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DOI: 10.1148/radiol.2333031734
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(Radiology 2004;233:857-867.)
© RSNA, 2004

Breast Imaging

Small (<2.0-cm) Breast Cancers: Mammographic and US Findings at US-guided Cryoablation—Initial Experience1

Marilyn A. Roubidoux, MD, Michael S. Sabel, MD, Janet E. Bailey, MD, Celina G. Kleer, MD, Katherine A. Klein, MD and Mark A. Helvie, MD

1 From the Departments of Radiology (M.A.R., J.E.B., K.A.K., M.A.H.), Surgery (M.S.S.), and Pathology (C.G.K.), University of Michigan Comprehensive Cancer Center, 1500 E Medical Center Dr, Room 2910H, Ann Arbor, MI 48109-0326. From the 2003 RSNA scientific assembly. Received October 29, 2003; revision requested January 16, 2004; revision received March 23; accepted April 1. Address correspondence to M.A.R.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To determine the mammographic and ultrasonographic (US) findings at cryoablation of small solitary invasive breast cancers and compare them with presence of residual malignancy after treatment.

MATERIALS AND METHODS: Institutional review board approval and informed patient consent were obtained. Nine patients with small solitary invasive breast cancers diagnosed at core biopsy were treated with US-guided cryoablation and a 2.7-mm cryoprobe. Mean cancer size was 12 mm (range, 8–18 mm); four were palpable. Tabletop argon gas–based cryoablation system with a double–freeze-thaw protocol was used to treat cancers in outpatient setting. Tumor sites were excised at lumpectomy 2–3 weeks after cryoablation. Findings at mammography and US before, during, and after cryoablation were assessed to categorize densities and masses on mammograms and masses on US images with Breast Imaging Reporting and Data System (BI-RADS); maximum cancer size was measured. Imaging findings and clinical breast examination data were compared with histologic findings from lumpectomy specimens to determine presence of intraductal or invasive cancer.

RESULTS: With US guidance, ice balls (maximal mean size, 4.4 cm) were formed around cancers. Before excision, eight patients underwent mammography; all had new focal densities (maximum size, 2.5–5.0 cm) at cancer sites. Six patients underwent preexcisional US; 100% of them had new hyperechogenicity in tissue surrounding cancer site. Seven (78%) of nine patients had no residual cancer; specimens contained fat necrosis. One patient had a small focus of invasive cancer; one had extensive multifocal ductal carcinoma in situ. Patients with BI-RADS category 1 or 2 densities on mammograms or nonpalpable tumors had no residual malignancy. No residual invasive cancer occurred in tumors 17 mm or smaller or in cancers without spiculated margins at US.

CONCLUSION: After cryoablation, there was increased echogenicity at US and increased density at mammography; these findings were observed in areas that approximated location and size of the ice ball. Tumor size, mammographic density, and US characteristics may be indicators of likelihood of complete cryoablation.

© RSNA, 2004

Index terms: Breast neoplasms, therapy, 00.40 • Cryotherapy, 00.40 • Ultrasound (US), guidance, 00.12985


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Breast cancer is the most common malignant tumor in women, and it was estimated that there would be more than 215 000 new cases in 2004 (1). The increased use of breast cancer screening has resulted in more patients with smaller tumors being examined at presentation (2), with the mean size of tumors found in mammographic screening programs being only 15 mm (3). Along with this shift, the diagnosis and treatment of breast cancer have changed rapidly in the past 2 decades, with less invasive procedures replacing more extensive procedures (4,5). Percutaneous core-needle biopsy has replaced open surgical biopsy in a large proportion of cases. Lumpectomy with radiation therapy (breast conservation therapy) has obviated mastectomy in a majority of women (4,5). Complete axillary lymph node dissection is becoming less common because of sentinel lymph node mapping. These changes have resulted in more favorable cosmetic and functional outcomes, and these outcomes help enhance the patient’s body image, quality of life, and satisfaction with treatment.

The patient’s concern about the effect of breast carcinoma treatment on appearance is important (6). A lumpectomy, while a tremendous improvement over mastectomy, is still an invasive procedure, with potentially undesirable cosmetic results. For this reason, there has been significant interest in less invasive percutaneous ablation. Potential advantages would include better cosmetic results; fewer complications; and a decrease in operating room and anesthesia needs, recovery time, and health care costs. Such procedures would also be useful for those patients who have small tumors but are not candidates for surgery or pharmacologic therapy. Several methods are presently being investigated for the nonsurgical ablation of breast cancer, and these methods include radiofrequency ablation (5,7–9), cryosurgery (10,11), laser interstitial therapy (12–19), high-intensity focused ultrasound surgery (20–28), and focused microwave thermotherapy (29–32). We are investigating the possible advantages of cryoablation of breast cancer. Thus, the purpose of this study was to determine the mammographic and ultrasonographic (US) findings at cryoablation of small (<2.0-cm) solitary invasive breast cancers and to compare them with the presence of residual malignancy after treatment.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patients
Our patient group represents the nine patients we contributed to a prospective multi-institutional trial to evaluate the effectiveness of a commercially available cryoablation system in the treatment of small invasive breast malignancies (33). Institutional review board approval and informed patient consent were obtained. Women with solitary lesions of 1.8 cm or smaller that were visible at US were eligible. Those with core-needle biopsy results that suggested lobular carcinoma or abundant ductal carcinoma in situ (DCIS) were excluded, as were those who had undergone open surgical biopsy. Between August 2002 and February 2003, nine women were recruited into the study. Mean age was 58 years (range, 49–75 years). All cancer sites were verified to be visible at US, and tumors were fully characterized for histologic parameters and receptor studies with core-needle biopsy prior to cryoablation. At initial core-needle biopsy, seven patients had invasive ductal carcinoma, one had invasive colloid carcinoma, and one had invasive ductal carcinoma with DCIS.

