High-grade Abnormalities Research Articles

Choropleth Mapping of Cervical Cancer Screening in South Africa Using Healthcare Facility-level Data from the National Laboratory Network.

BackgroundIn South Africa, cervical cancer remains among the most common cancers and a leading cause of cancer death. Co-infection with HIV increases the risk of developing cervical pre-cancer and cancer. We analysed National Health Laboratory Service cervical cytology data to investigate geographic variations of Pap smear coverage, quality, and high grade lesions.MethodsFacility-level data were extracted from the NHLS for April 2013–March 2014. We present results and choropleth maps detailing coverage, adequacy and high-grade Pap smear cytology abnormalities defined as Pap smears suspicious for invasive carcinoma, high-grade squamous intraepithelial lesions (HSIL) or atypical squamous cells: cannot exclude HSIL (ASC-H).Results4,562 facilities submitted 791,067 cytology slides. The interquartile range (IQR) for Pap smear coverage among HIV-infected women was 26–41%; similar to coverage in women aged 30 and older (IQR: 26–42%). 6/52 districts had adequacy rates above the national standard (70%) and 2/52 districts had adequacy rates below 35%. We observed marked variation in Pap smear abnormalities across the country, with the proportion of high-grade cytology abnormalities ≥0.3% in 17/52 districts.ConclusionUsing district-level choropleth maps, we are able to display variations in Pap smear coverage, quality, and results across South Africa. This approach may be used to improve resource allocation, achieving better equity in cervical cancer prevention.

Cervical cancer prevention in Australia: Planning for the future.

The high rate of coverage that has been achieved to date by the Australian government's Human Papillomavirus (HPV) Vaccination Program has already led to profound reductions in the prevalence of biopsy-confirmed, high-grade abnormalities and of vaccine-preventable HPV types in Australia. Declines in the prevalence of vaccine preventable HPV have occurred not only in vaccinated women but also in unvaccinated women, suggesting a herd-immunity affect. These declines were anticipated on the basis of modelling and were the major drivers for the changes proposed to the Australian National Cervical Screening Program. The federal and state-based Australian governments established a "Renewal Steering Committee," which conducted a literature search and a review of the available evidence to assess its applicability and quality. Together with this information the committee also used modeling to determine the optimal screening pathway for cervical cancer screening and constructed a plan for implementing the changes that will be required to transition from the currently successful screening program to the renewed program. The committee recommended that Australia move to a screening program based on testing every 5 years using an HPV test with partial genotyping with reflex liquid-based cytology (LBC) triage for HPV-vaccinated and unvaccinated women ages 25 to 69 years, and an additional exit test for women up to age 74 years. Primary HPV testing and reflex LBC will be funded by government. Symptomatic women outside the screening program will also be able to access government funded testing. The new screening program, to be rolled out in 2017, will also provide a cost-effective framework for an evaluation of the national HPV vaccination program, enabling ongoing monitoring of HPV genotypes and cervical lesions in screened women.

Abstract 18669: A Simple Noninvasive Score for Predicting Permanent Pacemaker Implantation Following Transcatheter Aortic Valve Replacement

