- Email: [email protected]
Intraoperative Radiofrequency Ablation of Lung Metastases and Histologic Evaluation
Thomas Schneider, MD, Arne Warth, MD, Esther Herpel, MD, Philipp A. Schnabel, MD, PhD, Andreas von Deimling, MD, PhD, Ralf Eberhardt, MD, Felix J. F. Herth, MD, PhD, Hendrik Dienemann, MD, PhD, and Hans Hoffmann, MD, PhD Departments of Thoracic Surgery and Pneumology and Respiratory Critical Care Medicine, Thoraxklinik Heidelberg; Institute of Pathology, Department of General Pathology, University of Heidelberg, and Institute of Pathology, Department of Neuropathology, University of Heidelberg and DKFZ, Heidelberg, Germany
Background. Radiofrequency ablation (RFA) has received high interest in the treatment of primary and secondary lung neoplasms. Clinical experience continues to accumulate; however, the biologic effects after ablation remain poorly understood. This study evaluated the safety and feasibility of RFA in an open thoracotomy setting and investigated the early histopathologic changes after RFA. Methods. The study enrolled 18 subjects with multiple pulmonary metastases from a solid primary tumor. RFA was performed at an open thoracotomy setting, followed by wedge resection of the ablated tumor. Results. No intraoperative complications during the RFA procedure occurred. Immunostaining revealed a
complete ablation in 7 patients (39%). The grade of ablation was greater than 90% in 9 patients (50%), and less than 90% in 2 (11%). No correlation was found between the grade of ablation and the applied energy and the diameter of the lesion. Conclusions. Intraoperative RFA in an open thoracotomy setting appears to be a safe and feasible technique. Tumor devitalization sufficient for local control was achieved in 89% in our series. Ablation was incomplete in 11%, subject to the methods used in this study. This result appears to be inferior to metastasectomy by surgical resection. (Ann Thorac Surg 2009;87:379 – 84) © 2009 by The Society of Thoracic Surgeons
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technique and to investigate the safety and efficiency of the bipolar RFA method. It is an evaluation of an intraoperative “ablate and resect” protocol of lung metastases. Only patients with multiple pulmonary metastases from metastasizing solid tumors were enrolled, fulfilling the criteria for curative pulmonary metastasectomy [15]. Nonablated metastases served as the controls.
ercutaneous image-guided ablative techniques using thermal energy sources such as radiofrequency, laser, or cryotherapy have received much attention as minimally invasive strategies to treat malignant diseases. Radiofrequency-induced tissue ablation (RFA) is meanwhile implemented in the treatment of unresectable liver tumors and is increasingly in use on other solid tumors [1– 4]. The number of reports on the application of RFA on patients with primary and secondary lung tumors that were not considered to be surgical candidates is growing [5– 8]. However, it is still unclear whether RFA can reach the same standard in terms of radicality as surgical resection. The effect of RFA on the tumor is generally determined by measurements using computed tomography (CT), magnetic resonance imaging (MRI), or positron-emission tomography (PET) rather than histologic analysis [9]. Some authors have performed percutaneous biopsies to detect a persistent tumor [10 –12]; only few studies have investigated the histologic changes on tumor tissue after RFA [5, 13, 14]. This study was designed to examine histologic changes on tumor tissue immediately after RFA using a bipolar
Accepted for publication Oct 21, 2008. Address correspondence to Dr Hoffmann, Department of Thoracic Surgery, Thoraxklinik am Universitätsklinikum Heidelberg, Amalienstrasse 5, Heidelberg, D-69126, Germany; e-mail: hans.hoffmann@ urz.uni-heidelberg.de.
© 2009 by The Society of Thoracic Surgeons Published by Elsevier Inc
Patients and Methods Patients The study enrolled 24 patients with multiple pulmonary metastases from a solid primary tumor (colorectal cancer, 10; renal cancer, 7; melanoma, 2; and soft tissue sarcoma, 5) that fulfilled the criteria for curative metastasectomy [15]. Mean age was 60.9 years, with 13 women and 6 men. To limit the total operation time for study purposes, the maximum diameter of the pulmonary metastases to be ablated was 2.5 cm. The patients were recruited from November 2005 to September 2007. The Ethics Committee of the University of Heidelberg approved this study (Study No. 503/2005). Each patient was informed comprehensively about the RFA procedure and the operation and provided written consent before participation.
Surgery and RFA For RFA we used the bipolar CelonPro Surge radiofrequency ablation system (Celon AG Medical Systems, 0003-4975/09/$36.00 doi:10.1016/j.athoracsur.2008.10.088
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Teltow, Germany). The electric current is applied using a bipolar coagulation electrode with a conductive area of 20 or 30-mm length at the tip of the applicator. The energy is provided by a power control unit (CelonLab Power) that offers the opportunity to connect up to 6 bipolar applicators simultaneously for multifocal application. During the ablation procedure, targeted energy and impedance is monitored, but the tissue temperature cannot be controlled. The energy source for tissue heating is a rapid alternating electric current with a frequency in the range of radio waves, typically 460 to 500 kHz. Applied electric power ranges from 10 to 200 W, with a maximum current of 500 to 2000 mA. Monopolar techniques to ground the patient with electrosurgical dispersive pads on the patient’s thigh are widespread, whereas bipolar and multipolar techniques are more recent developments, at present increasingly in use especially in European countries. In this study, RFA was performed at an open thoracotomy setting. The pulmonary tumors were localized by manual palpation. One pulmonary tumor was resected by wedge-resection, followed by immediate intraoperative frozen sectioning. After histologic proof, the RFA needle electrode was placed through the thoracotomy incision into a pulmonary tumor. The correct placement of the electrode in the middle of the pulmonary tumor was verified by manual palpation. In tumor size smaller than 1 cm, the conductive electrode length was 20 mm; in tumor size exceeding 1 cm, a conductive electrode length of 30 mm was used. Only a single electrode was placed; we did not perform multiple placements with overlapping ablation zones. During the RFA procedure, the lung was ventilated with a continuous positive airway pressure (CPAP) of 10 mm Hg. The radiofrequency current was applied according to the manufacturer’s protocol for the treatment of lung tumors, which was a preliminary version for the evaluation of RFA in the lung. For tumor diameters of 0.5 to 1.0 cm, the energy was 4 kJ or maximum time of 10 minutes; for tumor diameters of 1.0 to 2.5 cm, the energy was 12 kJ or a maximum time of 15 minutes. Power and applied energy were continuously monitored during the RFA process. Wedge resection of the ablated tumor was performed. Further nonablated pulmonary tumors were resected subsequently and served as histologic controls. Systematic mediastinal and hilar lymphadenectomy was performed concurrently with all procedures.
Table 1. Radiofrequency Ablation Procedures: Failures for Technical Reasons Reason
No.
Failed electric contact Positioning of the electrode not central Histologic proof: nonmalignant lesion
3 2 1
Total
6
Fig 1. Applied energy depending on tumor size. Solid circles ⫽ grade of ablation 100%; solid squares ⫽ grade of ablation ⬎90%; triangle ⫽ grade of ablation ⬍90%.
