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• W1921323242 abstract "In the present issue, Herfs et al1 present an innovative assessment of the outcome of loop electrosurgical excision procedure (LEEP) in 131 women who had cervical intraepithelial neoplasia (CIN). Infection with high-risk types of human papillomavirus (HPV) at enrolment (n=125) and CIN2 or 3 in the cone biopsy (n=128) had been detected in the majority of study women. Authors were especially interested in the presence, at baseline and in subsequent visits, of a recently discovered population of cells of embryonic origin that derive from the squamous-columnar junction (SCJ) of the cervix (henceforth referred to as SCJ cells). These cells have a unique cuboidal morphology and express specific biomarkers, i.e., Krt7, AGR2, CD63, MMP7, and GDA.2 Unlike the stratified epithelia of the cervix and anogenital tract, SCJ cells are not permissive for the entire HPV life cycle but may harbour the virus for extended periods of time.3 Most importantly, Herfs et al2, 4 have proposed that SCJ cells are the source of most, if not all, high grade CIN and cervical carcinoma, and that they do not regenerate after ablation of the SCJ and the transformation zone. During follow-up (median: 89.5 weeks) Herfs1 detected CIN in 16 women (12.2%) and separated them into two main groups: 1) Residual disease (4 women): CIN2/3 that were found at the first follow-up visit after LEEP, and closely resembled the initial CIN in grade, and type of HPV infection suggesting incomplete excision; and 2) Delayed recurrences (12 women): lesions that manifested at later visits, were all low-grade lesions (CIN1), and frequently positive for different HPV types than those detected at enrolment. Interestingly, all residual CIN2/3 but one (also negative at baseline) were still positive for SCJ cell markers after LEEP versus none of recurrent CIN1. The findings from Herfs et al1 suggest, therefore, that the elimination of SCJ cells does not prevent HPV infection and its morphological manifestation (CIN1) but may avoid neoplastic transformation. Hopes in the beneficial effect of prophylactic ablation of the SCJ and the transformation zone preceded even the discovery of the causal link between HPV infection and cervical cancer. For decades gynaecologists have been concerned about the vulnerability to infections and neoplastic lesions of the columnar and metaplastic epithelia visible on the ectocervix (a condition referred to as ectopy and ubiquitous in young women).5 Large programmes of cervical cancer prevention based on electrodiathermy coagulation of the ectopy were carried out with some favourable outcomes6-8 but did not reach conclusive results on account of the weakness of study methods, i.e., lack of randomized controlled trials and sufficiently long and standardized follow-up. The recognition of the viral aetiology of cervical cancer and the rapid acquisition of HPV after the beginning of sexual intercourse prompted studies on the role of ectopy in the acquisition of HPV infection. A follow-up study on 13–21 year-old women showed that rapid maturation of the cervix rather than the size of ectopy increases the risk of HPV16 infection.5 High levels of endogenous or exogenous oestrogens (hormonal contraceptives) sustain the maturation process5 and increase cancer risk in the cervix of women,9-11 hybrid mice,12 and HPV transgenic mice.13, 14 In the cervix of HPV transgenic mice, cancer can be controlled by treatment with oestrogen-receptor modulators.15 No information is available on the possibility of hormonally modulating the carcinogenic process in the human cervix or on the susceptibility of SCJ cells to oestrogens. A bulk of studies have demonstrated the efficacy of cryotherapy16 and loop excision17 of the SCJ and transformation zone in the treatment of CIN2/3 and the tendency of residual or recurrent CIN2/3 disease to be detected relatively rapidly after treatment.17 If confirmed by other groups and larger studies, however, the work by Herfs et al1 would provide an incentive to re-evaluate prophylactic ablation, especially in low/middle-income countries in which the success of cervical cancer screening depends on the possibility of performing it well, but seldomly, i.e., once or twice in a lifetime. In fact, their report in the current issue ends with a plea to consider randomized controlled trials to determine the safest ways to perform prophylactic ablation and establish its efficacy in the more cervical cancer-prone, women (e.g. HIV-infected/multi-partner women). As in the past, a large randomized trial of prophylactic ablation would be very challenging especially due to concerns about adverse pregnancy outcomes in women who wish to have children. A meta-analysis18 and large prospective study19 of women treated for CIN showed an association of pre-term delivery with cold knife or laser conisation but provided reassuring findings for loop excision and cryotherapy. No increase in HIV shedding was found after cryotherapy in HIV-infected women who were taking antiretroviral therapy.20 A possible alternative to randomized trials may be a careful evaluation of the impact of prophylactic ablation in the framework of large screening programmes. According to the new “WHO guidelines for screening and treatment of precancerous lesions for cervical cancer prevention”,21 one of the best screening strategies in low/middle-income countries is to screen with an HPV test and treat all HPV-positive women above age 30 years with cryotherapy. A randomized screening trial conducted in 6,555 women 35 years or older in South Africa16 had provided strong support to this recommendation. The HPV-based screen-and-treat approach significantly reduced CIN2 or worse lesions through 36 months in both HIV-negative (relative risk=0.31; 95% confidence interval, CI: 0.20-0.50) and HIV-positive women (relative risk= 0.20; 95% CI: 0.06-0.69).22 The risk-to-benefit ratio of the approach was highly favourable: there was only one serious complication (bleeding leading to transfusion in an HIV-positive woman) and nearly all participants stated that they would recommend this type of screening programme to friends and family. It is highly probable that a fraction of HPV-positive women who underwent treatment had no cervical lesions at enrolment and, therefore, received prophylactic ablation. Of interest, Kuhn et al22 showed that CIN1 incidence after cryotherapy was not reduced in HIV-positive women. This observation is consistent with the hypothesis proposed by Herfs et al1 that the elimination of SCJ cells in high-risk women may protect from neoplastic transformation rather than from new HPV infection or re-emergence of latent infection. A cytological smear and a biopsy could be taken immediately prior to cryotherapy in a sufficiently large subset of HPV-positive women in an HPV-based screen-and-treat programme for post-hoc diagnosis of cervical lesions. Follow-up of lesion-free women would help us learn more about the role of SCJ cells and prophylactic ablation. If a benefit were demonstrated, the study would also provide much needed information on the risk-to-benefit ratio of treating all HPV-positive women in settings in which laborious and expensive methods of triage of a HPV-positive test are difficult to put in place." @default.
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• W1921323242 date "2014-07-03" @default.
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• W1921323242 title "Embryonic cells in the squamous-columnar junction of the cervix: scope for prophylactic ablation?" @default.
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• W1921323242 doi "https://doi.org/10.1002/ijc.29057" @default.
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