Long-term outcomes of ultrasound guided high intensity focused ultrasound ablation for patients with uterine fibroids classified by T2WI: a multicenter retrospective study

Abstract

Objective

To evaluate the long-term outcomes of ultrasound-guided high-intensity focused ultrasound (USgHIFU) ablation of uterine fibroids classified by T2-weighted magnetic resonance imaging (T2WI-MRI).

Materials and methods

The data of 1427 premenopausal women with symptomatic uterine fibroids who underwent USgHIFU at four teaching hospitals in China were analyzed retrospectively. The uterine fibroids were classified based on their T2WI-MRI signal intensities relative to that of skeletal muscle, myometrium and endometrium as: hypointense, isointense, heterogeneous hyperintense fibroids (HHF), slightly HHF (sHHF) and markedly HHF (mHHF), respectively. The rates of symptom relief and reintervention post-USgHIFU ablation were compared between the classified groups.

Results

A total of 1303 patients were followed up for 44 (40, 49) months. The symptom relief rate of the hypointense and isointense fibroids was 83.3% and 79.5%, respectively, which were significantly higher (p < .05) compared to that of HHF, sHHF and mHHF (58.3%, 44.2% and 60.4%), respectively. sHHF had the lowest symptom relief rate (p < .05). The cumulative reintervention rate for hypointense, isointense, HHF, sHHF and mHHF types were 8.8%, 10.8%, 21.4%, 39.9% and 19.8%, respectively. The reintervention rate of hypointense/isointense fibroids was significantly lower than that of HHF/mHHF/sHHF (p < .01), while sHHF had the highest re-intervention rate (p < .01). Thus, reintervention rate is inversely correlated to the rate of symptom relief.

Conclusions

USgHIFU ablation is effective for hypointense, isointense, HHF and mHHF with acceptable long-term follow-up outcomes. However, sHHF is associated with a higher reintervention rate.

Keywords:

• Uterine fibroids
• ultrasound guided high-intensity focused ultrasound (USgHIFU)
• T2-weighted MRI
• reintervention
• long-term followed-up outcomes

Introduction

High-intensity focused ultrasound (HIFU) ablation is a noninvasive treatment modality for symptomatic uterine fibroids [1,2]. However, the long-term outcomes including symptom recurrence and reintervention are still concerns for women who choose uterine preservation options for fibroid treatment and management. Therefore, it is necessary to select the appropriate candidate who will optimally benefit from HIFU treatment with improved long-term follow-up outcomes.

Recent studies show that the signal intensities (SI) of fibroids on T2-weighted magnetic resonance imaging (T2WI-MRI) is an important factor affecting the ablation efficiency and follow-up outcomes of HIFU treatment [3–8]. Currently, the Funaki system classifies uterine fibroids as hypointense, isointense and hyperintense based on the SIs of the fibroids relative to that of skeletal muscle and myometrium on T2WI-MRI [4]. The observation-based consensus is that hypointense and isointense fibroids are more suitable for HIFU ablation on the account of the satisfactory ablation efficiency and the acceptable long-term follow-up outcomes [4,6,7]. Hyperintense fibroids, characterized by rich cellular components and less collagen fiber content are not conducive to the deposition of ultrasonic energy at the target area during the treatment, resulting in an unsatisfactory non-perfused volume (NPV) ratio (a measurement of the ablation efficiency) [9,10]. Thus, hyperintense fibroids are regarded not suitable for HIFU treatment [4,6,7]. Nevertheless, some studies have shown that some hyperintense fibroids can also achieve comparable NPV ratios to that of isointense and hypointense fibroids [5,11].

