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RADIOLOGÍA

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Radiología. 2011;53(3):226-235

0033-8338/$ - see front matter © 2010 SERAM. Published by Elsevier España, S.L. All rights reserved.

KEYWORDSRadiofrequency;Ablation;Laser therapy;Focused ultrasound

PALABRAS CLAVERadiofrecuencia;Ablación;Laserterapia;

AbstractBreast imaging plays a signifi cant role in treatment. Ultrasonography to drain fl uid collections, vacuum-assisted biopsy to excise papillomas and fi broadenomas, and stereotactic excisional biopsy are a few examples of interventional procedures performed by radiologists in patients with breast disease. Moreover, there is a growing interest in the minimally invasive treatment of invasive tumors, which aims to achieve the same efficacy while minimizing morbidity and improving the esthetic outcome. Especially noteworthy are thermal ablation techniques, which involve destroying tumors with heat or cold. The most widely studied thermal ablation techniques are radiofrequency, high intensity focused ultrasound, laser therapy, microwaves, and cryoablation.

After a review of the literature, we conclude that the development of these treatment approaches will depend largely on the capacity of imaging techniques to plan the destruction of the tumor. Ultrasonography and magnetic resonance imaging are the current techniques of choice for this purpose.

The evidence suggests that small invasive carcinomas can be efficaciously treated with thermal ablation, especially by radiofrequency ablation; however, before this technique can be validated, phase III clinical trials must compare it with conservative surgery in terms of local progression and overall survival.© 2010 SERAM. Published by Elsevier España, S.L. All rights reserved.

Actualización en intervencionismo mamario terapéutico

ResumenLa radiología mamaria tiene una vertiente terapéutica importante. La ultrasonografía, para drenar colecciones, la biopsia de vacío para extirpar papilomas y fi broadenomas y la biopsia estereotáxica escisional, son ejemplos.

UPDATE

Review of interventional radiology techniques in breast disease

L. Apesteguia Ciriza*, A. Ovelar Ferrero, C. Alfaro Adrián

Departamento de Radiología, Complejo Hospitalario de Navarra, Pamplona, Spain

Received 29 September 2010; accepted 28 December 2010

*Corresponding author. E-mail: [email protected] (L. Apesteguía Ciriza).

Documento descargado de http://www.elsevier.es el 04/02/2013. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.

Review of interventional radiology techniques in breast disease 227

Existe creciente interés por el tratamiento mínimamente invasivo de tumores infi ltrantes, buscando similar efectividad con menor morbilidad y mejor resultado cosmético. Destacan las técnicas de ablación térmica, que consisten en destruir tumores mediante calor o frío. Las más estudiadas son: radiofrecuencia, ultrasonidos focalizados, laserterapia, microondas y crioablación.

Hemos revisado las publicaciones existentes. El desarrollo de estas terapias dependerá sustancialmente de la capacidad de las técnicas de imagen para planificar la destrucción tumoral. Ultrasonografía y resonancia magnética son actualmente las técnicas de elección.

Existe evidencia de que el carcinoma infi ltrante pequeño puede ser efi cazmente tratado mediante termoablación, particularmente por radiofrecuencia, pero antes de validarla, serán necesarios ensayos clínicos fase III, comparándola con la cirugía conservadora, en términos de progresión local y supervivencia global.© 2010 SERAM. Publicado por Elsevier España, S.L. Todos los derechos reservados.

Introduction

Breast screening programs and the greater appreciation of the benefi ts of early diagnosis of breast cancer have made possible to detect a growing number of tumors at early stages. Simultaneously, percutaneous image-guided biopsy methods have become increasingly effective and widespread in all developed countries. Surgical techniques have also evolved into less aggressive procedures, in such way as to fi rmly establish breast-conserving therapy as the standard approach for patients with early-stage breast cancer for the last two decades. Complementary radiotherapy is an integral part of breast conserving treatment, providing local control and survival rates similar to those of mastectomy1.

In order to avoid unnecessary lymphadenectomies in lymph node staging in patients with early-stage breast cancer, the technique of selective sentinel node biopsy was developed, providing similar sensitivity than axillary lymph node dissection with considerably lower morbidity, standing as the current modality of choice2.

The contribution of imaging techniques to the diagnosis of palpable and nonpalpable lesions is unquestionable. But it is also true that for more than 25 years, these techniques have played a remarkable role in the treatment of breast diseases.

