Page 123 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

not to be significantly prognostic for spontaneous regression.[4, 15] Ki67 staining was found to
be predictive in one study.[15] Smoking status was evaluated in two studies and was negatively
correlated with disease regression in both studies.[14, 15] In our study of patients with exclusively
hrHPV positive CIN2 lesions, we only identified smoking status and parity as prognostic factors.
We found no prognostic effect of the other studied factors. This may indeed be explained by
the fact that all lesions were hrHPV positive, reflecting a more ‘high-risk’ population, in which
previously determined prognostic factors are of less influence on the natural history of the lesion.
This theory is supported by the fact that the regression rate in the current study is lower than in the
previous study in the same cohort (61% vs 71%).[17] It cannot be excluded, however, that the lack of prognostic factors is the result of a relatively small patient population. Nevertheless, the findings
of our study indicate that conventional prognostic factors may not be of equal importance in a population with exclusively hrHPV positive CIN2 lesions, as compared to populations with both
hrHPV positive and negative CIN2 lesions. The relative lack of prognostic factors in hrHPV positive 6 CIN2 hampers individual patient counseling. Future research should therefore also focus on other
Prognostic factors for hrHPV positive CIN2
potential prognostic factors, among which may be molecular markers of oncogenic processes.
Although hrHPV positivity may diminish the effect of potential prognostic biomarkers in CIN2, hrHPV genotypes were not found to be prognostic of disease regression in the two studies in CIN2 lesions that assessed this potential biomarker.[15, 16] This is in contrast to previous studies in high-grade CIN lesions that quite consistently identified hrHPV genotypes as prognostic factors for disease progression or non-regression.[13] With regard to exclusively CIN2 lesions, Miyamoto et al. retrospectively included 112 women, of which 28 (25%) showed disease regression.[15] HPV genotyping was performed in only 40 women and nearly all were positive for high-risk HPV (n=38). Moreover, no classification into different genotypes (e.g. HPV16 and/or HPV-18) was performed. Because of the high prevalence of hrHPV infection, the study population seems unsuitable for testing hrHPV as possible prognostic factor. Moscicki et al. prospectively included 95 women with CIN2, of which 63% cleared their lesion after 2 years follow-up.[16] They studied the effect of HPV16/18 infection at baseline (and not all hrHPV types). They found a prognostic value of HPV16/18 with regard to disease regression in a univariable analysis, but this effect was no longer significant in a multivariable analysis. This is in accordance with our study, in which HPV 16/18 at baseline were not significantly related to disease outcome. Both results may be explained by the relatively small population, but it cannot be ruled out that HPV16/18 status is not a prognostic factor for disease outcome in CIN2. Further research in CIN2 populations could clarify the effect of hrHPV genotypes on disease outcome. Nevertheless, given the widespread implementation of HPV-based screening for cervical cancer, the identification of additional prognostic factors should be performed in hrHPV positive lesions in order to provide with clinically relevant results.
Our study identified smoking as a prognostic factor in hrHPV positive CIN2 lesions. This is in accordance with the two previous studies that studied the influence of smoking on the natural prognosis of exclusively CIN2 lesions. Smoking is an established risk factor for the development of cervical carcinoma and has also been identified as a risk factor for the development of CIN lesions in hrHPV positive women.[18] Several biological mechanisms for this effect have been proposed, among which are an altered immune response and direct cellular effects of exposure
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