Safety and Efficacy of Intratumoral Ethanol Injection Followed by High-intensity Focused Ultrasound Ablation for Hyperintense Uterine Fibroids on T2-weighted Magnetic Resonance Images

Uterine fibroids, also known as myomas or leiomyomas, are the most prevalent benign tumors of the uterus in reproductive-age women. The prevalence of uterine fibroids is age dependent and varies between different ethnic groups or races. Multiple studies have shown that the prevalence in African American women could reach 80% over the age of 50 years.[ 1 2 ] Uterine fibroids can cause excessive menstrual bleeding, pelvic pressure, bowel dysfunction, urinary frequency and urgency, urinary retention, constipation, and infertility. Treatments for uterine fibroids include hysterectomy, myomectomy, uterine artery embolization (UAE), medical therapy, and other minimally or noninvasive treatments. Hysterectomy is a definitive treatment for patients with symptomatic fibroids, but it is not suitable for patients who wish to preserve fertility. Myomectomy remains the treatment of choice for patients with uterine fibroids who desire future fertility, but the recurrence rate is high. An estimated 15% to 33% of fibroids recur, and around 10% of patients who undergo myomectomy will have a hysterectomy within 5–10 years.[ 3 ] UAE has become a routine treatment for patients with uterine fibroids who wish to preserve their uterus or avoid surgery in developed countries, but the high long-term reoperation rate and its adverse effects on ovarian function have limited the clinical application of this technique. Medical therapy can be used to effectively control fibroid-related symptoms, but symptoms can easily recur after medication withdrawal. Recently, minimally invasive and noninvasive therapeutic techniques have been used in the management of uterine fibroids. As a noninvasive treatment, high-intensity focused ultrasound (HIFU) ablation has been widely used in the treatment of uterine fibroids. Many studies have demonstrated the safety and efficacy of HIFU treatment for uterine fibroids.[ 4 5 6 7 ] HIFU treatment presents an excellent alternative for the patients with uterine fibroids who want to have a baby, are unsuitable for, or are unwilling to undergo the open surgery.[ 8 9 10 11 ] Moreover, an increasing number of physicians are embracing and pursuing training in HIFU treatment.[ 12 13 ] The long-term follow-up results showed that the 5-year recurrence rate after HIFU is comparable with myomectomy if the average nonperfused volume ratio (NPVR) of uterine fibroids achieved larger than 80%.[ 14 15 ] However, previous studies have shown that it is difficult to treat hyperintense uterine fibroids on T2-weighted image (T2WI) of magnetic resonance using HIFU.[ 15 ] The large NPVR may be achieved in some hyperintense uterine fibroids on T2WI using more sonication energy and sonication time, but the risk of complications may also increase with prolonged treatment time. Therefore, it is important to explore a pre-HIFU treatment for hyperintense uterine fibroids in patients who wish to avoid surgery to increase HIFU treatment efficiency. This study aimed to retrospectively analyze the efficacy and safety of intratumoral ethanol injection followed by HIFU ablation for hyperintense uterine fibroids on T2WI of magnetic resonance imaging (MRI).

The mean age of the 195 patients was 40.3 ± 6.8 years, and the mean BMI was 22.8 ± 3.2 kg/m 2 . Among them, 55 patients had a history of myomectomy or previous HIFU. Of the 195 patients, 70 had a solitary fibroid and 125 had multiple fibroids. In total, 209 hyperintense uterine fibroids were treated with intratumoral ethanol injection followed by HIFU. Among these fibroids, 49 located in the anterior wall of the uterus, 71 in the posterior wall, 47 in the lateral wall, 21 in the uterine fundus, and 21 in the cervix of the uterus. Among them, 37 were classified as submucosal fibroids, 68 were intramural fibroids, 83 were subserosal fibroids, and 21 were cervical fibroids. The median maximum diameter of the fibroids was 6.6 (interquartile range: 5.6–8.0) cm, and the median fibroids volume was 110.8 (interquartile range: 70.9–193.3) cm 3 [ Table 1 ]. Baseline characteristics of enrolled patients HIFU: High-intensity focused ultrasound, BMI: Body mass index All the 195 patients completed intratumoral ethanol injection successfully. Among the 209 fibroids in 195 patients, 114 fibroids were pretreated with transvaginal intratumoral ethanol injection, 94 fibroids were pretreated with percutaneous intratumoral ethanol injection, and 1 fibroid was treated with both transvaginal and percutaneous intratumoral ethanol injection. The volume of ethanol injection ranged from 1 ml to a maximum of 31 ml, with a median volume of 10 (interquartile range: 5.0–13.0) ml for each patient. During the procedure of intratumoral ethanol