Sentinel Node Identification Using Technetium-99m Neomannosyl Human Serum Albumin in Esophageal Cancer

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1 Sentinel Node Identification Using Technetium-99m Neomannosyl Human Serum Albumin in Esophageal Cancer Hyun Koo Kim, MD, PhD, SeungEun Kim, MD, PhD, Jong Jae Park, MD, PhD, Jae Min Jeong, PhD, Young Jae Mok, MD, PhD, and Young Ho Choi, MD, PhD Departments of Thoracic and Cardiovascular Surgery, Nuclear Medicine, Internal Medicine, and Surgery, College of Medicine, Korea University Guro Hospital, Seoul; and Department of Nuclear Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea Background. This study is a clinical trial designed to test the reliability and feasibility of sentinel node detection using a new mannose receptor radioactive binding agent in patients with esophageal squamous cell carcinoma. Methods. Twenty-three patients (21 men, 2 women; mean age years) who were candidates for esophagectomy with conventional lymph node dissection for thoracic esophageal cancer were enrolled. A total dose of 1mCi of 99m Tc-MSA [technetium-99m neomannosyl human serum albumin] in 0.2 ml was administered at 4 quadrants into the submucosal layer around the primary tumor under esophagoscopic guidance approximately 1 hour before surgery. Intraoperative sentinel node sampling was subsequently followed by esophagectomy. All harvested lymph nodes were cut into 2-mm slices and ultimately diagnosed using formalin-fixed and paraffin-embedded sections with hematoxylin and eosin staining. Results. The number of dissected lymph nodes per patient was (15 47). Among 23 patients, the sentinel lymph nodes could be identified in 21 patients (91.3%). The sentinel nodes could be identified in all 21 patients with ct1 or T2N0M0 (100%) disease; these patients were candidates for sentinel lymph node navigation surgery for the esophageal cancer. The mean number of sentinel nodes identified was (range, 1 5) per patient. No false-negative sentinel lymph nodes were detected in any of the 8 patients with node-positive disease (0%). Conclusions. Intraoperative sentinel lymph node identification using 99m Tc-MSA was feasible and reliable in patients with esophageal squamous cell carcinoma. (Ann Thorac Surg 2011;91: ) 2011 by The Society of Thoracic Surgeons Accepted for publication Jan 10, Address correspondence to Dr Choi, Department of Thoracic and Cardiovascular Surgery, Korea University Medical Center, 97 Guro-Dongkil, Guro-Ku, Seoul, , Republic of Korea; kughcs@korea.ac.kr. Esophageal cancer is one of the most aggressive malignancies. Lymph node metastasis is a significant prognostic factor for patients with esophageal cancer. The frequency of lymph node metastasis reaches 45% even in pt1b tumors [1]. Because the lymphatic drainage of the esophagus is multidirectional and has a unique lymph-capillary network in the submucosal space, esophageal cancer has unique characteristics; these include a widespread and random pattern of lymph node metastasis from the cervical to the abdominal areas and anastomotic skip metastasis in 50% to 60% of cases to the second or third compartment of the regional lymph nodes [1, 2]. Based on prior reports, radical esophagectomy with 3-field lymph node dissection has been recognized as the standard treatment procedure in some countries, even for clinically node-negative cases [1, 3]. However, this procedure has been related to a significant increase in patient morbidity and mortality and reduced quality of life [4, 5]. Moreover, its effect on prognosis remains controversial [6]. Therefore, individualized selective lymphadenectomy for esophageal cancer has been attempted as a surgical approach to avoid this highly invasive procedure. Miyata and colleagues [7] performed 3-field lymph node dissection when recurrent laryngeal lymph nodes were found on intraoperative histologic examination and (or) genetic analysis using real-time RT-PCR; in other cases, they performed a 2-field lymph node dissection. They found that cervical lymph node dissection for thoracic esophageal cancer could be avoided based on the intraoperative histologic and genetic diagnosis of recurrent laryngeal lymph nodes. Fang and colleagues [8] also reported findings similar to Miyata and colleagues confirming that selective 3-field lymph node dissection for thoracic esophageal squamous cell carcinoma, based on the results of intraoperative ultrasonography for cervical lymph nodes, was effective and useful. Therefore, sentinel lymph node (SLN) mapping may play a significant role in patient management by obtaining individual information that permits adjustments and modifications of the surgical procedure for each patient [9]. A SLN is defined as the first lymph node within the lymphatic basin reached by lymphatic drainage from a