, Jian Zhou1 and Qun Wang2
(1)
Department of Thoracic Surgery, Peking University People’s Hospital, No.11, Xizhimen South Street, Beijing, 100044, China
(2)
Department of Thoracic Surgery, Fudan University Zhongshan Hospital, No. 180, Fenglin Rd, Shanghai, 200032, China
The corresponding author of section 9.1 is Hui Zhao, Email: danfeng1974@yahoo.com.cn (✉);
The corresponding author of section 9.2 is Qun Wang, Email: doctorwangqun@aliyun.cn (✉);
9.1 Intraoperative Staging of Lung Cancer: The Sentinel Lymph Node Biopsy in the Intraoperative Staging of Non-small Cell Lung Cancer
(3)
Department of Thoracic Surgery, Peking University People’s Hospital, No.11, Xizhimen South Street, Beijing, 100044, China
9.1.1 Preface
In the staging of non-small cell lung cancer, the status of the drainage lymph nodes is of great concern. Radiological examinations such as computed tomography (CT) or fluoro-2-deoxy- d -glucose (FDG)-positron emission tomography (PET) scanning can aid in the preoperative staging of non-small cell lung cancer. But several meta-analyses has reported low sensitivities and specificities in the assessment of mediastinal lymph node status, which ranged from 50 to 65 %, and from 65 to 85 %, respectively [1]. PET and PET-CT are superior to CT in the preoperative nodal staging, which has been proved by a large number of studies and meta-analyses [1–6]. PET and PET-CT can provide comparable high sensitivities, and negative predictive values to mediastinoscopy. However, due to lack of pathological proof, the positive predictive value and the specificity pf FDG PET scan is lower than mediastinoscopy [1]. Cervical mediastinoscopy, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and esophagoscopy (EUS-FNA) are useful preoperative staging tools. They can provide reliable sensitivity and specificity [1]. But these preoperative staging examinations are performed in patients with enlarged lymph nodes and a high suspicion of N2-N3 disease [7], and they cannot reach all the stations of pulmonary drainage lymph nodes.
Intraoperative lymph node dissection is the most accurate way to determine the pathologic status of lymph node, and is considered as gold standard for the other method to evaluate the pathologic status of lymph node in resectable NSCLC cases.
As the number of the early stage lung cancer increases, more and more sublobar resection, including wedge resection and segmentectomy are performed. And selected lymph node sampling are proved to have a comparable prognosis with complete lymph node dissection in early stage NSCLC patients [8]. Reducing the extent of the lymphadenectomy procedure has been indicated for patients without metastasis to lymph nodes [9–12]. Thus, the point is how to reduce the extent of lymphadenectomy procedure while dissect all the possible metastatic lymph nodes. On the other hand, due to the micrometastasis of NSCLC tumor cells [13], the current pathology evaluation techniques may cause downstaging and undertreatment of the NSCLC patient. A more focused pathologic or molecular staging technique is needed to direct a more focused research for the metastatic disease. The sentinel lymph node identification technique may help in reducing excessive lymphadenectomy procedures and providing more focused pathologic studying,
9.1.2 The History of Sentinel Lymph Node Biopsy
The first sentinel lymph node biopsy was introduced by Cabanas in 1977 in penile cancer [14]. However, the method was found to be unreliable. Because the false negative rate was unacceptably high and too difficult to implement [15]. But in some superficial malignancies such as melanoma and breast cancer, the sentinel lymph node biopsy was well adopted [16, 17]. And used sometimes as standard procedures in the surgeries of these malignancies [18, 19].
In resectable NSCLC surgeries, mediastinal lymph node dissection (MLND) was considered as a standard procedure since Naruke and colleagues created a lymph node map and reported the significance of MLND [20]. And the first sentinel lymph node biopsy was performed by Little and colleagues [21] in 1999, and since then there has been an expanding body of literature.
9.1.3 The Definition and Indication of SLN Biopsy in NSCLC Surgery
The theory of sentinel lymph node is based on the hypothesis that the sentinel node is the first station of nodal drainage, and it can represent the status of the further stations of lymph node. So, the sentinel lymph node biopsy is defined as the first lymph node or group of lymph nodes encountered in lymphatic drainage from the primary tumor [14]. During sentinel lymph node biopsy, one or several tracers is injected near the primary tumor. And the path of lymphatic drainage is mapped using different techniques depending on the characteristics of the tracers. Intraoperative mapping permits selective biopsy of the intrapulmonary, hilar or the mediastinal lymph node. The biopsied specimen is then evaluated using frozen section, touch imprint cytology analysis technique [22] or more accurate techniques such as immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction to identify micro metastasis [23, 24].
The aim of SLN biopsy is to help the pathologic node-negative patients to avoid unnecessary lymphadenectomy without leaving out metastatic lymph nodes, and to reduce the lymphadenectomy complications. So the SLN biopsy should be performed in clinically T1N0M0 patients. The enlarged lymph node indicates increased possibility of metastasis and on the other hand, may block the lymphatic drainage, which may lead to false negative results of the SLN imaging. So the mediastinal lymph node dissection should be performed routinely in radiologically N1 and N2 patients, who might benefit from the thoroughly dissected drainage lymph nodes.
