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Eur J Cardiothorac Surg 2007;32:770-775. doi:10.1016/j.ejcts.2007.07.012
Copyright © 2007, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
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Subpleural injection of tracer improves detection of mediastinal sentinel lymph nodes in non-small cell lung cancer

Yoshihiro Minamiya*, Manabu Ito, Yukiko Hosono, Hideki Kawai, Hajime Saito, Yoshihisa Katayose, Satoru Motoyama, Jun-ichi Ogawa

Division of Thoracic Surgery, Department of Surgery, Akita University School of Medicine, 1-1-1 Hondo Akita City 010-8543, Japan

Received 3 May 2007; received in revised form 27 June 2007; accepted 13 July 2007.

* Corresponding author. Tel.: +81 18 884 6132; fax: +81 18 836 2615. (Email: minamiya{at}med.akita-u.ac.jp).


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Background: The advantages and disadvantages of various tracer injection protocols for sentinel lymph node (SLN) mapping have been extensively discussed in relation to breast and gastric cancer. But no such discussion has taken place in relation to SLN mapping in non-small cell lung cancer. We therefore studied the effect of two tracer injection protocols on SLN mapping in patients with non-small cell lung cancer; of particular interest was the relationship between subpleural tracer injection and identification of mediastinal SLNs. Methods: A quadrant injection group (n = 49) received 1.6 ml of ferucarbotran by peritumoral quadrant injection after thoracotomy. In the subpleural injection group, the same amount of ferucarbotran was injected into the peritumoral quadrants plus the subpleural region (n = 27). SLNs were then detected intraoperatively by measuring the magnetic force within lymph nodes using a hand-held magnetometer. After completing the SLN mapping, lobectomy and hilar and mediastinal lymph node dissection was performed. Results: The incidence of mediastinal SLNs was significantly higher in the subpleural injection group (45.4%) than in the quadrant injection group (14.6%) (p = 0.007). Moreover, nominal logistic regression analysis revealed subpleural injection to be a significant independent factor contributing to detection of mediastinal SLNs (p = 0.024, odds ratio 5.26). In the quadrant injection group, mediastinal lymph node metastasis was detected in two patients thought to have nonmetastatic parenchymal SLNs. By contrast, there were no false-negative cases in the subpleural injection group. Conclusion: Subpleural tracer injection significantly improves detection of mediastinal SLNs in non-small cell lung cancer.

Key Words: Lung cancer surgery • Lung cancer • Lymph nodes


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
The sentinel lymph node (SLN) concept is that the lymphatic flux from a primary tumor first flows into the SLN before flowing into more distal lymph nodes. If this concept is correct, then when metastasis is not found in a SLN, it most likely will not be present in more distal nodes. Although the benefits of SLN mapping and biopsy remain controversial, it has gained acceptance in recent years as a way to avoid the complications of lymph node dissection, and has become a common procedure in the treatment of breast cancer [1–4] and melanoma [5]. Moreover, a number of investigators have presented evidence of the existence of SLNs in non-small cell lung cancer (NSCLC) and have reported the efficacy of SLN mapping in the treatment of NSCLC [6–13].

The technique of SLN mapping basically involves injecting a tracer around the tumor and then detecting it when it reaches the first drainage lymph node downstream of the tumor. In other words, the method simply entails the use of tracers and respective detection devices. Two major types of tracers, isotope and dye, have been used to locate SLNs (e.g., Little et al. injected around lung tumor with isosulfan blue dye [14]; Liptay et al. injected technetium 99m sulfur colloid directly into lung tumors and detected SLNs with a gamma probe [11]). Unfortunately, none of these techniques is problem free: precautions must be taken to minimize exposure to radioisotopes; it is difficult to recognize isosulfan blue dye in thoracic black-appearing lymph nodes because of anthracosis. From the aspect of detection rate, the isotope method is mainly applied for SLN mapping in this time point. To solve these problems, we developed and reported a new method for SLN mapping using magnetic force [12,13]. As a tracer, we applied colloidal magnetite that has already been approved for clinical use as a contrast material for MRI. We also developed a highly sensitive, hand-held magnetometer to detect the magnetic force of the magnetite within SLNs. Although significantly improved, the sensitivity of our magnetometer is still less than that of a gamma probe. On the other hand, high sensitivity of gamma probe can be problematical. For instance, it is 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 [11]. In addition, even when a larger tracer (99m-tin colloid) was injected preoperatively, the strong signal from the injected radioisotope around the tumor, so-called ‘shine-through,’ interfered with the detection of radioactivity from intrapulmonary lymph nodes [15]. Although the SLN investigators argue the existence of SLNs and the efficacy of SLN mapping in the treatment of NSCLC, we must recognize limitations of SLN mapping. Nomori et al. reported that the SLN detection of the patient with emphysema is lower than that of patient with normal lung function [6]. Destruction of the lymphatic vessels in the alveolar septa and along the airway in emphysema may explain this phenomenon. The presence of gross metastatic disease within a lymph node would inhibit the ingress of tracer by clogging the lymphatic inflow and cause false-negative results. As mentioned above, there are still many problems to be solved. However, the detection rate of SLNs has been reported more than 80% and feasible. Therefore, we can say that SLN mapping remains useful for patients with small tumors and clinically negative lymph nodes and would be a practical procedure in NSCLC.