solid tumor and is the most common site of micrometastases [10]. Therefore, when metastasis is not found in a 2011 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 1518 KIM ET AL Ann Thorac Surg SENTINEL NODE IN ESOPHAGEAL CANCER 2011;91: SLN, it most likely will not be present in more distal lymph nodes. Although the benefit of SLN mapping and biopsy remains controversial, it has gained acceptance as a way to avoid the complications of lymph node dissection and has become a standard procedure for breast cancer and melanomas [11, 12]. Recently, SLNs have been identified during surgery for gastrointestinal cancer and lung cancer to reduce the need for lymph node dissection [12 14]. The basic technique used for SLN mapping involves injecting a tracer around the tumor and then following it to where it reaches the first drainage lymph node downstream from the tumor. In other words, the method simply entails the use of tracers and their respective detection devices. Since Kitagawa and colleagues [15] first reported SLN mapping in patients with esophageal cancer, various colloidal radioisotopes, such as technetium-99m tin colloid [15, 16], technetium-99m nanocolloid [17], and technetium-99m rhenium sulfide [18], have been used for SLN mapping in patients with esophageal cancer. A variety of colloidal radioisotopes have been used in an attempt to increase the success rate of SLN detection, which depends largely on the colloidal particles used for the study. Particle size and surface characteristics can influence the rate of colloid drainage from the injection site to the lymphatic capillaries and phagocytosis by lymph nodes and macrophages [19, 20]. Recently, in an attempt to identify an agent more accurately representing the physiological flow of lymphatic drainage and for improved accumulation at the SLN, receptor-binding agents of smaller molecular size, targeting mannose-binding proteins in the lymph nodes, have been designed. In a previous report [21], in order to simplify the synthesis and labeling procedure and to improve the biologic properties, a novel mannose receptor-binding agent, technetium-99m neomannosyl human serum albumin ( 99m Tc-MSA) was developed by this lab for SLN identification. The feasibility of SLN mapping using this novel 99m Tc-MSA material has been reported in patients with early-stage lung cancer [22]. This study was designed to test the reliability and feasibility of SLN identification using this new radioactive agent in patients with esophageal cancer. Material and Methods Patients Twenty-three patients (21 men, 2 women; mean age years) who were candidates for esophagectomy with conventional lymph node dissection for thoracic esophageal cancer were consecutively enrolled in this study at the Korea University Guro Hospital. After approval by the Ethics Committee of the Korea University Guro Hospital, written informed consent was obtained from all patients in accordance with the Declaration of Helsinki. Each patient underwent esophagoscopy, esophagography, endoscopic ultrasonography, thoracic and abdominal computed tomography scanning, and positron-emitted tomography to preoperatively determine staging. Clinical staging and pathologic examination of the resected specimens were performed according to the tumor-nodes-metastasis classification as proposed by the 7th edition of the American Joint Committee on Cancer [23]. Injection of Radioisotope Tracer A total dose of 1mCi of 99m Tc-MSA in 0.2 ml was administered at 4 quadrants into the submucosal layer around the primary tumor under esophagoscopic guidance approximately 1 to 3 hours before surgery. A dynamic whole-body single photon emission computed tomography lymphoscintigraphic image was obtained at 30 minutes after injection (Fig 1). Surgery A 2-field lymph node dissection is routinely performed during esophagectomy for middle and lower thoracic esophageal cancer at this center. However, 3-field lymph node dissection is performed if the primary tumor is located at the upper thoracic area, or both recurrent laryngeal lymph nodes are found to have metastases on frozen biopsy during 2-field lymph node dissection in middle and lower esophageal cancer. During this study, 3-field lymph node dissections were performed in middle and lower thoracic esophageal cancer if a SLN was found in the cervical area on the preoperative lymphoscintigraphy or percutaneous gamma probing. Intraoperative Sentinel Lymph Node Mapping The radioactivity in the lymph nodes was counted with a handheld gamma probe (Neo2000; Johnson & Johnson, Cincinnati, OH). At first, SLNs located in the cervical area were identified by percutaneous gamma probing (in vivo counting) in the cervical area. Then samples were ob- Fig 1. Sentinel lymph nodes (arrows) of esophageal cancer on preoperative lymphoscintigraphy.