To examine the observed differential responses to HIFU ablation among the hyperintense fibroids, Zhao et al. further divided hyperintense fibroids into three subtypes based on the SI of the fibroid tissue relative to that of myometrium and endometrium on T2WI-MRI – namely heterogeneous hyperintense fibroids (HHF), slightly HHF (sHHF) and markedly HHF (mHHF). The NPV ratio is the lowest for sHHF, whereas HHF and mHHF can achieve comparable NPV ratios to that of hypointense and isointense fibroids [5]. However, the long-term follow-up studies of all five types of fibroids post HIFU are lacking, and the evidence of stratifying hyperintense fibroid patients for HIFU treatment is limited. Therefore, the aim of this study was to evaluate the long-term follow-up outcomes of the different types of uterine fibroids after ultrasound-guided HIFU (USgHIFU) in order to optimize the selection of fibroid patients who will benefit from HIFU.

Materials and methods

Patients

Patients with symptomatic uterine fibroids who underwent USgHIFU ablation at four clinical centers in China from January 2017 to December 2018 were enrolled in the current retrospective study. This study was approved by the ethics committee of the institutions (approval number: KY2021005), and informed consent was obtained from all participants. All procedures followed were in accordance with ethical standards and the Declaration of Helsinki.

Inclusion criteria for the patients were as follows: (1) premenopausal women over 18 years of age, (2) MRI diagnosis of one dominant uterine fibroid with maximum diameter of 3 to 10 cm, accompanied by no more than three small fibroids with maximum diameter ≤ 2 cm, (3) symptoms related to the dominant uterine fibroid, (4) fibroids types 1–6 according to the International Federation of Gynecology and Obstetrics (FIGO) classification and (5) underwent dynamic contrast-enhanced MR scanning before and after HIFU treatment. Patients with uterine fibroids compounded with adenomyosis, those who underwent hysterectomy for non-fibroid related reasons after USgHIFU or had hormonal therapy six months before USgHIFU were excluded.

MRI data

T2WI-MRI was performed before and after USgHIFU treatment. MRI was performed using the 3.0 T MR unit (Siemens Healthineers, Prisma, Erlangen, Germany) with the patient placed in a prone position seven days before USgHIFU treatment. The MRI sequence is as follows: sagittal and axial T2W fast-recovery fast spin-echo: TR 3500 ms, TE 90 ms, layer thickness 5 mm, slice gap 1.5 mm, flip 130˚, matrix size, 250 × 320 mm, DFOV 30 × 30 cm; sagittal and axial contrast-enhanced T1-weighted gradient-echo: TR/TE, 5.4/2.5; layer thickness, 5 mm; matrix size, 250 × 320 mm; DFOV 30 × 30 cm; flip 10˚. An intravenous mass injection of 15–20 ml contrast agent gadodiamide ((Gd3+; 0.1 mmol/kg; Omniscan GE Healthcare Life Sciences, Chalfont, UK)) was administered at 2 ml/s, contrast-enhanced fat-saturated T1‑weighted images in axial planes were acquired. MRI data including fibroids volume, location (anterior wall, posterior wall, lateral wall, fundus) and type (submucous/FIGO type 1–2; intramural/FIGO type 3–5; subserous/FIGO type 6), contrast enhancement type and uterine position (anteposition, horizontal position, retroposition) were collected. The classification of enhancement type are as follows: (A) slight enhancement – lower degree of enhancement of the fibroid compared to the myometrium; (B)irregular enhancement – irregular distribution of the enhanced signal interspersed with the slightly enhanced signal; (C) regular enhancement – uniformly distributed enhanced signal and the degree of enhancement equal to or greater than that of the myometrium [12]. The fibroid volume was calculated using the following equation: V = 0.5233 $\times$ D1 $\times$ D2 $\times$ D3 (D1, longitudinal; D2, anteroposterior; D3, transverse). The NPV was measured on the contrast-enhanced T1WI-MRI acquired within a week after HIFU treatment using the same method as above (Figure 1(A3–E3)). NPV ratio (%) was calculated as (NPV/fibroid volume) $\times$ 100.

