Should Ultrasound-Guided High Frequency Focused Ultrasound Be Considered as an Alternative Non-Surgical Treatment of Uterine Fibroids in Non-Asiatic Countries? An Opinion Paper

Minimally invasive interventions for myomata treatment have gained acceptance due to the possibility of preserving fertility with reduced trauma induced by laparotomy as way of entrance. There are insufficient data regarding outcomes of high intensity focused ultrasound (HIFU) in non-Asiatic women. Therefore, we revised the available evidence to present an expert opinion that could support physicians, patients and policy-makers for considering this approach in other populations. We revisited systematic reviews, randomized controlled trials and cohort studies from January 2018 to August 2021 using PubMed and Google scholar, regarding short and long term outcomes after ablation with focused ultrasound waves. In total, 33 studies, including 114,810 adult patients showed that outcomes of this approach depend on several parameters directly related with resistance to thermal ablation, especially fibroid size and vascularization. Two studies report satisfactory outcomes in Afro-American women. In accordance to the technique used, fibroid volume reduction showed to be higher in fibroids <300 cm3 after ultrasound guided HIFU than after MRI guided. Compared to myomectomy and uterine artery embolization, HIFU seems to have shorter hospital stay, higher pregnancy rates and similar adverse events rates, with skin burn being the most reported. Symptoms and quality of life improvement is similar to myomectomy but lower than embolization, however reintervention rate is higher after HIFU. Lacks evidence about long-term sarcoma risk after ablation. Available evidence shows that HIFU can be considered as a uterine sparing treatment for women of different ethnicities suffering of uterine myomatosis, especially for those wishing to preserve their fertility.


Introduction
In clinical practice, non-invasive gynecological interventions have gained acceptance due to the possibility of preserving fertility and reducing the risks associated with invasive surgery but with similar results with respect to symptoms resolution [1]. Recently, thermal ablation of tissues has been introduced to treat benign and malignant tumors by using different types of energies including radiofrequency current, micro-laser and ultrasound waves [2]. The latest, have been used based on their ability to penetrate deep into tissues and to induce molecular reactions through mechanical and thermal mechanisms [2]. The beam of high intensity focused ultrasound (HIFU) can be guided by MRI (MRgHIFU) or ultrasound (USgHIFU) to accurately localize and treat the lesion [3]. MRgHIFU has limited clinical application because the need of a radiologist at all times of the procedure and being more time consuming than USgHIFU [4]. Before starting therapy and to avoid skin burn and damage to nearby organs or tissues, an acoustic window is created, then the device brings the acoustic energy through the skin via a coupling gel or a water balloon [5]. The waves pass through the tissues and arrive at the target lesion, raising the temperature of the focal point leading to irreversible coagulative necrosis by absorption of ultrasound energy (thermal effect) and thereby ultrasound-induced cavitation damage (mechanical effect) [5]. The blood perfusion of the lesion is reduced and a defined border between the treated area and surrounding tissue is created [2]. These changes are easy to recognize post-procedure by contrast-enhance MRI or ultrasound. Moreover, membrane hormone receptors are impaired making them less sensitive to hormones, which in turn could prevent fibroids [6]. Though several cohort studies report HIFU outcomes to be better than surgery, the use of this technology is not worldwide approved, available or used [7].
In gynecology, HIFU is proposed for treating symptomatic uterine myomata [2,7,8], a benign disease that affects 33-77% of women worldwide, threatening their fertility and quality of life [9]. Furthermore, HIFU is being increasingly used in Asiatic countries as a non-invasive intervention for adenomyosis, and different primary malignant and metastatic tumors, such as hepatocellular carcinoma, breast, prostate and pancreatic cancer, small size renal tumors, carcinoma of esophagus, glioblastoma and bone tumors [2]. It is also considered as a treatment for non-cancerous lesions such as prostate hypertrophy, solid and complex thyroid nodules, blood-brain barrier disruption, intracerebral hemorrhage, glaucoma, atrial fibrillation and methicillin-resistant staphylococcus aureus-induced abscess [2]. Additionally, it is being investigated as an alternative treatment of various brain disorders such as Parkinson's disease, essential tremor, Alzheimer's disease, depression, anxiety and pain syndromes [2]. Undeniably, the scientific community should be aware of the possible advantages and risks of this novel technology.
Considering that gynecologists and patients are interested in having access to noninvasive alternatives for the management of uterine myomatosis, but having insufficient data on HIFU long-term effects, we present an evidence-based expert opinion that could support physicians, patients and policy-makers for eventually considering the HIFU as an alternative to surgery and uterine artery embolization (UAE) to treat patients presenting with uterine myomatosis. Evidence comparing HIFU with available medical therapies is out of the scope of this paper.

