Focused ultrasound treatment of cervical human papillomavirus infection and squamous intraepithelial lesions: A narrative review.

FUS is a form of thermal ablation in which energy is delivered in the form of ultrasound waves extra-corporeally to a targeted area deep beneath the skin. During treatment, multiple high-energy ultrasound waves are generated and focused at one particular area, which causes tissue ablation through heating, cavitation, and direct damage to tumour blood vessels, with minimal damage to the surrounding tissues [10] . In addition, when tissues are exposed to lower-energy ultrasound, some cells stop proliferating and undergo some subtle cellular changes such as changes in cell membrane permeability, intracellular environment, electrolyte balance and proteins in locations where DNA synthesis and polymerization are controlled [16] . All these changes can cause slow cell death, which in turn, facilitates destruction of tumour cells FUS treatment of the cervix is carried out using a FUS therapeutic device (Model-CZF-300, Chongqing Haifu Medical Technology Co., Ltd. China), which is approved by the China Food and Drug Administration for the treatment of cervical ectopy and cervicitis (in addition to non-cervical lesions including vulval non-neoplastic epithelial disorders and condyloma acuminata). Although, it is still under application for use in the treatment of cervical HPV infection and SIL, some studies have shown its effectiveness in using for these indications. This FUS treatment system (Model-CZF-300) consists of the main system, power source, treatment probe and water treatment system ( Fig. 1 ). The main system provides output electricity to the power source that transforms the electricity into an ultrasonic beam. The water treatment system is used to pump water to the head of the treatment probe. Frequencies of the transducer range from 9 to 11 MHz. Therapeutic ultrasound energy was emitted from a 1 mm diameter transducer with a short ellipsoidal focal region ( Fig. 2 ). The ultrasound power is set at 3.5–4 W. Fig. 1 The FUS treatment system (Model-CZF-300). Fig. 1 Fig. 2 The treatment transducer. Fig. 2 The FUS treatment system (Model-CZF-300). The treatment transducer. In general, women during menstrual period, pregnancy and lactation, and those with severe cardio- and cerebro-vascular disease, liver and kidney dysfunction, acute inflammation of genital organ, and suspicious of cervical malignancy are contraindicated for FUS treatment. For the treatment of cervical SIL, lesion specific indications include lesion should be completely visualized on colposcopy, covering less than three quadrants of the ectocervix, and not extending inside the cervical canal [17] , [18] . The standardized treatment is performed on days 3–10 after menstruation. The patients are placed in the lithotomy position, and the cervix is exposed using a sterile speculum. Anaesthetic medication will be applied to the cervix for approximately 30 minutes before treatment. The vaginal wall and cervical surface are sterilized, and the treatment probe is placed in close contact with the cervical surface using an ultrasonic coupling agent as the medium. The lesion on the cervix is located using iodine application. Circular scanning motion is performed at a speed of 5–10 mm/s with the external cervical os as the center. Scanning can be strengthened on the lesions. The treatment lasts until the treatment area shrinks in size and appears slightly whitish, and the external cervical os becomes slightly depressed inward. At the end of the procedure, the cervix is disinfected again. The patient is kept under observation for approximately 30 minutes before discharge and is advised to have no tub bath, sex intercourse and vaginal douche for two months.

None.

Only limited evidence are available on pregnancy after FUS of the cervix. Yao et al. and Zhang et al. reported 17 and 12 pregnancies, respectively, after this treatment [23] , [24] . Of these 29 pregnancies, 11 were ongoing, 1 had spontaneous miscarriage, and 1 had pregnancy termination. Fifteen pregnancies were delivered at term and 1 twin pregnancy was delivered preterm. In another retrospective cohort study, Shen et al. compared the pregnancy outcomes of 46 patients treated with FUS and 46 patients treated with LEEP. There were no significant difference in the rates of preterm birth (FUS versus LEEP = 0.0 % and 6.5 %, P > 0.05) and the rates of premature rupture of membranes (FUS versus LEEP = 21.7 % and 15.2 %, P > 0.05) between the two groups [25] .