Figure 1. Five types of uterine fibroids classified based on the T2WI and enhanced MRI (sagittal view). A1–E1: T2WI of the five types of fibroids. A1, hypointense fibroids; B1, isointense fibroids; C1–E1, hyperintense fibroids: C1 heterogeneous hyperintense fibroids (HHF); D1, slightly homogeneous hyperintense fibroids (sHHF); E1, markedly homogenous hyperintense fibroids (mHHF). A2–E2: Enhanced MRI before HIFU counterpart to A1–E1. A3–E3: Enhanced MRI after HIFU counterpart to A2–E2, The NPV was visible inside uterine fibroids, the sHHF have the smallest NPV ratio.

Classification of fibroids based on T2WI-MRI signals

Two radiologists made independent classification of the fibroids based on T2WI-MRI signals. The sagittal T2WI without fat suppression, which encompassed the largest section of the fibroids, was selected. The fibroids were classified into three main categories on the basis of the intensities of sagittal T2WI-MRI signals without fat suppression pretreatment relative to that of skeletal muscle and myometrium: (1) hypointense – SI shown as that of skeletal muscle, (2) isointense – SI lower than that of myometrium but higher than that of skeletal muscle and (3) hyperintense – SI similar to or higher than myometrium. Hyperintense fibroids were further classified into three subtypes based on the T2WI-MRI signals relative to that of myometrium and endometrium: (3.1) heterogeneous hyperintense fibroids (HHF) – barred (> 5 mm) or lamellar high SI approximating or equivalent to that of the endometrium or barred (> 5 mm) or lamellar low SI like skeletal muscle inside the fibroid; (3.2) slightly homogenous hyperintense fibroids (sHHF) – uniformly distributed high SI equivalent to or slightly higher than that of the myometrium; (3.3) markedly homogenous hyperintense fibroids (mHHF) – uniformly distributed high SI similar to the endometrium and markedly higher than the myometrium [5] (Figure 1(A1–E1)). In the case of inconsistent SI classification, the decision was made by the two radiologists through discussion.

HIFU ablation

The procedure for USgHIFU has been described in details in our previous study [5]. Briefly, USgHIFU was performed using the Focused Ultrasound Tumor Therapeutic System (Model-JC200, Chongqing Haifu Medical Technology Co. Ltd., Chongqing, China) equipped with an ultrasound imaging probe (MyLab70; Esaote, Genoa, Italy) situated in the center of the transducer for real-time guidance during HIFU treatment (Figure 2(A)). Patients were under continuous intravenous infusion of oxytocin during the whole HIFU treatment procedure (40 units of oxytocin added into 500 ml of 5% glucose solution and 5 ml/min were administrated intravenously) to reduce blood supply to the fibroids during the treatment. The procedure was performed under conscious sedation (0.8–1 mg/kg fentanyl and 0.02–0.03 mg/kg midazolam hydrochloride was injected intravenously every 30–40 min alternately) to ensure that the doctor was informed of any discomfort the patients might incur during treatment. In addition, the focal position of the fibroids and the therapeutic parameters were adjusted according to the patient’s reaction and the grey-scale changes shown by real-time ultrasonography. Patients were instructed to report any discomfort, and vital signs such as heart rate, blood pressure, respiration and oxygen saturation were monitored continuously. Once the gray-scale changes were distributed evenly throughout the targeted fibroid (Figure 2(B)), oxytocin was stopped for 10 min. If real-time ultrasonography showed complete disappearance of blood supply in the fibroids (Figure 2(C)), 2 ml (23.6 mg/mL), a contrast-enhanced micro-bubble agent (SonoVue, Bracco, Milan, Italy) was intravenously administered to evaluate the completeness of the ablation. Treatment was terminated when a satisfactory absence of blood supply was observed in the fibroids under contrast-enhanced ultrasound (Figure 2(D)).