9.1.4 The Tracers Used in SLN Mapping
The first application of sentinel node detection of SLN in non-small cell lung cancer was conducted by Little and colleagues [21] in 1999 using isosulfan blue. The tracer resulted in less than 50 % identification rate. And the primary drawback was the frequently encountered black anthracosis nodes in lung. Since then, a variety of tracers have been reported, including radioactive tracer, fluorescence tracers, magnetic materials, CT contrast agents, and carbon nano-particles. The detection rates and sensitivity of SLN mapping varies between different tracers. A meta-analysis in 2013 shows the pooled detection rate was 80.6 % [76.8–84 %] and pooled sensitivity was 87 % [83–90 %] [25].
9.1.5 Dye
The clinical trial conducted by Little et al. [21] in 1999 was the first application on SLN mapping. In this trial, the group prospectively injected isosulfan blue in 36 patients. Sentinel lymph nodes was identified in 47 % of the patients. The unsatisfying results was caused by original black color of the anthracotic pulmonary lymph nodes and the steep learning curve. Sugi and colleagues [26] and Rzyman and colleagues [27] also reported trials using blue dye staining method for SLN identification and showed inadequate identification rate of SLN.
9.1.6 Radioactive Tracers
9.1.6.1 Intraoperative Injection
The Technetium 99m (Tc 99m) was first used in breast cancer, and the accuracy was reported to exceed 90 % [28, 29]. Liptay et al. reported the first study of Tc 99m sulfur colloid in NSCLC SLN biopsy [30]. They included 148 consecutive patients who underwent completely resected non-small cell lung cancer. Colloid suspension was injected into tumor and outer margins of the tumor and a standard dissection was performed to anatomic resection of the tumor. A hand held gama-counter was used to read the radiation intensity. They observed successful migration of radioisotope through lymphatics in 120 of 148 patients (81 %), and sentinel lymph nodes was identified in 104 of 120 patients. The identification rate was 70 %, and is much higher than blue dye. In the study, they used immunohistochemistry and serial sectioning and detected eight cases of micrometastatic disease. And they found 25 of 104 patients (24 %) with N2 mediastinal nodes as sentinel nodes. But in the following multicenter phases II trial [31], Cancer and Leukemia Group B 140203 (CALGB140203), the identification rate of SLN was only 61.5 % (24 of the 39 patients). Twenty of 24 patients (83.3 %) was found to be true negative (no other nodes were positive if SLN was found to be negative). The overall true negative rate was 20 of 39 patients (51.2 %). The group contributed the lower identification rate to a difficult learning curve. Rzyman et al. [32] reported sentinel node identification rate of 74 % afterwards.
9.1.6.2 Preoperative Injection
Due to restrictions of handling radioactive substances in Japan, Japanese surgeons performed several preoperative injection of radioactive tracers. Nomori and colleagues [33] performed the largest serials based on Tc 99m tin colloid, a larger particle which can last longer in lymph nodes. SLNs were identified in 40 (87 %) of 46 patients, and no false negative SLNs were detected in 14 patients with N1 or N2 disease.
Kim and colleagues [34, 35] also developed a mannose receptor-binding agent called Tc99m neomannosyl human serum albumin (Tc99m MSA). They performed both preoperatively and intraoperatively. The SLN identification rate was high in both groups: 95.8 in preoperative group and 97.1 % in intraoperative group, with no significant difference. They also proved that intraoperative injection is time-saving and less expensive.
Preoperative injection may have some logistical benefits: (1) Avoid intraoperative handling of radioactive substances, (2) Better identification rate in some trials, which is also proved by a meta-analysis study [25]. On the other hand, it has the risk of pneumothorax, hemopneumothorax, metastasis along the needle tract, and may take longer time in total.
The radioactive tracers may have the following shortcomings: (1) Shine-through effect, which is the tumor and background radioactivity aerosolization phenomenon, may cause low identification rate in hilum or interlobar SLNs. (2) The endobronchial migration of radioactivity may lower the identification rate. (3) Difficult learning curve. (4) Handling of radioactive substance may face restrictions and cause potential damage to both patients and surgeons.
9.1.7 Near Infrared Fluorescent Tracers
Near infrared light can penetrate around 1 cm of solid tissue and can be visualize. Using the real-time visible and NIR images, it is possible to simultaneously display the color and NIR images or overlay the two images. Thus we can get an image which can show the exact location of the fluorescent lymph nodes while the color of the mediastinum is not changed. And NIR imaging can avoid the disadvantage of shine-through effect and the government regulations on the radioactive materials. Currently, there are commercial available NIR cameras for both open and thoracic surgery. Several groups have studied on these non-radioactive tracers and there have been promising results.