Cryoablation Procedures
All procedures were performed on an outpatient basis in the Breast Imaging Department in our room for US-guided core-needle breast biopsy. A commercial unit (Logic 700; GE Medical Systems, Milwaukee, Wis) with a linear array transducer (M12; GE Medical Sytstems) was used. Three experienced breast imaging radiologists (M.A.R. [14 years], J.E.B. [5 years], K.A.K. [4 years]) performed the procedures. Patients were placed in the supine position, with the ipsilateral arm placed either above the head or in a position appropriate for the procedure, as is done for US-guided core-needle breast biopsy. A tabletop argon gas–based cryoablation system (Visica; Sanarus Medical, Pleasanton, Calif), which was designed to create probe temperatures of –160°C, was used to treat all tumors in an outpatient setting. This cryoablation system had previously been approved for the treatment of breast fibroadenomas (34).

The mass was identified by using US, and the most convenient access to the mass was determined in the same way that is typically used for US-guided core-needle breast biopsy. Less than 1 mL of 2% lidocaine was injected into the skin at the planned insertion site, and afterward a small incision was made in the skin by using a scalpel. This procedure is identical to that used for US-guided core-needle biopsy in our department. For local anesthesia, 2–5 mL of 1% lidocaine was injected into the deeper tissues proximal to the mass along the expected course of the cryoprobe. Thereafter, the cryoprobe (CRYOprobe) was percutaneously inserted through the skin opening, with US guidance, into the center of the mass, and the tip was advanced 1.0–1.5 cm beyond the distal edge of the tumor (Fig 1). The cryoprobe was a 2.7-mm-diameter vacuum-insulated trocar-tipped instrument, which allowed cooling to occur only at its distal 4 cm. Central placement within the tumor was confirmed in two orthogonal planes (parallel to and perpendicular to the axis of the probe) by using US to ensure symmetric placement of the probe prior to activation of the cryoablation system. In cases in which masses were asymmetrically larger in one plane, the planned trajectory was oriented such that the longitudinal axis of the probe would be in the same plane as the longest dimension of the mass. This was done because the ice ball forms more like an oval than a ball; that is, it is longer in the longitudinal plane along the length of the probe. The goal was to create an ice ball to rapidly engulf a tumor plus a circumferential margin of normal tissue.



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  		Figure 1a. Longitudinal US images relative to transducer show placement of cryoprobe in tumor (arrows). (a) Invasive cancer. (b) Cryoprobe placed through tumor with US guidance. Procedure is similar to US-guided core-needle biopsy. Tip (arrowhead) of probe was advanced 1.0-1.5 cm beyond distal aspect of tumor and allowed ice ball to engulf entire tumor.

 


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  		Figure 1b. Longitudinal US images relative to transducer show placement of cryoprobe in tumor (arrows). (a) Invasive cancer. (b) Cryoprobe placed through tumor with US guidance. Procedure is similar to US-guided core-needle biopsy. Tip (arrowhead) of probe was advanced 1.0-1.5 cm beyond distal aspect of tumor and allowed ice ball to engulf entire tumor.

 
The cryoablation procedure consisted of a double–freeze-thaw protocol. Cell destruction is caused by not only the freezing of the cell but also the thawing of the cell (35). A double–freeze-thaw cycle has been reported to increase the extent of cell damage and to ensure complete cell destruction at final freezing temperatures (35). As determined from data in previous studies performed by the manufacturer about treatment of fibroadenomas and cancers, the freezing time was based on the maximum tumor diameter as assessed with US to avoid excessive freezing of uninvolved tissue around smaller lesions (34). Each freezing cycle was split between a high-freeze and a low-freeze period; the time for each period was determined by using a maximum tumor size according to a protocol established by the manufacturer in previous studies. The high-freeze period was 1.5–5.0 times longer than was the low-freeze period, depending on maximum tumor size, with longer durations for larger cancers. The low-freeze period varied from 2 to 4 minutes, and the high-freeze period varied from 6 to 10 minutes. When freezing begins, the cancer is quickly obscured by the shadowing that grows around the probe. During the high-freeze period, the system operates at a 100% duty cycle (argon flows continuously), while during the low-freeze period, it operates at a 10% duty cycle (argon gas flows for 1 second and is off for 9 seconds of every 10-second period). This 10% duty cycle maintains cold temperatures within the ice ball while it slows the overall growth of the ice ball. At formation of the second ice ball, the goal was for the ice ball to encompass the tumor plus an approximately 8–10-mm margin. The diameter of the ice ball in the longitudinal and transverse planes was measured during each freeze-and-thaw cycle to ensure appropriate width and length so that the ice ball encompassed the cancer with an additional margin of 8–10 mm. The time parameters set for the freeze-and-thaw cycles allowed a predictable steady growth in the ice ball length and width over time so that the ice ball sizes were appropriate for the cancer size within the time parameters set for the freeze-and-thaw cycles. A passive thaw that lasted 10–12 minutes (depending on the cycle used) was interposed between the two freezing cycles, and an active thaw with helium gas was performed after the second freezing cycle, which thereby facilitated probe removal. The total time involved in the freezing and thawing aspects of the procedure was 32–40 minutes. During cryoablation, multiple static US images were obtained to document the tumor size and location before probe placement, the probe placement within the tumor, and the maximum length and width of the ice ball. Color Doppler flow imaging was performed in three patients during cryoablation to observe whether blood flow could be seen in the tissue surrounding the ice ball.

To protect the skin from injury during the procedure, approximately 5–15 mL of sterile saline was injected subcutaneously through a 20-gauge needle whenever the anterior surface of the ice ball was seen to approach within 5 mm of the skin surface at US, and these injections were repeated as necessary. Approximately three to five injections were needed in each case. The saline increases the distance from the ice ball to the skin; thus, the skin is protected from frostbite. After the probe was withdrawn, pressure was maintained on the breast for approximately 20 minutes, and a pressure dressing was applied to decrease the risk of hematoma formation. Patients were assessed prior to discharge for any evidence of skin injury.

