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Experimental Studies |
1 From the Department of Radiology (J.P.M., J.M.B., C.D.J., S.Z.); Comparative Pathology Laboratory (S.M.G.); and Department of Surgery, Division of Surgical Oncology (P.D.S.); University of California–Davis Medical Center, 4860 Y St, Ste 3100, Sacramento, CA 95817. Received August 31, 1999; revision requested October 12; final revision received February 18, 2000; accepted February 28. J.P.M. supported by a grant from RadioTherapeutics, Mountain View, Calif. Address correspondence to J.P.M. (e-mail: john.mcgahan@ucdmc.ucdavis.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Eighteen RF treatments were performed in the mammary tissue of three domestic swine under ultrasonographic (US) guidance. Histopathologic examination was performed immediately after (acute animal); 2 weeks after (subacute animal); and 4 weeks after (chronic animal) treatment.
RESULTS: In the acute animal, lesions were firm nodules on palpation and had a distinct line of demarcation between necrotic and viable mammary tissue (mean lesion volume, 14.24 cm3; largest volume, 29.06 cm3). In the subacute animal, there was diffuse coagulation necrosis with neutrophilic infiltrates at the periphery (mean lesion volume, 6.46 cm3; largest volume, 9.47 cm3), and two treatment areas had a secondary bacterial infection. In the chronic animal, lesions were still palpable and firm (mean lesion volume, 11.67 cm3; largest volume, 25.5 cm3), and five of six treatment sites had an area of gray to white fibrotic tissue that blended with the surrounding tissue. However, one site had a pale yellow area of central necrosis surrounded by a fibrotic area. In both the subacute and chronic animals, two and one treatment site, respectively, had minimal areas of skin necrosis.
CONCLUSION: RF ablation of breast tissue is feasible in this animal model. Problems included minimal skin erythema, residual firm treatment regions at 4 weeks, slightly variable margins of coagulation necrosis, and occasional bacterial infection.
Index terms: Animals • Breast, US, 00.1299 • Breast neoplasms, experimental studies, 00.1299 • Radiofrequency (RF) ablation, 00.1299
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To address the consequences of treatment and to avoid unnecessary treatment, a number of alternatives have been proposed that emphasize breast-conserving therapy (3). Improved outcomes are being observed as a result of earlier diagnoses; therefore, less invasive methods for the treatment of breast malignancies are being sought. One treatment method, with limited research in human breast cancer, is radio-frequency (RF) electrocautery (4). This study was conducted to establish the size, configuration, and pathologic features of lesions produced with, acute, subacute, and chronic RF electrocautery treatment of mammary tissue in swine.
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MATERIALS AND METHODS |
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A 15-gauge LeVeen (RadioTherapeutics) needle was placed into the subcutaneous mammary tissue and was opened to 2 cm by using an umbrella-type mechanism with radially placed stainless steel wires (Fig 1). Three animals were used, one for each of the subacute, acute, and chronic animals that underwent histopathologic examination immediately after, 2 weeks after, and 4 weeks after treatment, respectively. The central or subareolar portion of the mammary tissue was always targeted for treatment.
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In all animals, the needle position was documented by using palpation and ultrasonography (US). US of the treatment area was performed with a 7-MHz linear-array US transducer and a 3-MHz vector transducer (Acuson, Mountain View, Calif). Hard-copy images were obtained at baseline and during RF treatments (Fig 2). US appearance of the treatment area was noted by two of the authors (J.P.M., J.M.B.). Animals underwent treatment in either one or two phases.
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of resistance, the application of RF was stopped. This rapid rise of impedance prevented current flow and thus stopped the RF application. The time from initial application until the RF current stopped was recorded. The power gradually and automatically increased the maximum setting that was modulated by changes in impedance to the maximum wattage, such as 8 or 15 W. The technique slowly created a firm palpable lesion, which was monitored by US guidance. Ten watts to 12 W was chosen as the optimal wattage, as this resulted in a fairly large treatment zone at US. At higher wattages (15 W), the impedance rapidly increased and immediately stopped the RF current. In the second phase of treatment in the acute animal, a repeat treatment was performed without moving the needle from its original location in the first treatment phase. Three treatments had been administered at 12 W in first phase; therefore, treatments in the second phase were administered at 6 (50%), 9 (75%), or 12 W (100%). One treatment was attempted at 10 W in the first phase and at 5 W in the second phase. All treatments lasted 15 minutes unless impedance of the system automatically stopped the RF treatment. After autopsy, the setting (12 W in the first phase and 9 W in the second phase) that created the largest volume of coagulation was used in the subacute and chronic animals.
The acute animal was euthanized after treatment. The acute animal treatment sites were harvested, and a central cross section through the affected area detected by means of palpation was made. A 5-mm parallel section was obtained from half of the treatment site and incubated for 30 minutes in 10 mL of 
-nicotinamide adenine dinucleotide diaphorase (2.5 mg/mL) and nitroblue tetrazolium chloride (2.0 mg/mL) to determine the area of tissue viability. Following incubation, one of the authors (S.M.G.) photographed the sections from each site for measurement of the cross-sectional area, depth, and width of nonviable tissue. Volume calculations were made by using the formula of the width, length, and height multiplied by 0.52 for each lesion. These volume calculations were also determined for the sections obtained in the subacute and chronic animals.
