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The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer

Open ArchivePublished:February 29, 2016DOI:https://doi.org/10.1016/j.jtho.2015.12.114

      Abstract

      Introduction

      Separate tumor nodules with the same histologic appearance occur in the lungs in a small proportion of patients with primary lung cancer. This article addresses how such tumors can be classified to inform the eighth edition of the anatomic classification of lung cancer. Separate tumor nodules should be distinguished from second primary lung cancer, multifocal ground glass/lepidic tumors, and pneumonic-type lung cancer, which are addressed in separate analyses.

      Methods

      Survival of patients with separate tumor nodules in the International Association for the Study of Lung Cancer database were analyzed. This was compared with a systematic literature review.

      Results

      Survival of clinically staged patients decreased according to the location of the separate tumor nodule relative to the index tumor (same lobe > same side > other side) in N0 and N-any cohorts (all M0 except possible other-side nodules). However, there was also a decrease in the proportion of patients resected; among only surgically resected or among nonresected patients no survival differences were noted. There were no survival differences between patients with same-lobe nodules and those with other T3 tumors, between patients with same-side nodules and those with T4 tumors, and patients with other-side nodules and those with other M1a tumors. The data correlated with those identified in a literature review.

      Conclusions

      Tumors with same-lobe separate tumor nodules (with the same histologic appearance) are recommended to be classified as T3, same-side nodules as T4, and other-side nodules as M1a. Thus, there is no recommended change between the seventh and eighth edition of the TNM classification of lung cancer.

      Keywords

      Introduction

      Patients with primary lung cancer sometimes present with separate solid pulmonary tumor nodules (called intrapulmonary metastases in the pathology community) that have the same or a similar radiologic and histologic appearance and are viewed as metastatic from one another as opposed to separate primary tumors. These may occur in the same lobe as the primary tumor site, or in a different lobe either on the same or the contralateral side. The presence of such separate nodules has implications in the tumor, node, and metastasis (TNM) classification of the tumor. The stage classification system undergoes periodic updates to reflect new knowledge. This article details an analysis of available information to inform development of proposals for the forthcoming (eighth) edition of the TNM classification of malignant tumors.
      A difficulty in addressing this topic is that the distinction between second primary lung cancers, separate tumor nodules, and multifocal ground glass/lepidic (GG/L) tumors and pneumonic-type of lung cancer has not been made very clearly in the past. As a result there has been ambiguity in the literature and confusion in how stage classification should be applied.
      • Fonseca A.
      • Detterbeck F.C.
      How many names for a rose: inconsistent classification of multiple foci of lung cancer due to ambiguous rules.
      • Homer R.
      Pathologists' staging of multiple foci of lung cancer.
      In conjunction with preparing this article (on separate tumor nodules) this larger issue has also been addressed: details are provided in other articles
      • Detterbeck F.C.
      • Franklin W.A.
      • Nicholson A.G.
      • et al.
      The IASLC Lung Cancer Staging Project: background data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM Classification for Lung Cancer.
      • Detterbeck F.C.
      • Marom E.M.
      • Arenberg D.A.
      • et al.
      The IASLC Lung Cancer Staging Project: background data and proposals for the application of TNM staging rules to lung cancer presenting as multiple nodules with ground glass or lepidic features or a pneumonic type of involvement in the forthcoming eighth edition of the TNM classification.
      and summarized in an article that outlines proposed TNM classification of all patients with multiple pulmonary sites of lung cancer.
      • Detterbeck F.C.
      • Nicholson A.G.
      • Franklin W.A.
      • et al.
      The IASLC Lung Cancer Staging Project: summary of proposals for revisions of the classification of lung cancers with multiple pulmonary sites of involvement in the forthcoming eighth edition of the TNM classification.
      In the following text these definitions are applied as best as possible to the available data, thus reporting on outcomes specifically for cohorts with separate tumor nodules as opposed to cohorts consisting largely of patients with second primary cancers or multifocal cancers with ground glass features.
      Patients should be classified as having separate tumor nodule(s) when there is a dominant “classic” lung cancer (i.e., solid, spiculated) and one (or more) solid separate lung nodules, either presumed or proved to have the same histologic features (although sometimes the distinction between a dominant and an additional nodule may be subtle). These should be distinguished from synchronous second primary cancers (which can often be of the same histotype but are deemed to be independent cancers on review of all available clinical and histologic information), multifocal tumors that have a prominent ground glass or lepidic component, and pneumonic-type adenocarcinoma that manifests as diffuse or multinodular areas of consolidation similar in appearance to a pneumonia.
      • Detterbeck F.C.
      • Franklin W.A.
      • Nicholson A.G.
      • et al.
      The IASLC Lung Cancer Staging Project: background data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM Classification for Lung Cancer.
      • Detterbeck F.C.
      • Marom E.M.
      • Arenberg D.A.
      • et al.
      The IASLC Lung Cancer Staging Project: background data and proposals for the application of TNM staging rules to lung cancer presenting as multiple nodules with ground glass or lepidic features or a pneumonic type of involvement in the forthcoming eighth edition of the TNM classification.
      Further descriptions of these types of tumors and criteria to identify them are provided in a summary article.
      • Detterbeck F.C.
      • Nicholson A.G.
      • Franklin W.A.
      • et al.
      The IASLC Lung Cancer Staging Project: summary of proposals for revisions of the classification of lung cancers with multiple pulmonary sites of involvement in the forthcoming eighth edition of the TNM classification.

