Review of the options for triage of women found to be HPV positive at cervical screening.
Review of proposed approaches and preliminary data.
Approaches for triage of HPV positive women may be divided into those which seek additional information from cytologic slide preparations and those which utilize molecular testing independent of intact cells. Slide-based options include improvements in computerized interpretation of standard cytologic preparations, and immunohistochemistry staining of cytology preparations for recognition of p16 and Ki67. Investigation of possible improvements in computer imaging is being actively considered. Preliminary data on p16/Ki67 triage from Kaiser Permanente Northern California indicate that p16/Ki67 dual staining is as sensitive and has better specificity, NPV and PPV than cytology for CIN2+ in 1669 HPV positive women, which could permit a significant reduction in colposcopy.1
Molecular approaches include risk stratification by more complicated sorting of HPV types or subtypes,2 which are associated with significantly different risk. Among the DNA types identified as "high risk" there is a wide variation in risk, informing variations in clinical management. Among the subtypes of HPV 16 identified to date, unpublished data suggests a significant variation in risk and variation in association with squamous versus glandular cancers. DNA methylation at specific sites has been shown to be predictive of CIN3+, and recognition of methylation at CADM1 and MAL sites is associated with dysplasia but not normal cervical tissue on biopsy and can be assessed on cervical scrape specimens.3
Multiple options are possible but not yet commercially available in the U.S. for risk assessment of the HPV positive woman. Increasing specificity of screening in the age of vaccination will be paramount. A test more effective than cervical cytology would permit triage of HPV positive women to risk-appropriate management, facilitate introduction of primary HPV screening, decrease colposcopy, and likely decrease identification and treatment of dysplasia that would not be progressive or persistent. Accomplishing this without decreasing programmatic screening sensitivity and thus cancer prevention would be a significant advance.
1. [Wentzensen, JNCI, 2015]
2. [Cullen, Papillomavirus Res, 2015]
3. [van Baars et al, Int J Cancer, 2015]