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Rijswijk, Netherlands

Doorbar J.,UK National Institute for Medical Research | Quint W.,DDL Diagnostic Laboratory | Banks L.,International Center for Genetic Engineering and Biotechnology | Bravo I.G.,Institute Catala dOncologia Catalan Institute of Oncology ICO | And 3 more authors.
Vaccine | Year: 2012

Human papillomaviruses (HPVs) comprise a diverse group, and have different epithelial tropisms and life-cycle strategies. Many HPVs are classified as low-risk, as they are only very rarely associated with neoplasia or cancer in the general population. These HPVs typically cause inapparent/inconspicuous infections, or benign papillomas, which can persist for months or years, but which are eventually resolved by the host's immune system. Low-risk HPVs are difficult to manage in immunosuppressed people and in individuals with genetic predispositions, and can give rise to papillomatosis, and in rare instances, to cancer. The high-risk HPV types are, by contrast, a cause of several important human cancers, including almost all cases of cervical cancer, a large proportion of other anogenital cancers and a growing number of head and neck tumours. The high-risk HPV types constitute a subset of the genus Alphapapillomavirus that are prevalent in the general population, and in most individuals cause only inconspicuous oral and genital lesions. Cancer progression is associated with persistent high-risk HPV infection and with deregulated viral gene expression, which leads to excessive cell proliferation, deficient DNA repair, and the accumulation of genetic damage in the infected cell. Although their life-cycle organisation is broadly similar to that of the low-risk HPV types, the two groups differ significantly in their capacity to drive cell cycle entry and cell proliferation in the basal/parabasal cell layers. This is thought to be linked, at least in part, to different abilities of the high- and low-risk E6 proteins to modulate the activity of p53 and PDZ-domain proteins, and the differential ability of the E7 proteins to target the several different members of the retinoblastoma protein family. © 2012 Published by Elsevier Ltd. All rights reserved.

Pirog E.C.,Cornell University | Quint K.D.,DDL Diagnostic Laboratory | Yantiss R.K.,Cornell University
American Journal of Surgical Pathology | Year: 2010

The classification of anal intraepithelial neoplasia (AIN) in mucosal biopsies is subject to considerable interobserver variability. Previous studies have shown that Ki-67 and p16/CDKN2A immunostains aid detection of dysplasia in biopsy samples from the uterine cervix. The aim of this study was to determine whether Ki-67 and p16/CDKN2A immunolabeling enhanced diagnostic accuracy in the assessment of anal mucosal biopsies from patients with suspected human papillomavirus (HPV) infection. The study consisted of 75 cases that were originally interpreted to represent normal anal transitional zone (n=15), fibroepithelial polyp (n=10), condyloma accuminatum (n=10), low-grade AIN (AIN1, n=20), and high-grade AIN (n=20), including 10 cases each of AIN2 and AIN3. The histologic features of all cases were re-reviewed and categorized based upon consensus agreement, which resulted in reclassification of 16 cases. Thus, the final study group consisted of 17 samples of normal anal transition zone, 14 fibroepithelial polyps, 6 condylomata accuminata, and 38 cases of AIN (11 AIN1, 16 AIN2, and 11 AIN3). Each case was tested for the presence of HPV DNA by a SPF10 polymerase chain reaction and LiPA 25 genotyping assay and immunostained for Ki-67 and p16/CDKN2A. A positive Ki-67 result was defined as the presence of a cluster of at least 2 strongly stained epithelial nuclei in the upper two-thirds of the epithelial thickness. A positive result for p16/CDKN2A was defined as diffuse moderate-to-strong cytoplasmic and nuclear staining. None of the anal transition zone samples or fibroepithelial polyps showed Ki-67 or p16/CDKN2A staining. All condylomata and samples of AIN contained HPV DNA and showed positive Ki-67 labeling. All cases of high-grade AIN showed positive p16/CDKN2A staining. We conclude that Ki-67 labeling detects anal HPV-related changes with a high degree of sensitivity and specificity, whereas increased p16/CDKN2A staining is strongly associated with high-grade squamous neoplasia. These results indicate that a combination of these markers may aid interpretation of anal mucosal biopsy samples. © 2010 by Lippincott Williams & Wilkins.

Pimenta J.M.,Glaxosmithkline | Galindo C.,Glaxosmithkline | Jenkins D.,DDL Diagnostic Laboratory | Taylor S.M.,Glaxosmithkline
BMC Cancer | Year: 2013

