Cell cycle proteins as molecular markers of malignant change in vulvar lichen sclerosus

Rolfe, K. J.; Eva, L. J.; Maclean, A. B.; Crow, Julie; Perrett, C. W.; Reid, W. M. N.

doi:10.1046/j.1525-1438.2001.00087.x

Cited by 11 publications

(18 citation statements)

References 15 publications

(17 reference statements)

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“…27 Only scoring the MIB1 pattern or using a semiquantitative scoring method is less accurate. 28 Owing to deep rete pegs the measurement of the entire epithelium, as previously published by Bulten et al 15 for cervical lesions, is technically not possible in differentiated VIN lesions. We calculated the MIB1 positivity index by dividing the measured MIB1-positive nuclear area by the total nuclear area.…”

Section: Discussionmentioning

confidence: 99%

MIB1 expression in basal cell layer: a diagnostic tool to identify premalignancies of the vulva

et al. 2007

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Lichen sclerosus, high-grade usual vulvar intraepithelial neoplasia (VIN) and differentiated VIN have a different malignant potential. The objective of this study was to quantify the proliferative activity in the basal region of the epithelium of vulvar premalignancies. Furthermore, we investigated whether MIB1 expression in the basal region of vulvar epithelium can be helpful in diagnosing differentiated VIN, which may be hard to discern from normal epithelium. MIB1 was used to immunohistochemically visualise proliferating cells within formalin-fixed, paraffin-embedded, archival tissue sections of different vulvar premalignancies (N ¼ 48) and normal vulvar epithelium (N ¼ 16). Automatic digital image analysis software was developed to quantify the proliferating fraction in different parts of the epithelium (MIB1 positivity index). MIB1 expression differed among the various vulvar premalignancies; a MIB1-negative basal cell layer was a distinct feature of normal vulvar epithelium. No MIB1-negative basal cell layer was noted in differentiated VIN or other vulvar premalignancies. Owing to this negative cell layer, the MIB1 proliferation index in normal vulvar epithelium was significantly lower than in vulvar premalignancies. In conclusion, MIB1 expression can be a helpful tool in diagnosing a premalignancy and has additional value especially to distinguish differentiated VIN neoplasia from normal vulvar epithelium, but cannot explain the differences in malignant potential.

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Section: Discussionmentioning

confidence: 99%

MIB1 expression in basal cell layer: a diagnostic tool to identify premalignancies of the vulva

et al. 2007

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“…The IHC procedure has been described previously (Rolfe et al, 2001(Rolfe et al, , 2002. Briefly, sections were dewaxed in xylene and rehydrated through different grades of ethanol up to distilled water.…”

Section: Immunohistochemical Analysismentioning

confidence: 99%

“…It has previously been demonstrated that there is increased cell proliferation in LS and LS adjacent to SCC (Rolfe et al, 2001(Rolfe et al, , 2002 and there may therefore be an increased likelihood of a spontaneous mutation (Hietanen et al, 1995). Inflammatory processes may also be involved in oxidative damage caused by free radicals (Carlson et al, 1998).…”

Section: Tp53 Mutation Profile In Sccmentioning

confidence: 99%

TP53 mutations in vulval lichen sclerosus adjacent to squamous cell carcinoma of the vulva

et al. 2003

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Non-neoplastic epithelial lesions of the vulva (NNEDV) lichen sclerosus (LS) and squamous hyperplasia (SH) have been implicated in the pathogenesis of squamous cell carcinoma of the vulva (SCC). To date, there have been no recognisable precursor lesions for SCC associated with NNEDV. TP53 is the most frequent genetic change in human cancers and can indicate both aetiology and molecular pathogenesis of tumours. A total of 27 SCC patients underwent immunohistochemistry (IHC) and TP53 mutational analysis using microdissection and direct sequencing. There were 19 patients with areas of adjacent epidermis: 17 had NNEDV (four SCCs had more than one adjacent lesion) and two had normal epidermis. In all, 70.4% of the SCCs, 40% LS and 22.2% SH demonstrated overexpression of p53. In total, 77.8% of SCCs, 46.7% of LS and 22.2% SH demonstrated mutations in TP53, with the majority of lesions having a mutation in codon 136. Eight cases were identified where the same mutation was identified in the SCC and in the adjacent area. These data suggest that TP53 mutations develop in NNEDV and are intrinsic to the clonal evolution that leads to SCC. The type of mutation detected is more likely to occur due to endogenous cellular changes rather than exogenous carcinogen exposure. British Journal of Cancer (2003) Lichen sclerosus (LS) is an inflammatory disease of unknown aetiology and pathogenesis. It is a disorder of the skin, which is most common in the genital area but can occur anywhere on the body. It affects both sexes and all age groups. In a review by Meffert et al (1995) of 5207 patients, the female-to-male incidence was reported as 6 : 1, with genital involvement in 83% of cases. The majority of sufferers of anogenital LS are either middle-aged or elderly women. The predominant symptom in females is an intractable itch, which is often associated with dysuria, dyspareunia, dryness of the skin, labial stenosis or fusion and, in children, constipation (Laude et al, 1980).There have been many studies assessing the risk of squamous cell carcinoma of the vulva (SCC) in inflammatory diseases of the vulva. Wallace (1971) reported that 12 of 290 (4%) patients developed SCC following a history of LS during a 12-year period but further follow-up studies have shown a wide range of risk of progression (Hart et al, 1975;Meffert et al, 1995;Carlson et al, 1998). Others (Rueda et al, 1994;Scurry et al, 1997;Vilmer et al, 2000) have looked at the skin adjacent to SCC which, not uncommonly, shows epithelial disorders; the most common are LS and squamous hyperplasia (SH).The TP53 gene is located on chromosome 17p13.1; it consists of 11 exons with 10 introns. Exon 1 is noncoding, while exons 5 -8 are part of the highly evolutionarily conserved domain. Mutations in the TP53 gene are the most frequent genetic changes in human cancers, and the spectrum of mutations can indicate tumour aetiology and molecular pathogenesis (Levine et al, 1991;Greenblatt et al, 1994). In addition, a comparison of the mutation profile between malignant and potential p...