Materials and Methods
A search was conducted using the PubMed and Google scholar databases from January 2018 to August 2021. Systematic reviews, randomized controlled clinical trials and observational studies regarding outcomes of HIFU were collected. Outcomes of interest were: role of different technical parameters on symptoms resolution, adverse events, fibroid shrinkage, reintervention, pregnancy and risk of sarcoma. The following inclusion criteria were used: studies including women diagnosed with uterine fibroids (systemic review, meta-anmeta-analysis, randomized controlled trial, cohort studies, both comparative and non-comparative), published in English. Commentaries, case reports, technical reports, animal studies, letters to editor, published papers without an available full-text and non-English articles were excluded. Data Extraction and Outcome Measure We selected articles according to the above mentioned inclusion and exclusion criteria. We scrutinized titles and abstracts and then gathered all potentially relevant studies for full text evaluation. We extracted information about authors, year of publication, study design, interventions, participant age, participant ethnicity, post-procedure results. To illustrate the safety and efficacy of HIFU, we considered outcome measures such as, complications, adverse events, serious adverse events, time to recovery, hospital stay, time to tumor remission, pregnancy rate, reintervention rate and sarcoma-risk.

Results
In total, 47 studies were retrieved and identified for possible evaluation (Figure 1). Duplicates and studies that not met the inclusion criteria were removed. A total of 32 met the inclusion criteria and remained for full text reviews. Overall, four of these were systemic reviews, six were meta-analysis, eight were prospective clinical trials and 14 were retrospective cohort studies. In addition, seven articles describing technical parameters that affect HIFU outcomes were analyzed.  (Tables 1 and 2). In total, 19 were conducted in China, three in The Netherlands, two in Taiwan, one in Hong Kong, two in USA, two in Vietnam, one in Finland, two in South Africa, one in Canada. Most of the studies evaluate treatment outcomes on the basis of resolution of symptoms, complications, fibroid volume reduction, reintervention rate for recurrent symptoms and relapse of disease, and pregnancy A total of 32 studies representing 114,810 women with symptomatic uterine fibroids underwent HIFU were revisited (Tables 1 and 2). In total, 19 were conducted in China, three in The Netherlands, two in Taiwan, one in Hong Kong, two in USA, two in Vietnam, one in Finland, two in South Africa, one in Canada. Most of the studies evaluate treatment outcomes on the basis of resolution of symptoms, complications, fibroid volume reduction, reintervention rate for recurrent symptoms and relapse of disease, and pregnancy outcomes. All studies considered patients aged more than 18 years (range 26 to 51 years).    Pooled mean fibroid volume reduction ± SD: UAE: 3 mo: 44% ± 9%; 6 mo: 54% ± 10%; 9 mo: 61%; 12 mo: 66% ± 10%; 24 mo: 70% ± 11% RFA: 3 mo: 55% ± 9%; 6 mo: 70% ± 5%; 9 mo: 78%; 12 mo: 75% ± 15%; 24 mo: 83% ± 8%; 36 mo: 84% ± 10%, HIFU: 3 mo: 21% ± 6%; 6 mo: 32% ± 11%; 12 mo: 28% ± 16%; 24 mo: 34% ± 8%; 36 mo: 32%

Ethnicity
Most of the reported outcomes are from studies conducted in Asiatic populations. Only two studies had specifically reported the ethnicity of their participants. Zhang CHJ, et al. [4] evaluated efficacy and safety of HIFU in 26 premenopausal African women. The study showed a 52.5 ± 36.3% tumor reduction in six months, no major complications and two reinterventions due to persistent heavy menstrual bleeding [4]. Suomi V, et al. [10] reported treatment outcomes in Asian, White and Black population. However, in this study most of the patients were white (80/89) and the results were not adjusted according to ethnicity [10].