Surgery and Histologic Evaluation
Between 14 and 23 days after the cryoablation procedure, the tumor sites in eight of nine patients were excised by using conventional lumpectomy with wire localization guidance, and in one patient, lumpectomy was performed with palpation. Eight patients underwent mammography at the time of wire localization–guided biopsy, and six underwent breast US. Surgical excision was performed by four breast surgeons (including M.S.S.), who had 3–20 years of experience with lumpectomy. A minimum of 7 days of delay between cryoablation and lumpectomy is required to enable routine (hematoxylin-eosin) staining to confirm tumor death, because immediately after cryosurgery, the histologic demarcation of fatally injured cells from normal cells is not possible. Histologic evaluation was performed on a routine basis at our institution by our breast pathologist (C.G.K.), who had knowledge that cryoablation had been performed. This pathologist evaluated these lumpectomy specimens for the presence of invasive or intraductal carcinoma, tumor necrosis, fat necrosis, coagulation necrosis, collagen, and normal structures. The breast pathologist had 5 years of experience in histologic evaluation of breast disease and was fellowship trained in surgical pathology.

Follow-up and Imaging
Patients were evaluated by a breast surgeon to determine cosmetic results and adverse events, which included pain, fever, infection, tenderness and/or firmness of the cryoablation site, and damage to the skin and surrounding tissues. Patients were surveyed for pain during and after the procedure and were evaluated for immediate complications by a breast surgeon (M.S.S.) or the Breast Care Center nurse after the cryoprobe was withdrawn and until discharge from the department, which was approximately 45 minutes afterward. No patient reported any pain associated with the freezing cycles during ice ball formation. Discomfort was minimal after the procedure. Patients were again evaluated clinically prior to lumpectomy.

Three patients had been referred to our Breast Care Center after a core-needle biopsy was performed at an outside institution. At our institution, cancer was detected at core-needle biopsy in six patients. Information about the core-needle biopsy procedures was obtained from the procedure reports and the images by one radiologist (K.A.K.). Before cryoablation, all patients underwent mammography and breast US of the tumor and/or tumor core-needle biopsy site. Findings at imaging performed before, during, and after cryoablation were retrospectively reviewed in consensus by two Mammography Quality Standards Act of 1992–certified radiologists (M.A.R., J.E.B.) who specialized in breast imaging at our institution and had a mean of 9 years of experience in breast imaging (M.A.R., 14 years; J.E.B., 5 years). Screen-film and/or digital mammograms were obtained at our institution with commercially available equipment (DMR Digital; GE Medical Systems). At our institution, US images were obtained with the same unit and transducer as mentioned previously or with a different unit (ATL; Philips Medical Systems, Andover, Mass). Three patients underwent prebiopsy mammography at other institutions prior to undergoing core-needle biopsy, and findings of mammography performed at outside institutions were reviewed. In nine patients, we reviewed findings from a total of 29 (15 US, 14 mammographic) sets of imaging studies performed before cryoablation, nine sets of US studies performed during cryoablation, eight mammographic and six US studies performed after cryoablation (immediately before lumpectomy), and eight mammographic and three US studies of specimens performed after lumpectomy.

All images and imaging reports in a given patient were reviewed at the same time. Images were not randomized for review, and the reviewers were not blinded to information because they were personally involved in one or more aspects of the imaging, diagnosis, or procedures in the cases. The masses were categorized according to American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) lexicons for masses observed at mammography and at US by using the BI-RADS descriptors in the clinical mammography and US reports for the 29 precryoablation and 14 postcryoablation imaging studies (36). These studies originally were performed by eight Mammography Quality Standards Act of 1992–certified radiologists who specialized in breast imaging.

Precryoablation Imaging Studies
Information about the mammographic density classified according to the BI-RADS lexicon, the cancer location categorized according to quadrant, and the palpability of the cancer was obtained from the precryoablation mammography reports. Maximum cancer size was obtained from the precryoablation US measurements in the report or from measurements made on the US images. In cases in which the imaging findings were incompletely described in the clinical report, readers (J.E.B., M.A.R.) assigned BI-RADS terms in consensus. Distances from the skin surface and the chest wall margin to the mass were measured on the US images by one reader (M.A.R.).

Postcryoablation Imaging Studies
The clinical reports of the imaging studies performed after cryoablation were for the wire localization procedures and did not contain descriptors of the cancers. Findings of these studies were reviewed, and the mammographic and US findings were assessed by two readers (J.E.B., M.A.R.) in consensus. We also evaluated whether the cancers were visible at mammography and US (M.A.R., J.E.B.) after cryoablation. The eight mammographic images and three US images of the specimens were evaluated by only one reader (M.A.R.) in regard to whether a mass was identifiable in the specimen.

The features of masses at mammography were categorized as follows: shape (round, oval, lobular, irregular, or architectural distortion), margins (circumscribed, microlobulated, obscured, indistinct, or spiculated), focal density or developing density, and microcalcifications (distribution and morphology). Features of masses at US were categorized as follows: shape (oval, round, or irregular), margins (circumscribed, indistinct, angular, microlobulated, or spiculated), echo pattern (complex, hypoechoic, or isoechoic), and posterior acoustic features (enhancement, shadowing, no posterior features, or combined pattern) (36).

Imaging at Cryoablation
Findings in the nine US studies performed at the time of cryoablation were reviewed by the readers (J.E.B., M.A.R.). From images obtained at these studies, the maximum sizes of the ice balls in two dimensions and their measurements on the images were recorded. Three patients underwent color Doppler flow imaging after the ice ball had formed to observe vascularity in the tissue around the ice ball, and these images were saved as AVI files. These AVI files were evaluated by the two readers in consensus for the presence of a twinkling artifact or other vascularity. The clinical history of whether or not the cancer was palpable was determined from the mammography records. The mammographic and US features before cryoablation, as described according to the BI-RADS lexicon and classifiers that included mammographic density, maximum cancer size, palpability of the cancer, and location in the breast, were compared with the presence of residual invasive or intraductal tumor at final excisional histologic evaluation after cryoablation by the two readers.

