Page 18 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 1
to reduce side effects, strategies are needed towards conservative management of high-grade CIN, without increasing the risk of lesion progression to cervical cancer.
Strategies towards observational and non-surgical management of high-grade CIN
Two strategies can be identified with the aim to reduce surgical (over)treatment of high-grade CIN. These include (1) observational management of CIN lesions that are likely to show spontaneous regression and (2) non-surgical treatment modalities for CIN lesions.
Observational management of CIN
A first strategy is observational management of CIN lesions that are likely to show spontaneous regression. As discussed before, (inter)national guidelines now advice upon observational management of CIN2 lesions in younger women.[36] However, for reasons unknown, observational management is not applied to all young women, leaving a subset at risk for side effects of – potentially unnecessary – surgical treatment.[37] Additionally, a subset of women with a CIN3 lesion undergoes unnecessary treatment, as their lesions would show spontaneous regression if left untreated. Ideally, the individual disease outcome would be predictable, in order to select those women with CIN2 lesions and CIN3 lesions in which spontaneous regression is expected. Current histopathological examination cannot distinguish those lesions that will regress from those that will not. Therefore, other markers are needed: individual or combined markers that predict the natural course of individual CIN lesions. Such prognostic biomarkers are clinical or biological characteristics that are objectively measurable and provide information on the likely outcome of disease in an individual.[38] In case of CIN lesions, prognostic biomarkers should be identified at the different levels of interaction between viral and host factors in their natural history. Potential prognostic biomarkers may be identified at the level of general patient and lesion characteristics (such as smoking status, HPV genotype and lesion size) or on the level of functional cellular mechanisms in the pathogenesis and regression of CIN lesions (such as proliferation markers, immune markers or genetic markers). Clinically suitable biomarkers should meet several criteria, regarding assessment, test characteristics and decision-making. There should be an accurate and reproducible analytical method and the assay should be readily available at reasonable cost. There must be a strong and consistent association between the biomarker and disease outcome, preferably verified in multiple studies. Finally, decision-limits should be available and validated. [39] A variety of prognostic molecular markers in the natural history of both low- and high-grade CIN lesions has been reported in the literature. An overview of these markers and critical appraisal of their clinical applicability, however, is lacking. Determination of the clinical applicability of the identified markers can be performed according to the prospective-specimen-collection, retrospective-blinded-evaluation (PROBE) design. This design advises upon the development of a functional biomarker and consists of four key components: clinical context and outcome, biomarker performance criteria, biomarker test characteristics and study size. [40] An overview of the natural history of high-grade CIN and critical appraisal of previously studied prognostic molecular markers according to the PROBE criteria could clarify their clinical applicability. Furthermore, it could identify molecular markers that deserve further evaluation as prognostic biomarkers in high-grade CIN.
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