Comparative outcomes of excision and active surveillance for cervical intraepithelial neoplasia 2 in women under 35: a single institutional retrospective study

Abstract

Objective

This study aimed to compare the outcomes of excision (conization) and active surveillance in women under 35 years of age diagnosed with cervical intraepithelial neoplasia 2 (CIN 2) on disease regression to normal cervical cytology and the effectiveness of nonsurgical management.

Methods

This retrospective cohort study was conducted at CHA University Ilsan Medical Center. Women under 35 diagnosed with CIN 2 were included and divided into two groups based on the management strategy: excisional treatment or active surveillance. Data on patient outcomes, including the regression time to normal cytology, were retrospectively collected and analyzed.

Results

The follow-up period ranged from 2.73 months to 42.6 months, with a median follow-up period of 6.8 months. Management strategies between the excisional procedure and active surveillance were not associated with the cytological normalization from CIN 2 (P=0.32). The median time to achieve normal cytology was 7.4 months (95% confidence interval [CI], 6.08–8.77) in the excision group and 12.8 months (95% CI, 10.34–15.22) in the active surveillance group (P=0.22). This trend was observed across the following age groups: 20–24, 25–29, and 30–34 years (20–24, P=0.96; 25–29, P=0.67; and 30–34, P=0.99).

Conclusion

There was no significant difference between the excisional procedure and active surveillance in terms of achieving normalized cytology from CIN 2. Active surveillance is a feasible option for managing CIN 2 in women under 35 years of age.

Introduction

Cervical intraepithelial neoplasia (CIN) encompasses a spectrum of premalignant lesions that have the potential to progress to invasive cervical cancer. CIN 3 has a substantial risk of malignant transformation if left untreated, with a reported cumulative incidence of 31.3% over 30 years [1]. In contrast, CIN 2 has a reported regression rate of 50–60%, with a cumulative cancer risk of 0.5% within 2 years, according to a recent meta-analysis [2]. Although the regression rate of CIN 2 is lower than that of CIN 1, which ranges between 70–90%, this still supports the rationale for the conservative management of CIN 2, as is done for CIN 1 [3]. Thus, the optimal management strategy for CIN 2 remains controversial, with an ongoing debate between conservative observation and excisional treatment.

The incidence of CIN 2 has been increasing, particularly among young women. Data from the Korean Health Insurance Review and Assessment Service indicate that CIN 2 is most prevalent among women aged 25–34 years in Korea [4]. Globally, its incidence reaches up to 1.5 per 1,000 women in this age group, with the highest rates observed among younger women [5]. This trend highlights the need for effective and safe management strategies that prioritize fertility preservation in young women diagnosed with CIN 2.

Excisional procedures, the standard treatment for CIN, are associated with an increased risk of cervical insufficiency and preterm birth [6]. The 2019 guidelines from the American Society of Colposcopy and Cervical Pathology (ASCCP) recommend conservative management of CIN 2 in women younger than 25 years, prioritizing future reproductive health [7]. With the global trend of delayed marriage and childbearing, concerns about the impact of CIN 2 treatment on fertility have grown. Thus, assessing whether conservative management guidelines can be safely extended beyond the age of 25 years, potentially up to the mid-30s, without compromising oncologic outcomes is essential. Although a recent meta-analysis suggested expanding conservative management to women under 30, data on its safety and efficacy in women under 35 remain limited [2]. This study aimed to compare the regression rate over time between excisional treatment and active surveillance in women younger than 35 diagnosed with CIN 2, providing evidence to inform optimal management strategies for this patient population.

Materials and methods

1. Study population

The study protocol was reviewed and approved by the Institutional Review Board (IRB) of CHA University Ilsan Medical Center (IRB number: 2021-07-008-002). The requirement for informed consent was waived due to the retrospective nature of the study and patient data were anonymized to ensure confidentiality.

The study population included women aged 20–34 years who were diagnosed with biopsy-confirmed CIN 2 between December 2019 and July 2021 at CHA University Ilsan Medical Center. Patients were followed-up until December 2023. CIN 2 is classified as N87.1 by the International Classification of Diseases, 10th revision system, and is diagnosed based on histopathological findings of P16 positivity.

