HPV testing as a triage for borderline or mild dyskaryosis on cervical cytology: results from the Sentinel Sites study

BACKGROUND: Earlier pilot studies of human papillomavirus (HPV) triage concluded that HPV triage was feasible and cost-effective. The aim of the present study was to study the impact of wider rollout of HPV triage for women with low-grade cytology on colposcopy referral and outcomes. METHODS: Human papillomavirus testing of liquid-based cytology (LBC) samples showing low-grade abnormalities was used to select women for colposcopy referral at six sites in England. Samples from 10 051 women aged 25-64 years with routine call or recall cytology reported as borderline or mild dyskaryosis were included. RESULTS: Human papillomavirus-positive rates were 53.7% in women with borderline cytology and 83.9% in those with mild dyskaryosis. The range between sites was 34.8-73.3% for borderline cytology, and 73.4-91.6% for mild dyskaryosis. In the single site using both LBC technologies there was no difference in rates between the two technologies. The positive predictive value of an HPV test was 16.3% for CIN2 or worse and 6.1% for CIN3 or worse, although there was considerable variation between sites. CONCLUSION: Triaging women with borderline cytological abnormalities and mild dyskaryosis with HPV testing would allow approximately a third of these women to be returned immediately to routine recall, and for a substantial proportion to be referred for colposcopy without repeat cytology. Variation in HPV-positive rates results in differing colposcopy workload. British Journal of Cancer (2011) 105, 983-988. doi:10.1038/bjc.2011.326 www.bjcancer.com Published online 6 September 2011 (C) 2011 Cancer Research U

Psychosocial impact of alternative management policies for low-grade cervical abnormalities : results from the TOMBOLA randomised controlled trial

Background: Large numbers of women who participate in cervical screening require follow-up for minor cytological abnormalities. Little is known about the psychological consequences of alternative management policies for these women. We compared, over 30-months, psychosocial outcomes of two policies: cytological surveillance (repeat cervical cytology tests in primary care) and a hospital-based colposcopy examination. Methods: Women attending for a routine cytology test within the UK NHS Cervical Screening Programmes were eligible to participate. 3399 women, aged 20–59 years, with low-grade abnormal cytology, were randomised to cytological surveillance (six-monthly tests; n = 1703) or initial colposcopy with biopsies and/or subsequent treatment based on colposcopic and histological findings (n = 1696). At 12, 18, 24 and 30-months post-recruitment, women completed the Hospital Anxiety and Depression Scale (HADS). A subgroup (n = 2354) completed the Impact of Event Scale (IES) six weeks after the colposcopy episode or first surveillance cytology test. Primary outcomes were percentages over the entire follow-up period of significant depression (≥8) and significant anxiety (≥11; “30-month percentages”). Secondary outcomes were point prevalences of significant depression, significant anxiety and procedure-related distress (≥9). Outcomes were compared between arms by calculating fully-adjusted odds ratios (ORs) for initial colposcopy versus cytological surveillance. Results: There was no significant difference in 30-month percentages of significant depression (OR = 0.99, 95% CI 0.80–1.21) or anxiety (OR = 0.97, 95% CI 0.81–1.16) between arms. At the six-week assessment, anxiety and distress, but not depression, were significantly less common in the initial colposcopy arm (anxiety: 7.9% vs 13.4%; OR = 0.55, 95% CI 0.38–0.81; distress: 30.6% vs 39.3%, OR = 0.67 95% CI 0.54–0.84). Neither anxiety nor depression differed between arms at subsequent time-points. Conclusions: There was no difference in the longer-term psychosocial impact of management policies based on cytological surveillance or initial colposcopy. Policy-makers, clinicians, and women themselves can be reassured that neither management policy has a significantly greater psychosocial cost

Biopsy and selective recall compared with immediate large loop excision in management of women with low grade abnormal cervical cytology referred for colposcopy : multicentre randomised controlled trial

Peer reviewedPublisher PD

Psychosocial morbidity in women with abnormal cervical cytology managed by cytological surveillance or initial colposcopy:longitudinal analysis from the TOMBOLA randomised trial

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 NHS Cervical Screening Programme were randomised to cytological surveillance or initial colposcopy. 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 12 and 18 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

Lifestyle and socio-demographic factors associated with high-risk HPV infection in UK women

The world age-standardised prevalence of high-risk HPV (hrHPV) infection among 5038 UK women aged 20–59 years, with a low-grade smear during 1999–2002, assessed for eligibility for TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears) was 34.2%. High-risk HPV prevalence decreased with increasing age, from 61% at ages 20–24 years to 14–15% in those over 50 years. The age-standardised prevalence was 15.1, 30.7 and 52.7%, respectively, in women with a current normal, borderline nuclear abnormalities (BNA) and mild smear. In overall multivariate analyses, tertiary education, previous pregnancy and childbirth were associated with reduced hrHPV infection risk. Risk of infection was increased in non-white women, women not married/cohabiting, hormonal contraceptives users and current smokers. In stratified analyses, current smear status and age remained associated with hrHPV infection. Data of this type are relevant to the debate on human papillomavirus (HPV) testing in screening and development of HPV vaccination programmes

Strategies to improve retention in randomised trials.