Pathologic Workup The tumors were bisected through the largest diameter in a right angle referring to the RFA electrode direction and marked by a sterile plastic tube that was introduced into the duct of the coagulation electrode immediately after the RFA procedure. The specimens for routine diagnostics and immunohistochemistry were fixed in 4% nonbuffered formalin-solution. For each tumor treated with RFA, a corresponding tumor of the same size not treated with RFA was taken for control. The specimens were examined by light microscope. Routine staining was done with hematoxylin and eosin (H&E). Analysis of cellular vitality was performed with mouse antihuman mitochondria monoclonal antibody (MAB 1273; Millipore UK, Hertfordshire, UK) and nicotinamide dinucleotide-diaphorase (NADH) [16, 17]. MAB 1273 recognizes a 65-kD protein of human mitochondria by immunoprecipitation that gives a “spaghetti-like” staining pattern in the cytoplasm. The histopathologic criterion for cell death in MAB 1273 immunohistochemistry was the lack of staining in the RFA-treated tissue. NADH staining relies on the reduction of nitroblue tetrazolium chloride by cells expressing NADH. Nonviable cells lack staining; subsequently, positive staining implies cellular viability. For NADH staining, the tumors were bisected after resection as described. One section of the ablated tumor as well as one section of a nonablated tumor were snap-frozen in liquid nitrogen and stored immediately at – 80°C. NADH staining was performed in eight of the total 18 RFA procedures. The effect of RFA on histology of the tumors was evaluated by 2 experienced pathologists and was categorized into three groups. A completely negative staining (MAB 1273 or NADH, or both) of tumor tissue of ablated lesions compared with controls was regarded as 100% nonviable cells present. Incomplete ablation was categorized in more than 90% and less than 90% nonviable cells, respectively.
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Table 2. Tumor Characteristics and Grade of Ablation Diameter Primary Tumor Colorectal cancer Renal cancer Melanoma Sarcoma Total
Grade of Ablation, No. (%)
No.
Range (cm)
100%
⬎90%
⬍90%
7 4 2 5
1.0–2.5 0.9–2.5 0.7–2.5 0.7–2.0
1 2 0 4
4 2 2 1
2 0 0 0
18
0.7–2.5
7 (39)
9 (50)
2 (11)
Results The study enrolled 24 patients. For technical reasons, 6 had to be excluded from the evaluation (Table 1). In three procedures, contact of the electric current was interrupted, and the RFA procedure was terminated prematurely. In two earlier procedures, the coagulation electrode was not correctly placed in the center of the tumor; the pathologist detected the insertion channel on the edge or beside the tumor. In 1 patient with multiple metastases from renal carcinoma, histology of the ablated metastasis finally proved to be an intrapulmonary lymph node free from tumor. The remaining 18 patients were included for further analysis. Maximum diameter of the ablated tumors was 0.7 to 2.5 cm, and applied energy during the RFA procedure was 3.25 to 13.2 kJ. There was a linear correlation between applied energy and the diameter of the lesions (Fig 1). Colorectal cancer (n ⫽ 7) and renal cancer (n ⫽ 4) were the most common primary tumors (Table 2). Complete surgical resection of the metastases was possible in all patients. In all evaluated patients, the intraoperative placement of the electrode into the tumors under digital control in the nonventilated lung was successful, and the
Fig 2. Pulmonary tumor bisected after radiofrequency ablation procedure shows central lesion after correct positioning of the coagulation electrode and the vessel in the marginal area of the tumor (arrow).
Fig 3. Positive mitochondria monoclonal antibody (MAB) 1273 staining at the margin of a lung metastasis indicates incomplete devitalization of tumor tissue.
positioning of the electrode into the tumor tissue remained stable under CPAP ventilation. No intraoperative complications during the RFA procedure occurred, and there was no evidence of intraoperative bleeding or thermal injury along the coagulation electrode tract. No sign of prolonged air leak or bronchopleural fistula subsequent to surgical resection was evident. Indeed, in 1 patient the follow-up CT scan showed an intrapulmonary pseudoaneurysm in the left lower lobe adjacent to the position of the previous RFA (primary melanoma, tumor diameter 2.5 cm; applied energy, 7.73 kJ); in the further follow-up, the patient had one event of hemoptysis, but further interventions were not necessary up to now (12 months).
Fig 4. Positive nicotinamide dinucleotide-diaphorase staining at the margin of a lung metastasis indicates incomplete devitalization of tumor tissue.
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Histopathologic Examination In the macroscopic examination of the RFA-treated lesions, the RFA electrode duct was located in a central position of the tumors in all cases included in the analysis (Fig 2). No aspect of thermal damage neither with tumor tissue nor with adjacent lung tissue was evident in gross sectioning. In routine H&E staining, the cytoplasm of the RFAtreated tissue appeared in increased cytoplasmic eosinophilia and with streaks of chromatin. Changes such as cytoplasmic dissolution, nuclear elongation, and blood vessel dilation inconsistent with cautery artifacts were also noted. The tissue architecture of the tumor cells in all patients was preserved, and nonviable cells subsequent to RFA could not be differentiated from viable cells in standard H&E staining. The previous RFA-procedure did not hamper histologic diagnosis in the specimens. Immunostaining was performed using antihuman MAB 1273 and NADH staining. The histopathologic proof of tumor cell viability revealed a complete ablation in 7 patients (39%). The grade of ablation exceeded 90% in 9 patients (50%) and was less than 90% in 2 (11%; Table 2). No correlation was found between the grade of ablation and the applied energy or the diameter of the lesion (Fig 1). In the incompletely ablated tumors, distinct patterns of positive staining were recognized. In 5 subjects, positive staining was located only in marginal areas of the tumor tissue (Fig 3 and 4); whereas in 6 patients, focal areas of positive staining were spread variably over the tumor tissue. Staining of the surrounding lung tissue was present in all patients using MAB 1273, detecting no thermal damages next to the ablated tumor tissue. In NADH staining, small areas with a lack of staining in tumor-adjacent lung tissue—attributable to thermal injury—was seen in 5 subjects.