After surgery, patients were treated according to the standard of care for their cancer type, stage, and grade. Cancer size was determined from size on images, since it was expected that the cancers would be ablated and would not be detectable or measurable at excision. Biopsy of sentinel lymph nodes was performed at the time of excision.

Data Analysis
The data were entered into a spreadsheet (Excel; Microsoft, Redmond, Wash) to facilitate analysis of the comparisons described previously. The primary effectiveness rate is defined as the percentage of tumors that were successfully eradicated after the initial procedure or a defined course of treatment (37). This rate was calculated by dividing the number of cancers for which no invasive or intraductal cancer was found in the excised lumpectomy specimen by the total number of cancers that were treated with cryoablation. No statistical analyses were performed because of the small number of patients.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Clinical Data
All nine patients completed the cryoablation protocol according to the methods described. Maximum cancer size at US or mammography before core-needle biopsy was 8–18 mm (mean, 12 mm). No procedure was prematurely terminated because of patient discomfort or patient request, and no patient needed any conscious sedation or postprocedural narcotic pain medications. There were no major or minor complications, which included immediate or periprocedural (within the time period up to extirpative surgery) complications.

Prior to cryoablation, the mean distance from the most superficial margin (relative to the transducer and the skin) of the tumor or the biopsy site to the skin surface, as measured at US, was 9 mm (range, 5–12 mm); that is, the surface of some tumors was only 5 mm deep from the skin surface. The mean distance between the posterior margin of the tumor and the anterior side of the chest wall (ie, pectoralis muscle) was 8 mm (range, 0–18 mm); that is, at the time of US, some tumors appeared to be immediately adjacent to the pectoralis muscle. Despite the close margins of some tumors to either the skin or the chest wall, no complications occurred. There was no skin injury to suggest thermal injury, and there were no large hematomas or delayed occurrences of them.

The results are summarized in Tables 1 and 2, and they include precryoablation clinical patient data, maximum tumor size, core-needle biopsy data, mammographic and US findings and before and after cryoablation, and histologic data. The patients are listed in chronologic order (ie, patient 1 was the first one to undergo cryoablation and patient 9 was the last).


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  		TABLE 1. Clinical Data and Tumor Characteristics

 

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  		TABLE 2. Imaging Findings at Cancer Site before and after Cryoablation

 
Precryoablation Imaging and Histologic Evaluation
The mammographic appearance of the tumors was that of a spiculated mass in six patients, an architectural distortion in one patient, and an oval smooth mass in two patients. Only one patient had microcalcifications in the suspicious mass, and these were fibrocystic calcifications at histologic evaluation. On mammograms, five of nine patients had heterogeneous density, two had fat density, and two had a fatty appearance with scattered densities. Initially, US-guided core-needle biopsy was performed in five patients, and stereotactic core-needle biopsy was performed in four patients. Initial histologic results from the core-needle biopsies were invasive ductal carcinoma in seven patients, invasive ductal carcinoma with DCIS in one patient, and invasive colloid carcinoma in one patient. Metallic markers were placed in three patients at the time of biopsy.

Imaging during Cryoablation
The ice ball was readily identifiable as an enlarging hypoechoic circumscribed mass with an echogenic anterior surface and extensive acoustic posterior shadowing (Fig 2). Mean maximum size of the ice ball was 4.4 cm (range, 4.2–5.5 cm) in the longitudinal plane and 2.8 cm (range, 2.6–3.0 cm) in the transverse plane, with ice ball sizes directly proportional to cancer sizes. The depth (anteroposterior distance) of the ice ball was not measurable because of extensive posterior acoustic shadowing, which precluded accurate measurement. No color signal consistent with blood flow was observed in the three patients who underwent color Doppler flow imaging, but a twinkling artifact was present in all cases at the anterior surface of the ice ball (Fig 3).



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  		Figure 2a. US images depict ice ball formation. At maximum size, ice ball is an oval mass with echogenic anterior surface and dense posterior acoustic shadowing. Distance between margin of ice ball and skin (arrowheads) was greater on b because of injection of sterile saline, which was intermittently instilled between ice ball and skin to maintain an ice ball-to-skin distance of at least 5 mm to prevent hypothermic injury to skin. (a) Longitudinal and (b) transverse orientation of US transducer relative to ice ball.

 


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  		Figure 2b. US images depict ice ball formation. At maximum size, ice ball is an oval mass with echogenic anterior surface and dense posterior acoustic shadowing. Distance between margin of ice ball and skin (arrowheads) was greater on b because of injection of sterile saline, which was intermittently instilled between ice ball and skin to maintain an ice ball-to-skin distance of at least 5 mm to prevent hypothermic injury to skin. (a) Longitudinal and (b) transverse orientation of US transducer relative to ice ball.

 


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  		Figure 3a.  Color Doppler US images of ice ball show twinkling artifact (arrows), which is a US artifact that occurs at highly reflective objects. Twinkling artifact appears as rapidly alternating red and blue color Doppler signal, which gives the appearance of movement, at surface of ice ball. No definite vascular flow was identified anterior to ice ball with color Doppler imaging. Amount of signal varies from (a) small or (b) moderate to (c) large.

 


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  		Figure 3b.  Color Doppler US images of ice ball show twinkling artifact (arrows), which is a US artifact that occurs at highly reflective objects. Twinkling artifact appears as rapidly alternating red and blue color Doppler signal, which gives the appearance of movement, at surface of ice ball. No definite vascular flow was identified anterior to ice ball with color Doppler imaging. Amount of signal varies from (a) small or (b) moderate to (c) large.

 


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  		Figure 3c.  Color Doppler US images of ice ball show twinkling artifact (arrows), which is a US artifact that occurs at highly reflective objects. Twinkling artifact appears as rapidly alternating red and blue color Doppler signal, which gives the appearance of movement, at surface of ice ball. No definite vascular flow was identified anterior to ice ball with color Doppler imaging. Amount of signal varies from (a) small or (b) moderate to (c) large.