Patients were divided into two groups based on the treatment received: an active surveillance group and an excision group. Active surveillance was chosen for women who preferred a noninvasive approach to avoid surgical excision, particularly if they desired future pregnancy. The included women were managed conservatively with at least 3 months follow-up cytology. The excision group included women who underwent conization via a loop electrosurgical excision procedure. Women were excluded if they had a history of cervical cancer or CIN 3, were immunocompromised, or were pregnant at the time of diagnosis.

2. Data collection

Data were collected by retrospectively extracting information from electronic medical records, including age group at 5-year intervals, body mass index (BMI) (kg/m²), parity, smoking status, high-risk human papillomavirus (HPV) infection and genotype, histopathological findings, such as resection margin involvement of the conization tissue, and the period from the initial biopsy to normalized negative cytology.

Follow-up was censored when the cytological results were negative for malignancy. Cervical cytology was performed using the ThinPrep^® Pap test (Hologic, Marlborough, MA, USA). High-risk HPV was detected using real-time polymerase chain reaction with STARMag 96×4 Universial Cartridge Kit (Seegene, Seoul, Korea) and HPV subtypes 16, 18, 31, 26, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 69, 73, and 82 were identified using the Anyplex™ II HPV28 Detection assay (Seegene).

3. Outcome measures and statistical analysis

The primary outcome measure was the rate of regression to normal cytology from CIN 2 within the follow-up period in the active surveillance and excision groups. Secondary outcomes included the time to normalization and factors influencing regression.

Statistical analyses were performed using the IBM SPSS statistics software version 25.0 (IBM, Armonk, NY, USA). Descriptive statistics were used to summarize the baseline characteristics of the study population, with chi-square tests used for categorical variables such as age group, parity, smoking status, and HPV infection, and t-tests for continuous variables including BMI, time to normalized cytology, and follow-up period. Kaplan-Meier survival analyses with log-rank tests were performed to analyze the normalized rates according to the follow-up time. Cox proportional hazard models identified predictors of hazard ratios for covariates affecting normalization from CIN 2. Statistical significance was defined as a two-sided P-value <0.05.

Results

1. Patient allocation

A total of 192 women were included in this study. After excluding 28 women with a follow-up period of less than 2 months, 164 participants were included in the final analysis (Fig. 1). The included women were followed up until their cytology results normalized or the end of the study. The follow-up period ranged from 2.73 months to 42.6 months, with a median follow-up period of 6.8 months.

Fig. 1.

Flowchart of study population. CIN, cervical intraepithelial neoplasia; ASCUS, atypical squamous cells of undetermined significance; LSIL, low-grade squamous intraepithelial lesions; HSIL, high-grade squamous intraepithelial lesions; ASC-H, atypical squamous cells that cannot exclude HSIL.

The control group for active surveillance initially consisted of 63 women, but 27 women were excluded owing to loss to follow-up. Finally, a total of 36 women were followed-up with cytology. Among these, 19 women achieved a negative Pap smear, while 17 had abnormal Pap smear results during the follow-up period: eight cases of atypical squamous cells of undetermined significance (ASC-US), two with low-grade squamous intraepithelial lesions (LSIL), one with high-grade squamous intraepithelial lesions (HSIL), and six with atypical squamous cells that cannot exclude HSIL (ASC-H). Among the women with abnormal Pap smears, seven with HSIL or ASC-H underwent conization. Of these, three were diagnosed with CIN 3, three with CIN 2, and one with chronic cervicitis.

The conization group initially consisted of 101 women; however, 11 patients were excluded due to loss to follow-up. Finally, a total of 90 women were included in the final group. The pathological results after conization varied: seven (7.7%) had chronic cervicitis or inflammation, nine (10.0%) had CIN 1, 39 (43.3%) had CIN 2, and 35 (38.9%) had CIN 3. A positive resection margin of the conization specimen was found in six cases (6.7%). After the excisional procedure, 70 patients achieved normal cytology, while 20 showed abnormal cytology during the follow-up periods: 12 cases of ASCUS, six of LSIL, and two of ASC-H. Of these, 18 patients continued with observation, and two underwent laser vaporization as they declined further excisional treatment.

2. Baseline characteristics

The baseline characteristics of the study population in the active surveillance and excision groups are summarized in Table 1. There was a trend of a higher proportion of patients aged ≥25 in the excision group compared to the active surveillance group, but the difference was not statistically significant. BMI, parity, and smoking status were not significantly different between the groups. High-risk HPV infection, multiple high-risk HPV infections, and HPV 16 or 18 genotypes were also not significantly different between groups. During the study period, the time from CIN 2 to the normalization of cytology was not significantly different between the active surveillance group and the excision group.

