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The IASLC Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forthcoming Seventh Edition of the TNM Classification for Lung Cancer

      Introduction

      Accurate staging of lymph node involvement is a critical aspect of the initial management of nonmetastatic non-small cell lung cancer (NSCLC). We sought to determine whether the current N descriptors should be maintained or revised for the next edition of the international lung cancer staging system.

      Methods

      A retrospective international lung cancer database was developed and analyzed. Anatomical location of lymph node involvement was defined by the Naruke (for Japanese data) and American Thoracic Society (for non-Japanese data) nodal maps. Survival was calculated by the Kaplan-Meier method, and prognostic groups were assessed by Cox regression analysis.

      Results

      Current N0 to N3 descriptors defined distinct prognostic groups for both clinical and pathologic staging. Exploratory analyses indicated that lymph node stations could be grouped together into six “zones―: peripheral or hilar for N1, and upper or lower mediastinal, aortopulmonary, and subcarinal for N2 nodes. Among patients undergoing resection without induction therapy, there were three distinct prognostic groups: single-zone N1, multiple-zone N1 or single N2, and multiple-zone N2 disease. Nevertheless, there were insufficient data to determine whether the N descriptors should be subdivided (e.g., N1a, N1b, N2a, N2b).

      Conclusions

      Current N descriptors should be maintained in the NSCLC staging system. Prospective studies are needed to validate amalgamating lymph node stations into zones and subdividing N descriptors.

      Key Words

      Accurate staging of lymph node involvement is a critical aspect of the initial management of patients with nonmetastatic non-small cell lung cancer (NSCLC) that influences decisions about the appropriateness and timing of surgery, radiation, and systemic therapy. Since the lung cancer staging system was first developed in 1973,
      • Martini N
      Mediastinal lymph node dissection for lung cancer. The Memorial experience.
      lymph node involvement has been categorized as N0 (no nodes involved), N1 (peribronchial, interlobar, or perihilar lymph nodes involved), N2 (ipsilateral mediastinal nodes involved), or N3 (contralateral mediastinal or supraclavicular nodes involved). The classification of these N descriptors into the overall tumor stages of I through III has been used to predict outcomes and to assist in treatment selection. During the past 20 years, numerous studies have evaluated the validity of the N descriptors and have suggested that these could be refined to provide more accurate prognostic stratification by subdividing them either according to specific anatomical locations (e.g., N1 peribronchial versus N1 perihilar) or the number of involved lymph nodes (e.g., single versus multiple N2 nodes).
      • Ferguson MK
      • Little AG
      • Golomb HM
      • et al.
      The role of adjuvant therapy after resection of T1 N1 M0 and T2 N1 M0 non-small cell lung cancer.
      • Maggi G
      • Casadio C
      • Mancuso M
      • et al.
      Resection and radical lymphadenectomy for lung cancer: prognostic significane of lymphatic metastases.
      • Martini N
      • Burt ME
      • Bains MS
      • et al.
      Survival after resection of stage II non-small cell lung cancer.
      • Yano T
      • Yokoyama H
      • Inoue T
      • et al.
      Surgical results and prognostic factors of pathologic N1 disease in non-small-cell carcinoma of the lung. Significance of N1 level: lobar or hilar nodes.
      • van Velzen E
      • Snijder RJ
      • de la Rivière AB
      • et al.
      Type of lymph node involvement influences survival rates of T1N1M0 non-small cell lung carcinoma. Lymph node involvement by direct extension compared with lobar and hilar node metastases.
      • van Velzen E
      • Snijder RJ
      • de la Rivière AB
      • et al.
      Lymph node type as a prognostic factor for survival in T2 N1 M0 non-small cell lung carcinoma.
      • van Velzen E
      • de la Rivière AB
      • Elbert HJJ
      • et al.
      Type of lymph node involvement and survival in pathologic N1 stage III non-small cell lung carcinoma.
      • Sawyer TE
      • Bonner JA
      • Gould PM
      • et al.
      Factors predicting patterns of recurrence after resection of N1 non-small cell lung carcinoma.
      • Riquet M
      • Manac'h D
      • Le Pimpec-Barthes F
      • et al.
      Prognostic significance of surgical-pathologic N1 disease in non-small cell carcinoma of the lung.
      • Yoshino I
      • Nakanishi R
      • Osaki T
      • et al.
      Unfavorable prognosis of patients with stage II non-small cell lung cancer associated with macroscopic nodal metastases.
      • Asamura H
      • Suzuki K
      • Kondo H
      • et al.
      Where is the boundary between N1 and N2 stations in lung cancer?.
      • Marra A
      • Hillejan L
      • Zaboura G
      • et al.
      Pathologic N1 non-small cell lung cancer: correlation between pattern of lymphatic spread and prognosis.
      • Naruke T
      • Suemasu K
      • Ishikawa S
      Lymph node mapping and curability at various levels of metastasis in resected lung cancer.
      • Martini N
      • Flehinger BJ
      • Nagasaki F
      • et al.
      Prognostic significance of N1 disease in carcinoma of the lung.
      • Miller DL
      • McManus KG
      • Allen MS
      • et al.
      Results of surgical resection in patients with N2 non-small cell lung cancer.
      • Goldstraw P
      • Mannam GC
      • Kaplan DK
      • et al.
      Surgical management of non-small cell lung cancer with ipsilateral mediastinal node metastasis (N2 disease).
      • Riquet M
      • Manac'h D
      • Saab M
      • et al.
      Factors determining survival in resected N2 lung cancer.
      • Okada M
      • Tsubota N
      • Yoshimura M
      • et al.
      Prognosis of completely resected pN2 non-small cell lung carcinomas: what is the significant node that affects survival?.
      • Asamura H
      • Nakayama H
      • Kondo H
      • et al.
      Lobe-specific extent of systematic lymph node dissection for non-small cell lung carcinomas according to a retrospective study of metastasis and prognosis.
      • Sagawa M
      • Sakurada A
      • Fujimura S
      • et al.
      Five-year survivors with resected pN2 nonsmall cell lung carcinoma.
      • Andre F
      • Grunewald D
      • Pignon JP
      • et al.
      Survival of patients with resected N2 non-small cell lung cancer: evidence for a subclassification and implications.
      • Naruke T
      • Tsuchiya R
      • Kondo H
      • et al.
      Prognosis and survival after resection for bronchogenic carcinoma based on the 1997 TNM-staging classification: the Japanese experience.
      • Ichinose Y
      • Kato H
      • Koike T
      • et al.
      Completely resected stage IIIA non-small cell lung cancer: the significance of primary tumor location and N2 station.
      • Ueda K
      • Kaneda Y
      • Sakano H
      • et al.
      Independent predictive value of the overall number of metastatic N1 and N2 stations in lung cancer.
      • Inoue M
      • Sawabata N
      • Takeda SI
      • et al.
      Results of surgical intervention for p-stage IIIA (N2) non-small cell lung cancer: acceptable prognosis predicted by complete resection in patients with single N2 disease with primary tumor in the upper lobe.
      • Keller SM
      • Vangel MG
      • Wagner H
      • et al.
      Prolonged survival in patients with resected non-small cell lung cancer and single-level N2 disease.
      This study was undertaken as part of the effort by the staging committee of the International Association for the Study of Lung Cancer (IASLC) to determine whether the current international lung cancer staging system required revision in preparation for the seventh edition of the Union Internationale Contre le Cancer (UICC) and American Joint Commission on Cancer (AJCC) cancer staging manuals. We sought to define whether the current N descriptors for NSCLC should be maintained or revised.