 
Postcryoablation Imaging
All postcryoablation mammograms depicted the tumor sites, with new vague adjacent focal densities that ranged from 2.0 to 5.0 cm in maximum size (Figs 4, 5). These new densities were more conspicuous in patients who had fat density on mammograms and more subtle in those with heterogeneous density on mammograms. These new densities were more indistinct than the densities sometimes seen at biopsy sites after core-needle biopsy. In six of eight patients, masses on postcryoablation mammograms were still visible, and in six patients, masses on postcryoablation US images were still visible. In addition, there was new hyperechogenicity in the tissues around the tumor sites in all these patients (Fig 6). These findings are summarized in Table 2. In the imaging studies of the specimens (eight mammographic, three US), the mass was present.



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  		Figure 4. Mammograms show appearance of invasive ductal cancer after cryoablation. This cancer originally manifested as a circumscribed slightly lobulated mass (arrow) surrounded by only fat. After cryoablation, a new halo of density (arrowheads) surrounded the mass. Patient had no residual carcinoma after cryoablation. A, B, Craniocaudal views. C, D, Mediolateral oblique views. A, C, Before cryoablation. B, C, At wire localization 24 days after cryoablation. Images show a change in mammographic appearance. E, Radiograph of specimen shows in greater detail that the mass and adjacent fatty tissue were surrounded by halo of density (arrowheads).

 


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  		Figure 5a. US images of invasive cancer (arrow). (a) Before cryoablation, hypoechoic mass was observed with spiculated margins. (b) After cryoablation, mass was visible but more ill-defined, with a larger region of hyperechogenicitiy surrounding it.

 


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  		Figure 5b. US images of invasive cancer (arrow). (a) Before cryoablation, hypoechoic mass was observed with spiculated margins. (b) After cryoablation, mass was visible but more ill-defined, with a larger region of hyperechogenicitiy surrounding it.

 


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  		Figure 6. Image shows histopathologic specimen of breast tissue obtained after cryoablation and lumpectomy. Extensive areas of coagulative necrosis (thick arrow) were observed, as well as high eosinophilic staining (pink) of tissue (thin arrow), which was amorphous and demonstrated areas of hemorrhage without visible carcinoma. (Hematoxylin-eosin stain; original magnification, x2.)

 
Histologic Findings
Histologic examination of the lumpectomy specimens revealed extensive areas of coagulative necrosis, fat necrosis, and scars (Fig 7). The coagulative necrosis was characterized by cell death, with relative preservation of the basic outline of the coagulated cell. There were outlines or "ghosts" of malignant cells mixed with cellular debris and rare neutrophils, all of which were features typical of coagulative necrosis that occurs as a result of denaturation of cellular proteins secondary to hypoxia. In all cases, in the vicinity of the coagulative necrosis, there were areas of fat necrosis, which were characterized by fat globules of different sizes surrounded by foamy macrophages and occasional lymphocytes. Collagen deposition–forming scars and large thick vessels were also present.



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  		Figure 7. Image shows histopathologic specimen of breast tumor tissue in patient with residual invasive ductal carcinoma next to resection margin obtained after cryoablation and lumpectomy. Residual tubules and single cells with slight pleomorphism, which represent residual invasive ductal carcinoma (arrows), were observed. (Hematoxylin-eosin stain; original magnification, x20.)

 
Primary Effectiveness Rate
The primary effectiveness rate was 78% (seven of nine patients); these patients had complete tumor necrosis, with no invasive or intraductal tumor present. Patient 7 had a small focus of invasive tumor and patient 6 had DCIS (Table 1), and both of these findings were observed at the posterior surgical margin (Fig 7). Patient 7 had the largest tumor (18 mm), with very irregular margins, extensive shadowing, and very spiculated margins at US. Of the patients with tumors that were 17 mm or smaller in maximum size, none had residual invasive tumor, but one (patient 6) had extensive multifocal DCIS. This patient underwent surgical excision a second time to obtain clear surgical margins, but DCIS was again present, and it extended to the chest wall. This DCIS was occult at mammography and US, and DCIS had not been present in the initial core-needle biopsy specimen. There was no residual invasive or intraductal tumor in the four patients who had BI-RADS category 1 or 2 density on mammograms. All patients with tumors that were nonpalpable at presentation had no residual tumor at excision, whereas two of four patients with palpable tumors had residual tumor. All patients who had tumors that were without spiculated margins at US were free of residual tumor at excision.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Seven of nine cancers were successfully treated with cryoablation, with no residual invasive or intraductal tumor present at excision. At the initiation of this prospective cryoablation trial, the criteria for inclusion were determined on the basis of maximum tumor size of 17 mm or smaller and initial histologic findings (no lobular carcinoma, multifocality, or abundant DCIS). Our results suggest that additional imaging factors, such as density on mammograms and US features, might be helpful for patient selection. We also observed that for tumors detected by using imaging alone (ie, nonpalpable tumors) no residual tumor was present at excision, although this correlation may be a function of smaller tumor size or coincidence. The only tumor with both extensively spiculated margins and shadowing was the one with residual invasive tumor. Whether residual tumor was related to the tumor size, the spiculated margins, the posterior shadowing, or all three factors is indeterminate. It is possible that the cryoprobe was positioned too anteriorly in the tumor, because tumor extensions toward the posterior aspect might be obscured by shadowing. The second patient with residual tumor had extensive DCIS, which was not detected by using mammography, US, or initial US-guided core-needle biopsy. The fact that incomplete cryoablation occurred in both these patients at the posterior margins may be coincidental, but it is also possible that the temperature was slightly warmer at the chest wall side of the ice ball, and the warmer temperature resulted in a suboptimal freezing temperature and incomplete cell death.