The placement of a wire guide is merely a therapeutic contribution to conserving therapy that has been used since the 1980s and remains indispensable in most Breast Disease units.

Drainage of collections has been performed with radiologic guide for many years now. The integration of real-time ultrasound (US) was a major development in this respect, and ultrasonography is now indispensable for draining all kind of collections including sebaceous cysts, galactoceles, infected cysts, seromas or abscesses, thus contributing to their resolution.

Continuing with non-malignant lesions, the therapeutic contribution of vacuum-assisted biopsy with large gauge cannulas and of excisional biopsy techniques is noteworthy. The former has proved useful as US-guided treatment for papillomas and fibroadenomas, although with higher recurrence rates the larger the size of the excised tumor3.

Stereotactic excisional biopsy has been successfully used for the excision of atypical benign lesions and occasionally for the local treatment of small malignant lesions4, particularly in situ.

However, the minimally invasive treatment of invasive lesions has aroused a growing interest in the last decade. This constant trend of reducing the aggressiveness of treatments has led to the development of less invasive alternatives than surgery, able to provide similar effectiveness, less morbidity and better cosmetic outcome. In this respect, thermal ablation procedures are worth mentioning. They are still in the investigational phase but are offering promising preliminary results, although some practical and cost-related factors seem to be limiting the number of published series.

The present review provides an account of the current status of interventional techniques for the treatment of malignant lesions, their presence in international publications and future prospects.

Minimally invasive techniques for breast cancer treatment. Thermal ablation technique

Thermal ablation involves the application of heat or cold directly to the tumors to destroy them. Ablation techniques include radiofrequency ablation (RFA), high-intensity focused ultrasound ablation (HIFU), laser and microwave ablation and cryotherapy 5,6.

Except for US ablation, a transcutaneous technique, the rest of modalities involve the percutaneous insertion of a cannula or applicator into the tumor. The lesion geometry is usually oval or spheroidal. The aim of the technique is to destroy the tumor and a surrounding margin of 5-10 mm. To that end, the cannula-electrode needs to be positioned in the center of the tumor, when possible in the direction of its long axis, in order to ensure that the planned target volume is included in the ablated area (Figure 1). The type and size of the applicator must provide a thermal effect of enough volume.

US is the most common technique used to guide the applicator, followed by magnetic resonance (MR) and, more less commonly, stereotaxy.

Ultrasonidos focalizados


228 L. Apesteguia Ciriza et al

In order to use US-guidance the lesion must be clearly depicted by US and well demarcated from the surrounding parenchyma. Since precise applicator insertion is required, this procedure must be performed by radiologists with experience in US-guided puncture and with high-resolution equipments 7 (Figure 2). The main limitation of the technique is the inability to monitor the treatment outcome due to the slow and gradual appearance of an ill-defi ned hyperechoic area, which is not an accurate indicator of the volume coagulated tissue since it hides the tumor and hampers visualization of the underlying tissue. This area seems to be caused by steam microbubbles and other cell products result of tissue vaporization during the active heating.

MR imaging is superior to US in the determination of the local extent of the infiltrative carcinoma, allowing non-invasive monitoring of the treatment by means of specifi c thermosensitive sequences. In addition, MRI enables temperature monitoring with the insertion of thermosensors, some of them come already attached to the tip of the applicators, and provides information about the ablation outcome (total or part ia l reduction of contrast enhancement) 8,9. Nonetheless, except for US ablation, the use of MR imaging remains limited due to practical and

logistical issues including less availability, the considerable time the MRI room is in use, the frequent incompatibility of most ablation systems with MRI and susceptibility artifacts caused by the applicator.

Figure 1 Percutaneous thermal ablation. A) Tumor. B) Percutaneous insertion of the applicator into the geometric center of the tumor. C) Formation of a spheroidal thermal ablation area. D) Area of tissue coagulation (cellular death).

Figure 2 US-guided percutaneous thermal ablation. Applicator introduced by the radiologist under US guidance.



Next, we describe the current ablation techniques available, whether they use heat or cold.

Heat ablation techniques

They are based on slow and gradual heating of the tissues that induces coagulation. The different techniques differ only in the physical method of generating heat.

Radiofrequency ablation (RFA)

Physical basisRFA is an electromagnetic method of tissue destruction that uses generators of electric energy. This method involves the i n se r t i on o f an e lec t rode in to the tumor. A high-frequency alternating current flows through the electrode inducing ionic agitation in the tissues and creating friction heat that increases local temperature, leading to necrosis. The dispersion of the heat generated in the proximity of the electrode is due to conduction and convection effects 10.

