Magnetic Resonance-guided Focused Ultrasound for Uterine Fibroids

Leiomyomas of the uterus, myomas, or uterine fibroids are the most common benign tumors affecting women, accounting for up to one in three gynecology clinic referrals. Macroscopically, these tumors are firm and round, oval or irregular in shape. Uterine fibroids are formed from mesenchymal connective tissue, a type of undifferentiated loose connective tissue that is derived mostly from mesoderm. Despite the term fibroid, these  tumors are composed of elastin, collagen and extracellular matrix proteins in addition to smooth muscle.¹ Fibroids can occur singly, but more usually, there are multiple fibroids in the same uterus of varying dimensions and location

The prevalence of clinically symptomatic fibroids peaks toward the end of a woman’s reproductive life and declines after menopause.² The reported incidence of uterine fibroids varies dramatically in the literature. As many women with fibroids may not have symptoms related to their tumors, many are undiagnosed. A study examining 1364 randomly selected pre-menopausal women found evidence of fibroids on ultrasound in 80% of Black women by 50 years of age, and 70% of white women by this same age.³ Many authors state that around 50% of women with fibroids will be asymptomatic; however, it has been suggested that this may be an underestimate.⁴ There appears to be a genetic predisposition to uterine fibroids, and fibroids are particularly common in Black women, with a three-fold increase in incidence compared to that in Caucasian women.⁵ Furthermore, the clinical symptoms of Black women tend to be more severe at presentation.⁶

Although common, the risk factors for uterine fibroids are poorly understood. Elevated adult body mass index (BMI) is associated with a modest increased risk of uterine fibroids among premenopausal women,⁷ as is a familial tendency to develop fibroids. Several studies have demonstrated an inverse relationship between parity and risk of developing uterine fibroids, with one study finding women with five term pregnancies having a quarter of the risk of nulliparous women.⁸Whether uterine fibroids are actually the cause of infertility remains unclear.

The presence of fibroids is more common in women who consume red meats, whereas a high intake of green vegetables seems to have a protective effect.⁹ There appears to be a reduced risk of fibroids among women with a greater dietary intake of fruit and preformed vitamin A.¹⁰ Elevated diastolic blood pressure may increase fibroid risk through uterine smooth muscle injury, not unlike atherosclerosis. In a 10-year prospective follow-up study of 104,233 premenopausal nurses with no history of cancer or fibroids at enrolment, elevated blood pressure exerted an independent increase in risk of clinically detectable fibroids.¹¹

The Black Women’s Health Study is a US prospective cohort study of Black women who completed biannual mailed health questionnaires from 1997 through 2001. Among Black premenopausal women with intact uteri and no prior diagnosis of uterine leiomyomata, high BMI and weight gain exhibited a complex relation with risk for uterine leiomyomata. Interestingly, weight gain was positively associated with risk among parous women only.¹²

This study also noted a positive association with current consumption of alcohol, particularly beer, but found that cigarette smoking and caffeine consumption were unrelated to overall risk.^12, After adjustment for age, BMI, smoking, and alcohol intake, the risk of leiomyomata (confirmed by ultrasound or at hysterectomy) was inversely associated with age at menarche, parity, and age at first birth, and positively associated with years since last birth. Overweight or obesity appeared to attenuate the inverse association between parity and uterine leiomyomata. Current use of progestin-only injectables was inversely associated with risk. No consistent patterns were observed for other forms of hormonal contraception.¹³

The etiology and pathogenesis of fibroids remains unclear. The theory that fibroids are steroid dependent is supported by observations that they decrease in size at the menopause and during other hypoestrogenic conditions such as down-regulation treatment with gonadotropin-releasing hormone (GnRH) agonists.^14, Although estrogen has been implicated as the dominant hormone, there is increasing evidence that progesterone also has an important role in controlling uterine fibroid growth. Progesterone is known to decrease overall apoptosis within fibroids by decreasing the expression of tumor necrosis factor α (TNFα) and increasing the expression of Bcl-2 protein.^{15, 16}

Fibroids are classified by their location within the uterus (Fig. 1). Uterine fibroids may be subserosal, submucosal or intramural and frequently occur at multiple sites. Subserosal fibroids on the external surface of the uterus may be sessile or pedunculated. This type of fibroid is the easiest to remove laparoscopically. Submucous fibroids which project into the endometrial cavity may be removed by hysteroscopic resection. Intramural fibroids in the myometrial wall of the uterus may distort the uterine cavity and/or cause an irregular external uterine contour. Historically, these lesions have usually required open pelvic surgery.