Comment RFA has in recent years received high interest in the treatment of primary and secondary lung neoplasms. Mostly performed as a CT-guided procedure, the efficacy is usually controlled by radiologic means. Clinical experience continues to grow; nonetheless, the biologic effects after ablation remain poorly understood [18, 19]. The objective of this study was to evaluate the safety and feasibility of RFA in an open thoracotomy setting and to investigate the early histopathologic changes after RFA. Patients with a minimum of 3 pulmonary metastases were included. The first tumor was used for intraoperative frozen sectioning, the second for RFA procedure, and the third as the histologic control. RFA was performed with a bipolar ablation system in a single-needle technique. Tumors with a maximum diameter of 2.5 cm (mean diameter, 1.4 cm) were suitable for the bipolar single-needle technique. In tumors with a diameter exceeding 3 cm, an overlapping multipolar ablation technique with the insertion of 2 to 3 ablation catheters, and an even longer ablation period, would be necessary; for that reason, we limited the diameter of the metastases to
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2.5 cm to restrict the length of the operation for study purposes. The maximum power output during the RFA procedure was regulated by a microprocessor-controlled power control unit on the basis of tissue resistance and impedance. Grounding of the patient is not required in bipolar ablation; therefore, thermal damage at the site of the grounding electrodes, which in monopolar technique is reported in up to 2% of the patients, cannot occur [20, 21]. Early thermal impairment of tumor surrounding lung tissue was proven in 5 subjects. A distinct margin of inflammation or necrosis was not seen in our series; this effect is in conformity with Ambrogi and colleagues [13]. In their series, those lesions that were resected at a later stage after RFA treatment (CT-guided RAF) presented with a better demarcation than those resected immediately after intraoperative RFA [13]. The observed incidence of an intrapulmonary pseudoaneurysm in the same lobe occurring 6 weeks after RFA and surgical resection may be interpreted as late thermal side effect. Histopathologic evaluation of 18 intraoperative RFA procedures showed complete devitalization of tumor tissue in 39% of the lung tumors, nearly complete (⬎90%) devitalization in 50%, and incomplete ablation in 11%. Only a few reports have published histopathologic evaluations after RFA in lung tumors [5, 13, 14, 22]. Our results are in conformity with two comparable protocols of intraoperative RFA on early stage non-small cell lung carcinoma (NSCLC). In one series of eight intraoperative RFA procedures, followed by surgical resection in patients with primary respectable NSCLC, supravital NADH staining showed 100% nonviability in 3 tumors (37.5%), more than 80% nonviability in 4 tumors (50%), and less than 80% nonviability in 1 tumor (12.5%) [5]. Another series of 10 patients with NSCLC found complete necrosis in 6 tumors (67%) [13]. In this protocol, RFA was performed intraoperatively as well as CTguided. Viability of tumor cells was evaluated in this study with H&E staining only. From our experience and in conformity with others, H&E staining may not be an apt method to assess histopathologic changes of ongoing necrosis after RFA [5, 23]. On the other hand, standard tissue-specific protocols for interpretation of histologic findings after RFA do not exist. To investigate early histologic alterations after RFA, the following techniques have been used: NADH supravital-staining, polyclonal rabbit anti-single-stranded DNA, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) method, mouse antihuman MAB 1273, and antimitochondrial antibody 113-1 [5, 16, 17, 23]. We decided on mouse antihuman MAB 1273 because the immunostaining can be made on sections from the formalin-fixed tissue; and we decided on NADH supravital staining, which requires sampling of fresh frozen tissue specimens. Both methods yielded consistent and comparable results assessing the grade of ablation in our series. Although several authors have used NADH staining to assess of tissue viability after RFA in different tumor types, limitations of this method, especially in the early
post-RFA findings, must be discussed. In renal tumors, a short interval between ablation and resection may result in false-positive NADH staining in ablated tumor tissue [24 –27]. The exact timeframe needed for complete inactivation of NADH diaphorase after cell necrosis is not known. Animal models suggest that the full extent of lethal injury may occur after 24 to 72 hours after ablation treatment [22, 28]. Freezing of the ablated tumor tissue in our study was performed after the operation, within 2 to 3 hours after ablation. Of course, this early evaluation after the ablation procedure is a weak point in every “ablate and resect” concept and may lead in a certain number to false-positive results. In our series of 18 patients, we saw complete negative cell viability in only 7 patients (39%). In 9 (50%) the pathologist found tiny spots of viable cells with a share of less than 10% of ablated tumor tissue. With regard to the limitations of the method, we and other authors [5] consider this grade of ablation sufficient for local control on tumor growth. In 2 subjects more than 10% of the ablated tumor tissue remained with positive staining; and these two ablation procedures in our opinion have to be stated as incomplete. The biology of the residual viable tumor cells after RFA remains vague, however; one cannot exclude the possibility that these cells would die off within a few days, thus possibly converting the procedure to 100% success. In this series of intraoperative RFA, 5 patients had to be excluded from analysis for technical reasons caused by our learning curve with this technique: in two procedures, the RFA probes were placed away from the tumor; and in three procedures, the pleural surface shrank because the ablation-induced tissue heating caused repeated interrupted electric contact. We then changed the direction of placement of the RFA probes. In the immediate subpleural tumors, the RFA probes were introduced in an oblique transpulmonary direction, and no interruptions occurred with this technique. During the RFA procedure, we could not foresee what grade of ablation might result, nor was there any warning during the procedure that the ablation might be incomplete. In the two incomplete ablations, the applied energy was within the range recommended by the manufacturer for the treatment of lung tumors, and compared with other procedures in this series, the radiofrequency current was in the upper range (Fig 1). As such, an underestimation of the ablation variables relative to the tumor size is not likely to be the reason for the two failures. The primary tumor in both patients was colorectal cancer; however, the total number of procedures done on metastases of colorectal cancer is far too small for further conclusions concerning differences depending on tumor type. We have no simple explanation for this phenomenon; a possible explanation may be heat loss due to adjacent vessels in the ventilated and perfused lung. In conclusion, intraoperative RFA in an open thoracotomy setting appears to be a safe and feasible technique. Tumor devitalization sufficient for local control was achieved in 89% in our series. Ablation was incomplete in 11%, subject to the methods used in this study. This
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result is inferior to metastasectomy by surgical resection; therefore, patients fulfilling the criteria for curative pulmonary metastasectomy should undergo complete surgical resection of pulmonary metastases. RFA is an option to achieve local control in patients who refuse surgery or are considered poor surgical candidates.