The thermal tissue damage depends on the temperature and on the duration of the heating. Cellular homeostasis can be maintained below 40 °C. Cells become more susceptible to chemotherapy and radiation when temperatures increase beyond 42 °C (hyperthermia). Heating at 45 °C for several hours leads to irreversible cellular damage, whereas heating at 50-55 °C results in the same effect in only a few minutes. Between 60-100 °C, instantaneous tissue coagulation occurs that manifests as irreversible damage to the cytosolic and mitochondrial enzymes. Temperatures greater than 100 °C result in tissue vaporization and carbonization 11,12.(Figure 3).

Monopolar RF techniques are usually used in breast cancer. These techniques use an active electrode

inserted into the tissue completed with a dispersive electrode, usually return pads, placed on the patient’s thighs.

ProcedureUS is normally used as guidance for RFA. It is important to apply a low power and increase it progressively in order to prevent rapid coagulation necrosis of the tissue close to the electrode tip that would hinder subsequent heat propagation. The type and size of the electrode determine the extent of the ablation area. There are different types of electrodes including expandable multifi laments, internally cooled and perfusion electrodes13. Currently available systems provide spheroidal ablation volumes of 2-5 cm in diameter. Hung et al. compared two types of electrode reporting similar effi cacy14.

There are systems autoregulated by tissue impedance, which is registered in the generator monitor, and others based on temperature monitoring using a thermometer placed close to the electrode tip. When the ablation is about to conclude, the impedance increases and the power decreases accordingly without the possibility of increase it from the commutator. The procedure must be stopped when the impedance exceeds a certain value. After a 30-second pause, a second heating phase is recommended. This phase is shorter than the fi rst one and must be stopped when the impedance rises. The technique takes 10 to 30 minutes, but the patient preparation, instrumentation and postablation care make the whole process longer.

Although uncommon, complications of RFA include skin and chest wall burns; for this reason, this technique is not recommended for tumors located at a distance < 1 cm from these structures7.

A comprehensive histological study is imperative before the RFA. This study must include the histological type and degree of the tumor, hormone receptors and expression of the Her-2/NEU oncogene. Some of the cores provided by the percutaneous biopsy must be placed in alcohol, so they can be used as control samples to validate the NADH-diaphorase staining. This is an enzymatic technique for the study of the mitochondrial oxidative activity and, therefore, of cellular viability.

On conventional hematoxylin and eosin staining, the surgical specimen may show different degrees of coagulation necrosis characterized by cellular dehydration, nuclear pyknosis, cytoplasmic eosinophilia of variable intensity, and even complete cellular destruction. Some apparently normal cells in the area of coagulation may, however, appear non-viable in the NADH-d study 15. This technique involves the reduction of nitroblue tetrazolium by the NADH-diaphorase enzyme in the cytoplasm that stains dark blue. The activity of NADH-d, which is present in viable cells, ceases immediately after cell death, thus allowing precise and immediate determination of cell death and its extent. NADH-d staining is more objective than conventional hematoxylin and eosin staining as its interpretation is based only in the presence or absence of blue intracytoplasmatic pigment 16. Nonetheless, this technique and its interpretation are not without complications, making difficult for the pathologist the sectioning for freezing of fatty and/or necrotic tissues, as

Tis

sue

tem

pera

ture

Effect of heat on tissue

Tissue vaporization and carbonization

Immediate (irreversible cellular

damage)

Optimal ablation

temperature

Irreversible cellular damage

Susceptible to chemotherapy or radiation therapy

Homeostasis

Figure 3 Effect of heat on tissue. In order to achieve appropriate thermal ablation, tissue temperature must be maintained within the ideal ablation range.



well as the selection of the optimal area and the amount of material to be frozen in small tumors.

A careful evaluation of the tumor characteristics (size, morphology, margins, intraductal component and multiplicity) and of its local-regional extent is required prior to the RFA procedure. These are determining factors in the selection of cases, for this reason, the diagnostic procedure must include all the imaging techniques available, including MRI if possible. Previous staging by means of US-guided puncture of suspicious axillary lymph nodes or sentinel node biopsy is required. Axil lary involvement is not a contraindication to ablation.

