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Original Research: Lung Cancer |

Prognostic Impact of the Current Japanese Nodal Classification on Outcomes in Resected Non-small Cell Lung CancerPrognostic Impact of Nodal Classification FREE TO VIEW

Junji Ichinose, MD; Tomohiro Murakawa, MD; Haruaki Hino, MD; Chihiro Konoeda, MD; Yuta Inoue, MD; Kentaro Kitano, MD; Kazuhiro Nagayama, MD; Jun-ichi Nitadori, MD; Masaki Anraku, MD; Jun Nakajima, MD
Author and Funding Information

From the Department of Thoracic Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

CORRESPONDENCE TO: Tomohiro Murakawa, MD, Department of Thoracic Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; e-mail: murakawa-tky@umin.ac.jp


This study was presented at the 15th World Conference on Lung Cancer, October 27-30, 2013, Sydney, NSW, Australia.

FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(3):644-649. doi:10.1378/chest.14-0159
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BACKGROUND:  The prognosis of N2 non-small cell lung cancer (NSCLC) has been reported to be heterogeneous. The recently revised Japanese nodal classification subcategorizes N2 disease according to the tumor-bearing lobe. We evaluated the prognostic impact of the Japanese nodal classification and its ability to define favorable N2 disease in resected NSCLC.

METHODS:  A total of 496 patients with NSCLC who underwent lobectomy with systematic lymph node dissection between 1998 and 2009 were analyzed retrospectively. N2 status was subdivided into N2a-1 and N2a-2, according to the Japanese nodal classification. Overall survival (OS), disease-free survival (DFS), and clinicopathologic features were compared between the two groups.

RESULTS:  There were 67 cases with N2 disease. The outcome of resected N2a-2 NSCLC was far poorer than that of the N2a-1 group (5-year OS, 28% vs 62%, P < .001; 5-year DFS, 5% vs 35%, P < .001). Multivariate analysis revealed that pathologic N2a-2 was an independent prognostic factor (hazard ratio, 2.86; P < .05). Patients in the N2a-2 group showed more involved nodes and stations, less skip metastasis, and more locoregional recurrence than did patients in the N2a-1 group. The outcome of the N2a-1 group was satisfactory, and there was no significant difference in OS and DFS between N1 and N2a-1.

CONCLUSIONS:  The Japanese nodal classification is able to identify a favorable N2 subgroup in resected NSCLC. Nodal staging by the Japanese system should be considered when a clinical trial of N2 disease is designed.

Figures in this Article

The presence and extent of lymph node (LN) metastases are powerful prognostic factors in completely resected non-small cell lung cancer (NSCLC). Many studies have demonstrated that pathologic N2 NSCLC exhibits a heterogeneous prognosis. Various prognostic factors have been evaluated to identify a more accurate system than the current nodal classification.116The General Rule for Clinical and Pathologic Record of Lung Cancer was first published in 1978 and has been revised repeatedly by the Japan Lung Cancer Society to standardize the format of recording the operative notes and pathologic reports. The seventh edition17 was revised in 2010, and it subcategorizes N2 according to the tumor-bearing lobe based on studies of the difference in patterns of the LN metastases13,18 and on the validity of lobe-specific selective lymphadenectomy.19,20 Few studies have validated this Japanese nodal classification.16 In this study, we evaluated the prognostic impact of the Japanese nodal classification on resected NSCLC and investigated whether the patient groups with favorable N2 disease could be identified.

Patient Cohort

A total of 496 patients with NSCLC who underwent lobectomy with systematic LN dissection at our institute between 1998 and 2009 were analyzed retrospectively. Before the study, the research review board of the University of Tokyo Hospital examined and approved our research protocol in accordance with the Declaration of Helsinki (project approval No. 2406). All patients provided written informed consent for the review of their medical charts before the surgery. Patients who had evidence of small-cell carcinoma, distant metastases, dissemination, malignant effusion, or N3 disease were excluded. Patients who underwent neoadjuvant therapy or limited resection were also excluded. The definition of systematic nodal dissection followed the European Society of Thoracic Surgeons guidelines,21 which recommended that at least three mediastinal nodal stations (always including the subcarinal nodes) should be excised. We excluded patients who underwent LN dissection that did not satisfy the criteria, such as LN sampling or lobe-specific LN dissection.

