Safety and Efficacy of High-intensity Focused Ultrasound Ablation for Patients with Submucosal Fibroids without Fertility Needs: A Single-center Real-world Data Retrospective Study.

Uterine fibroids are one of the common benign gynecological diseases with an incidence rate of 25%–40%. Based on their relationship with the uterine wall, they are classified as submucosal fibroids, intramural fibroids, and subserosal fibroids, with submucosal fibroids accounting for 10%–15%. Patients with submucosal uterine fibroids often present with increased menstrual flow, prolonged menstrual periods, irregular vaginal bleeding, abdominal pain, and vaginal discharge. Submucosal fibroids may also cause secondary anemia, recurrent miscarriage, premature birth, infertility, and postpartum hemorrhage.[ 1 ] Conventional treatments of submucosal uterine fibroids include medical treatment and surgery. Medications such as gonadotropin-releasing hormone analogues (GnRH-a) and selective estrogen receptor modulators may be used to control symptoms and fibroid growth. However, the symptoms often return after medication withdrawal, and their side effects also limit their long-term use.[ 2 ] Current surgical treatment for submucosal fibroids includes transcervical resection of myoma (TCRM).[ 3 4 ] TCRM is the preferred treatment for symptomatic patients with submucosal fibroids.[ 5 ] However, TCRM has a higher rate of complications, including uterine perforation, excessive bleeding, and fluid overload, and must be performed by an experienced surgeon.[ 6 ] Therefore, TCRM is not suitable for large submucosal fibroids.[ 7 ] As a noninvasive treatment, high-intensity focused ultrasound (HIFU) is a good alternative to avoid incisions to the uterus, especially in young reproductive women by avoiding adhesions and uterine rupture in pregnancy.[ 7 ] Several studies showed that HIFU may significantly reduce the risk of viral transmission because it is without blood loss, pneumoperitoneum, and general anesthesia, so HIFU is the best choice during infectious disease epidemics.[ 8 9 ] However, the treatment of submucosal fibroids is a controversial topic.[ 10 ] Lee showed that the complication rate of HIFU treatment for submucosal fibroids was 4.6%, such as lower abdominal pain and vaginal fluid, and no permanent adverse reactions were observed.[ 11 ] Other studies have confirmed that HIFU ablation of submucosal uterine fibroids can reduce fibroid volume or lead to fibroid expulsion through the vagina, resulting in significant improvement or relief of symptoms related to uterine fibroids.[ 12 ] However, the clinical efficacy of HIFU ablation therapy for different types of submucosal fibroids in the real world with large samples is still an unknown issue worthy of further discussion, with no relevant research reported to date. Therefore, this study aimed to evaluate the safety and efficacy of HIFU or combined HIFU therapy for submucosal fibroids by retrospectively analyzing real-world clinical data from a single center and exploring the factors influencing prognosis.

The age of patients ranged from 23 to 55 years, with a mean age of 42.68 ± 5.90 years. Among the 626 patients, there were 106 cases with type 0 submucosal fibroids, 191 cases with type I, and 330 cases with type II, with 1 case of type 0 combined with type I, and 1 case of type 0 combined with type II. The maximum diameter of all fibroids measured by preoperative MRI ranged from 8 to 117 mm, with an average diameter of approximately 41.54 ± 17.98 mm. The main clinical symptoms were increased menstrual volume in 25.24% (158/626) of patients, prolonged menstrual period in 16.93% (106/626) of patients, lower abdominal pain in 5.59% (35/626) of patients, and anemia in 39.46% (247/626) of patients [ Table 1] . Baseline characteristics of patients with different types of submucosal fibroids BMI: Body mass index The average power of HIFU ablation for type 0, type I, and type II submucosal uterine fibroids was 387.11 ± 25.00 W, 387.02 ± 24.81.00 W, and 390.71 ± 25.67 W, respectively, with no significant statistical difference between the three groups ( P = 0.785). The HIFU treatment time (entry to exit) for type 0, type I, and type II submucosal uterine fibroids was 82.06 ± 44.22 min, 80.02 ± 45.56 min, and 90.48 ± 69.32 min, respectively, with no significant statistical difference between the three groups ( P = 0.23). The HIFU irradiation time for type III submucosal fibroids (HIFU ablation power emission time) was 713.03 ± 462.87 s, 692.25 ± 442.28 s, and 812.65 ± 544.78 s, respectively, with a statistical difference between the three groups ( P = 0.02). The HIFU treatment dose for type III submucosal fibroids was 279342.00 ± 193290.03 J, 272770.47 ± 