      METHODS

      Data Acquisition and Analysis

      The process for the development of the IASLC lung database has been described previously.
      • Goldstraw P
      • Crowley JJ
      The International Association for the Study of Lung Cancer international staging project on lung cancer.
      Briefly, the database was developed through an international consortium of institutions and clinical trials groups that submitted staging and outcomes data on a total of 100,869 lung cancer cases managed within the time frame of 1990 to 2000. Data were collected retrospectively from 47 preexisting databases, which varied widely in terms of the levels of detail provided. Data management and statistical analyses were provided by coinvestigators at Cancer Research and Biostatistics in Seattle, Washington. Of the 81,015 lung cancer patients and the 67,725 NSCLC patients who met the initial screening requirements of a complete set of tumor, node, metastasis (TNM) by either clinical or pathological staging, known histological type, and survival follow-up, 38,265 patients with no clinical evidence of metastatic disease (cM0) had information on clinical N staging (cN), and 28,371 surgically managed patients provided information on pathologic N staging (pN). Clinical staging included all tests and imaging studies done for initial extent-of-disease evaluation and information obtained from mediastinoscopy, but not from thoracotomy. Positron emission tomography (PET) was not in widespread use internationally during the time frame of this study, so PET data for clinical staging were not available. Pathological staging included all of the information available from clinical staging plus the pathological information from specimens obtained at thoracotomy. Twelve of the 47 databases submitted to the project included data on sampling results (positive, negative, not done) for individual nodal stations. Further analyses of overall survival in relation to subsets of pN1 and pN2 stages were performed for 2876 patients who underwent R0 (microscopically complete) resection without induction therapy and who successfully met logic checks of pN stage for data accuracy (pN stage in relation to highest positive nodal station recorded). Of these, 1721 cases (60%) were submitted from Japan, 701 cases (24%) came from Europe, 380 (13.2%) were from North America, and 74 (2.6%) were from Australia or Taiwan. The minimum lymph node stations for which documentation was available from all contributing groups included nodal level 2 and levels 4 through 9. All but one group provided documentation for levels 11 and 12, and most groups provided documentation for supraclavicular lymph nodes and nodes at levels 1, 13, and 14. Documentation of level 3 nodes was available from half of the contributing groups.
      Surgical cases from Japan were staged according to the Naruke lymph node map, adopted by the Japan Lung Cancer Society as the official staging map (Figure 1).
      • The Japan Lung Cancer Society
      Those from all other countries were staged according to the Mountain-Dresler modification of the American Thoracic Society (MD-ATS) map (Figure 2).
      • Mountain CF
      • Dresler CM
      Regional lymph node classification for lung cancer staging.
      • Jett J
      • Feins R
      • Kvale P
      • et al.
      Pretreatment evaluation of non-small cell lung cancer.
      • Tisi GM
      • Friedman PJ
      • Peters RM
      • et al.
      Clinical staging of primary lung cancer.
      From the perspective of grouping lymph node stations into N1 versus N2 categories, the main discrepancy between these two lymph node maps is that the Naruke map considers lymph nodes in the subcarinal space along the inferior border of the mainstem bronchus to be station 10 (hence, N1), whereas these are labeled as level 7 (and, therefore, N2) in the MD-ATS map. Within the context of a retrospective analysis, there was no way to reconcile this inherent difference in the designation of subcarinal lymph nodes. A lesser discrepancy between these two maps occurs in the labeling of lymph nodes from the right paratracheal region. Lymph nodes located between the right main pulmonary artery and the origin of the innominate artery are labeled as right level 4 (R4) in the MD-ATS map, whereas in the Naruke map the upper half of this region is considered level 2 (R2), and only the nodes located between the right main pulmonary artery and the superior border of the azygos vein are considered 4R. Nevertheless, all of these lymph nodes would be considered N2 according to either mapping system. This difference in nomenclature introduces an irreconcilable but likely small discrepancy in data analysis (Table 1).
      Figure thumbnail gr1
      FIGURE 1Naruke lymph node map. From: The Japan Lung Cancer Society. Classification of Lung Cancer, 1st English Ed. Tokyo: Kanehara & Co., 2000.
      • The Japan Lung Cancer Society
      Used with permission.
      Figure thumbnail gr2
      FIGURE 2Mountain-Dresler lymph node map. The lymph node “zones― used for analyses in this study are shown superimposed on the MD-ATS map. From: Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997;111:1718–1723.
      • Mountain CF
      • Dresler CM
      Regional lymph node classification for lung cancer staging.
      Used with permission.
      TABLE 1Comparison of Nomenclature of Lymph Node Stations in the Japanese (Naruke) vs. Mountain-Dresler Modification of American Thoracic Society (ATS) Maps
      JapaneseMountain-Dresler (ATS)
      Level 1 Levels 1 and 2
      Levels 2, 3, 4R, 4L Levels 4R and 4L
      Levels 7 and 10 (subcarinal) Level 7

