Page 215 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

An introduction to the subjects in this thesis is provided in chapter 1. High-grade Cervical Intraepithelial Neoplasia (CIN2 and CIN3) is the precursor of cervical cancer and is caused by cervical infection with the human papillomavirus (HPV). In the Netherlands, approximately 5,000 women are treated for high-grade CIN every year. On the long term, approximately 30% of high-grade CIN lesions will progress to cervical cancer. On the other hand, 20-40% would show spontaneous regression when left untreated, but these lesions cannot be identified by current histopathological assessment. Spontaneous regression of CIN2 is even more common: up to 74% of these lesions are cleared without treatment. Clearance of CIN lesions is performed by the human immune system. Historically, all high-grade CIN lesions were treated by surgical excision, most commonly by Large Loop Excision of the Transformation Zone (LLETZ). This is an effective treatment modality, but is associated with an approximate twofold increased risk of premature birth in subsequent pregnancies. For this reason, guidelines now advice upon observational management of CIN2 in younger women. Adherence to this recommendation is not optimal, though. CIN3 is still routinely treated with surgical excision, due to its higher potential for malignant evolution. Taken together, a significant number of women is subjected to surgical treatment of high-grade CIN with associated side effects, many of whose lesions would have regressed spontaneously. To reduce overtreatment of CIN, one would ideally be able to predict the disease outcome in individual women to select for observational treatment. Additionally, to reduce side effects of surgical treatment, non-surgical treatment modalities could be applied. Imiquimod, a cream with antiviral and antitumor properties, is the only non-surgical treatment modality currently included in the Dutch treatment guideline for CIN. Clinical application of imiquimod is limited, though, for reasons unknown. Based on these findings, the aims of this thesis were (1) assessment of clinical and molecular biomarkers as predictors of spontaneous regression of high-grade CIN and (2) assessment of clinical applicability of imiquimod cream as a non-surgical treatment modality for high-grade CIN.
Assessment of clinical and molecular biomarkers as predictors of spontaneous regression of high-grade CIN
Prognostic biomarkers could be applied to predict the natural disease outcome of high-grade CIN. Cervical oncogenesis and regression of CIN is the result of a complex interaction between the human immune system, viral factors and functional cellular mechanisms in the cervical epithelium. Biomarkers should be identified at the different levels of this interaction. In chapter 2, we therefore first provided an overview of the pathophysiological processes in cervical oncogenesis and regression of CIN. Next, we conducted a review on previously studied prognostic biomarkers in high-grade CIN. None of the included studies was performed according to established criteria for biomarker research (PROBE criteria). We concluded that none of the studied biomarkers are currently fit for clinical implementation, but several promising biomarkers were identified. These include viral genotype and viral DNA methylation (viral factors), HLA-subtypes, markers of lymphoproliferative response, telomerase amplification and HPV-induced epigenetic effects (host factors) and Ki67, p53 and pRb (cellular factors).
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