Non-Perfused Volume Ratio
Non-perfused volume ratio (NPVR) is defined as percentage of non-perfused volume (NPV) in the uterine fibroids on MRI done after USgHIFU or MRgHIFU; that is, NPV divided by original tumor volume targeted. It is considered as a marker for assessing the efficacy and primary outcome of HIFU ablation [11,12]. Fan HJ et al. [11] reported that the goal of HIFU treatment should be to get maximum NPVR which is measured immediately through MRI by calculating fibroid shrinkage volume (FVS) after procedure and at the 1st and 3rd month on follow-up visits. They observed a NPVR variation between 16.7 to 97.9% (SD 74.7 ± 15.1%) in 207 patients. Higher NPVR was achieved by patients having fibroids in anterior location, hypointensity SI on T2WI and anteverted uterine position. Transmural myomata, hyperintensity SI on T2WI, longer distance from myoma's ventral side to skin and posterior fibroids were more difficult to ablate and showed low NPVR [11].

Thickness of Abdominal Subcutaneous Tissues
Four studies demonstrated that the subcutaneous fat layer attenuates ultrasound energy [5,36]. Heating efficacy of ultrasound field is significantly reduced as fat tissues easily absorb thermal energy, which potentially causes thermal injury and low NPV ratio [5,36]. Additionally, total treatment time become longer as a thick fat layer affects cooling time between sonication (abdominal wall thickness: OR = 1.570, 95% CI = 1.329-1.854; p = 0.000 and BMI OR = 2.097, 95% CI = 1.575-2.745; p = 0.000) [5]. Abdominal wall thickness, BMI, sonication time per hour (time of ablation when energy was being delivered to the target) and total energy applied are potential factors for thermal damage in abdominal wall structures [13]. Moreover, thickness of abdominal subcutaneous tissues was second in the ranking feature selection method proposed by Suomi V, et al. [10], better than patient weight (rank 13) and height (rank 15), despite subcutaneous fat thickness being strongly correlated with weight, as total weight includes fat and muscle mass and does not reflect localized fat content.

Perfusion of Fibroids
Ablation capability of HIFU depends on perfusion characteristics of fibroids like blood flow velocity and perfusion volume, which could be evaluated before procedure by contrast enhanced ultrasound (CEUS) [30]. More perfusion to fibroids means more resistance towards HIFU [12]. Wang YJ, et al. [12] reported that myomata which showed lower blood flow velocity and higher perfusion volume have fast rise and decline in blood flow, and therefore were more resistant to HIFU and had a reduced ablation effect.