Fig. 1. Classification of fibroids according to their location.

Fibroids present with a variety of symptoms depending on their size, location, and the reproductive status of the woman. Typically they cause abnormal uterine bleeding, pain, and pelvic pressure symptoms.¹⁷

The most common type of abnormal bleeding associated with leiomyomas is menorrhagia or polymenorrhea, prolonged or excessively heavy menstruation. The heavy bleeding frequently results in iron deficiency anemia and the frequent change of tampons or pads may cause a significant disruption to the woman’s lifestyle.

Acute pain is rare, but can occur in situations where there is degeneration of the fibroid due to an insufficient blood supply; so called red degeneration, which characteristically may occur during a pregnancy. Acute pain may also be due to torsion of a pedunculated fibroid or to cervical dilatation caused when a submucous fibroid prolapses into the cervical canal from the uterine cavity.

Pelvic pressure symptoms are caused by enlargement of the uterus by the fibroid mass. The pelvic and abdominal discomfort may be similar to the discomfort women experience during pregnancy. If neighboring structures are compressed by the fibroid, this may lead to difficulty with urination in the case of an anterior fibroid or problems with defecation and dyspareunia in the case of a posterior wall fibroid.

The diagnosis of uterine fibroids is based on the clinical history and examination. Typically the patient presents with a gradual increase in abdominal size, heavy but regular periods, and a negative pregnancy test. Other causes for an increased abdominal girth include adenomyosis and ovarian pathology. It is difficult to differentiate between these by abdominal palpation alone, and therefore radiological examination is required for confirmation. Ultrasound may be used to confirm the diagnosis and exclude other conditions (Fig. 2). Transabdominal or transvaginal ultrasound is a sensitive tool for the detection of an enlarged uterus, but identification of the precise location of the fibroids is dependent on the expertise of the operator.

Fig. 2. Ultrasound image of uterine fibroid.

Magnetic resonance imaging (MRI) has gained widespread use and popularity for use in pelvic imaging. It is non-invasive and safe, with no radiation effects, a particularly important consideration for younger women. The multiplanar sequences allow differentiation of the substructure of the uterus, cervix, vagina, and ovaries (Fig. 3). MRI allows the radiologist to differentiate uterine anatomy and localizes pelvic pathology with precision. The routine use of both T1- and T2-weighted (T1W and T2W) sequences, before and after the injection of intravenous gadolinium, provides further information on specific characteristics of the fibroid and optimizes the soft tissue contrast available with MRI.

Fig. 3. MRI of normal uterus.

MRI offers special advantages for the imaging of fibroids. It confirms the diagnosis, provides accurate size and volume measurements, and also characterizes the fibroids into hyperintense or hypointense, according to how vascular they are (Figs. 4 and 5). By using intravenous contrast, the perfusion and, therefore, presence of necrosis and degeneration can also be determined.

Fig. 4.  MRI T2 weighted sagittal image of multiple uterine fibroids.

Fig. 5. MRI T2 weighted sagittal image of hyperintense fibroid.

Uterine fibroids can generally be managed expectantly unless they are causing symptoms. Historically, where treatment is warranted, surgery has been the mainstay – either myomectomy or hysterectomy.¹⁸ However, recent changes in cultural attitudes together with an increase in maternal age at childbirth have resulted in women becoming increasingly reluctant to undergo open pelvic surgery. During the past decade societal changes have led to a decline in hysterectomy rates and an increased uptake of non-surgical interventions such as the Mirena intrauterine system (IUS) and uterine artery embolization. However, many women find the unpredictable bleeding pattern associated with the Mirena coil to be unacceptable and the safety of uterine artery embolization women in wishing to preserve their fertility is still under investigation.¹⁹ As a result, the need for a non-invasive, fertility preserving solution to the treatment of fibroids has arisen.