Tissues were then fixed in 10% phosphate-buffered formalin for routine histologic processing. Tissues in all treatment areas were analyzed for nonviability, histologic appearance, and demarcation from surrounding viable tissue. The RF parameters that produced the largest lesion in the acute animal were used in for the subacute and chronic animals.
In the subacute and the chronic animals, the same RF settings were used in all treatments. Four (subacute animal) and six (chronic animal) treatments of mammary tissue were administered by using a similar LeVeen needle with 12 W in the initial phase and 9 W in the second phase. Treatments lasted 15 minutes unless impedance of the system stopped the RF treatment. Animals were housed under standard conditions, with no bandages over the areas of treatment.
The subacute animal was euthanized at 2 weeks after treatment, and the chronic animal was euthanized 4 weeks after treatment. In both of these two animals, cross sections of the treatment sites were obtained and photographed in a manner similar to that used in the acute animal. However, viability staining was not performed. These sections were similarly fixed for routine histologic processing. The overlying skin and findings on palpation for the acute, subacute, and chronic animals were also noted (S.M.G.).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the acute animal, wattages, duration of treatment, and corresponding volumes of tissue necrosis in phases 1 and 2 are listed in the Table. In the acute animal, the largest lesion was 29.06 cm3 and was produced with 12 W administered for 9 minutes 30 seconds in the first phase and with 9 W administered for 10 minutes in the second phase. At autopsy, lesions were well demarcated from surrounding viable glandular tissue. This line of demarcation was confirmed with -nicotinamide adenine dinucleotide diaphorase and nitroblue tetrazolium chloride staining (Fig 4a). At histologic examination, acute lesions consisted of coagulation necrosis with a distinct line of demarcation from viable tissue (Fig 4b). These results correlated well with gross observations.
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In the chronic animal, the parameters were 12 W for a mean of 14 minutes 15 seconds in phase 1 and 9 W for a mean of 10 minutes in phase 2. In the chronic lesions at 4 weeks after treatment, volume ranged from 4.63 to 25.5 cm3, with a mean of 11.67 cm3 in five lesions. Five of the six treatment sites consisted of gray to white fibrotic tissue that blended with the surrounding tissue (Fig 6a). In the sixth treatment site, there was a pale yellow central area of necrosis with a volume of 2.64 cm3. This area was surrounded by fibrotic tissue similar to those of the other five treatment sites, and bacterial cultures were negative.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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More recently, there has been interest in the use of RF electrocautery in treatment of patients with breast cancer. In a series by Jeffrey et al (4), percutaneous RF treatment was performed in five women with breast cancer before they underwent mastectomy. A LeVeen needle with deployable wires of 2-cm diameter was used for the RF treatment. At histologic examination after surgical resection, they found a clear definition of the area treated with the RF probe that was distinct from the nontreated breast. They concluded that RF ablation of the breast tumor results in a focus of tissue necrosis (4).
In our experiment, we were encouraged by several features. First, US was shown to reliably demonstrate the position of the needles and deployed prongs within the breast (Fig 2). Jeffrey et al (4) had also used US to monitor probe placement. US alone can be used to monitor treatment. Solbiati et al (14) showed that contrast material–enhanced US may depict residual tumor after percutaneous RF ablation of hepatic metastasis. It is possible that contrast-enhanced US could be used in the breast.
In our experimental animal, we were encouraged that monopolar RF was able to produce coagulation necrosis in the breast tissue with a single treatment, as it does in other organs. In addition, at 4 weeks the necrotic tissue had been completely replaced by fibroblastic scar tissue in five of the six treatment sites, with no evidence of acute (ongoing) inflammation. We have found in prior experiments (15) that chronic liver lesions have areas of fibrosis in the treatment zone that persist.
Our experiment was performed by using a needle that expanded to a diameter of 2 cm with separate expandable and retractable prongs or wires (Fig 1). This size is not the largest commercially available. Also, this needle is just one of two types of expandable needles that are commercially available. The other expandable needle is manufactured by Rita Medical Systems (Mountain View, Calif). A third needle (Radionics Instruments, Burlington, Mass) has a cool-tip monopolar design that allows tissue necrosis surrounding the needle tip (16). Differently sized needles and higher-output RF generators could potentially create larger volumes of treated breast tissues. A larger treatment zone would ensure that an adequate surgical RF margin would surround the tumor. This margin would be needed if RF treatment is considered as an alternative to surgical resection. Thus, RF ablation could be used to treat fairly large tumors.
