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DOI: 10.1148/radiol.2361040312
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(Radiology 2005;236:196-203.)
© RSNA, 2005

Genitourinary Imaging

Uterine Fibroids: Diffusion-weighted MR Imaging for Monitoring Therapy with Focused Ultrasound Surgery—Preliminary Study1

Michael A. Jacobs, PhD, Edward H. Herskovits, MD, PhD and Hyun S. Kim, MD

1 From the Russell H. Morgan Department of Radiology and Radiological Science (M.A.J., H.S.K.) and Department of Vascular and Interventional Radiology (H.S.K.), the Johns Hopkins University School of Medicine, Traylor Bldg, Room 217, 712 Rutland Ave, Baltimore, MD 21205; and Department of Radiology, University of Pennsylvania, Philadelphia, Pa (E.H.H.). Received February 17, 2004; revision requested April 23; revision received August 24; accepted October 20. M.A.J. supported in part by National Institutes of Health grants P50 CA09630 and 1R01CA100184. Address correspondence to M.A.J. (e-mail: mikej{at}mri.jhu.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To prospectively determine the feasibility of using diffusion-weighted (DW) imaging and apparent diffusion coefficient (ADC) mapping before (baseline) and after treatment and at 6-month follow-up to monitor magnetic resonance (MR) image–guided focused ultrasound surgical ablation of uterine fibroids.

MATERIALS AND METHODS: Informed consent was obtained from patients before treatment with our study protocol, as approved by the institutional review board, and the study complied with the Health Insurance Portability and Accountability Act. Fourteen patients (mean age, 46 years ± 5 [standard deviation]) who underwent DW imaging were enrolled in this study, and 12 of 14 completed the inclusive MR examination with DW imaging at 6-month follow-up. Treatment was performed by one radiologist with a modified MR image–guided focused ultrasound surgical system coupled with a 1.5-T MR imager. Pre- and posttreatment and 6-month follow-up MR images were obtained by using phase-sensitive T1-weighted fast spoiled gradient-recalled acquisition, T1-weighted contrast material–enhanced, and DW imaging sequences. Total treatment time was 1–3 hours. Trace ADC maps were constructed for quantitative analysis. Regions of interest localized to areas of hyperintensity on DW images were drawn on postcontrast images, and quantitative statistics were obtained from treated and nontreated uterine tissue before and after treatment and at 6-month follow-up. Statistical analysis was performed with analysis of variance. Differences with P < .05 were considered statistically significant.

RESULTS: T1-weighted contrast-enhancing fibroids selected for treatment had no hyperintense or hypointense signal intensity changes on the DW images or ADC maps before treatment. Considerably increased signal intensity changes that were localized within the treated areas were noted on DW images. Mean baseline ADC value in fibroids was 1504 mm–6/sec2 ± 290. Posttreatment ADC values for nontreated fibroid tissue (1685 mm–6/sec2 ± 468) differed from posttreatment ADC values for fibroid tissue (1078 mm–6/sec2 ± 293) (P = .001). A significant difference (P < .001) between ADC values for treated (1905 mm–6/sec2 ± 446) and nontreated (1437 mm–6/sec2 ± 270) fibroid tissue at 6-month follow-up was observed.

CONCLUSION: DW imaging and ADC mapping are feasible for identification of ablated tissue after focused ultrasound treatment of uterine fibroids.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Noninvasive treatment of tumors is highly desirable and provides an alternative to surgery. One such treatment undergoing active research is focused ultrasound surgery (1–7). The energy from focused ultrasound surgery can be accurately focused, which causes heating of the desired tissue to induce cell damage or death, protein denaturation, and/or coagulative necrosis while the surrounding tissue or structures are not affected (8).

