MRI-guided focused U/S: novel therapy for leiomyomata


New, noninvasive treatments are always welcomed by women with fibroids and their clinicians. MRI-guided focused U/S holds promise as a nonsurgical way to accurately target fibroids with no damage to adjacent tissue and minimal side effects.



MRI-guided focused U/S:
novel therapy for leiomyomata

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Choose article section... Focused ultrasound surgery (FUS) Image-guided therapy Fibroids as an optimal target History of FUS Mechanism of action Breast cancer Guided FUS in animal models for fibroids The protocol for MRgFUS in humans Equipment Results of feasibility studies Conclusion

By Tali Silberstein, MD, Clare M.C. Tempany, MD, and Elizabeth A. Stewart, MD

New, noninvasive treatments are always welcomed by women with fibroids and their clinicians. MRI-guided focused U/S holds promise as a nonsurgical way to accurately target fibroids with no damage to adjacent tissue and minimal side effects.

Ultrasound (U/S) imaging is one of the most useful diagnostic tools in medicine. It has permeated almost every specialty and is used extensively for evaluating everything from the gallbladder to the fetal brain. In obstetrics and gynecology practice, U/S is a basic tool. The benefits of using diagnostic U/S are clear: U/S imaging is a painless, low-cost examination that is widely available and easy to use. It uses no ionizing radiation and provides real-time imaging. U/S is also used increasingly in therapeutic interventions and has the advantage of producing real-time images required for procedures such as needle biopsies and in utero interventions. The ability to evaluate results immediately after performing the procedure is another advantage.

Focused ultrasound surgery (FUS)

Focused ultrasound surgery (FUS) is a novel noninvasive technique that has the potential to treat tissue abnormalities by selectively producing thermal damage within a small focal volume. In contrast to diagnostic U/S, in which the transducer directs sound waves that are then reflected back to generate an image, the sound waves in FUS are focused to a single point, generating heat there (Figure 1). The focused U/S beam thus uses heat to destroy only cells at its focus with no known harm to overlying or surrounding tissue.1,2 U/S energy penetrates through soft tissues, can be focused to target sites, and causes localized high temperatures (55° to 90°C) for a few seconds. Within the full spectrum of electromagnetic and sound waves, only FUS can be used to noninvasively generate local tissue coagulation.3 As a result, well-defined areas of protein denaturation, irreversible cell damage, and coagulative necrosis are produced.



The ability of specific tissues to absorb and dissipate heat via blood perfusion, which carries heat away from the treated area, plays an important role because it can alter the temperature distributions achieved in the tissue (Figure 2).4 Conductivity and perfusion are tissue-specific and can also be influenced by patient-specific parameters. Furthermore, the tissue perfusion and conductivity of tumors and normal tissue vary.5



Image-guided therapy

An important factor contributing to the clinical application of FUS is the use of a high-quality method of medical imaging to guide, monitor, and control the size and location of the therapeutic focal beam. Since FUS works by causing tissue coagulation, optimal control of the treatment can be achieved by monitoring and controlling the temperature. Magnetic resonance imaging (MRI) can be used for both precise imaging and FUS targeting and real time monitoring of temperature (thermometry).5-10 It has excellent anatomic resolution for targeting and high sensitivity for localizing tumors. For real-time procedure monitoring and control, MRI and FUS are integrated into a single system—MR-guided FUS (MRgFUS)—in which thermal energy from a FUS source is used to coagulate tissue while MRI is used to guide and monitor the procedure. Real-time monitoring of the temperature from each point in the tumor maximizes specificity and efficacy. Thermometry also enhances safety by ensuring that the heating is confined to the targeted area (Figure 3).



Fibroids as an optimal target

Uterine leiomyomas, commonly known as fibroids or myomas, are well-circumscribed, benign smooth-muscle-cell tumors arising from the myometrium. Histologically, monoclonal proliferation of smooth muscle cells occurs. Fibroids are the most common pelvic neoplasm in women and occur in 20% to 50% of those older than 30 years, more commonly in black than white women, and in women with a high body mass index. Treatment of symptomatic fibroids ranges from monitoring only to hysterectomy depending on the severity of symptoms, age, desire for future pregnancies, general health, and tumor characteristics such as size and location.11

Fibroids are an optimal target for the MRgFUS technique for many reasons. They are benign with an indolent pattern of symptoms so that there is no "expensive" loss of time as with suboptimal treatment of malignant tumor. Fibroids are common and since there are other treatment options, both medical and surgical, it is easy to compare the benefits and success of the technique with existing methods. Because fibroids are relatively large masses and easy to image, it is easy to accurately assess a change in volume. It is also easy to evaluate the end points of successful treatment: decreased bleeding, disappearance of pressure-related symptoms, objective measurements of volume reduction, and improvement in quality of life.