Table 1.

Baseline characteristics and follow-up outcomes by the management group

Characteristic	Active surveillance (n=36)	Excision (n=90)	P-value
Age (yr)			0.05
20–24	11 (30.5)	11 (12.2)
25–29	14 (39.0)	43 (47.8)
30–34	11 (30.5)	36 (40.0)
BMI (kg/m2)	20.4±2.2	20.9±2.7	0.35
Parity			0.28
0	34 (94.4)	75 (83.3)
1	2 (5.6)	13 (14.5)
2	0 (0.0)	2 (2.2)
Smoking			0.43
Never	29 (87.9)	72 (79.8)
Current smoker	4 (12.1)	18 (20.2)
High-risk HPV infection			1.00
High-risk HPV positivity	33 (94.3)	82 (94.3)	1.00
Multiple high-risk HPV infection	16 (45.7)	40 (46.0)	0.08
HPV 16 or 18 genotyping	6 (17.6)	31 (35.6)	0.08
Period to normal cytology (months)	9.9±6.4	8.3±6.1	0.32
Follow-up periods (months)	12.3±8.7	14.8±9.9	0.18

Values are presented as number (%) or mean±standard deviation or number.

BMI, body mass index; HPV, human papillomavirus.

3. Variables for normalized cytology

The analysis of the variables associated with the time to achieve normalized cytology, including the management method, is summarized in Table 2. The following factors were not significantly associated with achieving cytologic normalization: age group 30–34 compared to 20–29, smoking status, and high-risk HPV infection. Additionally, the management method such as active surveillance or excisional procedure was not significantly associated with cytologic normalization (hazard ratio for excision, 1.33; 95% confidence interval [CI], 0.76–2.35; P=0.32; with active surveillance as a reference).

Table 2.

Factors to involve normalized cytology from CIN

	HR	95% CI	P-value
Age group (yr)
20–29		Reference
30–34	0.70	0.44–1.11	0.13
Smoking
No history of smoking		Reference
Current smoker	1.00	0.54–1.82	0.99
High-risk HPV infection
No high-risk HPV infection		Reference
High-risk HPV infection	1.26	0.45–3.51	0.66
Management
Active surveillance		Reference
Excision	1.33	0.76–2.35	0.32

CIN, cervical intraepithelial neoplasia; HR, hazard ratio; CI, confidence interval; HPV, human papillomavirus.

4. The cumulative probability of achieving a normal Pap smear

Fig. 2 illustrates the cumulative probability of achieving a normal Pap smear during the follow-up period by comparing the active surveillance and excision groups. The excision group showed a rapid increase in the rate of normal cytological findings during the early months of follow-up. The median time to achieve normal cytology was 12.8 months (95% CI, 10.34–15.22) in the active surveillance group and 7.4 months (95% CI, 6.08–8.77) in the excision group (P=0.22). The Kaplan-Meier curves for the two groups converged at approximately 18.8 months.

Fig. 2.

Kaplan-Meier curves of cumulative probability for normalized Pap test from CIN 2 on initial cervical biopsy during follow-up periods. CIN, cervical intraepithelial neoplasia.

Similar to the overall population, the excision groups in the age ranges of 20–24, 25–29, and 30–34 years achieved a normal Pap smear earlier in the follow-up period than the active surveillance group (Fig. 3). There was no significant difference in the time to achieve cytologic normalization between the two groups across all age categories (ages 20–24, P=0.96; ages 25–29, P=0.67; ages 30–34, P=0.99, respectively). Median time to cytologic normalization from CIN 2 for active surveillance versus excision was 19.5 months vs. 8.1 months (ages 20–24), 15.3 months vs. 7.6 months (ages 25–29), and 6.8 months vs. 6.7 months (ages 30–34).

Fig. 3.

Kaplan-Meier curves of cumulative probability for normalized Pap test based on age groups. (A) Ages 20–24, (B) ages 25–29, and (C) ages 30–34. HR, hazard ratio; CI, confidence interval.

