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Objective: To determine whether human papillomavirus (HPV) immunisation has affected the prevalence of HPV genotypes and colposcopic features of cervical intraepithelial neoplasia (CIN) in young women referred for colposcopy.Design: A two-centre observational study including vaccinated and unvaccinated women.Setting: Colposcopy clinics serving two health regions in Scotland, UK.Population: A total of 361 women aged 20-25 years attending colposcopy following an abnormal cervical cytology result at routine cervical screening.Methods: Cervical samples were obtained from women for HPV DNA genotyping and mRNA E6/E7 expression of HPV 16, 18, 31, 33, and 45. Demographic data, cytology, and histology results and colposcopic features were recorded. Chi-square analysis was conducted to identify associations between vaccine status, HPV genotypes, and colposcopic features.Main Outcome Measures: Colposcopic features, HPV genotypes, mRNA expression, and cervical histology.Results: The prevalence of HPV 16 was significantly lower in the vaccinated group (8.6%) compared with the unvaccinated group (46.7%) (P = 0.001). The number of cases of CIN2+ was significantly lower in women who had been vaccinated (P = 0.006). The HPV vaccine did not have a statistically significant effect on commonly recognised colposcopic features, but there was a slight reduction in the positive predictive value (PPV) of colposcopy for CIN2+, from 74% (unvaccinated) to 66.7% (vaccinated).Conclusions: In this group of young women with abnormal cytology referred to colposcopy, HPV vaccination via a catch-up programme reduced the prevalence of CIN2+ and HPV 16 infection. The reduced PPV of colposcopy for the detection of CIN2+ in women who have been vaccinated is at the lower acceptable level of the UK national cervical screening programme guidelines.Tweetable Abstract: Reduction of hrHPV positivity and CIN in immunised women consistent with lower PPV of colposcopy for CIN2+. [ABSTRACT FROM AUTHOR]

Objective: To compare psychosocial outcomes (follow-up related worries and satisfaction with follow-up related information and support) over 30 months of two alternative management policies for women with low-grade abnormal cervical cytology.Methods: Women aged 20-59 years with low-grade cytological abnormalities detected in the National Health Service Cervical Screening Programme were randomised to cytological surveillance or initial colposcopy. A total of 3399 women who completed psychosocial questionnaires at recruitment were invited to complete questionnaires at 12, 18, 24 and 30 months. Linear mixed models were used to investigate differences between arms in the two psychosocial outcomes. Each outcome had a maximum score of 100, and higher scores represented higher psychosocial morbidity.Results: On average, over 30 months, women randomised to colposcopy scored 2.5 points (95%CI -3.6 to -1.3) lower for follow-up related worries than women randomised to cytological surveillance. Women in the colposcopy arm also scored significantly lower for follow-up related satisfaction with information and support (-2.4; -3.3 to -1.4) over 30 months. For both outcomes, the average difference between arms was greatest at 12th- and 18th-month time points. These differences remained when the analysis was stratified by post-school education.Conclusions: Women with low-grade cytology, irrespective of their management, have substantial initial psychosocial morbidity that reduces over time. Implementation of newer screening strategies, which include surveillance, such as primary HPV screening, need to consider the information and support provided to women. © 2016 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective Worldwide, each year, large numbers of women are referred for colposcopy following low-grade abnormal cervical cytology. Many have no visible abnormality on examination. The risk of cervical intra-epithelial neoplasia grade 2/3 ( CIN2/3) in these women is low. It is unknown whether, for women, a normal colposcopy resolves the anxiety which often follows the receipt of an abnormal cytology result. We investigated the prevalence of adverse psychological outcomes over 30 months following a normal colposcopy. Methods This cohort study was nested within the UK TOMBOLA randomized controlled trial. Women aged 20-59 years, with recent low-grade cytology, who had a satisfactory colposcopy examination and normal transformation zone, completed the Hospital Anxiety and Depression Scale ( HADS) and Process Outcome Specific Measure ( POSM) at recruitment and during follow-up (12, 18, 24 and 30 months post-recruitment). Outcomes included percentages reporting significant anxiety ( HADS anxiety subscale score ≥11), significant