The high content of extracellular matrix in fibroids makes them good targets for the MRgFUS because tissues rich in this substance seem to absorb heat well. Minimally invasive therapies for guided fibroid imaging, such as thermoablation and laser ablation, already are in use but FUS carries thermoablation therapy a step further in that it is a noninvasive. The large vascular plexus that surrounds most fibroids provides an efficient cooling mechanism. And finally, women with fibroids are constantly looking for noninvasive alternative treatments.

History of FUS

Lynn and colleagues raised the potential of surgical application of FUS more than five decades ago, but the first report of its application in humans did not appear until 1960.12,13 The early reports described its use for treatment of Parkinson's disease and painful neuromata. Since then, FUS has been investigated for noninvasive treatment of hepatic metastasis, breast fibroadenoma, benign prostatic hyperplasia, prostatic carcinoma, and bladder and renal carcinoma.10 Nonhuman studies showed that FUS with either MRI guidance or diagnostic U/S guidance can destroy tumors very precisely.7,10,14,15

Mechanism of action

The complete mechanisms of the tumor damage with FUS are not yet fully understood but they probably involve both direct and indirect damage.16 The direct damage is primarily thermal: the energy from sound waves is converted to heat. The total energy transmitted by the sound waves is termed the sound power. Heating electromagnetic sound power should be kept below 100°C to avoid boiling intracellular water and thus gas formation, which can lead to cavitation. Cavitation, which is mainly mechanical in origin, can lead to tissue disruption. The indirect tissue damage is caused by disruption of the local blood supply, and therefore is dependent on blood vessel distribution in the tissue adjacent to the treated area. Thermal damage appears to be the predominant factor.15

Breast cancer

Huber and colleagues examined the possibility of transferring MRI-guided FUS technology from animal studies to noninvasive treatment of human breast cancer.9 This group demonstrated that human breast cancer could be effectively treated with noninvasive FUS thermal therapy in a single treatment session using MRI planning and real-time MRI thermometry without marked side effects. The treatment caused localized interruption of blood perfusion and induction of tumor cytotoxicity. Immunohistochemical analysis of the resected specimen demonstrated that FUS induced lethal and sublethal tumor damage, with subsequent up-regulation of p53 and loss of proliferative activity as shown by the strong staining for estrogen receptor and progesterone receptor that became negative after the treatment.

Guided FUS in animal models for fibroids

Vaezy and colleagues investigated the potential efficacy of U/S-guided high-intensity focused U/S (which they termed HIFU) for the treatment of uterine fibroid tumors in a nude mouse model simulating uterine fibroids.14 They reported an average reduction in tumor of 91% within 1 month of treatment with a single high-intensity focused ultrasonic procedure. Histologic examination of the tumors showed coagulation necrosis and nuclear fragmentation of tumor cells. Vaezy and colleagues subsequently have extended their studies and built a prototype device for U/S-guided transvaginal HIFU treatment of submucosal uterine fibroids.16 The device's performance was characterized in sheep, and imaging capabilities were tested in six healthy human volunteers. In the ewe uterus, histologic analysis showed sharply demarcated regions of disrupted smooth muscle tissue and damaged glandular structure where HIFU was applied. Although treatment was not attempted in the humans, the U/S-guided HIFU device with a transvaginal treatment probe and a transabdominal imaging guidance probe was shown to be an ergonomically viable treatment option.

The protocol for MRgFUS in humans

The feasibility and safety of the FUS guided by MRI for the treatment of human fibroids was tested in a multicenter clinical trial, with the only US site being at the Brigham and Women's Hospital.17,20 The other sites were Hadassah Jerusalem and Sheba Tel Aviv, Israel; Saint Mary's Hospital, London; and Charite, Berlin, Germany. Women enrolled in the study had symptomatic fibroids requiring treatment and were scheduled for elective hysterectomy. Although in theory any fibroid can be treated by MRgFUS, only intramural fibroids less than 10 cm with an overall uterine size less than 20 cm were included in this initial study. Success was judged on the ability to visualize the sonications and the temperature history using MRI guidance and to demonstrate tissue necrosis in the uterus at the time of subsequent hysterectomy.

All women had pretreatment MRI scans after administration of intravenous gadolinium contrast material. Injection of gadolinium into a vein allows the MRI to identify areas of thermal ablation with greater clarity since these sites have no blood flow and therefore do not enhance with gadolinium. Side effects of gadolinium are minimal and include mild headache, nausea, and local pain. Since some fibroids naturally undergo degeneration and are gadolinium non-enhancing, this step allowed us to identify the true treatment effect (Figure 4).



