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The IASLC Lung Cancer Staging Project: Analysis of Resection Margin Status and Proposals for Residual Tumor Descriptors for Non–Small Cell Lung Cancer

Open ArchivePublished:November 12, 2019DOI:https://doi.org/10.1016/j.jtho.2019.10.019

      Abstract

      Objective

      Our aim was to validate the prognostic relevance in NSCLC of potential residual tumor (R) descriptors, including the proposed International Association for the Study of Lung Cancer definition for uncertain resection, referred to as R(un).

      Methods

      A total of 14,712 patients undergoing resection with full R status and survival were analyzed. The following were also evaluated: whether fewer than three N2 stations were explored, lobe-specific nodal dissection, extracapsular extension, highest lymph node station status, carcinoma in situ at the bronchial resection margin, and pleural lavage cytologic examination result. Revised categories of R0, R(un), R1, and R2 were tested for survival impact.

      Results

      In all, 14,293 cases were R0, 263 were R1, and 156 were R2 (median survivals not reached, 33 months, and 29 months, respectively). R status correlated with T and N categories. A total of 9290 cases (63%) had three or more N2 stations explored and 6641 cases (45%) had lobe-specific nodal dissection, correlated with increasing pN2. Extracapsular extension was present in 62 of 364 cases with available data (17%). The highest station was positive in 942 cases (6.4%). The pleural lavage cytologic examination result was positive in 59 of 1705 cases (3.5%): 13 had carcinoma in situ at the bronchial resection margin. After reassignment because of inadequate nodal staging in 56% of cases, 6070 cases were R0, 8185 were R(un), 301 were R1, and 156 were R2. In node-positive cases, the median survival times were 70, 50, and 30 months for R0, R(un) (p < 0.0001), and R1 (p < 0.001), respectively, with no significant difference between R0 and R(un) in pN0 cases.

      Conclusions

      R descriptors have prognostic relevance, with R(un) survival stratifying between R0 and R1. Therefore, a detailed evaluation of R factor is of particular importance in the design and analyses of clinical trials of adjuvant therapies.

      Keywords

      Introduction

      The basis of the definition of complete resection is the Union for International Cancer Control residual tumor classification, which considers the presence or absence of tumor in the primary site, lymph nodes, and distant sites after treatment.
      • Wittekind C.
      • Compton C.C.
      • Greene F.L.
      • Sobin L.H.
      TNM residual tumor classification revisited.
      It has established clinical relevance, given that it reflects the effectiveness of treatment and may be used by clinicians to determine whether further therapy is indicated. Furthermore, it has established prognostic relevance.
      • Smeltzer M.P.
      • Lin C.C.
      • Kong F.S.
      • Jemal A.
      • Osarogiagbon R.U.
      Survival impact of postoperative therapy modalities according to margin status in non-small cell lung cancer patients in the United States.
      However, it is recognized that there are deficiencies in the basic R0, R1, and R2 categories, in that local or regional recurrence may occur after an apparent R0 resection. This led surgeons to propose refined definitions of complete resection that incorporated quality standards of tumor resection and lymph node staging.
      • Naruke T.
      • Suemasu K.
      • Ishikawa S.
      Lymph node mapping and curability at various levels of metastasis in resected lung cancer.

      Mountain CF. Biologic, physiologic, and technical determinants in surgical therapy for lung cancer. In: Straus MJ, ed. Lung Cancer. Clinical Diagnosis and Treatment. 2nd ed. New York: Grune & Stratton; 1983:245–260.

      • Martini N.
      • Ginsberg R.J.
      Surgical management.
      In 1998, the Spanish Society of Pneumology and Thoracic Surgery proposed the following definition of complete resection
      Grupo de Trabajo de la SEPAR
      Normativa actualizada (1998) sobre diagnóstico y estadificación del carcinoma broncogénico.
      : (1) the resection margins must be proved microscopically to be free of tumor, (2) there must be a complete mediastinal lymphadenectomy, (3) there must be no extracapsular nodal invasion, and (4) the most distant nodal stations (the highest in the superior paratracheal node and the lowest in the pulmonary ligament) must be negative.
      Guidelines for intraoperative staging of lung cancer acknowledged the role of systematic nodal dissection (SND) in gaining a complete resection. A concept of lobe-specific SND (LSND) was proposed as an alternative when SND was not performed. In LSND, the mediastinal lymph nodes dissected were mandated according to the lobar location of the primary tumor.
      • Rami-Porta R.
      • Wittekind C.
      • Goldstraw P.
      Complete resection in lung cancer surgery: proposed definition.
      ,
      • Lardinois D.
      • De Leyn P.
      • Van Schil P.
      • et al.
      ESTS guidelines for intraoperative lymph node staging in non-small cell lung cancer.
      In 2001 the Complete Resection Subcommittee was tasked by the Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer (IASLC) to prepare a proposal for the definition of complete resection based on expert opinion.
      • Rami-Porta R.
      • Wittekind C.
      • Goldstraw P.
      Complete resection in lung cancer surgery: proposed definition.
      It was recognized that there were resections that did not fulfill the definition of complete resection, albeit with no evidence of residual disease. The subcommittee proposed the term uncertain resection, henceforth referred to as R(un), with a resection defined as uncertain when the resection margins have been proved to be free of disease microscopically but one of the following circumstances exists: (1) the intraoperative lymph node evaluation has been less rigorous than SND or LSND, (2) the highest mediastinal node removed is positive, (3) the bronchial resection margin (BRM) shows carcinoma in situ (CIS), and (4) the pleural lavage cytologic (PLC) examination result is positive (R1(cy+).
      Notably, this proposal classified cases with a positive PLC examination result as R(un), rather than R1. Cases with extracapsular extension (ECE) of tumor in nodes removed separately, or those at the margin of the main lung specimen, were classified as R1, instead of R0.
      The database informing the seventh edition of the TNM classification, collected from 2002 to 2005 and covering patients treated between 1990 and 2000, included a field to capture R0, R1, and R2 status, but not the criteria necessary to refine the R factor according to the proposal published in 2005.
      • Rami-Porta R.
      • Wittekind C.
      • Goldstraw P.
      Complete resection in lung cancer surgery: proposed definition.
      In this study, we have analyzed data collected by the IASLC and used to inform the current eighth edition of the TNM to seek to establish the validity of the proposed definition.

      Methods

      Data Acquisition and Analysis (The IASLC Lung Cancer Staging Project)

      The methods of data collection and analysis within the IASLC Lung Cancer Staging Project database have been described elsewhere.
      • Rami-Porta R.
      • Bolejack V.
      • Giroux D.J.
      • et al.
      The IASLC Lung Cancer Staging Project: the new database to inform the eighth edition of the TNM classification of lung cancer.
      The database was newly created for revision of the previous seventh edition of the TNM staging system for lung cancer to the current eighth edition. The characteristics and sources of the whole population of the present staging project have been described in detail previously.
      • Rami-Porta R.
      • Bolejack V.
      • Giroux D.J.
      • et al.
      The IASLC Lung Cancer Staging Project: the new database to inform the eighth edition of the TNM classification of lung cancer.
      In brief, the new database for the revisions incorporated into the eighth edition of the TNM staging system consisted of data on 94,708 patients in whom NSCLC and SCLC were diagnosed from 1999 to 2010. This database was an amalgamation of various established databases (covering 90,041 patients) and cases from an electronic data capture system developed by Cancer Research And Biostatistics (Seattle, WA) (4667 patients). The geographic distribution of the origin of the data was as follows: 46,560 patients from Europe, 41,705 from Asia, 4660 from North America, 1593 from Australia, and 190 from South America. These data came from 35 sources in 16 countries. Among these patients, 17,552 with an unknown or different histologic type and incomplete stage information were excluded and the remaining 77,156 patients (70,967 patients with NSCLC and 6189 with SCLC) were used as subjects for further analyses. The data for analysis in this study of the R factor descriptors were taken from the subset of patients from the eighth edition database used for analysis of the proposed N descriptors.
      • Asamura H.
      • Chansky K.
      • Crowley J.
      • et al.
      The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer.
      Among 70,967 patients with NSCLC, data on the N component were available in 38,910 patients (54.8%) for clinical (c) N status and in 31,426 patients (44.3%) for pathologic (p) N status. From the cohort of 31,426 patients with pN status, cases were excluded if neoadjuvant therapy was administered or if data regarding R status and survival were incomplete, leaving 14,712 patients for analysis. The geographic and institutional origins of the patients are shown in the Supplementary Data, (Supplementary Table 1, showing the geographic origin, and Supplementary Table 2, showing the institutional origin of the patients included). Japan was the most common country of origin, with 86% of the 14,712 patients, from two Japanese registries. All the other patients were derived from institutional databases or entered through the electronic database collection system.

