HPV E6/E7 mRNA Testing Is More Specific than Cytology in Post-Colposcopy Follow-Up of Women with Negative Cervical Biopsy

Sveinung Wergeland Sørbye,Silje Fismen,Marc Arbyn,Elin Synnøve Mortensen,Tore Jarl Gutteberg,Syed A Aziz

doi:10.1371/journal.pone.0026022

Abstract

BackgroundIn Norway, women with negative or low-grade cervical biopsies (normal/CIN1) are followed up after six months in order to decide on further follow-up or recall for screening at three-year intervals. A high specificity and positive predictive value (PPV) of the triage test is important to avoid unnecessary diagnostic and therapeutic procedures whereas a low risk of high-grade disease among triage negative women assures safety.Materials and MethodsAt the University Hospital of North Norway, cytology and the HPV mRNA test PreTect HPV-Proofer, detecting E6/E7 mRNA from HPV types 16, 18, 31, 33 and 45, are used in post-colposcopy follow-up of women with negative or low-grade biopsy. In this study, women with negative biopsy after high grade cytology (ASC-H/HSIL) and/or positive HPV mRNA test in the period 2005–2009 were included (n = 520). Histologically confirmed cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) was used as study endpoint.ResultsOf 520 women with negative or low-grade biopsy, 124 women (23.8%) had CIN2+ in follow-up biopsy. The sensitivity and specificity of the HPV mRNA test were 89.1% (95% CI, 80.1–98.1) and 92.5% (95% CI, 88.2–96.7), respectively. The ratios of sensitivity, specificity and PPV of HPV mRNA testing compared to repeat cytology for finding CIN2+ was 1.05 (95% CI: 0.92–1.21), 1.21 (95% CI: 1.12–1.32), and 1.49 (95% CI: 1.20–1.86), respectively. The PPV of mRNA was 77.3% (95% CI, 59.8–94.8) in women aged 40 or older.ConclusionWomen with negative cervical biopsy require follow-up before resumption of routine screening. Post-colposcopy HPV mRNA testing was as sensitive but more specific than post-colposcopy cytology. In addition, the HPV mRNA test showed higher PPV. A positive mRNA test post-colposcopy could justify treatment in women above 40 years.

Highlights

Cervical cancer is the third most common cancer affecting women worldwide [1]
The sensitivity and specificity of the Human Papillomavirus (HPV) mRNA test were 89.1% and 92.5%, respectively
The ratios of sensitivity, specificity and positive predictive value (PPV) of HPV mRNA testing compared to repeat cytology for finding CIN2+ was 1.05, 1.21, and 1.49, respectively

Summary

Introduction

Cervical cancer is the third most common cancer affecting women worldwide [1]. In Norway, about 300 women get cervical cancer annually and 80–100 die from the disease [2]. In Norway, a cervical cancer screening program was introduced in 1995, recommending all women between 25 and 69 years of age to have a cytological cell sample (Pap-smear) every three years [4]. Women with cytological diagnoses of either high grade squamous intraepithelial lesion (HSIL) or atypical squamous cells, cannot rule out a high grade lesion (ASC-H) are referred to colposcopy and biopsy [4], as recommended in European guidelines [6,7]. The same is the case in women with atypical squamous cells of undetermined significance (ASC-US) or lowgrade squamous intraepithelial lesion (LSIL) and positive HPV test [8]. In Norway, women with negative or low-grade cervical biopsies (normal/CIN1) are followed up after six months in order to decide on further follow-up or recall for screening at three-year intervals. A high specificity and positive predictive value (PPV) of the triage test is important to avoid unnecessary diagnostic and therapeutic procedures whereas a low risk of high-grade disease among triage negative women assures safety

Methods

Results

Conclusion