Introduction: Cardiac conduction abnormalities requiring permanent pacemaker (PPM) are well-recognized complications of TAVR. However, a clinical prediction tool for assessing the risk of post-TAVR PPM placement is not available. Hypothesis: The purpose of this study was to create a novel clinical prediction tool for assessing the risk of PPM following TAVR. Methods: A total of 114 patients who underwent TAVR using the balloon-expandable Edwards SAPIEN valve at the University of Iowa Hospitals and Clinics were identified. We then excluded patients with a pre-existing PPM, who required conversion to an open/salvage procedure, and those without available CT data. Binomial logistic multivariate regression was performed to construct a scoring system. Results: A total of 84 patients were included in the study and PPM was placed in 9 patients (10.7%). From the binomial logistic regression analysis using RBBB, valve size to Sinus of Valsalva diameter ratio, and sex as predictors, pre-existing RBBB (odds ratio [OR]: 6.5, 95% confidence ratio [CI]: 1.1-37.1, p=0.035) and the ratio of valve size to diameter of Sinus of Valsalva (OR: 1.2, 95% CI: 1.03-1.3, p=0.012) were identified as significant predictors of PPM post-TAVR. We created a novel clinical prediction tool for PPM post-TAVR with patients being designated with score 0 if they had no RBBB and valve size to diameter of sinus of Valsalva ratio < 81.4 (optimal cut-off based on ROC curve) and score 1 if they had RBBB, or valve size to diameter of sinus of Valsalva ratio ≥ 81.4, or both (OR: 12.6, 95% CI: 1.5-106.8, p=0.009; sensitivity, 0.90; specificity, 0.59). Conclusions: Our clinical prediction score for PPM following TAVR expands upon the available literature for pre-procedural risk-stratification. The components of the score have biological plausibility, as pre-existing conduction system disease and relative valve prosthesis oversizing would be expected to confer a higher risk of post-procedural AV block. Implantation of PPM prior to TAVR in patients at risk for high-grade AV conduction abnormalities, based on this simple risk score, could have important implications for morbidity/mortality, length of stay, and cost. Moving forward, this prediction score requires validation in multicenter cohorts.

Cytologic findings in stratified mucin-producing intraepithelial lesion of the cervix: A report of 34 cases.

Stratified mucin-producing intraepithelial lesion (SMILE) is an uncommon variant of in situ carcinoma of the cervix. This study aimed to identify the cytologic features of SMILE since these have not been well documented previously. The study group comprised 34 consecutive cases of SMILE encountered at a single institution in which a corresponding Papanicolaou smear, taken up to 12 months before histologic diagnosis, was available for review. The presence of associated cervical neoplastic lesions including cervical intraepithelial neoplasia (CIN), adenocarcinoma in situ (AIS), and invasive carcinoma was recorded. The linear extent and distribution of the SMILEs was also noted. Most Pap smears had been reported to show possible or definite high-grade CIN although 3 cases reported the presence of a high-grade glandular abnormality. No case had a prospective cytologic diagnosis of SMILE. Histology revealed concurrent CIN and/or AIS in all cases, and 1 specimen (3%) showed invasive adenocarcinoma. Following smear review, 23 of the 31 cases that included endocervical material showed recurrent cytologic features that appeared consistent with SMILE. These included three dimensional cell clusters with nuclear stratification and crowding, mild nuclear atypia, cytoplasmic vacuoles, mitotic figures, and apoptosis. SMILE is almost always associated with additional HPV-related neoplastic lesions although only one patient (3%) had invasive carcinoma, a lower rate than recorded in other studies. Consistent cytologic features associated with SMILE were identified but these were relatively subtle. However, increased awareness of these features may permit prospective diagnosis and this could influence patient management.

Age Specific Cytological Abnormalities in Women Screened for Cervical Cancer in the Emirate of Abu Dhabi.

Cervical cancer is the second most common cancer in women worldwide, with about 500,000 new cases and 270,000 deaths each year. Globally, it is estimated that over one million women currently have cervical cancer, most of whom have not been diagnosed, or have no access to treatment that could cure them or prolong their lives. In the United Arab Emirates (UAE) cervical cancer is the third most common cancer in women. A population-based cross-sectional retrospective survey of cervical smear abnormalities was conducted in the Emirate of Abu Dhabi, UAE, from January 2013 to December 2013 by collecting consecutive liquid-based cytology samples from the Department of Pathology at the SKMC Hospital in Abu Dhabi city. The total number of women screened for cervical cancer for the year 2013 at SKMC was 4,593, with 225 (4.89%) abnormal smears. The majority of the abnormal smear results were atypical squamous cells of undetermined significance (ASCUS) 114 (2.48%). This study showed 60% increase in the rate of abnormal cervical smears in the UAE over the last 10 years. In this study the highest incidence of high grade abnormalities were seen in women above the age of 61 years (1.73%), this might be due to the fact that this group of women missed the chance of screening of cervical cancer earlier in their lives or could be explained by the well-known second peak of HPV infection seen in many prevalence studies. We conclude that the rate of abnormal cervical smear in the screened Abu Dhabi women is not different from the rate in developed countries. A notable increase in both low and high grade abnormalities has occurred within the last decade.

