Cervical cytology showing low grade squamous intra-epithelial lesions (L-SIL) is the hallmark of human Papillomavirus (HPV) virion production. When the terminally differentiated non-dividing squamous cells from the cervix are ready to desquamate a new horde of newly formed virions is ready to be released. Most triage algorithms for women with L-SIL is based on detection of high-risk HPV combined with risk calculation to detect high-grade cervical intraepithelial neoplasia (CIN) and cancer (CIN3+). Although some try partial genotyping and only send HPV 16 and or HPV 18 positive women to colposcopy, the majority of these women do not have CIN3+. Moreover no solution is given for women positive for non-HPV 16/18 types. We recently showed that serial viral load measurement allows triage of HPV positive women in transient virion producing infections and HPV transformed clonal populations that can lead to CIN3+. Because these two pathways can occur simultaneously a new algorithm identifying clonal progressing populations was used to triage women with L-SIL.
Retrospective study using the RIATOL cervical cancer screening and diagnostic follow up database. Since 06/2006, all cervical samples were tested for presence of HPV DNA (18 different quantitative PCRs), before performing cytology. Using the database, we selected women who had a L-SIL smear result in June 2009, had ≥2 viral load measurements, and had a subsequent histological result. Changes in HPV specific load between measurements were assessed by linear regression, with calculation of coefficient of determination (R²) and slope. All detected HPV infections were classified into one of five categories: 1) clonal progressing process (R²≥0,85; positive slope), 2) simultaneously occurring clonal progressive and transient infection, 3) clonal regressing process (R²≥0,85; negative slope), 4) serial transient infection with latency (R²<0,85; slopes (2 points) between 0,0010 and -0,0010 HPV copies/cell/day) and 5) transient productive infection (R²<0,85; slope +/-0,0099 HPV copies/cell/day).
260 women with L-SIL were included. Histology results showed that 7.3% developed CIN3, 8.5% CIN2, 27.3% CIN1 and in 41.2% of women the HPV infection regressed. Single HPV infections were detected in 55.8% and multiple HPV infections in 44.2%. In women who developed CIN3, 14 women had multiple infections (73.7%) and only 5 women had single infections (26.3%). In all women with CIN3 a clonal progressive infection could be detected for one of the present HPV types.
Serial type specific viral load measurement detects the HPV type with the clonal progressing viral-load course responsible for CIN3+ in women with LSIL cytology.