Spontaneous regression rates of CIN2 of women over the age of 25 vary between 40 and 74%. It is important to note that CIN2 is the least reproducible of all cervical diagnoses and it is possible that the "regression" of CIN2 be due to a subjective interpretation of the pathologist who made the diagnosis. Thus "equivocal" CIN2 lesions increase the overall regression rate and, as a consequence, the regression may have been reported in excess [9]. The diagnosis of CIN2 cannot be reliably differentiated only with histopathological criteria.
The literature indicates a better agreement between pathologists of diagnosis of CIN2 when the H&E morphology is used together with p16 compared to the H&E morphology alone. The p16 protein when positive in a CIN2 suspect gives us the confidence of having selected true CIN2 cases. These are the cases for which the spontaneous regression rate must be studied, therefore the need for a prospective study that studies the regression potential of true CIN2 (positive CIN2 p16) in women over the age of 25.
Not all preneoplastic lesions will progress to cancer, therefore regardless of the positivity of p16 we cannot yet accurately predict which lesions would become malignant if left untreated. According to the 2006 American Society for Colposcopy and Cervical Pathology guidelines [6], positive CIN2 p16 in women over the age of 25 should be managed with excisional treatments. Treatment should be effective in eradicating CIN2 lesion and have minimum adverse effects on future fertility and pregnancy outcomes, particularly in young women. However, excisional treatments are associated with physical, psychological [10] and obstetric [11] morbidity and can have a negative impact on sexual function [12, 13].
In our study we sought to identify a clear management strategy, address the impact of routine use of p16 immunohistochemistry in this population and identify appropriate criteria for patient selection with the aim of reducing over-treatment.
LEEP (Loop Electrosurgical Excision Procedure), as an excisional procedure of the cervix, is the most used surgical treatment for programs of cervical screening in developed countries. [14]. Some advantages of LEEP have been shown, among which is the excision of the entire transformation zone, the conservation of tissue samples for histological evaluation, low-cost equipment and the rapid rehabilitation of the cervix [11]. Thanks to these advantages, both in diagnosis and in CIN treatment, the ASCCP recommends LEEP as the excisional procedure for CIN2 +.
Kyrgiou et al. [11] reported higher rates of preterm membrane rupture after LEEP compared to ablative surgery, indicating that ablative surgery such as laser vaporization should be chosen as the least invasive surgery for CIN. In a meta-analysis [15], LEEP was associated with significantly higher risks of perinatal mortality, preterm birth. Cochrane’s revision reported three comparative studies on laser ablation with respect to LEEP [14] and did not show significative differences in the risk of residual disease in the women who had received laser ablation or LEEP.
Other author [16] reported a relapse of only 2.5% at 5 years after laser treatment of high-grade lesions, with adequate biopsies, with completely visible margins, carried out by colposcopy experts.
In the laser treated women in this study, we found only one case of progression to CIN3 and no relapse at 2 years of follow-up. Multiple infections showed a greater regression rate, unlike single infections with a greater rate of histological persistence. Undoubtedly, single infection, the presence of genotype 16 and one lesion greater than three quarters of the cervix are positively associated with persistence and progression, Castle [5, 17] reported that CIN2 caused by HPV 16 may be more likely to progress than CIN2 caused by other HR genotypes. In our study, we noticed that cases associated with multiple infection respond well to conservative therapy. Of course, the selection of cases to be treated is vital and, given that the literature [18] shows a risk of recurrence for up to 10 years for ablative treatments, strict post-treatment follow-up protocols are necessary, which contemplate the use of the HPV test. In recent years, several studies have shown that the HPV test performed 6–12 months after treatment is more sensitive than cytology in identifying women with recurrent disease and has a very hight negative predictive value [19, 20, 21].
Therefore, in patients correctly selected such as non-immunocompromised women, young women (younger than 25 years) with infections from HPV16 (CIN2 in the presence of HPV 16 has less probability of regression), cases in which the squamocolumnar junction is completely visible, the lesion is not very extended, and with multiple infections, a more conservative management of the CIN2 p16 positive is possible. Notwithstanding the limits of the retrospective analysis of the data, our results indicate that laser therapy is efficacious in the conservative treatment of CIN2 p16 positive in carefully selected women. The persistence of the infection from high-risk HPV at follow-up is a significative predictive factor of residual or recurrent CIN after surgery [22, 23]. Vaccination with the nonovalent HPV vaccine [24] among the patients aged between 20- and 45-years old undergoing treatment for CIN2 is a valid addition in the prevention of recurrence.