Difference of Sentinel Lymph Node Identification Between Tin Colloid and Phytate in Patients With Non Small Cell Lung Cancer

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1 of Sentinel Lymph Node Identification Between Tin Colloid and Phytate in Patients With Non Small Cell Lung Cancer Hiroaki Nomori, MD, PhD, Yasuomi Ohba, MD, Kentaro Yoshimoto, MD, Hidekatsu Shibata, MD, Takeshi Mori, MD, PhD, Shinya Shiraishi, MD, PhD, Koichi Kawanaka, MD, and Toshiaki Kobayashi, MD, PhD Departments of Thoracic Surgery and Diagnostic Imaging, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, and Department of Assistive Diagnostic Technology, National Cancer Center Hospital, Tokyo, Japan Background. The advantages and disadvantages of technetium Tc 99m tin colloid and technetium Tc 99m phytate as tracers for sentinel node (SN) identification in patients with clinical stage I non small cell lung cancer were examined retrospectively. Methods. Sentinel node identification was conducted using tin colloid and phytate, respectively, in 73 and 74 patients with clinical stage I non small cell lung cancer. We compared these two tracers in terms of identification rates, numbers of SNs, characteristics of patients whose SNs could not be identified, and the pathologic results of SNs. Results. The tin colloid tracer identified SNs in 54 of the 73 patients (74%), which was significantly lower than the 89% (66 of 74 patients) in the phytate group (p 0.02). The number of SNs per patient was in the tin colloid group, which was significantly less than the in the phytate group (p 0.002). Although patients in the tin colloid group whose SNs could not be identified had a significantly lower forced expiratory volume in 1 second to forced vital capacity ratio than those whose SNs could be identified (p 0.04), the phytate group did not show such a difference. Eleven of 120 patients whose SNs could be identified had pathologic N1 or N2 disease, but neither group showed any false-negative results for SN identification. Conclusions. Both tin colloid and phytate are reliable tracers for identifying SNs in non small cell lung cancer. The advantage of phytate is that SNs can be detected more frequently than with tin colloid, even in patients with a low forced expiratory volume in 1 second to forced vital capacity ratio. However, tin colloid requires fewer nodes than phytate to identify SNs. (Ann Thorac Surg 2009;87:906 10) 2009 by The Society of Thoracic Surgeons Sentinel node (SN) identification using radioisotopes has been applied to various tumors in an effort to minimize lymph node dissection or for intraoperative N staging. In Japan, technetium Tc 99m ( 99m Tc) tin colloid and 99m Tc-phytate have generally been used for SN identification. The main difference between the two is particle size, ie, 400 to 1,000 nm for tin colloid [1] and 200 to 400 nm for phytate [2, 3]. The advantage of phytate is that it can easily reach SNs because of its small particle size, thereby increasing the SN identification rate. However, phytate has the possible disadvantage of increasing false-negative results because it could pass readily through true SNs, continuing to flow further up the chain of lymph nodes. Interestingly, whereas 99m Tc-sulfur colloid, whose particle size is 50 to 100 nm, is generally used in the United States [4], the hottest node identified by this tracer is not always the SN in patients with melanoma [5]. On the other hand, tin colloid, because of its large particle size, can be retained within the SN for a longer time than phytate, possibly lowering the false-negative Accepted for publication Dec 22, Address correspondence to Dr Nomori, Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, , Japan; hnomori@qk9.so-net.ne.jp. rate. Therefore, one of us (H.N.) used tin colloid for SN identification in patients with stage I non small cell lung cancer (NSCLC) from July 2000 to March 2005 at the Saiseikai Central Hospital, Tokyo, Japan [6, 7]. Starting in April 2005 at the Kumamoto University Hospital, we identified SN for intraoperative N staging, again using tin colloid, focusing especially on determining the final indication for segmentectomy in patients with clinical stage Ia NSCLC [8, 9]. However, SN identification using tin colloid was insufficient, particularly in patients with emphysema [6]. Therefore, in January 