In our series of patients, there was no residual tumor in the four patients with mammograms with findings classified as BI-RADS 1 or 2 density, even though in one of these, the second largest tumor, which was 17 mm, was observed on the mammogram. This may be a coincidence, but it is likely that assessment of tumor extent and configuration may be more precise on mammograms with fat density because of improved visualization of margins and lower likelihood for a tumor to be occult at mammography. Accurate precryoablation determination of tumor size, extent, and margins at mammography and US is probably important in assessment of whether a patient is a candidate for this type of procedure. Our findings suggest that the ideal candidate would have a tumor smaller than 15 mm with low density on a mammogram and discrete margins and a visible posterior wall at US. Our patients did not undergo magnetic resonance (MR) imaging before cryoablation. Although not all DCIS is detected by using MR imaging, MR imaging might depict DCIS that is occult with other imaging methods. MR imaging and/or an additional biopsy in patients who do not have fat density on mammograms might be helpful to accurately assess tumor extent and the possibility of occult DCIS. Since accurate precryoablation evaluation may be important in the selection of patients for this procedure, the method of core-needle biopsy and the number of samples obtained may also be relevant, because of the possibility of underestimation of tumor extent when few core samples are obtained, especially for DCIS. Since details of the initial core-needle biopsy in some of our patients were unavailable, we were unable to evaluate biopsy details as a contributing factor to residual DCIS after cryoablation.

Most cancers are now readily diagnosed with core-needle biopsy instead of excisional biopsy. Surgical treatment options in breast cancer treatment have evolved toward more conservative procedures, such as lumpectomy, because of the lack of a survival benefit from mastectomy (4,38). Screening and diagnostic imaging with mammography and US have resulted in the detection of a substantial proportion of small unifocal cancers (< 1.5 cm). An effective minimally invasive form of treatment would be highly desirable for such tumors.

Cryoablation is tissue destruction by using controlled freezing and has been investigated as an alternative to conventional surgery in the treatment of benign and malignant neoplasms (10,11,33,34,39–42). The technique has its origins in the 1800s when advanced carcinomas of the breast and uterine cervix were treated with iced saline solution. Cryosurgery has been explored as a treatment for locally advanced unresectable breast cancers that are resistant to radiation therapy and chemotherapy (43,44) and, more recently, as a treatment of primary breast cancers (11,33). Among the latter trials, Pfleiderer et al (11) found that two limitations of cryoablation were undetected DCIS prior to intervention and incomplete necrosis of tumors larger than 15 mm. These findings are extremely similar to our results, wherein residual invasive tumor occurred in the patient with the 18-mm mass and occult DCIS was found in another patient.

There are, however, several advantages to cryoablation with US as an ablation procedure. Up to one-half of invasive tumors detected by using mammographic screening might be treated with cryoablation. US is used for both guidance and real-time monitoring, inasmuch as the ice ball formation is obvious. Patients experience very little pain; hence, only local anesthesia with lidocaine is necessary, and the technical aspects of the procedure are very similar to those of US-guided core-needle breast biopsy. The lack of complications despite proximity to the skin (as close as 5 mm in our series of patients) is promising. Cosmetic outcome would be very positive, as scarring is minimal, and the scar would be unlikely to be misinterpreted as a potential tumor. In a sheep model, the cryoablation site was not identifiable up to 5 months after treatment by using US, mammography, or MR imaging. The reduced morbidity and mortality compared with those of surgery and compared with those of nonsurgical options in patients who are not candidates for surgical therapy are also advantages. There is also some evidence that cryoablation may induce an immunologic response that may be potentially beneficial to the patient (44–47).

Limitations include underestimation of tumor margin and tumor extent before cryoablation with imaging methods. The ice ball is intensely echogenic, and once it has formed, the tumor is no longer visible; therefore, there can be some uncertainty about adequacy of localization. For long-term follow-up, it is unknown whether the fat necrosis in the tumor site would limit subsequent imaging or clinical breast examinations. We found that the tumors and/or tumor sites were identifiable after cryotherapy by using US and mammography 2–3 weeks later; however, there were changes. There was new extensive hyperechogenicity around the tumor, and this hyperechogenicity approximated the location where the ice ball had been. Correspondingly, by using mammography, vague but focal density up to 5.0 cm in size also occurred after cryoablation, and this occurrence made tumor margins more indistinct. These changes correspond to the coagulative necrosis and possible fat necrosis due to cryoablation. Fat necrosis, which results from mechanical or surgical trauma, has a wide spectrum of mammographic and US findings, varying from cysts to masses to normal tissue (48,49). This spectrum of findings may be related to differences in the age, duration, or precise cause of the fat necrosis. On US images, increased echogenicity in the subcutaneous fat has been reported in other studies (45,46) as a manifestation of fat necrosis, and this finding was similar to the US findings we described in the cryotherapy cases in our series of patients. These initial imaging findings, all seen at 2–3 weeks after cryosurgery, do not appear extensive enough to be an impediment to long-term imaging follow-up of cryoablation sites, although evolution of fat necrosis into masses and calcifications could be problematic. With placement of markers at the time of biopsy, precise identification of the tumor site can be established.

During cryoablation, the enlarging ice ball is very obvious on US images as a hypoechoic circumscribed mass with dense shadowing. The ice ball margin is particularly visible anteriorly and longitudinally, but the posterior margin is less discernible because of the shadowing. This may be a limitation in the evaluation of whether the tumor has been completely encased. We also observed that a twinkling artifact can be seen with color Doppler flow US; this artifact occurs at highly reflective objects, such as stones in the urinary tract or at the calvaria (50). This artifact could be mistaken for intense blood flow around the ice ball. The twinkling artifact appears as a rapidly alternating red and blue color Doppler signal, which gives the appearance of movement. The twinkling artifact is highly dependent on machine settings and, therefore, would have a variable appearance. We observed no significant color Doppler flow signal in the tissue around the ice ball at color Doppler flow imaging, which would be consistent with the vasoconstriction that occurs because of the cold temperature.