The preoperative examination for staging included a CT scan of the chest and upper abdomen, CT scan or MRI of the brain, and bone scintigraphy or 18F fluorodeoxyglucose-PET scan. An LN > 1 cm in its short axis on the CT scan was clinically determined to be metastatic. The definition of an abnormal LN based on PET scan followed the diagnosis of the radiologists. Clinical nodal staging was defined by the combination of the findings of CT and PET scans. The treatment plan for patients with clinical discrete N2 was made by a multidisciplinary team. We considered patients with clinical infiltrative N2 to have a contraindication for surgery. Evaluation of nodal status was based on CT scan, PET scan, or both during the study period, although recently, preoperative endobronchial ultrasound-guided transbronchial needle aspiration has become the preferred choice for clinically suspected N2 disease.

LN Assessment and Follow-up

The tumor stage was determined according to the seventh edition of the TNM staging system of the International Union Against Cancer,22 and the histologic tumor type was determined according to the third edition of the World Health Organization classification.23 All the dissected LNs were classified by the International Association for the Study of Lung Cancer node map,24 and the number of resected and involved LNs of each station were confirmed on the pathologic report.

In the current Japanese nodal classification, the mediastinal nodal stations are subcategorized according to the tumor-bearing lobe (Table 1). Our systematic nodal dissection includes N2a-1 and N2a-2, but does not cover the area of N2b. We determined overall survival (OS) and disease-free survival (DFS) as the end points. OS was calculated from the date of surgery to the time of death; DFS was measured from the date of surgery to the date of relapse or death from any cause. Follow-ups occurred every 3 months for the first 2 years and then every 4 months for up to 5 years. A full examination was performed and a chest radiograph was taken at each visit, and a CT scan was performed annually. Other investigations were determined by clinical necessity.

Table Graphic Jump Location
TABLE 1  ] Japanese Nodal Classification for Resected Lung Cancer According to the Tumor-Bearing Lobe

The rows of mediastinal nodes were extracted from the reference. Each number refers to the station of lymph nodes in the International Association for the Study of Lung Cancer node map.24 This classification does not take into account the number of involved nodes. (Adapted from The Japan Lung Cancer Society.17)

Recurrence was classified as locoregional when the disease developed in the hilar or mediastinal LNs, the surgical margin, or the ipsilateral pleural space (pleural dissemination or carcinomatous pleuritis). Recurrence was classified as distant when the disease emerged in distant organs, including in a separate lung. When a recurrent tumor was identified simultaneously in both local and distant areas, it was considered a local recurrence. The diagnoses of metachronous lung cancer and recurrence were made according to the criteria of Martini and Melamed,25 together with consideration of histologic findings such as the subtypes of adenocarcinoma and the degree of atypism.

Statistical Analysis

A statistical analysis was performed using JMP 10 software (SAS Institute Inc). The cutoff number of metastatic nodes and metastatic stations was determined using the receiver operating characteristic curve method. The comparison of the clinicopathologic features was analyzed using the Student t test, Welch’s method, or the χ2-test. OS and DFS were estimated by the Kaplan-Meier method and were compared by the log-rank test. Univariate and multivariate analyses of prognostic factors were assessed by Cox’s proportional hazards regression model.

There were 384 cases (77%) with N0 disease, 45 cases (9%) with N1 disease, and 67 cases (14%) with N2 disease. In the Japanese nodal classification, there were 43 cases with N2a-1 and 24 cases with N2a-2 disease. The clinicopathologic features of the patients with N2a-1 and the patients with N2a-2 are shown in Table 2. In 75% of the N2a-2 group, the tumors were located in the lower lobes. Patients in the N2a-2 group showed more involved LNs, more involved stations, and less skip metastasis than did patients in the N2a-1 group. The risk of locoregional recurrence was higher in the N2a-2 group than in the N2a-1 group, although there was no significant difference in histologic type, T factor, the number of resected LNs, or the frequency of distant metastasis. The clinicopathologic features of the patients with N1 are also shown in Table 2. There was no significant difference in the risk of locoregional and distant recurrence between N2a-1 and N1.