      Statistical Methodology

      Survival was measured from the date of entry (date of diagnosis for registries, date of registration for protocols) for clinically staged data and from the date of surgery for pathologically staged data; it was calculated by the Kaplan-Meier method. Prognostic groups were assessed by Cox regression analysis, using the SAS System for Windows version 9.0 PHREG procedure.

      RESULTS

      Overall Survival According to Clinical N Staging

      The overall survival by cN staging for all 38,265 cM0 (any T stage) patients is shown in Figure 3. These survival curves show clear differences in outcome for each of the cN categories. Additional analyses indicate that these differences in outcome occurred predominantly among the clinically staged patients who underwent surgical treatment. For the clinically staged cM0 patients who were managed nonsurgically (n = 15,451), the median and 5-year survival rates ranged, respectively, from 13 months and 9% for N0 to 9 months and 5% for N3 disease (data not shown). Whether the absence of survival differences for patients managed nonsurgically reflects the lack of efficacy of available treatment, the influence of medical comorbidities, or both, cannot be determined from this database.
      Figure thumbnail gr3
      FIGURE 3Survival by cN for all cM0 patients.

      Overall Survival According to Pathological N Staging

      The overall survival by pN staging for the 28,371 cM0 (any T stage) patients who were managed surgically (and who had no evidence of intrathoracic M1 disease at thoracotomy) is shown in Figure 4. These survival curves again show significant differences in outcome for each of the pN categories. Figure 4 also shows the survival rates for surgically managed patients for whom cN staging information was available (n = 22,814), again indicating distinct differences in outcome for each N category. Comparison of the survival rates by cN and pN indicates that the additional information provided from pathological staging defines a group of N0 stage tumors with better survival and a group of N3 stage tumors with worse survival than expected from clinical staging alone.
      Figure thumbnail gr4
      FIGURE 4Survival by cN for surgically managed patients.

      Relationships between the Site of the Primary Tumor and the Presence of Lymph Node Metastases

      Information on the site of the primary tumor in relationship to the presence of lymph node metastases (pN) was available from 2538 N1 and N2 cases. There were slightly more upper-lobe (n = 1385; 56%) than lower-lobe tumors. The upper-lobe tumors were associated with the highest frequency of N1 (n = 551; 53%) and N2 (59%) nodal metastases. The right middle lobe was the least common primary tumor site. Among the primary tumors that had only a single involved N2 lymph node station, the most common site of lymph node metastases was level 4R for right upper-lobe tumors (191/280; 68%), levels 5/6 for left upper-lobe tumors (195/251; 78%), and level 7 for middle- and lower-lobe tumors (228/353; 65%).

      Survival in Relationship to the Extent of N1 and N2 Disease in Cases with pN Staging

