Focused ultrasound versus the loop electrosurgical excision procedure to treat women with cervical high-grade squamous intraepithelial lesions under 40: a retrospective study

Appropriate management of HSILs is crucial for the success of screening programs aimed at reducing the incidence of cervical cancer. Unfortunately, the screening of HSILs in LMICs is not quite effective partly due to the lack of appropriate treatment available for women with HSILs. The major challenge in screening HSILs is the lack of well-trained medical personnel who can perform colposcopy and provide treatment in primary healthcare facilities [1, 20]. The removal of HSILs via LEEP is an effective and safe treatment option, with low recurrence rates and high HPV clearance rates [12]. However, compared with ablation, LEEP requires highly skilled medical personnel and expensive equipment, produces odor and possible viral-laden smoke, and increases the risk of preterm labor in subsequent pregnancies in women of reproductive age.

FUS is a new, promising, noninvasive ablation-based therapeutic modality for cervical lesions. Similar to other ablative therapies, it does not provide tissue samples for further histological assessment. However, compared with other ablative therapies, FUS is an “inside–out” treatment method with a remarkable penetration depth of 3–6 mm [14], which exceeds the reported average depth of cervical intraepithelial neoplasia grade 3 (CIN3) (1.4 mm) [21]. From a practical perspective, FUS offers several advantages over conventional treatment methods. First, FUS equipment is more economical than other surgical tools, making it a cost-effective option for patients and healthcare providers. Second, the duration of operative training required to perform FUS procedures is shorter than that required to perform traditional treatment methods. Therefore, medical professionals can quickly learn to perform FUS and administer quality treatments to patients. Lastly, FUS offers conformal therapy, which is achieved by moving the probe. Previous studies have confirmed that the effectiveness, acceptability, and safety of FUS for the treatment of HPV-related cervicitis or cervical lesions [13‐17]. Improvements in the availability and accessibility of precancer treatment can facilitate the use of FUS to treat patients with HSILs in low-resource settings, which can be appropriately performed by trained mid-level providers in primary healthcare services.

In this retrospective cohort study, patients in the LEEP group had higher median age and parity than those in the FUS group, which is consistent with observations made in clinical practice. Owing to the inherent biases of the retrospective study design, selection bias may have influenced the reported results. Therefore, we performed univariate and multivariate logistic regression analyses to reduce possible confounding factors. To ensure the comparability of the FUS and LEEP groups, we analyzed factors that may affect the treatment efficacy and HPV clearance using logistic regression. Both univariate and multivariate logistic regression analyses showed that no relevant factors significantly affected the cure and HPV clearance rates. However, future prospective randomized controlled trials are warranted to compare the efficacy of these two therapeutic approaches.

In terms of efficacy, the cure and recurrence rates of HSILs were comparable between the two treatment methods. The cure rate of LEEP in our study was slightly higher than that of FUS, although the difference was not statistically significant. The disease-free incidence was also higher in our study than that reported in most previous studies [22‐25];  however, the recurrence rate of LEEP was similar [11, 22]. Differences in the study methods, follow-up periods, and selection criteria may account for this discrepancy. Regarding FUS efficacy, our results showed that FUS was at par with LEEP, with a cure rate of 89.11% during the 3–6 months follow-up and a recurrence rate of 2.22% during the 6–12 months follow-up. These results are consistent with the effectiveness of FUS determined in similar settings in previous studies, such as our previous studies that reported cure rates of 88.90–89.70% [14‐15] and study conducted by Zhou et al. [17] that reported the cure rate of 82.80%. However, no recurrence was observed in patients with biopsy-proven HSILs receiving FUS in our previous studies. The higher recurrence rates in this study can be attributed to the difference in study methods and sample sizes. The role of persistent HR-HPV infection in determining the occurrence or recurrence of HSIL and cervical cancer is well established [2, 4‐7]. Recently, a retrospective study for the first time reported that the risk of HSIL recurrence increased with the duration of HPV persistence (< 1 year). However, the persistence of HPV for > 1 year was not considered a risk factor [26].