Table Graphic Jump Location
TABLE 2  ] Clinicopathologic Features of Patients With Lymph Node Metastases

CEA = carcinoembryonic antigen; − = negative; NS = not significant; + = positive.

The Kaplan-Meier curves for OS and DFS are shown in Figure 1. The median follow-up time was 4.9 years. The outcome of resected N2a-2 NSCLC was far poorer than that of N2a-1 (5-year OS, 28% vs 62%, P < .001; 5-year DFS, 5% vs 35%, P < .001). The OS and DFS of N0 were 86% and 74%, respectively, and the OS and DFS of N1 were 60% and 38%, respectively. The patients with resected N2a-1 disease showed favorable outcomes and there was no significant difference in OS and DFS between the N1 and N2a-1 cases.

Figure Jump LinkFigure 1  The overall survival (OS) and disease-free survival (DFS) curves of resected non-small cell lung cancer according to the Japanese nodal classification. A, The 5-y OS rates for N0, N1, N2a-1, and N2a-2 were 86%, 60%, 62% and 28%, respectively. B, The 5-y DFS rates for N0, N1, N2a-1, and N2a-2 were 74%, 38%, 35% and 5%, respectively. *P < .001.Grahic Jump Location

The various prognostic factors of patients with resected N2 NSCLC were evaluated by univariate analysis (Table 3) and by multivariate analysis (Table 4). The multivariate analysis revealed that the presence of positive N2a-2 node was an independent prognostic factor (hazard ratio, 2.86; P < .05), as well as histologic type and lymphatic invasion.

Table Graphic Jump Location
TABLE 3  ] Univariate Analysis of Prognostic Factors of Patients With Resected N2 NSCLC

Ad = adenocarcinoma; NSCLC = non-small cell lung cancer. See Table 2 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 4  ] Multivariate Analysis of Prognostic Factors of Patients With Resected N2 NSCLC

See Table 2 and 3 legends for expansion of abbreviations.

In this study, the prognosis of resected N2a-2 NSCLC was extremely poor, and N2a-2 was revealed as an independent prognostic factor. Patients with N2a-2 showed more involved nodes, less skip metastasis, and more locoregional recurrence than did patients with N2a-1.

In patients with pathologically confirmed discrete N2 disease, either definitive chemoradiation therapy or induction therapy followed by surgery is recommended, and primary surgical resection followed by adjuvant therapy is not recommended (except as part of a clinical trial) by the third edition of the American College of Chest Physicians (CHEST) evidence-based clinical practice guidelines.26 Surgical resection of proven N2 NSCLC is considered futile and is avoided in most cases. Recently, the prognosis of completely resected N2 disease has been greatly improved because of progress in imaging diagnosis, surgical and anesthesiology techniques, intensive care, and molecular-targeting drugs. Lung cancer surgery has become safer over the years, and the operative mortality of lobectomy for lung cancer has been lowered to 0.4% in Japan.27 The surgical outcome of N2 disease is favorable in appropriately selected patient groups.

Although various prognostic factors based on the number110 or the ratio11,12 of involved LNs have been evaluated, the Japanese nodal classification was a more powerful prognostic factor in our study. Moreover, the Japanese nodal classification appears to be optimal regarding the ability to define favorable N2 in resected NSCLC for the following reasons. The bias that arises from the handling maneuvers of dissected LNs is inevitable. A lumped LN may be divided into several parts. The cutoff values vary in different settings. The threshold of involved LNs has been set at three,8,9 four,5,10 and seven5 in previous studies. The definitions for distinguishing the groups, that may have an influence on results, should be consistent in different settings and data sources.28

The difference in clinicopathologic features between N2a-2 and N2a-1 is of great interest. The remarkable prognostic disparity appears to result from the difference in tumor aggressiveness in lymphatic infiltration, which was based on the number of involved LNs, the frequency of skip metastasis, and the risk of locoregional recurrence. There was no significant difference between N2a-1 and N1 in the risk of locoregional and distant recurrence. The outcome of surgical resection depends on whether the disease is local or systemic. The reason why N2 NSCLC exhibits a heterogeneous prognosis is that the group contains both local and systemic disease. Our results revealed that the Japanese nodal classification was able to identify patients with relatively local N2 disease.

