This chapter should be cited as follows:
Ng WL, Chung E, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.418593

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 4

Benign gynecology

Volume Editor: Professor Shilpa Nambiar, Prince Court Medical Centre, Kuala Lumpur, Malaysia

Chapter

Magnetic Resonance-Guided Focused Ultrasound for Uterine Fibroids

First published: May 2024

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EPIDEMIOLOGY OF UTERINE FIBROIDS

Uterine fibroids in general

Uterine fibroids or leiomyomas are common benign tumors of the uterus in women of reproductive age. They are the most common benign gynecological tumors in women of childbearing age, with prevalence of 20–25% and up to 80% of women by 50 years of age.^1,2 It often causes clinical symptoms such as menorrhagia or dysmenorrhea, pelvic pain, increased abdominal pressure and fertility problems, depending on their size and location. The presence of uterine fibroid in pregnancy has been associated with an increased rate of spontaneous abortions. The indication for cesarean delivery in these cases is most commonly due to malpresentation but may also be due to the presence of placenta previa. Symptoms of adenomyosis are very similar to those of fibroid and both can occur in the same patient. A junctional zone width of more than 12 mm is defined as adenomyosis. It is not uncommon to have patients referred for screening as fibroids but subsequently found to have adenomyosis (35–55%) after magnetic resonance imaging (MRI).³

Fibroid types

There are three types of uterine fibroids depending on their location; intramural (IM), submucosal (SM), and subserosal (SS) (Figure 1). Intramural fibroids lie within the wall of the uterus, separated from myometrium by a layer of connective tissue, submucosal fibroids usually protrude into the endometrial cavity and distort the endometrium, and subserosal fibroids are on the surface of the uterus and usually are growing outward. It is suggested that high-intensity focused ultrasound (HIFU) might be suitable treatment for pedunculated subserosal fibroids although the ablation of these fibroids might lead to stalk detachment of the fibroid from the uterus and expulsion into the abdominal cavity.⁴ The pathway of submucosal fibroids might cause severe endometrial impairment so it is suggested to treat up in the endometrial surface of women who do not wish to preserve their fertility.

Financial impact

The surgical and non-surgical therapies of uterine fibroids including the indirect costs contribute tremendously to the societal and economic burden. The greatest impact however is the cost of time lost from work rather than the direct treatment itself. The direct costs of uterine fibroids include surgery, hospital admission, outpatient visits, and medication. Based on an analysis done by Cardazo et al. on a 2010 population estimate, the annual direct cost of uterine fibroids ranged from $4.1–9.4 billion.⁵ Further break down of these figures showed that surgical treatment is significantly higher compared to non-surgical therapy (Table 1). Being absent from work and short-term disability contributed to annual lost work time cost. However, the total estimated annual lost work time cost is higher than the direct cost of uterine fibroids with a range of $1.55–17.2 billion.⁵ The highest group of patients are those that managed their fibroid non-surgically with an expense of $549 million–$9.4 billion.⁵ The lowest annual lost work time cost are those women who underwent endometrial ablation with a range of $4–248 million (Table 2).

Treatment options

Treatment options include surgical and non-surgical treatment. Surgical treatment would be more definitive with total removal of the lesion. In a hysterectomy, it eliminates the symptoms and recurrence, however it would not be suitable for women in the reproductive age group who plan to conceive. Myomectomy, MRgFUS, uterine artery embolization and gonadotropin-releasing hormone agonists are alternatives for women who wish for uterine conservation. However, MRgFUS is the only non-invasive approach. The table below lists the comparison of recommended therapies for uterine fibroid compiled by American Family Physician 2017 (Table 3).⁶

MAGNETIC RESONANCE-GUIDED FOCUSED ULTRASOUND SURGERY (MRGFUS)