Before arriving at the hospital, in preparation for FUS, patients shaved the hair from their anterior abdominal wall down to the pubic crest to allow better acoustic coupling. Failure to do so can result in minor skin burn. Patients also were told to fast overnight and to come to the hospital with a companion. They were instructed to empty their bladders to reduce target movement and an IV line then was placed for administration of sedation. FUS was done with patients prone and under sedation to reduce pain and prevent motion. After the treatment, they were discharged home and returned within 72 hours for a follow-up clinic visit and MRI. The women in the original protocol underwent hysterectomy within 1 month after the treatment.


The sonications were performed using a clinical MRgFUS system (Exablate 2000, InSightec, Haifa, Israel) that included improvements in transducer design, real-time thermometry feedback, and volumetric planning.17 A focused, piezoelectric transducer array with a 120-mm diameter and opera- ting frequency between 1.0 and 1.5 MHz generated the U/S field. The array was located in the MRI table in a water tank. It could electronically control the location of the focal spot and the volume of the coagulated tissue volume. Lateral motion of the transducer was achieved with a mechanical positioning device. A thin plastic membrane window covered the water tank and allowed the U/S to penetrate the patient's pelvis.

Results of feasibility studies

Treatment of 55 patients has been reported in the literature. The report by Tempany and colleagues emphasized the technical aspects of the MRgFUS in nine patients enrolled in the study, six of whom completed treatment.17 The MRI allowed for both monitoring of the sonications and safety of FUS. All of the treatment focal spots were visible and analyzable for temperature, thus ensuring that sonications were at the correct target in every instance of treatment. Five of the six patients underwent hysterectomy, and the presence of necrosis was pathologically confirmed. This study showed the feasibility and safety of MR-guided FUS in the treatment of uterine fibroids. The side effects were minimal and included pain when scar tissue was present in the pass zone and minor skin burns with blisters in the anterior abdominal wall.

Stewart and colleagues reported safety and feasibility results from a clinical point of view in 55 patients in the multicenter clinical trial.19 On pathologic examination, the area of the necrosis was well circumscribed and targeted appropriately without injury to adjacent structures (Figure 5). They concluded that the procedure is well tolerated and convenient for outpatient treatment.



Rabinovici and colleagues also reported preliminary results on the safety and feasibility of transcutaneous thermal ablation of uterine fibroids by MRgFUS in their series in Tel Aviv.18 Although the investigators originally intended to follow the protocol involving hysterectomy, the Israeli Health Authority insisted that the women be given a choice of subsequent hysterectomy or expectant management. In the study, 11 fibroids measuring 5 to 10 cm and with volumes of 70 to 1,000 mL were treated in nine women. The results suggested that MRgFUS could be performed safely without significant adverse effects and can induce a significant regression in fibroid size as soon as 1 month after therapy.

In a subsequent report on the same cohort, Rabinovici and colleagues reported treatment of 25 women with symptomatic uterine fibroids with MRgFUS thermal ablation.20 An MRI study was performed at 1, 3, and 6 months after the procedure to examine changes in fibroid volume. Clinical examinations were performed monthly to evaluate the effect of treatment. The findings showed a significant regression in mean fibroid size and clinical improvement in a majority of women at 3 to 6 months after MRgFUS.


Ablative management of tumors has traditionally been the domain of the surgeon alone. Today, tumor treatment is becoming more and more multidisciplinary. Modern medicine is constantly seeking new noninvasive methods for tumor therapy that will effectively attack the target with minimal side effects, that do not require opening the skin, and do not harm adjacent tissue. The novel method of MRgFUS discussed here for the treatment of fibroids represents a promising new technique that seems to meet all of these requirements. The uterus is readily accessible to U/S and the energy can be focused precisely at the target, thanks to the very accurate MR I. In the studies to date, tissue damage has been confirmed by histologic examination and side effects have been minimal. MRgFUS appears to be feasible for treatment of fibroids but larger studies are necessary to evaluate improvement in patients' symptoms and durability of the procedure's results.



The authors would like to gratefully acknowledge the contributions of other individuals to their work on MRgFUS as well as the entire staff of their collaborating sites. At Brigham and Women's Hospital, Department of Medical Physics, Kullervo Hynynen, PhD, Nathan McDannold, PhD; Department of Obstetrics and Gynecology, Elena Yanushpolsky, MD, Louise Greenberg, MS; Department of Radiology, Ferenc A. Jolesz, MD. At InSightec, Rob Newman, Kobi Vortman.



