History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

Annotated and edited transcript of a Witness Seminar held on 13 May 2008. Introduction by Professor Anne M Johnson, Division of Population Health and Institute for Global Health, UCL. First published by the Wellcome Trust Centre for the History of Medicine at UCL, 2009. ©The Trustee of the Wellcome Trust, London, 2009. All volumes are freely available online at: www.history.qmul.ac.uk/research/modbiomed/wellcome_witnesses/Annotated and edited transcript of a Witness Seminar held on 13 May 2008. Introduction by Professor Anne M Johnson, Division of Population Health and Institute for Global Health, UCLAnnotated and edited transcript of a Witness Seminar held on 13 May 2008. Introduction by Professor Anne M Johnson, Division of Population Health and Institute for Global Health, UCLAnnotated and edited transcript of a Witness Seminar held on 13 May 2008. Introduction by Professor Anne M Johnson, Division of Population Health and Institute for Global Health, UCLAnnotated and edited transcript of a Witness Seminar held on 13 May 2008. Introduction by Professor Anne M Johnson, Division of Population Health and Institute for Global Health, UCLThe history, largely untold, of the development of cervical cytology, of effective screening and its ultimate success in reducing cervical cancer incidence and mortality, and the viral cause of cervical cancer, took place within a complex social background of changing attitudes to women’s health and sexual behaviour. Dr Georges Papanicolaou’s screening method (the Pap smear) started in the US in the 1940s. It was widely used in the UK a decade later and a national programme of cervical screening was established in 1988. The association of sexually transmitted human papillomavirus (HPV) with cervical cancer was less readily accepted. The detection of HPV16 in cervical cancers at the end of the 1970s was aided by the explosion of laboratory, clinical, and public health research on new screening tests and procedures. These made possible the successful development, licensing and use of preventive vaccines against the major oncogenic HPV types, HPV16 and -18. The Witness Seminar was attended by virologists, cytologists, gynaecologists, epidemiologists and others and addressed the development of cytology as a pathological discipline. They discussed who became cytologists and screeners; the evolution of screening in the UK and elsewhere; the impacts of colposcopy and of HPV; and the discovery of virus-like particles and the development of the HPV vaccine. The meeting was chaired by Professor Glenn McCluggage and the topic was suggested by Professor David Jenkins. Contributors include: Professor Valerie Beral, Professor Saveria Campo, Professor Jocelyn Chamberlain, Professor Dulcie Coleman, Dr Lionel Crawford, Professor Heather Cubie, Professor Jack Cuzick, Dr Ian Duncan, Dr Winifred Gray, Dr Amanda Herbert, Professor David Jenkins, Dr Elizabeth Mackenzie, Dr Joan Macnab, Professor Anthony Miller, Professor Julian Peto, Dr Catherine Pike, Professor Peter Sasieni, Professor Albert Singer, Dr John Smith, Professor Margaret Stanley, Mrs Marilyn Symonds, Dr Anne Szarewski, Professor Leslie Walker, Mr Patrick Walker, Dr Margaret Wolfendale and Professor Ciaran Woodman. Two appendices with reminiscences from Professor Leopold Koss, Dr Arthur Spriggs and Dr O A N (Nasseem) Husain complete the volume. Reynolds L A, Tansey E M. (eds) (2009) History of cervical cancer and the role of human papillomavirus, 1960–2000, Wellcome Witnesses to Twentieth Century Medicine, vol. 38. London: The Wellcome Trust Centre for the History of Medicine at UCL. ISBN 978 085484 1233The Wellcome Trust Centre for the History of MedicineMat UCL is funded by the Wellcome Trust, which is a registered charity, no. 210183

High Interleukin-6, Low Cd4+ and Cd8+ T-lymphocytes Expressions as Risk Factors of Cervical Carsinoma Infected by Human Papilloma Virus Type-52