injection, 1 patient experienced facial flushing and 7 patients experienced coughing. All symptoms resolved spontaneously without any specific intervention. No other adverse effects were observed in the remaining patients [ Tables 2 and 3 ]. Injection path, anhydrous ethanol volume, and adverse effects of intratumoral ethanol injection Volume of ethanol injection for different sizes of fibroids All patients successfully completed HIFU treatment without any severe adverse effects or complications after intratumoral ethanol injection. The median sonication time for the 209 fibroids treated was 800 (interquartile range: 499–1300) s. Significant grayscale changes were observed in 133 fibroids, and homogeneous grayscale changes were observed in 76 fibroids, with a significant grayscale change rate of 63.6%. The average NPVR achieved was 81.2% ± 13.0%. There was no statistically significant difference in NPVR between fibroids pretreated with intratumoral injection of different amounts of anhydrous ethanol ( P > 0.05) [ Tables 4 , 5 and Figures 2 , 3 ]. Therapeutic parameters of high-intensity focused ultrasound NPVR: Nonperfused volume ratio Comparison of nonperfused volume ratio of fibroids pretreated with different volumes of anhydrous ethanol There was no significant difference in NPVR between groups ( P =0.485). NPVR: Nonperfused volume ratio Ultrasound images (a and b) obtained immediately after intratumoral ethanol injection before the procedure of high-intensity focused ultrasound showed an ultrasonographic hyperechoic area in the posterior part of the fibroid Magnetic resonance (MR) images obtained from a 41-year-old patient with a hyperintense uterine fibroid. The fibroid located at the lower segment of the left uterine, the size of the fibroid was 10.1 cm × 6.4 cm × 5.4 cm. Before high-intensity focused ultrasound (HIFU), 8 ml of anhydrous ethanol was injected at the center of the fibroid by transvaginal intratumoral ethanol injection. HIFU treatment was performed immediately after transvaginal intratumoral ethanol injection. 400 Watts of power was used, and the total sonication time was 680 s. (a) Pre-HIFU T2WI showed a hyperintense fibroid. (b) Pre-HIFU contrast-enhanced MR image showed significant enhancement of the uterine fibroid. (c) Post-HIFU contrast-enhanced MR image showed the fibroid was completely ablated The frequent intraprocedure adverse effects included lower abdominal pain, sacrococcygeal pain, skin-burning sensation, leg pain, and groin pain. Other rare adverse effects were discomfort in the anal or perineal area, back pain, and pubic symphysis pain. The median pain score during the procedure was 3 (interquartile range: 2.0, 3.0) points [ Table 6 ]. Adverse effects during the procedure of high-intensity focused ultrasound Adverse effects were classified according to the Society of Interventional Radiology (SIR) classification system. All adverse effects observed after HIFU in this study were classified as SIR class A or B. The frequent adverse effects included vaginal discharge and lower abdominal pain and sacrococcygeal pain. Rare adverse effects included slight vaginal bleeding, pubic symphysis pain, groin pain, abdominal wall pain, hematuria, and lower-limb paresthesia. All adverse effects completely disappeared within 1 week after HIFU. No severe adverse effects occurred in this study [ Table 7 ]. Adverse effects after high-intensity focused ultrasound treatment

Based on the results from this study, we concluded that intratumoral ethanol injection followed by HIFU is safe and effective in the treatment for hyperintense uterine fibroids. This strategy could significantly decrease sonication time and increase NPVR, thus it offers a new option for patients with hyperintense uterine fibroids who want to avoid surgery. Conceptualization, KY.Q and Y.X.; Methodology, M.Z. and Y.X.; Validation, KY.Q., Z.W., and W.Z.; Formal Analysis, KY.Q., Z.W; Investigation, J.W.; Data Curation, KY.Q, J.W.; Writing – KY.Q, Z.W.; Writing – Review & Editing, Y.X.; Supervision, Y.X.; Project Administration, Y.X.; Funding Acquisition, Y.X. All authors have read and agreed to the final version of the manuscript. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. There are no conflicts of interest