References 1. Mirza AN, Fornage BD, Sneige N, et al. Radiofrequency ablation of solid tumor. Cancer J 2001;7:95–102. 2. Noguchi M, Earashi M, Fujii H, Yokoyama K, Harada K, Tsuneyama K. Radiofrequency ablation of small breast cancer followed by surgical resection. J Surg Oncol 2006;93: 120 – 8. 3. Patriarca C, Bergamaschi F, Gazzano G, et al. Histopathological findings after radiofrequency (RITA) treatment for prostate cancer. Prostate Cancer Prostatic Dis 2006;9:266 –9. 4. Watanabe F, Kawasaki T, Hotaka Y, et al. Radiofrequency ablation for the treatment of renal cell carcinoma: initial experience. Radiat Med 2008; 26:1–5. 5. Nguyen CL, Scott WJ, Young NA, Rader T, Giles LR, Goldberg M. Radiofrequency ablation of primary lung cancer: results from an ablate and resect pilot study. Chest 2005;128: 3507–11. 6. Herrera LJ, Fernando HC, Perry Y, et al. Radiofrequency ablation of pulmonary malignant tumors in nonsurgical candidates. J Thorac Cardiovasc Surg 2003;125:929 –37. 7. Fernando HC, De Hoyos A, Landreneau RJ, et al. Radiofrequency ablation for the treatment of non-small cell lung cancer in marginal surgical candidates. J Thorac Cardiovasc Surg 2005;129:639 – 44. 8. Rossi S, Dore R, Cascina A, et al. Percutaneous computed tomography-guided radiofrequency thermal ablation of small unresectable lung tumours. Eur Respir J 2006;27: 556 – 63. 9. Bojarski JD, Dupuy DE, Mayo-Smith WW. CT imaging findings of pulmonary neoplasms after treatment with radiofrequency ablation: results in 32 tumors. AJR Am J Roentgenol 2005;185:466 –71. 10. Yasui K, Kanazawa S, Sano Y, et al. Thoracic tumors treated with CT-guided radiofrequency ablation: initial experience. Radiology 2004;231:850 –7. 11. Belfiore G, Moggio G, Tedeschi E, et al. CT-guided radiofrequency ablation: a potential complementary therapy for patients with unresectable primary lung cancer–a preliminary report of 33 patients. AJR Am J Roentgenol 2004;183: 1003–11. 12. Akeboshi M, Yamakado K, Nakatsuka A, et al. Percutaneous radiofrequency ablation of lung neoplasms: initial therapeutic response. J Vasc Interv Radiol 2004;15:463–70. 13. Ambrogi MC, Fontanini G, Cioni R, Faviana P, Fanucchi O, Mussi A. Biologic effects of radiofrequency thermal ablation on non-small cell lung cancer: results of a pilot study. J Thorac Cardiovasc Surg 2006;131:1002– 6. 14. Steinke K, Habicht JM, Thomsen S, Soler M, Jacob AL. CT guided radiofrequency ablation of a pulmonary metastasis followed by surgical resection. Cardiovasc Intervent Radiol 2002;25:543– 6. 15. Rusch VW. Pulmonary metastasectomy. Current indications. Chest 1995;107:322S–331S. 16. Itoh T, Orba Y, Takei H, et al. Immunohistochemical detection of hepatocellular carcinoma in the setting of ongoing necrosis after radiofrequency ablation. Mod Pathol 2002;15: 110 –5. 17. Bastide C, Garcia S, Anfossi E, Ragni E, Rossi D. Histologic evaluation of radiofrequency ablation in renal cancer. Eur J Surg Oncol 2006;32:980 –3. 18. Simon CJ, Dupuy DE, DiPetrillo TA. Pulmonary radiofrequency ablation: long-term safety and efficacy in 153 patients. Radiology 2007;243:268 –75.
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19. Sano Y, Kanazawa S, Gobara H, et al. Feasibility of percutaneous radiofrequency ablation for intrathoracic malignancies: a large single-center experience. Cancer 2007;109:1397– 405. 20. Rhim H, Dodd GD, Chintapalli KN, et al. Radiofrequency thermal ablation of abdominal tumors: lessons learned from complications. Radiographics 2004;24:41–52. 21. Steinke K, Gananadha S, King J, Zhao J, Morris DL. Dispersive pad site burns with modern radiofrequency ablation equipment. Surg Laparosc Endosc Percutan Tech 2003;13: 366 –71. 22. Goldberg SN, Gazelle GS, Compton CC, Mueller PR, McLoud TC. Radio-frequency tissue ablation of VX2 tumor nodules in the rabbit lung. Acad Radiol 1996;3:929 –35. 23. Margulis V, Matsumoto ED, Lindberg G, et al. Acute histologic effects of temperature-based radiofrequency ablation on renal tumor pathologic interpretation. Urology 2004;64:660 –3. 24. Stern JM, Anderson JK, Lotan Y, Park S, Cadeddu JA. Nicotinamide adenine dinucleotide staining immediately
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following radio frequency ablation of renal tumors-is a positive stain synonymous with ablative failure? J Urol 2006;176:1969 –72. Marcovich R, Aldana JP, Morgenstern N, Jacobson AI, Smith AD, Lee BR. Optimal lesion assessment following acute radio frequency ablation of porcine kidney: cellular viability or histopathology? J Urol 2003;170:1370 – 4. Thornell LE, Holmbom B, Eriksson A, Reiz S, Marklund S, Naslund U. Enzyme and immunohistochemical assessment of myocardial damage after ischaemia and reperfusion in a closed-chest pig model. Histochemistry 1992;98:341–53. Hsu TH, Fidler ME, Gill IS. Radiofrequency ablation of the kidney: acute and chronic histology in porcine model. Urology 2000;56:872–5. Patterson EJ, Scudamore CH, Owen DA, Nagy AG, Buczkowski AK. Radiofrequency ablation of porcine liver in vivo: effects of blood flow and treatment time on lesion size. Ann Surg 1998;227:559 – 65.
INVITED COMMENTARY Radiofrequency ablation (RFA) for the treatment of either primary or metastatic lung cancer has been used as an alternative, particularly for patients who have limited pulmonary reserve or who are otherwise considered to be “medically inoperable.” Although this emerging technology is the focus of an ongoing cooperative group pilot trial (American College of Surgeons Oncology Group Z4033) for patients with early stage nonsmall cell lung carcinoma, few studies have validated this technique biologically. Schneider and colleagues [1] present their study of intraoperative RFA with an “ablate and resect” approach for the treatment of pulmonary metastases. The purpose of their study was to evaluate the histologic changes in metastatic tumors after intraoperative RFA, with attention to assessing cellular viability at the ablation zone margins. Cellular viability at the tumor margins was determined by two methods: (1) determination of mitochondrial staining by mitochondrialspecific antibody and (2) assessment of nicotinamide adenine dinucleotide (NAD⫹) reduction by vital staining. Of 24 patients enrolled in the study, 6 were excluded, including 2 patients in whom the ablation probe placement was not within the center of the targeted lesion. With tumors ranging in size from 7 mm to 25 mm among the patients consenting to this study, only 39% (7 patients) were found to have complete tumor ablation with neither detection of mitochondrial staining nor NAD⫹-reducing activity noted. Near complete ablation (⬎90%) occurred in an additional 50% (9 patients) of centrally-treated tumors, with incomplete ablation occurring in 2 of the 18 patients studied. Had the 2 patients who were excluded because of tangential probe placement been included in histologic analysis, then incomplete ablation would have occurred in 4 of 20 patients. However, this study was not a trial of RFA efficacy, but rather a study of histopathologic correlation. The authors’ approach of determining cell viability by mitochondrial staining and NAD⫹ activity provides potentially more accurate assessment of tumor viability than standard histologic techniques. Furthermore, because tumors were resected immediately after ablation, continued cell death still might have occurred in situ, as discussed by the authors. Other measures discussed by Schneider and © 2009 by The Society of Thoracic Surgeons Published by Elsevier Inc