In Indonesia cervical carcinoma is the most common cancer in women and one of the leading cause of mortality. High risk human papillomavirus (HPV) is the major risk factor of cervical cancer. This study aims to know the role of IL-6, CD4+ and CD8+ T-lymphocyte for the risk of cervical carcinoma infected by HPV52. This study was a case control study, specimens of cervical carcinoma patients infected by HPV type-52 as the case group and HPV type-16 or 18 as the control group. HPV genotyping used SPF10 primer and type specific E7 primer by LiPA. Immunohistochemistry method was used to know expression of IL-6, CD4+ and CD8+ T lymphocyte. Pearson's c2 test was applied with statistical significance was set at the 2-sided 0.05 level. The odds ratios (OR) were calculated for the risk, with 95% confidence intervals on SPSS 16.0 for windows. PCR examination was performed in 185 paraffin-embedded tissue. The risk of high IL-6 expression in cervical carcinoma infected by HPV type-52 was statistically significant 6-fold higher compare with cervical carcinoma infected by HPV type 16 (OR = 6.00 ; CI 95% = 1.13-31.99; p = 0.03; p < 0.05) and HPV type 18 (OR = 6.00 ; CI 95% = 1.13-31.99; p = 0.03; p < 0.05). The risk of low CD4+ T lymphocyte expression in cervical carcinoma infected by HPV type 52 was statistically significant 6-fold higher and 7.43-fold higher respectively compare with cervical carcinoma infected by HPV type 16 (OR = 6.00 ; CI 95% = 1.003-35.91; p = 0.04; p < 0.05) and HPV type 18 (OR = 7.43 ; CI 95% = 1.23-45.01; p = 0.02; p < 0.05). The risk of low CD8+ T lymphocyte expression in cervical carcinoma infected by HPV type 52 was statistically significant 13.5-fold higher and 11-fold higher respectively compare with cervical carcinoma infected by HPV type 16 (OR = 13.50 ; CI 95% = 1.42-128.26; p = 0.01; p < 0.05) and HPV type 18 (OR = 11.00 ; CI 95% = 1.16-103.94; p = 0.02; p < 0.05). No significance different between cases and controls group in mean-age, parity and sexual activity (p > 0.05). In conclusion, this study found that high IL-6 expression, low CD4+ and CD8+ T lymphocyte expression were the risk factors of cervical carcinoma infected by HPV type 52

Oncogenic processes

No abstract available

Differential expression of microRNAs in bovine papillomavirus type 1 transformed equine cells

Bovine papillomavirus (BPV) types 1 and 2 play an important role in the pathogenesis of equine sarcoids (ES), the most common cutaneous tumour affecting horses. MicroRNAs (miRNAs), small non-coding RNAs that regulate essential biological and cellular processes, have been found dysregulated in a wide range of tumours. The aim of this study was to identify miRNAs associated with ES. Differential expression of miRNAs was assessed in control equine fibroblasts (EqPalFs) and EqPalFs transformed with the BPV-1 genome (S6-2 cells). Using a commercially available miRNA microarray, 492 mature miRNAs were interrogated. In total, 206 mature miRNAs were differentially expressed in EqPalFs compared with S6-2 cells. Aberrant expression of these miRNAs in S6-2 cells can be attributed to the presence of BPV-1 genomes. Furthermore, we confirm the presence of 124 miRNAs previously computationally predicted in the horse. Our data supports the involvement of miRNAs in the pathogenesis of ES

Triage of women with equivocal or low-grade cervical cytology results: a meta-analysis of the HPV test positivity rate

Introduction Methods Results Discussion Conclusion Abstract Consistent evidence underlines the utility of human papillomavirus (HPV) DNA testing in the management of women with equivocal cervical cytological abnormalities, but not in case of low-grade lesions. We performed a meta-analysis including studies where the high-risk probe of the Hybrid Capture-II is used to triage these two cytological categories. The triage test-positivity rate reflects the colposcopy referral workload.Data were pooled on the HPV test positivity rate in women with atypical squamous cells of undetermined significance (ASCUS/ASC-US) or low-grade squamous intraepithelial lesions (LSIL), derived from different cytological classification systems. The meta-analysis was restricted to studies, published between 1991 and 2007. A random-effect model was applied for meta-analytical pooling and the influence of covariates on the HPV positivity rate was analyzed by meta-regression. The variation by age was assessed within individual studies since age strata were not defined uniformly. On an average, 43% (95% CI: 40-46%) of women with ASCUS/ASC-US were high-risk HPV positive (range 23-74%). In women with LSIL, the pooled positivity rate was 76% (95% CI: 71-81%; range 55-89%). In spite of considerable inter-study heterogeneity, the difference in HPV positivity between the two triage groups was large and highly significant: 32% (95% CI: 27-38%). HPV rates dropped tremendously as age and cutoffs of test positivity increased. Other factors (cytological classification system, country, continent, collection method and year of publication) had no statistically significant impact, except in LSIL triage where HPV positivity was significantly lower in European compared to American studies. Women with LSIL, especially younger women, have high HPV positivity rates suggesting limited utility of reflex HPV triaging these cases. Research is needed to identify more specific methods to triage women with low-grade squamous cervical lesions