Table 1 , Table 2 summarizes the efficacy of FUS in the treatment of cervical HPV infection and SIL. In 2009, Li et al. reported for the first time that FUS therapy could be safe, effective and feasible in the treatment of patients with HPV-infected cervicitis [12] . That study was conducted on 20 patients, and demonstrated a HPV clearance rate of 75 % at 6 months after treatment [12] . Thereafter, other studies had reported the effectiveness of HIFU in the treatment of HPV and SIL. Based on the literature review, the overall efficacy of FUS on HPV clearance was 75.0–85.7 % at 3 months, 35.5–77.1 % at 6 months and 64.7–94.1 % at 12 months ( Table 1 ). While Its efficacy on low grade SIL and high grade SIL regression were 83.3–96.8 % and 70.9–96.6 % at 6 months, respectively, no 12 months or longer data was available in all studies ( Table 2 ). Table 1 Human papillomavirus clearance rate. Table 1 HPV clearance rate (%) a Author, year Study design Number 3 c or 6-month 12-month Li et al., 2009 [12] Prospective cohort 20 75.0 -- Fu et al., 2020 [13] Prospective cohort 28 85.7 b , c -- Wang et al., 2021 [14] Retrospective, comparative 300 47.3 64.7 Wang et al., 2022 [15] Prospective, comparative 86 75.6 -- Qin et al., 2022 [19] Retrospective, comparative 119 54.6 94.1 Tan et al., 2022 [20] Retrospective, comparative 109 77.1 b -- Zeng et al., 2022 [21] Prospective cohort 116 72.4 81 Wang et al., 2023 [22] Prospective cohort 32 75.0 c -- Yao et al., 2023 [23] Retrospective cohort 57 56.1 75.4 Xiao et al., 2024 [18] Retrospective, comparative 97 74.2 84.9 (n = 93) Zhang et al., 2025 [24] Retrospective cohort 31 35.5 71.5 HPV, human papillomavirus a only high-risk HPV studied except specified b all HPV types studied c 3-month follow up data Table 2 Squamous intraepithelial lesion reduction rate at 6 months. Table 2 Low-grade SIL High-grade SIL Author, year Study design Number Reduction rate (%) Number Reduction rate (%) Fu et al., 2020 [13] Prospective cohort 30 83.3 -- -- Wang et al., 2022 [15] Prospective, comparative 86 89.5 -- -- Tan et al., 2022 [20] Retrospective, comparative 117 92.3 27 88.9 Zeng et al., 2022 [21] Prospective cohort 125 96.8 29 96.6 Yao et al., 2023 [23] Retrospective cohort -- -- 57 73.7 Xiao et al., 2024 [18] Retrospective, comparative -- -- 101 89.1 Zhang et al., 2025 [24] Retrospective cohort -- -- 31 70.9 SIL. squamous intraepithelial lesion. Human papillomavirus clearance rate. HPV, human papillomavirus only high-risk HPV studied except specified all HPV types studied 3-month follow up data Squamous intraepithelial lesion reduction rate at 6 months. SIL. squamous intraepithelial lesion.

FUS appears to be effective and safe in the treatment of cervical HPV and related lesions. However, a larger-scale, prospective trial will be worthwhile to support this conclusion.