Although we showed that N2a-2 was a powerful “prognostic” factor, it remains to be proved whether N2a-2 is a “predictive” factor.29 To determine the treatment strategy for N2a-1 and N2a-2 disease, randomized clinical trials considering the Japanese nodal classification are required. Our results suggest that those trials would be promising and are worth carrying out.

This retrospective, observational and single-institution study has some limitations. Our results may be biased by sample selection. Some patients with clinical N2 disease were not even referred to the department of thoracic surgery. The outcome of resected N2a-1 was fairly good, and there was no significant difference in OS and DFS between N1 and N2a-1 in our study. This result seems to be partially because of the selection of surgical candidates. Patients with bulky N1 disease underwent resection, and patients with bulky N2a-1 disease were excluded. Our results could apply only to surgically treated patients. This study excluded 12 cases with induction therapy. More frequent induction therapy may have improved the outcomes. Although we considered adjuvant therapy for patients with N2 to be the standard of care, about one-half of them did not receive adjuvant therapy because of their older age, serious comorbidities, or patient preference. The variation in operative techniques should also be considered. The extent and thoroughness of LN dissection may have been different among surgeons and among cases.

The Japanese nodal classification could identify a favorable N2 subgroup in resected NSCLC. Nodal staging by the Japanese system should be considered when a clinical trial of N2 disease is designed.

Author contributions: T. M. is the guarantor of this article. J. I. and T. M. contributed to the planning of the study; J. I., T. M., H. H., C. K., Y. I., K. K., K. N., J. Nitadori, M. A., and J. Nakajima contributed to data collection; J. I. contributed to data analysis and writing of the manuscript; and T. M., H. H., C. K., Y. I., K. K., K. N., J. Nitadori, M. A., and J. Nakajima contributed to review of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

DFS

disease-free survival

LN

lymph node

NSCLC

non-small cell lung cancer

OS

overall survival

Suzuki K, Nagai K, Yoshida J, Nishimura M, Takahashi K, Nishiwaki Y. The prognosis of surgically resected N2 non-small cell lung cancer: the importance of clinical N status. J Thorac Cardiovasc Surg. 1999;118(1):145-153. [CrossRef] [PubMed]
 
Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol. 2000;18(16):2981-2989. [PubMed]
 
Ichinose Y, Kato H, Koike T, et al; Japan Clinical Oncology Group. Overall survival and local recurrence of 406 completely resected stage IIIa-N2 non-small cell lung cancer patients: questionnaire survey of the Japan Clinical Oncology Group to plan for clinical trials. Lung Cancer. 2001;34(1):29-36. [CrossRef] [PubMed]
 
Casali C, Stefani A, Natali P, Rossi G, Morandi U. Prognostic factors in surgically resected N2 non-small cell lung cancer: the importance of patterns of mediastinal lymph nodes metastases. Eur J Cardiothorac Surg. 2005;28(1):33-38. [CrossRef] [PubMed]
 
Fukui T, Mori S, Yokoi K, Mitsudomi T. Significance of the number of positive lymph nodes in resected non-small cell lung cancer. J Thorac Oncol. 2006;1(2):120-125. [CrossRef] [PubMed]
 
Wei S, Asamura H, Kawachi R, Sakurai H, Watanabe S. Which is the better prognostic factor for resected non-small cell lung cancer: the number of metastatic lymph nodes or the currently used nodal stage classification? J Thorac Oncol. 2011;6(2):310-318. [CrossRef] [PubMed]
 
Kang CH, Ra YJ, Kim YT, Jheon SH, Sung SW, Kim JH. The impact of multiple metastatic nodal stations on survival in patients with resectable N1 and N2 nonsmall-cell lung cancer. Ann Thorac Surg. 2008;86(4):1092-1097. [CrossRef] [PubMed]
 