      Recoding of the R Factor Descriptors

      The eighth edition data set for the IASLC Lung Cancer Staging Project included fields for the completeness of resection with options of R0 (no residual tumor), R1 (residual microscopic tumor, R2 (residual macroscopic tumor), or no data.
      • Giroux D.J.
      • Rami-Porta R.
      • Chansky K.
      • et al.
      The IASLC Lung Cancer Staging Project: data elements for the prospective project.
      If the R1 field was chosen, a field was available to describe the site of residual microscopic tumor (bronchial margin–in situ; bronchial margin–other; vascular (artery, vein, or both); peripheral; or no data). A free text box was available to describe the site of residual macroscopic tumor (R2). For each lymph node station, the positive or negative status for malignancy was recorded. There were fields in the data set for recording of the number of N1, N2 and N3 nodes explored, the number of nodes in these categories positive, and the presence or absence of extracapsular invasion in each category. There was a field to record the status of PLC examination.
      Cases that were positive for ECE that the submitting units had coded as R0 were reassigned to R1 in accordance with the 2005 IASLC proposal.
      • Rami-Porta R.
      • Wittekind C.
      • Goldstraw P.
      Complete resection in lung cancer surgery: proposed definition.

      Assignment of R(un)

      According to the IASLC proposed definition of R(un),
      • Rami-Porta R.
      • Wittekind C.
      • Goldstraw P.
      Complete resection in lung cancer surgery: proposed definition.
      the database of 14,712 patients was analyzed and reassignment to R(un) was performed if any of the following conditions existed: fewer than 3 N1 or 3 N2 nodes examined, less than LSND, positive highest mediastinal lymph node station, CIS at the BRM, and positive PLC examination result.
      LSND was defined for each case, according to the primary location of the tumour recorded in the database and by using the criteria proposed by the IASLC Staging and Prognostic Factors Committee
      • Rami-Porta R.
      • Wittekind C.
      • Goldstraw P.
      Complete resection in lung cancer surgery: proposed definition.
      and the European Society of Thoracic Surgeons.
      • Rami-Porta R.
      • Wittekind C.
      • Goldstraw P.
      Complete resection in lung cancer surgery: proposed definition.
      Although the IASLC proposal document recommended that for a complete resection (R0) to be achieved, the highest mediastinal node that has been removed must be negative, the eighth edition data set did not include a field specific to the status of the highest mediastinal lymph node. Hence, for each case, the reassignment to R(un) was performed if status of the highest lymph node station explored was positive for malignancy.
      The presence of CIS at the BRM, classified as R1(i.s.), or a positive PLC examination result (R1[cy+]) triggered assignment to the R(un) category in this study on the basis that these two situations were not considered invasive by the Staging and Prognostic Factors Committee when the 2005 proposal
      • Rami-Porta R.
      • Wittekind C.
      • Goldstraw P.
      Complete resection in lung cancer surgery: proposed definition.
      was prepared.

      Statistical Methodology

      The chi-square test was used to analyze the correlation between two categorical variables. Survival was measured from the date of surgery. Survival analyses were performed according to R categories within different T and N categories. In addition, survival was analyzed according to the number of involved pathologic nodal stations. For this staging project, the information on the number of metastatic nodes, not stations, was not provided outside of the cases submitted through the electronic data capture. Survival was calculated by the Kaplan-Meier method. Prognostic groups were assessed by Cox proportional hazards regression analysis models adjusted for histopathologic type, geographic region, and T or N category where appropriate by using SAS System for Windows software (version 9.4).

      Results

      Staging and Conventional R Status

      Cases were clinically staged as stage I or II in 87% of cases, and as stage IIIA in 8%, according to the seventh edition of the TNM classification. Less than 2% were clinically staged as stage IIIB or IV, and clinical stage was incomplete in 3% of cases. Completeness of R status data was an essential inclusion criterion for this study. The submitting units recorded 263 patients (1.8%) as R1 and in 156 (1.1%) as R2. There were positive associations between positive R status and increasing eighth edition pT and pN categories (p < 0.0001 [Table 1]). Of the 263 R1 cases, there were 13 cases with BRM CIS, 11 cases were coded as R1 (peripheral), one was codes as R1 (vascular), eight were codes as R1 (BRM other), and 230 were cases in which the reason for the R1 status was not otherwise specified. Extracapsular invasion was present in 61 of 365 cases for which data were recorded for this parameter (10.4% of 3494 node-positive cases).
      Table 1Distribution of Conventional R Status according to pT and pN Stage
      StageR0, nR1, nR2, nTotal with R Status Data, n
      pT16700 (99.1%)32 (0.5%)30 (0.4%)6762
      pT25039 (97.5%)86 (1.7%)44 (0.9%)5169
      pT31841 (93.9%)85 (4.3%)35 (1.8%)1961
      pT4713 (87.0%)60 (7.3%)47 (5.7%)820
      pN011,058 (98.6%)106 (0.9%)54 (0.5%)11,218
      pN11395 (95.5%)44 (3.0%)21 (1.4%)1460
      pN21800 (90.9%)105 (5.3%)75 (3.8%)1980
      pN340 (74.1%)8 (14.8%)6 (11.1%)54
      Total14,293 (97.2%)263 (1.8%)156 (1.1%)14,712
      Note: The percentages relate, within each pT or pN stage, to the percentage of each R category, relative to the total number of patients with R status data.
      R, resection; pT, pathologic tumor; pN, pathologic nodal.
      Both R1 and R2 status was associated with a significantly poorer survival than R0 status (R1 hazard ratio [HR] = 1.85, R2 HR = 2.14 [p < 0.0001 adjusting for origin of the case (Asia versus other]), T category, N category, and histologic type (Fig. 1). However, there was no significant difference in survival between the R1 and R2 categories (p = 0.27).
      Figure thumbnail gr1
      Figure 1Survival according to conventional R (resection) status. NR, not reached.

      R(u) Criteria

      Completeness of Data

      The completeness of data is indicated in Table 2. Considering the origin of the data set, it was possible to determine the number of N2 stations explored in all cases and whether LSND was performed in 98.4% of cases. However, data completeness was less for the numbers of lymph nodes explored (in approximately 12.5% of cases) and PLC examinations performed (in 1705 cases).
      Table 2Data Completeness and Distribution of Each R Factor
      FactorYes, nNo, nData Available, nNot Done or No Data, n
      ≥3 N2 stations explored9290 (63.1%)5422 (36.9%)14,712 (100%)0
      Lobe-specific nodal dissection6641 (45.1%)7918 (53.9%)14,559 (99.0%)153 (1.0%)
      ≥3 N1 nodes explored970 (52.9%)865 (47.1%)1835 (12.5%)12,877 (87.5%)
      ≥3 N2 nodes explored1146 (62.7%)681 (37.3%)1827 (12.4%)12,885 (87.6%)
      N1 extracapsular extension42 (70.0%)18 (30.0%)365 (2.5%)14,347 (97.5%)
      N2 extracapsular extension24 (40.0%)36 (60.0%)365 (2.5%)14,347 (97.5%)
      Positive status of highest lymph node station942 (6.4%)13,717 (93.6%)14,659 (99.6%)53 (0.4%)
      Presence of BRM CIS13 (0.8%)1533 (99.2%)1546 (10.5%)13,166 (89.5%)
      Presence of BRM CIS (among 263 R1 cases)13 (39.4%)20 (60.6%)33 (12.6%)230 (87.4%)
      Positive pleural lavage cytologic examination results59 (3.5%)1646 (96.5%)1705 (12%)13,007 (88%)
      Note: The percentages in italics indicate the split between positive and negative for each factor, for those cases where the data are available. Percentages in brackets indicate the split between data being available, versus not available.
      R, resection; BRM CIS, carcinoma in situ at the bronchial resection margin.
      Regional variations in the completeness of data recording and in the distribution between different R(un) factor categories are displayed in Table 3 The Japanese registries did not, for this time period, record the number of lymph nodes involved in the N1 and N2 stations, whether ECE of involved lymph nodes was present, or the reason for the assignment of R1 status. PLC examination was performed in 12% of cases, which were contributed by 14 institutions and one Japanese registry.
      Table 3Regional Variations in the R(un) Factor Data
      FactorAustraliaSouth AmericaPeople's Republic of ChinaJapanUnited StatesEuropeTotal
      Total, n (%)2 (0.01)60 (0.41)215 (1.46)12,590 (85.58)958 (6.51)887 (6.03)14,712
      R0
       Negative25421312,24592585414,293
      R1
       BRM CIS022ND1813
       BRM other000ND628
       Vascular000ND011
       Peripheral040ND2511
       Positive but ND00022460230
      R20001211817156
      Incomplete rate, (R1 + R2)/total0.0%10.0%0.9%2.7%3.4%3.7%2.8%
      SND
       ≥3 N2 stations explored100%58%79%65%38%64%63%
      LSND0%33%49%49%14%28%45%
       ≥3 N1 nodes explored0%40%65%ND35%53%7%
       ≥3 N2 nodes explored0%43%76%ND45%59%8%
      Extracapsular extension from positive nodes
       Yes0%13%0%0%5%15%2%
       No100%50%96%0%22%49%9%
       No data0%38%4%100%73%36%90%
      Status of highest station
       Negative100%87%80%94%88%92%93%
      Pleural lavage cytologic examination
       Positive resultNDND0%4%0%1%3%
       Negative result0%0%5%9%0%11%9%
       Not done50%93%51%17%37%73%23%
       Not recorded50%7%44%70%62%15%66%
      R(un), uncertain resection; R, resection; BRM, bronchial resection margin; BRM CIS, carcinoma in situ at the bronchial resection margin; ND, not defined; SND, systematic nodal dissection; LSND, lobe-specific systematic nodal dissection.