2007, we switched the tracer to 99m Tc-phytate to take advantage of the smaller particle size relative to 99m Tc-tin colloid, with the aim of increasing the SN identification rate in our patient population. We retrospectively analyzed the advantages and disadvantages of these two tracers for SN identification in patients with NSCLC. Material and Methods Eligibility The study protocol using radioisotopes for SN identification in patients with clinical stage I NSCLC was approved by the ethics committee of the Graduate School of Med by The Society of Thoracic Surgeons /09/$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg NOMORI ET AL 2009;87: SENTINEL LYMPH NODE IDENTIFICATION IN NSCLC 907 Table 1. Patient Characteristics Characteristic Tin Colloid Phytate Mean SD Range Sex (n) Male Female Mean SD Range Mean SD Range Tumor location (n) Right upper lobe Right middle lobe 6 5 Right lower lobe Left upper lobe Left lower lobe 13 6 Histologic type (n) Adenocarcinoma Squamous cell carcinoma Carcinoid 0 1 Operative procedure (n) Lobectomy Segmentectomy Pathologic N stage (n) N N1 3 1 N2 3 6 Total FEV 1 forced expiratory volume in 1 second; capacity; SD standard deviation. FVC forced vital ical Sciences, Kumamoto University, in March Clinical staging was performed using body computed tomography scanning, brain magnetic resonance imaging, and positron emission tomography. All patients provided informed consent after fully discussing the risks and benefits with their surgeons. Eligible patients had clinical stage I peripheral type NSCLC less than 5 cm in diameter and were candidates for lobectomy or segmentectomy with systematic lymph node dissection. Patients From April 2005 to December 2006, 99m Tc-tin colloid was used for SN identification in 73 patients with stage I NSCLC, and 99m Tc phytate was used in 74 patients from January 2007 to May 2008 (Table 1). There were no significant differences in age, sex, functional forced expiratory volume in 1 second to forced vital capacity ratio (FEV 1 /FVC), tumor size, tumor location, histologic type, operative procedure, or pathologic N stage between the two groups. The lymph node nomenclature was based on the original lymph node map for lung cancer [10]. Operative Procedures Whereas lobectomy procedures were basically conducted by means of video-assisted thoracoscopic surgery, segmentectomy was always carried out using open thoracotomy. According to our previous data, there was no difference in the number of lymph nodes dissected between the video-assisted thoracoscopic surgery and open thoracotomy approaches [11]. Administration of Radioactive Colloid Administration of radiotracers was based on a method reported previously [6 9]. According to our previous data [6], approximately 18 hours before surgery, 6 to 8 mci of 99m Tc-tin colloid or 99m Tc-phytate, which had been suspended in a volume of 1 to 1.5 ml, was injected into the peritumoral region. This procedure was carried out in a room with a coregistered single-photon emission computed tomography and computed tomography imaging. Sentinel Node Criteria The radioactivity of the dissected lymph nodes was measured intraoperatively for 10 seconds using a handheld gamma probe (Navigator, Auto Suture Japan, Tokyo, Japan). A node was defined as an SN when the radioactivity count was higher than 10 times the background level. The identified SNs were submitted for intraoperative frozen section. Any patient in whom none of the lymph nodes showed radioactivity 10 times higher than the background level was defined as having no identifiable SN. False-negative results were defined as any metastatic lymph nodes that were not identified as SN in patients whose SNs could be identified. Pathologic Examination Sentinel nodes were examined by intraoperative frozen section with 2- to 3-mm-thick sections. Further histologic examination of the dissected lymph nodes was performed using formalin-fixed and paraffin-embedded sections with hematoxylin and eosin staining. Table 2. Results of Sentinel Node Identification Variable Tin Colloid Phytate Identification rate Number of patients (%) 54/73 (74.0) 66/74 (89) p 0.02 Number of SNs in patients with identifiable SNs Mean SD p Range Radioactive count of SNs Hottest SN Mean SD NS Range ,126 All SNs Mean SD NS Range ,126 NS not significant; SD standard deviation; SN sentinel node.