189643.74 J, and 326761.44 ± 271499.35 J, respectively, with a statistical difference between the three groups ( P = 0.01). The NPV ratio of type 0, type I, and type II submucosal uterine fibroids were 89.00%, 88.54%, and 85.33%, respectively, with no significant statistical difference between the three types ( P = 0.08) [ Table 2] . Type II submucosal uterine dosage, but all three groups achieved consistent NPV ratio with no statistically significant difference. High-intensity focused ultrasound ablation results with different types of submucosal fibroids HIFU: High-intensity focused ultrasound According to the classification standards of the Society of Interventional Radiology (SIR), adverse reactions of HIFU treatment for uterine fibroids are divided into grades A–F, a total of 6 grades:[ 14 ] Grade A: no treatment required, no adverse consequences; Grade B: simple treatment, observation, no adverse consequences; Grade C: hospitalization required, hospital stay 48 h; Grade E: permanent sequelae; and Grade F: death. Based on the SIR classification, all patients experienced one or more adverse reactions during and after the procedure, among which there were 11 cases of SIR B-class adverse reactions, including skin damage (first-degree burns), decreased heart rate, difficulty urinating, and abnormal sensation in the lower limbs; the remaining 615 cases of patients experienced different degrees of SIR A-class adverse reactions, including pain in the treatment area, lumbosacral pain, skin flushing, groin pain, radiation pain, vaginal discharge, etc., There were no cases of SIR C-F [ Table 3 ]. The adverse reactions during the treatment in all patients were mainly pain in the treatment area, lumbosacral pain, and skin burning sensation, among which two patients experienced decreased heart rate during the operation, which was effectively relieved after rest and symptomatic treatment with atropine [ Table 4 ]. The postoperative adverse reactions were mainly lumbosacral pain, vaginal discharge, etc., among which three patients experienced skin damage, all of which were first-degree burns [ Table 4 ]. Number of cases classified by Society of Interventional Radiology adverse effect classification SIR: Society of Interventional Radiology Adverse reactions during and after HIFU and managrment measures HIFU: High-intensity focused ultrasound During the average follow-up period of 6.22 ± 3.24 (range: 1–13) years, 25 patients opted for reintervention treatment due to the recurrence of clinical symptoms, including re-HIFU treatment, laparoscopic or abdominal myomectomy, and hysterectomy, with 3 cases of type 0, 8 cases of type I, and 15 cases of type II. Of these, 22 patients chose re-HIFU treatment (13 cases with recurrent clinical symptoms and 9 cases with new fibroids), and 4 patients underwent surgical intervention, including 1 patient who underwent hysterectomy 1 year after HIFU intervention due to increased menstrual bleeding. Further analysis revealed no statistically significant differences in NPV ratio, age, number, size, and type of fibroids between the reintervention and nonreintervention groups ( P ≥ 0.05). However, there was a significant correlation between the reintervention and nonreintervention groups in terms of postoperative combined treatment (HIFU treatment combined with GnRH-a within 12 months or placement of Mirena or hysteroscopy) ( P < 0.05) [ Table 5 ]. Specifically as follows: In the nonreintervention groups, HIFU combined treatment included 13 cases of combined hysteroscope, 9 cases of GNRH-a, 2 cases of Mirena intrauterine system, 2 cases of combined GnRH-a and Mirena intrauterine system, and 2 cases of combined hysteroscope and GnRH-a. However, in the reintervention group, there were only 5 cases of combined treatment after HIFU, including 3 cases of combined GnRH-a and 2 cases of combined hysteroscopy. Analysis of patients with high-intensity focused ultrasound procedure reintervention and nonreintervention

HIFU ablation for submucosal fibroids in women without fertility requirements is safe and effective. The combination management mode after HIFU could reduce the chance of reintervention treatment. Conceptualization, Xue Shao, Guohua Huang and Shuang Luo; Methodology, Xue Shao, Guohua Huang; Software, Xue Shao, Yanglu Liu; Validation, Yanglu Liu, Rui Liu; Formal Analysis, Xue Shao, Yanglu Liu; Investigation, Xue Shao, Guohua Huang; Data Curation, Xue Shao, Guohua Huang; Writing – Original draft preparation, Xue Shao, Shuang Luo; Writing – Review and Editing, Xue Shao, Hao Zhang, Rui Liu; All authors have read and agreed to the final version of the manuscript. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. There are no conflicts of interest.