Loss to follow-up from randomised trials can introduce bias and reduce study power, affecting the generalisability, validity and reliability of results. Many strategies are used to reduce loss to follow-up and improve retention but few have been formally evaluated

Human papillomavirus testing versus repeat cytology for triage of minor cytological cervical lesions

Background: A typical squamous cells of undetermined significance (ASCUS) and low-grade squamous intra-epithelial lesions (LSIL) are minor lesions of the cervical epithelium, detectable by cytological examination of cells collected from the surface of the cervix of a woman. Usually, women with ASCUS and LSIL do not have cervical (pre-) cancer, however a substantial proportion of them do have underlying high-grade cervical intra-epithelial neoplasia (CIN, grade 2 or 3) and so are at increased risk for developing cervical cancer. Therefore, accurate triage of women with ASCUS or LSIL is required to identify those who need further management. This review evaluates two ways to triage women with ASCUS or LSIL: repeating the cytological test, and DNA testing for high-risk types of the human papillomavirus (hrHPV) - the main causal factor of cervical cancer. Objectives Main objective: To compare the accuracy of hrHPV testing with the Hybrid Capture 2 (HC2) assay against that of repeat cytology for detection of underlying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) or grade 3 or worse (CIN3+) in women with ASCUS or LSIL. For the HC2 assay, a positive result was defined as proposed by the manufacturer. For repeat cytology, different cut-offs were used to define positivity: Atypical squamous cells of undetermined significance or worse (ASCUS+), low-grade squamous intra-epithelial lesions or worse (LSIL+) or high-grade squamous intra-epithelial lesions or worse (HSIL+). Secondary objective: To assess the accuracy of the HC2 assay to detect CIN2+ or CIN3+ in women with ASCUS or LSIL in a larger group of reports of studies that applied hrHPV testing and the reference standard (coloscopy and biopsy), irrespective whether or not repeat cytology was done. Search methods: We made a comprehensive literature search that included the Cochrane Register of Diagnostic Test Accuracy Studies; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (through PubMed), and EMBASE (last search 6 January 2011). Selected journals likely to contain relevant papers were handsearched from 1992 to 2010 (December). We also searched CERVIX, the bibliographic database of the Unit of Cancer Epidemiology at the Scientific Institute of Public Health (Brussels, Belgium) which contains more than 20,000 references on cervical cancer. More recent searches, up to December 2012, targeted reports on the accuracy of triage of ASCUS or LSIL with other HPV DNA assays, or HPV RNA assays and other molecular markers. These searches will be used for new Cochrane reviews as well as for updates of the current review. Selection criteria: Studies eligible for inclusion in the review had to include: women presenting with a cervical cytology result of ASCUS or LSIL, who had undergone both HC2 testing and repeat cytology, or HC2 testing alone, and were subsequently subjected to reference standard verification with colposcopy and colposcopy-directed biopsies for histologic verification. Data collection and analysis: The review authors independently extracted data from the selected studies, and obtained additional data from report authors. Two groups of meta-analyses were performed: group I concerned triage of women with ASCUS, group II concerned women with LSIL. The bivariate model (METADAS-macro in SAS) was used to assess the absolute accuracy of the triage tests in both groups as well as the differences in accuracy between the triage tests. Main results: The pooled sensitivity of HC2 was significantly higher than that of repeat cytology at cut-off ASCUS+ to detect CIN2+ in both triage of ASCUS and LSIL (relative sensitivity of 1.27 (95% CI 1.16 to 1.39; P value < 0.0001) and 1.23 (95% CI 1.06 to 1.4; P value 0.007), respectively. In ASCUS triage, the pooled specificity of the triage methods did not differ significantly from each other (relative specificity: 0.99 (95% CI 0.97 to 1.03; P value 0.98)). However, the specificity of HC2 was substantially, and significantly, lower than that of repeat cytology in the triage of LSIL (relative specificity: 0.66 (95% CI 0.58 to 0.75) P value < 0.0001). Authors' conclusions: HPV-triage with HC2 can be recommended to triage women with ASCUS because it has higher accuracy (significantly higher sensitivity, and similar specificity) than repeat cytology. When triaging women with LSIL, an HC2 test yields a significantly higher sensitivity, but a significantly lower specificity, compared to a repeat cytology. Therefore, practice recommendations for management of women with LSIL should be balanced, taking local circumstances into account

The role of human papillomavirus testing in the management of women with low-grade abnormalities : multicentre randomised controlled trial

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 investigatio