      Assignment to R(un) and R1

      There were 8185 cases (56%) that were assigned to R(un) status; of these, 8174 had been assigned to R0 by the submitting unit. There were 11 R1 cases assigned to R(un); these had the presence of CIS at the BRM, which was coded as R1 BRM CIS in the original database. The pathologic stage and other clinical characteristics after assignment to R(un) are shown in Table 4.
      Table 4Patient Characteristics according to the Revised R Status
      CharacteristicR0, nR(un), nR1, nR2, nTotal
      n
      pTNM stage (eighth edition)
       I3606 (40.8%)5185 (58.7%)28 (0.3%)16 (0.2%)8839
       II1338 (45.9%)1484 (50.9%)80 (2.7%)25 (0.9%)2913
       IIIA930 (40.5%)1182 (51.5%)127 (5.5%)74 (3.2%)2294
       IIIB230 (35.6%)324 (50.2%)62 (9.6%)39 (6.0%)646
       IIIC4 (20.0%)10 (50.0%)4 (20.0%)2 (10.0%)20
      Region
       Asia5776 (45.1%)6682 (52.2%)224 (1.7%)121 (0.9%)12,805
       Australia02 (100%)002
       Europe239 (26.6%)625 (69.6%)48 (5.3%)17 (1.9%)898
       North or South America93 (9.2%)876 (87.0%)29 (2.9%)18 (1.8%)1007
      Cell type
       Adenocarcinoma4161 (41.9%)5557 (56.0%)143 (1.4%)80 (0.8%)9924
       Adenosquamous99 (40.7%)134 (55.1%)8 (3.3%)4 (1.6%)243
       Squamous1526 (42.1%)1939 (53.5%)116 (3.2%)57 (1.6%)3623
       Other322 (34.9%)555 (60.2%)34 (3.7%)15 (1.6%)922
      Total6108 (41.5%)8185 (55.6%)301 (2.0%)156 (1.1%)14,712
      Note: The percentages correspond to each row of data.
      R, resection; R(un), uncertain resection; pTNM, pathologic TNM.
      Table 5 indicates the reasons why cases were recoded to the R(un) category; 95.7% of cases were assigned to R(un) owing to the standard of lymph node dissection being lower than proposed (i.e., fewer than three N1 or three N2 nodes examined or less than LSND). In 312 cases (3.8%), the highest lymph node station was positive. The pN status of the cases assigned as R(un) is indicated in Table 6. Among the 11,218 pN0 cases, R(un) accounted for 6391 (56.9%), whereas the corresponding figure for node-positive cases was 1794 of 3494 (51.3%). With use of the criterion of at least three N2 stations being explored to indicate SND, 5422 cases (36.9%) would be reassigned to R(un) (Table 7), whereas with the definition of LSND, 7918 cases (53.8%) would become R(un) (Table 8). With regard to the number of N1 and N2 lymph nodes resected, these data were available for 1835 (number of N1 nodes) and 1827 (N2) cases, representing 12.5% and 12.4% of the total of 14,712, respectively. The numbers reassigned to R(un) owing to fewer than three N1 or three N2 nodes dissected were 865 N1 cases (47.1%) and 681 N2 cases (37.3%) (Table 9).
      Table 5Reasons for Reassignment to the R(un) Category from the R0 Category
      Reasonn%
      Highest station positive only3123.8%
      Pleural lavage positive only340.5%
      Pleural lavage positive and highest station positive40.05%
      Any of the following: <3 N1 nodes, <3 N2 nodes, no station 7 nodes, no systematic nodal dissection, no lobe-specific nodal dissection782495.7%
      R(un), uncertain resection; R, resection.
      Table 6pN Status of the Proposed R Categories Once Cases Had Been Reassigned to R(un) Status
      pN StatusR0, nR(un), nR1, nR2, nTotal
      pN05672 (50.6%)6391 (57.0%)101 (0.9%)54 (0.5%)11,218
      pN1665 (45.5%)706 (48.4%)68 (4.7%)21 (1.4%)1460
      pN2725 (36.6%)1057 (53.4%)123 (6.2%)75 (3.8%)1980
      pN38 (14.8%)31 (57.4%)9 (16.7%)6 (11.%)54
      Total6070 (41.3%)8185 (55.6%)301 (2.0%)156 (1.1%)14,712
      R, resection; pN, pathologic nodal; R(un), uncertain resection.
      Table 7Reassignment of Cases to R(un) according to the Type of Lymph Node Dissection Performed: Systematic Nodal Dissection, Defined as at Least 3 N2 Stations Explored
      pN Status<3 N2 Stations Explored, R(un), n≥3 N2 Stations Explored, nTotal, n
      pN04554 (40.6%)6664 (59.4%)11,218
      pN1437 (29.9%)1023 (70.1%)1460
      pN2420 (21.2%)1560 (78.8%)1980
      pN311 (20.4%)43 (79.6%)54
      Total5422 (36.9%)9290 (63.1%)14,712
      Note: The percentages relate to that of each nodal exploration category according to the total for each nodal stage.
      R(un), uncertain resection; pN, pathologic nodal.
      Table 8Reassignment of Cases to R(un) according to the Type of Lymph Node Dissection Performed: Lobe-Specific Nodal Dissection
      pN StatusLSND, No

