Age: The Most Important Risk Factor for Cervical Stenosis and Cervical Intraepithelial Neoplasia Recurrence After Cervical Conization

Cervical conization is the gold standard for treating cervical precancerous lesions, even in elderly patients who no longer desire fertility preservation [1].Cervical stenosis,a complication of conization, can occasionally lead toan unsatisfactory followup and post-conization unsatisfactory cytology or colposcopy. Reportedly, the frequency of cervical stenosis after loop excision and conization ranges from 5.4%-16.8% [2-6]. Moreover, the rate of recurrence after conization is approximately 6.6% [1]. Additionally, patients who were previously treated for cervical intraepithelial neoplasia (CIN) were observed to have an increased risk of cervical cancer[7], and the long-term risk of invasive cancer remained higher among women who were treated for CIN[8]. Cervical stenosis and unsatisfactory cytology or colposcopy are the significant factors preventing accurate cytology and colposcopy follow-up without missing relapses. This study aimed to evaluate the incidence of cervical stenosis and rate of recurrence after laser cone biopsy and to identify risk factors for these conditions.


Introduction
Cervical conization is the gold standard for treating cervical precancerous lesions, even in elderly patients who no longer desire fertility preservation [1].Cervical stenosis,a complication of conization, can occasionally lead toan unsatisfactory followup and post-conization unsatisfactory cytology or colposcopy. Reportedly, the frequency of cervical stenosis after loop excision and conization ranges from 5.4%-16.8% [2][3][4][5][6]. Moreover, the rate of recurrence after conization is approximately 6.6% [1]. Additionally, patients who were previously treated for cervical intraepithelial neoplasia (CIN) were observed to have an increased risk of cervical cancer [7], and the long-term risk of invasive cancer remained higher among women who were treated for CIN [8]. Cervical stenosis and unsatisfactory cytology or colposcopy are the significant factors preventing accurate cytology and colposcopy follow-up without missing relapses. This study aimed to evaluate the incidence of cervical stenosis and rate of recurrence after laser cone biopsy and to identify risk factors for these conditions. were reviewed from patient charts. This retrospective study was approved by the Institutional Review Board of our university (#1297) on June 6, 2018.
All patients were preoperatively diagnosed using cervical cytology, colposcopy, and directed biopsy. All patients underwent the same surgical protocol:CO 2 laser conizationusing a 40-W beam power and a 0.5-mm width spot. A Nelaton catheter (8Fr.) was retained in the cervical canal for 7 days after the procedure. The diameters of the excised cone samples were measured, and the samples were then pathologically diagnosed. Follow-up examinations were performed every alternate month for the first year and every 3-6 months thereafter. Cytological sampling was conductedat the same visit. Cervical stenosis wasdefined as cervical os narrowing, which prevented the insertion of acytobrush. Recurrence was defined as a histologically confirmed CIN2 or worse.
All statistical analyses were performed using JMP software version 10.0 (SAS Institute, Cary, NC, USA).Fischer's exact test wasused for analyzing categorical data. Multivariate analyses were used to evaluate associationsbetween clinical variables and postoperative cervicalstenosis or CIN recurrence. For multivariate analyses, a logistic regression model for cervical stenosis and a Cox proportional hazard model for CIN recurrence were used to identify variables with independent effects. CIN recurrence-free curves were estimated using the Kaplan-Meier method, and differences were assessed using the log-rank test. A p-value less than 0.05 was considered statistically significant.

Result
The enrolled patients had a median age of 43 (range, 27-89) years. The median follow-up period was 27 (range, 1-103) months. The pathological diagnoses of patients are shown in Table 1. Most of the patients (68.4%) were diagnosed with CIN3 or AIS. The median excised cone height was 11 (range, 2-30) mm. Additionally, surgical margins could be assessed in all patients. Pathological diagnoses revealed that CIN was involved in endocervical and vaginal surgical margins of 51(13.8%) and 13 patients (3.5%), respectively.  (Table 3). After CIN recurrence, six patients underwent reconization, seven underwent hysterectomy, and eight were closely followed-up.  In our study, only patient age (≥44 years) was a significant risk factor for both cervical stenosis and CIN recurrence. Eight of 29 patients (27.6%) who were ≥44 years and had positive surgical margins had CIN recurrence; the Kaplan-Meier curve of the CIN-free period of these patients was significantly shorter than that of patients with negative surgical margins (log-rank test, p < 0.0001) (Figure 1).

Discussion
In our study, 35 of 167 patients (21.0%) who were ≥44 years had cervical stenosis after laser conization, which occurred at a significantly higher rate than that in younger patients (2 of 203 patients, 1.0%). The multivariate analysis revealed that laser conization was a highly significant risk factor for cervical stenosis. Reportedly, old age is a risk factor for cervical stenosis.
Houlard et al. demonstrated that age was the only significant independent predictor of cervical stenosis, as identified in 40 of 375 patients treated with laser cone biopsy [4]. Penna et al. [5] stressed that the rate of cervical stenosis was higher in postmenopausal patients, leading to an unsatisfactory follow-up. Furthermore, a report from Japan showed that in a retrospective analysis of 522 cases, elderly patients (≥46 years) were at a higher risk of cervical stenosis and CIN recurrence [6]. Formerly, the volume of removed tissue and excision height were the primary factors associated with cervical stenosis [2,3]. However, recent publications show that patient age is a much stronger risk factor for cervical stenosis [4][5][6] because many elderly patients were treated with conization in recent studies, as in our study.
The surgical margin status represented the most important predictor for CIN recurrence after conization [1,9,10]. In our study, positive surgical margins were the most important risk factor for CIN recurrence after conization, which is consistent with previous reports. Furthermore, recent reports demonstrated that patient age was associated with a high risk of CIN recurrence [5,6]. These recent reports stressed the existence of a significantly higher association between cervical stenosis and CIN recurrence in elderly patients than that in young patients, which was consistent with our results.
In our study, only patient age (≥44 years) was a significant risk factor for both cervical stenosis and CIN recurrence. Furthermore, patients aged ≥44 years and with positive surgical margins exhibited a significantly higher rate of CIN recurrence and significantly shorter CIN-free period than those with negative surgical margins. Other surgical options such as subsequent hysterectomymay be considered and can be beneficial for such elderly patients.