Human Papillomavirus Infection and p16INK4a Protein Expression in Vulvar Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma

Rufforny, Irina; Wilkinson, Edward J.; Liu, Chen; Zhu, Haizhen; Buteral, Michael; Massoll, Nicole A.

doi:10.1097/00128360-200504000-00007

Cited by 43 publications

(25 citation statements)

References 17 publications

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“…Thin-section microtome sections were prepared from biopsy tissue and sections adjacent to those used for histologic diagnosis were tested for HPV DNA to ensure genotyping was done on abnormal tissue. VIN lesions were obtained from women in developed and developing countries, whereas most other studies to date have examined the distribution of HPV types in VIN lesions from a single region or medical institution (4)(5)(6)(26)(27)(28)(29)(30).…”

Section: Cancer Epidemiol Biomarkers Prev 2009;18(6) June 2009mentioning

confidence: 99%

Human Papillomavirus Infections and Vulvar Disease Development

Garland

Insinga²,

Sings³

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: We describe the prevalence of 14 common types [human papillomavirus (HPV)-6/11/16/18/ 31/33/35/39/45/51/52/56/58/59] in vulvar intraepithelial neoplasia grades 1 to 3 (VIN 1-3) and HPV genotype-specific infection in relation to the development of VIN 1-3. Methods: Data were analyzed from women enrolled in the placebo arms of three randomized double-blind trials. Anogenital examinations, including collection of labial/vulvar/perineal/perianal swabs, occurred at day 1 and every 6 to 12 months through 48 months. Lesions that were possibly, probably, or definitely HPV related or of unknown etiology were biopsied. Biopsies and swabs were HPV typed. Biopsies were read for endpoint determination (VIN 1-3) by up to four pathologists.

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Section: Cancer Epidemiol Biomarkers Prev 2009;18(6) June 2009mentioning

confidence: 99%

Human Papillomavirus Infections and Vulvar Disease Development

Garland

Insinga²,

Sings³

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…INK4a has been described in VIN [21][22][23] and is thought to arise from interaction of the viral protein E7 with Rb, thus inhibiting Rb function, which results in upregulation of p16 INK4a . Although p16 upregulation is a very sensitive marker for VIN, it does not result in downregulation of the cell cycle because downregulation of its downstream effectors cyclinD1 and cyclinD2 is successfully neutralized by upregulation of cyclinE1, cyclinE2, cyclinA2, cyclinB1 and cyclinB2.…”

Section: Ink4amentioning

confidence: 99%

HPV related VIN: Highly proliferative and diminished responsiveness to extracellular signals

Santegoets

Seters

Helmerhorst

et al. 2007

Intl Journal of Cancer

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Vulvar intraepithelial neoplasia (VIN) is a premalignant disorder caused by human papillomaviruses. Basic knowledge about the molecular pathogenesis of VIN is sparse. Therefore, we have analyzed the gene expression profile of 9 VIN samples in comparison to 10 control samples by using genome wide Affymetrix Human U133A plus2 GeneChips. Results were validated by quantitative real-time RT-PCR analysis and immunostaining of a few representative genes (TACSTD1, CCNE2, AR and ESR1). Significance analysis of microarrays (SAM) showed that 1,497 genes were differentially expressed in VIN compared to controls. By analyzing the biological processes affected by the observed differences, we found that VIN appears to be a highly proliferative disease; many cyclins (CCNA, CCNB and CCNE) and almost all prereplication complex proteins are upregulated. Thereby, VIN does not seem to depend for its proliferation on paracrine or endocrine signals. Many receptors (for example ESR1 and AR) and ligands are downregulated. Furthermore, although VIN is not an invasive disease, the inhibition of expression of a marked number of cell-cell adhesion molecules seems to indicate development towards invasion. Upon reviewing apoptosis and angiogenesis, it was observed that these processes have not become significantly disregulated in VIN. In conclusion: although VIN is still a premalignant disease, it already displays several hallmarks of cancer. 1 Differentiated type VIN is mostly found in postmenopausal women and is associated with lichen sclerosus. In contrast, Usual type VIN (undifferentiated) is often diagnosed in premenopausal women and is strongly associated with sexually transmitted Human papilloma virus (HPV) infections. In this report, we will focus on HPVrelated, Usual Type VIN.During the last decade, VIN has been diagnosed with increasing frequency in relatively young women in western countries. This rise in incidence could be the result of a higher awareness and knowledge of VIN, but is more likely to be due to the overall increase in sexually transmitted diseases, and especially the rise in HPV infections. Around 40% of young, sexually active women are infected with high-risk HPV. 2 Fortunately most women are able to clear the infection, and less than 10% of infected women develop a persistent HPV infection which causes dysplasia of the lower genital tract and might cause VIN.3 Such a persistent infection with high-risk HPV (mostly HPV16, 18, 31 or 33) may trigger VIN to further develop into invasive vulvar cancer. What percentage of women with VIN eventually develop cancer is difficult to assess, because most patients with VIN will be treated effectively.van Seters et al. have reviewed data on 3,322 published patients with VIN and found 88 untreated patients, of whom 8 (9%) progressed to vulvar cancer. 4 A critical step in the defence against high-risk HPV is a good immune response. Accordingly, being immunocompromised is a risk factor for the development of VIN and subsequent vulvar cancer. For example, VIN is observed more often ...