The use of focused ultrasound surgery for treatment of different diseases has evolved from experimental studies (9,10) to ongoing clinical trials (11,12). Several applications of focused ultrasound surgery for treatment of lesions in the prostate (13), kidney (14), bladder (15), and breast (11) have been reported. One drawback of using focused ultrasound surgery, however, has been the determination of the location of the ultrasound beam in the tissue for accurate tissue ablation. To overcome this difficulty, magnetic resonance (MR) imaging has been used to guide the application of focused ultrasound surgery to treat lesions. MR image–guided focused ultrasound has been shown to be quite successful in both experimental (4,16,17) and clinical settings (18) for guidance and monitoring of this treatment. For example, recent reports have shown that MR image–guided focused ultrasound surgery can be used for the treatment of uterine leiomyomas, commonly referred to as uterine fibroids (12), or breast fibroadenomas (11). To identify ablated tissue after treatment, the authors used T1-weighted MR imaging after administration of a gadolinium-based contrast agent. In theory, after the administration of a contrast agent and successful treatment, the area of ablated tissue will appear hypointense because of disruption of the tissue hemodynamics, but contrast-enhanced imaging gives no information about the cellular environment.

On the other hand, diffusion-weighted (DW) imaging is sensitive to changes in the microdiffusion of water within the intracellular and intercellular environments (19). For example, after an event that has caused a disruption or restriction of the flow of water within a tissue, such as an ischemic event (eg, stroke), cytotoxic edema occurs (19,20). These changes in the diffusion of water result in areas of increased signal intensity on the DW images and within the region of ischemia (21,22). The reason for these signal intensity changes on DW images is not known; however; there is evidence that these changes may be attributable to many factors, such as shifts of water from the extracellular space to the intracellular space, increased tortuosity of the pathways of diffusion, restriction of the permeability of the cellular membrane, cellular density, and disruption of cellular membrane depolarization (23,24).

Moreover, DW imaging also provides a quantitative biophysical parameter, called the apparent diffusion coefficient (ADC) of water. The ADC is an indicator of the movement of water within the tissue (19). It gives an average value of the flow and the distance a water molecule has moved. For example, the ADC has been related to the state of tissue during the evolution of cerebral ischemia (21), tumor progression (25), and experimental thermal heating of ex vivo tissue (26,27). Specifically, cells respond to a decrease in blood flow and try to conserve energy in an attempt to maintain homeostasis, and this behavior leads to changes in the sodium-potassium pump and a decrease in the adenosine triphosphate available for cellular energy metabolism during the initial ischemic event.

These response mechanisms lead to a reduced flow of water in and around the cells by means of shifting of the water from the extracellular space to the intracellular space, and the ADC value is decreased (21,22). The ADC will remain reduced until the restrictions to the flow of water are removed by either the restoration of blood flow or the breakdown of the cell membrane, as occurs during the transition from acute to chronic ischemia. When this occurs, the ADC will pseudonormalize (return to near-normal) and increase to values that are greater than those for nonischemic tissue (28). The ADC has been used to monitor the progression of ischemic tissue in experimental (21,22) and clinical stroke (29–31).

In addition, the induction of thermal necrosis with the MR image–guided focused ultrasound surgical treatment may present a different evolution of the ADC than is currently seen in ischemic tissue. For example, thermal coagulation can induce a range of tissue changes from protein denaturation (unfolding of proteins), cell membrane rupture or dysfunction, increased vasoconstriction, disruption of fiber networks, and cauterization of blood vessels (26,27). These changes within the tissue can lead to a heterogeneous pattern of both restricted and nonrestricted movement of water and, hence, a range of ADC values within uterine fibroids. The evolution of the ADC in tissue treated with MR image–guided focused ultrasound surgery is currently unknown. Experimental evidence observed with thermal therapy suggests that changes detected by means of different MR image parameters (eg, T1- and T2-weighted images) can vary with different tissues and time of treatment (32–35). Since changes in the water within the tissue can be detected at the earliest times with DW imaging, this technique may provide a method of early detection. Thus, DW imaging may provide a noninvasive method to identify and monitor ablated tissue in focused ultrasound surgical treatment of uterine fibroids.