Intratumoral ethanol injection has been used clinically to treat solid tumors for many years.[ 17 18 ] However, the effectiveness is unsatisfactory as anhydrous alcohol in the tumor is difficult to control and the intratumor alcohol retention time is short and unevenly distributed. Recently, multiple studies have shown that intratumoral ethanol injection could reduce the heat-sink effect of radiofrequency ablation.[ 19 20 ] Yang et al . treated 16 patients with T2WI hyperintense fibroids with an average diameter of 5.7 cm by HIFU alone.The median sonication time was as high as 2334s but the average NPVR achieved was only 50.2% ± 27.3% (0%–78.6%).[ 21 ] Zhao et al . showed that the treatment time and NPVR of HIFU alone in the treatment of T2WI hyperintense fibroids were 121 min and 65.5% ± 27.8%, respectively.[ 22 ] Wang et al . showed that an average NPVR of 67.8% ± 16.6% was achieved with a median of 1000 s of sonication time using HIFU alone in the treatment of T2WI hyperintense fibroids.[ 14 ] In this study, after a median of 800 s of sonication, an average NPVR of 81.2% ± 13.0% was achieved in 209 hyperintense fibroids with a size of 6.6 cm in diameter. Therefore, our study demonstrated that intratumoral ethanol injection as a pre-HIFU treatment significantly improved the treatment efficacy of HIFU for hyperintense uterine fibroids on T2WI of MRI. Many studies have consistently shown that a large NPVR is closely associated with sustained long-term improvement of clinical symptoms, low recurrence, and low re-intervention rate.[ 14 15 23 24 ] To achieve a long-term therapeutic effect equivalent to that of traditional surgery, it is necessary to obtain a satisfactory NPVR. Several studies have shown that the 5-year recurrence and re-intervention rate after myomectomy was approximately 20%.[ 25 26 ] The long-term results from patients who received HIFU revealed a recurrence rate of 20.5% at a median of 69 months follow-up after treatment, with a mean NPVR of 73% in the group of recurrent patients and 89% in the group of nonrecurrent patients.[ 15 ] Another study with a large number of subjects showed a re-intervention rate of 13.1% at a median of 70 months follow-up after HIFU with a mean NPVR of 81.9%.[ 27 ] In our study, the average NPVR of 81.2% ±13.0% was achieved, suggesting that intratumoral ethanol injection followed by HIFU for hyperintense fibroids may achieve satisfactory long-term therapeutic effect. Previous studies have revealed that MRI signal intensity on T2WI and the enhancement degree of contrast-enhanced MRI are independent risks affecting NPVR.[ 4 28 29 30 31 ] Multiple studies have demonstrated that the histological characteristics of hyperintense fibroids on T2WI include a high cellular composition, low collagen fiber content, low tissue density, and high water content, making it difficult for ultrasound energy to deposit in the treatment area, resulting in an unsatisfactory NPVR.[ 32 33 ] A study showed that intraoperative infusion of ethanol into the tumors immediately leads to devascularization. Incremental tumor devascularization was achieved by careful injection of small amounts of ethanol directly into the lesion, producing immediate and complete regional tumor devascularization.[ 34 ] An experimental study showed that intratumoral injection of ethanol induces microthrombus formation to occlude tumor blood vessels, thereby reducing “heat sink effect” and improving the effectiveness of thermal ablation.[ 20 ] Therefore, as a pre-HIFU treatment, intratumoral ethanol injection of fibroids could improve the acoustic environment by producing regional tumor devascularization to make ultrasound energy easier to deposit to achieve a larger NPVR than HIFU alone for hyperintense fibroids, thus a sustained long-term symptom relief. The goal of intratumoral ethanol injection of fibroids was to improve the acoustic environment to make ultrasound energy easier to deposit. Therefore, the safety was our main concern. In this study, the amount of anhydrous alcohol injected for fibroids in each patient was from 1 to 31 ml, with larger fibroids requiring higher volumes. We only observed that 1 patient experienced facial flushing and 7 patients experienced coughing. These minor adverse effects subsided quickly without any specific treatment. This strategy also decreased the risks of adverse effects of HIFU treatment. In this study, the most frequent adverse effects during HIFU were lower abdominal and sacrococcygeal pain. A previous study showed a significant decrease of pain score in patients treated with intratumoral ethanol injection followed by HIFU in comparison with patients treated with HIFU alone (3.55 ± 1.64 points vs. 4.80 ± 1.54 points, P < 0.05).[ 35 ] Despite the fibroids treated in our study being challenging cases, the median pain score during the procedure was 3 points, indicating that intratumoral ethanol injection followed by HIFU may alleviate the pain during the procedure and increase the comfort of treatment. Extensive clinical evidence also supported the safety of HIFU for uterine fibroids with a low incidence of severe adverse effects. Chen et al .