Our study was limited by the small number of patients, which in turn limited our ability to determine which types of patients were most likely to have successful treatment of breast cancer with cryoablation. Certainly, the results of the larger multi-institutional trial will contain more meaningful conclusions regarding the effectiveness of cryoablation as a percutaneous treatment of breast cancer. Other larger trials can provide more detailed information about the role of cryoablation in the armamentarium of breast cancer therapy.

Three of nine patients did not undergo postcryoablation US; therefore, our US findings after cryoablation are preliminary. There also were limitations inherent in the accuracy of measurements of cancer size because of user differences in US measurements and because whole-volume US before cryoablation was not conducted so that multiple measurements could be performed. In addition, interobserver variability may occur in the use of BI-RADS classifications for mammographic and US characteristics. In future studies with larger numbers of patients, evaluation of blinded readers and precise tumor measurements may be helpful to assess the usefulness of imaging characteristics in the prediction of the success of cryoablation.

In summary, residual tumor occurred at the posterior margin in two of nine patients, and this finding may possibly relate to factors such as size of tumor, visibility of posterior tumor margins with US before and during cryoablation, and presence of intraductal tumor that is occult at US and mammography. It is possible that more accurate determination of tumor extent and patient selection that is based on imaging characteristics may be useful to achieve complete tumor ablation by using minimally invasive treatments such as cryoablation.


   FOOTNOTES
 
Abbreviations: BI-RADS = Breast Imaging Reporting and Data System, DCIS = ductal carcinoma in situ

Authors stated no financial relationship to disclose.