Recently, Athanassiou et al17 have analyzed the effect of fat content in breast tumors and concluded that fat may decrease the thermal effect of RFA due to its lower conductivity.

When used as an alternative to conserving surgery, one limitation of RFA is the impossibility of performing histological analysis of the margins of the ablated area. For this reason, pure ductal carcinoma in situ and invasive tumors with an extensive intraductal component, frequently undetectable at US, are not treated with RFA. Similarly, patients who undergo neoadjuvant treatment are not candidates to RFA because chemotherapy may lead to tumor shrinkage with radiologically occult areas. Invasive lobular carcinoma is also an exclusion criterion in many series due to its poor US visualization.

ResultsRFA is undoubtedly the most widely used thermal ablation method for the experimental local treatment of malignant breast tumors. The classic study by Jeffrey et al. published in 1999 is considered the pioneer publication on RFA18. They treated five women with locally advanced breast cancer who were undergoing surgical resection and concluded that RFA causes cell death; however, due to the extent of the ablation zone, this technique is suitable only for tumors < 3 cm.

Subsequently, many case series have been published, mostly phase 2 trials in which RFA is performed before surgical resection, in order to determine its safety and the effects of ablation on the surgical specimen7-9,19-29. US guidance has been used in all these studies, except one that used MR guidance24. Most RFA procedures were performed in the operating room under general anesthesia, immediately before surgical resection although some procedures were performed under local anesthesia with sedation8,9,20,24 and one with local anesthesia and no sedation27. The technique is generally well tolerated and complications are uncommon and limited to mild skin burns. Most treatments were performed on invasive tumors < 2 cm.

The results of different studies are consistent: RFA causes complete tumor destruction in 90-100 % of cases.

In 2005, our teamwork started a phase II trial that involved RF ablations of invasive breast carcinomas, 2 cm in size, followed by deferred surgical excision27. The 35 procedures were performed in the US examination room under local anesthesia with no sedation. In total, 85.7 % of patients reported no discomfort; 11.4 % reported mild pain controllable by the administration of additional anesthesia.

In one patient with intense pain, the procedure was discontinued. No complications occurred. Histologically, signs of coagulation necrosis were observed in all cases. Coagulation necrosis was classifi ed as complete in 91.4 % of cases. NADH-d was negative in 27 of the 32 cases in which it was performed; one case was slightly positive and the other four were non-assessable. Our results are in line with other studies 7,19-21.

Errors when obtaining samples of the surgical specimen are an inherent limitation of these studies since, despite extensive and thorough sampling, isolated foci of residual viable cells may be missed. The main causes of incomplete destruction are size > 2 cm 7 and radiologically occult areas, especially in intraductal carcinoma 7,18-21.

The number of series in which RFA was not followed by surgery is lower30-36 and they are all longitudinal trials with no control group. The follow-up of the tumor bed is essential in these cases but remains a matter of debate and, although most authors suggest a combination of imaging techniques (mainly MR) with percutaneous puncture, there is still no consensus regarding the type and sequences of studies required for the early detection of local recurrence.

Oura et al30 reported the largest series with no confirmation by surgery. They treated 54 patients with breast cancer ≤ 2 cm and detected no local tumor invasion, lymph node metastasis or distant metastasis. They used puncture cytologt, MR imaging, physical examination and US. The tumor was visible after RFA in 30 cases and undetectable in 22. Cosmetic results were considered satisfactory in most patients, superior to conserving surgery. Three patients developed a mass in the ablation area whose volume decreased progressively.

There is not enough information on the natural history of the changes occurring after RFA. It seems likely that the cosmetic results of this technique are better than those of conserving surgery due to the smaller volume treated and the absence of scar. However, this fact has to be proved by longitudinal studies. In addition, local changes may occur after RFA, followed or not by radiation therapy (secondary to abnormal reaction of peritumoral tissue or fatty necrosis), whose frequency, intensity and progression are unknown. The placement of a metal marker at the tumor bed is useful to identify the tumor site and detect potential tumor progression in radiological follow-up studies.

In conclusion, RFA is an effective technique that may be performed under local anesthesia in an outpatient setting, it is well tolerated and with few complications. Nonetheless, the absence of cellular viability in the tumor tissue must be demonstrated by the long-term follow-up in patients who do not undergo surgery, comparing the local tumor progression and survival rates in patients treated with RFA and radiotherapy and in patients treated with the standard therapy (conserving surgery and radiotherapy). One of the most active researcher groups in this fi eld, the MD Anderson Cancer Center (Houston, EE. UU.), is conducting a non-randomized trial with these characteristics37.

