Clonal History of Papillomavirus-Induced Dysplasia in the Female Lower Genital Tract

Vinokurova, Svetlana; Wentzensen, Nicolas; Einenkel, Jens; Klaes, Ruediger; Ziegert, C.; Melsheimer, Peter; Sartor, Heike; Horn, Lars Christian; Höckel, Michael; Doeberitz, Magnus von Knebel

doi:10.1093/jnci/dji428

Cited by 103 publications

(72 citation statements)

References 31 publications

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“…A significantly higher number of cases with a single HR type had severe dyskaryosis compared with other cytology grades and no such correlation with disease progression was found in cases with multiple HR types. Others have recognised the clonal expansion of a single integrated HR type and subsequent cervical neoplasia development (Vinokurova et al, 2005) and our data would support this observation and suggests that there is little, if no, synergy between multiple HPV types in terms of neoplastic effect (Fife et al, 2001). However, the overall HPV type-specific distribution in cases with multiple HR types is not a direct reflection of that observed in cases with a single HR type, and of interest was the equivalent representation of HPV 16 (Figure 1).…”

Section: Discussionsupporting

confidence: 81%

“…In contrast, clonal expansion of a single integrated HR type and cervical neoplasia development has been reported (Vinokurova et al, 2005). Social deprivation has been associated with cervical cancer incidence, but other co-factors such as age, smoking, education and reduced participation in screening also require consideration (de Sanjosé et al, 1997;Krieger et al, 1999;Parikh et al, 2003).…”

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confidence: 99%

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Human papillomavirus prevalence in women attending routine cervical screening in South Wales, UK: a cross-sectional study

et al. 2008

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In this cross-sectional population-based study we determine human papillomavirus (HPV) prevalence in South Wales to provide comprehensive baseline data for future assessment of the impact of prophylactic HPV vaccination and to help inform future screening strategies. Liquid-based cytology samples from women attending routine cervical screening were collected (n ¼ 10 000: mean age 38 years, 93% cytology negative, and 64.8% from the 50% least deprived LSOA according to social deprivation score (SDS)). High-Risk (HR) and Low-Risk HPV screening was performed using HPV PCR-EIA with genotyping of HR positives and data correlated with age, SDS and cytology. Overall HPV prevalence was 13.5% (9.3% age standardised) and the most frequent HR types were HPV 16, 31, 18 and 58. In HR HPV-positive cases 42.4% had a single HR type and they were predominant in women with severe cytological abnormalities. Here, 66% of all HR HPV cases were in women aged 30 years of age or less and SDS had no significant effect on HPV status. HPV prevalence increased significantly with degree of dyskarosis from 7% in cytology negative samples to 80% in samples with severe cytological abnormalities (P-value o0.0001). Overall, 46% of HR HPV cases were positive for the two HR types targeted by the prophylactic vaccines (HPV 16 and HPV 18). The data presented represents the largest type-specific investigation of HPV prevalence in an unselected UK population.

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Section: Discussionsupporting

confidence: 81%

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confidence: 99%

Human papillomavirus prevalence in women attending routine cervical screening in South Wales, UK: a cross-sectional study

et al. 2008

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“…1,[4][5][6][7] Previous studies regarding HPV types in VAIN and vaginal cancer or comparisons of HPV types between incident vaginal and previous cervical lesions were limited by small sample sizes and inconsistent conclusions. 3,4,[8][9][10][11][12][13][14][15] Smith et al 8 published a systemic review of 725 abstracts, in which the HPV detection rates among 166 cases of VAIN2/3 and 66 cases of VAIN1 were 92.6% and 98.5%, respectively. Another systemic review of 22 U.S. studies found HPV16/18 to be the predominant type in VAIN3 (n ¼ 97, 65.1%).…”

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confidence: 99%

Human papillomavirus in vaginal intraepithelial neoplasia

Chao

Chen

Hsueh

et al. 2011

Intl Journal of Cancer

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There are limited data on the prevalence and distribution of human papillomavirus (HPV) genotypes in vaginal intraepithelial neoplasia (VAIN). We sought to clarify this issue in a series of 450 VAIN cases with a confirmed diagnosis between 1990 and 2006. HPV genotyping was performed using paraffin-embedded specimens and polymerase chain reaction (PCR)-based methods. Multiple HPV types were validated by E6 type-specific PCR and direct sequencing. The HPV genotypes of the vaginal and cervical neoplasms were compared for those with incident VAIN and a history of previous/concomitant cervical neoplasms. Ki-67 was performed for supporting diagnosis of VAIN. Of these 450 VAIN cases (median age, 59 years; range, 19-93), two with missing paraffin blocks and 54 with poor DNA quality were excluded. HPV was detected in 273/394 (69.3%) VAIN, and multiple infections were found in 17.9% of HPV-positive samples. The leading types were HPV16 (35.5%), HPV58 (9.9%), HPV52 (9.9%), HPV39 (8.4%), HPV33 (7.3%) and HPV53 (7.0%). Among the 156 cases with a history of previous cervical neoplasia, 29.0% had concordant HPV genotypes, while synchronous VAIN samples (n 5 49) were more likely to harbor concordant genotypes (58.7%) with the concomitant cervical neoplasm (p 5 0.0003). Whether those HPV types in the incident VAIN lesions had existed in the vaginal epithelium at the time of the previous cervical neoplasia or a new acquisition needs to be clarified in prospective follow-up studies.The natural history of invasive vaginal cancer and preinvasive lesions (vaginal intraepithelial neoplasia [VAIN]) has been minimally investigated compared to invasive cervical cancer and cervical intraepithelial neoplasia (CIN). 1,2 Many previous research efforts have indicated that invasive vaginal cancer and VAIN share common risk factors with cervical neoplasms, including the number of lifetime sexual partners, smoking and infection with human papillomavirus (HPV). 1,3,4 Previous radiation exposure, a previous history of cervical neoplasms, diethylstilbestrol exposure and an immune-compromised state were also associated with an increased risk of vaginal cancer and VAIN. 1,[4][5][6][7] Previous studies regarding HPV types in VAIN and vaginal cancer or comparisons of HPV types between incident vaginal and previous cervical lesions were limited by small sample sizes and inconsistent conclusions. 3,4,[8][9][10][11][12][13][14][15] Smith et al. 8 published a systemic review of 725 abstracts, in which the HPV detection rates among 166 cases of VAIN2/3 and 66 cases of VAIN1 were 92.6% and 98.5%, respectively. Another systemic review of 22 U.S. studies found HPV16/18 to be the predominant type in VAIN3 (n ¼ 97, 65.1%). 10 A meta-analysis of 93 studies 9 including 298 cases of VAIN from four continents noted that HPV testing was positive in 100% of VAIN1 and 90.1% of VAIN2/3. In VAIN2/3 (n ¼ 191), the most common HPV types were HPV16 (57.6%), HPV 18 (6.9%) and HPV 58 (5.9%). 9 With the advent of HPV vaccines, cervical neoplasms of the HPV types included in th...

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“…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.…”

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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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Clonal History of Papillomavirus-Induced Dysplasia in the Female Lower Genital Tract

Abstract: These data indicate that high-grade dysplastic lesions in the female lower genital tract may emerge primarily as monoclonal lesions from a transformed cell population derived from the uterine cervix.

Cited by 103 publications

References 31 publications

Human papillomavirus prevalence in women attending routine cervical screening in South Wales, UK: a cross-sectional study

Human papillomavirus prevalence in women attending routine cervical screening in South Wales, UK: a cross-sectional study

Human papillomavirus in vaginal intraepithelial neoplasia

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

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