      R(un), n
      LSND, Yes, nLack of Data, nTotal, n
      pN06348 (57.0%)4781 (43.0%)8911,218
      pN1735 (51.6%)690 (48.4%)351460
      pN2808 (41.4%)1144 (58.6%)281980
      pN327 (50.9%)26 (49.1%)154
      Total7918 (54.54%)6641 (45.6%)15314,712
      Note: The percentages relate to that of each nodal dissection category according to the total for each nodal stage (for which there are data).
      R(un), uncertain resection; LSND, lobe-specific systemic nodal dissection.
      Table 9Reassignment to R(un) according to the Number of Lymph Nodes Dissected
      pN StatusNo. of N1 Nodes DissectedNo. of N2 Nodes DissectedTotal, n
      <3 R(un), n≥3, nNo Data, n<3 R(un), n≥3, nNo Data, n
      pN0688 (51.9%)638 (48.1%)9892544 (41.1%)778 (58.8%)989611,218
      pN177 (29.7%)182 (70.3%)120183 (33.1%)168 (66.9%)12091460
      pN296 (41.9%)133 (58.1%)175147 (20.2%)186 (79.8%)17471980
      pN34 (47.1%)17 (52.9%)337 (33.3%)1433 (66.7%)54
      Total865 (47.1%)970 (52.9%)12,877681 (37.3%)1146 (62.7%)12,88514,712
      Note: Fewer than three N1 or N2 nodes were criteria for reassignment to R(un) status. The percentages relate to that of each nodal number category, according to the total for each nodal stage (for which there are data). The number of N1 nodes dissected was available for 12.5% of cases compared with for 12.4% of cases for N2 nodes.
      R(un), uncertain resection; pN, pathologic nodal.
      Of the 365 cases for which data regarding ECE were available, 344 were coded as having a complete resection by the submitting site. Of those, 26 N1 cases, 21 N2 cases, and 3 N3 cases with nodes with ECE were coded as R1. The PLC examination result was positive in 59 of the 1705 cases (3.6%) in which it was performed. The pT distribution is indicated in Table 10. There was a positive correlation between pT status and positive PLC examination result (p < 0.0001).
      Table 10Distribution of Pleural Lavage Cytologic Examination Results according to pT Category
      pT CategoryPLC Positive, nPLC Negative, nPLC Not Done, nPLC Not Recorded, nTotal, n
      pT16 (0.8%)750 (99.2%)148845186762
      pT2a34 (6.8%)466 (3.2%)90526954100
      pT2b3 (2.4%)122 (97.6%)2277171069
      pT311 (4.8%)219 (95.2%)47512561961
      pT45 (5.3%)89 (94.7%)229497820
      Total3446690526954100
      The percentages relate to that of each pleural lavage cytologic examination result category, according to the total for each pT stage (for which there are data).
      pT, pathologic tumor; PLC, pleural lavage cytology.
      R(un) was correlated with combined pT and pN status (Table 11) to give an indication of the frequency of R(un) status in categories for which adjuvant chemotherapy might not be indicated (e.g., pT1 N0 and pT2a N0 cases). There were 5185 cases in these categories.
      Table 11Correlation of R(un) Status with pT and pN Status Combined
      StageTotal,Proposed R Status,
      pT StagepN StagenR0, nR(un), nR1, nR2, n
      pT1aN0733233 (31.8%)500 (68.2%)00
      N1188 (44.4%)9 (50.0%)1 (5.6%)0
      N2207 (35.0%)12 (60.0%)01 (5.0%)
      N3101 (100.0%)00
      pT1bN029641113 (37.6%)1835 (61.9%)7 (0.2%)9 (0.3%)
      N114249 (34.5%)90 (63.4%)2 (1.4%)1 (0.7%)
      N219373 (37.8%)108 (56.0%)5 (2.6%)7 (3.6%)
      N3201 (50.0%)01 (50.0%)
      pT1cN02252939 (41.7%)1304 (57.9%)6 (0.3%)3 (0.1%)
      N119287 (45.3%)98 (51.0%)5 (2.6%)2 (1.0%)
      N224291 (37.6%)137 (56.6%)8 (3.3%)6 (2.5%)
      N3303 (100.0%)00
      pT2aN028901325 (45.8%)1546 (53.5%)15 (0.5%)4 (0.1%)
      N1477225 (47.2%)224 (47.0%)22 (4.6%)6 (1.3%)
      N2710262 (36.9%)384 (54.1%)40 (5.6%)24 (3.4%)
      N3233 (13.0%)13 (56.5%)5 (21.7%)2 (8.7%)
      pT2bN0687338 (49.2%)343 (49.9%)4 (0.6%)2 (0.3%)
      N117483 (47.7%)81 (46.6%)7 (4.0%)3 (1.7%)
      N220375 (36.9%)113 (55.7%)13 (6.4%)2 (1.0%)
      N351 (20.0%)3 (60.0%)01 (20.0%)
      pT3N01223534 (43.7%)639 (52.2%)39 (3.2%)11 (0.9%)
      N1304144 (47.4%)140 (46.1%)15 (4.9%)5 (1.6%)
      N2421144 (34.2%)223 (53.0%)37 (8.8%)17 (4.0%)
      N3134 (30.8%)4 (30.8%)3 (23.1%)2 (15.4%)
      pT4N0469190 (40.5%)224 (47.8%)30 (6.4%)25 (5.3%)
      N115369 (45.1%)64 (41.8%)16 (10.5%)4 (2.6%)
      N219273 (38.0%)80 (41.7%)20 (10.4%)18 (9.4%)
      N3706 (85.7%)1 (14.3%)0
      Total14,7126070 (41.3%)8185 (55.6%)301 (2.0%)156 (1.1%)
      Note: The percentages relate to that of each proposed R status category, according to the total for each pTN stage.
      R(un), uncertain resection; nN, pathologic nodal; pT, pathologic tumor.

      Survival Impact of Individual R Factor Criteria

      For N2-positive cases assigned as R0 by the submitting unit, there was a significantly worse survival when the highest lymph node station was positive (median survival 41 months versus 55 months for highest lymph node–negative N2 R0 cases [adjusted HR = 1.32, p < 0.0001] [Fig. 2]). However, for R1 cases, there was no significant difference in survival (p = 0.55). There was no statistical difference in survival between cases with and without N1 or N2 extracapsular invasion in the N1 and N2 subsets that had information about extracapsular invasion.
      Figure thumbnail gr2
      Figure 2Survival according to the status of the highest mediastinal node station for any T, pN2 R0 cases.

      Survival Impact of the R(un) Category

      The Kaplan-Meier survival curves among the 11,218 pN0 cases, according to the reassigned R status, are shown in Figure 3. Survival for R(un) was significantly less than for R0 (adjusted p = 0.04). Whereas there was a significant difference between R0 and R(un) compared with R1 (p < 0.0001), there was no significant difference between R 1 and R2 status (p = 0.65).
      Figure thumbnail gr3
      Figure 3Survival according to the reassigned R (resection) status in pN0 cases. R(un), uncertain resection; NR, not reached.
      For the 3494 node-positive cases there were significant differences between R0 and R(un) status (HR = 1.27, p < 0.001), as well as between R(un) and R1 (HR = 1.36, p = 0.002). As for the N0 cases, there was no difference between R1 and R2 (p = 0.10 [Fig. 4]), which may be a function of the small sample sizes. There was a difference in median survival of 20 months between pN-positive R0 and R(un) cases (70 months versus 50 months), equating to a 10% difference in 5-year survival rate (55% versus 45%). The difference in survival rates for pN1 and pN2 cases separately was similar (Fig. 5A and B).
      Figure thumbnail gr4
      Figure 4Survival according to R (resection) status in node-positive cases. R(un), uncertain resection.
      Figure thumbnail gr5
      Figure 5(A) Survival according to R (resection) status in pN1 cases. (B) Survival according to R status in pN2 cases. NR, not reached.
      There was a small but statistically significant difference in survival between the combined pT1N0 R(un)/pT2aN0 R(un) cases and the pT1N0 R0/pT2aN0 R0 cases (HR = 1.22, p = 0.0007 [Fig. 6]). This equated to a difference of 4% in 5-year survival (87% versus 83%). Although cases from Asia did have better survival prognosis, inclusion of this geographic factor in multivariable models did not appreciably change the HRs for the factors in question, including R status (data not shown).
      Figure thumbnail gr6
      Figure 6Survival for T1N0 R(un) and T2N0 R(un). R, resection; R(un), uncertain resection; NR, not reached.

