Page 17 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

screening method. It leads to an earlier detection of persistent high-grade lesions, a 60-70% 1 decrease in cervical carcinoma and requires less screening tests than primary cytological screening.[29-33] For this reason, many countries have changed or are changing their cervical
screening program to an (at least partial) HPV-based screening method. Among these are the Netherlands, the UK, the USA, Australia, New-Zealand, Norway, Denmark, Finland, Italy, Sweden
and Portugal. In this HPV based screening method, cervical cytology is first tested for the presence of hrHPV, after which cytological assessment is only done in hrHPV positive cases. Colposcopy is performed upon the finding of atypical cells. During colposcopy, either diagnostic biopsies or therapeutic excision is performed on lesions suspect for dysplasia. A definitive diagnosis (i.e. extent of dysplasia) is established based on histological examination.
Current treatment of high-grade CIN and its pitfalls
Until recently, guidelines advised to treat all high-grade CIN lesions, with the aim to prevent cervical cancer. The standardized treatment modality is surgical excision, which is usually performed by Large Loop Excision of the Transformation Zone (LLETZ). Surgical treatment of CIN lesions is associated with short-term side effects such as pain, prolonged bleeding and vaginal discharge, but also with the more serious long-term risk of premature birth in subsequent pregnancies.[34, 35] A recent meta-analysis shows that treatment of CIN with LLETZ increases the risk of overall premature birth (<37 weeks, RR 1.58 [1.37-1.81]), but also the risk of severe (<32- 34 weeks) and extreme premature (<28-30 weeks) birth (RR 2.13 [1.66-2.75] and 2.57 [1.97-3.35] respectively).[35] Interestingly, women with CIN showed a baseline increased risk of prematurity, regardless of treatment procedure. Nevertheless, increasing cone depth and repeated treatment further increased this risk, indicating that the increased risk of premature birth is at least in part due to cervical insufficiency after partial cervical excision. As CIN commonly affects young women in their fertile ages, this is a relevant side effect and prevention of unnecessary surgical treatment should be pursued in women with a future pregnancy desire. For this reason, guidelines have recently introduced the option of observational management for CIN2 lesions for younger women, as these lesions often show spontaneous regression and progression of CIN2 to cervical carcinoma on short term is rare.[36] Follow-up is performed by cytological examination. The recommendation upon conservative management of CIN2 lesions has led to a decrease in LLETZ treatment of CIN2 lesions, as was shown in a study among Boston women: LLETZ treatment of CIN2 decreased from 55% to 18% (p=0.04) in women aged 18-23. For women over 24, however, the LLETZ rate remained stable (70% vs 74%, p=0.72).[37] Although the treatment rate for CIN2 has declined, not all (young) women with a CIN2 lesion receive conservative management, for reasons unknown. Many of these women may become pregnant in the future and are thus at risk for premature birth. CIN3 lesions remain to be primarily treated by LLETZ, as they carry a higher risk of progression to cervical carcinoma than CIN2 and their potential of spontaneous regression is lower. These women too, are at risk for side effects. Importantly, a subset of their lesions would show spontaneous regression if left untreated, so overtreatment also occurs in women with CIN3. Taken together, a significant number of women with high-grade CIN is at risk for complications as a result of surgical treatment, including a subset of women whose lesions would show spontaneous regression if left untreated. To reduce the surgical treatment rate of high-grade CIN lesions, with the aim
Introduction
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