Soltecz et al. [36] reported the use of NIR fluorescing quantum dots in pigs. They used a camera system that can merge visible image and the near infrared fluorescence. This technique was found to be reliable in identifying the SLNs in pigs. They also proved lymphatics and nodes could be seen through 1 cm of solid tissue and 5 cm of lung parenchyma.
Yamashita and colleagues applied the NIR guided SLN biopsy in thoracoscopic lobectomy and segmentectomy, and reported the SLN identification rate of 80.7 % They also described some technical difficulties such as steep learning curve and factors that impeded detection of signal such as adhesions to pleura, incomplete fissure, and deep nodes. Gilmore et al. [37] utilized NIR and FLARE system in conducting the clinical phase I trial in 38 patients. They performed an dose-efficacy study, which starts from 3.8 μg of peritumorally injected ICG up to 2,500 μg. Concentrations of dye 1,000 μg or greater were associated with an excellent 89 % SLN identification without adverse reactions, whereas doses of less than 600 μg were associated with poor 25 % identification. They also reported 27 % patients with “skip metastasis” directly to N2 nodal stations. A phase II trial is to be anticipated in the future.
9.1.8 CT Contrast Agents
In 2004, Suga and colleagues [38] reported a method of preoperative CT-guided injection of iopamidol in to peritumoral lung tissue. They reported successfully SLN identification in all nine patients without any complications. Takizawa and colleagues [39] also reported a method of inserting an ultrathin bronchoscope into the target bronchus with the guidance of virtual bronchoscopic navigation system. Then the CT image was acquired at 0.5 and 5 min after injection of 2 or 3 mL of iopamidol through a microcatheter. The SLN identification rate was 92.3 % (12 of 13 patients). Although the number of patients studied was small, the SLN identification rate was high.
9.1.9 Combined Tracers/Mutimodal Imaging in SLN Identification
In order to improve the identification rate of SLNs, some researchers tried to combine different tracers or used a tracer that contain combined features of different tracers.
Schmidt et al. [40] attempted to inject blue dye and Tc99m. They reported SLN identification rate of 81 % in 31 patients, which is comparable to Liptay’s study. But in another study conducted by Tiffet et al. [41], they had less success with this combination method, with only 54 % of identification rate in 24 patients. The unsatisfying result may be caused by rushed biopsy of SLN.
Jinzi et al. [42] reported a dual-modality nano liposomal agent (CF800), which can be used as computed tomography contrast and near-infrared fluorescence agent. They performed the application of this agent for preoperative CT three-dimensional surgical planning (>200 Hounsfield units enhancement) and NIR fluorescence guided resection (>5-fold tumor to background ration). This study showed a promising future of this multimodal agent.
9.1.10 Other Tracers
There are also some reports of using positron emission tomography agent (18F-flourodeoxyglycose, FDG) or magnetite in identification of SLN.
9.1.10.1 Positron Emission Tomography/CT Lymphoscintigraphy
Nwogu et al. reported SLN mapping using 18F-flourodeoxyglycose (FDG) peritumoral injections in ten patients [13]. They found three of the ten patients had FDG-positive nodes containing micrometastasis, although these were not SLNs. The group proposed using PET/CT and FDG injections for “ultrastaging” rather than SLN mapping. Eo et al. [43] also reported use of gallium tracer in 34 patients with an identification of 100 %. Although promising, the application was limited by the expense and the small number of the studies.
9.1.10.2 Magnetite
Nakagawa and colleagues [44] reported a method using ferumoxide, a colloidal superparamagnetic iron oxide of nonstoichiometric magnetite, as a tracer. They injected 5 mL of the magnetite in to paratumoral lung tissues intraoperatively. Lung resection and lymph nodes biopsy were performed 15 min late. The resected lymph nodes were examined ex vivo. After the initial study, they developed a more sensitive and sterilizable magnetometer for in vivo examination [45]. The in vivo SLN detection rate was 80 %.
9.1.11 Conclusions
In cases of melanoma and breast cancer, SLN biopsy techniques has been proven to be useful and effective, and have become standard procedures. In NSCLC surgery, the study of the present tracers has progressed. The identification rate was less than 90 % with blue dyes or Tc 99m, complicated by the anthracosis-obscuring dye visualization or shine-through effect. New technologies using different agents such as near infrared fluorescent tracers, CT-contrast agents, multi-modal agent et al. are promising but need additional trials the evaluate the use of various injection strategies.
In future, the SLN biopsy technology may have the potential to reduce the excessive lymphadenectomy. On the other hand, it may also help in identification of the isolated tumor cells (single tumor cells of < =0.2 mm in diameter) or micrometastasis (0.2–2 mm in diameter). Future studies are needed to find more ideal tracers and application strategies.
9.2 Mediastinal Lymph Node Dissection
(4)
Department of Thoracic Surgery, Fudan University Zhongshan Hospital, No. 180, Fenglin Rd, Shanghai, 200032, China
9.2.1 Technical Points
Discriminate adjacent structures of regional lymph nodes, and make en-bloc resection of lymph nodes and surrounding fat tissue.
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