Introduction

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is an alternative to myomectomy that is without a surgical incision or any major complication. It is a non-invasive technique that causes immediate coagulative necrosis in 1–3 s and can be performed under either magnetic resonance imaging (MRI) guidance or ultrasound guidance and in a well circumscribed area measuring a few mm in diameter.⁷ The biological effects of HIFU were investigated by Wood and Loomis in 1927 and the first therapeutic trial with focused ultrasound was performed by Lynn et al. in 1940s.⁸ The HIFU ablation of uterine fibroids is affected by internal structures such as blood supply, water content, and fiber composition and also by location, type, and size of the uterine fibroids.⁹ MRgFUS is capable of monitoring dangerous temperature elevations, which ensure the safety and effectiveness of the procedure. The temperature at the focal region can accurately predict the ablation effect in the treatment of uterine fibroids. The procedure also provides real-time feedback to adjust the sonification energy and power. The success of the treatment is measured post procedure by measuring the non-perfused volume (NPV) on contrast-enhanced MR imaging.

Principle

This system combines MRI and focused ultrasound to form a “closed-loop therapy and feedback system” that enables the physician to adjust treatment parameters and control the treatment, helping to maintain a high level of safety and efficacy. The system which received FDA approval in 2004 is known as ExAblate 2000 (InSightec, Haifa, Israel) is used with a 1.5 Tesla MR scanner (GE Medical Systems, Milwaukee).

• An MRI scanner is used for 3D imaging of anatomical and thermal mapping, which permit high-resolution visualization of the patient's anatomy for planning of treatment, and quantitative information on the change in tissue temperature to monitor and control the treatment (Figure 2).
• Therapeutic focused ultrasound (FUS) energy on a specific point is where sound waves converge and produce the highest energy to heat and ablate the tissue within the body without damaging the tissue along the beam path. Known as ‘sonication’, the focused ultrasound destroys tissues at a temperature of 60–85°C. Multiple sonications (focal delivery of energy) are required to ablate a specific tissue (Figure 3).

Patient selection

If the patient is clinically eligible and interested in MRgFUS, they are then referred for screening MRI scans. Screening should be performed in the prone position and the MRI protocol consists of T2 weighted images, T1 weighted images pre and post gadolinium injection in three planes. The T2 weighted imaging is to determine anatomy and pathological conditions and the T1 weighted imaging with and without contrast agent is to identify fibroid viability. Patients are deemed technically suitable for MRgFUS if their fibroids are accessible by the system and treatable within a reasonable time (Figure 4).

There are four factors that are important in patient selection:

• Number of fibroids;
• Fibroid volume;
• Fibroid intensity;
• Subcutaneous fat layer.

1. Number of fibroids

The guideline recommends treating patients with up to six fibroids and not more than 4 cm in size. In the case of multiple fibroids, some may be inaccessible or not treatable. In patients with symptoms of bleeding, the fibroids with a submucosal component should be targeted. A fibroid that causes pressure symptoms should have as much volume ablated as possible. Fibroids, which are located at the posterior wall, should have meticulous planning as structures such as the sacral bone and the adjacent lumbosacral nerves are in close proximity. Sciatic nerve injury can occur due to heat accumulation in the bone, which is transferred to the perineural fat and adjacent nerves.⁸

Fibroid with interposing bowel loops located along the potential beam path can be displaced by filling the urinary bladder with saline, filling the rectum with ultrasound gel, or using a convex gel pad. If the bowels cannot be shifted, the fibroid should be excluded from ablation as air bubbles or hard particles present in the bowel may reflect or absorb the ultrasonic energy and may cause bowel perforation.

2. Fibroid volume

A large fibroid volume may not be completely ablated in a single session and may require a second treatment. Improvement of pressure symptoms caused by large fibroids may take a longer time and repeated sessions to allow for sufficient shrinkage. Patients who have a total fibroid volume of more than 500 cm³, or a hyper-intense fibroid on T2 weighted imaging are suggested to be pre-treated with a GnRH analogs for 3 months in an effort to reduce the size and vascularity of the fibroid.¹⁰ GnRH analogs are known to decrease the vascularity of fibroids, as evidenced by a decrease in a microvascular density marker, CD34, in surgical specimens.¹¹

3. Fibroid intensity

Fibroid intensity correlates with energy absorption and thus, the ability to achieve NPV. Assessment of uterine fibroids on T2-weighted images can predict the outcome of ablation. (Funaki et al. classified uterine fibroids into three types according to T2 signal intensity:

• type 1, low signal intensity comparable to that of skeletal muscle
• type 2, intermediate signal intensity, lower than that of the myometrium and higher than that of the skeletal muscle
• type 3, high signal intensity, equal to or higher than that of the myometrium¹²

Uterine fibroids, which demonstrate low signal intensity on T2-weighted images (type 1) usually yield the best energy absorption. Intermediate signal intensity fibroids (type 2) might show moderate energy absorption. Hyper-intense fibroids (type 3), which represent vascularization, fluid-rich tissues, or degeneration are more resistant to heating and may show poor energy absorption, thus are not suitable for MRgFUS. A study showed that peripheral rim high density around uterine fibroid on T2-weighted images, which is commonly found at submucosal location lowers the efficacy of ablation.¹³ Thermal dissipation occurs due to the additional cooling or heat-sink effect resulting from the flows in the lymphatic vessels, dilated veins, and/or edema.¹⁴

4. Subcutaneous fat layer

A thick fat layer might result in beam aberration. The majority of the fibroid mass should be no more than 12 cm depth away from the skin line, as this is the upper limit of the scanner.¹⁵ The subcutaneous tissue layer has a lower specific heat capacity, insulating properties, and lower blood supply than those of other tissues in the abdominal wall.¹⁶

Studies done by Mikami et al., Kim et al., and a recent study by Keserci et al., suggested that the thick subcutaneous and visceral fat tissue attenuates the energy from exposure to sonification and causes accumulation of heat at the near field of the ultrasound beam path.^17,18,19 The accumulation of heat increases the risk of fat burn and decreases the beam focus quality, limiting the degree of tissue ablation of uterine fibroids.

Patients with scar tissue have a higher risk of skin burns due to higher ultrasound absorption than the surrounding tissue. As scar tissue has reduced blood supply and reduced nerve sensation, the cooling rate is reduced, and the patient is less likely to feel heat over the scar during the treatment. Patients with longitudinal scars in the beam path, including those that cannot be seen on the MR images, were previously excluded, as scar tissue may absorb the ultrasound energy and cause pain or even a skin burn. However, several techniques have been used to avoid the scar without affecting the clinical efficacy of the treatment. By angling the transducer to increase the protected the scar could be avoided by the energy beam (Figure 5). Another technique is to fill the bladder to push the targetted area away from the scar (Figure 6).²⁰ Beam-shaping feature can be also used to reduce intensity of the ultrasound field (Figure 7).²¹

Scar patches such as acoustic patches and water-resistant polyethylene foam scar have been introduced to reflect the ultrasound energy.^22,23 No serious adverse effects or significant difference of volume reduction were reported.

Advantages

• Non-invasive without the trauma of surgery;
• Outpatient procedure, no hospitalization;
• Fast recovery, women generally return to normal activity within days;
• Quality of life, most patients report a significant relief from symptoms during the weeks following treatment;
• Safe, minimal side effects with no drugs;
• Uterine-sparing, maintains natural hormonal function;
• May be considered in patients who seek fertility sparing options.

Indications²⁴

• Definitive diagnosis of the uterine fibroid(s) or adenomyosis as the source of symptoms;
• Lesion(s) clearly visible on non-contrast MRI;
• Patient is able to fit into MRI unit;
• Patient can tolerate the procedure under conscious sedation or no sedation; the treatment does not require general anesthesia;
• Patient is able to communicate sensations to the physician during the procedure.

Exclusion criteria²⁴

Besides location and size of the fibroid, the other exclusion criteria are derived from the ExAblate commercial treatment guidelines:

• Hemoglobin <10 mg/dL;
• Patient has hemolytic anemia;
• Patient has unstable cardiac status including the following:
  • Unstable angina pectoris on medication;
  • Documented myocardial infarction within 6 months of protocol entry;
  • Congestive heart failure requiring medication (other than diuretic);
  • Currently taking anti-arrhythmic drugs;
  • Severe hypertension (diastolic BP >100 on medication);
  • Presence of cardiac pacemaker;
• Patient has severe cerebrovascular disease (multiple CVA or CVA within 6 months);
• Patient is on anti-coagulation therapy or has an underlying bleeding disorder;
• Evidence of uterine pathology other than leiomyoma;
• Patient has an active pelvic infection;
• Patient has an undiagnosed pelvic mass outside the uterus;
• Patient's weight >110 kg;
•  Patient with extensive longitudinal abdominal scarring in an area of the abdomen directly anterior to the treatment area;
•  Patient with standard contra-indications for MR imaging such as non-MRI compatible implanted metallic devices;
•  Individuals who are not able or willing to tolerate the required prolonged stationary prone position during treatment (approximately 3 h).

Steps to perform MRgFUS²⁵

• Patient preparation:
  • The patient’s abdomen is shaved and cleaned to remove any hair and also checked for the presence of any moles or scars as these may result in skin burns.
  • A urinary catheter is inserted to control uterine movement during treatment.
  • Adequate analgesia including suppository 100 mg diclofenac sodium, i.v. paracetamol 1 g, i.v. midazalom and i.v. pethidine in titrated dose.
  • The patient is then positioned prone on the ExAblate treatment table with her abdomen over the water bath containing the ultrasound transducer.
  • The patient's legs may be wrapped with compression stockings to reduce the risk of deep vein thrombosis.
  • Patient’s blood pressure, heart rate, oxygenation, and comfort level are monitored throughout the treatment.
  • Communication is provided through a two-way intercom and an emergency button.
• Calibration:
  • A three-plane localizer and T2-weighted imaging are performed. This provides the system with information, which include patient’s position, MRI scan plane, and transducer location to maximize the window available for the treatment of fibroids (Figure 8).

  

  8

  Calibration is done using a three-plane localizer and T2-weighted imaging providing information to correlate with patient's positioning. Reproduced with permission from InSightec.²⁴

• Draw:
  • The region of treatment (ROT) is drawn such that a margin of at least 1 cm is kept from the serosal surfaces to minimize the risk of ablating the serosa, which causes severe pain. The volume of the fibroid is calculated for ablation. A safety line is drawn at the lower energy density region, which includes intestines, pubic bone, and lumbosacral spine (Figure 9).
  • If the fibroid lies too close to the sacral area, then ultrasound gel (approx 250cc) can be inserted rectally to displace the fibroids away from the area. A safe distance of 4 cm is necessary. If bowel has migrated anteriorly to the fibroid, then saline can be infused into the bladder. This may need to be followed with insertion of rectal gel.

  

  9

  Drawing of the area of sonication under MRI guidance. Reproduced with permission from InSightec.²⁴

• Plan (Figure 10):
  • The system automatically creates a treatment plan, based on the ROT prescribed and protocol selected.
  • The ablation of each focal volume of a tissue is called a sonication.
  • It is important to avoid the bowel as it can cause perforation. Manipulation using urinary bladder and rectal is helpful to reposition the fibroid.
  • Refrain from other obstacles on the beam path, as IUD, surgical clips, and surgical scars.

  

  10

  Number of sonication planned by machine based on the size of the fibroid. Reproduced with permission from InSightec.²⁴

• Treat (Figure 11):
  • Actual delivery of the energy to each of the planned locations for ablation of the planned region.
  • This shows real-time delivery of energy to the fibroid and areas that are not receptive to treatment.
  • There is no limit to the percentage of fibroid volume that can be treated though generally a 60–70% of ablation is necessary for good outcomes.²⁶ The operator then chooses the treatment plan depending on the size and type of fibroid being treated. For “white fibroids”, a nominal high-density plan should be selected, otherwise a medium-density plan would be suitable.
  • The length of the sonication can then be selected and may vary from 10 to 45 mm. Based on the treatment plan chosen, the FUS system automatically displays a series of sonication to cover the region of treatment. Each spot is cylindrically shaped, 25 to 45 mm in length and 5 mm in diameter for a nominal fibroid.
  • The sonication beam path is carefully checked to ensure that it does not pass through any structure that should be avoided – such as the small bowel that can fall in front of the uterus. Generally, treating and ablating an 8 cm fibroid takes approximately 3 h of sonication (that is excluding the patient preparation and planning), depending on energy absorption and location of the fibroid. Fibroids that are larger than 10 cm are less suitable for the treatment because of the long treatment time. However, two options are available: (1) Treating the fibroid over two sessions performed preferably with the fibroid volume being split into a superior and an inferior region for each of the treatment. This is to avoid the ultrasound beam in the second treatment from passing through already treated regions if an anterior-posterior division was made. (2) Or as mentioned previously, use pre-treatment with GnRH agonist prior to MRgFUS to shrink the fibroid and improve treatment outcomes.¹⁵
  • After the last sonication, post contrast T1 weight images were obtained to assess the NPV%.