Human papillomavirus-associated increase in p16INK4A expression in penile lichen sclerosus and squamous cell carcinoma

Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2·5, which does not permit commercial exploitationBackground: Human papillomaviruses (HPVs) are sexually transmitted human carcinogens that may play a role in the oncogenesis of penile cancer. Objectives: To investigate the role of HPV infection and expression of the tumour suppressor protein p16INK4A in the pathogenesis of penile cancer. Methods: By means of polymerase chain reaction amplification and reverse hybridization line probe assay to detect HPV infection, and immunohistochemical staining for p16INK4A and Ki67, we analysed 26 penile squamous cell carcinomas (SCCs) and 20 independent penile lichen sclerosus (LS) lesions from 46 patients. Results: HPV DNA was found in 54% of penile SCCs and 33% of penile LS cases in single and multiple infections. High-risk HPV 16 was the predominant HPV type detected. No relationship between Ki67 expression and HPV infection was observed. Strong immunostaining for p16INK4A correlated with HPV 16/18 infection in both penile LS and penile SCC. In our penile SCC series the cancer margins were also associated with penile LS in 13 of 26 lesions, and HPV was detected in seven of the 13 SCC cases associated with LS and in six of the 11 SCC lesions not involving LS. Conclusions: Our study shows a high prevalence of HPV 16 and p16INK4A expression in penile lesions, consistent with an active role for HPV in interfering with the retinoblastoma pathway. High-risk HPV infection could be involved in the tumorigenic process in 50% of penile cancers, and the use of prophylactic HPV vaccines has the potential to prevent these cancers.Peer reviewedFinal Published versio

Evaluation of the management of Hr-HPV+/PapTest- women. Results at 1-year recall

With cervical cancer screening the choice of 1-year as a period of follow-up in positive high-risk HPV women without cytological lesions is still under discussion. We evaluated the management of these women and the role of HPV genotyping test. We did a cervical cancer screening study of women aged 35-64 with primary high-risk HPV test. Women positive for high-risk HPV with negative cytology were followed-up after 1 year. In this study we selected women with high-risk HPV+/PapTest- resulted high-risk HPV+ at recall and performed the PapTest and HPV genotyping test. The detection rate of squamous high grade (CIN2+) relative to the total screened cohort was 2.1‰, and it was 0.2‰ at the 1-year recall. The colposcopy performed in women referred at the 1-year recall accounted for 48.8% of the total (baseline + 1-year recall), and 84.3% of these women had no cytological lesions. The most frequent hr-HPV genotype detected was HPV16 and 66.7% of co-infections were due to HPV16 and HPV18. 54.5% of women presented a persistent infection at 1-year recall with the same HPV subtype, 50% of persistent infections was due to HPV16 and 16.7% of these were determined to be CIN2+ histological lesions. Our data show that it may be useful to extend the period of follow-up for women hr-HPV+/PapTest- so as to reduce the number of unnecessary colposcopies due to the transitory infections and that the genotyping test could help to identify the persistent infections in which HPV16 is involved

Liquid-based cytology - new possibilities in the diagnosis of cervical lesions [Tekuća citologija - nove mogućnosti u dijagnostici lezija vrata maternice]