Background: Data on the current burden of adenocarcinoma (ADC) and histology-specific human papillomavirus (HPV) type distribution are relevant to predict the future impact of prophylactic HPV vaccines.Methods: We estimate the proportion of ADC in invasive cervical cancer, the global number of cases of cervical ADC in 2015, the effect of cervical screening on ADC, the number of ADC cases attributable to high-risk HPV types -16, -18, -45, -31 and -33, and the potential impact of HPV vaccination using a variety of data sources including: GLOBOCAN 2008, Cancer Incidence in Five Continents (CI5) Volume IX, cervical screening data from the World Health Organization/Institut Català d'Oncologia Information Centre on HPV and cervical cancer, and published literature.Results: ADC represents 9.4% of all ICC although its contribution varies greatly by country and region. The global crude incidence rate of cervical ADC in 2015 is estimated at 1.6 cases per 100,000 women, and the projected worldwide incidence of ADC in 2015 is 56,805 new cases. Current detection rates for HPV DNA in cervical ADC tend to range around 80-85%; the lower HPV detection rates in cervical ADC versus squamous cell carcinoma may be due to technical artefacts or to misdiagnosis of endometrial carcinoma as cervical ADC. Published data indicate that the five most common HPV types found in cervical ADC are HPV-16 (41.6%), -18 (38.7%), -45 (7.0%), -31 (2.2%) and -33 (2.1%), together comprising 92% of all HPV positive cases. Future projections using 2015 data, assuming 100% vaccine coverage and a true HPV causal relation of 100%, suggest that vaccines providing protection against HPV-16/18 may theoretically prevent 79% of new HPV-related ADC cases (44,702 cases annually) and vaccines additionally providing cross-protection against HPV-31/33/45 may prevent 89% of new HPV-related ADC cases (50,769 cases annually).Conclusions: It is predicted that the currently available HPV vaccines will be highly effective in preventing HPV-related cervical ADC. © 2013 Pimenta et al.; licensee BioMed Central Ltd.

Del Pino M.,VU University Amsterdam | Bleeker M.C.G.,VU University Amsterdam | Quint W.G.,DDL Diagnostic Laboratory | Snijders P.J.F.,VU University Amsterdam | And 2 more authors.
Modern Pathology | Year: 2012

The role of human papillomavirus (HPV) infections in the development of verrucous carcinoma, a well-differentiated variant of squamous cell carcinoma with difficult differential diagnosis, is controversial in the literature. In this study, we analysed verrucous carcinoma from different origins for the presence and activity of a broad spectrum of HPV types, and carefully reviewed the histopathological features. A random series of 27 formalin-fixed, paraffin-embedded specimens of verrucous carcinoma was taken, representing the head and neck region (n6), anogenital area (n16) and extragenital skin region (n5). After review of the histological slides, all samples were subjected to different polymerase chain reaction-based HPV detection techniques, together detecting a total of 83 HPV types, including both mucosal and cutaneous types. Histological revision was carefully performed. Lesions with keratinised papillae, blunt stromal invaginations and minimal cytological atypia were considered verrucous carcinoma. Condylomatous lesions with viral changes were defined as giant condyloma. Verrucous lesions that did not meet those criteria were classified as verrucous hyperplasia. Tumours with stromal infiltration were considered as invasive squamous cell carcinoma. Histological revision revealed that 13 out of 27 cases were verrucous carcinoma (one showing a double infection with HPV 35 and 45), 5 invasive squamous cell carcinomas, 5 verrucous hyperplasia (one with a double infection with HPV 4 and 8), 1 pseudoepitheliomatous hyperplasia and 3 giant condylomas. All three giant condylomas were low-risk HPV positive (HPV 6 and 11) and showed active mRNA transcription. None of the HPV-positive samples tested positive for diffuse p16 INK4A staining. In conclusion, our results do not support a causal role of HPV in the development of verrucous carcinoma. Testing for LR-HPV, particularly HPV 6 and 11, may help in the differential diagnosis of lesions suspicious of verrucous carcinoma as those testing positive for LR-HPV most likely represent giant condylomas. © 2012 USCAP, Inc. All rights reserved.

Van Baars R.,DDL Diagnostic Laboratory | Bosgraaf R.P.,Radboud University Nijmegen | Ter Harmsel B.W.A.,Reinier de Graaf Groep | Melchers W.J.G.,Radboud University Nijmegen | And 2 more authors.
Journal of Clinical Microbiology | Year: 2012

Primary screening using high-risk human papillomavirus (hrHPV) detection has been suggested as a way of improving cervical cancer prevention. Women currently not attending screening (nonresponders) are more likely to participate when given the opportunity of self-sampling for hrHPV testing. The Evalyn Brush is a new cervicovaginal self-sampling device, developed specifically to meet women's demands, which is user-friendly and easy to use. The aims of this study were to investigate agreement of hrHPV detection by two PCR methods between the Evalyn Brush and physician-obtained samples and to study women's acceptance of this self-sampling device. Each of 134 women visiting the gynecology outpatient clinic collected a self-obtained sample (self-sample) and completed a questionnaire. The brush was stored dry. After self-sampling, a trained physician obtained a conventional cervical cytology specimen in ThinPrep medium. HrHPV detection was performed using the SPF10-DEIA-LiPA25 and GP5+/6+-LQ-test. The overall agreement for hrHPV detection using SPF 10-DEIA-LiPA25 between the self-sample and the physician- taken sample was 85.8% (kappa value, 0.715; 95% confidence interval [CI], 0.597 to 0.843; P = 1.000). The overall agreement for hrHPV detection using GP5+/6+-LQ between the self-sample and the physician-taken sample was 86.6% (kappa value, 0.725; 95% CI, 0.607 to 0.843; P = 0.815). Ninety-eight percent of the women rated their experience as good to excellent. Moreover, 95% of women preferred self-sampling to physician sampling. Self-sampling using the dry Evalyn Brush system is as good as a physician-taken sample for hrHPV detection and is highly acceptable to women. To validate this self-sampling device for clinical use, a large screening cohort should be studied. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

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