1. Quesson B, Vimeux F, Salomir R, et al. Automatic control of hyperthermic therapy based on real-time Fourier analysis of MR temperature maps. Magn Reson Med. 2002;47:1065-1072.

2. Chen L, ter Haar G, Robertson D, et al. Histological study of normal and tumor-bearing liver treated with focused ultrasound. Ultrasound Med Biol. 1999;25:847-856.

3. ter Haar GR. High intensity focused ultrasound for the treatment of tumors. Echocardiography. 2001;18:317-322.

4. Reinhold HS, Endrich B. Tumour microcirculation as a target for hyperthermia. Int J Hyperthermia. 1986;2:111-137.

5. Lagendijk JJ, Hofman P, Schipper J. Perfusion analyses in advanced breast carcinoma during hyperthermia. Int J Hyperthermia. 1988;4:479-495.

6. Cheng HL, Plewes DB. Tissue thermal conductivity by magnetic resonance thermometry and focused ultrasound heating. J Magn Reson Imaging. 2002;16:598-609.

7. Vimeux FC, De Zwart JA, Palussiere J, et al. Real-time control of focused ultrasound heating based on rapid MR thermometry. Invest Radiol. 1999;34:190-193.

8. Hynynen K, Pomeroy O, Smith DN, et al. MR imaging-guided focused ultrasound surgery of fibroadenomas in the breast: a feasibility study. Radiology. 2001;219:176-185.

9. Huber PE, Jenne JW, Rastert R, et al. A new noninvasive approach in breast cancer therapy using magnetic resonance imaging-guided focused ultrasound surgery. Cancer Res. 2001;61:8441-8447.

10. Chen L, Bouley D, Yuh E, et al. Study of focused ultrasound tissue damage using MRI and histology. J Magn Reson Imaging. 1999;10:146-153.

11. Stewart EA. Uterine fibroids. Lancet. 2001;357:293-298.

12. Lynn JG, Zwemer RL, Chick AJ, et al. A new method for the generation and use of focused ultrasound in experimental biology. J Gen Physiol. 1942;26:179-193.

13. Fry WJ, Fry FJ. Fundamental neurological research and human neurosurgery using intense ultrasound. IRE Trans Med Electron. 1960;17:858-876.

14. Vaezy S, Fujimoto VY, Walker C, et al. Treatment of uterine fibroid tumors in a nude mouse model using high-intensity focused ultrasound. Am J Obstet Gynecol. 2000;183:6-11.

15. Chen L, ter Haar G, Hill CR, et al. Treatment of implanted liver tumors with focused ultrasound. Ultrasound Med Biol. 1998;24:1475-1488.

16. Chan AH, Vaezy S, Moore DE, et al. Image-guided high intensity focused ultrasound: potential for minimally-invasive treatment of uterine fibroids. Fertil Steril. 2002;78(suppl 1):S1. Abstract.

17. Tempany CM, Stewart EA, McDannold N, et al. MRI-guided focused ultrasound surgery of uterine leiomyomas: a feasibility study. Radiology. 2003;226:897-905.

18. Rabinovici J, Inbar Y, Zalel Y, et al. Uterine fibroid shrinkage after non-invasive transcutaneous thermal ablation by magnetic resonance imaging-guided high intensity focused ultrasound. J Soc Gynecol Investig. 2002;(suppl 9):67. Abstract.

19. Stewart EA, Gedroyc WM, Tempany CM, et al. Focused ultrasound treatment of uterine fibroids: safety and feasibility of a noninvasive thermoablative technique. Am J ObGyn. 2003. In press.

20. Rabinovici J, Inbar Y, Zalel Y, et al. Significant clinical improvement following non-invasive transcutaneous thermal ablation of uterine fibroids by magnetic-resonance-imaging-guided high-focus ultrasound. Fertil Steril. 2002;78(suppl 1):S80. Abstract.

Dr. Tempany has received research grant support from InSightec. Dr. Stewart is a limited consultant and clinical trial investigator with InSightec.
Dr. Silberstein is a fellow in the Center for Uterine Fibroids at Brigham and Women's Hospital. Dr. Tempany is a radiologist affiliated with the Center for Uterine Fibroids at Brigham and Women's Hospital and an Associate Professor of Radiology at Harvard Medical School. Dr. Stewart is the Clinical Director of the Center for Uterine Fibroids at Brigham and Women's Hospital and an Assistant Professor of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School, Boston, Mass.


Elizabeth Steward, Tali Silberstein, Claire Tempany. MRI-guided focused U/S: novel therapy for leiomyomata. Contemporary Ob/Gyn 2003;48:22-30.

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