Energy Efficiency Factor
The energy efficiency factor (EEF) represents the ultrasonic energy required for uterine fibroids ablation per unit volume (1 mm 3 ) [11]. It reflects the energy deposition efficiency of HIFU and is considered one of the most accurate quantitative indicators of HIFU ablation. The smaller the EEF, the lower energy needed to ablate a volume of uterine fibroids and to achieve a higher HIFU ablation efficiency [11]. Different factors are negatively correlated to EEF, including: size of uterine fibroids, anterior location of myoma, hypointensity SI on T2WI, positive co-relation with distance from the uterine fibroid ventral side to skin, enhancement type on T1WI and transmural type of myomata [11]. It is more difficult to ablate myomata with long distance from its ventral side to skin, in retroverted uterus, significant enhancement on T1WI, hyperintensity SI on T2WI, small size, transmural type and posterior location [11], and, in the same way, correlated with NPVR.
Wang Y et al. [15] observed a higher symptomatic relief in the USgHIFU than in myomectomy group (95.9% vs. 89.1%), with a mean decrease of 30.5 points at the tSSS scale from baseline 40 (range 12-66) to 10.2 (range 0-14) during six months follow-up as well as, a lower symptom recurrence rate (11.9% vs. 27.8%) [15]. Similarly, Chen J, et al. [37] showed that QoL was improved significantly in the HIFU group in three aspects, bodily pain, vitality and emotions, as compared to myomectomy, at six months (10.20 ± 10.18 vs. 7.09 ± 8.25; p = 0.000) and 12 months (7.73 ± 9.65 vs. 5.77 ± 7.77). Thereafter all groups showed no differences in QoL. In the non-comparative study from Lozinski T et al., 2021 [19] a 69% improvement in the uterine fibroid-related symptoms scale was observed at third month post MRgHIFU, which increased up to 76% at sixth month, which were directly related with fibroid size reduction. Similar results were found in the meta-analysis from Sandbreg EM, et al. [31] and Verpalena IM et al. [32].
In comparison to UAE, the meta-analysis conducted by Liu L, et al. [8] found that the effect of UAE was superior in terms of alleviation of myoma-related symptoms and improvement in QoL for treatment with a significantly decrease in symptomatology and increase in QoL in UAE group (overall mean difference 19.54; 95% CI 15.21-23.13; p < 0.001; I 2 = 73%). However, patients were older in UAE group (41.2 y-o; range 33.6-55.3 vs. HIFU 36.1 y-o; range: 27.7-41), which affects the observed difference.
Regarding hospital stay, Chen J, et al. [37] reported that HIFU showed better results as compared to surgical intervention, with faster return to work and lower cost.

Adverse Events
Several studies report that complication rates after HIFU are low (<1%) and decline over time, from 0.9565% to 0.2852% over seven years [3,22,28,37], which is attributed to the learning curve of physicians [21]. A list of the complications and short-term adverse events (AE) reported from different studies are shown in Tables 4 and 5. Major complications are infrequent or rare, being skin burn, fever and venous thrombosis the most reported, which usually resolve without sequela. Bowel injuries can occur when the bowel is in the acoustic pathway or when fibroids are over treated, being diagnosed up to 12 days after therapy [20,21]. Pubic symphysis pain and hydronephrosis are reported to appear after treating cervical fibroids, due to transient increase of fibroid size and edematous compression of ureter [21]. In addition, peritoneal adhesions after HIFU, have been reported to develop in the same frequency, location and severity than after surgical myomata removal (43.75% vs. 36.14%; p = 0.132) [20].
Minor complications are attributed to the inflammation response to the thermal effect of HIFU, including mild lower abdominal pain, sacrococcygeal pain and abnormal vaginal discharge, subsiding in few days, as reported by several studies (Table 5) [3,4,13,14,17,22,32,37]. Some factors not related with the thermal effect could lead to interruption of the MRgHIFU, including stress, impatience or claustrophobia [20]. Discharged necrotic tissue usually began in the first cycle after therapy and resolve spontaneously within eight months after therapy [13,17,31], which was observed in up to 60% of patients. The meta-analysis from Jeng CJ et al. [28] reports that abdominal pain and abnormal vaginal discharge are more prevalent in MRgHIFU (mean 37.0% and 20.3%, respectively) as compared to USgHIFU (mean 31.2% and 11.3%, respectively), as timely adjustments could be made according to patient's pain feedback during USgHIFU. In contrast, sciatic nerve pain and thermal skin injury was found to be less frequent in MRgHIFU, according to the meta-analysis of Yu L et al. [29].

