Challenges of False Positive and Negative Results in Cervical Cancer Screening

Abstract Background : Liquid-based cytology (LBC) molecular testing for human papillomavirus (HPV) infection andcombinations are practical modalities for cervical-screening. While life-saving, false positive and negative results are possible, leading to potential over or under treatment. Quantifying this is complicated by the increasing number of options available, including parallel co-testing and sequential triage. As HPV vaccination rates increase, it also has a potential impact onscreening test performance and interpretation of results. Methods: A modelling approach was used to compare different screening modalities in terms of Cervical intra-epithelial neoplasia (CIN) grade 2 and 3 detected and missed, false positives leading to excess colposcopy, and number of tests required to achieve a given accuracy. The positive predictive value (PPV) and negative predictive value (NPV) of different modalities were simulated under varying levels of HPV vaccination. Results: The model suggested that in a cohort of 1000 women, LBC screening typically misses 4.9 cases (95% Confidence Interval (CI) 3.5-6.7), with 95 (95% CI: 93-97%) excess colposcopies. With primary HPV testing, 2.0 (95% CI:1.9-2.1) were missed with 99 (95% CI:98-101) excess colposcopies. Co-testing reduced missed cases to 0.5 (95% CI:0.3-0.7) but dramatically increased excess colposcopy referral (184, 95% CI:182-188). Conversely, triage testing with reflex screening substantially reduced excess colposcopy to 9.6 (95% CI:9.3-10) at the cost of missing more cases (6.4, 95% CI:5.1-8.0). Over a life-time of screening, women who always attend co-testing hada 93.8-100% chance of a false positive over screening life-time. For annual, 3-year, and 5-year triage testing (either LBC with HPV reflex or vice-versa), lifetime risk of a false positive is 35.1%, 13.4%, and 8.3% respectively.Results of this work indicate that as HPV vaccination rates increase, HPV based screening approaches result in fewer unnecessary colposcopies than LBC approaches. Conclusion: Clinical relevance of cervical cancer screening is crucially dependent upon prevalence of cervical dysplasia and/or HPV infection or vaccination in a population, and the sensitivity and specificity of modalities employed. Although screening is life-saving, false negatives and positives inevitably occur, and over-testing runs risk of significant harm, including potential over-treatment. As HPV becomes less common, HPV-based modalities may have greater utility.