lichen sclerosus without vulvar carcinoma, then to lichen sclerosus with vulvar carcinoma (p<0.0001). These data suggest elevated TP53 is a feature of vulvar lichen sclerosus. Seventy-four percent of vulvar carcinoma had chromosome 17p-linked loss of heterozygosity, whereas 47% of adjacent lichen sclerosus featured loss of heterozygosity, but only 31% of vulvar carcinoma had p53 mutations, a frequency less than reported previously. Seven percent of adjacent lichen sclerosus had mutations, showing for the first time the presence of an identical mutation to the matched vulvar carcinoma. These data, however, implicate p53 mutations as a later event in vulvar carcinoma and in marked contrast to the original expectation, our loss of heterozygosity data are consistent with loss of another locus (not p53) on 17p operating as a tumor suppressor in lichen sclerosus destined to develop vulvar carcinoma.

Scurry J, Flowers L, Wistuba I, Vanin K, Mulvany N, Reyes H, Gazdar A. Human papillomavirus, lichen sclerosis and vulvar squamous cell carcinoma. Int J Gynecol Cancer 1998; 8: 298–306. The objective of the study was to compare human papillomavirus (HPV) detection, adjacent lesions, age and prognosis in different histologic types of overtly invasive squamous cell carcinoma (SCC). One hundred and thirty consecutive cases of overtly invasive vulvar SCC were assayed for HPV DNA by the polymerase chain reaction (PCR). The carcinomas were classified into keratinizing and basaloid types, on the basis of cytoplasmic maturation and keratin production. Changes in the adjacent epidermis were recorded as lichen sclerosis, squamous cell hyperplasia, differentiated vulvar intraepithelial neoplasia (VIN), undifferentiated VIN or normal. Prognosis was assessed as unfavorable or favorable according to whether at least one of recurrence, groin node or distant metastasis was present. Results showed HPV DNA was present in 29 (22%) of SCCs and absent in 101 (78%), with HPV 16 being the commonest type, found in 23 cases. One hundred and four SCCs (80%) were classified as keratinizing and 26 (20%) as basaloid. Twelve (12%) of the keratinizing and 17 (65%) of the basaloid SCCs contained HPV DNA. Women with HPV‐positive carcinomas had a mean age of 63 years compared with 73 in those with HPV‐negative tumors. HPV‐positive tumors were associated with undifferentiated VIN in the adjacent skin and HPV‐negative with lichen sclerosis, squamous cell hyperplasia and differentiated VIN. HPV status and histologic type did not confer different prognosis. In conclusion, histologic classification of vulvar SCCs was of value in determination of etiology and some clinical features and is therefore likely to be of use in managing patients, epidemiological research and tumor registry surveillance. While this study showed no difference in prognosis with HPV detection and histologic type, it will be impossible to conclude definitively that different types of vulvar carcinoma have a similar prognosis without performing a large population‐based study.

Scurry J, Vanin K, Östör A. Comparison of histologicalfeatures of vulvar lichen sclerosis with and without adjacent squamous cellcarcinoma. Int J Gynecol Cancer 1997; 7: 392–399. To compare the histological features of vulvar lichen sclerosis with andwithout adjacent squamous cell carcinoma, sections of 132 consecutive cases ofvulvar squamous cellcarcinoma were examined to determine the characteristics of the epidermisadjacent to the carcinoma. Where lichen sclerosis was observed, its featureswere compared to those ofvulvar lichen sclerosis from 86 women without associated carcinoma. Lichensclerosis was seen in adjacent skin of 63 of 132 (48%) women with vulvarsquamous cell carcinoma. In61 of these 63, the epidermis was also significantly thickened. The changescausing the thickened epidermis could not be distinguished from superimposedlichen simplex chronicus in21 women. In the other 40, the main, but not the only, distinguishing featurewas differentiated vulvar intraepithelial neoplasia (basal atypia), which wasseen in 33. Otherdifferences were alterations in the ratios of hyperkeratosis, granulosis,acanthosis, and irregular prolongation of rete ridges. In lichen sclerosiswithout cancer, 73 women hadassociated epidermal thickening and in 69 of these the changes could not bedistinguished from superimposed lichen simplex chronicus; the other 4 showeddifferentiated andundifferentiated vulvar intraepithelial neoplasia in two women each. Weconclude that epidermal thickening is common in vulvar lichen sclerosis,whether occurring alone or inassociation with squamous cell carcinoma. Superimposed lichen simplex chronicuscannot fully explain the histological features of the epidermal thickening inlichen sclerosis inthe majority of women with carcinoma, but can do so in the majority of womenwithout carcinoma. In individual cases, however, there are no definitehistological criteria to distinguish hyperplasia from superimposed lichensimplex chronicus.

There are two clinicopathological types of vulvar squamous cell carcinoma, human papillomavirus (HPV)-positive and HPV-negative, which can be distinguished to some degree on routine histology. Human papillomavirus-positive carcinomas account for one-quarter to one-third of cases, occur in women on average 20 years younger than in HPV-negative, and are associated with multiple lower genital tract neoplasia. Human papillomavirus negative carcinoma is linked to lichen sclerosus. Of all carcinomas, 7-96% show lichen sclerosus in skin adjacent to the carcinoma, the majority being the first presentation of lichen sclerosus, and up to 5% of patients with lichen sclerosus develop carcinoma after long-term follow up. Where lichen sclerosus is associated with malignancy, it is often hyperplastic, may show a subtle form of intraepithelial neoplasia termed 'differentiated vulvar intraepithelial neoplasia', and may lose its pathognomonic oedematous-hyaline layer. The local additional factors causing lichen sclerosus to develop malignancy on the vulva are not known.