The ability of ultrasound energy to interact with biologic tissues has been recognized for many years. The earliest medical uses of ultrasound were therapeutic rather than diagnostic, and the ability of ultrasound energy to cause a rise in tissue temperature was recognized as long ago as 1927.²⁰ Limitations of accuracy and temperature monitoring have hampered clinical development of this technique until the recent introduction of modern image guidance. The feasibility of an MRI guided system was first described in 1995 .^21, High intensity ultrasound can be focused into a small volume to produce a rise in tissue temperature sufficient to cause lethal cell damage in the target at depth within the body.²² Concurrent MR imaging allows accurate tissue targeting and real-time temperature feedback, thereby achieving controlled localized thermal ablation without causing damage to surrounding tissues. Focused ultrasound energy holds the promise of being not only minimally invasive, but also a completely non-invasive, low-risk therapy for treating uterine fibroids. Using this technique, complete areas of tissue within a solid organ can be destroyed without breaching the skin.

Our fibroid center at St Marys’ Hospital, London, UK, was one of the first in the world to be involved in the clinical development of a focused ultrasound treatment modality. The Exablate 2000^TM (Insightec, Haifa, Israel) fully integrates with a standard closed 1.5 tesla MRI system. A specially integrated patient bed containing an ultrasound transducer, upon which the patient is positioned supine, is used. An ultrasound beam is generated from the phased array transducer which travels through a gel pad and water bath, all helping to create acoustic coupling (Fig. 6). The ultrasound travels easily through the skin and propagates through the tissue focusing at a specific target within the body. The tissue at the focus reaches temperatures sufficient to cause cell coagulation. It is important to remember that there is no damage to adjacent tissue and only the target tissue undergoes necrosis.

Fig. 6. Patient positioned prone, with abdomen placed in a waterbath containing the gel pad.

Concurrent MR imaging allows:

·         three-dimensional anatomic information for exact tumor targeting

·         beam path visualization for safe treatment

·         real-time MR thermometry to achieve planned outcome

·         post-treatment contrast imaging for evaluating treatment outcome.

This closed loop therapy concept provides the operator with immediate feedback, the ability to react to that feedback and immediate knowledge of the outcome of therapy. This provides the clinician with total control of the procedure, thereby ensuring both safety and efficacy.

Since January 2011 St Mary’s Hospital has been using the ExAblate 2100 ^TM system (InSightec). The initial use of the ExAblate 2100 system was as a part of a phase 4 study conducted by the company InSightec to evaluate safety and ablation efficacy of the system when treating symptomatic uterine fibroids. The new system differs significantly from the previous ExAblate 2000 system. Following feedback from the various clinicians performing MRgFUS a number of alterations to the focused ultrasound transducer were made to allow for a greater volume of fibroid tissue to be treated in a shorter time period and with the aim of improving safety to the patient. The ExAblate 2100 system uses a three-dimensional treatment planner that automatically arranges sonication spots to cover a maximum targeted fibroid volume. The system is also able to adjust the shape of the spot, the aperture of the transducer, height and tilt of the transducer, thereby producing a more customized area of treatment energy compared with the earlier ExAblate 2000 system (Fig. 7).

Fig. 7. Changes in the size and shape of sonication spots in the new Exablate 2100 system compared with the former system

There are several reasons why uterine fibroids are well suited to treatment with MRgFUS. Fibroids are generally well defined and clearly seen on MRI. They are rich in extracellular matrix, which makes them relatively easy to target with thermoablative energy.

