Ann Thorac Surg 2006;81:327-330
© 2006 The Society of Thoracic Surgeons
New technology
Intraoperative Sentinel Lymph Node Mapping Using a New Sterilizable Magnetometer in Patients with Nonsmall Cell Lung Cancer
Yoshihiro Minamiya, MD, PhD
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,
Manabu Ito, MD,
Yoshihisa Katayose, MD, PhD,
Hajime Saito, MD, PhD,
Kazuhiro Imai, MD,
Yusuke Sato, MD,
Jun-ichi Ogawa, MD, PhD
Division of Thoracic Surgery, Department of Surgery, Akita University School of Medicine, Hondo Akita City, Japan
Accepted for publication June 3, 2005.
* Address correspondence to Dr Minamiya, Division of Thoracic Surgery, Department of Surgery, Akita University School of Medicine, 1-1-1 Hondo Akita City, 010-8543 Japan (Email: minamiya{at}med.akita-u.ac.jp).
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Abstract
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PURPOSE: We recently developed a novel method for sentinel lymph node mapping using magnetic force. However, problems with the sterility and sensitivity of the magnetometer made intraoperative sentinel lymph node mapping impossible. The purpose of this study was to test the utility of a new, more sensitive, sterilizable magnetometer developed in our institute for in vivo sentinel lymph node mapping in patients with nonsmall cell lung cancer.
DESCRIPTION: Ferumoxides (magnetite) served as the tracer. Twenty patients with nonsmall cell lung cancer participated in the study. Each received 5 mL of ferumoxides, which were injected around their tumor. Magnetic force was then measured intraoperatively using the new sterilizable magnetometer.
EVALUATION: The in vivo sentinel lymph node detection rate was 80.0% (16 of 20). The accuracy, sensitivity, and false-negative rates were 100% (16 of 16), 100% (4 of 4) and 0% (0 of 12), respectively. Our preliminary study indicates that our new magnetometer enables in vivo sentinel lymph node mapping in patients with nonsmall cell lung cancer.
CONCLUSIONS: This device safely and accurately detected sentinel lymph nodes in nonsmall cell lung cancer patients.
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Introduction
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The sentinel lymph node (SLN) concept is that lymphatic flux from a primary tumor initially flows into an SLN. If this concept is correct, then when metastasis is not found in an SLN, it almost certainly will not be present in more distal lymph nodes. The primary benefit of SLN mapping and biopsy is that it enables surgeons to avoid nontherapeutic lymph node dissection and the complications that it can cause. Indeed, SLN mapping and biopsy were developed as techniques for staging the lymphatic basin without the potential morbidity of lymphedema and nerve injury in cases of melanoma [1], or lymphedema of the arm in cases of breast cancer [2]. However, the utility of SLN mapping in patients with nonsmall cell lung cancer (NSCLC) remains controversial.
The controversy arises in large part from the fact that two tracers, radioisotope and isosulfan blue dye, have been used to locate SLNs. The SLN concept was applied to patients with NSCLC for the first time by Little and colleagues [3] who were using isosulfan blue dye as the tracer [3]. Thereafter, Liptay and colleagues [4] reported detecting the SLN in NSCLC patients using a radioisotope, thereby confirming the applicability of the SLN concept to patients with NSCLC. However, neither of these techniques is problem free. It is difficult to detect isosulfan blue dye in thoracic lymph nodes because of anthoracosis [5]; moreover, anaphylactic reactions to the dye have been reported [6]. And although Liptay and colleagues [4] reported a high detection rate using radioisotopes, disadvantages of the isotope method have also been reported. For instance, Ueda and colleagues [7] argued that the strong signal from radioisotope injected around the tumor, so-called "shine-through," interferes with detection of radioactivity from intrapulmonary lymph nodes making it difficult to detect the SLN when it is situated in the vicinity of an intrapulmonary bronchus. In addition, precautions must be taken to minimize exposure to radioisotopes. Thus, the best method for SLN mapping in NSCLC has not yet been established. To solve these problems, we developed a new method for detecting SLNs in NSCLC patients using magnetic force [8]. However, our magnetometer was not suitable for in vivo SLN mapping because of the inadequate sterility and sensitivity of the device. Here we describe a new sterilizable and more sensitive magnetometer that we have now used to detect SLNs intraoperatively in patients with NSCLC.