To date, there have been no published investigations about the application of DW imaging or ADC values in the treatment of uterine fibroids by using MR image–guided focused ultrasound. Our hypothesis is that ablated uterine fibroid tissue may exhibit characteristics similar to those of ischemic tissue. In particular, in regions of ablated tissue, DW imaging will demonstrate changes in the ADC values that may provide a method by which to noninvasively obtain information about the cellular environment. Therefore, the purpose of our study was to prospectively determine the feasibility of using DW imaging and ADC mapping before (baseline) and after treatment and at 6-month follow-up to monitor MR image–guided focused ultrasound surgical ablation of uterine fibroids.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Partial financial and equipment support was received by the authors from InSightec, Haifa, Israel, for starting an MR image–guided focused ultrasound surgical treatment center. The authors, however, had control over all data, development of study designs, and information for publication.

Clinical Subjects
Patients with symptomatic fibroids were enrolled in this prospective study for 6 months at the Johns Hopkins University School of Medicine. Of 16 consecutive patients, two did not undergo DW imaging at the time of treatment (as discussed later). Therefore, 14 patients (mean age, 46 years ± 5 [standard deviation]) who underwent DW imaging were finally enrolled in the study, and 12 of the 14 completed the inclusive MR imaging examination with DW imaging at 6-month follow-up. Fibroids thought to be responsible for the clinical symptoms were identified and characterized at a pretreatment MR imaging examination with T2-weighted MR imaging and contrast-enhanced T1-weighted MR imaging. These fibroids were treated with MR image–guided focused ultrasound surgery; patients received conscious sedation and were continuously monitored by a physician (H.S.K.). Intravenously administered sedatives consisted of midazolam hydrochloride (Versed; Bedford Laboratories, Bedford, Ohio), with a mean dose of 3.0 mg (range, 0.5–6.0), and fentanyl citrate (Fentanyl; Baxter Healthcare, Deerfield, Ill), with a mean dose of 150 µg (range, 25–300 µg). Informed consent was obtained from the patients before treatment with our study protocol, as approved by the institutional review board. The study complied with the Health Insurance Portability and Accountability Act. The Table summarizes the number, location, and size of fibroids and patient age.


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  		Patient Demographics, Number of Treated Fibroids, and Location and Size of Primary Lesion

 
MR Image–guided Focused Ultrasound Surgery
Ultrasound treatment was performed by using a modified MR image–guided focused ultrasound surgical system (TX Sonics; InSightec, Haifa, Israel) coupled with a 1.5-T MR imaging system (Excite; GE Medical Systems, Waukesha, Wis) (12) supplied by the developers of the system. The MR image–guided focused ultrasound surgical system has been fully described elsewhere (12). Several days before treatment, baseline MR images were obtained with T2-weighted MR imaging, contrast-enhanced T1-weighted MR imaging, and DW imaging for localization of the fibroid. Imaging was performed ahead of treatment for a few reasons: convenience for the patient, ease of scheduling purposes, and provision of appropriate pretreatment data for a more accurate diagnosis and for location of the fibroids that were determined by the radiologist (H.S.K.) to be treated with high-intensity focused ultrasound surgery.

On the day of treatment, the patient was placed on the modified MR image–guided focused ultrasound surgical table, with the 120-mm-diameter ultrasound piezoelectric transducer array operating in a frequency range between 1.0 and 1.5 MHz, in a water tank. The transducer has the capability to be moved along two axes with a mechanical positioning device (36) and to be tilted upward to 18°. To improve acoustic coupling, a thin (2–4-cm-thick) gel membrane (Parker Laboratories, Fairfield, NJ) was placed in degassed water between the patient and the transducer. Then, a series of coronal, sagittal, and transverse T2-weighted fast spin-echo images (repetition time msec/echo time msec, 5000/100; echo train length, 12; section thickness, 4.0 mm; matrix, 256 x 100; field of view, 36 x 36 cm) were acquired for calibration and treatment planning. Calibration was performed to ensure that the patient was properly positioned and to align the focused ultrasound surgical unit with the MR imaging coordinate system. To accomplish this calibration, the transducer and the skin line were outlined by the user (H.S.K., M.A.J.), and the beam path was constructed to verify that no adjacent structure could be injured from the ultrasound beam (such as the bowel or the nerve bundles). Next, a board-certified body radiologist (H.S.K.) with 9 years of diagnostic radiology experience manually drew an outline of the lesion volume targeted for the treatment plan; this lesion volume was viewed in all three planes and is shown in Figure 1. Finally, a series of low-power ultrasound sonications were performed interactively within the tumor region and viewed by the radiologist in at least two different planes by using real-time MR imaging to provide accurate calibration of the unit to the MR imaging coordinate space.