Hanagiri T, Takenaka M, Oka S, et al. Clinical significance in the number of involved lymph nodes in patients that underwent surgery for pathological stage III-N2 non-small cell lung cancer. J Cardiothorac Surg. 2011;6:144. [CrossRef] [PubMed]
 
Matsuguma H, Oki I, Nakahara R, et al. Proposal of new nodal classifications for non-small-cell lung cancer based on the number and ratio of metastatic lymph nodes. Eur J Cardiothorac Surg. 2012;41(1):19-24. [PubMed]
 
Saji H, Tsuboi M, Shimada Y, et al. A proposal for combination of total number and anatomical location of involved lymph nodes for nodal classification in non-small cell lung cancer. Chest. 2013;143(6):1618-1625. [CrossRef] [PubMed]
 
Nwogu CE, Groman A, Fahey D, et al. Number of lymph nodes and metastatic lymph node ratio are associated with survival in lung cancer. Ann Thorac Surg. 2012;93(5):1614-1619. [CrossRef] [PubMed]
 
Wang CL, Li Y, Yue DS, Zhang LM, Zhang ZF, Sun BS. Value of the metastatic lymph node ratio for predicting the prognosis of non-small-cell lung cancer patients. World J Surg. 2012;36(2):455-462. [CrossRef] [PubMed]
 
Okada M, Tsubota N, Yoshimura M, Miyamoto Y, Matsuoka H. Prognosis of completely resected pN2 non-small cell lung carcinomas: what is the significant node that affects survival? J Thorac Cardiovasc Surg. 1999;118(2):270-275. [CrossRef] [PubMed]
 
Riquet M, Assouad J, Bagan P, et al. Skip mediastinal lymph node metastasis and lung cancer: a particular N2 subgroup with a better prognosis. Ann Thorac Surg. 2005;79(1):225-233. [CrossRef] [PubMed]
 
Nakagiri T, Sawabata N, Funaki S, et al. Validation of pN2 sub-classifications in patients with pathological stage IIIA N2 non-small cell lung cancer. Interact Cardiovasc Thorac Surg. 2011;12(5):733-738. [CrossRef] [PubMed]
 
Baba T, Uramoto H, Kuwata T, et al. Survival impact of node zone classification in resected pathological N2 non-small cell lung cancer. Interact Cardiovasc Thorac Surg. 2012;14(6):760-764. [CrossRef] [PubMed]
 
The Japan Lung Cancer Society. General Rule for Clinical and Pathological Record of Lung Cancer.7th ed. Tokyo, Japan: Kanehara & Co, Ltd; 2010.
 
Asamura H, Nakayama H, Kondo H, Tsuchiya R, Naruke T. Lobe-specific extent of systematic lymph node dissection for non-small cell lung carcinomas according to a retrospective study of metastasis and prognosis. J Thorac Cardiovasc Surg. 1999;117(6):1102-1111. [CrossRef] [PubMed]
 
Okada M, Sakamoto T, Yuki T, Mimura T, Miyoshi K, Tsubota N. Selective mediastinal lymphadenectomy for clinico-surgical stage I non-small cell lung cancer. Ann Thorac Surg. 2006;81(3):1028-1032. [CrossRef] [PubMed]
 
Ishiguro F, Matsuo K, Fukui T, Mori S, Hatooka S, Mitsudomi T. Effect of selective lymph node dissection based on patterns of lobe-specific lymph node metastases on patient outcome in patients with resectable non-small cell lung cancer: a large-scale retrospective cohort study applying a propensity score. J Thorac Cardiovasc Surg. 2010;139(4):1001-1006. [CrossRef] [PubMed]
 
Lardinois D, De Leyn P, Van Schil P, et al. ESTS guidelines for intraoperative lymph node staging in non-small cell lung cancer. Eur J Cardiothorac Surg. 2006;30(5):787-792. [CrossRef] [PubMed]
 
Sobin LH, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours.7th ed. Hoboken, NJ: Wiley-Blackwell; 2009.
 
Travis WDBE, Muller-Hermelink HK. World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; 2004.
 