      Discussion

      This analysis of the IASLC Lung Cancer Staging Project database confirms that the IASLC-proposed definition for complete resection has relevance. We have shown that high-quality surgical staging gives the most accurate assignment of stage group and that this leads to the most favorable stage by stage survival data. Although we are unable to prove this, the effects may be due (at least in part) to the stage migration.
      The finding that the classical R1 and R2 status confers a worse prognosis is consistent with the data presented from the seventh edition database
      • Krasnik M.
      • Rami-Porta R.
      • Chansky K.
      Survival rates of R0, R1, R2 resection in lung cancer.
      and other large studies.
      • Smeltzer M.P.
      • Lin C.C.
      • Kong F.S.
      • Jemal A.
      • Osarogiagbon R.U.
      Survival impact of postoperative therapy modalities according to margin status in non-small cell lung cancer patients in the United States.
      ,
      • Osarogiagbon R.U.
      • Lin C.C.
      • Smeltzer M.P.
      • Jemal A.
      Prevalence, prognostic implications, and survival modulators of incompletely resected non-small cell lung cancer in the U.S. National Cancer Data Base.
      It is noted, however, that the proportion of patients with an incomplete resection in this study (2.9%) is lower than that in other large studies. Osarogiagbon et al. noted an incomplete resection rate of 4.8% in a study of 112,998 patients within the National Cancer Database,
      • Osarogiagbon R.U.
      • Lin C.C.
      • Smeltzer M.P.
      • Jemal A.
      Prevalence, prognostic implications, and survival modulators of incompletely resected non-small cell lung cancer in the U.S. National Cancer Data Base.
      and Gagliasso et al. reported a rate of 7.0% in an institutional study of 1277 patients.
      • Gagliasso M.
      • Migliaretti G.
      • Ardissone F.
      Assessing the prognostic impact of the International Association for the Study of Lung Cancer proposed definitions of complete, uncertain, and incomplete resection in non-small cell lung cancer surgery.
      It is not known whether there was a selection bias favoring entry of completely resected cases into the IASLC database, or given the country of origin of the cases that we analyzed, whether there is a geographic variation in the R0 rate.
      The cases chosen for this study were those in the main IASLC database for which the conventional R factor was known and for which there were detailed nodal staging data, thus allowing assignment to R(un) according to the IASLC proposal document.
      • Rami-Porta R.
      • Wittekind C.
      • Goldstraw P.
      Complete resection in lung cancer surgery: proposed definition.
      The completeness of the other pertinent data was variable, mainly because of geographic and institutional factors. For example, the data suitable for interpretation for this project were dominated by the two Japanese registries, which contributed 85.6% of cases, but neither the number of N1 and N2 lymph nodes nor the status of ECE was recorded in these registries. One of the two Japanese registries and 14 of the 43 other institutions recorded data regarding the PLC examination result, but the others did not.
      Most of the cases were reassigned to R(un) status because of nodal staging being less than LSND. The data regarding the number of N1 and N2 lymph nodes dissected is shown for illustrative purposes. It is assumed that those cases with fewer than three N2 lymph nodes had samples taken from fewer than three N2 stations (and hence did not meet the criteria of either LSND or SND, unless samples were analyzed and found to contain no lymph nodes). It is accepted that there was a great amount of missing data regarding the numbers of lymph nodes. Also given the relative lack of data regarding the presence of CIS at the BRM and a positive PLC examination result, there may not be a true representation of their incidence in our data, nor of their overall contribution to the R(un) status. Despite the IASLC proposal,
      • Rami-Porta R.
      • Wittekind C.
      • Goldstraw P.
      Complete resection in lung cancer surgery: proposed definition.
      there is not yet enough evidence to say whether R1(i.s.) and R1(cy+) should be moved to R(un).
      The low incidence of LSND (46%) is in keeping with the findings of other studies in showing that complete mediastinal lymph node dissection was performed in only approximately one-third of cases.
      • Verhagen A.F.
      • Schoenmakers M.C.J.
      • Barendregt W.
      • Smit H.
      Completeness of lung cancer surgery: is mediastinal dissection common practice?.
      • Little A.G.
      • Rusch V.W.
      • Bonner J.A.
      • et al.
      Patterns of surgical care of lung cancer patients.
      • Van Schil P.
      Action point: intraoperative lymph node staging.
      Although three or more N2 stations were dissected in a greater proportion of cases (63%), the definition of LSND was not reached in many cases because the dissection that did take place did not respect the lobar location of the primary tumor. There are common situations in which this takes place, for example, when there are no station 8 or 9 lymph nodes analyzed at lower lobectomy.
      The assessment of the number of lymph nodes in N1 and N2 stations is limited by the relative lack of data, being recorded in about 12% of cases. Similarly, use of the term highest lymph node in the IASLC Proposed Definition is limited in two ways in this work. First, lymph node drainage patterns are variable, resulting in debate about the hierarchical order of lymph node stations.
      • Riquet M.
      • Rivera C.
      • Pricopi C.
      • et al.
      Is the lymphatic drainage of lung cancer lobe-specific? A surgical appraisal.
      In this study, we simply defined the lowest numerically numbered station as the highest station. Second, as data regarding the highest individual lymph node were not available, we were forced to revise the definition to become the highest lymph node station. Despite being an appropriate aspiration, we believe that there could be difficulty for the surgeon and pathologist in accurately assigning an individual lymph node as the highest node, either during dissection in vivo intraoperatively or in the laboratory analysis of the sample. Given the difference in survival, within the pN2 R0 group, between the highest station positive, and negative cases, we believe that the methodology applied by us is appropriate. With only a small number of cases in which despite the definition of SND being met, there was a positive PLC examination result (see Table 6), we could not determine the individual prognostic impact of this factor.
      The justification of the presence of ECE in N1 or N2 nodes giving rise to R1 status is a matter of debate and has not been proved by these data. The 2005 statement
      • Rami-Porta R.
      • Wittekind C.
      • Goldstraw P.
      Complete resection in lung cancer surgery: proposed definition.
      does not specify whether the ECE to which the proposal refers is present in N1 or N2 stations or both. The eighth edition data set asked whether ECE was present or absent or whether there were no data in N1, N2, and N3 nodes. There was no inquiry as to whether the nodes were “removed separately, or those at the margin of the main lung specimen.” It is possible, therefore, that there was ECE in N1 nodes within the envelope of the main specimen, not at the margin, which we would have reassigned as R1. Furthermore, it is possible that there was ECE from N2 nodes, where the actual nodal specimen contained abundant fat around the nodes, giving a “negative margin.” We were unable, with this database, to determine whether such pN2 ECE–positive cases (which were otherwise R0) had a survival rate equivalent to that of the pN2 R0, R(un) or R1 groups.
      With regard to the survival impact of the R(un) category in pN0 cases, the trend toward an association between worse survival and R(un) status is of interest, but it did not reach statistical significance. This is in keeping with the finding of the ACOSOG Z0030 trial, where detailed mediastinal lymph node dissection did not improve sampling in cases in which the results of systematic preresection sampling of at least three mediastinal stations and one hilar station were negative.
      • Darling G.E.
      • Allen M.S.
      • Decker P.A.
      • et al.
      Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non–small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 trial.
      There may be a contribution to the trend toward poorer survival in this analysis by undetected “skip” pN2a1 (pN1-negative but pN2-positive) cases. This could be explained by more extensive lymph node assessment (reaching the definition of SND), ensuring more accurate stage assignment, whereas the chance of undetected nodal metastases is greater when fewer intrapulmonary
      • Osarogiagbon R.U.
      • Eke R.
      • Sareen S.
      • et al.
      The impact of a novel lung gross dissection protocol on intrapulmonary lymph node retrieval from lung cancer resection specimens.
      or mediastinal lymph node stations are examined. The prognostic impact of the proposed category pN2a1 has been discussed previously.
      • Asamura H.
      • Chansky K.
      • Crowley J.
      • et al.
      The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer.
      The prognostic impact of the R(un) status assessed in node-positive cases, however, was highly significant. The median survival in R(un) cases was mid way between the R0 and R1. We have not conducted multivariate analyses to see whether there are consistent factor(s) among those causing the assignment to R(un) that are responsible for this impact. For example, within the pN2 cases, whether the survival difference between R0 and R(un) is due to the highest lymph node station being positive, non-SND, a positive PLC examination result, or BRM CIS is unclear. Given the dominance of non-SND in the reassignment to R(un), it seems that the quality of lymph node dissection in pN-positive cases (whether categorized as pN1, pN2, or combined) is associated with a worse survival. Whether this is an associative or causal effect is not known. The pN2 status itself remains the same whether SND is carried out. It is possible that the higher-quality lymph node dissection picks up “unexpected” cases with a lower burden of nodal disease, which carry a better prognosis than that which can be identified with a lesser extent of mediastinal nodal assessment. These cases with a “higher-quality” dissection and lower burden of involvement are assigned as R0, bringing a better prognostic subset into the R0 category. With the converse being true for pN2 cases despite a less extensive mediastinal nodal assessment, the survival curves thus separate, illustrating the so-called Will Rogers phenomenon.
      • Feinstein A.R.
      • Sosin D.M.
      • Wells C.K.
      The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer.
      However, there is an alternative hypothesis that can be proposed, namely, that there is a survival benefit from the resection of oligometastatic lymph node disease, including the resection of additional involved lymph nodes in node-positive patients. It should be noted that the Z0030 trial
      • Darling G.E.
      • Allen M.S.
      • Decker P.A.
      • et al.
      Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non–small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 trial.
      specifically excluded these patients and addressed only the role of further lymph node dissection in node-negative patients, having already ensured a significantly higher quality of nodal dissection (in all patients, as part of the eligibility for randomization) than that which would be assigned R(un) according to this study.
      Also, recent data show that specific process measures, including quality of resection and the ratio of the observed rate of incomplete resection to the expected rate, are directly related to survival. The better the quality of nodal staging, the better survival becomes with a more profound discrimination between pN0, pN1 and pN2.
      • Donington J.S.
      • Kim Y.T.
      • Tong B.
      Progress in the management of early-stage non-small cell lung cancer in 2017.
      • Smeltzer M.P.
      • Faris N.R.
      • Ray M.A.
      • et al.
      Association of pathologic nodal staging quality with survival among patients with non–small cell lung cancer after resection with curative intent.
      • Choe G.
      • Schipper P.
      Quality of lymph node assessment and survival among patients with non–small cell lung cancer.
      • Osarogiagbon R.U.
      • Ray M.A.
      • Faris N.R.
      • et al.
      Prognostic value of National Comprehensive Cancer Network lung cancer resection quality criteria.
      • Lin C.C.
      • Smeltzer M.P.
      • Jemal A.
      • Osarogiagbon R.U.
      Risk-adjusted margin positivity rate as a surgical quality metric for non–small cell lung cancer.
      Optimal staging data also allow the most appropriate decision making for routine adjuvant therapy and accurate interpretation of survival data in clinical trials of adjuvant therapy. It is interesting to note that for the group of pT1 and pT2a N0 cases, for which adjuvant chemotherapy would not normally be indicated,
      • Burdett S.
      • Pignon J.P.
      • Tierney J.
      • et al.
      Adjuvant chemotherapy for resected early-stage non-small cell lung cancer.
      R(un) cases carried a worse prognosis (with a 4% reduction in 5-year survival). Whether this finding has clinical relevance remains to be determined.
      We acknowledge that there are several limitations to this study, some of which have been discussed earlier in this article. The geographic variation in the degree of data completeness is noted, resulting in a dominance of this database by Japanese cases. Different registries, which submitted large numbers of cases, did not record the complete set of data elements, which gives rise to apparently missing data. This does not allow, for example, the breakdown of the R1(not otherwise specified) cases to determine whether there were additional R1 BRM CIS cases to assess and assign to the R(un) category. It is hoped that the promotion of the electronic data capture system for the ninth edition database will lessen the issue of incomplete recording of all data elements. The relevance of ECE remains unknown, and analyses of greater numbers of ECE cases are required to determine the level of associated prognostic impact. There have been proposals for the adoption into the residual tumor factor classification of the measurement of the distance from the tumor to the margin of the specimen and also to categorize further R2 status according to the extent of residual macroscopic disease.
      • Wittekind C.
      • Compton C.
      • Quirke P.
      • et al.
      A uniform residual tumor (R) classification: integration of the R classification and the circumferential margin status.
      We have been unable to consider these aspects in this study.
      Several of these limitations also applied to the recent work of Gagliasso et al., who applied the 2005 R(un) proposal to a series of 1277 cases from a single institution.
      • Gagliasso M.
      • Migliaretti G.
      • Ardissone F.
      Assessing the prognostic impact of the International Association for the Study of Lung Cancer proposed definitions of complete, uncertain, and incomplete resection in non-small cell lung cancer surgery.
      In that study, PLC examination was not performed. Whether the N1 nodes with ECE were included in the definition of distal lymph nodes is not clear. The R(un) category comprised 185 cases (14.5%), whereas there were 89 (7.0%) incomplete R cases, without separate categorization between R1 and R2. There were significant differences between the survival or R0, R(un), and R1/2 groups, although the low number of N1 and N2 cases did not allow subgroup analyses.
      In conclusion, this study confirms that aspects of the proposal made in 2005 have prognostic relevance. It is clear that the performance of high-quality surgical staging results in the most favorable survival data for each stage, which is important when comparing institutional data. Hence an accurate assessment of the R(un) factor is important in determination of the quality of surgery. To summarize, the proposals by Rami-Porta et al. in 2005
      • Rami-Porta R.
      • Wittekind C.
      • Goldstraw P.
      Complete resection in lung cancer surgery: proposed definition.
      were as follows.

