Cervical squamous intraepithelial lesions (SIL) are identified as early pathological changes that may develop into cervical cancer [1]. According to the 2014 World Health Organization (WHO) classification, these lesions are categorized into low-grade (LSIL) and high-grade (HSIL) [2, 3]. Globally, LSIL accounts for approximately 1.7% of all cervical cytology results, while HSIL comprises about 0.3% [4, 5]. Although many LSIL cases may regress spontaneously, a subset can progress to HSIL and eventually to cervical cancer. The progression from LSIL to carcinoma in situ or invasive cervical cancer typically spans 5 to 10 years [6]. Once progression to cervical cancer occurs, it poses a significant threat to women’s health. Cervical cancer ranks as the fourth most common cancer among women worldwide, leading to substantial morbidity and mortality [7]. It can result in compromised fertility and diminished quality of life. What’s more, epidemiological data indicate an annual incidence of approximately 1.39 cases of cervical precancerous lesions per 1000 women [8]. LSIL is more prevalent among women under 30, whereas the incidence of HSIL increases with age, particularly in those over 40 [9]. These patterns underscore the critical importance of early screening and monitoring to identify high-risk individuals, thereby reducing the incidence of cervical cancer [10].

Currently, there is a significant difference in the treatment strategies for LSIL and HSIL. LSIL patients are typically associated with human papillomavirus (HPV) infection, which may resolve spontaneously. Therefore, conservative management, primarily involving regular follow-up and monitoring, is generally employed [11]. In contrast, HSIL patients have a higher risk of progressing to cervical cancer and require more aggressive interventions, such as conization, cryotherapy, or laser treatment [12]. Clinically, it has been observed that some LSIL patients may be overtreated, leading to unnecessary medical interventions and potential complications [13]. Over-treatment not only increases the psychological and financial burden on patients but may also have adverse effects on fertility. Given that LSIL can resolve over time, monitoring rather than invasive interventions is usually recommended, especially for patients who wish to conceive. On the other hand, monitoring of HSIL relies on cytological screening, and the success of early detection depends on the effectiveness of screening techniques and management of high-risk populations [14]. However, some high-risk women may not receive adequate follow-up after screening, allowing the lesions to progress [15]. Therefore, accurately identifying individuals at high risk for progression and providing preventive advice and lifestyle modification strategies are crucial for improving patient outcomes.

Based on this, the present study focused on patients diagnosed with LSIL at our institution who underwent monitoring only, without receiving treatment. These patients were observed over a 3-year period to assess whether they progressed to HSIL or malignant tumors. Clinical and pathological data were collected and analyzed to develop a predictive model for evaluating the risk of progression. This model aims to assist clinicians in identifying high-risk patients and implementing timely interventions. For low-risk patients, enhanced monitoring can be adopted to avoid unnecessary treatment, thereby facilitating individualized clinical management and optimizing the utilization of healthcare resources.

