Journal of Thoracic Oncology:
State of the Art: Concise Review
Lymph Node Dissection for Lung Cancer: Significance, Strategy, and Technique
Watanabe, Shun-ichi MD; Asamura, Hisao MD
Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.
Disclosure: The authors declare no conflicts of interest.
Address for correspondence: Shun-ichi Watanabe, MD, Division of Thoracic Surgery, National Cancer Center Hospital, Tsukiji 5-1-1, Tokyo 104-0045, Japan. E-mail: email@example.com
Since Cahan (1960) reported the first 48 cases that successfully underwent lobectomy with regional lymph node dissection, which was called “radical lobectomy”, this procedure was universally accepted and has remained a standard surgery for lung cancer. In recent decades, the intrathoracic reevaluation of disease at thoracotomy for lung cancer has evolved into a detailed and sophisticated assessment of disease extent. Central to this is an evaluation of nodal involvement at the mediastinal and hilar levels. This technique, termed “systematic nodal dissection” (SND), has been accepted by the IASLC to be an important component of intrathoracic staging. In this manuscript, the significance, recent strategy, and technique of lymph node dissection for lung cancer are described.
In 1951, Cahan et al.1 suggested that pneumonectomy with regional lymph node dissection should be a routine procedure for lung cancer. Then in 1960, Cahan reported the first 48 cases that successfully underwent lobectomy with regional lymph node dissection, which was called “radical lobectomy.”2 Since then, this procedure was universally accepted and has remained a standard surgery for lung cancer. The descriptions of mediastinal lymph node dissection in Cahan’s reports were very similar to our routine lymph node dissection today.1,2
In recent decades, the intrathoracic reevaluation of disease at thoracotomy for lung cancer has evolved into a detailed and sophisticated assessment of disease extent. Central to this is an evaluation of nodal involvement at the mediastinal and hilar levels. This technique, now termed “systematic nodal dissection (SND),” has been accepted by the International Association for the Study of Lung Cancer (IASLC) to be an important component of intrathoracic staging.3 The consensus for SND could unify the nomenclature and establish the minimal technical requirements for nodal dissection in lung cancer surgery. In this article, the significance, recent strategy, and technique of lymph node dissection for lung cancer are described.
Definition of Lymph Node Dissection
First, the definition of “lymph node dissection” should be reconfirmed. “Dissection” means to remove the tissue from adjacent organs and skeletonize the anatomic structures. Thus, “lymph node dissection” means the en block removal of all tissue that may contain cancer cells, including the lymph nodes and surrounding fatty tissue within anatomic landmarks such as the trachea, bronchus, superior vena cava, and the aorta and its branches, pulmonary vessels, and pericardium (Figures 1A, B). European Society of Thoracic Surgeons guidelines have defined that the aim of SND is to dissect and remove all mediastinal tissue containing the lymph nodes within anatomic landmarks.4 Excision of at least three mediastinal nodal stations, including the subcarinal node, is recommended as a minimum requirement.4 The nodes are separately labeled and histologically examined after dissection according to recommendations for processing and reporting of lymph node specimens.5
In addition, “sampling” means a lesser excision of certain nodal stations that seem to be representative or abnormal in preoperative evaluations or intraoperative findings (Figure 1C). Doddoli et al.,6 Gajra et al.7 and Massard et al.8 suggested that sampling was inferior to SND in terms of proper staging. The term “systematic sampling” refers to a routine biopsy of lymph nodes at some levels of nodal station.4,9 Keller et al.9 and Gajra et al.7 reported that systematic sampling was as effective as SND for accurately staging patients.
The Significance of Lymph Node Dissection
The significance of lymph node dissection can be discussed from two clinical aspects, accurate staging and survival benefit.
