p53 immunostaining in lichen sclerosus is related to ischaemic stress and is not a marker of differentiated vulvar intraepithelial neoplasia (d‐VIN)

Liegl, Bernadette; Regauer, Sigrid

doi:10.1111/j.1365-2559.2005.02321.x

Cited by 89 publications

(55 citation statements)

References 17 publications

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“…7,11,12,19,20 The immunohistochemistry signal observed in lichen simplex chronicus and lichen sclerosus is usually weak and confined to a single, un-expanded layer of basal Tp53 mutations in differentiated vulvar intraepithelial neoplasias cells. 12,21 In these entities, Tp53 mutations are usually not found; therefore, the p53 protein signal has been attributed to upregulation of p53 wild-type protein, possibly reflecting a stress response to inflammation or ischemia. 21 In contrast, p53 immunohistochemistry signals in differentiated vulvar intraepithelial neoplasia have been described as strong and constant, and often involving more than a single layer of basal-type cells, as observed in the majority (4/5) of our cases (Figures 1b, 2a-c).…”

Section: Discussionmentioning

confidence: 99%

“…12,21 In these entities, Tp53 mutations are usually not found; therefore, the p53 protein signal has been attributed to upregulation of p53 wild-type protein, possibly reflecting a stress response to inflammation or ischemia. 21 In contrast, p53 immunohistochemistry signals in differentiated vulvar intraepithelial neoplasia have been described as strong and constant, and often involving more than a single layer of basal-type cells, as observed in the majority (4/5) of our cases (Figures 1b, 2a-c). 12,22,23 The immunohistochemistry signal observed in this context has been presumed to derive from an abnormal (mutated) p53 protein.…”

Section: Discussionmentioning

confidence: 99%

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Differentiated vulvar intraepithelial neoplasia contains Tp53 mutations and is genetically linked to vulvar squamous cell carcinoma

et al. 2010

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Differentiated vulvar intraepithelial neoplasia is a unique precursor to vulvar squamous cell carcinoma that is typically HPV-negative and frequently associated with nuclear p53 staining. These features imply a mode of pathogenesis involving somatic mutations. However, the genetic relationship of differentiated vulvar intraepithelial neoplasm and vulvar squamous cell carcinoma and the role of Tp53 mutations in this process have not been resolved. We analyzed 11 differentiated vulvar intraepithelial neoplasms and 6 associated vulvar squamous cell carcinomas. Sections were stained for p53 and p63 and DNA from multiple epithelial sites, representing normal control tissues (n ¼ 10), differentiated vulvar intraepithelial neoplasias (n ¼ 18), and vulvar squamous cell carcinomas (n ¼ 6), were obtained by laser capture microdissection, and sequenced for exons 2-11 of Tp53. Six of 10 cases contained at least one Tp53 mutation-positive differentiated vulvar intraepithelial neoplasia focus; 4 strongly p53 immuno-positive and 2 negative. Staining for p53 and p63 co-localized, targeting the immature epithelium, but surface epithelium was Tp53 mutation-positive. Four of five vulvar squamous cell carcinomas were Tp53 mutation-positive; two shared identical Tp53 mutation with adjacent differentiated vulvar intraepithelial neoplasia. Disparate foci of differentiated vulvar intraepithelial neoplasia often showed different mutations consistent with multiple neoplastic clones. Differentiated vulvar intraepithelial neoplasia is, with few exceptions, associated with Tp53 mutations and will be p53 immunopositive when missense mutations (versus some nonsense and all deletion mutations) are present. Multiple Tp53 mutations in different sites supports the presence of multiple independent genetic events, but shared Tp53 mutations in both differentiated vulvar intraepithelial neoplasia and vulvar squamous cell carcinoma support a genetic relationship between the two. The confinement of p53 staining to immature cell nuclei is consistent with maturation-dependent degradation of mutant p53 protein.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differentiated vulvar intraepithelial neoplasia contains Tp53 mutations and is genetically linked to vulvar squamous cell carcinoma

et al. 2010

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“…P53 immunoexpression, however, is neither sensitive nor specific marker of differentiated VIN, 56 neither it correlates with the actual p53 gene mutation in benign or malignant vulvar squamous epithelium. 57,58 These two problems with p53 immunostaining have been widely illustrated by numerous previous publications 11,15,19,20,[56][57][58] and in the authors own experience p53 immunostain is not useful in differential diagnosis of HPV-negative vulvar lesions.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of mucosal and cutaneous human papillomaviruses in different histologic subtypes of vulvar carcinoma