      Exploratory analyses were performed to determine whether, in patients with pN staging, survival was influenced by the anatomical location of involved lymph nodes, by the presence of “skip metastases― (N2 disease in the absence of N1), or by the number of involved lymph node stations. The 522 N1 cases with involvement of peribronchial levels 12 to 14 were evaluated to determine whether survival was influenced by involvement of the peribronchial (levels 12–14) versus the interlobar (level 11) or hilar (level 10) lymph nodes, or by combinations of these. No significant differences in survival could be identified (Table 2a), apart from the general finding that survivorship decreased as the number of positive stations increased.
      TABLE 2Comparison of Survival According to Involvement of Specific Peripheral Lymph Node Stations (2a), Single Lymph Node Zones (2b), and Presence of Skip Metastases (2c)
      2a: Specific Peripheral Lymph Node Stations
      Lymph Node StationnMedian Survival (mo)p
      12 (or higher) vs. 11, 10
       12+ only36151
       12+ 11+ 10-844812+ 11 + 10- vs 12+ only0.5876
       12+ 11- 10+463612+ 11 – 10+ vs 12+ only0.0592
       12+ 11+ 10+312812+ 11 + 10+ vs 12+ only0.0974
      12+ 11+ 10- vs 12+ 11- 10+0.2340
      2b: Single Lymph Node Zones
      Lymph Node StationnMedian Survival (mo)p
      Single zone: right
       P only32456
       H only4563H only vs P only0.8548
       LM only834LM only vs P only0.2303
       S only15137S only vs P only0.0535
      S only vs LM only0.7775
       U only15137U only vs P only0.0069
      U only vs LM only0.7131
      U only vs S only0.8869
      Single zone: left
       P only26252P only
       H only5140H only vs P only0.8156
       LM only939LM only vs P only0.1422
       S only1743S only vs P only0.2039
      S only vs LM only0.6688
       AP only6444AP only vs P only0.3923
      AP only vs LM only0.3189
      AP only vs S only0.5149
      2c: Presence of Skip Metastases
      Lymph Node StationnMedian Survival (mo)p
      RUL upper zone+, figure
       U+ P– H–14237
       U+ P+ H–9744U+ P+ H– vs U+ P– H–0.5373
       U+ P- H+2340U+ P– H+ vs U+ P– H–0.8266
       U+ P+ H+5528U+ P+ H+ vs U+ P- H-0.1878
      LUL AP zone+, figure
       AP+ P– H–8644
       AP+ P+ H–4532AP+ P+ H- vs AP+ P- H-0.3878
       AP+ P- H+1327AP+ P- H+ vs AP+ P- H-0.6433
       AP+ P+ H+3824AP+ P+ H+ vs AP+ P- H-0.0427
      U, upper mediastinal (levels 1–4); AP, aortopulmonary (levels 5 and 6); S, subcarinal (level 7); LM, lower mediastinal (levels 8 and 9); H, hilar (levels 10 and 11); P, peripheral (levels 12–14); RUL, right upper lobe; LUL, left upper lobe.
      To reconcile the Naruke and MD-ATS lymph node maps and to permit analyses of cases with N1 and, especially, N2 disease to include larger numbers of patients, lymph node stations were grouped together into anatomical “zones.― Lymph nodes at levels 1 through 4 were grouped together into the upper zone, levels 5 and 6 into the aortopulmonary (AP) zone, level 7 into the subcarinal zone, levels 8 and 9 into the lower zone, levels 10 and 11 into the hilar zone, and levels 12 to 14 into the peripheral zone (Figure 2). The appropriateness of grouping lymph node stations into zones was suggested by exploratory analyses that failed to identify significant differences in survival in relation to disease in all of the various N1 and N2 lymph node stations in the data submitted from Japan, from non-Japanese groups, or both (data not shown). As shown in Table 2b, significant differences in survival for patients with lymph node metastases confined to a single zone were seen only for cases of right-sided tumors with upper- or subcarinal zone disease compared with peripheral zone metastases. No differences in survival were identified among patients who had single-zone N2 disease.
      Potential differences in survival were analyzed for cases with skip metastases, focusing on upper-lobe tumors, which are thought to be most frequently associated with these. AP zone disease in the absence of N1 metastases was associated with a better survival rate in patients with left upper-lobe tumors, but similar differences in survival were not identified for right upper-lobe tumors with right paratracheal nodal metastases (Table 2c).
      The potential impact of the number of involved lymph node zones on survival was then examined. As can be seen in Figure 5, three groups were found to have significantly different survival rates: patients who had N1 single-zone disease, those who had either multiple N1 or single N2 zone metastases, and those who had multiple N2 lymph node zones involved. These prognostically distinct groups suggested that it might be appropriate to subdivide the current N staging descriptors into N1a (single N1 zone), N1b (multiple N1 zones), N2a (single N2 zone), and N2b (multiple N2 zones). To determine whether such a revision to the staging system should be considered, these additional N categories were analyzed in conjunction with each T stage category (e.g., T1N1a, T1N1b, T1N2a, T1N2b, etc.) rather than across all T stages, as was done for all of the preceding analyses. Nevertheless, the number of patients available in each of these subsets was too small to yield statistically valid analyses. Therefore, on the basis of the available data, we cannot recommend altering the current N stage descriptors.
      Figure thumbnail gr5
      FIGURE 5Survival by N status and number of involved N zones.

