Knowledge is sparse concerning proportions of normal cervical smears (Pap smears) that are positive for HPV mRNA and/or for HPV DNA among women who develop cervical intraepithelial neoplasia 3+ (CIN3+) or adenocarcinoma in situ (AIS). The aim is to compare proportions HPV mRNA- and HPV DNA-positivity of baseline cytology-samples before development of CIN3+ and AIS.
In Malmö of Sweden 2012 women were diagnosed with histopathology confirmed CIN3+ or AIS between 2007 through 20015, and also had a baseline biobank cytology sample at -80°C. Overall, 1204 cytology samples were eligible for HPV testing out of which 578 and 626 had normal and ASCUS+ cytology, respectively. The mean age at CIN3+ was 34 years (range 23-86) at diagnosis. The cell pellet from each LBC-sample (2mL SurePath solution) was suspended in 420 uL STM (Qiagen). Then a split sample approach was used where 100 uL was analyzed for high-risk HPV types by APTIMA (Hologic) and 100 uL by Cobas 480 (Roche).
Among women with normal cytology 74% and 80% had HPV mRNA and HPV DNA, respectively. Among women with ASCUS+, 88% and 91% had HPV mRNA and HPV DNA, respectively. The overall agreement between the HPV mRNA and HPV DNA assays was 87% (K=0.64) and 92% (K=0.60) for those with normal and ASCUS+ cytology, respectively.
Among HPV-positive women with normal cytology, 8 years before diagnosis of CIN3+ 64% and 82% had detectable HPV mRNA and HPV DNA, respectively. Seven years before diagnosis: 85% vs 82%, 6 years: 69% vs 78%, 5 years: 73% vs 78%, 4 years: 73% vs 79% P=0.0108, 3 years: 78% vs 88%, 2 years: 79% vs 79%, 1 year: 58% vs 58%.
The median period between normal cytology and CIN3+ was 44 months (range 5-96) both for women with positive HPV mRNA-test and/or HPV DNA-test. Among HPV mRNA-positive (427 women) and/or HPV DNA-positive (460 women) cytologically normal women, 22% from each group had CIN3+ within 3 years.
The median period between ASCUS+ cytology and CIN3+ was 8 months (range 4 to 85) and 8 months (range 4 to 92) for women with positive HPV mRNA-test and/or HPV DNA-test, respectively.
Among 22 cases with histology of AIS, 95% (21/22) and 91% (20/22) had detectable HPV mRNA and HPV DNA in the cytology samples (all ASCUS+), respectively. The overall agreement between the HPV mRNA and HPV DNA assays was 95% (K=0.64).
High proportions of HPV positivity (74%-80%) were observed for HPV mRNA and HPV DNA assays among cytologically normal women who developed CIN3+. About a fifth of these HPV-positive cytologically normal women had diagnosis of CIN3+ within 3 years. Further studies are needed in order to predict which of HPV-infected women who will progress to high-grade dysplasia.