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Breast Imaging |
1 From the Department of Radiology, Hôpital Saint-Luc du Centre Hospitalier de l’Université de Montréal, 1058 St-Denis, Montreal, Quebec, Canada H2X 3J4. Received January 15, 2002; revision requested March 15; final revision received September 27; accepted October 21. Supported by a grant from InSightec-TxSonics, Dallas, Tex. Address correspondence to D.G. (e-mail: yvan.boulanger@umontreal.ca).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Before undergoing tumor resection, 12 patients with invasive breast carcinomas were treated with MR imaging–guided focused US ablation consisting of multiple sonications of targeted points that were monitored with temperature-sensitive MR imaging. The patients were treated with either one of two focused US systems. The effectiveness of the treatment was determined at histopathologic analysis of the resected mass that was performed to determine the volumes of necrosed and residual tumor. Complications resulting from the procedure were assessed by means of questionnaires, medical examinations, and MR image analysis.
RESULTS: US ablation was well tolerated by the patients, and with the exception of minor skin burns in two patients, no complications occurred. Histopathologic analysis of resected tumor sections enabled quantification of the amount of necrosed and residual tumor and visualization of the surrounding hemorrhage. In three patients treated with one of the US systems, a mean of 46.7% of the tumor was within the targeted zone and a mean of 43.3% of the cancer tissue was necrosed. In nine patients treated with the other US system, a mean of 95.6% of the tumor was within the targeted zone and a mean of 88.3% of the cancer tissue was necrosed. Residual tumor was identified predominantly at the periphery of the tumor mass; this indicated the need to increase the total targeted area (ie, with an increased number of sonications).
CONCLUSION: Thermal coagulation of small breast tumors by means of MR imaging–guided focused US appears to be a promising noninvasive ablation procedure.
© RSNA, 2003
Index terms: Breast neoplasms, MR, 00.121411, 00.121412, 00.121416, 00.12143 • Breast neoplasms, therapeutic ultrasound, 00.32, 00.459 • Breast neoplasms, US, 00.12981, 00.12986, 00.12989 • Magnetic resonance (MR), guidance, 00.1214 • Magnetic resonance (MR), temperature monitoring, 00.121411, 00.121412, 00.121416, 00.12143 • Ultrasound (US), therapeutic, 00.12981, 00.12986, 00.12989
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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One of the most attractive methods of destroying tissue noninvasively is the use of focused ultrasound beams that are generated by a piezoelectric transducer. Ultrasound beams penetrate soft tissue and can be focused on tissue volumes with dimensions of a few cubic millimeters. The absorbed energy leads to tissue temperature elevations with such high thermal gradients that the boundaries of the treated volume are sharply demarcated without damage to the surrounding tissue (6). The tissue in the treated volume may reach temperatures on the order of 55°C to 90°C in a few seconds; these temperatures lead to protein denaturation and tissue necrosis (6,7).
High-intensity focused US ablation was proposed as a treatment for soft tissue masses deep in the body almost 4 decades ago (8). Investigations of the applications of focused US for the destruction of cancer tissue in the central nervous system, prostate, kidney, bladder, and eye have been reported (9–13). However, the inherent inhomogeneity of human anatomy—for example, the variability in skin thickness and in characteristics of fat and muscle—and the effect that this inhomogeneity has on the scattering, absorption, and reflection of energy make a priori predictions impossible. Therefore, the development of focused US ablation as a method of destroying cancer cells has been hampered by the inability to accurately predict the shape, size, US energy intensity, and location of the focal treatment point.
In recent years, there has been renewed interest in focused US ablation as a result of its association with an accurate noninvasive imaging method, magnetic resonance (MR) imaging. MR imaging yields good anatomic resolution, has high sensitivity in the detection of tumors, and enables one to monitor in real time the US ablation procedure and its outcome (14,15). MR imaging–guided focused US ablation usually involves the use of gradient-echo MR imaging techniques for temperature monitoring based on the temperature sensitivity of the proton chemical shift (16). In addition, the occlusion of the microvasculature in sonicated tissue can be detected by evaluating the concentration of the intravenously administered contrast agent (17). Hence, combining focused US as a noninvasive thermal therapy with MR imaging as a means of planning, guiding, and controlling the US therapy yields a real-time, imaging-controlled noninvasive soft tissue coagulation system that may be useful for a wide range of applications in the body.