The MRI employed before, during, and after this therapy helps in screening and patient selection as well as in the evaluation of treatment outcome. Objective measurements of volume reduction can be made and since studies have suggested that the non-perfused volume correlates with treatment outcome, another objective predictor of treatment success is provided.^23, The only validated measure of fibroid symptomatology, the uterine fibroid specific quality of life questionnaire (UFS-QOL), can be used to measure treatment success in terms of symptom improvement, as determined by the patient.²⁴

To date over 400 women have taken part in formal multicenter international research trials and since FDA approval was granted for commercial treatments in 2004, globally over 4000 women have been treated.^25, The FDA approved the system based on a review of clinical studies of safety and effectiveness conducted by the manufacturer and on the recommendation of a panel of outside experts convened by the agency to review the device.

The original goal of the first study was to ensure safety of the treatments, while investigating the level of efficacy possible. As such, restrictions were placed on the volume of fibroid tissue that could be treated in any patient. This study compared the results of 109 women who underwent MRgFUS with those of 82 women who had a hysterectomy at seven medical centers around the world, including our unit at St Mary’s. Only nine adverse events were reported, including pre-existing medical conditions and continued heavy menses. There was only one device-related adverse incident, with a patient experiencing leg numbness which resolved spontaneously. When the MRgFUS-treated women were reviewed 6 months later, 79.3% reported successful reduction in fibroid-related symptoms. The mean reduction in fibroid volume was 13.5%.²⁶

Having established the safety of the MRgFUS device and the fibroid ablation procedure, the FDA expanded the allowable treatment volume. The Continued Access Study followed 160 women of whom 96 were treated under the original restricted treatment guidelines and 64 women were treated under the expanded treatment guidelines. In the latter group, 84.6% of women experienced significant symptomatic improvement at 24 months post-treatment versus 76.2% in women treated under the original guidelines. This study concluded that MRgFUS treatment results are consistent and reproducible. Furthermore, the expanded treatment guidelines demonstrated that the greater the volume of tissue treated the greater the symptomatic improvement.²⁷

At present the evidence for the longer-term effectiveness of MRgFUS in the treatment of uterine fibroids is limited. The 2-year re-intervention rate from a cohort of 91 women undergoing MRgFUS in Japan was 14.0% in women with fibroids of hypo- or isointensity related to signal intensity of skeletal muscle. These women had a mean percentage non-perfused volume of 55% and the mean fibroid volume treated was 129.0 ml (SD 145.2 ml).²⁸ At present, our experience at St Mary’s suggests that the overall safety of MRgFUS is exceptionally good, but in women with greater than 50% of the total fibroid tissue treated the re-intervention rate at 3 and 5 years is 35 and 50%, respectively. These re-intervention rates are high when compared to uterine artery embolization (28–34% at 5 years^{29, 30}) and myomectomy (4–23% at 5 years^{29, 31}). However, these figures are from women treated by the Exablate 2000 system and we anticipate that the higher treatment volumes achieved using the Exablate 2100 system will be translated into lower subsequent intervention rates.

Initially our research treatment protocol dictated a maximum fibroid diameter of 10 cm because the time required to perform the procedure is volume dependent. This limitation had important clinical implications, since fibroids may be asymptomatic until this size threshold has been crossed, particularly amongst Black women in whom presentation at a younger age with larger fibroids is common.^32, Our team at St Mary’s undertook the GnRH large fibroid study, where we postulated that by administering GnRH agonists to produce a temporary reduction in fibroid volume, prior to carrying out MRgFUS, that we could extend this innovative treatment to a much wider patient group. This was a prospective study, with a 12-month follow-up. Women received a 3-month course of GnRH agonist treatment followed by MRgFUS treatment. The primary outcome measurement reported was a change in symptom severity score (SSS) as judged by the Uterine Fibroid Symptoms and Quality of Life Questionnaire (UFS-QOL). Comparison was made at enrolment, treatment and at 3, 6, and 12 months post-treatment. A secondary outcome was the measured change in target fibroid volume. Fifty women were enrolled in the study. There was a 50% reduction in mean SSS at 6 months and 48% at 12 months post-treatment with 83% of women achieving at least a 10-point reduction in symptom scoring (p <0.001). An average reduction in target fibroid volume of 21% overall at 6 months (p <0.01) and 37% at 12 months was achieved (Fig. 8). No serious infective complications or emergency operative interventions were reported during this study.³²

Fig. 8. MR images pre-GnRH, post-GnRH, and post-treatment.

