Page 193 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

and negative lesions. In order to provide with prognostic factors for women with exclusively hrHPV positive CIN2, we performed a second study in this subgroup of women and identified smoking and parity as prognostic factors. Disease regression occurred in 85% of nulliparous women who did not smoke, as compared to 33% of smoking, parous women. These findings are in accordance with existing literature on risk factors for high-grade CIN. Smoking is an established risk factor for the development of CIN and cervical carcinoma.[39] Smoking has also previously been associated with disease outcome of CIN2, in mixed populations of hrHPV positive and negative lesions.[40, 41] Several biological mechanisms for this effect have been proposed, among which are an altered immune response and direct cellular effects of exposure to nicotine and other tobacco products. [39] The immune response in smokers is characterized by an unbalanced production of pro-and anti-inflammatory cytokines, suppression of T lymphocyte activity and lower numbers of Th cells and NK cells. Moreover, smoking women have decreased numbers of cervical Langerhans cells. An impaired immune response as a result of smoking may lead to less effective clearance of CIN lesions. Direct cellular effects of exposure to nicotine include increased cell proliferation, inhibition of apoptosis and stimulation of vascular endothelial growth factor, all of which contribute to oncogenesis and may reduce the potential of lesion regression.[39, 42, 43] Parity, too, has been previously associated with an increased risk of CIN and cervical cancer and increased parity has been shown to decrease the likelihood of HPV clearance.[44-46] Interestingly, a recent study by Jensen et al. shows that parity is associated with an increased risk for CIN3 and cervical cancer in women with a persistent HPV infection. This implies that the association between parity and CIN may not be caused by an increased risk for HPV infection or persistence of HPV infection, but that giving birth itself seems to be a risk factor for high-grade CIN.[47] Proposed mechanisms for this increased risk are increased hormone levels and impaired immune response during pregnancy, increased exposure of the transformation zone in parous women as a result of a longer ectocervical position and local tissue damage during vaginal delivery. In clinical practice, smoking status and parity can be considered in individual patient counseling regarding the choice between immediate treatment or conservative management of hrHPV positive CIN2 lesions.
Non-surgical treatment of high-grade CIN
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Discussion
For those women in whom treatment cannot be avoided, because their lesion is a CIN3 or observational management of a CIN2 lesion is unwanted, the development of a non-surgical treatment modality may reduce side effects of surgery. Imiquimod cream is the only non-surgical treatment modality for high-grade CIN incorporated in the Dutch guideline for CIN. Imiquimod is a Toll-like receptor (TLR) agonist, with anti-tumor and anti-viral properties.
Toll like receptors and cervical carcinogenesis
TLRs are the key molecules of the innate immunity. They are pattern recognition receptors (PRRs) that recognize specific pathogen associated molecular patterns (PAMPs) in viruses and other pathogens.[48-50] Ten functional TLRs have been described in humans, which recognize different PAMPs and are differentially expressed in human tissues. Upon recognition of a PAMP, TLRs trigger the nuclear factor kappa B (NF-kB) signaling pathways to develop antigen-specific acquired immunity, predominantly through pro-inflammatory cytokines interferon (IFN)-α,
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