Fibroid Volume Reduction
Resolution of symptoms and reduction in fibroid-and uterine volume are the indicators of treatment efficacy. Nevertheless, there is heterogeneity regarding the way this reduction was measured: some studies reported changes in the dominant or single fibroid and others documented all treated fibroids.
Most of the studies showed overall fibroid volume shrinkage ranging from 18% at three months [32] up to 84% at 36 months [3,[17][18][19]37] (Table 6). The reduction depends on the initial fibroid volume and that there is a positive relationship between fibroid shrinkage and NPV ratio; the more the NPV, the higher the volume reduction [19]. Yu L, et al. [29] found in his meta-analysis higher reduction rates after USgHIFU (65.55%) than in MRgHIFU 36.44% for patients having <300 cm 3 fibroid volume. He M, et al. [17] observed no significant difference in reduction rate between hypointense, isointense and hyperintense fibroids at one, three and six months (32.5% ± 24.0, 42.3 ± 32.2% and 52.5 ± 36.3%, respectively). Studies made with portable-HIFU showed 45.1 ± 25% volume reduction five months after therapy, because the treatment beam speed of portable-HIFU is similar to the speed obtained with MRgHIFU (1.30 mL/min ± 1.08 mL/min vs. 1.49 mL/min) [17].
Furthermore, HIFU has been reported to be a good option for patients who have recurrent symptomatic uterine fibroids after myomectomy, because they will not need renewed surgical procedures. Liu X et al. [24] found out that after HIFU the symptom recurrence-time leading to a reintervention is longer as compared to secondary myomec-tomy (54 vs. 34 months; p = 0.024). The cumulative risk of reintervention at one and three years after myomectomy was higher than after HIFU (4.8% vs. 0%; 11.9% vs. 3.2%, respectively), which was attributed to surgical complications because of the first myomectomy. However, no significant difference was found between secondary myomectomy and HIFU at 5 and 8 years (15.5% vs. 9.5%; 17.9% vs. 13.7%, respectively) [24].
He M et al. [17] evaluated the pregnancy rate in African women with pregnancy desire up to 6 months after HIFU and myomectomy. Out of 81 patients, only one was conceived after 3 months of completed HIFU for multiple fibroids and had a term vaginal delivery without any obstetrical complication.
In addition, Qu K, et al. [38] reported that ovarian reserve is probably not impaired by HIFU. They evaluated the AMH level of 67 patients prior to USgHIFU in accordance to age, <35 years, 36-40 years, >40 years. A significant difference in AMH level was observed in the group of patients with ages between 36 and 40 years, but no significant difference in AMH levels was observed in the other two groups (p > 0.05). Hence, the short follow-up period of this study does not allow to elucidate the impact of AMH-level changes on pregnancy rates of women between 36 and 40 years-old. Recently, Anneveldt KJ, et al. [35] retrospectively analyzed 21 studies on reproductive outcomes after MRgHIFU and USgHIFU. They found that the time to conceive is reported to be longer in USgHIFU groups (mean, 8 m vs. 16 m). From a total of 460 pregnancies, miscarriage was observed higher after MRgHIFU (0% to 50%) than after USgHIFU (0% to 15%) and live-birth rate was lower after MRgHIFU (73% vs. 91%).
Furthermore, the recent prospective study conducted by Liu X, et al. [26] including 174 women having desire of pregnancy, a total of 88 pregnancies (46.6%) occurred after USgHIFU within a median follow up period of 76 months. In total, 10% (9/88) of cases presented were miscarriages and 6% (5/88) chose elective termination. Caesarean section was elected by 50% of women, 11 additional caesarean sections were performed due to pregnancy-related complications and the rest successfully delivered vaginally.