Persistent HPV infection is the main risk factor for the persistence or recurrence of HSIL after treatment [27]. It has been shown that HPV test is highly sensitive, with a negative predictive value of approximately 98% for detecting recurrence at 6 months after treatment [28]. This indicates that women with negative HPV results after the treatment are at a low risk of recurrence [18]. Furthermore, persistent HPV infection might be an important cause of preterm labor [29, 30]. These findings indicate that patients with a negative HPV post-treatment status have a low risk of preterm labor. Therefore, the HPV post-treatment status should be considered when further determining the impact of FUS and LEEP on fertility outcomes. Notably, our study found no significant difference in HPV negativity rates after either FUS or LEEP (74.23% vs. 82.79% during the 3–6 months follow-up and 84.95% and 89.17% during the 6–12 months follow-up). The HPV of FUS was consistent with that reported in our previous studies [14‐15], but it was lower than that reported by Qin et al. [13]. The lower clearance rate can be attributed to the difference in factors included in the inclusion criteria, such as age, type of transformation zone, and HPV status, as well as the difference in the criteria for clearance. These factors must be considered in future prospective, multicenter large-sample studies. Compared with the HPV clearance rate of 60–87% within 12 months of treatment reported in previous studies [22, 31‐34], the accumulated clearance rate observed in our study was higher, possibly because of the differences in regions and age ranges of patients with HSILs analyzed.

This study found that both FUS and LEEP were safe and well-tolerated procedures for treating women with HSILs. Adverse effects and complications were rare and minor, and no significant difference was found in their incidence rates between the two treatments. Adverse effects or complications experienced by patients were majorly easily manageable, such as postoperative bleeding or lower abdominal cramps. This observation is consistent with those of previous reports on the safety of the two procedures [14‐15, 17, 35]. Advancements in surgical techniques have led to the development of noninvasive or minimally invasive procedures that are viable alternatives for HSILs or cervical cancer [36, 37]. However, to better ensure the safety of treatment, clinical practitioners have been seeking other feasible and effective noninvasive or minimally invasive therapeutic approaches to further reduce the side effects or complications.

The main strength of this study is that it evaluated and compared the efficacy and safety of FUS and LEEP in treating HSILs in patients of reproductive age. In addition, this retrospective study analyzed the results obtained in actual clinical scenarios. Notably, it was found that younger women who desire to preserve their fertility preferred FUS over HSIL when the ablation criteria were met. We found that the cure, recurrence, and HPV clearance rates of the two HSIL treatment methods were similar. We also confirmed that both FUS and LEEP are safe and well-tolerated procedures for treating women with HSILs. However, the present study is limited by its retrospective design and the missing data on some patient characteristics. These limitations may affect the power of the study. However, these issues are common in clinical practice. Another major limitation was that women with HSILs who underwent FUS or LEEP were followed up for only 1 year after treatment, which was insufficient for evaluating their prognosis. Therefore, longer follow-ups should be implemented in future investigations to collect sufficient information regarding the prognosis of patients and tailor the most appropriate surveillance strategies for patients. Additionally, in our study, we found that cervical specimens were mainly recorded based on a two-tier terminology as recommended by the 2014 WHO classification of female genital tumours, which means the majority of HSILs were not specifically classified as CIN2 and CIN3. However, since the publication of 2020 WHO classification of female genital tumours [38], cervical specimens have been accurately recorded based on a two-tier terminology with specific grades (CIN1, CIN2 and CIN3). As the retrieval time for patient enrollment coincidentally covered the alternating period of the two editions of the WHO classification, we could not accurately classify HSILs as CIN2 or CIN3, which considerably differ in their ability for spontaneous regression. For a better assessment of the outcomes, the classification and distribution of CIN2 and CIN3 between the two treatment groups should be considered in further studies. Furthermore, the study was conducted in only one hospital with a small sample size. Furthermore, our population only included patients aged < 40 years; thus, our results cannot be generalized for all age clusters. Owing to the small population size, the results could not be generalized to the entire population. Sampling should be expanded to include pregnant women to determine the impact of FUS and LEEP on fertility outcomes. Therefore, further prospective studies with a larger sample, multicenter design, and homogeneity of patients are required to confirm these results.