      Complete Resection: R0

      For a lung resection to be defined as complete it requires that all of the following circumstances apply: (1) free resection margins has been proved microscopically (resection margins should be considered to be the bronchial, venous, and arterial stumps; peribronchial soft tissue; or any peripheral margin near the tumor or of additionally resected tissue); (2) SND in its wider form must be performed, or if it is not, then LSND must be performed; (3) there is no ECE of tumor in nodes removed separately or in those at the margin of the main lung specimen; and (4) the highest mediastinal node that has been removed must be negative.

      Incomplete Resection: R1 or R2

      The definition of incomplete resection includes the requirements established for R1 (microscopic residual tumor) and R2 (macroscopic residual tumor) resections. Therefore, in any of the following circumstances, a resection would be considered incomplete: (1) tumor involvement of resection margins; (2) ECE of tumor in nodes removed separately, or those at the margin of the main lung specimen; (3) nodes known to be positive but not removed (this would be an R2 resection if recognized by the surgeon); and (4) positive results of cytologic examination of pleural or pericardial effusions.
      Hence, in an incomplete resection, there is either evidence by microscopic or macroscopic assessment of tumor remaining in the chest or a high suspicion of residual microscopic disease (extracapsular nodal involvement or positive pleural or pericardial effusions in the absence of macroscopic pleural or pericardial metastases).

      R(un)

      There are resections in cases in which there is no evidence of residual invasive tumor, but the resection does not fulfil all of the criteria required to be designated as a complete resection. R(un) resections are defined as those in which the resection margins are free of disease microscopically (as for R0), but one of the following circumstances exists: (1) the intraoperative lymph node evaluation has been less rigorous than SND or LSND, (2) the highest mediastinal node removed is positive, (3) the BRM shows CIS, and (4) the PLC examination result is positive.
      Therefore, in an uncertain resection, although there is no evidence of residual invasive tumor, the resection does not fulfil all of the criteria required to be designated as a complete resection.
      It is clear that there is a need for increased awareness of R factor criteria
      • Hoffmann H.
      • Junker K.
      • Kugler C.
      • Schnabel P.A.
      • Warth A.
      Application and interpretation of the R classification for lung cancer: results of a survey of certified lung cancer centers.
      and that the R factor should follow the pathologic TNM after tumor resection. Furthermore, this study emphasizes the need for improved pathologic nodal staging and the consideration of institutional and national guidelines to promote this.
      However, further acquisition of high-quality data and detailed analyses will be required to clarify the components of the 2005 proposal for which there were insufficient data in this study, such as BRM CIS and a positive PLC examination result. The data set for current acquisition to the IASLC Lung Cancer Staging Project will allow these analyses, as long as there is wide participation of complete data.
      • Giroux D.J.
      • Van Schil P.
      • Asamura H.
      • et al.
      The IASLC Lung Cancer Staging Project: a renewed call to participation.
      Participation of units worldwide in the contribution of high-quality data is strongly encouraged.

      Acknowledgments

      We would like to extend our deepest gratitude to the dedicated contributors over the years for sending their data to explore these many fascinating questions and to improve our understanding of the important factors that influence the prognosis of our patients with lung cancer. The authors wish to thank Patricia Vigués for administrative assistance in the preparation of this manuscript.