One of the most avidly debated issues with respect to SLN mapping in patients with breast or gastric cancer has been where to deposit the tracer. In breast cancer, several tracer injection protocols have been reported, including peritumoral injection [1], intralesional injection [3], subdermal injection [16] and subareolar injection [4]. Each has its advantages and disadvantages, and there is not yet consensus as to the best approach. In gastric cancer, both submucosal [17] and subserosal [18,19] injections are still being considered. In NSCLC, however, there has not yet been discussion as to the best tracer injection protocol. The protocols that have thus far been applied to SLN mapping in NSCLC are peritumoral quadrant injections [7,11–13] and single peritumoral injection [6,8–10]. We previously made use of peritumoral quadrant injections and found that the frequency with which mediastinal SLNs were identified was lower than expected [13].

Riquet et al. described subpleural lymphatics that flowed directly into the mediastinal lymph nodes [20]. With that in mind, we tried a five-point injection method (peritumoral quadrant injections plus a subpleural injection) in the present study. Our findings indicate that the five-point injection method is better than quadrant injection in that it reduces the likelihood that mediastinal SLNs will be overlooked in NSCLC.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
2.1 Tracer
Ferucarbotran, a hydrophilic colloidal solution of superparamagnetic iron oxide coated with carbodextran (Resovist, Schering, Tokyo, Japan), was used as the tracer. Particle diameters ranged from 70 to 140 nm; the average size was about 100 nm.

2.2 Patients
This study was approved by the Institutional Review Boards at Akita University School of Medicine and University Hospital. Seventy-six patients with peripheral NSCLC were enrolled in the study between January 2005 and March 2007 after obtaining written 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.

2.3 The groups and detection of SLNs
After thoracotomy, ferucarbotran was injected around the tumor as illustrated in Fig. 1 . In patients operated on between January 2005 and December 2005, 1.6 ml of ferucarbotran was injected into the four quadrants around the tumor (quadrant injection group). In patients operated on between January 2006 and March 2007, the same amount of ferucarbotran was injected into the four quadrants plus the subpleural region around the tumor (subpleural injection group). Our method for measuring magnetic force within lymph nodes has been described previously [13]. Briefly, to avoid surgical destruction of the lymphatic system of the pleura and along the bronchi and vessels, we waited 15 min after injecting the tracer before proceeding. Ventilation was continued during the waiting period to promote migration of the tracer throughout the lymphatic vessels. The lymph node stations were based on the classification by Naruke et al. [21]. During the operation, the magnetic force within lymph nodes was measured in vivo using a highly sensitive, hand-held magnetometer developed at our institute. After completing the SLN mapping, lobectomy and hilar and mediastinal lymph node dissection was performed (number of dissected lymph nodes: 25–40).


Figure 1
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  		Fig. 1. Injection of ferucarbotran. In the quadrant injection group, 1.6 ml of ferucarbotran was injected into the four quadrants around the tumor. In the subpleural injection group, the same amount of ferucarbotran was injected into the four peritumoral quadrants plus the subpleural region.

 
2.4 Pathological evaluation
All dissected lymph nodes were sectioned and conventionally examined using hematoxylin and eosin staining.

2.5 Statistics
Differences between the quadrant injection and subpleural injection groups were assessed using contingency tables and Chi-square tests. To evaluate factors affecting detection of mediastinal SLNs, multinominal logistic regression analysis was performed using the statistical software JMP IN 5.1.1 (SAS Institute, Inc., Cary, NC). Values of p < 0.05 were considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
The patients’ characteristics are summarized in Table 1 . There were no differences between the quadrant injection and subpleural injection groups with respect to sex, age, T-status, N-status, pathological stage, tumor location or histology. Table 2 summarizes the SLN identification in the two groups. SLNs were detected intraoperatively in 41 (83.6%) of the 49 patients in the quadrant injection group, and in 22 (81.5%) of the 27 patients in the subpleural injection group. There was no difference between the quadrant injection and subpleural injection groups with respect to the SLN detection rate.