Breast tumors are especially suitable for treatment with focused US owing to their peripheral body location, which allows easier treatment targeting and limits the risk of damage to the surrounding tissues. In a relatively recent study (18), MR imaging–guided focused US ablation was used to thermally treat benign breast fibroadenomas in 11 patients, and the posttherapy MR images demonstrated partial or complete tumor ablation in eight of these patients. Therefore, the results of that study demonstrated the feasibility of MR imaging–guided focused US ablation for treatment of benign breast lesions. The purpose of our study was to evaluate the effectiveness of MR imaging–guided focused US ablation in the treatment of breast carcinomas.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Equipment
All MR images were acquired with a 1.5-T MR imaging unit (Signa; GE Medical Systems, Milwaukee Wis) by using a breast or surface coil that was especially designed for the described treatments. Focused US ablation was performed with a special US treatment table (ExAblate 2000; InSightec-TxSonics, Haifa, Israel and Dallas, Tex) inserted into the MR imaging unit. The complete system is divided into four interconnected modules: the MR imaging unit, the focused US table, the control personal computer, and the focused US workstation and console.
The focused US table is a regular MR imaging table that is modified to contain a transducer that is mounted on a mechanical positioning arm and immersed in a water bath (Fig 1). The acoustic ultrasound beam generated by the transducer can focus on a point that is up to 20 cm inside the body. The front-end electronic components consist of a digital beam former, power amplifiers, and extensive safety monitoring circuits that are used in real time during sonication to monitor the status of the system. The control personal computer communicates with the beam former, the transducer positioner, the safety circuits, and the system power supplies. The focused US workstation consists of a personal computer that communicates with the MR imaging console computer and the control personal computer. Hence, the operator controls the integrated MR imaging–guided focused US ablation procedure from the focused US workstation.
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MR Imaging–guided Focused US Ablation Protocol
Pretreatment MR imaging.—Seven to 21 days before the tumors were treated with MR imaging–guided focused US ablation, two authors (D.G., A.B.) in consensus performed MR imaging of the breast in three planes (ie, sagittal, coronal, and transverse) with the patient in the prone position to locate and measure the lesion. The MR imaging protocol consisted of acquiring localizer images in the sagittal, coronal, and transverse planes and then acquiring sets of T1-weighted spin-echo (600/10 [repetition time msec/echo time msec], 512 x 192 matrix) and T2-weighted fast spin-echo (4,000/100, echo train length of 14, 384 x 224 matrix) images in the sagittal and transverse planes. Following the acquisition of the localizer and T1- and T2-weighted MR images, dynamic MR images enhanced with an intravenous administration of 0.1 mmol of gadopentetate dimeglumine (Magnevist; Berlex Canada, Lachine, Canada) per kilogram of body weight with a 15-mL saline flush, and fast spoiled gradient-echo MR images (6.4/2.4, 22-msec preparation time, 10° flip angle, 4-mm section thickness, no intersection gap, 256 x 128 matrix, 32 measurements, acquisition time of 6.5 minutes) were obtained. Next, T1-weighted spin-echo MR images (600/10, 512 x 192 matrix, fat saturation) were obtained in the sagittal and transverse planes.
MR imaging–guided focused US ablation.—First, the patient was placed in a prone position on the treatment table and the targeted breast was placed in the center of a ring-shaped MR surface coil (Fig 1). To enhance acoustic coupling, degassed water was placed between the breast and the ultrasound transducer. For patients 9–12, the breast was placed in a gel-filled container to improve acoustic coupling and to avoid focused US refraction (Fig 1). Before beginning the sonications and as needed during the treatment, the patients were given analgesic (fentanyl citrate, 50 µg per dose, one to four doses; Faulding Canada, Dorval, Canada) and sedative (midazolam, 1 mg per dose, two to four doses; Sabex, Boucherville, Canada) agents intravenously to reduce or alleviate pain, unnecessary motion, anxiety, and claustrophobia. The number of analgesic and sedative agent doses was determined by the radiologist (D.G.) on the basis of his assessment of the patient’s need (20–22). During the entire course of the treatment, the patient’s blood pressure, heart rate, and partial pressure of oxygen were monitored by using standard MR imaging–compatible devices.
To design a treatment plan, we first acquired a series of T1-weighted spin-echo MR images (600/10, 512 x 192 matrix) in the sagittal, transverse, and coronal planes. These images were then transferred to the focused US workstation. The radiologist (D.G.) manually drew an outline of the targeted lesion, including approximately 5 mm of surrounding tissue, by using the software utilities on the focused US workstation. Gadopentetate dimeglumine–enhanced MR images and mammograms that had been acquired before the US ablation were used to determine the exact location of the tumor.