Treatment of cervical HPV related SIL are quite standardized, with continual observation and follow-ups for LSIL and LEEP or other excisional procedures for HSIL and persistent LSIL [3] , [4] . However, the awareness of this cervical abnormality and the need for repeated follow-ups can result in different levels of psychological distress and financial burden to some patients [7] , [8] . Therefore, some women diagnosed with LSIL and/or HR-HPV infection may prefer treatment with a hope to achieve earlier elimination of the cervical infection and related lesion. The commonly performed excisional procedure for treating women with SIL is LEEP, which has the advantage of providing a tissue specimen for histological confirmation of the diagnosis. However, there are potential complications such as intraoperative and postoperative bleeding, and concerns with subsequent pregnancies, in particular preterm labour and birth [9] . Recently, FUS has also been introduced to treat cervical HPV infections and related lesions and initial results appear promising [12] , [13] , [14] , [15] . It induces tissue necrosis by thermal destruction of the target tissue at depth without damaging surrounding or overlying tissues [10] . It also appears to improve microcirculation through its thermal, mechanical and cavitation effects [10] , [16] . There is also a potential impact of FUS treatment on vaginal microbiota and local immune responses, which may facilitate disease regression and assist in clearing HPV [21] , [22] . Nevertheless, the findings from this review seem encouraging, as FUS appears to be effective in eliminating cervical HPV infection and reducing SIL, and its efficacy seems to be as good as LEEP [18] . According to study by Qin et al., for HPV-positive HSIL patients under 30, FUS had a better HR-HPV clearance than LEEP 1 year after treatment (94.1 % versus 79.2 %) [19] . In addition, when compared with LEEP, FUS seems to have less risk of bleeding complication (3.5 %), and has a theoretical advantage on reduced likelihood of cervical shortening. Although, the current available evidence on pregnancy after FUS of the cervix seems favourable, its potential benefits of reducing complications and concerns with cervical shortening and subsequent pregnancies require further evaluation. This review has limitations. The lack of primary data in most studies made it impossible to carry out comparison between studies. The long-term efficacy remained unknown, as only 6-month data for SIL were provided in all studies. The definitions of certain complications were not provided, which made it difficult to accurately determine the complication rates. Nevertheless, despite these shortcomings, the availability of this FUS technology is indicative of the potential of advancements in treatment of cervical HPV and related lesions.

A review of the literature was obtained from the PubMed electronic database from inception through February 2025, using the search words ‘‘cervix” and squamous intraepithelial lesion’’, “SIL”, human papillomavirus” or “HPV” and “high-intensity focused ultrasound”, “HIFU”, “focused ultrasound” or “FUS” supplemented by hand-searching the references of the relevant articles. The acceptability of the articles to be included in the review was decided by reading the articles’ abstracts and full text if necessary, and only those articles that evaluated the use of only FUS in the treatment of cervical HPV and/or SIL and included complete interpretable information with relevant outcome data were reviewed. Ultimately, 11 articles were reviewed [12] , [13] , [14] , [15] , [18] , [19] , [20] , [21] , [22] , [23] , [24] . The information that was retrieved from the eligible articles included the number of patients, effectiveness of FUS in clearing cervical HPV infection and reducing cervical LSIL, and related complications.

A summary of the clinical trials comparing between FUS and other interventions is outlined in Table 3 . They were all comparative cohort studies with no randomized trial. These studies suggested that FUS appeared similar in efficacy to LEEP, and superior to cryotherapy, interferon drugs, and observation in the treatment of cervical HPV infection and SIL. Table 3 Summary of comparative studies. Table 3 Author, year Study design Outcomes FUS versus Loop electrosurgical excision procedure (LEEP) Qin et al., 2022 [19] Retrospective cohort For HPV-positive HSIL patients under 30, FUS had a better HR-HPV clearance than LEEP 1 year after treatment (94.1 % versus 79.2 %) Xiao et al., 2024 [18] Retrospective cohort FUS and LEEP had similar efficacy, safety, and reliability in treating women (aged < 40 years) with HSIL; the incidence of complications was comparable. FUS versus cryotherapy Tan et al., 2022 [20] Retrospective cohort FUS was superior to cryotherapy in the treatment of LSIL (regression 92.3 % versus 80.2 %); no significant differences with HPV clearance and HSIL. FUS versus interferon drugs Wang et al., 2021 [14] Retrospective cohort FUS was significantly superior to that of interferon drugs in eliminating HR-HPV infection (47.3 % versus 5.8 % at 6 months; 64.7 % versus 16.1 % at 12 months; 68.7 versus 26.7 % at 18 months). FUS versus observation Wang et al., 2022 [15] Prospective cohort FUS had significantly higher HR-HPV clearance rate than observation (75.6 % versus 25.6 % at 6 months), and had significantly higher LSIL regression rate than observation (89.5 % versus 56.4 % at 6 months) Summary of comparative studies.