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“…Multiple authors have suggested that vulvar cancer comprises two separate diseases, the first type occurring with high prevalence among young women and developing from vulvar intraepithelial neoplasia caused by HPV, and a second type afflicting older women and developing from non-neoplastic epithelial disorders such as lichen sclerosus or chronic inflammation. [2][3][4]12,13,15,18,24,25 However, these studies of HPV prevalence in invasive squamous vulvar carcinoma also utilized different methods of detection, including in-situ, [13][14][15][16][17][18] dot blot, 20,21 and Southern blot 20 hybridization, immunohistochemistry, 15 and PCR-based assays, 2,7,12,18,19,[22][23][24][26][27][28][29][30][31][33][34][35][36] each with different analytic sensitivities. Moreover, the particular HPV genotype(s) targeted in previous work is inconsistent between studies; many early reports documented only HPV16, 18, 33, and/or 6/11, 18,20,21,26,[28][29]…”

mentioning

confidence: 99%

“…12,22 Also, some studies tested only a few cases of invasive squamous vulvar carcinoma, which limits the predictive value of the resulting data. 14,17,21,23 Despite these shortcomings, this body of work indicates that HPV16 is the most common genotype present in invasive squamous vulvar carcinoma. 2,7,[16][17][18][19]22,24,[26][27][28][29][30][31] The prevalence of other high-and low-risk HPV types in invasive squamous vulvar carcinoma, however, remains less certain.…”

mentioning

confidence: 99%

“…In contrast, squamous cell carcinoma, not otherwise specified, is generally believed to be less likely HPV-related, 12,18,32 often does not have associated vulvar intraepithelial neoplasia or has simplex type, differentiated, non-HPV associated vulvar intraepithelial neoplasia, 12,30,35,45 and occurs in older women in their seventh to ninth decades. The reported difference in average, 23,30,44 or median 35,46 patient age between HPV-positive and -negative invasive squamous vulvar carcinomas ranges from 12 to more than 20 years in some studies. However, our set of 116 cases demonstrated an average age of patients with HPV-positive invasive squamous vulvar carcinoma that was only slightly lower (65 ± 16 years) than that of patients with HPV-negative invasive squamous vulvar carcinoma (70±15 years), and this difference was not statistically significant.…”

mentioning

confidence: 99%

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Distribution of human papillomavirus genotypes in invasive squamous carcinoma of the vulva

et al. 2008

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Many studies have established a critical role for human papillomavirus (HPV) in the development of anogenital squamous neoplasia. In this report, we show the distribution of 37 high-and low-risk HPV types in 116 cases of invasive squamous vulvar carcinoma. Sections from paraffin-embedded tissue blocks were dissected as necessary to select areas of invasive carcinoma. Clinical and pathologic variables were analyzed using t-tests, univariate odds ratios and logistic regression analysis. Seventy percent of cases were HPV-positive, with an average patient age of 65 years (n ¼ 81). HPV-negative cases (n ¼ 35) had a higher average age (70 years), but these populations were not statistically different (t ¼ 1.65, P ¼ 0.10). HPV16 was most common (n ¼ 65). Other HPV types were less frequent (HPV33, n ¼ 12; HPV45, n ¼ 4; HPV52 and 6, each n ¼ 3; HPV18, 53 and 62, each n ¼ 2). Additional HPV types were identified only once. Multiple infections typically included HPV16 (12/14 cases). Tumors showing low-risk HPV (11 cases) and low-risk HPV only (three cases) were uncommon. Regional node metastasis was documented in 29 of 116 tumors, and 8/9 HPV-positive nodes contained HPV types identical to the primary tumor. Of tumor types, warty carcinoma was most strongly associated with highrisk HPV (odds ratio 4.34, 95% confidence interval 1.32-18.45), particularly high-risk HPVs other than type 16 (odds ratio 9.04, 95% confidence interval 1.60-54.00). Tumors associated with any HPV type (odds ratio 0.40, 95% confidence interval 0.14-1.17), any high-risk type (odds ratio 0.36, 95% confidence interval 0.12-1.08), or type 16 alone (odds ratio 0.34, 95% confidence interval 0.11-1.12) were less likely to metastasize than HPV-negative tumors. Correcting for possible confounding variables, such as patient age and tumor histology, linear logistic regression analysis confirmed this association (high-risk HPV odds ratio 0.28, 95% confidence interval 0.09-0.89).

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Human Papillomavirus Infection and p16INK4a Protein Expression in Vulvar Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma

Cited by 43 publications

References 17 publications

Human Papillomavirus Infections and Vulvar Disease Development

Human Papillomavirus Infections and Vulvar Disease Development

HPV related VIN: Highly proliferative and diminished responsiveness to extracellular signals

Distribution of human papillomavirus genotypes in invasive squamous carcinoma of the vulva

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