Does Cervical Screening in Young Women Aged 20-25 Years Lead to Unnecessary and Harmful Interventions?

Cervical human papillomavirus (HPV) infection among young women (20-25 years of age) is common and normally transient. There are growing concerns that referral to a colposcopy clinic may lead to unnecessary treatment with an increased risk of obstetric complications. Therefore, the purpose of this study was to determine the level of intervention for cervical abnormalities in this age group of the Northern Ireland population. A review of all serial new patients under 25 years of age, who were referred to colposcopy clinics in Northern Ireland between January 1, 2009 to June 30, 2009 formed the basis of this study. During the study period, a total of 4,767 women under 25 years of age were screened. Two-hundred-and- thirty-four (4.9%) cases were referred to the colposcopy clinics. The cervical cytology results were: high-grade abnormality in 35%, and low-grade abnormality in 31% of these cases. One-hundred-and-seventy-eight (76%) of the referred women received at least one treatment. One-hundred-and-twenty-one of 234 (51.5%) women underwent an excisional treatment with histology showing the presence of high-grade abnormalities (CIN2-3) in 52%, CIN1 in 28%, and Koilocytosis or normal tissue in 20% of this sub-group of cases. Screening women under the age of 25 years cause unnecessary referral for colposcopy. This may also result in considerable anxiety and psychosexual morbidity. It leads to an over-treatment with a potential of negative impact on the future pregnancy outcomes (including pre-term delivery, low birth weight, and pre-term premature rupture of membranes).

Impact of opportunistic testing in a systematic cervical cancer screening program: a nationwide registry study.

BackgroundSystematic screening for precancerous cervical lesions has resulted in decreased incidence and mortality of cervical cancer. However, even in systematic screening programs, many women are still tested opportunistically. This study aimed to determine the spread of opportunistic testing in a systematic cervical cancer screening program, the impact of opportunistic testing in terms of detecting cytological abnormalities and examine the associations between sociodemography and opportunistic testing.MethodsA nationwide registry study was undertaken including women aged 23–49 years (n = 807,624) with a cervical cytology between 2010 and 2013. The women were categorised into: 1) screening after invitation; 2) routine opportunistic testing, if they were either tested more than 9 months after the latest invitation or between 2.5 years and 3 years after the latest cervical cytology and 3) sporadic opportunistic testing, if they were tested less than 2.5 years after the latest cervical cytology. Cytological diagnoses of women in each of the categories were identified and prevalence proportion differences (PPD) and 95 % confidence intervals (CIs) were used to explore group differences. Associations between sociodemography and undergoing opportunistic testing were established by multinomial logistic regression.ResultsIn total, 28.8 % of the cervical cytologies were due to either routine (20.7 %) or sporadic (8.1 %) opportunistic testing. Among women undergoing routine opportunistic testing, a larger proportion had high-grade squamous intraepithelial abnormalities than invited women (PPD: 0.6 %, 95 % CI: 0.03–1.17 %). A similar proportion of cytological abnormalities among women undergoing sporadic opportunistic testing and invited women was found. In multivariate analyses, younger age, being single or a social welfare recipient and residence region (North Denmark) were especially associated with opportunistic testing (routine or sporadic).ConclusionsOne fourth of cervical cytologies in this study were collected opportunistically. Compared to invited women, women undergoing routine opportunistic testing were more likely to be diagnosed with abnormal cytologies. Hence, routine opportunistic testing might serve as an important supplement to the systematic screening program by covering non-participating women who may otherwise be tested with a delay or not tested at all. Among women tested more often than recommended (sporadic testing), no benefits in terms of detecting more cytological abnormalities were identified.