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  		Figure 1a. Patient 5. Representative images demonstrate example of an MR image–guided focused ultrasound surgical treatment plan in 48-year-old woman. (a) Sagittal T2-weighted MR image (5000/100) obtained during treatment for visualization. The green cylinders and fans (near and far zones) show the total treatment area of the high-intensity focused ultrasound beam. The blue fan area (near and far zones from ultrasound beam) shows each individual treatment area and the underlying structures that may be affected. (b) Coronal T2-weighted MR image of the same region. These views demonstrate the power of using MR imaging to guide focused ultrasound surgical treatment. Areas away from the treated regions can be visualized, and treatment can be tailored to avoid critical adjacent structures. (c) Images represent the treatment plan outline for the fibroid of interest and proposed regions to be treated. Note, this treatment plan is in progress.

 


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  		Figure 1b. Patient 5. Representative images demonstrate example of an MR image–guided focused ultrasound surgical treatment plan in 48-year-old woman. (a) Sagittal T2-weighted MR image (5000/100) obtained during treatment for visualization. The green cylinders and fans (near and far zones) show the total treatment area of the high-intensity focused ultrasound beam. The blue fan area (near and far zones from ultrasound beam) shows each individual treatment area and the underlying structures that may be affected. (b) Coronal T2-weighted MR image of the same region. These views demonstrate the power of using MR imaging to guide focused ultrasound surgical treatment. Areas away from the treated regions can be visualized, and treatment can be tailored to avoid critical adjacent structures. (c) Images represent the treatment plan outline for the fibroid of interest and proposed regions to be treated. Note, this treatment plan is in progress.

 


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  		Figure 1c. Patient 5. Representative images demonstrate example of an MR image–guided focused ultrasound surgical treatment plan in 48-year-old woman. (a) Sagittal T2-weighted MR image (5000/100) obtained during treatment for visualization. The green cylinders and fans (near and far zones) show the total treatment area of the high-intensity focused ultrasound beam. The blue fan area (near and far zones from ultrasound beam) shows each individual treatment area and the underlying structures that may be affected. (b) Coronal T2-weighted MR image of the same region. These views demonstrate the power of using MR imaging to guide focused ultrasound surgical treatment. Areas away from the treated regions can be visualized, and treatment can be tailored to avoid critical adjacent structures. (c) Images represent the treatment plan outline for the fibroid of interest and proposed regions to be treated. Note, this treatment plan is in progress.

 
The acoustic power used during treatment was 100–120 W and was varied on the basis of the power needed to achieve a temperature of 65°–85°C at the focal point. Before each focused ultrasound surgical sonication, pretreatment phase-sensitive MR imaging was performed within the treatment region before and with each sonication, lasting for approximately 30 seconds, followed by a 60–90-second cooling period in which the temperature was continuously monitored by using phase-sensitive MR imaging (4,37). Total MR image–guided focused ultrasound surgical treatment time was 1–3 hours, depending on size and number of fibroids. Possible adverse effects from the focused ultrasound surgical treatment, such as abdominal skin burns, excessive bleeding, or leg paresthesia, were evaluated in each patient. There were no follow-up treatments after the initial session with this study design.