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Technology
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Tracer
Ferumoxides, a colloidal superparamagnetic iron oxide of nonstoichiometric magnetite (Feridex, Eiken Chemistry Co, Japan), were used as the tracer. Particle diameters ranged from 70 to 140 nm; the average size was about 100 nm.
Patients
This study was approved by the Institutional Review Boards at Akita University School of Medicine and University Hospital. Twenty consecutive patients with NSCLC were enrolled in the study between April 2004 and December 2004 after obtaining signed informed consent. After preoperative evaluation, the patients were taken to an operating room, and the standard preparations were made for a thoracotomy and lung resection. None of the patients received preoperative chemotherapy or radiotherapy.
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Technique
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Detection of SLN
After thoracotomy, ferumoxides were injected around the tumor; a total of 5.0 mL were administered in four 1.25 mL doses in a four-quadrant region. To avoid surgical destruction of the lymphatic system of the pleura and along the bronchi and vessels, we waited for 15 minutes after the injection before proceeding. To promote migration of ferumoxides throughout the lymphatic vessels, ventilation was continued during the waiting period. The lymph node stations were based on the classification by Naruke and colleagues [9]. During the operation, the magnetic force within the lymph nodes was measured in vivo using a highly sensitive, handheld magnetometer (Fig 1) developed in our institute. This device enabled us to measure the magnetic force of the ferumoxides for as much as 5 mm from the sensor top, which meant we needed to roughly bare the lymph node of interest before making measurements. In addition, we always measured the magnetic force of muscle and skin as a negative control. The values of the negative controls averaged –83.1 ± 30.0. We defined the SLN as the lymph node in which the magnetic force value was more than zero. After completing the SLN mapping, lobectomy, hilar, and mediastinal lymph node dissection was performed, and the number of dissected lymph nodes were 25 to 40.
Pathological Evaluation
All dissected lymph nodes were sectioned and conventionally examined using hematoxylin and eosin staining.
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Clinical Experience
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The patients' characteristics are summarized in Table 1. Pathological analysis revealed that 16 of the 20 patients had no nodal metastasis. No complications related to the injection of ferumoxides or intraoperative measurements of magnetic force were observed. Table 2
summarizes the results of our in vivo detection of SLNs using our new sterilizable magnetometer. After injection of ferumoxides around a tumor, the mean migration time was 28.4 ± 9.1 min (17 
47 min) (Fig 2). Sentinel lymph nodes were detected intraoperatively in 16 (80%) of the 20 patients, and in 12 of those 16 patients a unique SLN station was identified. Two separate stations were classified as SLNs in the remaining 4 patients (Table 2), and in 1 patient the SLN was detected only in N2 (mediastinal lymph node), a so-called "skip SLN pattern" (Table 2, case 4). SLNs were found in parenchymal or hilar nodes (N1), or both in the other 15 patients (Table 2). Histological analysis revealed metastases in 4 patients, all of which were detected in ferumoxide-positive lymph nodes. Of those, 2 patients showed metastasis in both ferumoxide-positive and ferumoxide-negative nodes, whereas the other 2 patients showed metastasis only in ferumoxide-positive nodes. Thus, we accurately identified the SLN in 16 of 16 patients (100%) and inaccurately identified the SLN in no patients, making the sensitivity and false-negative rates 100% and 0%, respectively (Table 3).
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Fig 2. Migration of ferumoxides after injection. The figure depicts a representative plot of the time-dependent migration of ferumoxides after injection. After injecting 5 mL of ferumoxides around the tumor, the lung was ventilated for 15 minutes to promote lymphatic drainage of the tracer. We then measured the magnetic force of the ferumoxides within lymph nodes to detect the sentinel lymph node (SLN). The arrowhead indicates ferumoxide injection at zero minutes.