PWE-052 Low uptake of cervical screening in immunosuppressed patients with inflammatory bowel disease at a district general hospital

Introduction ECCO guidelines strongly recommend regular cervical screening for women with inflammatory bowel disease (IBD), especially if treated with immunomodulators. We wanted to investigate if our immunosuppressed female IBD patients were being screened in accordance with the NHS Cervical Screening Programme (CSP) and identify if they were at increased risk of cytological abnormalities. Method We searched our database for patients commenced on azathioprine, mercaptopurine, methotrexate, infliximab or adalimumab from June 2005 to October 2013. We excluded patients who were on these drugs for less than one year, were not of cervical screening age (25–64) or had had a hysterectomy. Information provided from general practitioners, local cytology department and Open Exeter (CSP database) were used to identify women participating in CSP and if they showed any abnormalities. Results 153 patients met the criteria to participate in the CSP. 115 (75%) were up-to-date compared to a national participation rate of 78.3%. 25 (16%) had participated in the CSP but were not up-to-date at the time of report. 9 (6%) had not participated in the CSP and 4 (3%) actively declined participation. Date from the 2013 National CSP demonstrates that 5.3% of those screened displayed low grade abnormalities and 1.2% had high grade abnormalities. Of our 153 patients 13 (8.5%) had cytological abnormalities. 5 (3%) patients had abnormalities before immunosuppressive therapy with 1 (0.7%) patient showing high grade abnormality (moderate dyskaryosis with CIN1 confirmed) which subsequently remained negative whilst on immunosuppression. Our results identified 7 (4.6%) patients with low grade abnormal cytology results after commencing immunomodulators (3; borderline nuclear changes in squamous cells, 2; mild dyskaryosis, 2; low grade dyskaryosis and high risk HPV detected). Only 1 (0.7%) patient had high grade dyskaryosis during immunosuppression but their follow up cytology was negative. Conclusion IBD patients are at increased risk of cytology abnormalities which is concerning since our CSP participation is below the national average. However data from our unit suggests that commencing immunosuppression therapy did not increase that risk any further. This data underlines that IBD specialists need to educate and encourage patients to participate in the CSP programme. Disclosure of interest K. Wade Conflict with: Abbvie sponsorship to attend ECCO, H. Johnson: None Declared, H. Dewhurst: None Declared, S. Weaver Conflict with: been on advisory board for MSD and Abbvie but not for past 12 months, S. McLaughlin Conflict with: Abbvie sponsorship to attend DDW, Abbvie Advisory board, Ferring sponsorship to attend ECCO.

Evaluation of p16INK4a immunostaining for the detection of high-grade changes in cervical cytology

Since its introduction in Australia in 2007, the human papillomavirus (HPV) vaccine has led to a markedly lower prevalence of vaccine targeted HPV genotype infections as well as HPV disease including genital warts and histologically confirmed high-grade (HG) cervical abnormalities. To increase the ability to identify abnormal cells in lower prevalence, adjunct markers can be incorporated to improve the sensitivity and specificity of cytology test. One such marker is p16(p16), which is detectable in cells expressing the E7 oncogene encoded by high-risk HPVs (HR-HPV). In this study, the sensitivity and specificity of p16 immunostaining in detection of underlying HG lesions was evaluated in a cohort of 454 women undergoing surgical treatment for biopsy proven cervical dysplasia. Overall, p16 positive cells were detected in 321 (71%) of cytology preparations evaluated. Comparison of p16 staining on cytological preparations to histology diagnosis available on 212 patients, showed 26 (54%), 41 (78%) and 80 (90%) of cytology preparations to be p16 positive in women with CIN1, CIN2 and CIN3, respectively (p < 0.005). HPV16 and 18 were the most prevalent genotypes in HG lesions and were highly correlated with p16 staining. p16 staining provides an additional marker which can assist in better detecting underlying HG lesion in cytology smears with low disease prevalence.

