Patient selection

This study was approved by the Ethics Committee of the Affiliated Hospital of North Sichuan Medical College (Approval Code: 2023ER429-1). We adhered to the principles of the Declaration of Helsinki, as well as domestic and international standards. Patients with a diagnosis of HSIL/CIN2 and HR-HPV infection at the affiliated hospital of North Sichuan Medical College from January 2019 to December 2022 were identified. All charts were reviewed, and patient demographics and pertinent medical information were recorded.

The inclusion criteria were: (i) aged between 18 and 35 y old with a future conception plan; (ii) confirmed diagnosis of CIN2 on biopsies; (iii) tested positive for at least one HR-HPV; (iv) cervical lesions covering less than three quadrants with clear margins on colposcopy; (v) clear squamous-columnar junction; (vi) cytologic findings of negative intraepithelial lesions or malignancy (NILM), negative atypical squamous cells of undetermined significance (ASC-US), negative low-grade squamous intraepithelial lesions (LSIL) and HSIL.

The exclusion criteria included: (i) a history of abnormal cytologic findings indicating atypical squamous cells, ASC—cannot exclude high grade squamous intraepithelial lesion highly, or more severe lesions; (ii) previous cervical surgery, pelvic radiation or chemotherapy; (iii) a history of recurrent spontaneous abortion or preterm delivery; (iv) presence of organic diseases that could impact pregnancy outcomes; (v) acute inflammation of the reproductive system; (vi) histopathological grading necessitating additional treatment; (vii) combined immune system deficiency disorders; (viii) unsuccessful colposcopy or lesions in the cervical canal; (ix) patients needing adjuvant therapy or other treatment during follow-up; (x) a history of previous cervical procedures like conization or ablation; (xi) patients with recurrent HSIL; (xii) patients with severe cardiac, hepatic, renal, hematologic or autoimmune diseases; (xiii pregnant women or post-partum women who were breastfeeding; (xiv) patients who were using medications vaginally. Written informed consent was obtained from all participants.

FU treatment protocol

A Model-CZF300 FU therapeutic device (Chongqing Haifu Medical Technology Co., Ltd., China) was used. This device operated within a treatment force ranging from 3.5 to 4.5 W, at a frequency of 10.0 MHz, with pulses at 1000 Hz. The patient was placed in the lithotomy position, and a skilled gynecologist identified and exposed the cervix by using a sterile speculum. Following cervix disinfection, ultrasound coupling gel was applied, and the FU probe was then placed at the cervix. A circular scan was conducted from the lesions toward healthy tissue, extending approximately 2 mm beyond the lesion margin.

The criteria for treatment termination included: (i) the treatment area shrank and the external cervical os being slightly depressed inward and appearing slightly white; and (ii) negative results of staining post-treatment showing the cervix coated with a 1% Lugol’s iodine solution with negative staining results.

Post-treatment follow-up

After treatment, all patients were asked to strictly abstain from sexual intercourse for 2 mo and recommended to abstain for an additional 3 mo to minimize complications. Clinical assessment, including vaginal bleeding, wound infection, wound healing, cervical adhesions and scaring, was performed by a skilled gynecologist. Colposcopy and multi-point cervical biopsies were also performed. The HR-HPV genotyping test and ThinPrep cytologic test (TCT) were repeated every 6 mo. The cervical length was reassessed 3–6 mo post-surgery via transvaginal ultrasound, and then compared to the preoperative baseline data. Information regarding the time to conception and pregnancy outcomes following treatment was gathered through telephone interviews, with the final interview conducted on February 29, 2024.

TCT and HR-HPV subtypes

During the 6-mo follow-up period, cervical specimens were collected by using an endocervical brush. A TCT was performed for all samples, and the results were interpreted according to the Bethesda System terminology. An HPV genotyping real-time polymerase chain reaction kit (Shanghai ZJ Bio-Tech Co., Ltd., China) was used to identify 15 subtypes of HR-HPV DNA, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 and 82.