depression ( HADS depression subscale score ≥8) or worries about the result of the next cytology test, cervical cancer, having sex, future fertility and general health at each time point (point prevalence) and during follow-up (cumulative prevalence). Results The study included 727 women. All psychological measures (except depression) had high prevalence at recruitment, falling substantially by 12 months. During follow-up, the cumulative prevalence of significant anxiety was 27% and significant depression was 21%. The most frequently reported worry was that the next cytology test would be abnormal (cumulative prevalence of 71%; point prevalence of ≥50% at 12 and 18 months). The cumulative prevalence values of worries about cervical cancer, having sex and future fertility were 33%, 20% and 16%, respectively. Conclusions For some women who have low-grade cytology, a normal colposcopy does not appear to provide psychological reassurance. [ABSTRACT FROM AUTHOR]

L. Sharp, S. Cotton, A. Thornton, N. Gray, D. Whynes, L. Smart, N. Waugh, I. Duncan, M. Cruickshank and J. Little, on behalf of the TOMBOLA Group Which women default from follow-up cervical cytology tests? A cohort study within the TOMBOLA trial Objective: To identify factors associated with default from follow-up cervical cytology tests. Methods: A cohort study was conducted involving 2166 women, aged 20-59, with recent low-grade cervical cytology taken within the NHS Cervical Screening Programmes in Scotland and England, and managed by 6-monthly cytology in primary care. For the first (6-month) and second (12-month) surveillance cytology tests separately, women were categorized as 'on-time attendees' (attended ≤6 months of test being due), 'late attendees' (attended greater than 6 months after test was due) or 'non-attendees' (failed to attend). Multivariate odds ratios (ORs) were computed for factors associated with late and non-attendance. Results: For the first surveillance test, risk of non-attendance was significantly higher in younger women, those without post-secondary education, and non-users of prescribed contraception. Factors significantly associated with late attendance for the first test were the same as for non-attendance, plus current smoking and having children. The most important predictor of non-attendance for the second surveillance test was late attendance for the first test (OR = 9.65; 95% CI, 6.60-16.62). Non-attendance for the second test was also significantly higher among women who were younger, smokers and had negative cytology on the first surveillance test. Late attendance for the second surveillance test was higher in women who were younger, smokers, had children and attended late for the first test. Conclusions: Women at highest risk of default from follow-up cytology tend to be young, smoke, lack post-secondary education, and have defaulted from a previous surveillance appointment. Tackling default will require development of targeted strategies to encourage attendance and research to better understand the reasons underpinning default. [ABSTRACT FROM AUTHOR]

Background: The debate continues regarding the best management for women with low-grade abnormal cervical cytology attending colposcopy. We compared psychosocial outcomes of alternative management policies in these women.Methods: In all, 989 women, aged 20-59 years, with low-grade abnormal cytology, were randomised to immediate large loop excision (LLETZ) or two to four targeted punch biopsies taken immediately with recall for LLETZ if these showed cervical intra-epithelial neoplasia 2/3. At 6 weeks after the last procedure, women completed the hospital anxiety and depression scale (HADS) and the impact of event scale (IES). At 12, 18, 24 and 30 months post recruitment, women completed the HADS and process outcome specific measure (POSM). Prevalence of significant depression (≥ 8), significant anxiety (≥ 11) and distress (≥ 9) and median POSM scores were compared between arms. Multivariate odds ratios (ORs) for immediate LLETZ vs biopsy and recall were computed.Results: Over the entire follow-up, there was no significant difference between arms in cumulative prevalence or risk of significant depression (OR=0.78, 95% CI 0.52-1.17) or significant anxiety (OR=0.83, 95% CI 0.57-1.19). At 6 weeks post procedure, distress did not differ significantly between arms. At later time points, 8-11% had significant depression and 14-16% had significant anxiety but with no differences between arms. The POSM scores did not differ between the arms.Conclusions: There is no difference in long- or short-term psychosocial outcomes of immediate LLETZ and punch biopsies with selective recall. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Cotton S, Sharp L, Little J, Cruickshank M, Seth R, Smart L, Duncan I, Harrild K, Neal K, Waugh N, The TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears) Group. The role of human papillomavirus testing in the management of women with low-grade abnormalities: multicentre randomised controlled trial. BJOG 2010; DOI: 10.1111/j.1471-0528.2010.02519.x. Objective To assess the value of a single human papillomavirus (HPV) test in making decisions on management of women with cervical cytology showing borderline nuclear abnormality (BNA) or mild dyskaryosis. In particular, to determine whether information on high-risk (hr) HPV status would be valuable in the choice between (1) cytological surveillance versus immediate referral to colposcopy, and (2) at colposcopy, between biopsy and recall versus immediate large loop excision of the transformation zone (LLETZ). Design Multicentre individually randomised controlled trial, nested within the NHS Cervical Screening Programmes, investigating the value of HPV testing by testing for interactions between HPV status and (1) cytological surveillance versus colposcopy, and (2) biopsy and recall versus immediate LLETZ. Setting Grampian, Tayside and Nottingham. Population Women ( n = 4439), aged 20–59 years, with a cytology test showing borderline nuclear abnormalities or mild dyskaryosis during October 1999 to October 2002. Methods High-risk HPV status was determined at recruitment using the polymerase chain reaction assay with the GP5+/6+ general primer system. The results of this HPV testing were not disclosed to either the participating women or to those involved in their management. Women were randomised to either (1) 6-monthly cytological screening in primary care or (2) referral for colposcopy. Human papillomavirus status was used to stratify both randomisations. All women were followed for 3 years, concluding with an invitation to an exit appointment at which colposcopic examination was undertaken. In addition, in women who were randomised to initial colposcopy and underwent colposcopy, the association between hrHPV status and presence of cervical intraepithelial neoplasia (CIN) grade 2 or more severe disease (henceforth CIN2 or worse) was examined. Main outcome measures Sensitivity, specificity, positive and negative predictive values of the HPV test for predicting CIN2 or worse and the implications for the choice of management between cytological surveillance and immediate referral for colposcopy. Results There were no significant interactions between management and HPV status. Hence, in women with mild dyskaryosis or BNA who are HPV positive, there is no advantage of (1) immediate colposcopy over cytological surveillance ( P = 0.76) or (2) immediate LLETZ over biopsy and recall ( P = 0.27). The sensitivity of HPV testing for detection of CIN2 or worse was 75.2% (95% CI 68.8–81.0%) among women with mild dyskaryosis and 69.9% (95% CI 61.7–77.3%) among those with BNA. Specificity was higher in those with BNA (71.3%; 95% CI 68.5–74.1%) than in those with mild dyskaryosis (46.9%; 95% CI 42.2–51.6%). Sensitivity decreased with increasing age whereas specificity increased. The negative predictive value was high, particularly among women with BNA (94.5%; 95% CI 92.9–96.0%). Across all ages, 22% of women who had CIN2 or worse were HPV negative. Conversely, 40% of those who were HPV positive did not have CIN. HPV was a much more reliable predictor in women aged over 40 years. Conclusions We conclude that in younger women with low-grade cytological abnormalities, a single HPV test would not be useful in determining who should be referred for colposcopy or the most effective management at colposcopy. In women over 40, a negative HPV test could be used to rule out further investigation. [ABSTRACT FROM AUTHOR]

Annually in the UK around 250 000 cervical smears show low-grade abnormalities. Alternative management policies following a low-grade smear are cytological surveillance or referral for colposcopy. Their effectiveness and cost-effectiveness, and the potential for human papillomavirus (HPV) testing to triage women to either management, has been debated. Trial of management of borderline and other low-grade abnormal smears (TOMBOLA) (a large RCT) addresses these uncertainties, considering clinical, psychosocial and economic outcomes. 