Vacuna frente al virus del papiloma humano. Eficacia y seguridad

Human papillomavirus (HPV) related disease remains a major cause of morbidity and mortality worldwide. Prophylactic vaccines have been recognized as the most effective intervention to control for HPV-related diseases. This article reviews the major phaseii/iii trials of the bivalent (HPVs16/18), quadrivalent (HPVs6/11/16/18), and the recently approved 9-valent vaccine (HPVs6/11/16/18/31/33/45/52/58).Large trials have been conducted showing the safety, immunogenicity and high efficacy of the bivalent and quadrivalent vaccines in the prevention of pre-invasive lesions and infection, especially when administered at young ages before exposure to HPV. Trials of the 9-valent vaccine have also demonstrated the safety, immunogenicity and efficacy of the vaccine in the prevention of infection and disease associated with the vaccine types, and its potential to substantially increase the overall prevention of HPV-related diseases.Post-licensure country reports have shown the recent and early impact of these vaccines at population level after the implementation of established HPV vaccination programs, including decreases in the prevalence of vaccine HPV types, the incidence of genital warts, and the incidence of high-grade cervical abnormalities. If widely implemented, current HPV vaccines may drastically reduce the incidence of cervical cancer and other HPV-related cancers and diseases.

Type-specific human papillomavirus infections and Pap test findings in Inuit and non-Inuit women in Nunavut, Canada.

To determine the prevalence and distribution of type-specific human papillomavirus (HPV) infections and their association with cytological outcomes in women living in the Canadian territory of Nunavut. Surveillance of type-specific HPV infection was conducted. Cervical specimens of all Inuit, First Nations and non-Aboriginal women in Nunavut who presented for a Pap test in any clinical setting between January 2008 and March 2009 were tested for HPV infection. The association between high-grade cervical lesions and HPV type was also examined. HPV results were available for 4,043 individual women (13 to 77 years). Of those with known ethnicity (N=4,033), 89.2% were Inuit, 0.4% were First Nations and 10.4% were non-Aboriginal. First Nations women were included in all analyses except those making comparisons by ethnicity, due to the small number of individuals in this group. Overall, 29.9% of women were found to be infected with HPV (any type) and 19.9% with any high-risk HPV (type 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 or 59). Most often, women were infected with HPV 16 (6.4%) followed by HPV 31 (3.1%). There were no statistically significant differences between Inuit and non-Aboriginal (reference group) women 20 years of age and older regarding the prevalence of any HPV (odds ratios (OR): 1.19, 95% confidence intervals (CI): 0.92-1.54), high-risk HPV (OR: 1.06, 95% CI: 0.78-1.44) or HPV 16 and 18 (OR: 0.81, 95% CI: 0.51-1.27). HPV 31 was the only type that was significantly more frequent among Inuit than non-Aboriginal women (OR: 3.95, 95% CI: 1.24-12.54). There was no difference in the overall occurrence of cervical abnormalities between non-Aboriginal and Inuit women (p-value = 0.17). HPV 16 was strongly associated with cervical dysplasia, being present in 50.9% of specimens with a high-grade lesion. HPV is a significant public health issue in the territory of Nunavut. The findings presented in this article are similar to those in other studies among Inuit women, with prevalence of HPV being higher than in studies conducted among non-Inuit women in other regions of Canada. These results provide a baseline of HPV prevalence that precedes the introduction of the Nunavut HPV Immunization Program in 2010 and will allow for future evaluation. The high prevalence of HPV infection among women living in Nunavut can be reduced through immunization and associated high-grade cervical abnormalities mitigated by regular cervical screening.

Efficacy of human papillomavirus 16 and 18 (HPV-16/18) AS04-adjuvanted vaccine against cervical infection and precancer in young women: final event-driven analysis of the randomized, double-blind PATRICIA trial.