MR imaging–guided focused US ablation was performed by a research assistant (M.A.). The center of the lesion was sonicated with a noneffective dose (2–60 W) of US energy to test the accuracy of lesion targeting in the patient. Subsequently, sonication at therapeutic power levels (up to 400 W) was successively performed on multiple overlapping tissue points until ablation of the targeted volume was completed (Fig 2). Each focused US treatment point was verified by using MR imaging phase maps that depicted temperature-dependent changes in resonance frequency (Fig 2). The fast spoiled gradient-echo MR imaging sequence was used with the following typical parameters: 36/8.4, 45° flip angle, 31-kHz bandwidth, 256 x 128 digital resolution, 20 x 20-cm2 field of view, and 3-mm section thickness. The parameters used to treat the breast lesions by means of MR imaging–guided focused US ablation in each patient are presented in Table 2. The number of sonications varied between 12 and 52 and resulted in a total treatment duration of 35–133 minutes.
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After completion of the focused US ablation and MR imaging procedures, another research assistant (A.B.) asked each patient to assess the level of pain and discomfort associated with the procedure by choosing one of four possibilities: no pain, slight pain, moderate pain, or intense pain. The patients were also asked if they felt tenderness in the treated zone and to grade the level of tenderness as mild, moderate, or severe. One of two authors (D.G. or A.B.) also examined the patients for possible short-term complications such as fever, skin burns, blisters, or skin ulcerations. When skin burns occurred, the degree (D.G.) and dimension (A.B.) of the burns were measured and they were treated with silver-sulphadiazine cream (Flamazine cream; Smith & Nephew, Lachine, Canada).
Posttreatment examination.—The patients underwent clinical and MR imaging follow-up examinations 3–14 days after the MR imaging–guided focused US ablation procedures and 0–10 days before resection surgery. At follow-up, a research assistant (A.B.) asked the patients if they had experienced any long-term complications such as chronic pain. MR imaging data acquired with the same conditions as in the pre–MR imaging–guided focused US ablation examinations were recorded to assess the possibility of nerve injury and/or damage to a small volume of normal tissue. In the cases of skin burn, the breast was examined by the radiologist (D.G.).
Resection Surgery
Patients underwent routine segmental tumor resection, which included resection of wide margins around the treated area. The surgeon used mammograms to localize the tumors and wire localization in those cases in which the tumor was not palpable. After tumor resection, routine patient care was rendered according to standard practice guidelines for the treatment of patients with breast cancer.
Histopathologic Evaluation
For evaluation of the effectiveness of the US treatment, complete mapping of the cancer and treated lesions was performed by using three-dimensional macroscopic and microscopic histopathologic measurements. The resected tumor specimens were analyzed immediately after surgery by a pathologist. The specimens were cut into 5-mm slices in the anteroposterior plane beginning from the lateral side. All six surgical margins (ie, medial, lateral, superior, inferior, anterior, and posterior) were stained with inks of different colors, and all slices were photographed. The stained tissue was then submerged in 10% buffered formalin for 24 hours. The tissue was then cut into 5-µm sections, and these preparations were stained with hematoxylin-eosin and enclosed in permanent histologic glass cover slips.
Before focused US treatment, carcinoma cells are identifiable by their cuboid shape, granular and vacuolated lavender-pink cytoplasm, and darkly stained nuclei (23). Coagulated necrotic tissue is evident from the shrinkage of some nuclei, the diffuse granular and foamy cytoplasmic degeneration, and the presence of larger cytoplasmic nuclei. Hemorrhage has a bright red color. Histopathologic evaluation of the microscopic specimens enabled us to determine the total tumor volume, the volume of tumor in the treated zone, and the volume of necrosed tumor. One of the authors (A.B.) determined these volumes (V) by measuring the largest tumor dimensions in each axis (ie, distances a, b, and c) and performing an ellipsoid volume calculation: V = 
/(6abc).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Following surgery, the excised mass was examined at macroscopic and microscopic histopathologic analyses. The macroscopic sections of the excised mass in Figure 3 show the presence of central necrosed tissue (yellow-white area) surrounded by hemorrhagic tissue (red area). Microscopic breast carcinoma specimens obtained from patient 10 3 days after MR imaging–guided focused US ablation are shown in Figure 4. The effects of necrosis and hemorrhage are apparent. Because the biopsy site overlapped with the treatment site, the changes seen in Figure 4, D, represent postbiopsy necrosis, inflammation, regeneration, and focused US treatment effects.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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During focused US ablation, the detection of temperature changes is also important, and focused US with MR imaging guidance enables rapid evaluation of dosimetric parameters. This application of MR imaging integrates physical temperature monitoring and biologic heat effects on the basis of biologic modeling, as elaborated by Sapareto and Dewey (7). Thus, the necrosed tumor volume can be predicted with this model. Therefore, the combination of MR imaging and focused US integrates, in our opinion, the best available localization and targeting methods and enables real-time planning of the treatment, volumetric control of the delivered thermal dose, and detection of the resulting tissue alterations.