      Methods

      Proposals for revisions of the TNM classification for lung cancer were developed under the auspices of the American Joint Committee on Cancer and Union for International Cancer Control by the Staging and Prognostic Factors Committee (SPFC) of the International Association for the Study of Lung Cancer (IASLC), which provided funding for the project. The IASLC formed a subcommittee to address the definition and classification of multiple pulmonary sites of lung cancer (consisting of the authors on this article). This subcommittee used a detailed analysis of the IASLC database as well as a systematic literature review to develop proposals. The article was then sent for critical review to an extended workgroup of individuals with particular interest and expertise in this topic (see the Appendix). This document was then further reviewed and eventually endorsed by the entire IASLC SPFC according to an established process.
      The IASLC has conducted an ongoing initiative to populate an international database on patients with lung cancer. For revisions to the eighth edition, after exclusions, 77,156 cases diagnosed from 1999 to 2010 were available for analysis in this database (70,967 with non–small cell lung cancer and 6189 with small cell lung cancer), as described in detail 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 analysis was carried out by Cancer Research And Biostatistics. Overall survival (OS) was measured from the date of diagnosis for clinically staged (c-stage) patients and date of surgery for pathologically staged (p-stage) patients using the Kaplan-Meier method. Prognostic groups were assessed using Cox proportional hazards regression analysis.
      • Cox D.
      Regression models and life-tables (with discussion).
      SAS software, version 9.2 (SAS Institute Inc., Cary, NC), was used to perform the survival and regression analyses.
      Additionally, the multiple lesions subcommittee carried out a systematic search for relevant literature from 1995 to 2015 with the help of a methodologist. The PICO questions, search, results, and inclusion and exclusion criteria are available on request. The search was structured to build on a prior systematic review of patients with lung cancer with multiple tumor lesions that was conducted during development of the American College of Chest Physicians Lung Cancer Guidelines (third edition).
      • Detterbeck F.C.
      • Lewi S.
      • Diekemper R.
      • Addrizzo-Harris D.
      • Alberts W.M.
      Executive summary: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.
      • Kozower B.
      • Larner J.M.
      • Detterbeck F.C.
      • Jones D.R.
      Special treatment issues in non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.
      Reference lists of identified articles were also examined, and each article in the American College of Chest Physicians review was revisited to ensure that the definitions of patient categories were applied appropriately and abstracted correctly.

      Results

      IASLC Database Analysis

      Outcomes by Location of Separate Tumor Nodules (Intrapulmonary Metastases)