Figure 2. Ultrasound images obtained during HIFU treatment. A, pre-HIFU ultrasound image showed the fibroid's location and blood supply (red arrows); B, post-HIFU utrasound image showed grey scale changes in the fibroids (red arrows); C, post-HIFU utrasound image showed that the blood supply disappeared in the fibroids (red arrows); D, post-HIFU contrast ultrasound image showed no perfusion in the fibroids (marked with green lines).

Follow-up data collection

Patients were followed up by telephone inquiry and outpatient review. The cutoff date of follow-up was December 2021. Due to the retrospective nature of this study, validated measures of leiomyoma symptomatology, such as the Quality-of-Life (UFS-QOL) questionnaire, could not be utilized to acquire more accurate information on symptom relief. Therefore, self-reported amelioration of symptoms was categorized as relief, no relief or recurrence. Symptom recurrence was defined as the reappearance of the fibroids several months or even years after the initial relief. The time of symptom relief intervals was also recorded. Reinterventions for the relief of fibroid-related symptoms included hysterectomy, myomectomy, secondary HIFU and interventional embolization [2,13]. The time of reintervention intervals was recorded and analyzed.

Statistical analysis

SPSS 26.0 software (SPSS Inc., Chicago, IL) was used for statistical analysis. Normally distributed data were presented as mean ± standard deviation. Data with skewed distribution were presented as the median and interquartile range (IQR). Weighted Kappa test was used to test the consistency of two radiologists’ judgment on SI classification of fibroids, a kappa value between 0.75 and 1 indicates good consistency. The baseline data, NPV ratio and follow-up outcome were statistically analyzed by one-way ANOVA, Mann–Whitney U test or the chi-square test. If baseline data between the five fibroid types show statistically significant differences, linear regression analysis will be used to analyze the differences in NPV ratio and reintervention rate among the five fibroid types by controlling the baseline data that with statistically significant differences. Kaplan–Meier method was used to estimate the cumulative reintervention rate over time. All p values were calculated from two-sided tests, and p < .05 was considered statistically significant.

Results

Baseline characteristics

A total of 1427 patients with single symptomatic uterine fibroids who underwent a single session of USgHIFU were enrolled in this study. The Kappa value of Weighted Kappa test was 0.808, suggesting that the consistency of two radiologists’ judgment on SI classification of fibroids was good. The frequencies of hypointense fibroids, isointense fibroids, HHF, sHHF and mHHF were 490 (39.3%), 329 (23.1%) 267 (18.7%), 228 (16%) and 113 (7.9%), respectively. The mean age was 42.4 ± 5.9 years. The median fibroid volume was 67.4 cm³ (37.7–122.7 cm³). The five types differed in terms of volume and enhancement type (p < .05). The median volume of sHHF was significantly less than that of isointense fibroids, HHF and mHHF, while the hypointense fibroids were the smallest. The proportion of sHHF with regular enhancement were significantly higher than that among the other four types, whereas irregular enhancement was most common in the HHFs and mHHFs (Table 1).

Table 1. Comparison of basic characteristics of five types of fibroids based on pretreatment T2WI-MRI.

Variable	Hypointense	Isointense	HHF	mHHF	sHHF	p
N	490	329	267	113	228
Age, Y	42.3 ± 5.0	41.6 ± 5.5	40.9 ± 5.9	41.9 ± 5.4	41.4 ± 6.2	.136
BMI, kg/m^2	23.2 ± 2.9	23.1 ± 3.2	22.6 ± 2.9	23.0 ± 3.2	22.6 ± 2.8	.053
Fibroids volume, cm^3	57.5 (32.1, 92.9)^a	78.3 (42.2,170.9)	76.0 (42.7,132.6)	85.2 (46.0,146.7)	69.8 (35.5,127.2)^b	.000*
Uterus position (A/M/R)	326/28/135	234/15/78	177/14/75	81/8/24	149/13/65	.727
Fibroids location (A/P/L/F), n	223/99/104/64	147/74/71/37	111/57/56/42	47/27/29/10	80/72/50/25	.086
Fibroids type (SM/IM/SS), n	139/229/121	119/141/68	106/128/31	37/65/10	92/110/25	.051
Enhancement type (Sl/IR/RE), n	207/74/209	90/68/71	14/172^d/81	17/86^d/10	25/19/184^c	.000*