We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n = 9,319; control, n = 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n = 5,822; control, n = 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (-1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.gov under registration no. NCT001226810.).

Recurrence of high-grade cervical abnormalities following conservative management of cervical intraepithelial neoplasia grade 2

Conservative management of cervical intraepithelial neoplasia (CIN) grade 2 in women younger than 25 years may reduce overtreatment. However, long-term efficacy remains uncertain. This retrospective cohort study aimed to determine the rate of recurrence of high-grade abnormalities among young women with a history of CIN 2 that spontaneously regressed within 2 years and compare this with the rate of high-grade abnormality in similar women with an initial diagnosis of CIN 1. We identified all women aged younger than 25 years who were diagnosed with CIN 1 or CIN 2 between January 2005 and August 2009 within 2 colposcopy units. Follow-up data from the National Cervical Screening Programme were obtained to identify those women who developed recurrent high-grade lesions before October 2012. Comparisons were made using Cox proportional hazards regression. A total of 683 women were included: 106 with CIN 2 that spontaneously regressed, 299 with treated CIN 2, and 278 with conservatively managed CIN 1. Median follow-up was 4 years. There was no significant difference in the risk of development of high-grade abnormalities after 2 years between the spontaneously regressing CIN 2 and CIN 1 groups (P = .83). Women with treated CIN 2 had a significantly lower risk of recurrence than women with untreated CIN 2 (P = .01). CIN 2 that has spontaneously regressed appears to behave as a low-grade lesion. This study contributes to the growing body of evidence that careful observation of CIN 2 is an efficacious and appropriate initial management option for women aged younger than 25 years at diagnosis.

27. Adrenal oncocytic pheochromocytoma with probable malignant potential: a unique case report

Oncocytic pheochromocytomas are exceedingly rare tumours. To date, there are 3 reported cases in the literature. We present a case of a 68-year-old man with moderate hypertension and an incidental adrenal mass on radiological investigations. The patient had normal levels of 24-hour urine cortisol, metanephrines and non-metanephrines. The tumour was subsequently excised. Macroscopic examination revealed a light brown, 45×35×35mm, 36g tumour of the adrenal gland. Histologically, the tumour cells showed oncocytic appearance with high-grade nuclear abnormalities and foci of extension into the peri-adrenal fat. Immunohistochemical studies revealed that the tumour was positive for chromogranin, S-100 and p53 and negative for inhibin, HMB-45 and EMA. The malignant potential of pheochromocytoma is known to be difficult to predict. Two scoring systems were used; PASS (phaeochromocytoma of adrenal scaled score) by Thompson and a Japanese scoring system by Kimura and colleagues. Both scoring systems predicted the tumour had a malignant potential. However, no recurrence was detected after 5 years of follow-up. In summary, this is the first reported case of oncocytic pheochromocytoma with probable malignant potential.

Increased cycling cell numbers and stem cell associated proteins as potential biomarkers for high grade human papillomavirus+ve pre-neoplastic cervical disease.

High risk (oncogenic) human papillomavirus (HPV) infection causes cervical cancer. Infections are common but most clear naturally. Persistent infection can progress to cancer. Pre-neoplastic disease (cervical intraepithelial neoplasia/CIN) is classified by histology (CIN1-3) according to severity. Cervical abnormalities are screened for by cytology and/or detection of high risk HPV but both methods are imperfect for prediction of which women need treatment. There is a need to understand the host virus interactions that lead to different disease outcomes and to develop biomarker tests for accurate triage of infected women. As cancer is increasingly presumed to develop from proliferative, tumour initiating, cancer stem cells (CSCs), and as other oncogenic viruses induce stem cell associated gene expression, we evaluated whether presence of mRNA (detected by qRT-PCR) or proteins (detected by flow cytometry and antibody based proteomic microarray) from stem cell associated genes and/or increased cell proliferation (detected by flow cytometry) could be detected in well-characterised, routinely collected cervical samples from high risk HPV+ve women. Both cytology and histology results were available for most samples with moderate to high grade abnormality. We found that stem cell associated proteins including human chorionic gonadotropin, the oncogene TP63 and the transcription factor SOX2 were upregulated in samples from women with CIN3 and that the stem cell related, cell surface, protein podocalyxin was detectable on cells in samples from a subset of women with CIN3. SOX2, TP63 and human gonadotrophin mRNAs were upregulated in high grade disease. Immunohistochemistry showed that SOX2 and TP63 proteins clearly delineated tumour cells in invasive squamous cervical cancer. Samples from women with CIN3 showed increased proliferating cells. We believe that these markers may be of use to develop triage tests for women with high grade cervical abnormality to distinguish those who may progress to cancer from those who may be treated more conservatively.