4439 women aged 20–59, resident in Grampian, Tayside or Nottingham with a low-grade smear were randomised to cytological surveillance (six-monthly smears in primary care) or hospital-based colposcopy. At colposcopy, women with visible abnormality were randomised to immediate treatment or biopsy and recall for treatment if necessary. Recruitment HPV status was assessed using PCR techniques. Women were followed for three years to an exit colposcopy. Cumulative incidence of CIN2 or more severe disease (CIN2+) in the colposcopy arm was 7.9% per year, higher than in cytological surveillance (5.8%; OR = 1.43, 95% CI 1.23–1.67). This difference was less marked for CIN3+ (OR = 1.27, 1.04–1.55), suggesting spontaneous regression of some CIN2, and that initial colposcopy can lead to over-treatment. There was little difference in psychosocial outcomes between arms. In comparison of biopsy and recall versus immediate treatment, there was no difference in cumulative incidence of CIN2+ or psychosocial outcomes. There was over-treatment and increased frequency/duration of bleeding with immediate treatment. There was no compelling economic reason to favour any one management method. Testing for HPV does not appear to be effective in triage. Based on these findings, we make management recommendations for women with low-grade smears. [ABSTRACT FROM AUTHOR]

Introduction: We report levels of default in women with low-grade cytological abnormalities managed by cytological surveillance and identify factors associated with default. Method: TOMBOLA is an RCT comparing cytological surveillance (repeat smears every 6 months in primary care) with hospital-based colposcopy in women with a low-grade smear. TOMBOLA recruits were aged 20–59, with a recent mild or borderline smear, plus up to one previous borderline smear, detected within the NHS-CSPs. This analysis includes 2224 women randomised to cytological surveillance. Default was defined as non-attendance within 6 months of each surveillance smear being due. Results: 11% (95% CI 9.3–12.0) of women defaulted from the first surveillance smear. 13% (11.0–14.1) of those having a first surveillance smear defaulted from the second. 14% (12.1–15.5) of those having a second surveillance smear defaulted from the third. The median time from the recruitment smear to the first surveillance smear was 7 months (interquartile range 6–8 months). In univariate analyses, at each surveillance smear, younger women were more likely to default (first smear: 16% aged 20–29 versus 2% aged 50–59). Default was slightly higher among women with a mild (12% for first smear) than a borderline (10%) recruitment smear. For the first surveillance smear, women with a college/university degree were less likely (7%) than those without a degree (11%) to default, but this difference was not apparent for subsequent smears. For the first and second surveillance smears, default was higher among smokers than non-smokers. Multivariate analyses of these and other sociodemographic factors will be presented. Conclusions: Default was 11% from the first surveillance smear and increased slightly with subsequent smears. Some sub-groups of women are more likely to default (eg younger women, smokers). Analyses such as these may help inform strategies to ensure maximum attendance by women for cytological follow-up of low-grade abnormal smears. [ABSTRACT FROM AUTHOR]

Introduction: There is ongoing debate about the terminology used in the classification of dyskaryosis, including whether BNA smears should be classified according to whether koilocytes are present or not. We explored the effect of koilocytosis in the management experiences and clinical outcomes of women with a single BNA smear. Methods: This study includes 410 women aged 20–59 years, resident in Tayside who had an ‘baseline’ BNA smear between 31/10/1999 and 31/10/2002 who were eligible for the TOMBOLA trial but who did not participate. Recommended follow-up for these women was a repeat smear in six months. Up to three-years follow-up data was collected on subsequent cytological smears, colposcopy examinations and any related histology. The baseline smear was re-read for the presence or absence of koilocytes. Women were classified according to their clinical outcomes during their three years. Results: 47% (192/410) of women were classified as having koilocytosis at baseline. The mean age was lower among these women (25 years) compared to those without koilocytosis (35 years). 55% (105/192) of women with koilocytosis at baseline had one or more negative smears and no further abnormal smears, compared to 63% (137/218) of those without koilocytosis, the difference was not statistically significant. 28% (53/192) of women with koilocytosis at baseline were referred to colposcopy after subsequent low-grade or high-grade smears compared to 19% (42/218) of those without koilocytosis; the difference was statistically significant. 14% (27/192) of women with koilocytosis at baseline were diagnosed with CIN2/3 or worse during follow-up compared to 10% (21/218) of women without koilocytosis; the difference was not statistically significant. Discussion: Our results suggest that the presence or absence of koilocytosis has little impact on the clinical outcomes of women with a BNA smear. [ABSTRACT FROM AUTHOR]