Notes: BMI: body mass index; T2WI-MRI: T2-weighted magnetic resonance imaging; HHF: heterogeneous hyperintense fibroids; mHHF: markedly HHF; sHHF: slightly HHF. Uterus position: A: anteposition; M: horizontal position; R: retroposition. Fibroids location: A: anterior wall; P: posterior wall; L: lateral wall; F: fundus. Fibroids type: SM: submucous; IM: intramural; SS: subserous. Enhancement type: Sl: slight; IR: irregular; RE: regular.

^ap < .05 vs isointense , vs HHF, vs mHHF and vs sHHF.

^bp < .05 vs isointense, vs mHHF and vs HHF.

^cp < .05 vs HHF, vs mHHF, vs hyperintense and vs isointense.

^dp < .05 vs hypointense, vs isointense and vs sHHF.

*p < .05.

The ablation efficiency of USgHIFU against the different types of fibroids

The mean NPV ratio of all fibroids was 84.1 ± 17.4%, and that of the hypointense, isointense, HHF, sHHF and mHHF types were 89.0%, 86.6%, 82.3%, 74.0% and 82.2%, respectively. Thus, the hypointense and isointense fibroids had significantly higher NPV ratios compared to that of HHF, mHHF and sHHF (p < .05), and the mean NPV ratio of sHHF was the lowest among all types (p < .05). No significant differences between the hypointense and isointense fibroids or between HHF and mHHF (p > .05) were observed. The results are summarized in Table 2 and Figure 1.

Table 2. The ablation efficiency and follow-up results of five types of fibroids based on pretreatment T2WI-MRI.

Variable	Hypointense	Isointense	HHF	mHHF	sHHF	p
N	443	297	247	106	208
NPV ratio, %	89.0 ± 12.1^a	86.6 ± 12.6^a	82.3 ± 19.7^b	82.2 ± 17.5^b	74.0 ± 24.3^c	.000*
Symptoms change, n(%)
Relief	369 (83.3)^a	236 (79.5)^a	144 (58.3)^b	64 (60.4)^b	92 (44.2)^c	.000 *
No relief	44 (9.9)^a	34 (11.4)^a	57 (23.1)	18 (17.0)	56 (26.9)^d	.000 *
Recurrence	30 (6.8)^a	26 (8.7)^a	46 (18.6)	24 (22.6)	60 (28.8)^c	.000 *
Interval of recurrence, m	27.9 ± 12.5	25.9 ± 9.5	27.6 ± 10.7	24.7 ± 9.2	26.6 ± 9.9	.780
Reintervention, (n)%
Total	39 (8.8)^a	32 (10.8)^a	53 (21.4)^b	21 (19.8)^b	83 (39.9)^c	.000 *
Interval of reintervention, m	22.3 ± 12.9	21.6 ± 13.2	21.6 ± 12.0	22.4 ± 9.4	22.5 ± 11.7	.775

Note: T2WI-MRI: T2-weighted magnetic resonance imaging; NPV ratio: nonperfused volume ratio; HHF: heterogeneous hyperintense fibroids; mHHF: markedly HHF; sHHF: slightly HHF.

^ap < .05 vs HHF, vs mHHF and vs sHHF.

^bp < .05 vs hypointense, vs isointense and vs sHHF.

^cp < .05 vs hypointense, vs isointense , vs mHHF and vs HHF.

^dp < .05 vs hypointense, vs isointense and vs mHHF.

*p < .05.