3 Ann Thorac Surg KIM ET AL 2011;91: SENTINEL NODE IN ESOPHAGEAL CANCER 1519 tained and radioactivity measured on the back table for the ex vivo counting to confirm the SLN status in order to determine whether cervical lymph node dissection should be performed. Next, intraoperative SLN sampling was performed subsequently followed by esophagectomy. The residual SLN in the resected specimen was carefully investigated using the gamma probe on the back table. The radioactivity count was recorded for a 10-second period. A SLN was defined as any node for which the count was 5 times the radioactivity of the esophageal tissue with the lowest count by ex vivo counting. Pathology Examination All harvested lymph nodes including SLNs identified during the operation were examined by frozen sections. They were cut into 2-mm slices and ultimately diagnosed by using formalin-fixed and paraffin-embedded sections with hematoxylin and eosin staining. Statistical Analysis The identification rate was defined as the percentage of patients with detected SLNs among the whole analyzed group. The false-negative rate for SLN identification was assessed by the presence of metastatic lymph nodes not identified as sentinel lymph nodes with the labeled SLNs appearing histologically uninvolved. Statistical analysis was carried out using statistical software (SPSS for Windows, release 12.0; SPSS Inc, Chicago, IL). Results Patient Clinical and Surgical Data The patient characteristics are summarized in Table 1. Nineteen patients had ct1 or T2N0M0 disease; ct3 or positive regional lymph nodes were found in 4 patients who had preoperative concurrent chemoradiation. The esophageal cancer was located at the upper thoracic area in 5 patients, middle in 7, and lower in 11 patients. Four patients with upper thoracic esophageal cancer and 4 patients with middle esophageal cancer underwent the McKeown operation. One patient with upper thoracic esophageal cancer, 3 patients with middle esophageal cancer, and 10 patients with lower esophageal cancer underwent the Ivor-Lewis operation. One patient with lower esophageal cancer underwent esophagectomy with a left thoracotomy due to severe right pleural adhesions. All patients had squamous cell carcinoma on the final pathology. Sentinel Lymph Node Identification The mean number of dissected lymph nodes per patient was (15 47) (Table 2). Cervical lymph node dissection was performed in 8 patients who underwent the McKeown operation. Among them, 4 patients who had esophageal cancer at the middle thoracic area underwent cervical lymph node dissection because SLNs were found at the cervical area on percutaneous gamma probing and the back table ex vivo counting. One patient Table 1. Patient Characteristics Variables No. of Patients (%) Sex Male 21 (91.3) Female 2 (8.7) Clinical TNM stage T1N0M0 10 (43.5) T2N0M0 9 (39.1) T3N0M0 1 (4.3) T1N1M0 1 (4.3) T3N1M0 1 (4.3) T4N1M0 1 (4.3) Preoperative concurrent chemoradiation therapy Yes 4 (17.4) No 19 (82.6) Tumor location Upper thoracic 5 (21.7) Middle thoracic 7 (30.4) Lower thoracic 11 (47.8) Type of surgery Ivor-Lewis 14 (60.9) McKweon 8 (34.8) Left thoracotomy 1 (4.3) Histopathology Squamous cell carcinoma 23 (100) Pathologic tumor-nodes-metastasis stage T1N0M0 8 (34.8) T2N0M0 5 (21.7) T3N0M0 2 (8.7) T2N1M0 1 (4.3) T3N1M0 6 (26.1) T4N1M0 1 (4.3) T2N2M0 3 (13.0) who had esophageal cancer in the upper thoracic area underwent 2-field lymph node dissection because the resection margin was expected to be adequate even if esophagogastrostomy was performed by an Ivor-Lewis procedure. Among 23 patients, SLNs were identified in 21 patients (91.3%). Two patients without SLNs had ct3n1m0 and ct4n1m0 stage disease and had preoperative concurrent chemoradiation therapy. Therefore, the SLNs could be found in all 21 patients who had ct1 or T2N0M0 disease and were candidates for sentinel lymph node navigation surgery for esophageal cancer. The mean number of SLNs identified was (range 1 5) per patient. Seven patients who had esophageal cancer at the lower thoracic area had lymph node metastasis at the intraabdominal area in 4 cases, at both the lower thoracic and intraabdominal area in 2 cases, and both the middle and lower thoracic area in 1 case. One patient who had esophageal cancer at the middle thoracic area had lymph node metastasis to the upper thoracic area. No falsenegative sentinel lymph nodes were detected in any of the patients (0%).