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  		Table 1 Patient characteristics
 

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  		Table 2 Summary of the sentinel lymph node identification
 
Among the patients in whom SLNs were detected, histological analysis revealed lymph node metastasis in 10 in the quadrant injection group and in 3 in the subpleural injection group. Metastatic SLNs were detected in 7 of the 10 patients in the quadrant injection group. Of those, one patient showed metastasis in both ferucarbotran-positive and ferucarbotran-negative nodes, while the other six showed metastasis only in ferucarbotran-positive nodes. Metastatic SLNs were detected in all three patients showing lymph node metastasis in the subpleural injection group. Of those, one patient showed metastasis in both ferucarbotran-positive and ferucarbotran-negative nodes, while the other two showed metastasis only in ferucarbotran-positive nodes. Thus, in the quadrant injection group we accurately identified the SLN in 38 of 41 patients (92.7%) and inaccurately identified the SLN in 3 patients, making the sensitivity and false-negative rates 92.7% and 7.3%. Table 3 summarizes the false-negative cases in the quadrant injection group. In two of these three patients, SLNs were thought to be detected among the parenchymal lymph nodes, but metastasis was found in the mediastinal and/or hilar nodes. The third patient's disease was advanced, with direct third rib invasion and node metastasis (lymph node #12u). We suggest that lymphatic flux from the tumor escaped lymph node #12u, and ferucarbotran flowed directly into lymph node #11. By contrast, we accurately identified the SLN in all 22 patients (100%) in the subpleural injection group, making the sensitivity and false-negative rates 100% and 0%, respectively.


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  		Table 3 False-negative cases in the quadrant injection group
 
Overall, SLNs were detected among the mediastinal lymph nodes (N2-SLN) significantly more often in the subpleural injection group than in the quadrant injection group (Table 4 ). This tendency was confirmed by nominal logistic regression analysis, which showed subpleural injection to be the only independent factor significantly contributing to the detection of mediastinal SLNs (Table 5 ).


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  		Table 4 Sentinel lymph node locations
 

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  		Table 5 Multinominal logistic regression analysis for mediastinal sentinel lymph nodes
 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
The tracer injection protocols used for SLN mapping have been extensively discussed in relation to breast and gastric cancer, but this has not been the case with NSCLC. For that reason, we compared the utility of two tracer injection protocols for SLN identification in a group of NSCLC patients. We found that a five-point injection method entailing peritumoral quadrant injections plus a subpleural injection enabled detection of significantly more mediastinal SLNs than conventional four-point quadrant injection, without false-negatives.

Although there is evidence for the existence of SLNs in NSCLC [6–13], SLN mapping is not yet widely used in the treatment of NSCLC because the procedure is complicated, and the benefits of SLN mapping in the practical treatment of NSCLC remain unclear. Still, more than 50 papers arguing the benefits of SLN mapping in NSCLC have been published in English since 1999, when Little et al. first described SLN mapping in NSCLC [14]. One reported potential benefit of SLN mapping in NSCLC is that it enables surgeons to more precisely stage the cancer, after which more sensitive techniques can be employed on a limited amount of tissue to detect occult micrometastases with less cost and effort. In addition, SLN mapping can be applied to video-assisted thoracic surgery (VATS) for NSCLC, enabling surgeons to avoid nontherapeutic and technically difficult mediastinal lymph node dissection often carried out with traditional open surgery.

Several protocols for tracer injection have been used to map SLNs in NSCLC patients. When injected intraoperatively, tracer has been mainly administered using four-quadrant peritumoral injection [7,11–13]. In Japan the use of radioisotope is only allowed in specific designated areas, so that they cannot be injected intraoperatively. Consequently, radioisotope tracers are preoperatively administered using a single peritumoral injection under CT-guidance [6,8]. Lardinois et al. injected tracer endoscopically into the peritumoral region [9]. We used four-quadrant peritumoral injections in both of our earlier studies [12,13], and rates of mediastinal SLN detection differed considerably between the two. Although in the first study 50% of SLNs were mediastinal nodes, this high value likely reflects a problem with SLN definition: lymph nodes with the two strongest magnetic signals were classified as SLNs. In the second paper we detected only one mediastinal SLN in 16 patients, which may reflect the small sample size in the study. In the present study, we found that 14.6% (6 of the 41 patients) of SLNs were mediastinal nodes when tracer was injected using the quadrant injection method, which is not different from the 20–25% values reported by others (data not shown, Chi-square test). The five-point injection method with subpleural injection, which is better able to get tracer into the subpleural lymphatics, thus represents a significant improvement over all SLN mapping methods used so far in NSCLC, in that it significantly increases the likelihood of identifying mediastinal SLNs.

Finally, the prognosis of patients with skip mediastinal lymph node metastasis (N1– and N2+) is controversial. Although some groups have reported the prognoses of patients with skip metastases to be better than those of patients with classical mediastinal lymph node metastases (N1+ and N2+) [22,23], others have reported that there is no difference between the prognoses in the two groups [24,25]. We would anticipate that using SLN mapping to determine the lymphatic drainage patterns from the primary lung tumor would be a good approach to investigating and classifying skip mediastinal lymph node metastases. And because it is essential that mediastinal SLNs are not overlooked under any circumstances, our five-point injection method should be carefully considered.

In summary, the five-point injection method with subpleural injection enabled detection of significantly more mediastinal SLNs than the quadrant injection method, without any false-negatives. The five-point injection method thus appears to be better than the conventional quadrant injection method for SLN mapping in NSCLC.


   Acknowledgments
 
The authors thank Ms Mitsuko Sato and Ms Jun Kodama for secretarial support.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

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