Follow-up results for the different types of fibroids treated by USgHIFU

A total of 1303 patients were followed up for a median duration of 44 months, of which 905 (69.5%) patients experienced symptom relief, whereas the rest 209 (16.1%) patients experienced the persistence of the symptoms. The rate of symptom relief for the hypointense, isointense, HHF, sHHF and mHHF types were 83.3%, 79.5%, 58.3%, 44.2% and 60.4%, respectively. Thus, symptom relief was most pronounced in patients with hypointense and isointense fibroids compared to those with HHF, mHHF and sHHF (p < .05), while sHHF was associated with the lowest symptom relief rate (p < .05). Furthermore, 186 (14.3%) patients experienced the recurrence of the symptoms after a period of relief. The rate of symptom recurrence was significantly lower in hypointense fibroids and isointense fibroids compared to that of HHF, mHHF and sHHF (p < .05), whereas sHHF had the highest recurrence rate among all types (p < .05). No significant difference was observed among the groups with respect to the recurrence intervals (p > .05; Table 2).

Persistent or recurrent fibroid-related symptoms warranted a reintervention in 228 patients (17.5%), of which 70 (30.7%) had hysterectomy, 150 (65.8%) had myomectomy, 6 (2.6%) underwent a second USgHIFU treatment and 2 (0.9%) underwent uterine artery embolization (UAE). The cumulative reintervention rates of hypointense, isointense, HHF, sHHF and mHHF fibroids were 8.8%, 10.8%, 21.4%, 39.9% and 19.8%, respectively. The reintervention rates for hypointense and isointense fibroids were significantly lower than that of HHF, mHHF and sHHF (p < .05), whereas sHHF required reintervention most frequently (p < .05). There was no significant difference between the reinterventions rates of hypointense and isointense fibroids or between HHF and mHHF (p > .05). In addition, reintervention intervals were also similar for all groups (p > .05; Table 2).

Kaplan–Meier analysis demonstrated that the reintervention rate of all fibroids began to increase 12 months after HIFU treatment. For hypointense fibroids, isointense fibroids, HHF and mHHF, the reintervention rate increased slowly with the extension of follow-up time and plateaued after 48 months. The reintervention rates of HHF and mHHF were significantly higher than that of hypointense and isointense fibroids at each follow-up. In contrast, the reintervention rate of sHHF increased gradually with the extension of follow-up time without plateauing and was significantly higher than that of the other four types at each follow-up (Figure 3).

Figure 3. The Kaplan–Meier curves showing the cumulative reintervention rate of five types of fibroids.

Discussion

The current consensus is that patients with hypointense or isointense uterine fibroids can benefit from HIFU treatment due to the satisfactory NPV ratios that yield acceptable follow-up outcomes. Nevertheless, the ablation efficiency of HIFU against hyperintense fibroids remains controversial, and only a few studies have compared the follow-up outcomes of the different types of fibroids classified on the basis of T2WI-MRI signals [3–7,11]. However, long-term follow-up studies were lacking. In this study, the proportion of symptomatic hyperintense fibroids that underwent HIFU treatment was 42.6%, which warrants the evaluation of the follow-up outcomes.

For any uterine preserving treatment strategy for uterine fibroids, the follow-up outcomes are still a major clinical concern. Myomectomy is the first-line uterine sparing therapeutic strategy of symptomatic uterine fibroids. Xu et al. [14] have reported that the cumulative reoperation rate after myomectomy, UAE and magnetic resonance-guided HIFU (MRgHIFU) were 9%, 14% and 22% at three years and 19%, 21% and 49% at five years, respectively. Wang et al. [2] reported that the cumulative reoperation rate after myomectomy and USgHIFU were 11.9% and 3.2% at three years and 15.5% and 9.5% at five years, respectively. We found that about 80% of the patients with hypointense or isointense fibroids achieved complete symptom relief, and the cumulative reintervention rates at 44 months (median duration of follow-up) were only 8.8% and 10.8%, respectively. Previous studies have reported similar reintervention rates for hypointense and isointense fibroids after USgHIFU treatment and myomectomy [2,14]. The NPV ratio of the uterine fibroids is the most important factor affecting the clinical outcome of HIFU treatment, and an NPV ratio of at least 80% is associated with greater volume shrinkage and better follow-up outcomes [15,16]. In this study, the mean NPV ratios of hypointense and isointense fibroids were 89.0% and 86.6%, respectively, which lead to sustained fibroids volume reduction and have ensured favorable long-term outcomes. Therefore, hypointense and isointense fibroids are good indications for HIFU treatment.