      DISCUSSION

      Accurate staging of lymph node involvement has long been recognized as a key aspect of the initial management of NSCLC that helps in selecting treatment and predicting outcome. In patients undergoing surgery for possible resection of NSCLC, careful assessment of potential nodal disease has gradually become an accepted part of the operation since Cahan first described radical mediastinal lymph node dissection in the early 1950s.
      • Martini N
      Mediastinal lymph node dissection for lung cancer. The Memorial experience.
      • Cahan WG
      • Watson WL
      • Pool JL
      Radical pneumonectomy.
      For similar reasons, mediastinoscopy and imaging studies such as CT (computed tomography) and PET scanning have become standard components of the initial clinical staging of NSCLC.
      • Jett J
      • Feins R
      • Kvale P
      • et al.
      Pretreatment evaluation of non-small cell lung cancer.
      The development of the Naruke and, subsequently, of the ATS lymph node maps, provided standard nomenclature used by all clinicians and pathologists involved in the care of NSCLC patients to assist in uniform N staging. Traditionally, these maps labeled N2 or N3 nodes with single-digit numbers (nodal stations 1–9) and N1 nodes with double-digit numbers (nodal stations 10–14). From the inception of the AJCC and UICC lung cancer staging systems in 1973, the N0, N1, N2, and N3 descriptors were used to help establish stage classifications for both clinical and pathological staging. The fifth edition of the lung cancer staging system, based on a database developed by Dr. Clifton Mountain of 5319 cases (4351 patients treated at the MD Anderson Cancer Center, and 968 from other North American centers), led to a revision of the stage classifications but maintained the existing distinctions among the N descriptors.
      • Mountain CF
      Revisions in the International System for Staging Lung Cancer.
      In the absence of compelling alternative data, no changes were made to the sixth edition of the AJCC and UICC staging system. The current IASLC database includes a much larger number of cases from databases around the world on which to test the validity of the current staging system. Our data show that the N0, N1, N2, and N3 descriptors, whether derived from clinical or pathological staging, clearly identify prognostically distinct groups of patients, and it is therefore appropriate to maintain these descriptors in the upcoming seventh version of the lung cancer staging system. Notably, the IASLC database is the first international database that has shown these descriptors to have internal and external validity.
      During the past 25 years, numerous studies have examined the patterns of lymphatic drainage of the lung and have analyzed the influence of N1 and N2 lymph node involvement on overall survival. These series are retrospective, are based on pathological staging, and include relatively small numbers of patients.
      • Ferguson MK
      • Little AG
      • Golomb HM
      • et al.
      The role of adjuvant therapy after resection of T1 N1 M0 and T2 N1 M0 non-small cell lung cancer.
      • Maggi G
      • Casadio C
      • Mancuso M
      • et al.
      Resection and radical lymphadenectomy for lung cancer: prognostic significane of lymphatic metastases.
      • Martini N
      • Burt ME
      • Bains MS
      • et al.
      Survival after resection of stage II non-small cell lung cancer.
      • Yano T
      • Yokoyama H
      • Inoue T
      • et al.
      Surgical results and prognostic factors of pathologic N1 disease in non-small-cell carcinoma of the lung. Significance of N1 level: lobar or hilar nodes.
      • van Velzen E
      • Snijder RJ
      • de la Rivière AB
      • et al.
      Type of lymph node involvement influences survival rates of T1N1M0 non-small cell lung carcinoma. Lymph node involvement by direct extension compared with lobar and hilar node metastases.
      • van Velzen E
      • Snijder RJ
      • de la Rivière AB
      • et al.
      Lymph node type as a prognostic factor for survival in T2 N1 M0 non-small cell lung carcinoma.
      • van Velzen E
      • de la Rivière AB
      • Elbert HJJ
      • et al.
      Type of lymph node involvement and survival in pathologic N1 stage III non-small cell lung carcinoma.
      • Sawyer TE
      • Bonner JA
      • Gould PM
      • et al.
      Factors predicting patterns of recurrence after resection of N1 non-small cell lung carcinoma.
      • Riquet M
      • Manac'h D
      • Le Pimpec-Barthes F
      • et al.
      Prognostic significance of surgical-pathologic N1 disease in non-small cell carcinoma of the lung.
      • Yoshino I
      • Nakanishi R
      • Osaki T
      • et al.
      Unfavorable prognosis of patients with stage II non-small cell lung cancer associated with macroscopic nodal metastases.
      • Asamura H
      • Suzuki K
      • Kondo H
      • et al.
      Where is the boundary between N1 and N2 stations in lung cancer?.
      • Marra A
      • Hillejan L
      • Zaboura G
      • et al.
      Pathologic N1 non-small cell lung cancer: correlation between pattern of lymphatic spread and prognosis.
      • Naruke T
      • Suemasu K
      • Ishikawa S
      Lymph node mapping and curability at various levels of metastasis in resected lung cancer.
      • Martini N
      • Flehinger BJ
      • Nagasaki F
      • et al.
      Prognostic significance of N1 disease in carcinoma of the lung.
      • Miller DL
      • McManus KG
      • Allen MS
      • et al.
      Results of surgical resection in patients with N2 non-small cell lung cancer.
      • Goldstraw P
      • Mannam GC
      • Kaplan DK
      • et al.
      Surgical management of non-small cell lung cancer with ipsilateral mediastinal node metastasis (N2 disease).
      • Riquet M
      • Manac'h D
      • Saab M
      • et al.
      Factors determining survival in resected N2 lung cancer.
      • Okada M
      • Tsubota N
      • Yoshimura M
      • et al.
      Prognosis of completely resected pN2 non-small cell lung carcinomas: what is the significant node that affects survival?.
      • Asamura H
      • Nakayama H
      • Kondo H
      • et al.
      Lobe-specific extent of systematic lymph node dissection for non-small cell lung carcinomas according to a retrospective study of metastasis and prognosis.
      • Sagawa M
      • Sakurada A
      • Fujimura S
      • et al.
      Five-year survivors with resected pN2 nonsmall cell lung carcinoma.
      • Andre F
      • Grunewald D
      • Pignon JP
      • et al.
      Survival of patients with resected N2 non-small cell lung cancer: evidence for a subclassification and implications.
      • Naruke T
      • Tsuchiya R
      • Kondo H
      • et al.
      Prognosis and survival after resection for bronchogenic carcinoma based on the 1997 TNM-staging classification: the Japanese experience.
      • Ichinose Y
      • Kato H
      • Koike T
      • et al.
      Completely resected stage IIIA non-small cell lung cancer: the significance of primary tumor location and N2 station.
