Page 124 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 6
to nicotine and other tobacco products.[18] 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. [18-20] Moreover, nicotine has been shown to promote cervical cell migration and invasion in vitro.[21]
These study results indicate a potential direct effect of smoking in the development of cervical dysplasia. Absence of this direct effect in non-smoking women may enable a more effective immune response, resulting in a higher likelihood of disease clearance.
Our study identified nulliparity as a prognostic factor in hrHPV positive CIN2 lesions, also after correction for age and HPV16/18 status. Previous studies with pooled data have shown a strong association between parity and cervical cancer and also an association between parity and high-grade CIN (CIN2-3).[22, 23] Interestingly, a recent study by Jensen et al. shows that parity is associated with an increased risk for CIN3+ in women with a persistent HPV infection.[24] This implies that the association between parity and CIN lesions 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. Proposed mechanisms for this increased risk are increased hormone levels and impaired immune response, increased exposure of the transformation zone in parous women as a result of a longer ectocervical position and local tissue damage during vaginal delivery. Evidence on the association between parity and exclusively CIN2 lesions is scarce. Wang et al. reported on the association between parity and the risk of high-grade CIN development and distinguished between CIN2 and CIN3.[25] Whereas parity was found to increase the risk of CIN3, it did not increase the risk of CIN2 lesions in HPV positive women. This may imply a less effective disease clearance of CIN2 in parous women, leading to more cases of progressive disease. Indeed, in a study with HPV-infected women with normal cervical cytology or CIN 1, it was shown that parity is significantly and inversely associated with HPV clearance.[26] The only previous study assessing disease regression of CIN2 in relation to parity was performed by Miyamoto et al.[15] Nearly of women in this study were hrHPV positive. They found no differences in nulliparity between women with CIN2 who showed disease regression, persistence or progression. However, the mean age in the group with disease regression was higher than in the groups with persistence or progression, while correction of parity for age was not performed. This may explain why their result for parity is not in accordance with our study, which does indicate parity as a prognostic factor for regression of hrHPV positive CIN2.
A point of particular interest in studies on CIN2 is the diagnostic difficulty of these lesions. Studies show that CIN2 is a much less reproducible diagnosis than CIN3 and distinction between CIN2 and CIN3 is not always clear.[27-30] Concordance in CIN2 diagnosis between different pathologists was found in only 19-53% of cases, compared to 48-62% in CIN3 lesions. This raises discussion
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