[ 5 ] conducted a systematic evaluation of treatment safety among 9988 patients with uterine fibroids or adenomyosis treated by HIFU and revealed that the major adverse effects were classified as SIR class A, with a proportion of 94.1%. The proportions of class B, C, and D adverse effects were 3.4%, 1.8%, and 0.6%, respectively, with no class E and F adverse effects. Another large-scale study based on real-world data reported the rate of adverse effects after HIFU as follows: class A (47.5030%), class B (0.7947%), class C (0.3327%), and class D (0.0518%), with a major adverse effect rate (class C and D) of 0.3844%. Frequent adverse effects included lower abdominal pain (30.5%), sacrococcygeal pain (10.5%), and abnormal vaginal discharge (4.7%).[ 36 ] In our study, the adverse effects of patients treated with HIFU combined with intratumoral ethanol injection were SIR class A (90.3%) or B (4.1%), requiring no specific treatment, and there was no class C or higher class adverse effects. The frequent adverse effects included abnormal vaginal discharge (59.5%), lower abdominal or sacrococcygeal pain (25.6%), and slight vaginal bleeding (2.6%). Compared with the previous study of HIFU alone, the incidence of lower abdominal and sacrococcygeal pain was lower in patients treated with intratumoral ethanol injection followed by HIFU, but the incidence of vaginal discharge was higher. This may be explained by that the local tissue is stimulated by puncture during transvaginal intratumoral ethanol injection, or the local deposition of ultrasound energy increases after intratumoral ethanol injection followed by HIFU, which stimulates the endometrium. The amount of vaginal discharge was minimal and light red in color, requiring no special treatment. A small number of patients had slightly more discharge, for which oral antibiotics were given for prevention of infection. Most patients recovered within 3 days, and all the patients completely recovered within 1 week. Our results suggest that the combination treatment of HIFU and intratumoral ethanol injection for uterine fibroids is safe. This study is limited because it is a retrospective observational study and lacks a concurrent comparative study involving T2WI hyperintense uterine fibroid patients treated by HIFU alone. In addition, for safety reasons, we only cautiously injected a relatively small amount of anhydrous ethanol into the uterine fibroids to reduce the blood supply of the fibroid by producing regional tumor devascularization to improve the efficiency of HIFU treatment. However, we did not optimize the anhydrous ethanol injection volume. Next, we will analyze the relationship between the volume of ethanol injection and the ablation effect of HIFU to determine the optimal injection volume to further improve treatment efficiency while ensuring treatment safety. Subsequently, we plan to conduct a prospective cohort study to compare the safety and efficacy of HIFU alone and anhydrous ethanol injection followed by HIFU for the treatment of hyperintense fibroids to further validate the findings of this study.

The protocol for this study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee at Chongqing Haifu Hospital (No. HF2023-010), and the requirement for informed consent was waived due to the observational nature of this retrospective study. Patients with hyperintense uterine fibroids who received intratumoral ethanol injection followed by HIFU in our hospital from January 2022 to February 2024 were enrolled in this study. Inclusion criteria were as follows: (1) premenopausal women, older than 18 years; (2) diagnosis of uterine fibroids was suspected by medical history and confirmed by ultrasound and pelvic contrast-enhanced MRI; (3) MRI showed the fibroids with high signal intensity on T2WI; and (4) voluntarily received intratumoral ethanol injection as a pretreatment and completed HIFU treatment. Exclusion criteria were as follows: (1) patients with uterine fibroids accompanied by adenomyosis and (2) patients who did not have complete treatment records. A total of 211 patients with hyperintense uterine fibroids who received intratumoral ethanol injection as a pretreatment and completed HIFU treatment were retrospectively reviewed. Of these patients, 16 patients were excluded due to concurrent presence of adenomyosis ( n = 5) or incomplete information ( n = 11). Finally, 195 patients were enrolled in the study [ Figure 1 ]. Flowchart of patient selection MRI examination was performed with a 1.5 T MRI system produced by Shanghai United Imaging Medical Technology Co., Ltd., China. A pelvic contrast-enhanced MRI examination was performed in all patients within 1 week before and 1 day after HIFU. The scanning sequences included T2WI (TR 4692 ms, TE 75 ms, layer thickness 5 mm, 1 mm), T1WI (TR 196 ms, TE 8.18 ms, layer thickness 6 mm, layer spacing 1.2 mm), and contrast-enhanced T1WI (TR 4 ms, TE 2 ms, layer thickness 5 mm, layer spacing 1.2 mm). Gadopentetate dimeglumine injection (0.5 mmol/ml concentration, 15 ml in vials) was used for contrast-enhanced MRI. Gadopentetate dimeglumine 0.2 ml/kg was administered at an injection rate of approximately 2 ml/s. MRI images obtained from patients were evaluated by two