colleagues [1], particularly terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, have been evaluated. Most recently, for example, Clasen and colleagues [2] evaluated percutaneous RFA followed by scheduled resection 3 days post-ablation. Of 11 tumors treated in 9 patients, 10 had evidence of tumor necrosis by TUNEL staining and electron microscopy, even though hematoxylin and eosin staining indicated preserved tissue architecture. In addition, there was only minimal to no margin of tissue damage around 2 ablated tumors. Both of these reports demonstrate that validation of nonsurgical ablative technology should include not only standard histologic studies but also evaluation of cellular viability and/or pathomorphology. Ultimately the efficacy of RFA will depend on long-term oncologic outcomes. The authors adopt an appropriate cautionary tone regarding RFA for pulmonary metastasectomy. Their findings demonstrate that ablative techniques, such as RFA, even when properly targeted, still can result in incomplete ablation. Therefore, such an approach should be reserved only for patients considered “medically inoperable.” Surgical metastasectomy, when oncologically and medically feasible, remains the preferred approach. Andrew C. Chang, MD Department of Surgery University of Michigan Medical Center TC2120G/5344 1500 East Medical Center Dr Ann Arbor, MI 48109 e-mail: [email protected]
References 1. Schneider T, Warth A, Herpel E, et al. Intraoperative radiofrequency ablation of lung metastases and histologic evaluation. Ann Thorac Surg 2009;87:379 – 84. 2. Clasen S, Krober SM, Kosan B, et al. Pathomorphologic evaluation of pulmonary radiofrequency ablation. Cancer 2008;113:3121–9. 0003-4975/09/$36.00 doi:10.1016/j.athoracsur.2008.11.045
Background. Radiofrequency ablation (RFA) has received high interest in the treatment of primary and secondary lung neoplasms. Clinical experience continues to accumulate; however, the biologic effects after ablation remain poorly understood. This study evaluated the safety and feasibility of RFA in an open thoracotomy setting and investigated the early histopathologic changes after RFA. Methods. The study enrolled 18 subjects with multiple pulmonary metastases from a solid primary tumor. RFA was performed at an open thoracotomy setting, followed by wedge resection of the ablated tumor. Results. No intraoperative complications during the RFA procedure occurred. Immunostaining revealed a
complete ablation in 7 patients (39%). The grade of ablation was greater than 90% in 9 patients (50%), and less than 90% in 2 (11%). No correlation was found between the grade of ablation and the applied energy and the diameter of the lesion. Conclusions. Intraoperative RFA in an open thoracotomy setting appears to be a safe and feasible technique. Tumor devitalization sufficient for local control was achieved in 89% in our series. Ablation was incomplete in 11%, subject to the methods used in this study. This result appears to be inferior to metastasectomy by surgical resection. (Ann Thorac Surg 2009;87:379 – 84) © 2009 by The Society of Thoracic Surgeons
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technique and to investigate the safety and efficiency of the bipolar RFA method. It is an evaluation of an intraoperative “ablate and resect” protocol of lung metastases. Only patients with multiple pulmonary metastases from metastasizing solid tumors were enrolled, fulfilling the criteria for curative pulmonary metastasectomy [15]. Nonablated metastases served as the controls.
ercutaneous image-guided ablative techniques using thermal energy sources such as radiofrequency, laser, or cryotherapy have received much attention as minimally invasive strategies to treat malignant diseases. Radiofrequency-induced tissue ablation (RFA) is meanwhile implemented in the treatment of unresectable liver tumors and is increasingly in use on other solid tumors [1– 4]. The number of reports on the application of RFA on patients with primary and secondary lung tumors that were not considered to be surgical candidates is growing [5– 8]. However, it is still unclear whether RFA can reach the same standard in terms of radicality as surgical resection. The effect of RFA on the tumor is generally determined by measurements using computed tomography (CT), magnetic resonance imaging (MRI), or positron-emission tomography (PET) rather than histologic analysis [9]. Some authors have performed percutaneous biopsies to detect a persistent tumor [10 –12]; only few studies have investigated the histologic changes on tumor tissue after RFA [5, 13, 14]. This study was designed to examine histologic changes on tumor tissue immediately after RFA using a bipolar
Accepted for publication Oct 21, 2008. Address correspondence to Dr Hoffmann, Department of Thoracic Surgery, Thoraxklinik am Universitätsklinikum Heidelberg, Amalienstrasse 5, Heidelberg, D-69126, Germany; e-mail: hans.hoffmann@ urz.uni-heidelberg.de.
© 2009 by The Society of Thoracic Surgeons Published by Elsevier Inc
Patients and Methods Patients The study enrolled 24 patients with multiple pulmonary metastases from a solid primary tumor (colorectal cancer, 10; renal cancer, 7; melanoma, 2; and soft tissue sarcoma, 5) that fulfilled the criteria for curative metastasectomy [15]. Mean age was 60.9 years, with 13 women and 6 men. To limit the total operation time for study purposes, the maximum diameter of the pulmonary metastases to be ablated was 2.5 cm. The patients were recruited from November 2005 to September 2007. The Ethics Committee of the University of Heidelberg approved this study (Study No. 503/2005). Each patient was informed comprehensively about the RFA procedure and the operation and provided written consent before participation.
Surgery and RFA For RFA we used the bipolar CelonPro Surge radiofrequency ablation system (Celon AG Medical Systems, 0003-4975/09/$36.00 doi:10.1016/j.athoracsur.2008.10.088
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Teltow, Germany). The electric current is applied using a bipolar coagulation electrode with a conductive area of 20 or 30-mm length at the tip of the applicator. The energy is provided by a power control unit (CelonLab Power) that offers the opportunity to connect up to 6 bipolar applicators simultaneously for multifocal application. During the ablation procedure, targeted energy and impedance is monitored, but the tissue temperature cannot be controlled. The energy source for tissue heating is a rapid alternating electric current with a frequency in the range of radio waves, typically 460 to 500 kHz. Applied electric power ranges from 10 to 200 W, with a maximum current of 500 to 2000 mA. Monopolar techniques to ground the patient with electrosurgical dispersive pads on the patient’s thigh are widespread, whereas bipolar and multipolar techniques are more recent developments, at present increasingly in use especially in European countries. In this study, RFA was performed at an open thoracotomy setting. The pulmonary tumors were localized by manual palpation. One pulmonary tumor was resected by wedge-resection, followed by immediate intraoperative frozen sectioning. After histologic proof, the RFA needle electrode was placed through the thoracotomy incision into a pulmonary tumor. The correct placement of the electrode in the middle of the pulmonary tumor was verified by manual palpation. In tumor size smaller than 1 cm, the conductive electrode length was 20 mm; in tumor size exceeding 1 cm, a conductive electrode length of 30 mm was used. Only a single electrode was placed; we did not perform multiple placements with overlapping ablation zones. During the RFA procedure, the lung was ventilated with a continuous positive airway pressure (CPAP) of 10 mm Hg. The radiofrequency current was applied according to the manufacturer’s protocol for the treatment of lung tumors, which was a preliminary version for the evaluation of RFA in the lung. For tumor diameters of 0.5 to 1.0 cm, the energy was 4 kJ or maximum time of 10 minutes; for tumor diameters of 1.0 to 2.5 cm, the energy was 12 kJ or a maximum time of 15 minutes. Power and applied energy were continuously monitored during the RFA process. Wedge resection of the ablated tumor was performed. Further nonablated pulmonary tumors were resected subsequently and served as histologic controls. Systematic mediastinal and hilar lymphadenectomy was performed concurrently with all procedures.
Table 1. Radiofrequency Ablation Procedures: Failures for Technical Reasons Reason
No.
Failed electric contact Positioning of the electrode not central Histologic proof: nonmalignant lesion
3 2 1
Total
6
Fig 1. Applied energy depending on tumor size. Solid circles ⫽ grade of ablation 100%; solid squares ⫽ grade of ablation ⬎90%; triangle ⫽ grade of ablation ⬍90%.