LSIL represents early cervical changes that may precede the development of cervical cancer, with their progression influenced by the persistence or recurrence of cervical symptoms such as abnormal bleeding, increased discharge, and postcoital spotting [18]. These symptoms often reflect chronic cervical inflammation or persistent high-risk HPV infection, both of which can disrupt the cervical microenvironment. Chronic inflammation, driven by cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-$\alpha$), promotes cellular proliferation, reduces apoptosis, and induces oxidative stress, leading to DNA damage and genetic mutations [19]. Additionally, recurrent symptoms may indicate immune dysregulation, such as reduced antigen-presenting activity and a shift toward immune tolerance, allowing HPV persistence and increasing dysplasia risk [20]. Symptoms like bleeding and discharge may also physically disrupt the cervical epithelium, making it more susceptible to HPV integration and lesion advancement [21]. Given the critical role of monitoring in the progression of LSIL, a study has consistently observed varying rates of progression to higher-grade lesions depending on the presence of persistent symptoms and underlying immune dysregulation [22]. A previous study has shown that approximately 12% of untreated LSIL patients progress to HSIL within 2 years [23]. In this study, with a 3-year follow-up, 11 out of 122 LSIL patients who received monitoring only (9.01%) progressed to HSIL. This progression rate is slightly lower than the 12% reported in the previous study [23], which may be attributed to regional differences. In addition, we speculate that although patients diagnosed with LSIL declined pharmacological intervention, our healthcare team provided comprehensive guidance emphasizing the importance of maintaining a healthy vaginal environment, adhering to regular sleep patterns, practicing safe and consistent sexual habits, ensuring balanced nutrition, managing stress levels, and engaging in moderate physical exercise. During subsequent follow-up visits, most patients reportedly complied with these recommendations, which may have also contributed to the relatively low progression rate observed in our cohort. However, a follow-up study in Italy, which tracked the progression of LSIL in women over a 4-year period, involved biopsy every 6 months for all participants. The results showed that only 1.5% (7/475) of LSIL patients progressed to CIN3, and all of these cases were associated with persistent high-risk HPV infection [24]. The low incidence of CIN3 (1.5%) after LSIL diagnosis was attributed to possible underdiagnosis of HSIL at the time of initial biopsy. A similar study by Mahira Jahic and colleagues [25], monitoring the progression of LSIL patients from multiple private gynecology clinics between 2016 and 2019, found that 9.6% of LSIL cases progressed within one year, which is consistent with our findings. In our study, we identified for the first time that, unlike single HPV infections and vaginal symptoms, persistent high-risk HPV infection and recurrent symptoms were significantly associated with progression to HSIL. As a result, we have also developed a cumulative risk curve and a predictive model for progression. The cumulative risk curve reveals a significant increase in the risk of progression to HSIL after 25 months of follow-up, with a more pronounced escalation during the later stages. This trend may be linked to HPV clearance rates, as studies have shown that HPV clearance gradually declines over time, particularly after 24 months of infection [26, 27]. persistent high-risk HPV infection is strongly associated with the development of high-grade lesions. While the immune system may initially control the infection, prolonged persistence, especially involving high-risk HPV types such as HPV 16 and 18, can eventually overcome the host’s immune defenses. This process can lead to genomic instability and viral DNA integration into host cells [28].

This study found that persistent high-risk HPV infection is an independent risk factor for the progression of LSIL to HSIL and significantly increases the risk of progression (OR = 7.67, p = 0.027). This result is consistent with several existing studies [29, 30], which have shown that persistent high-risk HPV infection is a critical factor in the progression of LSIL to HSIL or cancer. Zhao et al. [31] noted that persistent high-risk HPV infection not only increases the incidence of cervical intraepithelial neoplasia (CIN) but is also closely associated with the development of cervical cancer. Furthermore, the antiretroviral therapy (ART) and HPV Review Group (2017) reported that immune dysfunction, such as in HIV-infected individuals, exacerbates the persistence of HPV infection and accelerates the progression of lesions. This is particularly evident in immunocompromised populations, where persistent high-risk HPV infection is the primary driver of cervical lesion progression [32]. Related studies also highlight the decisive role of persistent high-risk HPV infection and local inflammatory responses in the deterioration of LSIL [33, 34]. These findings further support the results of this study, emphasizing the critical role of persistent high-risk HPV infection in the progression of LSIL to HSIL.

In previous studies, age, socioeconomic status (SES), and sexual history have also been identified as significant risk factors for the progression of LSIL to HSIL [35, 36, 37]. According to research by Evered [38], younger women, particularly those under 30, often experience a higher prevalence of LSIL due to the transient nature of HPV infections in this age group; however, their risk of progression to HSIL is relatively low. In contrast, women with lower SES often face barriers to screening and treatment, leading to more advanced lesions at the time of diagnosis [39]. The number of sexual partners and engagement in high-risk sexual behaviors increase the likelihood of HPV exposure and the persistence of infection [32]. These social and behavioral factors are closely linked to the persistence of HPV infection, which is the fundamental cause of lesion progression. Ultimately, factors such as lower socioeconomic status or having multiple sexual partners increase the likelihood of sustained HPV exposure, which in turn raises the risk of lesion progression.