Submucosal fibroids, due to their proximity to the endometrial cavity and their tendency to grow toward it, can cause significant clinical symptoms even if they are small. As a new technology, HIFU has its unique advantages of noninvasive, safe, effective, and quick recovery. This study retrospectively analyzed the baseline characteristics, treatment parameters, combined treatment methods, and reintervention time of 626 patients with submucosal myoma treated with HIFU in our medical center and concluded that long-term management after HIFU combined with medications and hysteroscopy is helpful to reduce the rate of reintervention. It is expected to assist clinicians in the early development of chronic disease management plans to continuously reduce the size of fibroids, relieve related clinical symptoms, and ultimately improve patients’ long-term quality of life. All patients in this study underwent HIFU ablation safely and smoothly. Both intraoperative and postoperative adverse reactions were generally mild (SIR A-B grade), with no significant or severe adverse reactions (SIR C-F grade). Intraoperative SIR A grade mainly manifested as pain in the treatment area, lumbosacral pain, and skin-burning sensation. The adverse effects and complications were consistent with the previous study.[ 15 ] In this study, all patients were grouped according to the European Society of Gynecological Endoscopy[ 16 ] classification of submucosal fibroids. The main clinical manifestations of all patients were menorrhagia, prolonged menstruation, lower abdominal pain, and anemia, which were consistent with previous studies. The differences in fibroid volume, diameter, number, and the degree of anemia among the three types of submucosal fibroids were statistically significant ( P < 0.05), while there were no significant differences in age, BMI, presence of clinical symptoms, or parity. The difference in the probability of severe anemia among the groups can be considered that the severity of anemia is significantly associated with the type of submucosal fibroids, with the highest proportion of severe anemia occurring in patients with type 0 submucosal uterine fibroids, possibly due to their close association with endometriosis and an increase in endometrial area, affecting uterine contraction, leading to increased menstrual flow and prolonged menstruation, resulting in more severe anemia. A study reported that the lower the submucous myoma type, the more severe the degree of anemia,[ 17 ] which is consistent with the research results. Yang et al ., through a retrospective analysis of 259 women with a single submucosal fibroid, concluded that for patients with submucosal fibroids, the diameter and the uterine cavity protruding proportion (protruding %) are two factors that significantly determine the serum hemoglobin (Hb) level. Serum Hb levels decreased with the increase in the size of submucosal fibroids and protrusion percentage. However, the serum Hb levels remain unchanged irrespective of the protruding percentage when the size of submucosal fibroids is <2 cm.[ 18 ] The principle of HIFU ablation of uterine fibroids is to use ultrasound to focus on the inside of fibroids, and to cause irreversible degeneration of proteins and coagulative necrosis of tissues through thermal effect, so as to achieve the purpose of fibroid ablation.[ 19 ] HIFU achieved a satisfactory ablation rate of 85.33%–89.00% for three types of submucosal fibroids in this study, consistent with Qu’s report of an average ablation rate above 80% for different signals.[ 20 ] Studies have pointed out that HIFU focuses energy on target tissues to ablate fibroids, causing them to undergo ischemic necrosis. A 10% reduction in fibroid volume can alleviate symptoms associated with uterine fibroids.[ 11 21 ] In this study, the differences between these groups in treatment power and treatment time were not statistically significant, but the differences in irradiation time and treatment dose were statistically significant. The irradiation time and treatment dose of type II submucosal fibroids were larger, which may be related to the larger volume of fibroids. Previous study also showed that maximum fibroid diameter was the independent factor affecting the recurrence of fibroids after HIFU treatment.