Surgeons have long been aware that the situation at thoracotomy is not always as predicted by preoperative investigations. Several studies have shown that the sensitivity and specificity for computed tomography (CT) in assessing mediastinal nodal involvement is on the order of 52 to 79% and 69 to 78%, respectively.10,11 Although positron emission tomography is considered to be the most sensitive and accurate investigation for screening of lymph node involvement, with a sensitivity of 79 to 85% and specificity of 90 to 91% in a meta-analysis,12 the assessment of nodal status by positron emission tomography is not reliable in patients with microscopic nodal metastasis. Therefore, the intrathoracic evaluation of nodal involvement at the mediastinal and hilar levels during thoracotomy is considered to be an important component of the staging process.13
This technique was termed SND by the IASLC staging committee task force in 1996.3 In the task force, the term “radical” was discarded as inferring some therapeutic benefit from this evaluation. The term “mediastinal” was also discarded because it might fail to recognize the importance of the evaluation of N1 nodes. Graham et al.14 suggested that SND could disclose “unexpected” N2 disease irrespective of cell type, size, and location of the primary tumor, regardless of whether prior mediastinoscopy had been performed. In patients with adenocarcinomas, 60% of cN1 disease diagnosed by chest CT was histologically revealed to be N2 disease after thoracotomy.15 Even small-sized lung cancer less than 2 cm in size shows hilar and mediastinal nodal disease with an incidence of more than 20%.16,17 Furthermore, lung cancer has a phenomenon termed “skip metastasis” consisting of N2 disease without N1 involvement with the incidence of 20 to 38% in N2 patients.18–22 These facts indicate the significance of SND at the mediastinal and hilar levels during thoracotomy.
Among many clinicopathological factors, the pathologic nodal status is reported to be the most significant prognostic factor.23,24 Pathologic examination of dissected lymph nodes offers the most precise information for prognosis in patients with lung cancer. Furthermore, the recent results of some multi-institutional clinical trials evaluating the significance of adjuvant chemotherapy in patients with lung cancer showed the survival benefit of postoperative chemotherapy for node-positive patients.25,26 Ferguson27 reported the results of meta-analysis evaluating the cost-effectiveness of surgery for “unsuspected N2.” He suggested that delaying resection until after completion of neoadjuvant therapy provided the best survival and was more cost-effective for unsuspected N2 patients. The accurate identification of positive nodes leads to selection of the optimal therapy and suggests the prognosis for each patient.6,7
For the aforementioned reasons, an accurate pathologic assessment for metastasis of the lymph nodes is thought to have many advantages for those with lung cancer. Therefore, SND remains an important investigative process in all patients coming to surgery for lung cancer.28
Others have gone further, suggesting that cure rates could be improved by lymph node dissection. Keller et al.9 reported the comparison of survival between patients with resected stage II–IIIa non-small cell lung cancer who underwent SND and systematic sampling. This nonrandomized study showed that SND significantly improved the survival of patients with stage II–IIIa non-small cell lung cancer. Moreover, some other retrospective studies have shown the survival benefit of nodal dissection.29–33 The survival benefit of lymph node dissection for patients with lung cancer, however, has not been statistically clear, simply because few prospective randomized controlled trials (RCTs) have been conducted comparing SND with nodal sampling (Table 1).34–36 Izbicki et al.34 reported no significant difference in survival between the patients with clinical stage I–IIIA lung cancer who underwent SND and nodal sampling. However, the number of enrolled patients in each arm (SND versus sampling; n = 76 versus 93) might have been insufficient because more than half of the subjects were node-negative patients in the pathologic examination. In a subgroup analysis, they suggested a borderline effect of SND on overall survival (p = 0.058) in patients with pN1 or pN2 disease.34 Sugi et al.35 reported no significant difference in survival between patients with peripheral cancer less than 2 cm who underwent mediastinal dissection and sampling. However, the number of enrolled patients in that study (SND versus sampling; n = 59 versus 56) was much less than that of the study by Izbicki. Wu et al.36 reported the results of a prospective randomized trial with 532 patients and suggested that the SND group (n = 268) showed significantly better survival compared with the sampling group (n = 264). This study has been the only randomized study to suggest the survival benefit of nodal dissection. Wright et al.37 reported the results of meta-analysis of these three randomized RCTs comparing SND and sampling. There was a significant reduction in the risk of death in the group undergoing SND with a hazard ratio estimated at 0.78 (95% CI 0.65–0.93; p = 0.005). Detterbeck38 used the term “surprise N2” for microscopic N2 disease, and reviewed the intraoperative management of patients with “surprise N2.” Based on the results of these randomized studies, he concluded that resection was justified for this subset unless it was apparent that disease would be left behind. However, the description of the randomization method in these three studies is insufficient according to the recent CONSORT statement (Table 1).39 Collectively, whether lymph node dissection has a survival benefit is still unknown.