3 908 NOMORI ET AL Ann Thorac Surg SENTINEL LYMPH NODE IDENTIFICATION IN NSCLC 2009;87: Table 3. Characteristics of Patients With Identifiable and Nonidentifiable Sentinel Lymph Nodes With Tin Colloid Variable Sentinel Lymph Nodes Identifiable Nonidentifiable Mean SD NS Range Mean SD NS Range Operative procedure Lobectomy/ 14/40 5/14 NS segmentectomy Mean SD p 0.04 Range Pathologic N stage NS N N1 3 0 N2 2 1 Total FEV 1 forced expiratory volume in 1 second; FVC forced vital capacity; NS not significant; SD standard deviation. Statistical Analysis s in identification rate, sex, operative procedure, and pathologic N stage between the tin colloid and phytate groups were analyzed for statistical significance using the 2 test. s in the number of SNs, the radioactivity count of SNs, and age between the groups Table 4. Patient Characteristics With Identifiable and Nonidentifiable Sentinel Lymph Nodes With Phytate Variable Sentinel Lymph Nodes Identifiable Nonidentifiable Mean SD NS Range Mean SD NS Range Operative procedure Lobectomy/ 14/52 4/4 NS segmentectomy Mean SD NS Range Pathologic N stage NS N N1 1 0 N2 5 1 Total 66 8 FEV 1 forced expiratory volume in 1 second; FVC forced vital capacity; NS not significant; SD standard deviation. Table 5. Sentinel Node Mapping by Tin Colloid and Phytate Station were analyzed for statistical significance using the Student s t test. Probability values of less than 0.05 were accepted as indicating statistical significance. All values in the text and tables are given as mean standard deviation. Results Number of Patients (%) Tin Colloid Phytate Hilum (total) a 50/54 (93) 58/66 (88) NS Hilar 9/54 (17) b 19/66 (28) c NS Interlobar 8/54 (15) b 20/66 (30) d NS Lobar 24/54 (44) 27/66 (41) NS Segmental 28/54 (52) 34/66 (52) NS Mediastinum (total) 19/54 (35) 39/66 (59) p 0.01 Upper mediastinum 14/54 (26) 29/66 (44) NS Lower mediastinum 7/54 (13) 18/66 (27) NS a Sentinel nodes were identified less frequently in the hilar and interlobar stations than in the segmental station. b p vs segmental station. c p 0.01 vs segmental station. d p 0.02 vs segmental station. NS not significant. Table 2 shows the results of SN identification in the tin colloid and phytate groups. The SNs were identifiable in 54 of 73 patients (74%) in the tin colloid group, which was significantly lower than the 89% (66 of 74 patients) identified in the phytate group (p 0.02). The mean number of SNs identified by tin colloid was nodes/patient, which was significantly less than the in the phytate group (p 0.002). The mean radioactivity of the hottest SNs counted by the gamma probe were and in the tin colloid and phytate groups, respectively, of which the difference was not significant. Table 3 shows the characteristics of patients with identifiable and nonidentifiable SNs in the tin colloid group. The mean FEV 1 /FVC in 19 patients with nonidentifiable SNs was 66% 10%, which was significantly lower than the 72% 10% in 54 patients with identifiable SNs (p 0.04). There were no significant differences in age, tumor size, operative procedure, or pathologic N stage between patients with and without identifiable SNs. Table 4 shows the characteristics of patients with identifiable and nonidentifiable SNs in the phytate group. There were no significant differences in these factors, including FEV 1 /FVC, between patients with and without identifiable SNs. Table 5 shows the SNs identified at the hilum and mediastinum in the tin colloid and phytate groups. In both groups, segmental stations were more frequently identified as SNs than hilar or interlobar stations (p 0.02 to p 0.001). Whereas the SN identification rate did not differ significantly between the two groups at the