[ 22 ] In terms of prognosis, 16 submucosal fibroids were expelled spontaneously, including type 0 in 0.94% (1/106) of cases, type I in 6.28% (12/191) of cases, and type II in 1.52% (5/330) of cases, which can be explained by the uterus expelling necrotic components through uterine contractions, thereby facilitating the entry of uterine fibroids into the uterine cavity.[ 12 23 ] Among them, type I submucosal fibroids were the most common, which may be related to the conversion of type I fibroids to type 0 after HIFU treatment through necrosis and uterine contraction. Previous studies have reached the same conclusion. Liao observed that HIFU promoted the transformation of type 2 submucosal fibroids into type 0 or type 1, and even self-expulsion, and Wang et al . observed 76 patients with submucosal uterine fibroids treated with HIFU, with an average diameter of 5.7 ± 2.3 cm; among them, 44 patients experienced excretion of necrotic tissue after 2–4 menstrual cycles. During the follow-up period, two patients completely expelled the fibroids 1 month and 3 months after HIFU treatment.[ 24 ] Qu et al . reported two cases converted to type 0 and three cases converted to type I after HIFU.[ 15 ] Currently, there are no relevant guidelines or expert consensus on whether to adopt a combined approach after HIFU ablation of submucosal uterine fibroids to reduce postoperative complications or improve subsequent intervention. In this study, 4.0% (25/626) of patients underwent repeat HIFU or surgical removal of fibroids. The reintervention rate after HIFU in previous studies was 20%, and our results were even lower;[ 25 ] Dou et al . analyzed 5216 uterine fibroids treated with HIFU and the reintervention rate was about 1% 1 year after treatment, and with the extension of follow-up time, the reintervention rate gradually increased, and the 5-year reintervention rate could be as high as 29%, and they conclude that NPVR ≥50%, and hypo-/isointensity of fibroids on T2-weighted images were significant factors in reducing reintervention.[ 26 ] This may be related to sample size and selection bias. By grouping these patients according to whether or not they were reintervened after HIFU, the study found no statistically significant differences in age, fibroid type, fibroid size, or NPV ratio between patients who underwent reintervention and those who did not after HIFU ablation of submucosal fibroids. Patients with clinical symptoms before/after HIFU ablation of submucosal fibroids need active combination therapy to reduce the possibility of re-intervention or surgical hysterectomy. Long-term management through combination therapy after surgery can effectively reduce the rate of reintervention. Previous studies have also found that age, fibroid volume, and fibroid enhancement degree were identified as independent clinical imaging features.[ 27 ] After combined GnRH-a treatment, the proportion of reintervention was higher, suggesting that post-HIFU management of submucosal uterine fibroids may require hysteroscopy, levonorgestrel-releasing intrauterine system, etc., to achieve long-term management effects. This study has several limitations: (1) this is a single-center, retrospective study, and there may be inevitable selection bias. Future research should further expand the sample size and multicenter joint research; (2) this study did not dynamically follow up the changes of fibroid size after HIFU treatment and lacked a complete evaluation of efficacy; and (3) this study only discussed the effective reduction of the reintervention rate through long-term management through combination therapy and did not discuss the pros and cons of various combination therapy management and its effect on reducing the reintervention rate. Further studies can be conducted in the future to assist doctors in formulating personalized management plans to help patients improve their quality of life.