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Comment
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In an earlier article, we demonstrated a new ex vivo method for detecting the SLN using magnetic force [8]. At that time, we were unable to make intraoperative measurements because it was not possible to adequately sterilize the magnetometer, and the sensitivity of the instrument was comparatively low. Focusing on those weaknesses, we have now improved the magnetometer, making it both sterilizable and more sensitive. With this new instrument, we were able to detect SLNs intraoperatively in patients with NSCLC.
Although significantly improved, the sensitivity of the new magnetometer is still less than that of a gamma probe. For that reason, we needed to roughly bare the lymph node of interest before the magnetic force of the ferumoxides within could be measured. Because of its high sensitivity, there is no need to bare lymph nodes when using a gamma probe, but that high sensitivity can also be problematical. For instance, Liptay and colleagues [4] reported that when a small tracer (99 m-sulfur colloid) was used for mapping, it was difficult to obtain useful gamma counts from the upper mediastinal lymph nodes during surgery because of an interfering signal from radioisotope that had migrated into the trachea from the lung [4]. In addition, even when a larger tracer (99 m-tin colloid) was used, the strong signal from the injected radioisotope around the tumor, so-called "shine-through," interfered with the detection of radioactivity from intrapulmonary lymph nodes [7]. Presently, our ultimate aim is to develop a magnetometer that is sensitive enough to detect the magnetic force within an SLN of interest without baring it, but not so sensitive that "shine-through" becomes a problem if the SLN is an intrapulmonary lymph node. Alternatively, it may be possible to simply use ferumoxides with larger particle sizes as the tracer, but no such product is commercially available at this time.
In the present study, SLNs were mainly identified among the interlobar (number 11) and lobar (number 12) lymph nodes; a mediastinal lymph node station contained the SLN in only 1 of the 16 patients studied. By contrast, we and others previously reported that 20% to 50% of SLNs are found at the level of the mediastinal stations [4, 8, 10]. It is possible that this discrepancy reflects the limited number of patients in the present study and that more SLNs will be identified at the level of the mediastinal nodes as more cases are examined. Further investigation should resolve this issue.
In summary, we have developed a sterilizable magnetometer that enables us to detect SLNs intraoperatively. This method seems to have advantages compared with SLN mapping using radioisotope, although only a limited number of patients have been investigated. Further investigation will be required to confirm the utility and safety of this approach.
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Disclosures and Freedom of Investigation
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This work was partially supported by the Magnetic Health Science Foundation. Authors had full control of the design of the study, methods used, outcome measurements, data analysis, and production of the written report.
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Disclaimer
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The Society of Thoracic Surgeons, the Southern Thoracic Surgical Association, and The Annals of Thoracic Surgery neither endorse nor discourage use of the new technology described in this article.
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Acknowledgments
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The authors thank Mitsuko Sato and Jun Kodam for their secretarial support.
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References
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- Shen J, Wallace AM, Bouvet M. The role of sentinel lymph node biopsy for melanoma Semin Oncol 2002;29:341-352.[Medline]
- Petrek JA, Senie RT, Peters M, Rosen PP. Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis Cancer 2001;92:1368-1377.[Medline]
- Little AG, DeHoyos A, Kirgan DM, Arcomano TR, Murray KD. Intraoperative lymphatic mapping for non-small cell lung cancerthe sentinel node technique. J Thorac Cardiovasc Surg 1999;117:220-234.[Abstract/Free Full Text]
- Liptay MJ, Masters GA, Winchester DJ, et al. Intraoperative radioisotope sentinel lymph node mapping in non-small cell lung cancer Ann Thorac Surg 2000;70:383-390.
- Sugi K, Fukuda M, Nakamura H, Kaneda Y. Comparison of three tracers for detecting sentinel lymph nodes in patients with clinical N0 lung cancer Lung Cancer 2003;39:37-40.[Medline]
- Albo D, Wayne JD, Hunt KK, et al. Anaphylactic reactions to isosulfan blue dye during sentinel lymph node biopsy for breast cancer Am J Surg 2001;182:393-398.[Medline]
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Abstract
Introduction