Discussion

In this study, we compared the outcomes of excision and active surveillance in women aged <35 years who were pathologically diagnosed with CIN 2. Our findings demonstrate that although excision initially results in a higher rate of achieving a normal Pap smear rapidly, active surveillance can also lead to normalization over a longer follow-up period, with no statistically significant differences between the two approaches. This was consistent across the overall population as well as within the different age subgroups (20–24, 25–29, and 30–34 years). By approximately 18.8 months, the normalization curves for the excision and active surveillance groups converged in our study population.

While excisional procedures such as conization are effective in rapidly achieving normal cytology from CIN 2, they might induce cervical insufficiency to induce preterm labor and preterm delivery [8]. Conversely, active surveillance helps avoid these surgical risks and offers a noninvasive management option with comparable long-term outcomes. This study supports extending the eligible age for observation of CIN 2 to 35 years for women who desire pregnancy.

Our results align with those of previous studies, suggesting that conservative management such as active surveillance can be an effective alternative to surgical intervention for CIN 2 in young women. A study reviewing the management and outcomes of CIN 2 in women younger than 25 years reported that 71.1% of those managed conservatively experienced regression with no cases progressing to invasive cancer during a median follow-up of 15.1 months [9]. Furthermore, a meta-analysis demonstrated a high regression rate of CIN 2 in young women under 30 years, with a regression rate of 60% during a follow-up period of 24 months (95% CI, 57–63%) [2]. A nationwide register-based cohort study involving Danish women aged 18–44 years reported that the regression rate of CIN 2 did not differ significantly between women under 30 and those older than 30 years of age [10].

The 2019 ASCCP guidelines recommended the observation of young women under 25 years of age with CIN 2 given the high likelihood of regression and low risk of progression to invasive cancer. Observation is also considered an acceptable option for women over 25 years of age with CIN 2 who desire future pregnancy because it balances the benefits of conservative management with the potential risks associated with invasive procedures. However, these guidelines do not clearly specify the upper age which observation is no longer recommended.

The 2012 lower anogenital squamous terminology (LAST) project introduced a 2-tiered system of LSIL and HSIL, replacing the previous 3-tiered classification of CIN 1, CIN 2, and CIN 3 [11,12]. According to the LAST project, the clinical significance of CIN 2 diagnosis has become less distinct. However, in women under 35 years of age, a CIN 2 diagnosis remains important to determine management strategies for the reproductive needs of patients. Our study supports the evidence for extending the age limit for conservative management in women with CIN 2.

This study had some limitations. First, the retrospective design may have introduced selection bias, as the decision between conization and active surveillance depends on the physician’s judgement and the patient’s desire for future pregnancy. Indeed, the young women with CIN 2 had different needs for future pregnancy in our study. A well-designed prospective study is needed to validate these findings. Second, the relatively small sample size may impact the generalizability of our findings. However, our study was conducted at a single institution with a relatively small sample size and a sufficiently long follow-up period allowed of our study to deduce meaningful results of the normalization rate over time. Third, we adopted the Pap test to define normalization from CIN 2. Although cervical cytology alone is insufficient to confirm true normalization, and histologic verification via biopsy is required, performing biopsies in all patients with negative Pap test results is not feasible in routine clinical practice. Even in recent large observational studies, cervical cytology has been regarded as a key parameter for assessing disease progression or regression of CIN 2 [13]. A prospective study incorporating cervical biopsies with informed consent would be needed to address this limitation. Finally, the study did not assess high-risk HPV eradication or recurrence during follow-up periods. HPV clearance typically occurs within 18 months of infection [14,15], but persistent HPV infection following treatment, such as excision, has been identified as a risk factor for recurrent CIN [16]. Future prospective studies are needed to evaluate the outcomes associated with persistent high-risk HPV infections according to the management methods for CIN 2.

While conization offers a rapid method for achieving normal cytology, active surveillance represents a viable and noninvasive alternative with comparable long-term outcomes in women under the age of 35 with CIN 2. These findings support the need for consideration of active surveillance as part of individualized treatment strategies for these patients above, to provide a balance between effective disease management and minimizing unnecessary surgical interventions. Future research should focus on prospective studies to validate these findings and further explore the long-term outcomes of active surveillance versus conization. Additionally, investigating the psychological impact and quality of life of women undergoing these different management strategies will provide a more comprehensive understanding of the adequate approaches for managing CIN 2.