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“…Thus, expression of cyclin D1 was shown to be overexpressed in 51% of squamous cell carcinomas and in 50% of lichen sclerosus but only in 31% of SCH. 3 Similarly, loss of pRb expression was shown to occur in lichen sclerosus at a percentage (40%) more similar to the one observed in squamous cell carcinomas (37%) than in SCH (62%). 3 Similar results have been also reported for p53 expression and mutations 29,30 and a similar trend was previously observed for COX-2 expression.…”

Section: Discussionmentioning

confidence: 72%

“…Thus, an increased expression of p53 and Ki67 was reported to accompany histologic changes in the progression of vulvar premalignant lesions to malignancy. 3 On the other hand, a progressive loss of pRb, pRb2/p130 and of the CDK inhibitor p16 INK4 from benign lesions to invasive squamous cell carcinomas of the vulva has been reported [4][5][6] thus suggesting a role for these molecules in vulvar carcinogenesis.…”

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confidence: 99%

Expression of the CDK inhibitor p27kip1 and oxidative DNA damage in non-neoplastic and neoplastic vulvar epithelial lesions

et al. 2006

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Vulvar cancer represents an important medical problem worldwide whose incidence is increasing at an alarming rate in young females. Several factors have been linked to vulvar cancer development, but its exact pathogenesis remains to be determined. Vulvar tumorigenesis proceeds through intermediate dysplastic lesions, known as vulvar intraepithelial neoplasias, frequently associated with non-neoplastic epithelial disorders of the vulva, such as lichen sclerosus and squamous cell hyperplasia. In this study, the expression of the CDK inhibitor p27 Kip1 and the extent of endogenous oxidative DNA damage were evaluated in vulvar specimens, including normal tissues, lichen sclerosus, squamous cell hyperplasia, vulvar intraepithelial neoplasias and invasive squamous cell carcinomas. We found that p27 Kip1 was constantly expressed in normal vulvar epithelium cells while a progressive significant reduction in the percentage of p27 Kip1 -positive cells was observed in vulvar intraepithelial neoplasias (77%) and in invasive carcinomas (64%). Mean percentage of positive cells in invasive carcinomas, but not in vulvar intraepithelial neoplasias, was also significantly lower than squamous cell hyperplasia lesions (78%) while lichen sclerosus displayed a percentage of positive cells (45%) significantly lower than both vulvar intraepithelial neoplasias and invasive carcinomas. 8-hydroxydeoxyguanosine (8-OHdG) is considered a sensitive biomarker for oxidative stress. We observed a progressive significant increase in the levels of 8-OHdG and in the percentage of positive cells from normal vulvar epithelium to vulvar intraepithelial neoplasias (25%) and to invasive carcinomas (64%). Squamous cell hyperplasia displayed an intermediate percentage of positive cells comparable to vulvar intraepithelial neoplasias 2 but significantly higher than vulvar intraepithelial neoplasias 1 and lower than invasive carcinomas. Lichen sclerosus staining was significantly lower than carcinomas but higher than vulvar intraepithelial neoplasias and squamous cell hyperplasia. These results demonstrate that expression of p27 Kip1 is downregulated while oxidative DNA damage increases from early non-neoplastic epithelial alterations through vulvar intraepithelial neoplasias to invasive vulvar carcinomas. Thus, both parameters might play an important role in the development of this cancer and their study might contribute to our understanding of human vulvar carcinogenesis. Keywords: vulvar cancer; tumorigenesis; cell cycle; oxidative DNA damage Squamous cell carcinoma of the vulva accounts for 4% of all gynecologic malignancies and although its incidence rates in older women have remained relatively stable over the past few decades, diagnosed cases of vulvar cancer are increasing at an alarming rate in young females worldwide. 1 The type of vulvar squamous cell carcinoma usually found in younger women appears to be associated with human papillomavirus (HPV) infection. Indeed, specific genital HPV types, in particular HPV 16, are strongly implicated in the ...

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Cell cycle proteins as molecular markers of malignant change in vulvar lichen sclerosus

Cited by 11 publications

References 15 publications

MIB1 expression in basal cell layer: a diagnostic tool to identify premalignancies of the vulva

MIB1 expression in basal cell layer: a diagnostic tool to identify premalignancies of the vulva

TP53 mutations in vulval lichen sclerosus adjacent to squamous cell carcinoma of the vulva

Expression of the CDK inhibitor p27kip1 and oxidative DNA damage in non-neoplastic and neoplastic vulvar epithelial lesions

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