Pathologic Workup The tumors were bisected through the largest diameter in a right angle referring to the RFA electrode direction and marked by a sterile plastic tube that was introduced into the duct of the coagulation electrode immediately after the RFA procedure. The specimens for routine diagnostics and immunohistochemistry were fixed in 4% nonbuffered formalin-solution. For each tumor treated with RFA, a corresponding tumor of the same size not treated with RFA was taken for control. The specimens were examined by light microscope. Routine staining was done with hematoxylin and eosin (H&E). Analysis of cellular vitality was performed with mouse antihuman mitochondria monoclonal antibody (MAB 1273; Millipore UK, Hertfordshire, UK) and nicotinamide dinucleotide-diaphorase (NADH) [16, 17]. MAB 1273 recognizes a 65-kD protein of human mitochondria by immunoprecipitation that gives a “spaghetti-like” staining pattern in the cytoplasm. The histopathologic criterion for cell death in MAB 1273 immunohistochemistry was the lack of staining in the RFA-treated tissue. NADH staining relies on the reduction of nitroblue tetrazolium chloride by cells expressing NADH. Nonviable cells lack staining; subsequently, positive staining implies cellular viability. For NADH staining, the tumors were bisected after resection as described. One section of the ablated tumor as well as one section of a nonablated tumor were snap-frozen in liquid nitrogen and stored immediately at – 80°C. NADH staining was performed in eight of the total 18 RFA procedures. The effect of RFA on histology of the tumors was evaluated by 2 experienced pathologists and was categorized into three groups. A completely negative staining (MAB 1273 or NADH, or both) of tumor tissue of ablated lesions compared with controls was regarded as 100% nonviable cells present. Incomplete ablation was categorized in more than 90% and less than 90% nonviable cells, respectively.
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Table 2. Tumor Characteristics and Grade of Ablation Diameter Primary Tumor Colorectal cancer Renal cancer Melanoma Sarcoma Total
Grade of Ablation, No. (%)
No.
Range (cm)
100%
⬎90%
⬍90%
7 4 2 5
1.0–2.5 0.9–2.5 0.7–2.5 0.7–2.0
1 2 0 4
4 2 2 1
2 0 0 0
18
0.7–2.5
7 (39)
9 (50)
2 (11)
Results The study enrolled 24 patients. For technical reasons, 6 had to be excluded from the evaluation (Table 1). In three procedures, contact of the electric current was interrupted, and the RFA procedure was terminated prematurely. In two earlier procedures, the coagulation electrode was not correctly placed in the center of the tumor; the pathologist detected the insertion channel on the edge or beside the tumor. In 1 patient with multiple metastases from renal carcinoma, histology of the ablated metastasis finally proved to be an intrapulmonary lymph node free from tumor. The remaining 18 patients were included for further analysis. Maximum diameter of the ablated tumors was 0.7 to 2.5 cm, and applied energy during the RFA procedure was 3.25 to 13.2 kJ. There was a linear correlation between applied energy and the diameter of the lesions (Fig 1). Colorectal cancer (n ⫽ 7) and renal cancer (n ⫽ 4) were the most common primary tumors (Table 2). Complete surgical resection of the metastases was possible in all patients. In all evaluated patients, the intraoperative placement of the electrode into the tumors under digital control in the nonventilated lung was successful, and the
Fig 2. Pulmonary tumor bisected after radiofrequency ablation procedure shows central lesion after correct positioning of the coagulation electrode and the vessel in the marginal area of the tumor (arrow).
Fig 3. Positive mitochondria monoclonal antibody (MAB) 1273 staining at the margin of a lung metastasis indicates incomplete devitalization of tumor tissue.
positioning of the electrode into the tumor tissue remained stable under CPAP ventilation. No intraoperative complications during the RFA procedure occurred, and there was no evidence of intraoperative bleeding or thermal injury along the coagulation electrode tract. No sign of prolonged air leak or bronchopleural fistula subsequent to surgical resection was evident. Indeed, in 1 patient the follow-up CT scan showed an intrapulmonary pseudoaneurysm in the left lower lobe adjacent to the position of the previous RFA (primary melanoma, tumor diameter 2.5 cm; applied energy, 7.73 kJ); in the further follow-up, the patient had one event of hemoptysis, but further interventions were not necessary up to now (12 months).
Fig 4. Positive nicotinamide dinucleotide-diaphorase staining at the margin of a lung metastasis indicates incomplete devitalization of tumor tissue.
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Histopathologic Examination In the macroscopic examination of the RFA-treated lesions, the RFA electrode duct was located in a central position of the tumors in all cases included in the analysis (Fig 2). No aspect of thermal damage neither with tumor tissue nor with adjacent lung tissue was evident in gross sectioning. In routine H&E staining, the cytoplasm of the RFAtreated tissue appeared in increased cytoplasmic eosinophilia and with streaks of chromatin. Changes such as cytoplasmic dissolution, nuclear elongation, and blood vessel dilation inconsistent with cautery artifacts were also noted. The tissue architecture of the tumor cells in all patients was preserved, and nonviable cells subsequent to RFA could not be differentiated from viable cells in standard H&E staining. The previous RFA-procedure did not hamper histologic diagnosis in the specimens. Immunostaining was performed using antihuman MAB 1273 and NADH staining. The histopathologic proof of tumor cell viability revealed a complete ablation in 7 patients (39%). The grade of ablation exceeded 90% in 9 patients (50%) and was less than 90% in 2 (11%; Table 2). No correlation was found between the grade of ablation and the applied energy or the diameter of the lesion (Fig 1). In the incompletely ablated tumors, distinct patterns of positive staining were recognized. In 5 subjects, positive staining was located only in marginal areas of the tumor tissue (Fig 3 and 4); whereas in 6 patients, focal areas of positive staining were spread variably over the tumor tissue. Staining of the surrounding lung tissue was present in all patients using MAB 1273, detecting no thermal damages next to the ablated tumor tissue. In NADH staining, small areas with a lack of staining in tumor-adjacent lung tissue—attributable to thermal injury—was seen in 5 subjects.