Human papillomavirus 16/18 seroprevalence in unvaccinated women over 30years with normal cytology and with high grade cervical abnormalities in Australia: results from an observational study.

BackgroundAustralia commenced human papillomavirus (HPV) vaccination in 2007, with a two-year catch-up to the age of 26; catch-up cohorts are thus now entering their thirties. Plans for monitoring vaccine impact involve pre- and post-vaccination assessment of cervical HPV DNA in the general population and in high grade abnormalities. Although HPV serology is less sensitive than DNA genotyping, it assesses lifetime exposure and may be easier to measure in the general population. However, benchmark pre-vaccination seroprevalence of vaccine-included types in unvaccinated women with high grade abnormalities has not previously been reported.MethodsWe assessed seroprevalence for HPV16/18 from a population-based sample of 3,729 women with normal cytology and 971 women with confirmed high grade abnormalities (CIN2/3), aged 30–64 years, unvaccinated, and recruited in New South Wales in 2006–2010. We examined the variation in HPV16/18 seropositivity by age and in relation to a range of reproductive and behavioural characteristics in the subgroup of normal cytology women with no recent history of high grade cervical disease.ResultsThe HPV 16, 18 and combined seroprevalence was 19%, 7% and 24% among women with normal cytology, and 39%, 13% and 44% among women with CIN2/3, respectively. For both groups, HPV16/18 seroprevalence was highest at age 30–39 years and decreased with age. In multivariable analysis for women with normal cytology, HPV16 and HPV18 seropositivity were each associated with the number of lifetime sexual partners (p-trend <0.001 and 0.052, respectively) and for HPV16 this was also associated with age (p-trend <0.001) and prior diagnosis of Chlamydia (adjusted OR 1.89, 95% CI 1.27-2.80).ConclusionsThe findings of this study inform pre-vaccination estimates of HPV seropositivity in women with normal cytology and women with high grade abnormalities. Almost a quarter of unvaccinated women aged over 30 years with normal cytology, and more than 40% of those with CIN2/3, had seroconverted to HPV 16 or 18. These findings provide a potential additional benchmark for assessing the effects of HPV vaccination.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-014-0676-z) contains supplementary material, which is available to authorized users.

HPV vaccines in Brazil and the world

HPV vaccines in Brazil and the world

Reduction of low- and high-grade cervical abnormalities associated with high uptake of the HPV bivalent vaccine in Scotland.

Background:In Scotland, a national HPV immunisation programme began in 2008 for 12- to 13-year olds, with a catch-up campaign from 2008 to 2011 for those under the age of 18. To monitor the impact of HPV immunisation on cervical disease at the population level, a programme of national surveillance was established.Methods:We analysed colposcopy data from a cohort of women born between 1988 and 1992 who entered the Scottish Cervical Screening Programme (SCSP) and were aged 20–21 in 2008–2012.Results:By linking datasets from the SCSP and colposcopy services, we observed a significant reduction in diagnoses of cervical intraepithelial neoplasia 1 (CIN 1; RR 0.71, 95% CI 0.58 to 0.87; P=0.0008), CIN 2 (RR 0.5, 95% CI 0.4 to 0.63; P<0.0001) and CIN 3 (RR 0.45, 95% CI 0.35 to 0.58; P<0.0001) for women who received three doses of vaccine compared with unvaccinated women.Conclusions:To our knowledge, this is one of the first studies to show a reduction of low- and high-grade CIN associated with high uptake of the HPV bivalent vaccine at the population level. These data are very encouraging for countries that have achieved high HPV vaccine uptake.