Colposcopy and cervical biopsies

During the 6-mo follow-up period, colposcopy procedures were performed on all women who were enrolled in the study. The standard procedure comprised three sequential steps: initial cleansing of the vaginal and cervical surfaces using a saline solution; subsequent application of 3%–5% acetic acid to facilitate the detection of CIN; and, where warranted, utilization of Lugol’s iodine for a comprehensive examination. The interpretation of colposcopy images adhered to the 2011 International Federation for Cervical Pathology and Colposcopy terminology for colposcopy. Diagnoses were categorized as either normal, LSIL, HSIL or carcinoma based on the findings [ ].

After colposcopy, multi-point cervical biopsies were then performed, followed by histopathological examination. Suspicious areas identified during colposcopy were biopsied using biopsy forceps. In instances where no abnormalities were detected during colposcopy, biopsies were then systemically obtained from the squamous-columnar junction in four quadrants, along with an endocervical curettage. All collected samples were preserved in 10% formalin, processed with hematoxylin and eosin staining for microscopic examination and analyzed by experienced pathologists at our hospital. Histopathological results were categorized as normal, LSIL, HSIL or carcinoma according to the 2012 LAST guidelines [ ].

Definitions

The complete pathologic response of HSIL/CIN2 was identified by the absence of initial abnormalities and normal histology. The partial response was defined as histologic downgrading to LSIL or condyloma-like. Persistence of HSIL/CIN2 meant that no changes were observed during a colposcopy-directed biopsy. Progression was characterized by the detection of HSIL/CIN3 or cervical cancer on follow-up biopsy pathology.

Statistical analysis

Continuous variables with a normal distribution were expressed as the mean and standard deviation, while those deviating from normality were presented as the median and range. Categorical variables were expressed as frequencies and percentages. Pearson ^’ s chi-square test and the Wilcoxon test were used to compare the differences, and all statistical analyses were performed using SPSS version 26.0 (IBM, USA). A two-sided p < 0.05, with all tests being two-tailed, was considered statistically significant.

Patient enrollment and baseline characteristics

From January 2019 to December 2022, a total of 69 patients with HSIL/CIN2 and HR-HPV were identified initially at the Center for Vulvovaginal Cervical Diseases of the Affiliated Hospital of North Sichuan Medical College. Among them, 34 nulligravid women met the inclusion criteria. However, three patients were lost to follow-up, resulting in 31 patients completing the full study ( Fig. 1 ).

Study flowchart.

Table 1 summarizes the demographic and clinical characteristics of study participants. The mean age of this study cohort was 26.52 ± 3.67 y, ranging from 19 to 34 y. For HR-HPV genotyping, 17 patients were positive for HPV 16/18, and 14 cases had other subtypes. The TCT results showed 21 cases of NILM, three cases of ASC-US, four cases of LSIL and three cases of HSIL. Colposcopy findings revealed 13 patients with a type 1 transformation zone and 18 cases with a type 2 transformation zone. As for colposcopy grading, 12 patients were classified as minor and 19 as major grade.

HR-HPV clearance and TCT after treatment

Statistical analysis revealed a significant difference in the cumulative HR-HPV clearance rates between 6 and 12 mo post-treatment (35.48% vs. 71.49%, p = 0.005) ( Table 2 ) after treatment. The median time for HR-HPV clearance was 5 mo (95% confidence interval: 5.55–7.77). Furthermore, the remission rate of multiple HPV subtype infections was significantly different compared to single HPV at both 6 mo (8.33% vs. 52.63%, p = 0.034) and 12 mo (53.86% vs. 94.44%, p = 0.026). Although the clearance rate was higher for HPV 16/18 compared to non-HPV 16/18 (81.25% vs. 66.67%), the difference was not statistically significant ( p = 0.605). The 6-mo post-treatment HR-HPV clearance rate was associated with HPV subtype, TCT subtype and colposcopy grade. The 12-mo post-treatment HR-HPV clearance rate was not associated with age, HPV genotype, TCT subtypes or transform zone type ( Table 3 ); however, it was related to multiple coinfection subtypes and colposcopy grade.

Table 3

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