MR Imaging
All MR imaging was performed with the patient in the prone position in a 1.5-T MR imager (Excite; GE Medical Systems), with a dedicated phased-array pelvic coil (USA Instruments, Aurora, Ohio). Phase-sensitive T1-weighted fast spoiled gradient-recalled acquisition MR images (26/13; flip angle, 30°; field of view, 256 x 128 cm; matrix, 28 x 28; section thickness, 5.0 mm) were acquired after each sonication with MR image–guided focused ultrasound surgery. After treatment, DW images (5000/90; b value, 0 and 500–1000; matrix, 128 x 128 and 28 x 28; section thickness, 6.0 mm) and T1-weighted fast spoiled gradient-recalled acquisition pre- and postcontrast MR images (185/1.5; matrix, 256 x 100 and 28 x 28; section thickness, 6.0 mm) were acquired for verification of ablated tissue. Gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ), at a dose of 0.01 mg/kg, was injected into the antecubital vein, 5 seconds after the start of imaging, by using an MR imaging–compatible power injector (Medrad, Pittsburgh, Pa). The injection of the bolus of contrast agent was followed by a 20-mL saline flush. The current standard for monitoring MR image–guided focused ultrasound surgical treatment is postcontrast T1-weighted MR imaging (11,12). T2-weighted MR imaging, contrast-enhanced T1-weighted MR imaging, and DW imaging sequences were repeated at 6-month follow-up.

DW Imaging and MR Image Data Analysis
MR image analysis was performed by using a workstation (UltraSPARC60; Sun Microsystems, Mountain View, Calif), and processing was performed by using the Eigentool image analysis software (Image Analysis Laboratory, Henry Ford Hospital, Detroit, Mich) (38,39). Subimaging (subtraction of the background from images of the uterus) was accomplished by using threshold values and morphologic operations (40). After subimaging, an inhomogeneity correction method was applied to the MR image data set. Localization of fibroids was performed on the MR images by a board-certified body radiologist (H.S.K.), with subsequent image analysis performed by a medical physicist with 8 years of experience in diagnostic radiology (M.A.J.). Trace ADC maps were constructed on a pixel-by-pixel basis from the DW images for quantitative analysis according to the following equation:

where bi represents the diffusion gradient value, S0 is the signal intensity of the fibroid at baseline (b = 0), and Si is the signal intensity of the fibroid at the ith image (b = 500–1000).

Regions of interest were drawn to encompass most (approximately 50%–80%) of the treated fibroid, and care was taken to stay away from the edges of the fibroid to reduce any partial-volume effects between treated and nontreated regions. These regions of interest (within the fibroid) were drawn on the baseline, posttreatment contrast-enhanced, and follow-up T1-weighted MR images and regions of interest were localized to the DW images. Corresponding nontreated tissue areas were selected at a minimum of 1–2 cm from hypointense regions on T1-weighted MR images to reduce possible contamination of the surrounding tissue from the MR image–guided focused ultrasound surgical treatment. Quantitative data were obtained at baseline, posttreatment, and 6-month follow-up in treated and nontreated uterine tissue from the fibroid with the largest treated area. If two or more fibroids were treated in the same session, the fibroid with the largest dimension was used. Ratios of the ADC values were calculated by dividing ADC values for regions of treated tissue by those for nontreated tissue for each time.

Statistical Analysis
Descriptive statistics consisted of means and standard deviations for patient demographics. We employed a mixed-effects analysis of variance with the Tukey honestly significant difference test for post hoc comparisons (SPSS, version 11; SPSS, Chicago, Ill) to determine statistical significance among ADC values in treated and nontreated tissue. All parametric ADC map values are presented as mean ± standard deviation. Differences with P < .05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
General Observations
Contrast-enhancing fibroids that were observed on T1-weighted MR images and were selected for treatment had no discernible signal intensity changes (eg, hyperintense or hypointense areas) on the DW images or ADC maps before MR image–guided focused ultrasound surgical treatment. After treatment, images in all patients exhibited increased signal intensity changes localized in the treated fibroid regions (n = 14) on DW images. In addition, areas of hypointensity within the treated regions that were indicative of ablated tissue were observed on postcontrast T1-weighted MR images. Figure 2 demonstrates typical results and the capability of DW imaging in regard to visualization of changes in tissue treated with MR image–guided focused ultrasound surgery. On pretreatment MR images, contrast enhancement on the T1-weighted images was observed, and no areas of increased signal intensity were noted on the DW images (b = 1000) (Fig 2); the ADC map had no signal intensity changes. After treatment, however, on the contrast-enhanced T1-weighted MR images, a marked decrease in contrast agent uptake within the treated region was observed, with increased signal intensity on DW images in the same regions that had corresponding decreased signal intensity on the ADC map; these findings were indicative of cytotoxic edema. At 6-month follow-up, the area of decreased contrast agent uptake persisted, as shown on the postcontrast T1-weighted MR images. The signal intensity on DW images appears heterogeneous within the treated region, and increased signal intensity is exhibited on the ADC map. Similar results are shown in Figure 3. There were no discernible signal intensity changes on the DW images before treatment; however, after treatment, hyperintense signal intensity was noted in the treated area on the DW images. These areas of signal intensity abnormality on the DW images were colocalized with the decreased signal intensity on postcontrast T1-weighted MR images. Thus, Figures 2 and 3 demonstrate the ability of DW imaging and ADC mapping to demarcate regional diffusion abnormalities over a temporal period. Moreover, one (6%) of 16 patients had an adverse effect of temporary leg paresthesia and a minimal abdominal skin burn caused by the focused ultrasound surgical treatment. The remaining patients experienced no adverse effects related to the focused ultrasound surgical treatment.