      • Ueda K
      • Kaneda Y
      • Sakano H
      • et al.
      Independent predictive value of the overall number of metastatic N1 and N2 stations in lung cancer.
      • Inoue M
      • Sawabata N
      • Takeda SI
      • et al.
      Results of surgical intervention for p-stage IIIA (N2) non-small cell lung cancer: acceptable prognosis predicted by complete resection in patients with single N2 disease with primary tumor in the upper lobe.
      • Keller SM
      • Vangel MG
      • Wagner H
      • et al.
      Prolonged survival in patients with resected non-small cell lung cancer and single-level N2 disease.
      Among patients undergoing surgery for NSCLC, our data corroborate the findings of other studies, including a higher frequency of upper-lobe tumors and a predominance of lymphatic drainage to the superior mediastinum for right upper-lobe tumors, to the AP region for left upper-lobe tumors, and to the subcarinal area for middle- and lower-lobe tumors.
      • Riquet M
      • Manac'h D
      • Saab M
      • et al.
      Factors determining survival in resected N2 lung cancer.
      • Asamura H
      • Nakayama H
      • Kondo H
      • et al.
      Lobe-specific extent of systematic lymph node dissection for non-small cell lung carcinomas according to a retrospective study of metastasis and prognosis.
      • Ichinose Y
      • Kato H
      • Koike T
      • et al.
      Completely resected stage IIIA non-small cell lung cancer: the significance of primary tumor location and N2 station.
      • Ueda K
      • Kaneda Y
      • Sakano H
      • et al.
      Independent predictive value of the overall number of metastatic N1 and N2 stations in lung cancer.
      • Inoue M
      • Sawabata N
      • Takeda SI
      • et al.
      Results of surgical intervention for p-stage IIIA (N2) non-small cell lung cancer: acceptable prognosis predicted by complete resection in patients with single N2 disease with primary tumor in the upper lobe.
      • Vansteenkiste JF
      • De Leyn PR
      • Deneffe GJ
      • et al.
      Survival and prognostic factors in resected N2 non-small cell lung cancer: a study of 140 cases.
      Previous studies suggest that survival is significantly worse in patients who have hilar or interlobar rather than only peribronchial lymph node involvement or that multiple levels of N1 nodal disease are associated with a worse outcome than single-level disease (Table 3). We were unable to identify differences in outcome for patients with peripheral versus hilar N1 disease, but we found that survival was significantly worse in cases of multiple versus single levels of N1 nodal metastases.
      TABLE 3Results of Series Reporting the Outcome of Patients Who Underwent Resection for Non-small Cell Lung Cancer with N1 Disease
      Authors (Year)No. of Patients5-Year Survival (%)
      Overall(+) Hilar(+) Interlobar(+) Peripheral
      Ferguson et al.
      • Ferguson MK
      • Little AG
      • Golomb HM
      • et al.
      The role of adjuvant therapy after resection of T1 N1 M0 and T2 N1 M0 non-small cell lung cancer.
      (1986)
      3430.2NSNSNS
      Maggi et al.
      • Maggi G
      • Casadio C
      • Mancuso M
      • et al.
      Resection and radical lymphadenectomy for lung cancer: prognostic significane of lymphatic metastases.
      (1990)
      15746.1NSNSNS
      Martini et al.
      • Martini N
      • Burt ME
      • Bains MS
      • et al.
      Survival after resection of stage II non-small cell lung cancer.
      (1992)
      21439NSNSNS
      Yano et al.
      • Yano T
      • Yokoyama H
      • Inoue T
      • et al.
      Surgical results and prognostic factors of pathologic N1 disease in non-small-cell carcinoma of the lung. Significance of N1 level: lobar or hilar nodes.
      (1994)
      7849.239.7
      Hilar and interlobar were analyzed as a single group.
      64.5
      van Velzen et al.
      • van Velzen E
      • Snijder RJ
      • de la Rivière AB
      • et al.
      Type of lymph node involvement influences survival rates of T1N1M0 non-small cell lung carcinoma. Lymph node involvement by direct extension compared with lobar and hilar node metastases.
      (1996)
      5745.723.3
      Hilar and interlobar were analyzed as a single group.
      55.6
      van Velzen et al.
      • van Velzen E
      • Snijder RJ
      • de la Rivière AB
      • et al.
      Lymph node type as a prognostic factor for survival in T2 N1 M0 non-small cell lung carcinoma.
      (1997)
      36937.830.3
      Hilar and interlobar were analyzed as a single group.
      57.3
      van Velzen et al.
      • van Velzen E
      • de la Rivière AB
      • Elbert HJJ
      • et al.
      Type of lymph node involvement and survival in pathologic N1 stage III non-small cell lung carcinoma.
      (1999)
      11127.2NSNSNS
      Sawyer et al.
      • Sawyer TE
      • Bonner JA
      • Gould PM
      • et al.
      Factors predicting patterns of recurrence after resection of N1 non-small cell lung carcinoma.
      (1999)
      10732NSNSNS
      Riquet et al.
      • Riquet M
      • Manac'h D
      • Le Pimpec-Barthes F
      • et al.
      Prognostic significance of surgical-pathologic N1 disease in non-small cell carcinoma of the lung.
      (1999)
      25647.538.5
      Hilar and interlobar were analyzed as a single group.
      52.6
      Yoshino et al.
      • Yoshino I
      • Nakanishi R
      • Osaki T
      • et al.
      Unfavorable prognosis of patients with stage II non-small cell lung cancer associated with macroscopic nodal metastases.
      (1999)
      4350.247.4
      Hilar and interlobar were analyzed as a single group.
      55
      Asamura et al.
      • Asamura H
      • Suzuki K
      • Kondo H
      • et al.
      Where is the boundary between N1 and N2 stations in lung cancer?.
      (2000)
      180675470
      Interlobar and peripheral were analyzed as a single group.
      Marra et al.
      • Marra A
      • Hillejan L
      • Zaboura G
      • et al.
      Pathologic N1 non-small cell lung cancer: correlation between pattern of lymphatic spread and prognosis.
      (2003)
      53540303941
      NS, not shown.
      * Hilar and interlobar were analyzed as a single group.
      Interlobar and peripheral were analyzed as a single group.
      Differences in nomenclature between the Naruke and the MD-ATS lymph node maps pose challenges for the analysis of an international database. Reconciliation of these maps is the subject of a separate study (which is being undertaken by the IASLC staging committee) and is, therefore, not discussed in detail here. Nevertheless, our exploratory analyses suggested that for the purposes of analyzing N stages, it was statistically appropriate to consolidate several lymph node stations from both mapping systems together into zones. This approach allowed us to address the findings of previous studies that skip metastases and single-level N2 disease are both associated with better survival rates than involvement of multiple N2 lymph node stations (Table 4). In contrast with previous studies,