Somewhat discouraging, but almost predictable, was the finding that the lesions had irregular borders. Lesions were fairly spherical and well demarcated, but part of the border was irregular; this finding is not surprising when the nonuniformity of mammary tissue in the swine model is considered. The nonuniformity of mammary tissue leads to a nonuniform tissue impedance and a nonuniform area of coagulation. However, we were encouraged by the fact that there was always a well-demarcated central spherical volume, although some of the outer border was irregular. If this method were used to treat breast cancer in humans, the precise central volume of coagulation necrosis would have to be well known and predictable to ensure adequate tumor ablation. Also, tissue response to RF treatment of breast cancer in humans may be different than that of swine mammary tissue. Further human research will help define this difference.
Another potential problem was encountered with RF electrocautery. We found that if the needle prongs were too close to the skin, they caused superficial burn. There was an area of skin induration after two of the four treatments in the subacute animal and one of the six treatments in the chronic animal. This problem could potentially be monitored by using cutaneous thermometers or by watching for skin discoloration during treatment. The previous work by Jeffrey et al (4) revealed no acute skin damage at the time of mastectomy or at pathologic examination. RF treatment was performed in human breast cancers with the precautionary measure of placing ice on the skin during treatment. However, a problem could exist if the tumor was subareolar or subcutaneous. A good surgical margin of coagulation may not be possible in such superficial lesions without damaging the overlying skin.
In our experiment, we encountered secondary bacterial infections in two of the four treatment sites in the subacute animal and in one of the six sites in the chronic animal. It is possible that these animals had a subclinical mastitis that was exacerbated by the treatment. It is more probable that the bacterial infection was because of contamination after treatment. This secondary infection was probably due to the animals immediately removing their dressings. The treatment sites were then open to contamination from the floors of the cages in which they were housed. It is uncertain if this type of infection would cause problems if RF is used to treat breast malignancies in humans. Conservative assessment of this potentially serious complication following percutaneous ablation for cancer in the human breast must be considered.
Nests of squamous epithelium at the margins of the treatment site were encountered after our treatments in the subacute animal. This response was at the interface between the fully and partially treated lobules. In the subacute animal, these nests and islands were dysplastic and were the result of active adjacent inflammation and necrosis. By 4 weeks, the areas of squamous metaplasia did not show features of dysplasia.
Another problem is current unreliable diagnostic imaging to depict the actual extent of breast cancer. Currently with surgical lumpectomy, the specimen is obtained and is examined both radiographically and pathologically. In other areas, such as the liver, the size and extent of the tumor usually are well documented by using US, computed tomography (CT), or magnetic resonance (MR) imaging before treatment. This documentation may not always be feasible in the breast. However, with good correlation of both US and mammographic findings, a large volume of breast tissue could be treated by using RF to ensure an adequate surgical margin.
More recently, MR imaging techniques have been shown to be more precise in defining the extent of breast cancer before surgery. MR imaging was more accurate in defining tumor extent compared with mammography (98% vs 55%) (17). Thus, future MR imaging techniques may be helpful to more accurately define tumor extent and can be used with more conservative treatment such as percutaneous RF therapy. Further experimentation would be needed to access the feasibility of pretreatment determination of the extent of the tumor in the breast.
Follow-up of treated breast malignancy may also cause problems with mammography. We note that with CT follow-up of RF-treated liver tumor in humans, the lesions do not completely disappear but decrease in size and show lack of enhancement indicating lack of tumor viability. In the liver, there is no problem with a firm area of fibrosis, but in the breast, the patient may not desire a firm nodular area for cosmetic reasons. Furthermore, treatment areas would have to be discernible from an area of active or recurrent tumor. Contrast-enhanced MR imaging has been shown to be useful in routine screening for local recurrence following breast-conserving surgery (18).
The challenge of lesion selection and the appearance of treated areas at follow-up imaging, including mammography, MR imaging, and US, is a real one.
Practical application: Our initial experimental results demonstrate that RF ablation of mammary tissue is feasible but limited by a number of potential problems. Reasonable treatment volumes can be obtained with a single-needle treatment. With placement of multiple probes or with use of larger-diameter needles, an increased volume of breast tissue coagulation could be produced. Thus, it seems feasible that certain breast cancers may be treated with RF electrocautery. However, a number of problems still exist with this technique. First, a completely precise method of pretreatment demonstration of tumor extent is lacking, but knowledge of the extent is important for preoperative treatment planning. Second, there is a possibility of cutaneous erythema, which could be easily addressed but which may limit the treatment of some superficial lesions. Third, the need for a conservative approach to prevent possible infection of breast cancers in humans after RF treatment must be assessed. Fourth, a firm nodule is produced in an area of treated breast. This nodule may not be cosmetically desirable and could cause potential problems with imaging and follow-up performed to discern if there is recurrence. Future research must be directed at these problems before percutaneous RF electrocautery can be recommended in the treatment of breast malignancy.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, all authors; study concepts, J.P.M., P.D.S.; study design, J.P.M., S.M.G., P.D.S., J.M.B.; definition of intellectual content, all authors; literature research, J.P.M., S.M.G., P.D.S.; experimental studies, J.P.M., S.M.G., J.M.B., S.Z.; data acquisition and analysis, S.M.G., J.M.B.; statistical analysis, J.P.M., S.M.G., J.M.B.; manuscript preparation, editing, and review, all authors.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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