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  		Figure 2. Patient 5. Representative coronal postcontrast T1-weighted MR images (Contrast T1), DW images (DWI), T2-weighted MR images (T2WI), and ADC maps acquired in 48-year-old woman. Arrows show location of fibroid, and squares demonstrate the region of interest selected for quantification of ADC values. Row A, Enhancing fibroids were seen on baseline T1-weighted MR image (185/1.5) with no discernible signal changes on DW image (5000/90, b = 1000) or T2-weighted MR image (5000/90, b = 0). ADC map shows no discernible signal changes. Row B, After treatment, postcontrast T1-weighted MR image demonstrates area of hypointensity within the treated region, with increased signal intensity in the same regions on the DW image and corresponding decreased signal intensity on ADC map. Row C, At 6-month follow-up, a persistent area of hypointensity is noted in the area of treated fibroid as shown on the T1-weighted postcontrast image. The DW image signal intensity is heterogeneous with the treated region, and the central region shows increased signal intensity on the ADC map that is colocalized with the T1-weighted MR image.

 


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  		Figure 3. Patient 10. Representative coronal postcontrast T1-weighted MR images (Contrast T1), DW images (DWI), T2-weighted MR images (T2WI), and ADC maps acquired in 49-year-old woman. Arrows show the location of fibroid. Row A, On pretreatment MR images, there is contrast enhancement on the T1-weighted MR image (185/1.5) in the fibroid. DW imaging was not performed at this time. Row B, After treatment, postcontrast T1-weighted MR image shows decreased contrast agent uptake within the treated region. DW image (5000/90, b = 1000) demonstrates increased signal intensity in the same regions, with corresponding decreased signal intensity on ADC map. Row C, At 6-month follow-up, the decreased contrast agent uptake in the treated area has persisted, as shown on the T1-weighted postcontrast MR image with decreased signal intensity in the same region as that on the DW image. The ADC map is heterogeneous within the treated region, with increased signal intensity.

 
ADC Values at Baseline
The mean baseline ADC value in the fibroids was 1553 mm–6/sec2 ± 269 (n = 14), and that in patients (n = 12) with the full data set (T1- and T2-weighted images and DW images) over 6 months was 1504 mm–6/sec2 ± 290.

ADC Values after Treatment
Overall, the mean ADC value (1078 mm–6/sec2 ± 293) was significantly reduced in the treated fibroid (P = .001), compared with that in the nontreated fibroid (1685 mm–6/sec2 ± 468); the ADC ratio was 0.68. We, however, did not detect a significant difference between the mean baseline ADC value of the treated fibroid (1504 mm–6/sec2 ± 290) and that of the nontreated fibroid (1685 mm–6/sec2 ± 468) (P = .76).