Liquid-based cytology (LBC) enables the use of supplementary methods in the diagnosis and prognosis of cervical lesions. The aim of this study was to analyze the correlation between p16INK4a immunoexpression in ThinPrep cervical cytologic samples and human papillomavirus (HPV) detection by polymerase chain reaction (PCR) from the same sample. LBC-ThinPrep (Cytyc, USA) cervical cytology samples, prepared and stained by Papanicolaou method, were analyzed using modified Bethesda cytologic classification named »Zagreb 2002«. A second ThinPrep slide, prepared from the same sample, was immunostained for p16INK4a using CINtec p16INK4a Cytology Kit (DakoCytomation, Denmark). Increased expression of the high-risk (HR) HPV E6 and E7 oncogenes results in a highly specific increase in p16 protein expression and overexpression of p16INK4a acts as a potential biomarker for cervical cancer progression from premalignant lesions. Brown nuclear and/or cytoplasmic staining of abnormal cells was considered a positive result. Residual material was used for 13 HR HPV-DNA detection by the PCR based AMPLICOR HPV test (Roche Molecular Systems). A total of 120 ThinPrep Pap tests with the following cytologic diagnoses: 17 within normal limits, 17 atypical squamous cell (ASC) (7 ASC of undetermined significance /ASCUS/ and 10 ASC of high-grade squamous intraepithelial lesions cannot be excluded /ASC-H/), 26 low-grade squamous intraepithelial lesions (LSIL) corresponding cervical intraepithelial neoplasia (CIN) I, 57 high-grade SIL (HSIL) i.e. 24 CIN II and 33 CIN III and 3 squamous cell carcinoma (SCC) were included in the study. All CIN III (n=33) and SCC (n=3) specimens expressed p16INK4a immunoreactivity, whereas the HR HPV test was positive in 97% (32/33) of CIN III and 100% (3/3) of SCC specimens. The p16INK4a biomarker was positive in 87.5% (21/24) of CIN II and 69% (18/26) of CIN I, while the HR HPV was positive in 75% (18/24) of CIN II and 50% (13/26) of CIN I. In ASCUS cytology, p16INK4a and HR HPV showed the same rate of positivity (28.5%; 2/7). Expression of p16INK4a was detected in all cytologic (10/10) ASC-H lesions, in contrast to HR HPV detected in only 20% (2/10) of ASC-H cases. These data suggest the p16INK4a evaluation in ThinPrep cervical samples to be significantly associated with HR HPV testing by PCR in the same sample for the diagnosis of HSIL lesions and cervical carcinomas. A prospective study with longer follow up may clarify the predictive values in the management of LSIL and ASC diagnosis

MicroRNA-551b expression profile in low and high-grade cervical intraepithelial neoplasia

OBJECTIVE: To evaluate the expression of microRNA (miR)-551b in patients with low and high grade cervical intraepithelial neoplasia (CIN) and to find an association with high-risk Human Papillomavirus (HR-HPV) infection-related prognostic biomarkers. PATIENTS AND METHODS: The expression level of miR-551b was determined in 50 paraffin-embedded cervical specimens (10 normal squamous epithelium, 18 condylomas, 8 CIN1, and 14 CIN2-3) using quantitative Real-time polymerase chain reaction (qRT-PCR). χ2-test compared miR-551b expression in different diagnosis groups. An Ordered Logistic Regression and a Probit correlation were made to correlate miR-551b expression levels with the cervical tissue histological findings. The immunohistochemical distribution of p16 and Ki-67 according to histopathological findings was also assessed. RESULTS: The distribution of the miR-551b expression profile was significantly lower in CIN1-3 samples compared to other histological diagnosis groups (condyloma and negative). The expression levels were inversely correlated to the cervical pathological grade, from negative to CIN2-3. A 1% increase in miR-551b expression level produced an increase of 19% to the probability of a minor histological grade diagnosis in a range from negative to CIN2-3 and an increase of 13% to the probability of a negative histological grade diagnosis. Among the cases with miR-551b expression < 0.02 (considered as cut-off value) a significant statistical correlation was found between p16 and Ki-67 expression and the diagnosis of CIN2-3. CONCLUSIONS: O ur d ata s howed a s ignificant inverse correlation between miR-551b expression and the histological grading of the lesions, suggesting a tumor suppressive function in the different stages of cervical dysplasia

Vaccines in Current Culture: The HPV Vaccine Controversy

The use of vaccinations has drastically decreased mortality and morbidity rates related to infectious disease and has become an intrinsic part of modern health care. However, the fear of risks related to vaccines has been partially responsible for the decisions of many parents to delay or avoid vaccinating their children. The human papilloma virus (HPV) vaccine specifically is one of the most controversial vaccines in current culture due to reports of new onset or exacerbation of autoimmune diseases, infertility, and even death following its administration. This review synthesizes information regarding the relevance and safety of the HPV vaccine, as well as its efficacy in preventing cervical cancer and precancerous lesions. There appears to be a need for thorough education regarding concepts of immunity, infection, and vaccine function for those hesitant about receiving vaccines. Particularly regarding the HPV vaccine, practitioners should be familiar with common reasons for vaccine refusal and be prepared to respond with accurate information