Who Can Attain Oncological Benefit from Lymph Node Dissection?
The most frequent relapse pattern after complete resection for lung cancer surgery is distant metastasis, even in stage I patients,35,40 due to a distant micrometastasis that already existed at the time of surgery. Since lymph node dissection is a therapy used to achieve a better local control of cancer, this procedure does not improve the survival of the patient with distant metastasis. Moreover, in the patient who has no nodal metastasis, lymph node dissection has no impact on survival and can just prove the pathologic N0 status. Therefore, the patients who can obtain oncological benefit from nodal dissection would be those who have resectable pN2 and no distant micrometastasis, who may comprise a small group of patients with lung cancer.
Is it Possible to Conduct a Clinical Trial to Clear the Oncological Significance of Lymph Node Dissection?
Among patients with N2 disease, two types of nodal metastasis exist, the preoperatively diagnosed N2 disease (cN2-pN2) and postoperatively proven N2 disease (cN0, 1-pN2). The cN2-pN2 disease showed dismal prognosis of less than 10% of a 3-year survival after pulmonary resection.40,41 The standard of care for cN2 disease is a chemoradiotherapy, and the role of surgery for this subset is currently unknown as described in the IASLC consensus report.42 The patient who can attain oncological benefit from lymph node dissection should be the patient with cN0, 1-pN2 disease, i.e., “microscopic N2 disease.”43–45
However, preoperatively recognizing and randomizing the patients with microscopic N2 is difficult because these patients can be identified mostly after completing the nodal dissection and pathologic examination.28,46–49 Therefore, if a surgeon wants to demonstrate the oncological benefit of lymph node dissection in a RCT, extremely large numbers of patients must be enrolled in the study.
Again, thus far, the oncological benefit of lymph node dissection has not been demonstrated. To establish the survival benefit of nodal dissection in lung cancer surgery will be very difficult because of the difficulty in carrying out this sort of large RCT study and the lack of appropriate methodology. The American College of Surgery Oncology Group Z0030 study, which is a multi-institutional prospective randomized trial designed to compare the long-term survival after SND and sampling, may clear up this issue in the future.
The Concept and Technique of Lymph Node Dissection
At the time of pulmonary resection, evaluation of nodal status is performed before making any decision as to resectability.4 As a first step, all ipsilateral hilar and mediastinal nodal stations are checked immediately after thoracotomy. The macroscopic appearance or internal architecture of the nodes is assessed by the surgeon, and if necessary, examining frozen sections of key nodes is performed. This evaluation is then repeated for the N1 nodes, extending peripherally in a centrifugal fashion until the surgeon believes that sufficient information has been gathered to decide as to the desirability of resection and the extent required.4 This allows the surgeon to assess the feasibility and advisability of complete clearance before commencing resection.
In terms of technical aspect, SND is carried out by excising all tissue in the compartment surrounded by some anatomic structures with scissors or electrocautery. This procedure is similar to the one previously reported by Cahan in 1951.1 As shown in Figure 2, en block removal of all tissue that may contain cancer cells, including lymph nodes and surrounding fatty tissue within anatomic landmarks, as well as the trachea, bronchus, superior vena cava, and the aorta and its branches, pulmonary vessels, and pericardium, should be performed. Special care must be taken not to interrupt the lymphatic vessels or disrupt the lymph node itself. In addition, ligating the connective tissue, which may include the small lymphatic vessels, is sometimes necessary to prevent postoperative chylothorax.