Comment RFA has in recent years received high interest in the treatment of primary and secondary lung neoplasms. Mostly performed as a CT-guided procedure, the efficacy is usually controlled by radiologic means. Clinical experience continues to grow; nonetheless, the biologic effects after ablation remain poorly understood [18, 19]. The objective of this study was to evaluate the safety and feasibility of RFA in an open thoracotomy setting and to investigate the early histopathologic changes after RFA. Patients with a minimum of 3 pulmonary metastases were included. The first tumor was used for intraoperative frozen sectioning, the second for RFA procedure, and the third as the histologic control. RFA was performed with a bipolar ablation system in a single-needle technique. Tumors with a maximum diameter of 2.5 cm (mean diameter, 1.4 cm) were suitable for the bipolar single-needle technique. In tumors with a diameter exceeding 3 cm, an overlapping multipolar ablation technique with the insertion of 2 to 3 ablation catheters, and an even longer ablation period, would be necessary; for that reason, we limited the diameter of the metastases to
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2.5 cm to restrict the length of the operation for study purposes. The maximum power output during the RFA procedure was regulated by a microprocessor-controlled power control unit on the basis of tissue resistance and impedance. Grounding of the patient is not required in bipolar ablation; therefore, thermal damage at the site of the grounding electrodes, which in monopolar technique is reported in up to 2% of the patients, cannot occur [20, 21]. Early thermal impairment of tumor surrounding lung tissue was proven in 5 subjects. A distinct margin of inflammation or necrosis was not seen in our series; this effect is in conformity with Ambrogi and colleagues [13]. In their series, those lesions that were resected at a later stage after RFA treatment (CT-guided RAF) presented with a better demarcation than those resected immediately after intraoperative RFA [13]. The observed incidence of an intrapulmonary pseudoaneurysm in the same lobe occurring 6 weeks after RFA and surgical resection may be interpreted as late thermal side effect. Histopathologic evaluation of 18 intraoperative RFA procedures showed complete devitalization of tumor tissue in 39% of the lung tumors, nearly complete (⬎90%) devitalization in 50%, and incomplete ablation in 11%. Only a few reports have published histopathologic evaluations after RFA in lung tumors [5, 13, 14, 22]. Our results are in conformity with two comparable protocols of intraoperative RFA on early stage non-small cell lung carcinoma (NSCLC). In one series of eight intraoperative RFA procedures, followed by surgical resection in patients with primary respectable NSCLC, supravital NADH staining showed 100% nonviability in 3 tumors (37.5%), more than 80% nonviability in 4 tumors (50%), and less than 80% nonviability in 1 tumor (12.5%) [5]. Another series of 10 patients with NSCLC found complete necrosis in 6 tumors (67%) [13]. In this protocol, RFA was performed intraoperatively as well as CTguided. Viability of tumor cells was evaluated in this study with H&E staining only. From our experience and in conformity with others, H&E staining may not be an apt method to assess histopathologic changes of ongoing necrosis after RFA [5, 23]. On the other hand, standard tissue-specific protocols for interpretation of histologic findings after RFA do not exist. To investigate early histologic alterations after RFA, the following techniques have been used: NADH supravital-staining, polyclonal rabbit anti-single-stranded DNA, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) method, mouse antihuman MAB 1273, and antimitochondrial antibody 113-1 [5, 16, 17, 23]. We decided on mouse antihuman MAB 1273 because the immunostaining can be made on sections from the formalin-fixed tissue; and we decided on NADH supravital staining, which requires sampling of fresh frozen tissue specimens. Both methods yielded consistent and comparable results assessing the grade of ablation in our series. Although several authors have used NADH staining to assess of tissue viability after RFA in different tumor types, limitations of this method, especially in the early
post-RFA findings, must be discussed. In renal tumors, a short interval between ablation and resection may result in false-positive NADH staining in ablated tumor tissue [24 –27]. The exact timeframe needed for complete inactivation of NADH diaphorase after cell necrosis is not known. Animal models suggest that the full extent of lethal injury may occur after 24 to 72 hours after ablation treatment [22, 28]. Freezing of the ablated tumor tissue in our study was performed after the operation, within 2 to 3 hours after ablation. Of course, this early evaluation after the ablation procedure is a weak point in every “ablate and resect” concept and may lead in a certain number to false-positive results. In our series of 18 patients, we saw complete negative cell viability in only 7 patients (39%). In 9 (50%) the pathologist found tiny spots of viable cells with a share of less than 10% of ablated tumor tissue. With regard to the limitations of the method, we and other authors [5] consider this grade of ablation sufficient for local control on tumor growth. In 2 subjects more than 10% of the ablated tumor tissue remained with positive staining; and these two ablation procedures in our opinion have to be stated as incomplete. The biology of the residual viable tumor cells after RFA remains vague, however; one cannot exclude the possibility that these cells would die off within a few days, thus possibly converting the procedure to 100% success. In this series of intraoperative RFA, 5 patients had to be excluded from analysis for technical reasons caused by our learning curve with this technique: in two procedures, the RFA probes were placed away from the tumor; and in three procedures, the pleural surface shrank because the ablation-induced tissue heating caused repeated interrupted electric contact. We then changed the direction of placement of the RFA probes. In the immediate subpleural tumors, the RFA probes were introduced in an oblique transpulmonary direction, and no interruptions occurred with this technique. During the RFA procedure, we could not foresee what grade of ablation might result, nor was there any warning during the procedure that the ablation might be incomplete. In the two incomplete ablations, the applied energy was within the range recommended by the manufacturer for the treatment of lung tumors, and compared with other procedures in this series, the radiofrequency current was in the upper range (Fig 1). As such, an underestimation of the ablation variables relative to the tumor size is not likely to be the reason for the two failures. The primary tumor in both patients was colorectal cancer; however, the total number of procedures done on metastases of colorectal cancer is far too small for further conclusions concerning differences depending on tumor type. We have no simple explanation for this phenomenon; a possible explanation may be heat loss due to adjacent vessels in the ventilated and perfused lung. In conclusion, intraoperative RFA in an open thoracotomy setting appears to be a safe and feasible technique. Tumor devitalization sufficient for local control was achieved in 89% in our series. Ablation was incomplete in 11%, subject to the methods used in this study. This
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result is inferior to metastasectomy by surgical resection; therefore, patients fulfilling the criteria for curative pulmonary metastasectomy should undergo complete surgical resection of pulmonary metastases. RFA is an option to achieve local control in patients who refuse surgery or are considered poor surgical candidates.