ADC Values at 6-month Follow-up
Twelve patients returned at 6-month follow-up, with heterogeneous lesions that varied from isointense to hypointense on the DW images, as well as areas of hyperintensity on the ADC map. There was a significant difference (P < .001) in the treated fibroids between the mean posttreatment ADC value (1078 mm–6/sec2 ± 293) and the 6-month mean follow-up ADC value (1905 mm–6/sec2 ± 446), with a ratio of ADC values of 1.40 (range, 1.11–1.71). There was no difference, however, between the mean 6-month follow-up ADC value of nontreated tissue (1437 mm–6/sec2 ± 270) and the mean posttreatment ADC value of nontreated tissue (1685 mm–6/sec2 ± 468) (P = .46). Figure 4 summarizes the temporal evolution of the ADC values.



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  		Figure 4. Bar graph of ADC values within the fibroid at baseline, after treatment, and at 6-month follow-up (6mn) after MR image–guided focused ultrasound surgical treatment in all patients. ADC values for lesion after treatment are significantly (P < .001) lower than those at baseline or in nontreated uterine tissue and are increased at 6-month follow-up. ADC values at 6-month follow-up are significantly (P < .001) different from ADC values at baseline.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
We demonstrated that DW imaging and ADC mapping are feasible for identifying and monitoring ablated tissue in uterine fibroids after MR image–guided focused ultrasound surgical treatment. There was increased signal intensity on DW images within the area of ablated fibroid tissue, which was colocalized with the hypointense areas on the postcontrast T1-weighted MR images. In addition, the ADC value within this region was lower, on average, than that of the surrounding tissue, which indicates restricted water flow due to ischemia, cellular disruption that may evolve into infarction, and/or protein denaturation. Moreover, at 6-month follow-up, the average ADC value was increased within the ablated tissue, which presumably reflected cell loss and necrosis. The exact temporal evolution, however, of the ADC in uterine tissue is unknown at the present time and needs further elucidation. DW imaging has proved useful in defining ischemic tissue at early times after cerebral ischemia, with visualization of the acute changes in tissue water (ie, cytotoxic edema). It is believed that the ADC can be used to measure cytotoxic edema caused by swelling of cells (23), tortuosity of the path of diffusion (24), and structural dehydration of the fibers and is very sensitive to the acute changes in water in tissue (20). At later times, the barriers to restricted diffusion of water are removed by cell membrane breakdown, with concurrent changes in the water content within the intracellular and extracellular spaces. These changes can result in a corresponding increase in the ADC.

In this study, the general observation of an initial decrease and temporal increase in the ADC concurs with observations in previous reports about changes in brain tissue after a stroke that progressed to infarction (29–31). Specifically, after treatment, the ADC was decreased within the ablated tissue and was increased at 6-month follow-up. These changes in ADC, when taken together with the pseudonormalization from the initial to the final stages of MR image–guided focused ultrasound surgical treatment, may reflect a probable loss of membrane integrity and cell necrosis as the tissue undergoes transformation from a state of edema to infarction (29). The exact mechanism for the change of the ADC in tissue treated with MR image–guided focused ultrasound surgery is unknown at present, but this change may provide a measure by which to gauge the effectiveness of treatment. Results of this study demonstrate the potential use of DW imaging and ADC mapping for the identification of ablated tissue and the monitoring of treatment of uterine fibroids with MR image–guided focused ultrasound surgery.

There have not been any systematic studies of in vivo DW imaging and ADC characteristics of tissue after MR image–guided focused ultrasound surgical treatments of uterine tissue. Other reports about ex vivo tissue that was uniformly heated to mimic protein denaturation, however, demonstrated an increase in the ADC within the tissue (26,27). Investigators in other studies about focal tissue ablation with a laser in egg whites and muscle demonstrated that changes on the T2-weighted MR images of muscle indicated restricted water movement and that changes on those of egg whites indicated decreased ADC (27,32). Heat will change the motion of water and disrupt the bound and unbound proteins within the tissue; the amount of change is related to the tissue type and pattern of blood flow to the treated area and is unknown in relation to treated uterine tissue. Other MR imaging parameters, such as magnetization transfer, might provide insight about the suspected protein changes and provide data that are complementary to the data of the current study (27).