Cervical squamous intraepithelial lesion (SIL) is the histological manifestation of human papillomavirus (HPV) infection, which can be classified into low-grade (LSIL) and high-grade (HSIL) lesions. Because of high rate of spontaneous regression and low risk of malignant progression, women with LSIL are generally offered more conservative management. However, about 15 % of patients may progress to high-grade lesions and require treatment at a later date [1] , [2] . If a low-grade lesion is confirmed by colposcopy and biopsy, the patient can be observed and followed up with HPV testing or co-testing at 12 months, irrespective of age [3] , [4] . Alternatively, or if HPV testing is not available, patient can be followed up with cytology every 6 months for 3 times, then yearly for 3 years before returning to routine screening [4] . Although LSIL has a high rate of spontaneous regression, women with high-risk HPV (HR-HPV) infection have a longer duration of LSIL, lower rate of regression, and higher rate of progression than HR-HPV-negative women [5] , [6] . Moreover, the awareness of LSIL and the need for follow-ups can result in different levels of psychological distress and financial burden to patients [7] , [8] . Therefore, some women diagnosed with histological LSIL and/or HR-HPV infection at the first visit may prefer treatment rather than observation. In with HSIL, treatment is recommended because these lesions could progress to invasive cancer if left untreated [3] , [4] . The current recommended method for treating women with HSIL or persistent LSIL is loop electrosurgical excision procedure (LEEP), which has the advantage of providing a tissue specimen that is generally of sufficient quality for histological exclusion of occult invasion. However, there are potential complications such as intraoperative and postoperative bleeding (1–8 %), infection, cervical stenosis (1 %), cervical deformity and cervical incompetence and rarely injury to vagina, bladder and ureter. There are concerns with subsequent pregnancies after LEEP, as reports have shown an association with preterm delivery, low birth weight and premature rupture of membranes but there was no significant increase in neonatal morbidity [9] . Focused ultrasound (FUS) is a new thermal ablation technique that has gained popularity in treating benign gynaecological tumours including fibroids and adenomyosis [10] , [11] . Recently, FUS has also been used in treating cervical lesions and has attracted much attention because of its unique treatment modality by thermal destruction of the target tissue at depth without damaging surrounding or overlying tissues, good curative effect, and fewer side effects [12] , [13] . Previous retrospective cohort studies have demonstrated the efficacy of FUS for HR-HPV infection-related LSIL and HR-HPV clearance [14] , [15] . The aim of this article was to review the background, clinical use, and outcomes of FUS in the treatment of cervical HPV infection and SIL.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article

Complications arising from FUS in the treatment of cervical lesions were rare. Four of the 11 studies reported no adverse events or serious complications [12] , [13] , [15] , [22] . Two studies did not report on complications [14] , [19] . The complications reported in the other five studies are summarized in Table 4 . The most common complication was vaginal bleeding. Some women experience light bleeding after treatment, in which no special treatment was needed. However, a small number of patients (2.8–6.5 %) had moderate bleeding, which required some form of intervention including cervical packing. Table 4 Summary of complications. Table 4 Author, year Number Bleeding required intervention Cervical infection required antibiotics Others Tan et al., 2022 [20] 144 4 (2.8 %) 1 (0.7 %) 0 Zeng et al., 2022 [21] 154 5 (3.2 %) 0 0 Yao et al., 2023 [23] 57 3 (5.3 %) 0 0 Xiao et al., 2024 [18] 101 3 (2.9 %) 0 1 (1 %) a Zhang et al., 2025 [24] 31 2 (6.5 %) 1 (3.2 %) 16 (51.6 %) b Overall 487 17 (3.5 %) 2 (0.4 %) 15 (3.1 %) Data are presented as n (%) a Moderate abdominal cramps b Increased vaginal discharge Summary of complications. Data are presented as n (%) Moderate abdominal cramps Increased vaginal discharge While vaginal discharge was common and occurred in 51.6 % of women in one study [24] , the overall incidence of cervical infection requiring antibiotics treatment was rare (<1 %). Other non-specific complaints such as pelvic pain and abdominal cramps had been reported and seemed to have no significant sequelae.