Meanwhile, a potential indication of RFA includes elderly patients or with intercurrent disease that contraindicates surgery, always with informed consent32-35.



Lamuraglia et al38 studied the effect of RFA on recurrent breast carcinoma and reported difficulty to insert the electrode due to the high consistency of the tumor site.

New therapies of RFA in combination with liposomal chemotherapy may increase the volume of necrosis compared to RFA alone39.

Similarly, the intralesional administration of interleukins (IL-7 and IL-15) following RFA may trigger an anti-tumor immune response that may inhibit local tumor progression and metastasis, opening the possibility of future lines of treatment 40-42.

Ultrasound ablation

Physical basisUS ablation is the only thermal ablation technique that does not involve the insertion of an applicator into the tumor, therefore maintaining the skin integrity. An ultrasound beam with a frequency ranging 0.5 to 4MHz is directed at a specifi c point located at some distance from the generator. This way, the acoustic energy is converted to heat, heating the target tissue and ultimately leading to tissue coagulation. This causes no damage to skin and surrounding tissues or a negligible temperature increase.

ProcedureThe volume of tissue damaged by a single ultrasound beam has a spheroidal morphology and the size of a rice grain. For this reason, the whole volume of the tumor and the ablation margins are treated by overlapping multiple beams in a planned manner. This increases the duration of the procedure considerably, which may range from 45 minutes to 2.5 hours.

MRI guidance is the most commonly used technique for the treatment of breast carcinomas, allowing the monitoring of the ablation using specifi c thermosensitive techniques. The procedure is generally well-tolerated under local anesthesia and causes no severe complications; however, its application is limited due to the reduced availability of MRI and its long duration. US guidance has also been used, but all the references available come from the same research group43.

ResultsUS-guided series yielded, in general, better results probably because they involved wider ablation margins. Studies with this technique include series followed or not by surgical excision 43-48. The results are heterogeneous, with complete ablation rates ranging from 20 to 100 %.

Laser ablation

Physical basisThis technique uses optical fi bers inserted in the tissues that deliver light energy that increases local temperature ultimately resulting in tissue coagulation.

ProcedureDifferent imaging techniques may be used to guide the fibers. In particular, MR imaging may be used to guide

the fi bers and to monitor the ablation process by means of specifi c thermosensitive sequences. In addition, MR imaging offers information on treatment outcome49.

Laser ablation is usually well tolerated and has no major complications.

ResultsThe fi rst references about this technique date back to the early 90s and few series have been published since then49-55. Laser ablation seems to be effective in the percutaneous treatment of invasive ductal carcinoma of small size with no extensive intraductal component53-55.

Microwave ablation

Physical basisMicrowave ablation is the least known technique. It is an electromagnetic method that induces tumor destruction by means of devices that generate frequencies in the range of 900-2450 MHz56-58.

ProcedureAn antenna inserted into the center of the tumor delivers electromagnetic radiation that generates an oscillating electric field, which shakes the water molecules causing friction that produces heat. Unlike RFA, microwave ablation does not involved alternating electric current, therefore there is no need of return pads, although the resulting coagulation necrosis is similar for both techniques59,60.

The procedure is usually performed under US guidance.

ResultsThe few published series offer poor results61,62. The most relevant series62 is a prospective, multicenter study that comprised 25 patients who underwent microwave ablation with local anesthesia followed by deferred surgical excision. Tumor size ranged from 7-25 mm. Twenty-four patients tolerated the procedure, with or without pain, and in one patient with intense pain the procedure was discontinued. Tumoricidal temperatures were reached in 19 patients but the percentages of necrosis in these patients were very heterogeneous (between 0 and 100 %). The thermal dose proved to be the best predictor of tumor necrosis. Complications included erythema in a high proportion of patients, breast edema in five patients and skin burns in three patients.

Cold ablation techniques: cryoablation or cryotherapy

Physical basisCryoablation destroys tissue through freezing that leads to membrane rupture, causing cell death63. Its use as a palliative treatment in breast tumor has been reported in the literature since the fi rst half of the 20th century.

Technically, cryoablation involves the use of a cryoprobe to deliver cytotoxic temperatures (< —20 °C) into the tissues. In modern cryoprobes, the freezing at the tip is caused by argon decompression due to the Joule-Thompson effect.