Fluorescence In Situ Hybridization Testing for the Diagnosis of High-Grade Cervical Abnormalities

We examined the diagnostic performance of fluorescence in situ hybridization (FISH) tests on cervical cytology for precancerous lesions or cancer on cervical histology. A search was conducted in MEDLINE, the Cochrane Central Register of Controlled Trials, and Scopus through September 3, 2013. Eleven studies examined FISH tests for telomerase RNA component gene (TERC), myelocytomatosis oncogene (MYC), or human papillomavirus (HPV) type 16 or 18 in samples exhibiting atypical squamous cells of unknown significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). None examined HPV-positive, cytologically normal samples. We extracted data on the sensitivity and specificity for high-grade cervical intraepithelial neoplasia (CIN 2+ or CIN 3+). Fluorescence in situ hybridization test probes and thresholds varied across studies. Included populations were convenience samples. Only 1 study testing for TERC specified HPV status. In meta-analysis, FISH for TERC in LSIL (9 studies, 1,082 cases) had a summary sensitivity of 0.76 (95% confidence interval = 0.63-0.85) and a summary specificity of 0.78 (95% confidence interval = 0.57-0.91) for CIN 2+. Fluorescence in situ hybridization for TERC in ASC-US (3 studies, 839 cases) showed sensitivities ranging from 0.75 to 1.00 and specificities from 0.87 to 0.93 for CIN 2+. For CIN 3+, sensitivity and specificity appeared similar, although a small number of studies preclude firm conclusions. For FISH tests for HPV, we found only few studies with small sample sizes. The evidence on FISH testing is limited given the small number of studies for each cytology subgroup and the lack of studies in well-defined screening contexts stratifying participants by HPV status.

HPV genotype prevalence in Australian women undergoing routine cervical screening by cytology status prior to implementation of an HPV vaccination program

BackgroundData on the prevalence of cervical HPV genotypes in Australia by age and by grade of cytological abnormality are sparse. ObjectiveMeasure prevalence of HPV genotypes among 2620 Australian women by age and cytology status. Study designWomen presenting for routine Pap smear screening were recruited from diverse regions, including a significant sample of Indigenous women. DNA extracts prepared from Thinprep specimens were HPV genotyped by Roche LINEAR ARRAY HPV. ResultsHPV prevalence and genotype distribution were stratified by age (mean 32.6y) and Pap smear result (cytology normal in 86.7%). Overall HPV prevalence was 38.7% with high-risk HPV prevalence of 26.5%. Prevalence of HPV (66.3% in women<21y to 15.3% in women>40y), multiple HPV infection (45.5% in <21y to 5.8% in >40y) and vaccine-targeted genotypes (HPV 6/11/16/18) (34.1% in <21y to 2.4% in >40y) declined significantly with age. The six most common genotypes were: HPV 16 (8.3%), 51 (5.1%), 53 (4.7%), 62 (4.3%), 89 (3.9%) and 52 (3.8%). HR-HPV prevalence increased from 21.1% in women with normal cytology to 80.9% in those with cytologically predicted high-grade abnormalities (HGAs) (p<0.001). The most common genotypes in women with HGAs were HPV 16 (51.1%), 18 (14.9%), 52 (12.8%), 31 (10.6%), and 33 (10.6%): all HR-types. ConclusionPre-vaccination cross-sectional prevalence of HR-HPV infection was high in this sample of Australian women attending for screening. HPV 16 was the commonest high-risk type detected at all ages and cytological grades.