Cytology and Human Papillomavirus Testing 6 to 12 Months after ASCUS or LSIL Cytology in Organized Screening To Predict High-Grade Cervical Neoplasia between Screening Rounds

Abstract

We carried out a prospective study comparing the performance of human papillomavirus (HPV) E6/E7 mRNA (PreTect HPVProofer; NorChip, Klokkarstua, Norway) and DNA (Amplicor HPV test; Roche Diagnostics, Basel, Switzerland) triage testing of women 6 to 12 months after atypical-squamous-cells-of-undetermined-significance (ASCUS) or low-grade-squamous-intraepithelial-lesion (LSIL) cytology in organized screening to predict high-grade cervical intraepithelial neoplasia of grade 2 or worse (CIN2؉) between screening rounds. Between January 2005 and April 2008, 692 study women with screening-detected ASCUS/ LSIL cytology 6 to 12 months earlier returned for HPV mRNA and DNA testing and repeat cytology. The median follow-up time was 3 years, using existing health care facilities. Follow-up test results were available for 625 women. Of the 145 CIN2؉ cases detected during the study period, 95 (65.5%) were HPV mRNA positive 6 to 12 months after screening-detected ASCUS/LSIL, 44 (30.4%) were HPV mRNA negative, and 6 (4.1%) were invalid. The corresponding HPV DNA results were 139 (95.9%), 5 (3.4%), and 1 (0.7%), respectively. The cumulative incidences of CIN2؉ 3 years after a negative HPV mRNA and DNA test were 10.3% (95% confidence interval [CI], 7.2 to 13.3%) and 1.8% (95% CI, 0.0 to 3.6%), respectively. The cumulative incidences of CIN2؉ 3 years after positive HPV mRNA and DNA tests were 52.8% (95% CI, 40.1 to 60.1%) and 41.3% (95% CI, 35.5 to 46.6%), respectively. In conclusion, both positive HPV mRNA and DNA test results have a high enough long-term prediction of CIN2؉ risk to consider referral to colposcopy as good practice when performed in delayed triage of women with ASCUS/LSIL cytology. In addition, the low CIN2؉ risk among women with a negative Amplicor HPV test in our study confirms its safe use in a clinical setting. The 2-year cumulative risk of invasive cervical cancer for women with cytological results of atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) has been reported to be in the range of 0.10% to 0.25% (20). High-risk human papillomavirus (HPV) is recognized as the main cause of cervical cancer (40), and HPV DNA testing in the follow-up of women with ASCUS/LSIL cytology has proven to be a very sensitive method to further identify those at increased risk of cervical cancer, albeit at the cost of low specificity (3). Immediate high-risk HPV DNA testing (i.e., reflex testing) has proven useful in identifying women with ASCUS cytology who should be referred promptly to colposcopy. However, application of reflex testing among women with LSIL cytology is disputed, as three of four women generally test positive for highrisk HPV DNA (3, 15).European guidelines for quality assurance in cervical cancer screening recommend several different follow-up algorithms for women with ASCUS and LSIL cytology, but there is no consensus on the use of any one algorithm for a given cytological diagnosis. The guidelines recommend that women with LSIL or ASCUS be referre...

Long-term HPV type-specific risks for ASCUS and LSIL: A 14-year follow-up of a randomized primary HPV screening trial

“…3 Adjusted for follow-up time (1-year intervals), age at entry, and all HR HPV types. Reference category is HPV type negative for each HPV type respectively.…”

“…Reference category is HPV type negative for each HPV type respectively. 3 Adjusted for follow-up time (1-year intervals) and age at entry. Reference category is other non-HR type negative.…”

“…3,4 In Sweden, ASCUS and LSIL lesions were found in approximately 6% of cervical samples taken in 2012, triggering triage with HPV and subsequent follow-up testing, depending on HPV status.…”

“…1,2 Considerable resources are used in the follow-up and referral of women with low-grade lesions and a range of triage tests and management algorithms have been proposed for these lesions. 3,4 In Sweden, ASCUS and LSIL lesions were found in approximately 6% of cervical samples taken in 2012, triggering triage with HPV and subsequent follow-up testing, depending on HPV status. 5 HPV testing is increasingly used in triaging low-grade lesions and therefore studies have recently focused on quantifying the risk for lesion progression and comparing different follow-up strategies.…”

“…5 HPV testing is increasingly used in triaging low-grade lesions and therefore studies have recently focused on quantifying the risk for lesion progression and comparing different follow-up strategies. 3,4 Evidence suggests that risk of progression is dependent on HPV status of the index lesion, with high-risk (HR) HPV positive ASCUS lesions having an 18% probability of progressing to a higher grade lesion within 18 months and LSIL lesions having an 12% probability of progressing. 6 More detailed knowledge of the importance of different HPV types for ASCUS/LSIL development could therefore be of interest in the design and clinical use of HPV typing tests.…”