      • Misthos P
      • Sepsas E
      • Athanassiadi K
      • et al.
      Skip metastases: analysis of their clinical significance and prognosis in the IIIA stage of non-small cell lung cancer.
      • Prenzel KL
      • Monig SP
      • Sinning JM
      • et al.
      Role of skip metastasis to mediastinal lymph nodes in non-small cell lung cancer.
      • Libshitz HE
      • McKenna Jr, RJ
      • Mountain CF
      Patterns of mediastinal metastases in bronchogenic carcinoma.
      • Yoshino I
      • Yokoyama H
      • Yano T
      • et al.
      Skip metastasis to the mediastinal lymph nodes in non-small cell lung cancer.
      • Tsubota N
      • Yoshimura M
      Skip metastasis and hidden N2 disease in lung cancer: how successful is mediastinal dissection?.
      • Takizawa T
      • Terashima M
      • Koike T
      • et al.
      Mediastinal lymph node metastasis in patients with clinical stage I peripheral non-small cell lung cancer.
      • Okada M
      • Tsubota N
      • Yoshimura M
      • et al.
      Proposal for reasonable mediastinal lymphadenectomy in brocnhogenic carcinomas: role of subcarinal nodes in selective dissection.
      • Ohta Y
      • Shimizu Y
      • Minato H
      • et al.
      Results of initial operations in non-small cell lung cancer patients with single-level N2 disease.
      we were able to identify a better survival rate only for patients with left upper-lobe tumors with AP zone N2 disease—not for patients with right upper-lobe tumors with metastases confined to the superior mediastinum. These results should be interpreted with caution because the numbers of patients available for these subset analyses are relatively small.
      TABLE 4Results of a Series Reporting the Outcome of Patients Who Underwent Resection for Non-small Cell Lung Cancer with N2 Disease
      5-Year Survival (%)
      Author (Year)No. of PatientsOverallSingle LevelMulti Levelp
      Naruke et al.
      • Naruke T
      • Suemasu K
      • Ishikawa S
      Lymph node mapping and curability at various levels of metastasis in resected lung cancer.
      (1978)
      7718.8NRNRNR
      Martini et al.
      • Martini N
      • Flehinger BJ
      • Nagasaki F
      • et al.
      Prognostic significance of N1 disease in carcinoma of the lung.
      (1983)
      151292533NR
      Miller et al.
      • Miller DL
      • McManus KG
      • Allen MS
      • et al.
      Results of surgical resection in patients with N2 non-small cell lung cancer.
      (1994)
      14723.7300–30, depending on number of stations0.02
      Goldstraw et al.
      • Goldstraw P
      • Mannam GC
      • Kaplan DK
      • et al.
      Surgical management of non-small cell lung cancer with ipsilateral mediastinal node metastasis (N2 disease).
      (1994)
      14920.130 (3 yr)25 (3 yr)0.05
      Riquet et al. (1995)
      • Riquet M
      • Manac'h D
      • Saab M
      • et al.
      Factors determining survival in resected N2 lung cancer.
      23718.826.38.30.0003
      Vansteenkiste et al.
      • Vansteenkiste JF
      • De Leyn PR
      • Deneffe GJ
      • et al.
      Survival and prognostic factors in resected N2 non-small cell lung cancer: a study of 140 cases.
      (1997)
      14020.819.5220.20
      Okada et al.
      • Okada M
      • Tsubota N
      • Yoshimura M
      • et al.
      Prognosis of completely resected pN2 non-small cell lung carcinomas: what is the significant node that affects survival?.
      (1999)
      1412639110.0001
      Asamura et al.
      • Asamura H
      • Nakayama H
      • Kondo H
      • et al.
      Lobe-specific extent of systematic lymph node dissection for non-small cell lung carcinomas according to a retrospective study of metastasis and prognosis.
      (1999)
      1663548180.006
      Sagawa et al.
      • Sagawa M
      • Sakurada A
      • Fujimura S
      • et al.
      Five-year survivors with resected pN2 nonsmall cell lung carcinoma.
      (1999)
      1782841130.001
      Andre et al.
      • Andre F
      • Grunewald D
      • Pignon JP
      • et al.
      Survival of patients with resected N2 non-small cell lung cancer: evidence for a subclassification and implications.
      (2000)
      70218257<0.0001
      Naruke et al.
      • Naruke T
      • Tsuchiya R
      • Kondo H
      • et al.
      Prognosis and survival after resection for bronchogenic carcinoma based on the 1997 TNM-staging classification: the Japanese experience.
      (2001)
      73619.9NRNRNR
      Ichinose et al.
      • Ichinose Y
      • Kato H
      • Koike T
      • et al.
      Completely resected stage IIIA non-small cell lung cancer: the significance of primary tumor location and N2 station.
      (2001)
      402314317<0.0001
      Ueda et al.
      • Ueda K
      • Kaneda Y
      • Sakano H
      • et al.
      Independent predictive value of the overall number of metastatic N1 and N2 stations in lung cancer.
      (2003)
      963035190.019
      Inoue et al.
      • Inoue M
      • Sawabata N
      • Takeda SI
      • et al.
      Results of surgical intervention for p-stage IIIA (N2) non-small cell lung cancer: acceptable prognosis predicted by complete resection in patients with single N2 disease with primary tumor in the upper lobe.
      (2004)
      15428.142.715.50.0001
      Keller et al.
      • Keller SM
      • Vangel MG
      • Wagner H
      • et al.
      Prolonged survival in patients with resected non-small cell lung cancer and single-level N2 disease.
      (2004)
      172NR32NRNR
      NR, not reported.
      The most salient finding with respect to pN staging in our database is that patients fall into three prognostically distinct categories, depending on the extent of nodal metastases: single-zone N1, multiple-zone N1 or single-zone N2, and multiple-zone N2. In conjunction with our other analyses, these results suggest that the overall disease burden, rather than just the anatomical location of lymph node involvement, may have the most important influence on outcome. These three categories have not been clearly identified in previous studies (TABLE 3, TABLE 4), which have focused predominantly on comparing survival relative to varying levels of either N1 or N2 disease. Validating this finding in a way that would be statistically sound enough to warrant a change in the N descriptors for the staging system would clearly require a prospective study of even larger numbers of patients with meticulous pN staging. Nevertheless, our results provide the impetus for such a study and the rationale for stratifying patients according these three prognostic groups in clinical trials.
      In summary, analyses of clinical and pathological N staging in the IASLC database support the continued use of the current N descriptors in the lung cancer database. Additional analyses suggest that consolidation of multiple lymph node stations into zones and stratification of patients into three groups according to the extent of nodal disease may be appropriate and warrant inclusion in future studies.