4 1520 KIM ET AL Ann Thorac Surg SENTINEL NODE IN ESOPHAGEAL CANCER 2011;91: Table 2. Results of Sentinel Lymph Node Identification in Esophageal Cancer Mean no. of dissected lymph node Cervical (1 5) Thoracic (3 30) Abdominal (6 28) Total (15 47) Sentinel lymph node detection rate 21/23 (91.3%) Mean no. of sentinel lymph node (1 5) False negative sentinel lymph node 0/9 (0%) Distribution of SLNs in Esophageal Cancer Figure 2 shows the distribution of the SLNs according to the tumor location. For the upper thoracic esophageal cancer the SLNs were detected from the cervical to the lower thoracic area. However, SLNs were not detected at the abdominal area. For the middle thoracic esophageal cancer the SLNs were detected from the cervical to the abdominal area. For lower thoracic esophageal cancer SLNs were detected at the upper thoracic and abdominal areas. However, SLNs were not detected at the cervical area. Comment The most important factor for colloidal agents used for lymphoscintigraphy is the particle size. Smaller colloidal particles result in faster lymphatic drainage from the injection site, thereby enabling more rapid imaging. However, a particle size smaller than 5 nm is not ideal for lymphoscintigraphy because such particles can be cleared from the injection site through the lymphatic capillaries as well as the blood capillaries [24]. By contrast, a larger particle size such as technetium-99m tin colloid could become lodged within the SLNs for a longer period of time than a small particle size, which could lower the false negative rate [25]. A disadvantage of using colloids with a larger particle size is that their poor migration from the injection site consequently delays lymphatic drainage, which can make nuclear imaging and the surgical procedure very time consuming and a burden to patients and staff [21]. In addition, larger particles can be trapped in the interstitial space. The preferred particle size of radiocolloids ranges from 5 to 50 nm [24]; 99m Tc-ASC and 99m Tc-albumin nanocolloids fall within this range. Although various colloidal radioisotopes, such as technetium-99m tin colloid [15, 16], technetium-99m nanocolloid [17], and technetium-99m rhenium sulfide [18], have been used for SLN mapping in esophageal cancer, the optimum particle size for the radioisotope tracer for SLN identification in patients with esophageal cancer has not been determined. To obtain an agent more accurately representing the physiological flow of lymphatic drainage that will optimally accumulate at the SLN, receptorbinding agents of smaller molecular size, targeting mannose-binding proteins in the lymph nodes, have been designed. 99m Tc-diethylenetriaminepentaacetic acidmannosyl-polylysine was the first such agent reported [26]. In a previous report [21], 99mTc-neomannosyl human serum albumin ( 99m Tc-MSA) was synthesized and tested for its feasibility as a lymphoscintigraphic agent. The molecular diameter of human serum albumin (short axis, 6 nm; long axis, 8 nm) was thought to represent the smallest size that could be used without direct drainage into the blood pool through the blood capillaries. Thus, its speed of drainage into the lymphatic system was expected to be maximal, enabling fast imaging of the SLNs. In addition, there are advantages associated with the synthesis of the end product; mannose can easily be conjugated with the amino groups of lysine residues in human serum albumin without the use of a linker mol- Fig 2. The distribution of sentinel lymph nodes according to the tumor location. (A) upper thoracic esophageal cancer, (B) middle thoracic esophageal cancer, (C) lower thoracic esophageal cancer.