At the median 44-month follow up, the symptom relief rate for sHHF was only 44.2% and the symptom recurrence rate was 28.8%, which corresponded to an unfavorable reintervention rate of 39.9%. We also found that the sHHF has the lowest mean NPV ratio than other four groups in this study, which is consistent with the findings of a previous literature [5]. According to a number of studies [5,9,10], hypointense and isointense fibroids exhibit typical histopathological characteristics of fewer smooth muscle cells and abundant collagen fibers, HHF and mHHF exhibit typical fibroids histopathological characteristics accompanied by varying degree of necrotic components, while sHHF exhibited rich smooth muscle cells and a small amount of collagen fibers. Cellular fibroids are copiously supplied by vessels, while degenerative fibroids have reduced blood supply [17]. Fibroids with significant cellularity or rich blood flow may be resistant to HIFU, as the energy cannot be easily deposited. Instead, typical fibroids and degeneration fibroids can be easily ablated by HIFU because they contained sparing cellularity and fewer blood vessels [9,18,19]. Therefore, the abundant residual unablated tissues of sHHF then continue to grow after HIFU treatment, resulting in an unsatisfactory volume shrink rate and poor follow-up outcomes. Given the low NPV ratio and the high rates of symptom recurrence and reintervention, HIFU should be considered with caution for sHHF.

In this study, the cumulative reintervention rates of HHF and mHHF at 44 months were 21.4% and 19.8%, respectively, which were higher than that reported for myomectomy [2,14]. Whether HHF and mHHF can be effectively treated by HIFU requires more studies to validate. Symptomatic fibroids are treated by non-surgical methods [20], including uterine artery embolization (UAE) and HIFU, which are well-established uterine preserving treatments [1,2,14,21]. Daniels et al. [22] reported a cumulative reoperation rate of 24% at 48 months after UAE. The 60-month reintervention rate of UAE has been reported as 21% and 24% by Xu et al. and Davis et al. respectively [14,21]. In our study, the reintervention rates of HHF and mHHF after USgHIFU were comparable to that after UAE [14,21,22].

As mentioned earlier, an NPV ratio of at least 80% is associated with greater volume shrinkage and better follow-up outcomes [15,16]. In this study, the mean NPV ratio of HHF and mHHF was 82.3 ± 19.7% and 82.2 ± 17.5%, respectively, which had reached the ablation standard proposed in the current study [15,16]. In addition, 60% of the patients with HHF or mHHF achieved complete symptom relief and avoided invasive treatment, which can be attributed to the satisfactory NPV ratios acquired by a fraction of these patients. In Zhao’s study in 2013, fibroids were treated with USgHIFU, the NPV ratio of HHF and mHHF was 77.7 ± 17.1% and 74.0 ± 18.1%, respectively [5]. It is worth noting that the NPV ratio of HHF and mHHF in this study were higher than that reported by Zhao et al. We speculated that this may be related to the improvement of doctors’ treatment competency.

The blood flow is an important factor affecting the effect of HIFU ablation, rich blood supply may prevent ultrasound energy deposition and diminish heat sink in the target tissue of uterine fibroids, thereby affecting ablation outcomes [12,18]. Intravenous administration of oxytocin during HIFU therapy can significantly reduce or even block the blood perfusion in uterine fibroids with little or no effect on the blood flow of normal myometrium, thus improving the ablation efficiency of HIFU therapy without increasing the unsafety concerns [23,24]. In this study, oxytocin was used during the whole HIFU treatment process and significantly decreased the blood flow of all the fibroids. This result is consistent with the research results of Otokowski et al. [24]. Moreover, one recent study showed that the therapeutic outcomes of HHF may be enhanced by GnRH-a pretreatment with HIFU [25]. Therefore, pre-HIFU treatment strategies improve NPV ratio for HHF and mHHF and consequently, the follow-up outcomes, HIFU is also worth considering as an alternative treatment for HHF and mHHF in case the patient not willing to choose invasive surgery or cannot withstand invasive surgery.

