Evaluating the Visual Appearance of Cervical Lesions in Relation its Histological Diagnosis, Human Papillomavirus Genotype and Other Viral Parameters: a Prospective Cohort Study

Persistent infection with high-risk human papillomavirus (HR-HPV) types is
necessary for the development of cervical cancer. One of the most important
tools to reduce the incidence of this disease is the early diagnosis and
treatment of its precursor lesions, e.g. by cervical cytology.
In women with abnormal cytology, colposcopic evaluation is used to obtain
cervical biopsies for histological confirmation. However, the sensitivity of
this approach is limited. DNA techniques for detecting HR-HPV have shown to be
effective in the clinical management of patients with cervical disease. The
main contribution of these techniques is their high sensitivity and negative
predictive value. Nonetheless, this increase in sensitivity is accompanied by a
notable reduction in specificity; therefore a considerable number of transient
infections are detected, which have only minimal chance of progression, but
nevertheless require a thorough survey. Consequently, other specific markers
than the presence of HR-HPV, such as HPV genotype or molecular transformation
markers are needed to identify patients at significant risk of progression and
improve their management.
To date, 20*40% of HPV-positive women are reported to be infected with multiple
HPV types. Detailed understanding of the natural history and dynamics of HPV
infection, and the pathogenic effect of infection with multiple types is
crucial to monitor the impact of the recently introduced HPV-vaccination on the
risk of infection with individual HPV types.

In case abnormal cytology is diagnosed in a woman, she is referred for
colposcopy. Digitalized colposcopic imaging has been developed in the last
decade and comprises the recording of high quality digital photographs for
several purposes. Compared to conventional colposcopy it provides greater
objectivity to evaluate colposcopic images and to quantify the findings.
Furthermore it provides the opportunity of monitoring progression or regression
of the observed lesions. Digital colposcopy with a system to annotate the
lesions of interest, gives the opportunity to study the correlation between the
characteristics of colposcopic image, histological diagnosis, HPV genotype(s)
and molecular transformation markers.

Recently the Laser Capture Microdissection (LCM) method has been applied to
cervical biopsy specimens. This technique allows molecular assessment of
selected cell populations, e.g. HPV status, that are histologically or
pathologically distinct although topographically close. LCM can give more
insight in the pathogenesis of cervical premalignant lesions.

Primary objectives:
- Evaluate colposcopic visual appearance of cervical lesions in relation to its
histological substrate, HPV genotype(s) and molecular parameters.
- Study cervical disease on the lesion level using HPV genotyping and other
viral parameters.


Secondary objectives:
- Determine the incremental benefit of taking multiple biopsies to detect CIN.
- Compare visual assessment and biopsy placement between expert colposcopists.
- Set standards of documenting colposcopic impression and biopsy placement to
initiate a world-wide database of cervical images with clinical outcomes.
- Determine the predictive value of HPV self-sampling in the management and
follow-up of women with CIN.
- Study the clinical value of HPV self-sampling compared to physician obtained
HPV testing

This study is designed as a prospective multicenter observational cohort study.

Risks and burden are linked to protocol procedures, such as cervical sampling
and colposcopy. Although these are routine procedures, carried out by medically
qualified personnel, they may cause side effects or discomfort to the woman.
However, it is expected that these procedures will generally be well tolerated.
The only extra burden involves the self-sampling of cervical-vaginal cells
using a user-friendly self-sampling device. Self-sampling poses no threats to
the physical well-being of a woman.