Risk of Uterine Sarcoma
The incidence of sarcoma after HIFU has been reported by few research groups. Wang Q et al. [27] reported that from 15,713 patients who underwent HIFU, six cases (0.038%) were histologically confirmed but without dissemination signs at surgery. Interestingly, after data-imaging review, the NPV ratio of all these malignancies was high (86.8 ± 11.7%), indicating that sarcoma tissue could respond to HIFU. Furthermore, there was no statistical difference in overall survival rate of the six mentioned patients in comparison to 11 patients diagnosed with sarcoma who underwent surgery as first therapy during the same period (2008-2019). A slight lower incidence of sarcoma (1/3810; 0.26%) was reported by Li W et al. [23] within the follow-up period (58 m to 88 m) of patients who underwent USgHIFU. In this case, data-imaging review showed clues of sarcoma at pre-treatment MRI, including hyperintensity on T2WI and moderate enhancement on contrast MRI. The post-therapy MRI at three months showed fibroid regrowth and similar features, which was confirmed at surgery; the patient was free of disease five years later. Moreover, HIFU in combination with chemotherapeutic agents has been tested in a patient who presented a recurrent and difficult leiomyosarcoma [39]. Authors reported that patient's survival time was prolonged because tumor growth was controlled. It was hypothesized that the acoustic cavitation, radiometric force, shear stress and acoustic stream produced by HIFU could make tumor cells more sensitive to chemotherapeutic agents, especially low vascularized cells in resting period.