Clinical and experimental studies performed with histologic verification may provide insight for the previously noted claims about the changes in the ADC value. For example, Tempany et al (12) reported five cases that were successfully treated with focused ultrasound surgery in which subsequent uterine hysterectomy and histologic analysis were performed. These regions of treated fibroids revealed areas of necrosis. These clinical findings were consistent with results of animal experiments. Solomon et al (17) demonstrated histologic changes in the cytoskeletal components and vacuolization of the cells of rabbit muscle treated with focused ultrasound surgery at short- and long-term follow-up. These histologic changes are consistent with coagulative necrosis and provide indirect evidence for the changes seen on DW images and ADC maps. When all of the previously mentioned factors are considered together, the findings of this study support the hypothesis that a multiparametric approach by using DW imaging, ADC mapping, and conventional MR imaging can accurately be used to identify ablated uterine tissue after focused ultrasound surgical treatment. These findings also indicate the versatility of DW images and ADC maps in helping to define the state of the tissue treated with MR image–guided focused ultrasound surgery over a given time.

There are a number of potential advantages in regard to the use of DW imaging to monitor MR image–guided focused ultrasound surgical treatment. These advantages include the capability (a) to evaluate multiple treated lesions simultaneously after treatment; (b) to achieve a noninvasive method to gauge cellular activity; (c) to map the distribution of the ADC within the treated tissue, which may provide definition of lesion boundaries (which could be of value for further treatment planning and for follow-up); (d) to provide a faster imaging time by using DW imaging; and (e) to obviate contrast agent injection, since DW imaging is noninvasive, which decreases the chance of a possible systemic reaction to the contrast agent and may reduce costs.

There are, however, some technical limitations to the current study and to DW imaging of the uterus in general. First, there was no attempt to correlate the volume of tumor ablated with the volume of DW imaging or ADC volumes at postcontrast imaging; this study was undertaken to show the feasibility of the use of DW imaging in this setting. Second, motion artifacts can occur, but use of echo-planar DW imaging reduced these artifacts, and the examination was performed in patients who were lying prone and who were receiving conscious sedation. These factors allowed the examination to be completed in a reasonably short time with less breathing and abdominal motion, but they may be major limitations for the use of DW imaging. Third, the use of DW imaging and ADC mapping must be fully evaluated in a larger population of similar patients, and, if possible, with subsequent histologic evaluation, to fully understand the mechanisms involved in the focused ultrasound surgical treatment of fibroids. In this study, DW imaging was not used to alter treatment options but to demonstrate feasibility and the potential for identification of ablated tissue without the use of contrast agents.

In conclusion, we demonstrated that DW imaging and ADC mapping are feasible for identification of ablated uterine fibroids after MR image–guided focused ultrasound surgical treatment. DW images, coupled with ADC maps, have proved useful in the definition of ischemic tissue in acute cerebral ischemia. DW imaging is believed to measure cytotoxic edema and is very sensitive to acute changes in water in tissue. The time course of changes in the ADC in tissue treated with MR image–guided focused ultrasound surgery is unknown at present, but it may provide a measure by which to gauge the effectiveness of the treatment of affected tissue with MR image–guided focused ultrasound surgery.


   ACKNOWLEDGMENTS
 
We thank Diane Reyes, BS, for clinical support and Donald Peck, PhD, Hamid Soltanian-Zadeh, PhD, and Lucie Bower, BS, Henry Ford Hospital, Detroit, Mich, for the Eigentool image analysis software used for image processing.


   FOOTNOTES
 

Abbreviations: ADC = apparent diffusion coefficient • DW = diffusion weighted

See Materials and Methods for pertinent disclosures.

Author contributions: Guarantors of integrity of entire study, M.A.J., H.S.K.; study concepts, M.A.J., H.S.K.; study design, M.A.J., E.H.H., H.S.K.; literature research, M.A.J., H.S.K.; clinical studies, M.A.J., H.S.K.; data acquisition, M.A.J., H.S.K.; data analysis/interpretation, M.A.J., E.H.H., H.S.K.; statistical analysis, M.A.J., E.H.H., H.S.K.; manuscript preparation, editing, revision/review, and final version approval, M.A.J., E.H.H., H.S.K.; manuscript definition of intellectual content, M.A.J., H.S.K.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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