      Appendix 1. IASLC Staging and Prognostic Factors Committee and Advisory Boards to the Domains

      IASLC Staging and Prognostic Factors Committee

      Hisao Asamura (chair), Keio University, Tokyo, Japan; Valerie Rusch (chair-elect) Memorial Sloan Kettering Cancer Center, New York, New York; Ramón Rami-Porta (past chair), Hospital Universitari Mutua Terrassa, Terrassa, Spain; Luiz Henrique Araujo, Brazilian National Cancer Institute, Rio de Janeiro, Brazil; David Beer, University of Michigan, Ann Arbor, Michigan; Pietro Bertoglio, Division of Thoracic Surgery, Sacro Cuore-Don Calabria Research Hospital and Cancer Care Centre, Negrar-Verona, Italy; Ricardo Beyruti, University of São Paulo Medical School, Sao Paolo, Brazil; Andrea Bille, Guys Hospital, London, United Kingdom; Vanessa Bolejack, Cancer Research And Biostatistics, Seattle, Washington; Souheil Boubia, University Hospital, Ibn Rochd, Casablanca, Morocco; Elisabeth Brambilla, Centre Hospitalier Universitaire, Grenoble, France, University of Grenobles Alpes, Grenoble, France; James D. Brierley, Department of Radiation Oncology, Princess Margaret Cancer Centre, Toronto, Canada; A. K. Cangir, Ankara University Faculty of Medicine, Ankara, Turkey; David Carbone, The Ohio State University, Columbus, Ohio; Kari Chansky, Cancer Research And Biostatistics, Seattle, Washington; John Crowley, Cancer Research And Biostatistics, Seattle, Washington; Gail Darling, University of Toronto, Toronto, Canada; Frank Detterbeck, Yale University School of Medicine, New Haven, Connecticut; Xavier Benoit D’Journo, Aix-Marseille University, Marseille, France; Jessica Donnington, University of Chicago, Chicago, Illinois; Wilfried Eberhardt, West German Cancer Centre, University Hospital Essen, Essen, Germany; John Edwards, Northern General Hospital, Sheffield, United Kingdom; Jeremy Erasmus, M. D. Anderson Cancer Center, Houston, Texas; Conrad Falkson, Queen’s University in Kingston, Ontario, Canada; Wentao Fang, Department of Thoracic Surgery, Shanghai Chest Hospital, Jiaotong University Medical School, Shanghai, People’s Republic of China; Dean Fennell, Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester and University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom; Kwun Fong, University of Queensland Thoracic Research Centre, Brisbane, Australia; Françoise Galateau-Salle, Centre Hospitalier Universitaire, Caen, France; Oliver Gautschi, Cancer Center, Cantonal Hospital Lucerne, Lucerne, Switzerland; Ritu Gill, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; Dorothy Giroux, Cancer Research And Biostatistics, Seattle, Washington; Meredith Giuliani, Princess Margaret Cancer Centre, Toronto, Canada; Jin Mo Goo, Seoul National University, Seoul, Republic of Korea; Seiki Hasegawa, Hyogo College of Medicine, Nishinomiya, Japan; Fred Hirsch, University of Colorado Denver School of Medicine, Denver, Colorado; Hans Hoffman, Technical University of Munich, Munich, Germany; Wayne Hofstetter, M. D. Anderson Cancer Center, Houston, Texas; James Huang, Memorial Sloan Kettering Cancer Center, New York, New York; Philippe Joubert, Quebec Heart and Lung Institute, Quebec, Canada; Kemp Kernstine, The University of Texas Southwestern Medical Center, Dallas, Texas; Keith Kerr, University of Aberdeen, School of Medicine and Dentistry, Aberdeen, United Kingdom; Young Tae Kim, Seoul National University, Seoul, Republic of Korea; Hong Kwan Kim, Samsung Medical Center, Seoul, Republic of Korea; Hedy Kindler, The University of Chicago Medical Center, Chicago, Illinois; Yolande Lievens, Ghent University Hospital, Gent, Belgium; Hui Liu, Sun Yat-Sen University Cancer Center, Guangdong Sheng, People’s Republic of China; Donald E. Low, Virginia Mason Medical Center, Seattle, Washington; Gustavo Lyons, Buenos Aires British Hospital, Buenos Aires, Argentina; Heber MacMahon, University of Chicago, Chicago, Illinois; Mirella Marino, Regina Elena National Cancer Institute, Rome, Italy; Edith Marom, M. D. Anderson Cancer Center, Houston, Texas, and University of Tel Aviv, the Chaim Sheba Medical Center, Tel Aviv, Israel; José-María Matilla, Valladolid University Hospital, Valladolid, Spain; Jan van Meerbeeck, Antwerp University and Antwerp University Hospital, Antwerp, Belgium; Luis M. Montuenga, Center of Applied Medical Research, University of Navarra, Pamplona, Spain and Centro de Investigación Biomédica en Red de Cáncer, Spain; Andrew Nicholson, Royal Brompton and Harefield National Health Service Trust Foundation Trust and Imperial College, London, United Kingdom; Katie Nishimura, Cancer Research And Biostatistics, Seattle, Washington; Anna Nowak, University of Western Australia, Perth, Australia; Isabelle Opitz, University Hospital Zurich, Zurich, Switzerland; Meinoshin Okumura, Osaka University, Osaka, Japan; Raymond U. Osarogiagbon, Baptist Cancer Center, Memphis, Tennessee; Marcin Ostrowski Medical University of Gdansk, Poland; Harvey Pass, New York University, New York, New York; Marc de Perrot, University of Toronto, Toronto, Canada; Helmut Prosch, Medical University of Vienna, Vienna, Austria; David Rice, M. D. Anderson Cancer Center, Houston, Texas; Andreas Rimner, Memorial Sloan Kettering Cancer Center, New York, New York; Enrico Ruffini, University of Torino, Torino, Italy; Shuji Sakai, Tokyo Women’s Medical University, Tokyo, Japan; Paul Van Schil, Antwerp University and Antwerp University Hospital, (Edegem) Antwerp, Belgium; Navneet Singh, Postgraduate Institute of Medical Education and Research, Chandigarh, India; Amy Stoll-D’Astice, Cancer Research And Biostatistics, Seattle, Washington; Francisco Suárez, Clínica Santa María, Santiago, Chile; Ricardo M. Terra, University of Sao Paulo, Sao Paulo, Brazil; William D. Travis, Memorial Sloan Kettering Cancer Center, New York, New York; Ming S. Tsao, Princess Margaret Cancer Centre, Toronto, Canada; Paula Ugalde, Quebec Heart and Lung Institute, Quebec, Canada; David Waller, St. Bartholomew’s Hospital, London, United Kingdom; Shun-ichi Watanabe, National Cancer Center Hospital, Tokyo, Japan; Jacinta Wiens, IASLC, Aurora, Colorado; Ignacio Wistuba, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; Yasushi Yatabe, Aichi Cancer Center Hospital, Nagoya, Japan.

      Advisory Board to the Lung Cancer Domain

      Liyan Jiang, Shanghai Chest Hospital, Shanghai, People’s Republic of China; Kaoru Kubota, Nippon Medical School Hospital, Tokyo, Japan; Akif Turna, Istanbul University Cerrahpasa Medical School, Istanbul, Turkey; Benny Weksler, Allegheny General Hospital, Pittsburgh, Pennsylvania; Maria Teresa Tzukazan, Pontifícia Universidade Católica do Rio Grande do Sul Medical School Brazil; Carolle St. Pierre IUCPQ Institut Universitaire de Cardiologie et Pneumologie de Quebec, Quebec, Canada; Martin Tammemägi, Brock University, St. Catharines, Ontario, Canada; Charles Powell, Mount Sinai-National Jewish Health Respiratory Institute, New York, New York; David Naidich, New York University Langone Medical Center, New York, New York; Hongxu Liu, Cancer Hospital of China Medical University, Liaoning Cancer Hopital and Institute, Shenyang, People's Republic of China; Akif Turna, Institute for Aziz Sancar Experimental Medicine Research, İstanbul University, İstanbul, Turkey; Samuel Armato, University of Chicago, Chicago Illinois; Alex Brunelli, Leeds Teaching Hospitals National Health Service Trust, United Kingdom; Giuseppe Cardillo, Azienda Ospedaliera S. Camillo Forlanini, Rome, Italy; Elizabeth David, Keck School of Medicine of the University of Southern California, Los Angeles, California; Brigitte Fournier, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Canada; Mark Krasnik, Gentofte University Hospital, Copenhagen, Denmark; Kauro Kubota, Kaoru Kubota of Nippon Medical School, Tokyo, Japan; Catherine Labbe, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Eric Lim, Imperial College and the Royal Brompton Hospital, London, United Kingdom; Paul Martin Putora, Kantonsspital St. Gallen, St. Gallen, Switzerland; Gaetano Rocco, Memorial Sloan Kettering Cancer Center, New York, New York; Pier Luigi Filosso, University of Torino, Torino, Italy.