There have been reported alternative techniques for SND. Witte and Hürtgen50 reported video-assisted mediastinoscopic lymphadenectomy technique with two-bladed spreadable videomediastinoscope. They concluded that accuracy and radicality of video-assisted mediastinoscopic lymphadenectomy could equal those of open lymphadenectomy. Zieliński51 demonstrated transcervical extended mediastinal lymphadenectomy procedure through 5 to 8 cm collar incision in the neck. This technique enabled complete removal of all mediastinal nodal stations except for the pulmonary ligament nodes and the most distal left paratracheal nodes. Zieliński52 also reported the new technique of transcervical right upper lobectomy with transcervical extended mediastinal lymphadenectomy.
The Extent of Lymph Node Dissection
The extent of lymph node dissection for lung cancer has changed little since Cahan reported “radical lobectomy” in 1960.2 SND involves the identification of nodal stations and their labeling in accordance with an internationally recognized nodal chart. Several lymph node maps have been proposed,53,54 each with its advantages and disadvantages.55 The one most widely used is that proposed by Naruke in 1978.53 The Japan Lung Cancer Society published the detailed definitions of each nodal station, providing a definition for each station based on CT and surgical findings, and was intended for clinical use. The map has been used mostly in Japan because the explanatory manual only became available in English in 2000.56
In 1997, Mountain and Dresler54 published the new map, which has been widely favored by the American Thoracic Society and the European Respiratory Society, among others.57–59 This map is included in the American Joint Committee on Cancer handbook and in the Union Internationale Contre le Cancer tumor node metastasis atlas.60 With these maps, extensive nodal dissection, including the superior and inferior mediastinum (i.e., SND), has been universally performed in lung cancer surgery.6,7,61
The lobe-specific patterns of nodal metastases have become recognized due to increasing analyses of the lymph node metastatic pathway. Asamura et al.62 and Okada et al.63 reported that right upper lobe tumors and left upper segment tumors tend to metastasize to the superior mediastinum, but rarely metastasize to the subcarinal nodes without concomitant metastasis to the hilar or superior mediastinal nodes. In addition, Okada et al.63 suggested that lower lobe tumors seldom metastasize to the superior mediastinal nodes without concomitant metastasis to the hilar or subcarinal nodes. Considering the results of lobe-specific patterns of nodal metastases, the preoperative evaluation of the nodal status and strategy of nodal dissection has been changing, especially in stage I lung cancer (Table 2).64–67 As the detection of early lung cancer is increasing, the extent of nodal dissection should be tailored by considering, for example, the tumor location, tumor size, cell type, and percentage of ground glass opacity area on CT scan in each tumor. This type of tailored dissection was termed “lobe-specific SND” by European Society of Thoracic Surgeons guidelines.4 For lobe-specific SND, the “key nodes,” which are easily sampled and checked during surgery by examining frozen sections, has been explored in each lobe tumor.62–67 The definition of complete resection for lung cancer proposed by a subcommittee of IASLC staging committee includes the requirements of no residual tumor after SND or lobe-specific SND.68
Although clear evidence regarding the survival benefit of lymph node dissection for lung cancer is lacking, lobectomy with lymph node dissection has been a standard surgical procedure for lung cancer. It will take more several years to obtain the final results of the ACOSOG Z0030 randomized trial to establish whether SND will improve patient survival. However, SND remains an important investigative process in staging patients and takes just within 30 minutes40,69; moreover, the initial results of ACOSOG Z0030 randomized trial found no increase in morbidity or mortality from lymph node dissection.70 Thus, little benefit seems to currently exist in limiting nodal dissection.
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Lung cancer; Lymph node dissection; Systematic nodal dissection; Pulmonary resection
© 2009International Association for the Study of Lung Cancer
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