Discussion
It is well known that the introduction of new technologies in medical practice usually takes a long time, from device development up to approval by regulatory agencies. Moreover, their acceptance and introduction in guidelines as alternative to standard therapies can also depend on its affordability, especially in low-income countries. In the case of uterine myomatosis, surgical treatments impose a large burden on women's QoL and costs to health systems worldwide. Therefore, it is important to gain access to effective and safe minimally invasive approaches that increase the women s chances to preserve their uterus and fertility and, at the same, to have good cosmetic results. In the last decade, HIFU has been introduced as a promising technology, able to reduce fibroid volume and symptoms, and it is expected to be introduced in European countries. Until now, most of the evidence has been published from Asiatic countries, in other languages than English, possibly influencing this opinion paper.
The working principle of HIFU therapy is to use ultrasonic waves, guided by MRI or ultrasound, in order to ablate the tissue through thermal and cavitation effects that result in destruction of parenchymal and vascular endothelial cells of tumor and, finally, in fibroid size shrinkage and symptomatic relief [40]. The effective volume reduction depends mainly on size and localization of fibroids and achieved NPV ratio; the higher NPV achieved (>70%), the more fibroid size reduction is to be expected [8,12]. An important factor that strongly attenuates ultrasonic waves is the subcutaneous abdominal fat layer, leading to lower NPV ratios [10]; in consequence, the pre-treatment assessment of patient is necessary to calculate the beam intensity. In terms of preventing surrounding organ damage and to avoid major complications, it is suggested that USgHIFU could be better than MRgHIFU, because patients do not require sedation and could give feedback to the physician about pain during procedure, allowing physicians to relocate the beam or to modulate its intensity [15].
In order to avoid damage to nearby organs and determining the beam intensity to ablate the fibroids, distance from skin to tumor, as well as localization, number, size and perfusion pattern of fibroids should be evaluated by means of ultrasound or MRI before commencing therapy. Post procedure imaging should be completed to evaluate the achieved NPV ratio of treated area [12]. MRI, with or without contrast, is considered the standard examination method in most of developed countries. Thus, MRI is quite expensive, time consuming, not available in all medical centers and its cost mostly not covered by insurance companies. As an alternative, contrast enhanced ultrasound could be used before procedure because of its lower cost, allowing real time analysis [30]. Moreover, USgHIFU is more cost effective than MRgHIFU and UAE, as it can be performed by a gynecologist skilled to perform pelvic ultrasound. Secondly, patients are not exposed to ionizing radiation like UAE. Lastly, MRI is not needed during the procedure, so a radiologist is not needed. Hence, it is in accordance with the lean management approach of health organizations to optimize resources [41].
Several studies showed lower frequency of major complications and treatable minor complications, in which skin redness, abdominal pain or discomfort and sciatic nerve paresthesia or simply leg pain are the most common. SAE occur in less than 0.5% of cases including second degree skin burn, lesions to bowel, ureter and bladder [29]. These complications occur when organs are in acoustic pathway or when the thermal effect induces inflammatory response and edema [21]. In order to avoid complications, we recommend an accurate and individual pre-assessment of patients including physical and imaging examination by means of contrast enhanced ultrasound or MRI, good communication with patients prior to the procedure, strict preparation for degreasing and degassing of the skin and checking skin and patient reactions regularly during procedure.
Outcomes of HIFU depend on different matters. According to myoma localization, it is observed that intramural fibroids [11] with volume under 300 cm 3 [29] show higher volume reduction results due to less deep tissue and scared blood supply, as compared to transmural and submucosal uterine fibroids. Regarding signal intensity of fibroids, two retrospective studies reported contradictory results about fibroid shrinkage. He M, et al. [17] found no significant difference between hypointense, isointense and hyperintense fibroids, while Fan HJ, et al. [11] showed that hypointense fibroids exhibit higher reduction rates. This difference could be explained because the main population in He M et al. study was black women while Fan HJ, et al. included only Chinese women. Thus, other efficacy and safety studies conducted with Black, White and Afro-American women show similar results than those for Asiatic populations [4,6]. Therefore, ethnicity would not represent a problem in implementing this technique worldwide. However, high quality controlled trials should be conducted involving patients of all ethnicities to assert the efficacy of HIFU in high-risk of myoma development populations and to determine the relationship between ethnicity and tumor reduction after therapy.
Besides fibroid shrinkage, risk of recurrence, necessity of reintervention, pregnancy and sarcoma risk are concerns related to non-surgical therapies. In the longest followup study [15], 36 months was the median recurrent time reported after HIFU (range, 10 to 100 m) and 44 months after myomectomy (range 8 m to 96 m). In relation to reintervention, all reviewed reports show that this rate is higher in HIFU groups as compared to other approaches, especially statistically significant lower rates are reported after UAE [7]. Furthermore, USgHIFU has lower reintervention rates than MRgHIFU [29]. These differences could be attributed to the difference in myoma ablation mechanism between all techniques, as well as, to size, localization and FIGO type of myoma, signal intensity on T2 weighted image (T2WI), ablation temperature and higher levels of anti-müllerian hormone before therapy [2,7,12,16], which potentially correlates with the higher age of patients frequently included in the UAE studies. Additionally, in a retrospective study, HIFU showed to be more effective than secondary myomectomy for the treatment of recurrent symptomatic myomata, with a longer symptom free period, lower reintervention frequency and fewer side effects [24]. Multiple myomata in younger patients have more chances to reoccur after HIFU; some patients might also need multiple HIFU sessions.
Regarding pregnancy outcomes, studies show that conception can occur during the first three months in more than 67% of women seeking to be pregnant [4,17], with the average time to pregnancy shorter being after USgHIFU than myomectomy [25]. The rate of pregnancy-related complications do not differ from general population or from other myoma interventions, but the rate of uterine rupture was found to be lower compared with the rates reported for women with more than one caesarean section (<1% vs. 3.9%) [42]. A long latency period between HIFU and conception for safety reasons does not seem to be necessary to allow adequate postsurgical healing [43], which is usually advised after a myomectomy [44]. This evidence indicates that HIFU does not impair directly the fertility, pregnancy or delivery, which is especially beneficial for premenopausal women already struggling with lower pregnancy chances [35].
Patients and physicians should be aware of recurrence risks and strict necessity of follow up, including physical examination and imaging conducted to detect early recurrence and to prevent misdiagnosis in leiomyosarcoma. It is unknown at present whether leiomyosarcoma represents de novo growth or malignant transformation from benign uterine fibroids. This rare malignant tumor, less than 1 in 1000 of uterine wall diseases, is characterized by a rapid increase of uterine size, abnormal bleeding, pain and, sometimes, general symptoms related to metastases [45]. A very low incidence of sarcoma after HIFU (0.038% to 0.26%) has been reported from two studies within a follow-up period up to 88 months, without statistical difference in OS rate in comparison to myomectomy [23,27]. Due to this serious concern about leiomyosarcoma, it is important to obtain informed consent from patients, as there is a lack of histological confirmation before and after procedure [46].
In addition to tumor response, we consider that improvement in QoL plays a pivotal role in the patient s decision-making process to consent for therapeutically approaches. We found that HIFU and myomectomy have similar effects on QoL life after 12 months [30]. Although, after three months, HIFU showed better results than myomectomy in terms of pain scores, sexual satisfaction and symptoms related to compression by fibroids [3], while UAE showed better results in terms of symptoms alleviation than USgHIFU [3]. Improvements of QoL, tolerability and effectiveness of HIFU have been also observed in solid abdominal tumors other than uterine fibroids, as reported by Oxford HIFU research center [46]. Based on available evidence, HIFU could be a new safe and effective option for worldwide patients suffering from uterine myomatosis.