  

  11

  Indication of ablated areas and on-going sonication.

• Follow up:
  • Monitor as an inpatient for one day. The patient can return to normal activities the next day without event or
  • The patient should be reviewed by the interventional radiologist and gynecologist within 2 weeks. Patients for whom treatment could not be completed because of the large size or number of fibroids can have a repeat treatment anytime after 1 week.
  • The Uterine Fibroid Symptom and Health Related Quality of Life Questionnaire (UFS-QOL) is uterine fibroid-specific and can be used to evaluate outcomes post-treatment within the clinical setting.²⁷
  • Follow-up contrast-enhanced MRI is performed after 6 months to assess the fibroid size.

Complications

According to reported data from more than 10,000 commercial treatments with ExAblate (2004–2014), the device-related serious complications rate is approximately 0.3%.²⁴ Table 4 below shows the complication and number of cases reported.

Additional reported treatment-related side effects include abdominal pain, lumbar pain, fever, significant bleeding, and vaginal discharge. The cases of bowel perforation were due to movement of patient during treatment and the sonication focused directly on the patient’s intestine. In some cases, particularly in submucosal fibroids, the necrotic material was expelled via the vagina after treatment over the subsequent menstrual cycles.²⁸ Caution should be exercised when treating submucosal fibroids that detach into the endometrial cavity as the necrotic material may lead to septic shock. Skin burns occurred due to direct skin heating or heat accumulation in the fat or muscle that expended to the skin. This can be rectified by the techniques described previously.

Post-treatment outcome

Follow up NPV

To assess the respond on MRgFUS, follow up MRI measuring NPV is done at least 3 months post-treatment. Higher NPVs are associated with greater efficacy. However, in a systemic review of 19 studies, only 9 studies had an NPV over 50%. Nevertheless, symptom improvement was similar among the studies.²⁹ The different response despite an average NPV may be due to the various types of fibroids and the variation of signal intensity on T2 weight images as mentioned previously. A type 1 fibroid has the best energy absorption and thus produces a larger reduction in fibroid volume.

Quality of life

A systematic review based on UFS-QOL showed that patients who underwent MRgFUS with larger NPV had improvement of severe symptoms and overall quality of life.²⁹ Patients with intramural and submucosal fibroids experience improvement of symptoms such as menorrhagia, while patients with subserosal fibroids experience improvement of mass effect and abdominal volume.

Fertility

Promising post-MRgFUS results are described in patients with uterine fibroids who wish to conceive.³⁰ However, the inclusion criteria need to be selective by a thorough analysis of the case, patient’s age, tumor location, and related symptoms. Rabinovici et al. described 51 gestations in UF patients treated with non-perfused volume (NPV) of an average of over 40% (range: 5.5–100%). Among them, 45% had a solitary fibroid, 37% had two to six fibroids, 14% had more than six fibroids, and 4% had complicated adenomyosis. There were 21 cases and 22 delivery times, and the natural delivery rate was 64%.³¹ Zou et al. reported average time to pregnancy was 5.6 ± 2.7 month post-ablation in 80 gestations treated with ultrasound-guided HIFU.³² MRgFUS is safe and does not increase the rate of spontaneous abortions or pregnancy complications.³³ Some authors found that vaginal delivery is preferable post-MRgFUS as there is no surgery involved, no adhesion found and thus no risk of uterine wall rupture during gestation and delivery.^33,34

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