References 1. Mirza AN, Fornage BD, Sneige N, et al. Radiofrequency ablation of solid tumor. Cancer J 2001;7:95–102. 2. Noguchi M, Earashi M, Fujii H, Yokoyama K, Harada K, Tsuneyama K. Radiofrequency ablation of small breast cancer followed by surgical resection. J Surg Oncol 2006;93: 120 – 8. 3. Patriarca C, Bergamaschi F, Gazzano G, et al. Histopathological findings after radiofrequency (RITA) treatment for prostate cancer. Prostate Cancer Prostatic Dis 2006;9:266 –9. 4. Watanabe F, Kawasaki T, Hotaka Y, et al. Radiofrequency ablation for the treatment of renal cell carcinoma: initial experience. Radiat Med 2008; 26:1–5. 5. Nguyen CL, Scott WJ, Young NA, Rader T, Giles LR, Goldberg M. Radiofrequency ablation of primary lung cancer: results from an ablate and resect pilot study. Chest 2005;128: 3507–11. 6. Herrera LJ, Fernando HC, Perry Y, et al. Radiofrequency ablation of pulmonary malignant tumors in nonsurgical candidates. J Thorac Cardiovasc Surg 2003;125:929 –37. 7. Fernando HC, De Hoyos A, Landreneau RJ, et al. Radiofrequency ablation for the treatment of non-small cell lung cancer in marginal surgical candidates. J Thorac Cardiovasc Surg 2005;129:639 – 44. 8. Rossi S, Dore R, Cascina A, et al. Percutaneous computed tomography-guided radiofrequency thermal ablation of small unresectable lung tumours. Eur Respir J 2006;27: 556 – 63. 9. Bojarski JD, Dupuy DE, Mayo-Smith WW. CT imaging findings of pulmonary neoplasms after treatment with radiofrequency ablation: results in 32 tumors. AJR Am J Roentgenol 2005;185:466 –71. 10. Yasui K, Kanazawa S, Sano Y, et al. Thoracic tumors treated with CT-guided radiofrequency ablation: initial experience. Radiology 2004;231:850 –7. 11. Belfiore G, Moggio G, Tedeschi E, et al. CT-guided radiofrequency ablation: a potential complementary therapy for patients with unresectable primary lung cancer–a preliminary report of 33 patients. AJR Am J Roentgenol 2004;183: 1003–11. 12. Akeboshi M, Yamakado K, Nakatsuka A, et al. Percutaneous radiofrequency ablation of lung neoplasms: initial therapeutic response. J Vasc Interv Radiol 2004;15:463–70. 13. Ambrogi MC, Fontanini G, Cioni R, Faviana P, Fanucchi O, Mussi A. Biologic effects of radiofrequency thermal ablation on non-small cell lung cancer: results of a pilot study. J Thorac Cardiovasc Surg 2006;131:1002– 6. 14. Steinke K, Habicht JM, Thomsen S, Soler M, Jacob AL. CT guided radiofrequency ablation of a pulmonary metastasis followed by surgical resection. Cardiovasc Intervent Radiol 2002;25:543– 6. 15. Rusch VW. Pulmonary metastasectomy. Current indications. Chest 1995;107:322S–331S. 16. Itoh T, Orba Y, Takei H, et al. Immunohistochemical detection of hepatocellular carcinoma in the setting of ongoing necrosis after radiofrequency ablation. Mod Pathol 2002;15: 110 –5. 17. Bastide C, Garcia S, Anfossi E, Ragni E, Rossi D. Histologic evaluation of radiofrequency ablation in renal cancer. Eur J Surg Oncol 2006;32:980 –3. 18. Simon CJ, Dupuy DE, DiPetrillo TA. Pulmonary radiofrequency ablation: long-term safety and efficacy in 153 patients. Radiology 2007;243:268 –75.
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19. Sano Y, Kanazawa S, Gobara H, et al. Feasibility of percutaneous radiofrequency ablation for intrathoracic malignancies: a large single-center experience. Cancer 2007;109:1397– 405. 20. Rhim H, Dodd GD, Chintapalli KN, et al. Radiofrequency thermal ablation of abdominal tumors: lessons learned from complications. Radiographics 2004;24:41–52. 21. Steinke K, Gananadha S, King J, Zhao J, Morris DL. Dispersive pad site burns with modern radiofrequency ablation equipment. Surg Laparosc Endosc Percutan Tech 2003;13: 366 –71. 22. Goldberg SN, Gazelle GS, Compton CC, Mueller PR, McLoud TC. Radio-frequency tissue ablation of VX2 tumor nodules in the rabbit lung. Acad Radiol 1996;3:929 –35. 23. Margulis V, Matsumoto ED, Lindberg G, et al. Acute histologic effects of temperature-based radiofrequency ablation on renal tumor pathologic interpretation. Urology 2004;64:660 –3. 24. Stern JM, Anderson JK, Lotan Y, Park S, Cadeddu JA. Nicotinamide adenine dinucleotide staining immediately
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INVITED COMMENTARY Radiofrequency ablation (RFA) for the treatment of either primary or metastatic lung cancer has been used as an alternative, particularly for patients who have limited pulmonary reserve or who are otherwise considered to be “medically inoperable.” Although this emerging technology is the focus of an ongoing cooperative group pilot trial (American College of Surgeons Oncology Group Z4033) for patients with early stage nonsmall cell lung carcinoma, few studies have validated this technique biologically. Schneider and colleagues [1] present their study of intraoperative RFA with an “ablate and resect” approach for the treatment of pulmonary metastases. The purpose of their study was to evaluate the histologic changes in metastatic tumors after intraoperative RFA, with attention to assessing cellular viability at the ablation zone margins. Cellular viability at the tumor margins was determined by two methods: (1) determination of mitochondrial staining by mitochondrialspecific antibody and (2) assessment of nicotinamide adenine dinucleotide (NAD⫹) reduction by vital staining. Of 24 patients enrolled in the study, 6 were excluded, including 2 patients in whom the ablation probe placement was not within the center of the targeted lesion. With tumors ranging in size from 7 mm to 25 mm among the patients consenting to this study, only 39% (7 patients) were found to have complete tumor ablation with neither detection of mitochondrial staining nor NAD⫹-reducing activity noted. Near complete ablation (⬎90%) occurred in an additional 50% (9 patients) of centrally-treated tumors, with incomplete ablation occurring in 2 of the 18 patients studied. Had the 2 patients who were excluded because of tangential probe placement been included in histologic analysis, then incomplete ablation would have occurred in 4 of 20 patients. However, this study was not a trial of RFA efficacy, but rather a study of histopathologic correlation. The authors’ approach of determining cell viability by mitochondrial staining and NAD⫹ activity provides potentially more accurate assessment of tumor viability than standard histologic techniques. Furthermore, because tumors were resected immediately after ablation, continued cell death still might have occurred in situ, as discussed by the authors. Other measures discussed by Schneider and © 2009 by The Society of Thoracic Surgeons Published by Elsevier Inc
colleagues [1], particularly terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, have been evaluated. Most recently, for example, Clasen and colleagues [2] evaluated percutaneous RFA followed by scheduled resection 3 days post-ablation. Of 11 tumors treated in 9 patients, 10 had evidence of tumor necrosis by TUNEL staining and electron microscopy, even though hematoxylin and eosin staining indicated preserved tissue architecture. In addition, there was only minimal to no margin of tissue damage around 2 ablated tumors. Both of these reports demonstrate that validation of nonsurgical ablative technology should include not only standard histologic studies but also evaluation of cellular viability and/or pathomorphology. Ultimately the efficacy of RFA will depend on long-term oncologic outcomes. The authors adopt an appropriate cautionary tone regarding RFA for pulmonary metastasectomy. Their findings demonstrate that ablative techniques, such as RFA, even when properly targeted, still can result in incomplete ablation. Therefore, such an approach should be reserved only for patients considered “medically inoperable.” Surgical metastasectomy, when oncologically and medically feasible, remains the preferred approach. Andrew C. Chang, MD Department of Surgery University of Michigan Medical Center TC2120G/5344 1500 East Medical Center Dr Ann Arbor, MI 48109 e-mail: [email protected]
References 1. Schneider T, Warth A, Herpel E, et al. Intraoperative radiofrequency ablation of lung metastases and histologic evaluation. Ann Thorac Surg 2009;87:379 – 84. 2. Clasen S, Krober SM, Kosan B, et al. Pathomorphologic evaluation of pulmonary radiofrequency ablation. Cancer 2008;113:3121–9. 0003-4975/09/$36.00 doi:10.1016/j.athoracsur.2008.11.045