2008

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Two independent pathways of vulvar carcinogenesis have currently been identified, one related to infection with mucosal human papillomaviruses (HPVs) and a second related to chronic inflammatory or autoimmune processes. The goal of the study was to examine a possible role of cutaneous HPVs from the beta genus in vulvar carcinogenesis and to evaluate the distribution of intratypic variants of HPV 16 in HPV 16-positive vulvar cancer. Consecutive cases of vulvar carcinoma were retrieved from the files and included the following histologic subtypes: keratinizing (n ¼ 21), basaloid (n ¼ 7), warty (n ¼ 1), mixed basaloid-warty (n ¼ 4), verrucous (n ¼ 4), keratoacanthoma (n ¼ 1), basal cell carcinoma (n ¼ 1). All tumors were microdissected and tested for 25 beta HPV types and 25 mucosal HPV types. Cases identified as positive for HPV 16 were further tested for intratypic variants. All cases were immunostained for p16 INK4a . Beta HPVs were not detected in any of the tumor cases. Mucosal HPVs were detected in all but one basaloid/warty carcinomas; of these, nine cases (82%) were positive for HPV 16, including five European subtypes, one African subtype, one North American subtype and two indeterminate subtypes. Two of four verrucous carcinomas were positive for HPV 6. Mucosal HPVs were not detected in keratinizing carcinomas, keratoacanthoma and basal cell carcinoma. All cases of basaloid/warty carcinomas, but none of the remaining tumors, overexpressed p16 The pathogenesis of vulvar carcinoma is not entirely understood. Results of epidemiologic, clinicopathologic and virologic studies are in support of two independent pathways of vulvar carcinogenesis, one related to infection with oncogenic mucosal human papillomaviruses (HPVs) and a second related to a chronic inflammatory and/or autoimmune process involving vulvar mucosa and skin. [1][2][3][4][5][6] Vulvar cancers associated with oncogenic mucosal HPVs tend to occur in young women with past history of genital warts, cervical dysplasia and/or immunosuppression. These carcinomas typically belong to basaloid or warty histologic subtypes and develop from a well-characterized in situ lesion, namely, classic vulvar intraepithelial neoplasia grade 3 (VIN3).7 Approximately 80-90% of HPVpositive vulvar cancers are associated with HPV16 and nearly all remaining tumors are positive for HPV18 and HPV33. [4][5][6][8][9][10][11][12][13] Vulvar carcinomas not associated with mucosal HPVs occur in older women. These well-differentiated keratinizing squamous cell carcinomas histologically resemble conventional squamous cell carcinomas occurring in non-genital skin. 4 However, unlike the usual squamous cell carcinomas, vulvar cancers are not arising in the setting of actinic keratosis. In the vulva, these tumors develop in a background of squamous cell hyperplasia, a chronic inflammatory condition, or long-lasting lichen sclerosus, a lesion with strong links to autoimmune diseases. Although patients with lichen sclerosus

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“…8,12 In addition, despite the fact that differentiated VIN was first described in the 1960s by Abell 23 as a highly differentiated form of vulvar carcinoma in situ, until more recently, the entity has not gained wide attention because its existence as a clinicopathological entity has long been questioned. 18 As more insight is gained that vulvar squamous cell carcinomas originate from two different pathways, each with its own premalignant lesions, 24,25 differentiated VIN has been designated the direct precursor of the HPV-independent pathway. Earlier, all VIN lesions were classified as being HPV related, which explains the high incidence of lichen sclerosus with HPV-induced lesions, which turned out to be differentiated VIN instead of the nowadays socalled usual VIN lesions.…”

Section: Discussionmentioning

confidence: 99%

“…10 It has been hypothesized that differentiated VIN may develop from lichen sclerosus and that it carries a higher malignant potential than lichen sclerosus does, 3,13-17 but its role as a premalignant lesion has not been accepted by all pathologists. 18 We hypothesize that of all lesions that have been diagnosed as lichen sclerosus in the past, a substantial part might currently be diagnosed as differentiated VIN.…”

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confidence: 99%

Differentiated vulvar intraepithelial neoplasia is often found in lesions, previously diagnosed as lichen sclerosus, which have progressed to vulvar squamous cell carcinoma

et al. 2011

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Lichen sclerosus is considered to be the precursor lesion of vulvar squamous cell carcinoma, of which only 2-5% progress to squamous cell carcinoma. Differentiated vulvar intraepithelial neoplasia (VIN) has been proposed to be the direct precursor lesion, but this is a recently recognized, and a difficult to diagnose, entity, which may easily be mistaken for a benign dermatosis. The aim of this study was to test the hypothesis that of all lesions that have been diagnosed as lichen sclerosus in the past, a part might currently be diagnosed as differentiated VIN, and to identify histopathological differences between lichen sclerosus lesions with and without progression to vulvar squamous cell carcinoma. All lichen sclerosus slides were revised by two expert gynecopathologists and histopathological characteristics were documented. After revision of lichen sclerosus biopsies without progression (n ¼ 61), 58 were reclassified as lichen sclerosus. Revision of lichen sclerosus biopsies with progression yielded concordant diagnoses in 18 of 60 cases (30%). Of 60 lesions, 25 (42%) were reclassified as differentiated VIN. The median time from differentiated VIN to vulvar squamous cell carcinoma was shorter (28 months) than that from lichen sclerosus to vulvar squamous cell carcinoma (84 months) (Po0.001). Lichen sclerosus that progressed to squamous cell carcinoma, but did not meet the criteria for differentiated VIN, more often showed parakeratosis (P ¼ 0.004), dyskeratosis (Po0.001), hyperplasia (P ¼ 0.048) and basal cellular atypia (P ¼ 0.009) compared with lichen sclerosus without progression. In conclusion, differentiated VIN diagnosis has been frequently missed and is associated with rapid progression to squamous cell carcinoma. Patients with lichen sclerosus with dyskeratosis and parakeratosis, hyperplasia and/or basal cellular atypia should be kept under close surveillance as these lesions also tend to progress to squamous cell carcinoma.

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p53 immunostaining in lichen sclerosus is related to ischaemic stress and is not a marker of differentiated vulvar intraepithelial neoplasia (d‐VIN)

Abstract: d-VIN in LS is rare, while p53 staining is common and best explained as an ischaemic stress response due to poor oxygenation, vasculitis and inflammation rather than as a marker of a precancerous lesion in LS.

Cited by 89 publications

References 17 publications

Differentiated vulvar intraepithelial neoplasia contains Tp53 mutations and is genetically linked to vulvar squamous cell carcinoma

Differentiated vulvar intraepithelial neoplasia contains Tp53 mutations and is genetically linked to vulvar squamous cell carcinoma

Prevalence of mucosal and cutaneous human papillomaviruses in different histologic subtypes of vulvar carcinoma

Differentiated vulvar intraepithelial neoplasia is often found in lesions, previously diagnosed as lichen sclerosus, which have progressed to vulvar squamous cell carcinoma

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