This study also found that the persistence or recurrence of symptoms is an independent risk factor for the progression of LSIL to HSIL (OR = 21.07, p 0.001). This result suggests that persistent or recurrent symptoms, such as abnormal bleeding or increased discharge, may reflect ongoing HPV infection or local cervical inflammation, which could promote lesion progression through alterations in the immune microenvironment. Tengfei Long et al. [40] also found that chronic cervical inflammation can accelerate the transformation of epithelial cells by altering the local immune response, thereby driving the progression of lesions to higher grades. Therefore, for patients with persistent or recurrent symptoms, it is recommended to closely monitor their condition, improve lifestyle habits, and avoid detrimental factors such as excessive fatigue and unprotected sexual activity. Furthermore, early intervention should be promptly implemented when necessary, including regular follow-up and targeted treatments, to prevent further deterioration of the lesions. On the other hand, for women newly diagnosed with LSIL who have no HPV infection or recurrent, persistent vaginal symptoms, their condition is highly likely to cease progressing or even regress with lifestyle modifications and appropriate treatment, and there is no need for excessive concern.

Based on the results of the multivariate analysis in this study, we developed a predictive model that includes persistent high-risk HPV infection and the persistence or recurrence of symptoms. This model demonstrated good predictive ability in both the training cohort (AUC = 0.92) and the validation cohort (AUC = 0.88). Using this model, clinicians can identify high-risk patients and implement early interventions to prevent further progression of the lesions. This model not only showed excellent performance in this study but also aligns with the potential application of existing data-driven predictive tools in clinical practice [41]. Such a personalized risk prediction tool helps improve the precision of clinical decision-making, particularly in resource-limited settings, where it can effectively identify high-risk patients for early intervention.

Despite the valuable clinical insights provided by this study, several limitations remain. First, the sample size is relatively small, which may affect the generalizability of the results, particularly in the evaluation of rare factors [42]. Second, the data for this study were sourced from a single center, which may introduce limitations due to regional and ethnic factors, potentially affecting the external validity of the results. The retrospective design may lead to information bias, and the small number of events for some predictive factors could impact the stability of the model [43]. Additionally, handling of missing data may introduce bias into the analysis. Furthermore, the 3-year observation period may have missed cases where progression occurred after this time frame, potentially underestimating the true rate of progression. Nevertheless, this study explored early trends in the progression of cervical dysplasia and provides preliminary data for future research. We believe these findings are of exploratory significance and offer valuable insights for guiding clinical practice and subsequent studies. Therefore, future studies should aim to increase the sample size and incorporate multi-center data for validation, extend the follow-up period to capture long-term progression, and explore other potential risk factors, such as host immune status, to further refine the predictive model and enhance its ability to predict the risk of progression in LSIL patients.

This study confirms that persistent high-risk HPV infection and the persistence or recurrence of symptoms are independent risk factors for the progression of LSIL to HSIL, and it has developed an effective predictive model to assist clinicians in identifying high-risk patients. The model demonstrated good predictive ability in both the training and validation cohorts, showing strong clinical applicability. persistent high-risk HPV infection, as the core driver of progression, highlights the importance of effective monitoring and intervention for high-risk HPV infections. Additionally, the persistence or recurrence of symptoms may reflect chronic inflammation or changes in the immune microenvironment, which further accelerate the progression of lesions. Therefore, for patients exhibiting these clinical signs, enhanced follow-up and early intervention are crucial.

LSIL, low-grade squamous intraepithelial lesions; HSIL, high-grade squamous intraepithelial lesions; HPV, human papillomavirus; OR, odds ratio; AUC, area under the curve; SIL, cervical squamous intraepithelial lesions; ROC, the receiver operating characteristic curve; IUD, intrauterine device; CI, confidence interval; DCA, decision curve analysis; CIN, cervical intraepithelial neoplasia; ART, antiretroviral therapy; IC, internal control; MRI, magnetic resonance imaging; CT, computed tomography.

The data supporting the findings of this study are available upon reasonable request from the corresponding author.

HZ contributed to the design, data collection, supervision, compilation, and writing of the manuscript. YF was responsible for the organization, conceptualization, methodology, and revision of the study. Both authors read and approved the final manuscript. Both authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This research was carried out in accordance with the guidelines of the Declaration of Helsinki and was approved by the Wu Yi Maternal & Child Care Hospital Ethics Committee, with ethics approval number 2024112201. Throughout the study, the privacy of participants was safeguarded, and all data were subjected to anonymization processes to ensure confidentiality. All procedures were conducted in accordance with the participants’ signed informed consent.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/CEOG36364.