The initial FDA recommendation was that only women who had completed their families should be treated with MRgFUS. However, following consistently good safety and efficacy results being reported, multicenter fertility studies were commenced and are on-going. These studies are actively recruiting women with symptomatic uterine fibroids who wish to become pregnant. The non-invasive nature of ExAblate, whereby only the uterine fibroids undergo thermal ablation with no damage to healthy surrounding tissue, suggests that MRgFUS should be a safe approach for women who want to preserve their fertility. The initial results have been very promising and evidence is accumulating to suggest that women are able to conceive promptly and successfully deliver children after undergoing MRgFUS treatment for their uterine fibroids.^{33, 34, 35}

To date, 59 women have delivered healthy infants at term without complications and further pregnancies are on-going. Thirty-eight women have delivered vaginally and 21 by cesarean section. The miscarriage rate of 20% is comparable with the normal population rate. Most importantly there have been no reported cases of uterine rupture, preterm labor, placental abruption, abnormal placentation, or fetal growth restriction – the mean birth weight being 3.3 kg. This contrasts favorably with the higher preterm delivery rate and lower birth weights reported in the pregnancy outcome studies following uterine artery embolization. These results suggest that MRgFUS treatment has the potential to deliver safe and effective treatment for uterine fibroid symptoms without damaging patient fertility or creating additional pregnancy related risks. Accordingly the Conformitee Europeene (CE) marking for the ExAblate system has been changed to include patients wishing to preserve their fertility.

Adenomyosis is a common benign gynecological disorder affecting premenopausal women, which is characterized by the growth of ectopic endometrial glands and stroma deep within the myometrium.^36, The "benign invasion of endometrium into myometrium" that occurs in adenomyosis can lead to enlargement of the uterus, reactive hyperplasia, and hypertrophy of the neighboring myometrium.³⁷ Adenomyosis can be found in up to 30% of hysterectomy specimens.³⁸

Symptoms of adenomyosis include menorrhagia, dysmenorrhea, and diffuse uterine enlargement, which may result in pelvic pressure effects. The severity of symptoms correlates roughly with the extent of disease.³⁹ Clinically, adenomyosis is difficult to distinguish from uterine leiomyomas, since the symptoms are similar and the two pathologies are poorly distinguished by ultrasound. MRI is currently regarded as the best imaging tool for the differential diagnosis of leiomyomas and adenomyosis.⁴⁰

There have been several case reports describing the use of MRgFUS in the treatment of focal adenomyosis.^{41, 42, 43} The results reported a small reduction of the uterine volume, the junctional zone, and the myometrial zone within the uterus following MRgFUS.⁴³ Further investigation of the long-term outcomes following MRgFUS for adenomyosis are needed before this can be adopted as an established treatment for this condition.

In summary, MR-guided focused ultrasound treatment of uterine fibroids has been shown in phase I, II, and III clinical trials to be a safe treatment option. Efficacy, in terms of sustained symptomatic relief, correlates with the volume of fibroid ablation, and recent trials with adjuvant GnRH analogues prior to treatment have demonstrated efficacy in patients with larger fibroids, thus increasing the eligible patient population. Collectively these studies should secure a place for MRgFUS as a valid alternative to current therapies.

The non-invasive nature of the MRgFUS procedure holds particular attraction for patients who wish to become pregnant in the future. Currently available data are encouraging; with published case studies suggesting that fertility is not impaired and that pregnancies following MRgFUS are uncomplicated, although more experience will be required before we can effectively counsel patients of reproductive age. The National Institute of Clinical Excellence (NICE) has recently published guidelines which recognize MRgFUS as a treatment alternative for symptomatic fibroids and has encouraged our on-going research program. Further long-term data will provide more information regarding the effectiveness of this treatment. Improvements in the technology should lead to an increase in the overall volumes of fibroid tissue treated which should translate into better long-term outcomes for women. 

The authors of this chapter are grateful for support from the NIHR Biomedical Research Centre Funding Scheme.