      APPENDIX 1

      aIASLC International Staging Committee

      P. Goldstraw (chairperson), Royal Brompton Hospital, London, United Kingdom; D. Ball, Peter MacCallum Cancer Centre, Melbourne, Australia; E. Brambilla, Laboratoire de Pathologie Cellulaire, Grenoble Cedex, France; P.A. Bunn, University of Colorado Health Sciences, Denver, CO; D. Carney, Mater Misericordiae Hospital, Dublin, Ireland; T. Le Chevalier, Institute Gustave Roussy, Villejuif, France; J. Crowley, Cancer Research and Biostatistics, Seattle, WA; R. Ginsberg (deceased), Memorial Sloan-Kettering Cancer Centre, New York, NY; P. Groome, QueenEs Cancer Research Institute, Kingston, Ontario, Canada; H.H. Hansen (retired), National University Hospital, Copenhagen, Denmark; P. Van Houtte, Institute Jules Bordet, Bruxelles, Belgium; J-G. Im, Seoul National University Hospital, Seoul, South Korea; J.R. Jett, Mayo Clinic, Rochester, MN; H. Kato (retired), Tokyo Medical Centre, Tokyo, Japan; T. Naruke (deceased), Saiseikai Central Hospital, Tokyo, Japan; E.F. Patz, Duke University Medical Centre, Durham, NC; P.E. Postmus, Free University Hospital, Amsterdam, The Netherlands; R. Rami-Porta, Hospital Mutua de Terrassa, Terrassa, Spain; V. Rusch, Memorial Sloan-Kettering Cancer Centre, New York, NY; J.P. Sculier, Institute Jules Bordet, Bruxelles, Belgium; F.A. Shepherd, University of Toronto, Toronto, Ontario; Y. Shimosato (retired), National Cancer Center, Tokyo, Japan; L. Sobin, Armed Forces Institute of Pathology, Washington, DC; W. Travis, Memorial Sloan-Kettering Cancer Centre, New York, NY; M. Tsuboi, Tokyo Medical Centre, Tokyo, Japan; R. Tsuchiya, National Cancer Centre, Tokyo, Japan; E. Vallieres, Swedish Cancer Institute, Seattle, WA; Yoh Watanabe (deceased), Kanazawa Medical University, Uchinada, Japan; and H. Yokomise, Kagawa University, Kagawa, Japan.

      bCancer Research and Biostatistics

      J.J. Crowley, K. Chansky, D. Giroux, and V. Bolejack, Seattle, WA.

      cObservers to the Committee

      C. Kennedy, University of Sydney, Sydney, Australia; M. Krasnik, Gentofte Hospital, Copenhagen, Denmark; J. van Meerbeeck, University Hospital, Ghent, Belgium; J. Vansteenkiste, Leuven Lung Cancer Group, Leuven, Belgium.

      dParticipating Institutions

      O. Visser, Amsterdam Cancer Registry, Amsterdam, The Netherlands; R. Tsuchiya and T. Naruke (deceased), National Data from Japan; J.P Van Meerbeeck, Flemish Lung Cancer Registry–VRGT, Brussels, Belgium; H. Bülzebruck, Thorax-klinik am Universitatsklinikum, Heidelberg, Germany; R. Allison and L. Tripcony, Queensland Radium Institute, Queensland, Australia; X. Wang, D. Watson, and J. Herndon, Cancer and Leukmia Group B (CALGB) United States; R.J. Stevens, Medical Research Council Clinical Trials Unit, London, United Kingdom; A. Depierre, E. Quoix, and Quan Tran, Intergroupe Francophone de Cancerologie Thoracique (IFCT), Franceá; J.R. Jett and S. Mandrekar, North Central Cancer Treatment Group (NCCTG), United States; J.H Schiller and R.J. Gray, Eastern Cooperative Oncology Group (ECOG), United States; J.L Duque-Medina and A. Lopez-Encuentra, Bronchogenic Carcinoma Co-operative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCB-S), Spain; J.J. Crowley, Southwest Oncology Group (SWOG), Bimodality Lung Oncology Team (BLOT), United States; T.E. Strand, Cancer Registry of Norway; S. Swann and H. Choy, Radiation Therapy Oncology Group (RTOG), United States; R. Damhius, Rotterdam Cancer Registry, The Netherlands; R. Komaki and P. Allen, MD Anderson Cancer Center (MDACC), United States; J.P. Sculier and M. Paesmans, European Lung Cancer Working Party (ELCWP); Y.L. Wu, Guangdong Provincial People’s Hospital, People’s Republic of China; M. Pesek and H. Krosnarova, Faculty Hospital Plzen, Czech Republic; T. Le Chevalier and A. Dunant, International Adjuvant Lung Cancer Trial (IALT), France; B. McCaughan and C. Kennedy, University of Sydney, Australia; F. Shepherd and M. Whitehead, National Cancer Institute of Canada (NCIC). J. Jassem and W. Ryzman, Medical University of Gdansk, Poland; G.V. Scagliotti and P. Borasio, Universita E Degli Studi di Torino, S Luigi Hospital, Orbassano, Italy; K.M. Fong and L. Passmore, Prince Charles Hospital, Australia; V.W. Rusch and B.J. Park, Memorial Sloan-Kettering Cancer Center, United States; H.J. Baek, Korea Cancer Centre Hospital, Seoul, South Korea; R.P. Perng, Taiwan Lung Cancer Society, Taiwan; R.C. Yung and A. Gramatikova, John Hopkins University, United States; J. Vansteenkiste, Leuven Lung Cancer Group (LLCG), Belgium; C. Brambilla and M. Colonna, Grenoble University Hospital–Isere Cancer Registry, France; J. Hunt and A. Park, Western Hospital, Melbourne Australia; J.P. Sculier and T. Berghmans, Institute of Jules Bordet, Brussels, Belgium; A. Kayi Cangir, Ankara University School of Medicine, Ankara, Turkey; D. Subotic, Clinical Centre of Serbia, Belgrade, Serbia; R. Rosell and V. Aberola, Spanish Lung Cancer Group (SLCG), Spain; A.A. Vaporciyan and A. Correa, MD Anderson Cancer Center, United States; J.P. Pignon, T. Le Chevalier, and R. Komaki, Institut Gustave Roussy (IGR), France; T. Orlowski, Institute of Lung Diseases, Warsaw, Poland; D. Ball and J. Matthews, Peter MacCallum Cancer Institute, Australia; M. Tsao, Princess Margaret Hospital, Toronto, Canada; S. Darwish, Policlinic of Perugia, Italy; H.I. Pass and T. Stevens, Karmanos Cancer Institute, Wayne State University, United States; G. Wright, St Vincent’s Hospital, Victoria, Australia; and C. Legrand and J.P. van Meerbeeck, European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium.

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