Rusch VW, Asamura H, Watanabe H, et al. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4(5):568-577.
 
Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg. 1975;70(4):606-612. [PubMed]
 
Ettinger DS, Akerley W, Borghaei H, et al; NCCN (National Comprehensive Cancer Network). Non-small cell lung cancer. J Natl Compr Canc Netw. 2012;10(10):1236-1271. [PubMed]
 
Kuwano H, Amano J, Yokomise H. Thoracic and cardiovascular surgery in Japan during 2010: annual report by The Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg. 2012;60(10):680-708. [CrossRef] [PubMed]
 
Detterbeck FC. Lung cancer: is it node number or location? Pardon me, but what is the question? Chest. 2013;143(6):1527-1529. [CrossRef] [PubMed]
 
Simms L, Barraclough H, Govindan R. Biostatistics primer: what a clinician ought to know—prognostic and predictive factors. J Thorac Oncol. 2013;8(6):808-813. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1  The overall survival (OS) and disease-free survival (DFS) curves of resected non-small cell lung cancer according to the Japanese nodal classification. A, The 5-y OS rates for N0, N1, N2a-1, and N2a-2 were 86%, 60%, 62% and 28%, respectively. B, The 5-y DFS rates for N0, N1, N2a-1, and N2a-2 were 74%, 38%, 35% and 5%, respectively. *P < .001.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] Japanese Nodal Classification for Resected Lung Cancer According to the Tumor-Bearing Lobe

The rows of mediastinal nodes were extracted from the reference. Each number refers to the station of lymph nodes in the International Association for the Study of Lung Cancer node map.24 This classification does not take into account the number of involved nodes. (Adapted from The Japan Lung Cancer Society.17)

Table Graphic Jump Location
TABLE 2  ] Clinicopathologic Features of Patients With Lymph Node Metastases

CEA = carcinoembryonic antigen; − = negative; NS = not significant; + = positive.

Table Graphic Jump Location
TABLE 3  ] Univariate Analysis of Prognostic Factors of Patients With Resected N2 NSCLC

Ad = adenocarcinoma; NSCLC = non-small cell lung cancer. See Table 2 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 4  ] Multivariate Analysis of Prognostic Factors of Patients With Resected N2 NSCLC

See Table 2 and 3 legends for expansion of abbreviations.

References

Suzuki K, Nagai K, Yoshida J, Nishimura M, Takahashi K, Nishiwaki Y. The prognosis of surgically resected N2 non-small cell lung cancer: the importance of clinical N status. J Thorac Cardiovasc Surg. 1999;118(1):145-153. [CrossRef] [PubMed]
 
Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol. 2000;18(16):2981-2989. [PubMed]
 
Ichinose Y, Kato H, Koike T, et al; Japan Clinical Oncology Group. Overall survival and local recurrence of 406 completely resected stage IIIa-N2 non-small cell lung cancer patients: questionnaire survey of the Japan Clinical Oncology Group to plan for clinical trials. Lung Cancer. 2001;34(1):29-36. [CrossRef] [PubMed]
 
Casali C, Stefani A, Natali P, Rossi G, Morandi U. Prognostic factors in surgically resected N2 non-small cell lung cancer: the importance of patterns of mediastinal lymph nodes metastases. Eur J Cardiothorac Surg. 2005;28(1):33-38. [CrossRef] [PubMed]
 
Fukui T, Mori S, Yokoi K, Mitsudomi T. Significance of the number of positive lymph nodes in resected non-small cell lung cancer. J Thorac Oncol. 2006;1(2):120-125. [CrossRef] [PubMed]
 
Wei S, Asamura H, Kawachi R, Sakurai H, Watanabe S. Which is the better prognostic factor for resected non-small cell lung cancer: the number of metastatic lymph nodes or the currently used nodal stage classification? J Thorac Oncol. 2011;6(2):310-318. [CrossRef] [PubMed]
 
Kang CH, Ra YJ, Kim YT, Jheon SH, Sung SW, Kim JH. The impact of multiple metastatic nodal stations on survival in patients with resectable N1 and N2 nonsmall-cell lung cancer. Ann Thorac Surg. 2008;86(4):1092-1097. [CrossRef] [PubMed]
 