ProcedureThe method involves two consecutive freeze-thaw cycles. During the fi rst cycle, an anechoic “ice ball” is formed and gradually encompasses the planned target volume. One advantage of this technique over RF ablation is that the anterior margin of this ice ball is well defined (unlike the posterior margin, hidden behind the acoustic shadow) and may be visualized on US, allowing real-time determination of the extent of thermal destruction. The subsequent thaw process is passive, when the argon fl ow is discontinued, and aimed to sensitize the cells to the second freeze cycle. After the second freeze cycle, an active thaw cycle with helium gas helps withdraw the cryoprobe.

ResultsIts most common indication is the ablation of fi broadenomas. In this respect, several series with large number of patients have been published64-69.

The technique is virtually painless, due to the anesthetic effect of the freezing procedure, and has no complications. The results are usually very good in terms of disappearance of the palpable tumor and radiological imaging of the fi broadenoma; however, disappearance of the tumor after cryoablation is not immediate and may need months, even years.

The cytotoxic effect of the freezing is more effective on the epithelial than on the fibrous component. For this reason, a more cellular tumor is more responsive to the treatment.

Aberrant healing reactions with a persisting palpable mass have been described, but biopsy revealed normal breast tissue or fibrotic areas surrounding a fibroadenoma scar, with very few or absent epithelial component, an effect that has been known for a long time and that may also appear after surgical resections.

The FDA has approved cryotherapy as the preferred technique for patients with fi broadenoma who do not wish to undergo surgery66,68.

More recently published series of cryoablation of small (< 2 cm) invasive breast tumors70,71 reported good results in terms of effectiveness rates (78 % patients had complete tumor destruction) and absence of complications. As with other ablation techniques, the main cause of persistence of residual viable cells was the presence of intraductal component, not so much for the inability of the technique as for the well-known diffi culty of the imaging techniques to determine accurately the intraductal component of some tumors, which prevents an appropriate planning of the target volume.

Cryotherapy has also been used as a preoperative localization method in patients with non-palpable carcinomas, as an alternative to wire localization. A multicenter trial that compared both localization methods 72 reported that positive margin rates did not differ between the two groups, but the volume of breast tissue removed was significantly less in the cryo-assisted localization group (P = 0.002). In addition, cryotherapy was superior in ease of resection, short-term cosmetic results and patient satisfaction. Since this procedure may cause marked nuclear distortion in the histological analysis and alter the results of the immunohistochemical study, these studies must be performed in advance 73.

Experimental models in mice have reported that cryoablation may stimulate an immune response, leading to a response of the antitumor T-cells in the cryoablated tumor draining lymph nodes and a systemic response of the natural killers, that may result in reduced recurrence rates 74,75.

Conclusions

The local treatment of breast cancer is evolving toward less invasive procedures. Imaging techniques are essential for the accurate implementation of the currently available therapeutic armamentarium and future therapeutic developments.

These developments will depend greatly on the ability of current and future imaging techniques to accurately detect, plan and guide tumor destruction. US and MRI are the current techniques of choice. The latter is more precise for determining the local extent of invasive tumors allowing non-invasive monitoring of the ablation process using specifi c thermosensitive sequences as well as assessment of the outcome.

There is increasing evidence that small invasive breast carcinomas may be successfully treated with minimally invasive techniques, especially RF ablation, the best well-known technique so far. Nonetheless, carefully designed phase III trials are needed to compare RFA with conserving surgery in terms of local invasion and survival rates, in order to approve RFA as a valid alternative to standard therapy.

Authorship

1. Responsible for the integrity of the work: LAC 2. Conception of the study: LAC 3. Design: LAC, AOF 4. Acquisition of data 5. Analysis and intrepretation of data 6. Statistical analysis 7. Bibliographic search: LAC, AOF, CAA 8. Drafting of the paper: LAC, AOF 9. Critical review with intellectually relevant contributions:

LAC, AOF, CAA10. Approval of the fi nal version of the manuscript: LAC,

AOF, CAA

Confl ict of interest

The authors declare no confl ict of interest.

Acknowledgements

The authors thank Drs Fernando Domínguez Cunchillos, Ramón Trujillo Ascanio and Miguel Ángel Sanz de Pablo, surgeons at the Breast Disease Unit of our Hospital, for their invaluable help and contribution to the radiofrequency procedures performed in our Department, as well as for their contribution to the review of this work.



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