Some studies have shown that most uterine fibroids require reintervention two to four years post-HIFU, suggesting that this time window is suitable to evaluate reintervention rates [13,26]. In this study, the Kaplan–Meier curves of the cumulative reintervention rate showed that the reintervention rates of hypointense fibroids, isointense fibroids, HHF and sHHF increased slowly with the extension of follow-up time and stabilized after four years of follow-up. Interestingly, after four years of follow-up, about 40% of the patients with HHF and mHHF either had unrelieved symptoms or had experienced recurrence. These patients likely would undergo reintervention. Therefore, HHF and mHHF need longer follow-up time for evaluating the reintervention rates. The reintervention rate of sHHF steadily increased with the extension of follow-up time without plateauing, indicating that continuous follow-up is needed to evaluate the reintervention rate for these fibroids. In this study, we found that there was no difference in the reintervention intervals among all groups, possibly because the follow-up time were just within the ‘time window’ when the reintervention was relatively concentrated for all groups. Combining the results of the Kaplan–Meier curves in Figure 3 of this study, we speculate that after a longer follow-up, the reintervention intervals for sHHF may be different from other fibroids types. We are conducting an extended follow-up to verify this assumption.

This study has some limitations. First, due to the retrospective nature of this study, the data on symptom relief might be inaccurate and could not be used to accurately evaluate the improvement of fibroid-related symptoms and quality of life of the patients. Second, the differences in volume and enhancement type among the five fibroid types may have introduced some bias. However, linear regression analysis was used to reduce the risk of the bias by incorporating volume and enhancement type into consideration. Third, as the results of this study suggested, mHHF is the type suitable for HIFU treatment, but sHHF is not. When inconsistent readings occurred between two radiologists in this study, the signal intensity more similar to the myometrium is determined as sHHS, and the signal intensity more similar to the endometrium is determined as mHHF. Nevertheless, objective indicators for distinguishing between sHHF and mHHF is lacking, it need us further research to do appropriate selection of indications for HIFU treatment. In addition, the rate of shrinkage of the fibroids could not be evaluated since most patients did not undergo follow-up MRI. Further prospective studies that incorporate these factors need to be conducted in order to validate our findings.

Conclusions

Hypointense fibroids and isointense fibroids can benefit from USgHIFU treatment with low reintervention rates. USgHIFU is also worth considering as an alternative treatment for HHF and mHHF, despite their high reintervention rates. On the other hand, sHHF may be excluded since its reintervention rate was the highest.

Ethical approval

This study was performed according to the guidelines of the Helsinki declaration and was approved by the Ethics Committee of Southwest Medical University (No.: KY2021005).

Author contributions

All authors contributed to the study conception and design. The integrity of the entire study was overseen by Jinyun Chen and H. Rosie Xing. Ping Zhan and Jian Shu provide supervision and guarantee for the implementation of study executing and data collection. Yuan Yuan, Zhenjiang Lin, Mali Liu and Fan Xu executed the study and collected the data. Qiuling Shi and Wei Xu performed the data analysis. Yuan Yuan wrote the first draft of the manuscript which was reviewed by all the other authors. Huangpin Shen participated in the data analysis and interpretation and play an important role in revising the manuscript according to the reviewer’s suggestions. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data are not available due to ethical restrictions.

Additional information

Funding

This research was supported by the Luzhou Science and Technology Bureau under Grant [Fund code: 2022-SYF-57].