Hanagiri T, Takenaka M, Oka S, et al. Clinical significance in the number of involved lymph nodes in patients that underwent surgery for pathological stage III-N2 non-small cell lung cancer. J Cardiothorac Surg. 2011;6:144. [CrossRef] [PubMed]
 
Matsuguma H, Oki I, Nakahara R, et al. Proposal of new nodal classifications for non-small-cell lung cancer based on the number and ratio of metastatic lymph nodes. Eur J Cardiothorac Surg. 2012;41(1):19-24. [PubMed]
 
Saji H, Tsuboi M, Shimada Y, et al. A proposal for combination of total number and anatomical location of involved lymph nodes for nodal classification in non-small cell lung cancer. Chest. 2013;143(6):1618-1625. [CrossRef] [PubMed]
 
Nwogu CE, Groman A, Fahey D, et al. Number of lymph nodes and metastatic lymph node ratio are associated with survival in lung cancer. Ann Thorac Surg. 2012;93(5):1614-1619. [CrossRef] [PubMed]
 
Wang CL, Li Y, Yue DS, Zhang LM, Zhang ZF, Sun BS. Value of the metastatic lymph node ratio for predicting the prognosis of non-small-cell lung cancer patients. World J Surg. 2012;36(2):455-462. [CrossRef] [PubMed]
 
Okada M, Tsubota N, Yoshimura M, Miyamoto Y, Matsuoka H. Prognosis of completely resected pN2 non-small cell lung carcinomas: what is the significant node that affects survival? J Thorac Cardiovasc Surg. 1999;118(2):270-275. [CrossRef] [PubMed]
 
Riquet M, Assouad J, Bagan P, et al. Skip mediastinal lymph node metastasis and lung cancer: a particular N2 subgroup with a better prognosis. Ann Thorac Surg. 2005;79(1):225-233. [CrossRef] [PubMed]
 
Nakagiri T, Sawabata N, Funaki S, et al. Validation of pN2 sub-classifications in patients with pathological stage IIIA N2 non-small cell lung cancer. Interact Cardiovasc Thorac Surg. 2011;12(5):733-738. [CrossRef] [PubMed]
 
Baba T, Uramoto H, Kuwata T, et al. Survival impact of node zone classification in resected pathological N2 non-small cell lung cancer. Interact Cardiovasc Thorac Surg. 2012;14(6):760-764. [CrossRef] [PubMed]
 
The Japan Lung Cancer Society. General Rule for Clinical and Pathological Record of Lung Cancer.7th ed. Tokyo, Japan: Kanehara & Co, Ltd; 2010.
 
Asamura H, Nakayama H, Kondo H, Tsuchiya R, Naruke T. Lobe-specific extent of systematic lymph node dissection for non-small cell lung carcinomas according to a retrospective study of metastasis and prognosis. J Thorac Cardiovasc Surg. 1999;117(6):1102-1111. [CrossRef] [PubMed]
 
Okada M, Sakamoto T, Yuki T, Mimura T, Miyoshi K, Tsubota N. Selective mediastinal lymphadenectomy for clinico-surgical stage I non-small cell lung cancer. Ann Thorac Surg. 2006;81(3):1028-1032. [CrossRef] [PubMed]
 
Ishiguro F, Matsuo K, Fukui T, Mori S, Hatooka S, Mitsudomi T. Effect of selective lymph node dissection based on patterns of lobe-specific lymph node metastases on patient outcome in patients with resectable non-small cell lung cancer: a large-scale retrospective cohort study applying a propensity score. J Thorac Cardiovasc Surg. 2010;139(4):1001-1006. [CrossRef] [PubMed]
 
Lardinois D, De Leyn P, Van Schil P, et al. ESTS guidelines for intraoperative lymph node staging in non-small cell lung cancer. Eur J Cardiothorac Surg. 2006;30(5):787-792. [CrossRef] [PubMed]
 
Sobin LH, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours.7th ed. Hoboken, NJ: Wiley-Blackwell; 2009.
 
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