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


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

  1. American Cancer Society. Cancer facts and figures 2004. Available at: www.cancer.org. Accessed September 27 2004.
  2. Cady B, Stone MD, Schuler JG, Thakur R, Wanner MA, Levin PT. The new era in breast cancer: invasion, size and nodal involvement dramatically decreasing as a result of mammographic screening. Arch Surg 1996; 131:301-308.[Abstract]
  3. Roubidoux MA, Bailey JE, Wray L, Helvie MA. Invasive cancers detected after breast cancer screening yielded a negative result: relationship of mammographic density to tumor prognostic factors. Radiology 2004; 230:42-48.[Abstract/Free Full Text]
  4. Veronesi U, Cascinelli N, Mariani L, et al. Twenty year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002; 347:1227-1232.[Abstract/Free Full Text]
  5. Jeffrey SS, Birdwell RL, Ikeda DM, et al. Radiofrequency ablation of breast cancer: first report of an emerging technology. Arch Surg 1999; 134:1064-1068.[Abstract/Free Full Text]
  6. Stanton A, Krishnan L, Collins C. Form or function? I. Subjective cosmetic and functional correlates of quality of life in women treated with breast-conserving surgical procedures and radiotherapy. Cancer 2001; 91:2273-2281.
  7. Izzo F, Thomas R, Delrio P, et al. Radiofrequency ablation in patients with primary breast carcinoma: a pilot study in 26 patients. Cancer 2001; 92:2036-2044.[CrossRef][Medline]
  8. Fornage BD, Sneige N, Ross MI, et al. Small (< or = 2-cm) breast cancer treated with US-guided radiofrequency ablation: feasibility study. Radiology 2004; 231:215-224.[Abstract/Free Full Text]
  9. Singletary SE, Fornage BD, Sneige N, et al. Radiofrequency ablation of early-stage invasive breast tumors: an overview. Cancer J 2002; 8:177-180.[Medline]
  10. Staren ED, Sabel MS, Gianakakis LM, et al. Cryosurgery of breast cancer. Arch Surg 1997; 132:28-33; discussion 34.[Abstract]
  11. Pfleiderer SO, Freesmeyer MG, Marx C, Kuhne-Heid R, Schneider A, Kaiser WA. Cryotherapy of breast cancer under ultrasound guidance: initial results and limitations. Eur Radiol 2002; 12:3009-3014.[Medline]
  12. Robinson DS, Parel JM, Denham DB, et al. Interstitial laser hyperthermia model development for minimally invasive therapy of breast carcinoma. J Am Coll Surg 1998; 186:284-292.[CrossRef][Medline]
  13. Robinson DS, Parel JM, Denham DB, et al. Stereotactic uses beyond core biopsy: model development for minimally invasive treatment of breast cancer through interstitial laser hyperthermia. Am Surg 1996; 62:117-118.[Medline]
  14. Harries SA, Amin Z, Smith ME, et al. Interstitial laser photocoagulation as a treatment for breast cancer. Br J Surg 1994; 81:1617-1619.[Medline]
  15. Dowlatshahi K, Bauich D, Kluiber R. Histologic evaluation of rat mammary tumor necrosis by interstitial Nd:YAG laser hyperthermia. Lasers Surg Med 1992; 12:159-164.[Medline]
  16. Dowlatshahi K, Fan M, Gould VE, Bloom KJ, Ali A. Stereotactically guided laser therapy of occult breast tumors: work in progress report. Arch Surg 2000; 135:1345-1352.[Abstract/Free Full Text]
  17. Dowlatshahi K, Francescatti DS, Bloom KJ. Laser therapy for small breast cancers. Am J Surg 2002; 184:359-363.[CrossRef][Medline]
  18. Mumtaz H, Hall-Craggs MA, Wotherspoon A, et al. Laser therapy for breast cancer: MR imaging and histopathologic correlation. Radiology 1996; 200:651-658.[Abstract]
  19. Harms SE, Klimberg VS, Henry-Tilman R, Kourourian S, Mumtaz H, Lindquist D. MRI directed laser therapy for benign and malignant breast neoplasms: clinical follow-up and histologic correlation (abstr). Radiology 2000; 217(P):267.
  20. Hill CR, ter Haar GR. High intensity focused ultrasound: potential for cancer treatment. Br J Radiol 1995; 68:1296-1303.[Abstract]
  21. ter Haar G. Ultrasound focal beam surgery. Ultrasound Med Biol 1995; 21:1089-1100.[CrossRef][Medline]
  22. Bohris C, Jenne JW, Rastert R, et al. MR monitoring of focused ultrasound surgery (FUS) in a breast tissue model. Magn Reson Imaging 2001; 19:167-175.[CrossRef][Medline]
  23. Hynynen K, Darkazanli A, Unger E, Schenck JF. MRI-guided noninvasive ultrasound surgery. Med Phys 1993; 20:107-115.[CrossRef][Medline]
  24. Chung AH, Jolesz FA, Hynynen K. Thermal dosimetry of a focused ultrasound beam in vivo by magnetic resonance imaging. Med Phys 1999; 26:2017-2026.[CrossRef][Medline]
  25. Graham SJ, Chen L, Leitch M, et al. Quantifying tissue damage due to focused ultrasound heating observed by MRI. Magn Reson Med 1999; 41:321-328.[CrossRef][Medline]
  26. 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.[Abstract/Free Full Text]
  27. Huber PE, Jenne JW, Rastert R, et al. A new non-invasive approach in breast cancer therapy using magnetic resonance imaging guided focused ultrasound surgery. Cancer Res 2001; 61:8441-8447.[Abstract/Free Full Text]
  28. Gianfelice D, Khiat A, Amara M, Belblidia A, Boulanger Y. MR imaging-guided focused US ablation of breast cancer: histopathologic assessment of effectiveness—initial experience. Radiology 2003; 227:849-855.[Abstract/Free Full Text]
  29. Chaudhary SS, Mishra RK, Swarup A, Thomas JM. Dielectric properties of normal and malignant human breast tissue at radiowave and microwave frequencies. Indian J Biochem Biophys 1984; 21:76-79.[Medline]
  30. Joines WT, Zhang Y, Li C, Jirtle RL. The measured electrical properties of normal and malignant human tissues from 50 to 900 MHz. Med Phys 1994; 21:547-550.[CrossRef][Medline]
  31. Campbell AM, Land DV. Dielectric properties of female human breast tissue measured in vitro at 3.2 GHz. Phys Med Biol 1992; 37:193-210.[CrossRef][Medline]
  32. Gardner RA, Vargas HI, Block JB, et al. Focused microwave phased array thermotherapy for primary breast cancer. Ann Surg Oncol 2002; 9:326-332.[Abstract/Free Full Text]
  33. Sabel MS, Kaufman CS, Whitworth P, et al. Cryoablation of early-stage breast cancer: work-in-progress report of a multi-institutional trial. Ann Surg Oncol 2004; 11:542-549.[Abstract/Free Full Text]
  34. Kaufman CS, Bachman B, Littrup PJ, et al. Office-based ultrasound-guided cryoablation of breast fibroadenomas. Am J Surg 2002; 184:394-400.[CrossRef][Medline]
  35. Rui J, Tatsutani KN, Dahiya R, Rubinsky B. Effect of thermal variables on human breast cancer in cryosurgery. Breast Cancer Res Treat 1999; 53:185-192.[CrossRef][Medline]
  36. American College of Radiology. Breast Imaging Reporting and Data System Reston, Va: American College of Radiology, 2003.
  37. Goldberg S, Charboneau J, Dodd G, et al. Image-guided tumor ablation: proposal for standardization of terms and reporting criteria. Radiology 2003; 228:335-345.[Abstract/Free Full Text]
  38. Fisher B, Anderson S, Bryant J, et al. Twenty year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347:1233-1241.[Abstract/Free Full Text]
  39. Gage AA. Cryosurgery for oral and pharyngeal carcinoma. Am J Surg 1969; 118:669-672.[CrossRef][Medline]
  40. Bilchik AJ, Sarantou T, Wardlaw JC, Ramming KP. Cryosurgery causes a profound reduction in tumor markers in hepatoma and noncolorectal hepatic metastases. Am Surg 1997; 63:796-800.[Medline]
  41. Caleffi M, Borghetti K, Graudenz M, et al. Preliminary report of an argon-based cryosurgical system for the minimally-invasive treatment of breast disease (abstr). 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, La, May 20–24 2000.
  42. Gage AA, Huben R. Cryosurgical ablation of the prostate. Urol Oncol 2000; 5:11-19.
  43. Tanaka S. Cryosurgical treatment of advanced breast cancer. Skin Cancer 1995; 10:9-18.
  44. Suzuki Y. Cryosurgical treatment of advanced breast cancer and cryoimmunological responses. Skin Cancer 1995; 10:19-26.
  45. Johnson JP. Immunologic aspects of cryosurgery: potential modulation of immune recognition and effector cell maturation. Clin Dermatol 1990; 8:39-47.[CrossRef][Medline]
  46. Wood TF, Ravindranath MH, Perez CA, et al. Cryosurgical ablation of hepatic colorectal carcinoma metastases induces autoimmunization with tumor specific antibodies (abstr). 54th Annual Cancer Symposium of the Society of Surgical Oncology, Washington, DC, March 15–18 2001.
  47. Ablin RJ. An appreciation and realization of the concept of cryoimmunology. In: Onik GM, Rubinsky B, Watson G, Ablin RJ, eds. Percutaneous prostate cryoablation. St Louis, Mo: Quality Medical Publishing, 1995; 136-154.
  48. Bilgen IG, Ustun EE, Memis A. Fat necrosis of the breast: clinical, mammographic and sonographic features. Eur J Radiol 2001; 39:92-99.[CrossRef][Medline]
  49. Soo MS, Kornguth PJ, Hertzberg BS. Fat necrosis in the breast: sonographic features. Radiology 1998; 206:261-269.[Abstract]
  50. Kamaya A, Tuthill T, Rubin JM. Twinkling artifact on color Doppler sonography: dependence on machine parameters and underlying cause. AJR Am J Roentgenol 2003; 180:215-222.[Abstract/Free Full Text]



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