The duration of the MR imaging–guided focused US ablation ranged from 35 to 133 minutes. The duration depends on the number of sonication points, the sonication time, and the cooling time. The number of sonication points varies with the size of the tumor and the focal point volume. In the patients in this study, the tumor volumes varied by a factor of 80 and the focal point volumes varied by a factor of 1.85. The number of sonication points ranged from 12 to 52—that is, they varied by a factor of 4.3. The margins (approximately 5 mm) around the tumor that were treated tended to reduce the differences in treated volume between the small and large tumors. Although the sonication times were relatively consistent, the cooling times varied and contributed substantially to the total duration of treatment. For the last six patients, cooling times were set at 90 seconds to lower the risk of burns. The treatment durations were well tolerated by the patients.
Patient comfort was well maintained during the entire US ablation procedure. Pain and anxiety were reduced or alleviated by the administration of analgesic and sedative agents. None of the 12 patients had substantial problems controlling motion. The patients judged their discomfort to be slight in four cases and moderate in eight cases. The length of the procedure is a major factor that might contribute to patient discomfort and ideally should be kept to less than 90 minutes. As US ablation technology improves, this duration should be possible in most cases.
The histopathologic results showed that in the cases of remaining clusters of viable cancer that were not due to poor targeting, the residual tumor was mainly at the periphery of the treatment field. The definition of the outer limits of cancer zones depends on the density of cancer cells in the voxels, and, hence, signal intensity gradually decreases on the MR image as the tissue transition from 100% cancer cells to 100% normal cells occurs. When patients are treated surgically by means of wide local excision, ideally the lesion along with a margin of more than 10 mm of macroscopically normal boundary breast tissue should be resected to ensure that any microscopic cancerous tissue is removed. Similarly, our study results indicate that treating the cancerous mass plus a 10-mm layer of boundary tissue (instead of approximately a 5-mm layer, as was treated in this study) is necessary to ensure total thermal coagulation of the cancer zone, including the clusters at the periphery. This can be accomplished by using more focal points or by increasing the level of energy delivered to each point while keeping the interpulse delays long enough to avoid skin burning.
The noninvasive treatment of small breast carcinomas with MR imaging–guided focused US ablation should have advantages over conventional surgery (ie, lumpectomy). This treatment method allows one to preserve the integrity of the breast, is infection free, and does not necessitate a substantially long recovery period. An economic benefit might also result from the shorter hospital stays and recovery times. Compared with other thermal ablation techniques that are being developed, MR imaging–guided focused US ablation has several advantages: First, it is nonincisional and noninvasive. Unlike interstitial laser therapy and radio-frequency ablation (2,5), focused US ablation does not involve the insertion of a probe, and, therefore, no skin incision has to be made. Moreover, in contrast to interstitial therapy, in which the position of the probe is fixed, the focal point is changeable in focused US therapy, and thus, there is high flexibility in controlling the size and shape of the treatment zone to correctly match the targeted volume. It is also advantageous that focused US sonication is achieved in a few seconds, resulting in local temperature elevations that are independent of the perfusion rate and therefore reproducible from location to location.
In addition, the volume to which the energy is delivered is small, but the thermal gradient is minimal. This results in more homogeneous treatment zones. With interstitial therapy systems, most of the energy is delivered around the tip of the probes. Thus, these systems rely on thermal diffusion to spread the energy to a larger volume and require longer ultrasound beam exposure times—typically several minutes. In addition, interstitial therapy techniques yield a substantial thermal gradient, which results in an inhomogeneous treatment zone. Compared with radiosurgery, focused US therapy has the advantage of being repeatable if the ablation is unsuccessful or partially successful.
The histopathologic results for 12 patients with breast cancer who were treated with MR imaging–guided focused US ablation indicate that this treatment method is very safe and becoming increasingly effective. This noninvasive and easily tolerated therapy—used alone or in combination with other treatments—has the potential to become an important procedure for the treatment of malignant breast tumors. The results presented herein are based on histopathologic data because conventional surgery also was performed. However, for this method to be clinically relevant, it will have to rely on reliable noninvasive MR imaging data.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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