      Advisory Board to the Thymic Tumor Domain

      Pier Luigi Filosso, University of Torino, Torino, Italy; Kazuya Kondo, Tokushima University, Tokushima, Japan; Dong Kwan Kim, Asan Medical Center, Seoul, and University of Ulsan College of Medicine, Seoul, Republic of Korea; Giuseppe Giaccone, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C.; Professor of Medical Oncology and Pharmacology Conrad B. Falkson, Queen’s University, Kingston, Ontario, Canada; Marco Lucchi, Division of Thoracic Surgery, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; Maurizio Infante, Ospedale Borgo Trento, Verona, Italy.

      Advisory Board to the Esophageal Cancer Domain

      Thomas Rice, Cleveland Clinic, Cleveland, Ohio; Mark Ferguson, University of Chicago, Chicago, Illinois.

      Advisory Board to the Mesothelioma Cancer Domain

      Prasad Adsusmilli, Memorial Sloan Kettering Cancer Center, New York, New York.

      Appendix 2. Chairpersons and Members of the Subcommittees of the Lung Cancer Domain of the IASLC Staging and Prognostic Factors Committee

      IASLC Staging and Prognostic Factors Committee Chair

      Hisao Asamura.

      Lung Cancer Domain Chair

      Paul Van Schil.

      Lung Cancer Domain Vice Chair

      Kemp Kernstine.

      Lung Cancer Domain T Descriptors Subcommittee

      Hisao Asamura (chair), A. K. Cangir, Hui Liu, Yolande Lievens, Jessica Donnington, Wentao Fang, Gustavo Lyons, William Travis, Young Tae Kim, Shuji Sakai, Paula Ugalde, Pietro Bertoglio.

      Lung Cancer Domain N Descriptors Subcommittee

      James Huang (chair), Kemp Kernstine, Raymond U. Osarogiagbon, Francisco Suárez, Valerie Rusch, David Rice, Ricardo Beyruti, Hong Kwan Kim, Paul Van Schil, Shun-ichi Watanabe, Helmut Prosch, Edith Marom, Paul Martin Putora, Yolande Lievens, Andrea Bille, Giuseppe Cardillo, Kaura Kubota, Eric Lim, Gaetano Rocco.

      Lung Cancer Domain M Descriptors Subcommittee

      Kwun Fong (chair), Navneet Singh, Wilfried Eberhardt, Yolande Lievens, Mirella Marino, Jeremy Erasmus, Paul Martin Putora, Edith Marom, Francisco Suárez.

      Lung Cancer Domain Ground Glass Opacities and Adenocarcinoma In Situ Subcommittee

      William Travis (chair), Hisao Asamura, Shun-ichi Watanabe, Shuji Sakai, Yasushi Yatabe, Helmut Prosch, Hans Hoffman, John Edwards, Philippe Joubert, Ritu Gill, Jin Mo Goo, Andrew G. Nicholson, Young Tae Kim, Heber MacMahon, Frank Detterbeck, Edith Marom Ramón Rami-Porta, Valerie Rusch, Giuseppe Cardillo, David Naidich.

      Lung Cancer Domain Neuroendocrine Tumors Subcommittee

      Ming Tsao (cochair), Andrew G. Nicholson, (cochair), Wilfried Eberhardt, Ricardo Beyruti, Yasushi Yatabe, William Travis, José-María Matilla, Yolande Lievens, Frank Detterbeck, Eric Lim, Pier Luigi Filosso.

      Lung Cancer Domain Stage Subcomittee

      Hisao Asamura (chair), Ramón Rami-Porta, James Huang, Kwun Fong, William Travis, Ming Tsao, Shun-ichi Watanabe, Andrew G. Nicholson, Frank Detterbeck, John Edwards, Meredith Guiliani, Paul Van Schil, Kemp Kernstine, Edith Marom, Giuseppe Cardillo, Elizabeth David.

      Lung Cancer Domain Lymph Node Chart Subcommittee

      Shun-ichi Watanabe (chair), Hisao Asamura, Valerie Rusch, Ramón Rami-Porta, Hans Hoffman, Paul Van Schil, Kemp Kernstine, Raymond U. Osarogiagbon, Jin Mo Goo.

      Lung Cancer Domain Validation and Methodology Subcommittee

      Frank Detterbeck (chair), James Brierley, Raymond U. Osarogiagbon, Mirella Marino, Hisao Asamura, Valerie Rusch.

      Lung Cancer Domain Prognostic Factors Subcommittee

      Frank Detterbeck (chair), Andrew G. Nicholson, Kwun Fong, Young Tae Kim, James Huang, Jan van Meerbeeck, Ming Tsao, Akif Turna, Navneet Singh, Ricardo Terra, Ray Osarogiagbon, Luis Montuenga, James Brierley, Valerie Rusch, Hongwei Wang, Katie Nishimura, Martin Tammemägi, Mark Krasnik, Alex Brunelli.

      Lung Cancer Domain R Factor Subcommittee

      John Edwards (chair), Hans Hoffman, Souheil Boubia, Jun Nakajima, Paul Van Schil, Jessica Donnington, Elisabeth Brambilla, Edith Marom, Andrew G. Nicholson, Mirella Marino, Françoise Galateau, William Travis, Yasushi Yatabe, Ming Tsao, Maurizio Infante, Marcin Ostrowski.

      Lung Cancer Domain Radiology and Imaging Subcomittee

      Heber MacMahon (chair), Edith Marom, Jim Mo Goo, Ritu Gill, Paul Van Schil, Bill Travis, Charles Powell, Samuel Armato, David Naidich.

      Lung Cancer Domain Multiple Pulmonary Nodules Subcommittee

      Frank Detterbeck (chair), Edith Marom, Andrew G. Nicholson, William Travis, Paula Ugalde, Ricardo M. Terra, Eric Lim.

      Lung Cancer Domain Molecular Database Subcommittee

      David Carbone (cochair), Fred Hirsch (cochair), Ignacio Wistuba, Keith Kerr, Elisabeth Brambilla, Oliver Gautschi, Yasushi Yatabe, Luiz Henrique Araujo, Harvey Pass, Ming Tsao, Ramón Rami-Porta, William Travis, Frank Detterbeck, Andrew G. Nicholson, Hisao Asamura, Luis Montuenga, Ricardo M. Terra, Raymond U. Osarogiagbon, José-María Matilla, Dean Fennell, David Beer.

      Database Subcommittee

      Paula Ugalde (chair), Philippe Joubert, Gustavo Lyons, Ricardo Terra, Pietro Bertoglio, Jose Maria Matilla, Catherine Labbe, Brigitte Fournier, Carolle St. Pierre, Benny Weksler, Hongxu Liu, Ma Teresa Tzukazan.

      Thymic Tumors

      Enrico Ruffini (chair), James Huang (vice chair), Wentao Fang, Frank Detterbeck, Edith Marom, Mirella Marino, Souheil Boubia, A. K. Cangir, Andrea Bille, Andreas Rimner, Meinoshin Okumura, Andrew Nicholson, Nicholas Girard, Maurizio Infante, Giuseppe Giaccone, Pier Luigi Filosso, Kazuya Kondo, Marco Lucchi, Conrad Falkson, Dong Kwan Kim.

      Mesothelioma

      Valerie Rusch (chair), Anna Nowak (vice chair), Isabelle Opitz, Andrea Bille, Marc de Perrot, Andreas Rimmer, Ritu Gill, Hong Kwan Kim, David Rice, Hedy Kindler, Dean Fennell, Jan van Meerbeeck, Francoise Galateau, Seiki Hasegawa, Pietro Bertoglio, Ming Tsao, Harvey Pass, Prasad Adusumilli.

      Esophageal Cancer

      Gail Darling (chair), Xavier D'Journo (vice chair), Donald Low, Wayne Hofstetter, Hong Kwan Kim, Wentao Fang, Jeremy Erasmus, Paula Ugalde, Mark Ferguson.

      Cancer Research And Biostatistics

      John Crowley, Kari Chansky, Dorothy Giroux, Vanessa Bolejack, Amy Stoll-D’Astice, Katie Nishimura, Adam Rosenthal.

      Supplementary Data

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