Pathobiology of vulvar squamous neoplasia

Crum, Christopher P.; McLachlin, C. Meg; Tate, James E.; Mutter, George L.

doi:10.1097/00001703-199702000-00014

Cited by 76 publications

(53 citation statements)

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“…In summary, this study was able to establish that (1) distinct foci of differentiated vulvar intraepithelial neoplasia contain varied Tp53 mutations consistent with multiple neoplastic clones; (2) these neoplastic foci will be p53 immunopositive when missense mutations are present, and p53 immunonegative in the absence of mutations or when deletion or nonsense mutations are present; (3) differentiated vulvar intraepithelial neoplasia and vulvar squamous cell carcinoma share identical Tp53 mutations, supporting a pathogenetic connection between them; and (4) the restraint of p53 staining to immature cell nuclei is consistent with maturation-dependent degradation of mutant p53 protein, similar to its homolog p63. 16 …”

Section: Discussionmentioning

confidence: 69%

“…In the vulva, approximately 40% of malignancies can be linked to HPV. 2 In this HPVmediated pathway, E6 and E7 viral oncoproteins bind to host regulatory proteins, presumably leading to degradation of p53 protein and inactivation of the retinoblastoma gene protein Rb, two essential tumor suppressor gene products. 3 These interactions, enhanced by the viral genome integration, lead to a deregulation of the cell cycle that is manifested by an abnormal expression of cell cycle-associated proteins, among them p16, a cyclin-dependent kinase inhibitor that downregulates progression through the G1-S transition checkpoint of the cell cycle.…”

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confidence: 99%

“…In contrast, approximately 60% of vulvar carcinomas are not associated with HPV and are often coupled to a precursor lesion designated simplex or differentiated vulvar intraepithelial neoplasias. 2,6 As a result of their mature appearance and lack of the conspicuous atypia attributed to classic vulvar intraepithelial neoplasias, differentiated vulvar intraepithelial neoplasias are not as well defined. They typically develop in association with lichen sclerosus and lichen simplex chronicus.…”

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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: 69%

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confidence: 99%

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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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“…17 Therefore, although keratinizing and non-keratinizing squamous cell carcinoma occur in dissimilar age groups, both are strongly associated with HPV, in opposition with vulvar squamous cell carcinoma, in which keratinizing carcinomas are not associated with HPV infection. 28,29 To conclude, invasive squamous cell carcinoma of the vagina is frequently associated with HPV infection, and HPV16 is the most common genotype. Although without statistical significance, and similarly to vulvar squamous cell carcinoma, keratiniz- ing squamous cell carcinoma is more frequent in older patients, while non-keratinizing squamous cell carcinoma more frequently affects younger women.…”

Section: Discussionmentioning

confidence: 98%

HPV DNA detection and genotyping in 21 cases of primary invasive squamous cell carcinoma of the vagina

Ferreira¹,

Martins²,

Félix³

2008

Modern Pathology

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Primary invasive squamous cell carcinoma of the vagina is rare, and the role of human papilloma virus in its pathogenesis remains unclear. The aims of our study were to determine the distribution of human papilloma virus genotypes in 21 cases of primary invasive squamous cell carcinoma of the vagina and to correlate human papilloma virus genotype with histological subtypes. Patients' clinical records were reviewed for demographic data and the stage of the disease. Tumors (n ¼ 21) were classified according to the World Health Organization criteria. Human papilloma virus genotyping (INNO-LiPA HPV Genotyping) was performed in the whole series, and statistical analysis was performed with Fisher's Exact Test and with Student's t-test. The patients' age ranged from 36 to 88 (mean 65) years. Six cases were keratinizing squamous cell carcinoma, and 15 cases were non-keratinizing squamous cell carcinoma (seven non-keratinizing not otherwise specified, three basaloid, and five warty types). The median age of patients with keratinizing squamous cell carcinoma was 73.8 years and that of non-keratinizing squamous cell carcinoma patients was 61.5 years (P ¼ 0.08). Human papilloma virus DNA was detected in 17 cases (81%): 13 non-keratinizing squamous cell carcinoma (87%) and four keratinizing squamous cell carcinoma (67%) (P ¼ 0.31). The human papilloma virus genotypes identified were: 6,11,16,18, 31, 33, 35, 40, and 58, with human papilloma virus 16 DNA the most prevalent (33%). Invasive squamous cell carcinoma of the vagina is frequently associated with human papilloma virus infection, and human papilloma virus 16 is the most common genotype. Although without statistical significance, keratinizing squamous cell carcinoma is more frequent in older patients, whereas non-keratinizing squamous cell carcinoma more frequently affects younger women. All studied histological subtypes are strongly associated with human papilloma virus infection. Keywords: vagina; squamous cell carcinoma; human papillomavirus Human papillomavirus (HPV) has been clearly implicated in the pathogenesis of anogenital tract cancer. It has been detected in 90-100% of cervical squamous cell carcinomas 1-3 and in 70-100% of anal squamous cell carcinoma. [4][5][6][7] In vulvar carcinoma, reflecting the dual pathogenesis of these neoplasms, HPV has been detected in 75-100% of basaloid and warty squamous cell carcinoma and in less than 23% of keratinizing squamous cell carcinoma. [8][9][10][11] There are very few detailed studies of the distribution of HPV in invasive and in situ squamous cell carcinoma of the vagina 12-19 Therefore, it is not known if HPV is implicated in most cases, like in cervical carcinoma, or if there are multiple pathways of carcinogenesis, like in vulvar carcinoma. The aims of our study were to determine the distribution of HPV types in 21 cases of primary invasive squamous cell carcinoma of the vagina and to correlate the presence of HPV with histological subtypes. Materials and methodsWe searched the Department of Pathology database f...