experienced radiologists. Uterine fibroids were classified based on signal intensity on T2WI according to the Funaki classification:[ 16 ] hypointense (the signal intensity of fibroids was equal to or lower than that of skeletal muscle), isointense (the signal intensity of fibroids was higher than that of skeletal muscle but lower than that of the myometrium), and hyperintense fibroids (the signal intensity of fibroids was equal to or higher than that of the myometrium). The volume of fibroids and nonperfused volume (NPV) were obtained using the software program, which was programmed by the engineers from Chongqing Haifu Medical Technology Co., Ltd., to contour the fibroids and the nonperfused region in every slice of contrast-enhanced MRI images and then calculated. The NPVR = NPV/fibroid volume × 100%. Every patient received an ultrasound-guided intratumoral ethanol injection following a case discussion before HIFU treatment. Intratumoral ethanol injection was performed under intravenous anesthesia using propofol. A 21-gauge (6 holes, 20 cm long) percutaneous ethanol injection therapy needle was employed. According to the location of the fibroid in the uterus, ultrasound-guided percutaneous intratumoral ethanol injection or transvaginal intratumoral ethanol injection was performed. Percutaneous intratumoral ethanol injection was used for patients with uterine fibroids located in the anterior wall, lateral wall, or fundus of the uterus. Patients were asked to empty their bladders and placed on a supine position. The procedure was performed under the guidance of ultrasound to assess whether the needle approached the fibroid. Subsequent to the intravenous anesthesia, the needle was inserted with ultrasound guidance into the deeper region of the fibroid. After removing the core of needle and confirming no blood return upon aspiration, 1 ml of saline was injected to further verify the needle position, and anhydrous ethanol was then slowly injected into the site. The injection volume of anhydrous ethanol was based on the size of the fibroid and the diffusion of ethanol. In general, the injection amount of anhydrous ethanol was 1/10–1/20 of the fibroid volume (length × width × height × 0.5233), but the maximum amount for one patient was no more than 40 mL. After completing the ethanol injection, 1–2 ml of saline was injected to flush the needle, which was then removed. Transvaginal intratumoral ethanol injection was used for patients with the fibroids located in the posterior wall, lower segment of the uterine, or cervix. Patients were positioned on a lithotomy position. The procedure was performed under the guidance of ultrasound, and the needle was inserted with ultrasound guidance into the deeper region of the fibroid through the anterior or posterior vaginal fornix. The remaining procedure was the same as those of percutaneous intratumoral ethanol injection. The patients were transferred to the HIFU unit for HIFU treatment after intratumoral ethanol injection. The procedure of HIFU treatment was described previously in our earlier studies.[ 9 10 ] Briefly, HIFU was performed using the Focused Ultrasound Tumor Therapeutic System (Model-JC or JC200) produced by Chongqing Haifu Medical Technology Co., Ltd., China). Patients were positioned prone on the treatment table with the anterior abdominal wall in contact with degassed water. The procedure of HIFU treatment with ultrasound guidance was performed under conscious sedation. The sagittal ultrasound scanning mode was chosen for both pretreatment planning and sonication. The targeted fibroid was divided into a number of sections by real-time ultrasound with a distance of 5 mm between any two sections. Sonication began in the largest section of the fibroid and targeted the safe region with ethanol diffusion. The distance from the sonication focal point to the fibroid margin was at least 1 cm. During the procedure, the sonication power and therapeutic intensity were adjusted based on the patient’s response and grayscale changes in the treated region. The treatment was terminated when the grayscale in the fibroid significantly increased, and the contrast-enhanced ultrasound was then performed to assess the NPV of the fibroids. Additional treatment was performed if the NPV was deemed insufficient. Respiratory rate, heart rate, blood pressure, and oxygen saturation were monitored during the procedure. IBM SPSS Statistics 27.0.1 software was used for statistical analysis. Normally distributed data were presented as mean ± standard deviation, and data with skewed distribution were presented as median (with interquartile range). Differences between groups for normally distributed data were compared using analysis of variance (ANOVA), and differences for data with skewed distribution were compared using the Kruskal–Wallis H test. P < 0.05 was considered statistically significant.