5 Ann Thorac Surg KIM ET AL 2011;91: SENTINEL NODE IN ESOPHAGEAL CANCER 1521 ecule, and 99m Tc can be linked to the human serum albumin protein after reducing the intramolecular disulphide bonds. These unique properties enable 99m Tc- MSA to be injected just before surgery or during the operation, which could save time during the surgical procedure, reducing some of the patient and staff burdens. In a previous study of SLN mapping using 99m Tc-MSA for patients with early lung cancer, 30 minutes after injection, the radioisotope had been taken up by the lymph nodes and its detection did not change until 21 hours after the injection. Takeuchi and colleagues [9] reported that technetium-99m tin colloid used for SLN mapping in patients with esophageal cancer migrated to the SLNs within 2 hours and lasted for at least 20 hours. The timing of the tracer administration made no significant difference to the number of SLNs identified among the patients with tracer injection at 2 hours and 16 hours before surgery [27]. Therefore, the radiotracer was injected 1 day before the surgery; this is because a lot of air enters the stomach and small intestine when the radiotracer is injected on the same day as the surgery. However, we performed the surgery on the same day without any difficulty; this is more convenient for the patients and staff. The mean number of dissected lymph nodes per patient was (range 15 47), which was lower than reported in prior studies ( ) [9, 28]. This can be explained by the 2-field lymph node dissection performed in most patients with middle and lower thoracic esophageal cancer. In this study, only 8 patients had cervical lymph node dissection. The mean number of SLNs identified has been reported to range from 2.3 to 4.7 in patients with esophageal cancer [9, 17, 18, 18, 29]. In this study, the mean number of SLNs identified ( , range 1 5) was lower than in prior studies; this was due to the small number of dissected lymph nodes during surgery. The total number of SLN in each patient was relatively higher than in patients with breast cancer but similar to the patients with gastric cancer [27, 30]. The results of these studies suggest that the number of identified SLN may be organ-specific, based on the anatomy of the regional lymphatic network [9]. Fourteen out of 21 patients (66.7%) had multiple SLNs that were located in multiple areas. However, the focus of this study was whether cervical lymph node dissection should be performed. If the SLN were identified only in the mediastinum or abdominal areas and the SLN was pathologically negative in patients with ct1n0m0 middle or lower thoracic esophageal cancer, a cervical lymph node dissection would be unnecessary. If the SLN is pathologically positive for metastasis, a lymph node dissection of the SLN basin should be performed carefully and completely [9]. In particular, if a SLN is identified along the recurrent laryngeal nerves in the upper mediastinum and positive for metastasis, an extended lymphadenectomy including the upper mediastinum and (or) additional cervical lymphadenectomy might be considered. The SLN identification rate using radioisotopes has been reported to be from 90% to 100% in patients with esophageal cancer [9, 17, 18, 28, 29]. In this study, the SLN identification rate was 91.3%. However, 4 out of 23 patients had preoperative concurrent chemoradiation therapy. Therefore, the SLNs were identified in all 21 patients (100%) who had ct1 or T2N0M0 disease who were candidates for sentinel lymph node navigation surgery among the patients with esophageal cancer. This result suggests that SLN mapping should not be used for tumors greater than the ct3 stage, where the original lymphatic drainage routes might be obstructed and (or) altered [9]. The false negative rate was 0% in this study for all patients, which is consistent with the results of other studies (4% 8.7%) [9, 17, 18]. Takeuchi and colleagues [9] reported that the distribution of SLN in patients with thoracic esophageal cancer was widely spread from the cervical to the abdominal areas, and in particular the false negative rate of the SLNs was higher for middle thoracic esophageal cancer. In this study, the distribution of SLNs was similar to these previous results. In upper and middle thoracic esophageal cancer, the SLNs were distributed up to the cervical area; however, SLNs were not found in the cervical area in patients with lower thoracic esophageal cancer. These findings suggest that 2-field lymph node dissection might be adequate for patients with lower thoracic esophageal cancer. In particular, the SLNs were distributed from the cervical to the abdominal area in patients with middle thoracic esophageal cancer, which has a widespread and complicated lymphatic drainage route. These findings are consistent with those of Takeuchi and colleagues; therefore, care should be taken in cases with middle thoracic esophageal cancer. In addition, the SLN mapping for adenocarcinomas of the distal esophagus or esophagogastric junction is useful for modification of the surgical procedures [9]. For example, if a SLN were identified only in the abdominal area and pathologically negative in cases with ct1n0m0 adenocarcinoma of distal esophagus, the patient would be treated with limited resection of the distal esophagus by the transhiatal approach without extensive mediastinal lymph node dissection [31]. On the other hand, if the SLN were positive for metastasis by intraoperative diagnosis, the patient should be treated with an extended transthoracic lymphadenectomy. SLN identification using 99m Tc-MSA in patients with early-stage esophageal squamous cell carcinoma had excellent identification and false-negative rates. In addition, 99m Tc-MSA has the advantage of being simple and easy to use. Therefore, 99m Tc-MSA is a promising method for SLN identification in patients with earlystage esophageal cancer. References 1. Ando N, Ozawa S, Kitagawa Y, Shinozawa Y, Kitajima M. Improvement in the results of surgical treatment of advanced squamous esophageal carcinoma during 15 consecutive years. Ann Surg 2000;232:

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