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“…Over 200 different HPVs have been characterized and are classified as mucosal or cutaneous. The majority of HPVs are low risk and usually result only in benign warts, while infections with highrisk types are associated with epithelial lesions that have a propensity for malignant progression in the oral cavity, the anogenital tract, and, most notably, the cervix (9,14,23). High-risk HPVs are present in nearly all cervical carcinomas, the second most common malignancy in women worldwide (reviewed in reference 45).…”

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confidence: 99%

Human Papillomavirus E7 Oncoprotein Dysregulates Steroid Receptor Coactivator 1 Localization and Function

Baldwin

Huh

Münger

2006

J Virol

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High-risk human papillomaviruses (HPVs) are present in virtually all cervical carcinomas. However, the majority of women infected with high-risk HPVs do not develop cervical cancer. Therefore, cofactors must contribute to the development and progression of cervical cancer. Although numerous studies have implicated steroid hormones as cofactors in the initiation and progression of cervical neoplasia, the molecular mechanisms by which they contribute to cervical carcinogenesis are currently unknown. These observations led us to investigate a newly discovered association of the high-risk HPV type 16 (HPV16) E7 oncoprotein with steroid receptor coactivator 1 (SRC-1), an essential component of steroid hormone signaling. HPV16 E7 has been previously reported to interact with p300 and p300/CBP-associated factor (PCAF), members of some SRC-1 transcriptional complexes. We demonstrate here that HPV16 E7 associates in vivo and in vitro with SRC-1 independently of p300 and PCAF. Luciferase reporter constructs under the control of either the interleukin-8 promoter or a promoter containing multimerized synthetic estrogen response elements were used to determine the effect of high-and low-risk HPV E7 expression on SRC-1-mediated transcription. In addition, histone acetyltransferase (HAT) assays were performed to determine the effect of HPV E7 on SRC-1-associated HAT activity. These experiments reveal that HPV16 E7 expression down-regulates SRC-1-mediated transcription and SRC-1-associated HAT activity. SRC-1 localization experiments show that SRC-1 is relocalized to the cytoplasm in the presence of high-and low-risk HPV E7 proteins. Our data suggest that HPV E7 proteins dysregulate hormone-dependent gene expression by association with and relocalization of SRC-1. Dysregulation of SRC-1 localization and function by HPV E7 may provide insight into the molecular mechanisms by which steroid hormones act as cofactors in the induction and progression of cervical neoplasia.Human papillomaviruses (HPVs) are responsible for benign and malignant epithelial lesions such as common warts, genital warts, and cervical cancer. HPVs are icosahedral viruses that contain circular 8-kb double-stranded DNA genomes and are strictly epitheliotropic (reviewed in reference 44). Over 200 different HPVs have been characterized and are classified as mucosal or cutaneous. The majority of HPVs are low risk and usually result only in benign warts, while infections with highrisk types are associated with epithelial lesions that have a propensity for malignant progression in the oral cavity, the anogenital tract, and, most notably, the cervix (9, 14, 23). High-risk HPVs are present in nearly all cervical carcinomas, the second most common malignancy in women worldwide (reviewed in reference 45). HPV type 16 (HPV16) is by far the most prevalent of the high-risk types, followed by HPV types 18, 31, and others (reviewed in reference 46). Although virtually all cervical carcinomas contain high-risk HPVs, only a small fraction of women infected with high-risk HPVs...

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Pathobiology of vulvar squamous neoplasia

Cited by 76 publications

References 0 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

HPV DNA detection and genotyping in 21 cases of primary invasive squamous cell carcinoma of the vagina

Human Papillomavirus E7 Oncoprotein Dysregulates Steroid Receptor Coactivator 1 Localization and Function

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