Key Points to Consider in Clinical Practice
In accordance to the results of our analysis and to facilitate the clinical decisionmaking process regarding myoma treatment, HIFU could be considered as an alternative non-surgical treatment of uterine fibroids, according to an individualized benefit/risk ratio, irrespective of women ethnicity, and when the following aspects have been considered:

•
Localization, size and benign radiological appearance of the uterine masses are accurately assessed prior to ablation. It is more difficult to ablate myomata with long distance from its ventral side to skin, in retroverted uterus, significant enhancement on T1WI, hyperintensity SI on T2WI (MRI), small size, transmural type and posterior location; • Myoma perfusion (volume blood flow and velocity) is evaluated before procedure, e.g., by contrast enhanced ultrasound. The higher the perfusion, the higher the resistance towards ablation; • Beam intensity and total treatment time is modulated according to myoma characteristics and subcutaneous abdominal fat thickness. Obese patients are at a higher risk of thermal damage in abdominal wall structures; • An adequate acoustic window is assured before ablation. Bowel injuries can occur when the bowel is in the acoustic pathway or when fibroids are over treated; • Patients presenting recurrent symptomatic uterine fibroids after myomectomy benefit from ablation. Most of them do not require further surgery; • Patients are informed that discharged necrotic tissue will appear in the first cycle after therapy and resolve spontaneously within six to eight months; • Patients are informed that fibroid volume shrinkage is achieved months after first ablation (mean 6 m); • Patients are informed that reintervention is mostly required in younger women, when baseline anti-müllerian hormone level is >0.3 ng/mL or when fibroma volume is >300 cm 3 ; • Patients seeking to be pregnant are informed that average times to pregnancy are longer than after myomectomy, but pregnancy outcomes are similar and caesarean section as mode of delivery is not mandatory; • Patients undergoing USgHIFU are informed that radiologist and sedation are not mandatory, therefore they give feedback to the physician about pain during procedure eventually to relocate the beam or to modulate its intensity; • Patients are informed about potential AE, such as skin redness, abdominal pain or discomfort and sciatic nerve paresthesia or simply leg pain, skin burn, and in very seldom cases, nearby organs injury; • Close follow-up of patient regarding the risk of development of a uterine sarcoma, as the uterine fibroids are not previously sampled for a histological diagnosis.

Conclusions
Several studies have been conducted evaluating the safety and efficacy of HIFU and its impact on women's quality of life, but the quality of evidence relies mostly on retrospective cohort studies and meta-analysis (EBM Level IIa, IIb) conducted in Asiatic countries with a scarce representation of other populations. They report a low frequency of side effects, speedy recovery and high patient satisfaction; thus, treatment efficacy is similar to UAE, but better than surgical approaches. However, there are few reports differentiating the outcomes in non-Asiatic white populations, Afro-American and black women. We consider that ethnicity would not be a problem to implement this therapy in other countries, but the gap in the evidence should be evaluated in further trials involving different populations, to known whether ethnicity and other epigenetics factors could affect the outcomes of this new therapy. Additionally, it is necessary to prevent misdiagnosis of leiomyosarcoma, through strict imaging evaluation prior to therapy and close follow-up of patients.