4 Ann Thorac Surg NOMORI ET AL 2009;87: SENTINEL LYMPH NODE IDENTIFICATION IN NSCLC 909 Table 6. Sentinel Node Identification in Patients With N1 or N2 Disease No. Age/Sex Tumor Location p-tnm Sentinel Node Lymph Node With Metastasis Tin colloid 1 70/M RLL T1N1M0 #13 # /F LLL T1N2M0 #12 #7, 11, /M RLL T1N1M0 #11 # /M LUL T1N2M0 #5 #5, 12, /M LLL T1N1M1 #10, 13 # /M RML T1N2M0 not identified #1, 2, 3, 4, 11, 12 Phytate 1 70/F RUL T1N1M0 #4, 7, 12, 13 # /M LUL T1N2M0 #4, 5 #5 3 44/F RML T1N2M0 #7, 10 #7 4 68/M LUL T2N2M0 #5, 7, 11, 13 #5 5 61/F RLL T2N2M0 #7, 12 #7, 11, /F LUL T1N2M0 #5 #5, /F LUL T4N2M0 not identified #5, 7, 10, 11, 12, 13 LLL left lower lobe; LUL left upper lobe; RLL right lower lobe; RML right middle lobe; RUL right upper lobe. hilum, tin colloid identified SNs at the mediastinum in 19 of the 54 patients (35%), which was significantly lower than the 58% (39 of the 66 patients) identified in the phytate group (p 0.01). Six and 7 patients had pathologic N1 or N2 disease in the tin colloid and phytate groups, respectively (Table 6). Sentinel nodes could not be identified in 1 patient each of the two groups, because their hilar and mediastinal lymph nodes were completely occupied by metastatic tumors, which could be seen macroscopically during surgery. The remaining 5 and 6 patients with N1 or N2 disease in the tin colloid and phytate groups, respectively, had identifiable SNs. All of these 11 patients had metastases in SNs, resulting in the false-negative rate for SN identification being 0% in both groups. Even in 3 patients with skip metastasis to mediastinal lymph nodes (patients 2, 3, and 4 in the phytate group), the SN identification procedure detected these skip metastases. All 5 patients with N1 or N2 disease in the tin colloid group had metastases in the SNs with the highest radioactivity. On the other hand, of the 6 patients with N1 or N2 disease in the phytate group, 4 had metastases in the SNs with the highest radioactivity, whereas the remaining 2 patients had metastases in the SNs with the second or fourth highest radioactivity but not in that with the highest radioactivity. Comment The present study showed both the tin colloid and phytate to be capable of detecting metastatic SNs in patients with clinical stage I NSCLC. Our previous studies demonstrated the following advantages of identifying the SN in patients with NSCLS: (1) measurement of radioactivity in mediastinal lymph nodes before dissection, ie, in vivo identification of SN, could identify mediastinal SN, which allows mediastinal lymph node dissection to be minimized [7]; and (2) intraoperative N staging by submitting SNs for frozen section can determine the final indication for segmentectomy [8]. The results of the present study and our previous report allow us to conclude that SN identifications, using both tin colloid and phytate, can minimize the mediastinal lymph node dissection and determine the final indication of segmentectomy in patients with clinical stage I NSCLC. Although there have been no reports comparing the identification rate of SNs between tin colloid and phytate in patients with NSCLC, several reports on breast cancer have compared the rates between these two tracers, showing the identification rate with tin colloid to range from 36% to 63%, ie, generally lower than the 82% to 100% range with phytate [2, 12, 13]. Higashi and colleagues [14] examined the particle size of tin colloid at various ratios of a mixture of isotonic sodium chloride and tin colloid solution, showing mean particle sizes of 47, 96, 712, 925, and 1,079 nm at the ratios of 1:4, 1:2, 1:1, 2:1, and 4:1, respectively. In the present study, the ratio of 99m Tc and tin colloid was adjusted to 1:1 to make the 99m Tc-tin colloid in a volume of 1 to 1.5 ml have a radioactivity of 6 to 8 mci. Therefore, based on the data of Higashi and coworkers [14], the particle size of tin colloid in our present study would be approximately 712 nm, ie, larger than that of phytate at 200 to 400 nm [2, 3]. We demonstrated herein that phytate, owing to its smaller particle size, more frequently identifies SNs in patients with NSCLC than tin colloid. The present results show the FEV 1 /FVC ratio to be significantly lower in patients with nonidentifiable SNs than in those with identifiable SNs in the tin colloid group, results consistent with those of our previous study [6]. On the other hand, the phytate group showed no difference in FEV 1 /FVC between patients with and without identifiable SNs. In breast cancer, the SN identification rate is reported to be lower in older than in younger