A retrospective analysis was conducted on the relevant data of patients who visited the Department of Obstetrics and Gynecology at the Suining Central Hospital from November 1, 2010, to December 31, 2023, diagnosed with submucosal uterine fibroids according to the International Federation of Gynecology and Obstetrics staging and chose HIFU treatment. The subsequent data were complete, with a total of 626 patients. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Suining Central Hospital (Ethics No.: KYLLKS20240165). The informed consent was obtained from all patients. Patients diagnosed as submucosal fibroids by clinical, ultrasound, and pelvic magnetic resonance imaging (MRI) examinations and treated with HIFU or combined HIFU and GnRH-a or (and) levonorgestrel-releasing intrauterine system or combined hysteroscopy Premenopausal females aged 18–55 years of age with no desire for fertility. Patients diagnosed as submucosal fibroids by clinical, ultrasound, and pelvic magnetic resonance imaging (MRI) examinations and treated with HIFU or combined HIFU and GnRH-a or (and) levonorgestrel-releasing intrauterine system or combined hysteroscopy Premenopausal females aged 18–55 years of age with no desire for fertility. Patients with missing important clinical data Patients with malignant changes Patients who lost to follow-up. Patients with missing important clinical data Patients with malignant changes Patients who lost to follow-up. HIFU treatment was performed under conscious sedation. The JC HIFU tumor treatment system (Chongqing Haifu Medical Technology Co., Ltd., Chongqing, China) was used for HIFU treatment. The therapeutic ultrasound energy was generated by a transducer with a frequency of 1.0 MHz. Real-time imaging was provided by the Mylab 70 ultrasound imaging system (Esaote, Genova, Italy) to monitor the treatment. The patient was placed in a prone position on the HIFU operating table with the anterior abdominal wall in contact with degassed water. A degassed water balloon was placed between the abdominal wall and the transducer to help compress or displace the intestines away from the acoustic pathway. The power was set between 300 and 400 watts. During the procedure, the power was adjusted based on patient feedback and grayscale changes. The treatment was terminated when the grayscale in the fibroid significantly increased, and the contrast-enhanced ultrasound (CEUS) was then performed to assess the ablated volume of the fibroids. Additional treatment could be performed if the CEUS showed an unsatisfactory nonperfused volume ratio (NPVR). During the procedure, the vital signs of respiration rate, heart rate, oxygen saturation, and blood pressure were monitored, and patients were requested to report any discomfort. The treatment power, treatment time, and sonication time were recorded. The volumes of the fibroids, NPV, and uterus are calculated using V = 0.5233× (anteroposterior diameter) × (transverse diameter) × (longitudinal diameter). Fibroids larger than 4 cm were first treated with HIFU ablation and reduced volume and blood supply, and hysteroscopic myomectomy was performed within 6 months after HIFU. The procedure of hysteroscopic myomectomy was performed on the 3 rd day after menstruation. Cervical softening was conducted 1–2 days before the surgery. Intravenous anesthesia was administered during the operation, and the patient was placed in the lithotomy position. Olympus hysteroscopy was used to enter the uterine cavity through the cervix, initially exploring the uterine cavity and submucosal fibroids. Then, the cervix was dilated to size 10 using cervical dilators. Finally, the hysteroscope was replaced, and the fibroids were gradually excised using a loop electrode. The surgery was terminated in the absence of bleeding, and the patient was discharged 24-48 h postoperatively. For patients with uterine volume >10 weeks of pregnancy or uterine depth >10 cm, the Mirena intrauterine system was placed within 6 months after HIFU. Between the 3 rd and 5 th day of menstruation after surgery HIFU, Mirena intrauterine system was placed at the uterine fundus for treatment, followed by an ultrasound examination to confirm its position without displacement. Subcutaneous injection of leuprorelin microspheres was administered between the 3 rd and 5 th day of menstruation after surgery, with injections given every 28 days, for 3–6 cycles. Patients with submucosal fibroids who underwent HIFU ablation were followed up by telephone to report whether they had reintervention, the number of times of reintervention, the interval of reintervention, the reason for reintervention, and the treatment of reintervention. Reintervention was defined as any additional intervention such as re-HIFU ablation, myomectomy, or total hysterectomy after HFU ablation of uterine fibroids due to nonremission of symptoms, recurrence of symptoms, increase in fibroid volume, and increase in fibroid volume combined with recurrence of symptoms. No further intervention was defined as the absence of any additional intervention for fibroids such as re-HIFU ablation, myomectomy, or total hysterectomy, from HIFU ablation to the follow-up cutoff (December 2023). Clinical symptoms, HIFU treatment power, energy, irradiation time, treatment time, and intraoperative and postoperative adverse reactions, and the volumes of the fibroids, nonperfused fibroid volume, and uterine size (The volume calculation formula is V = 0.5233× [anteroposterior diameter] × [transverse diameter] × [longitudinal diameter]).[ 13 ] Statistical analysis was performed using SPSS software (SPSS 26.0, IBM, USA). Normally distributed continuous variables were expressed as mean ± standard deviation (± s) and compared using independent t -tests or analysis of variance. For nonnormally distributed continuous variables, statistical description was done using the median (interquartile range), and comparison was performed using the Mann–Whitney U -test. Categorical variables were presented as frequencies (percentages) ( n [%]) and compared using Chi-square tests. P < 0.05 was considered statistically significant.