5 910 NOMORI ET AL Ann Thorac Surg SENTINEL LYMPH NODE IDENTIFICATION IN NSCLC 2009;87: patients, which is attributable to breast tissue gradually being replaced by fat and decreased lymphatic vessel density with aging [15]. We consider that the lung tissue in patients with chronic obstructive pulmonary disease could also possibly have a lower density of lymphatic vessels or lower lymphatic flow than normal lung tissue, a situation comparable to that in breast tissue, which may account for the lower SN identification rate with the tin colloid tracer. However, the phytate might flow through lymphatic vessels more easily and thereby arrive at SNs even in chronic obstructive pulmonary disease patients because of its smaller particle size as compared with tin colloid. We therefore consider phytate to be more appropriate than tin colloid for patients with chronic obstructive pulmonary disease. The present study showed that although the number of SNs identified by tin colloid was higher than that by phytate, the lower number of SNs identified by the former was not associated with false-negative results in patients with N1 or N2 disease. Therefore, tin colloid can detect metastatic lymph nodes with fewer number of SNs submitted for intraoperative frozen section, as compared with phytate. In addition, the SNs with the highest radioactivity identified by tin colloid were consistently metastatic lymph nodes. This is probably attributable to the tin colloid being retained within a true SN for a relatively long time because of its large particle size. On the other hand, the SNs with the highest radioactivity identified by phytate were not always metastatic lymph nodes, probably because phytate can pass through the true SN relatively easily and continue to flow further up the chain of nodes because of its small particle size. We conclude that phytate more frequently identifies SNs than tin colloid, even in patients with low FEV 1 /FVC ratios, whereas the latter can identify SNs with fewer number of lymph nodes examined, thereby allowing the number of SNs submitted for intraoperative frozen section examination to be reduced. Although we are now using phytate for SN identification in patients with clinical stage Ia NSCLC, the limitation of this tracer should be kept in mind, ie, the SNs showing the highest radioactivity identified by phytate are not always metastatic lymph nodes. This work was supported, in part, by a Grant-in-Aid from the Ministry of Health, Labor and Welfare of Japan. References 1. Shimazu K, Tamaki Y, Taguchi T, Takamura Y, Nobuchi S. Comparison between periareolar and peritumoral injection of radiotracer for sentinel lymph node biopsy in patients with breast cancer. Surgery 2002;131: Tsugawa K, Inokuchi M, Miwa K, Noguchi M. Sentinel lymph node biopsy of breast cancer using blue dye and radioisotope. J Jpn Surg Soc 2001;102(Suppl):373 (in Japanese). 3. Campbell J, Bellen JC, Baker RJ, Cook DJ. Technetium-99m calcium phytate optimization of calcium content for liver and spleen scintigraphy: concise communication. J Nucl Med 1981;22: Liptay MJ, Masters GA, Winchester DJ, et al. Intraoperative radioisotope sentinel lymph node mapping in non-small cell lung cancer. Ann Thorac Surg 2000;70: McMasters KM, Reintgen DS, Ross MI, et al. Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed? Ann Surg Oncol 2001;8: Nomori H, Horio H, Naruke T, Orikasa H, Yamazaki K, Suemasu K. Use of technetium-99m tin colloid for sentinel lymph node identification in non-small cell lung cancer. J Thorac Cardiovasc Surg 2002;124: Nomori H, Watanabe K, Ohtsuka T, Naruke T, Suemasu K. 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