      Separate tumor nodules were reported in 1.7% of patients (505 of 29595) with clinical stage information and 3.5% of patients (1122 of 31537) with pathologic stage information (Supplementary Table 1, Supplementary Digital Content 1). There was no difference in the proportions of histologic types between cases with or without nodules (Supplementary Table 2, Supplementary Digital Content 1). The relationship of clinical to pathologic stage suggests that many of the same-lobe separate tumor nodules were discovered incidentally at resection (or at least not coded on clinical staging, perhaps owing to uncertainty whether the nodule was malignant). The number (and proportion) of cases recorded as having separate nodules (in any lobe) rose in 2007 (Supplementary Figs. 1A and B, Supplementary Digital Content 2). The percentage of all c-stage patients with separate tumor nodules rose from less than 3% from 1999 to 2005 to approximately 10% from 2007 to 2010; among p-stage patients, the percentage with separate tumor nodules increased from approximately 3% in 1999 to 2005 to approximately 6% in 2007 to 2010 (Supplementary Figs. 1A and B, Supplementary Digital Content 2).
      Outcomes for c-stage patients with separate solid tumor nodules are shown in (Figs. 1AD). There is a decrease in OS by location of the separate tumor nodule to the index tumor (same lobe > different ipsilateral lobe > different contralateral lobe). This is true in patients with either cN0 or cN-any tumors (all M0 except for possible contralateral nodules). However, the percentage of patients with same-lobe tumor nodules that were resected varies markedly. Separate analysis of surgically and nonsurgically treated patients shows no differences in outcomes relative to the tumor nodule location. (Figs. 1C and D). To compare groups that might be resectable, this comparison is shown for cohorts of patients who are cN0 M0 (except possible contralateral nodules). Thus, the data suggest a correlation of OS with the treatment modality rather than with the relative location of a separate tumor nodule.
      Figure thumbnail gr1
      Figure 1Overall survival of clinically staged (c-stage) patients. Overall survival of c-stage patients with separate solid tumor nodules (intrapulmonary metastases) by location. These patients had only the nodules account for the T3, T4, or M1a designation, but may have had lower T characteristics as well. The nonsurgical c-stage patients had separate nodules that were suspected or proved to be the same as the primary lung cancer (i.e., this may or may not have been histologically confirmed). *All tumors are M0 (except contralateral separate pulmonary tumor nodule allowed). (A) cN0 cohort; p = 0.051 for same-lobe versus same-side nodules, p = 0.058 for same-side versus other-side nodules; (B) cN-any cohort; p < 0.0001 for same-lobe versus same-side nodules, p = 0.055 for same-side versus other-side nodules; (C) c-stage nodule cases that were surgically resected (and nodule pathologically confirmed). cN0, R-any cohort; p = not significant; and (D) c-stage nodule cases treated nonsurgically, cN0 cohort; p = not significant.
      For p-stage cohorts, the impact of nodule location on OS is unclear (Figs. 2A and B). A statistically significant difference is observed for same-lobe versus same-side tumors in the pN0 M0 R0 (p = 0.032) and pN-any M0 R-any (p = 0.024) cohorts but not for other comparisons; however, there are more incidentally discovered separate tumor nodules in the same-lobe cohort. The OS by location is similar for pN-any R0 (data not shown) and pN-any, M0, R-any cohorts (all M0 except for possible contralateral nodules).
      Figure thumbnail gr2
      Figure 2Overall survival of pathologically staged (p-stage) patients. Overall survival of p-stage patients with separate solid tumor nodules (intrapulmonary metastases) by location. These patients had only the nodules account for the T3, T4, or M1a designation, but may have had lower T characteristics as well. Differences between same-lobe and same-side tumors are statistically significant; other comparisons are not significantly different. *All tumors are M0 (except contralateral separate pulmonary tumor nodule allowed). (A) pN0, R0 cohort; p = 0.0024 for same-lobe versus same-side nodules, p = not significant for same-side versus other-side nodules; (B) pN-any, R-any cohort; p = 0.0032 for same-lobe versus same-side nodules, p = not significant for same-side versus other-side nodules.
      Information on the size of separate tumor nodules was not available for most of the cases. There was little difference in the size of the primary tumor between same-lobe, same-side, and other-side cases (Supplementary Fig. 2, Supplementary Digital Content 2), although there was a slight shift toward smaller primary tumors in the p-stage other-side separate nodule group. A comparison of one versus two or more nodules was limited owing to a paucity of patients with two or more nodules. Among c-stage N0 M0 (except possible contralateral nodules) tumors there was a suggestion of worse survival for two or more nodules for same-lobe, same-side, and other-side nodules; sample size did not permit statistical analysis. Among p-stage cases there was little suggestion of such a trend.
      The OS of p-stage patients with separate tumor nodules (in any lobe) increased over time (5-year OS of 19%, 43%, and 71% for cohorts in 1999–2003, 2004–2006, and 2007–2010 of pN0 M0 [except other nodules] R0 non-Japanese cohorts [31, 52, and 95 patients]; patients from Japan were excluded because they are not represented in the 2007–2010 group and have generally better survival). For c-stage patients little change was observed, but the number of patients was very limited (5-year OS of 50%, 50%, and 62% for cohorts in 1999–2003, 2004–2006, and 2007–2010 of cN0 M0 [except other nodules] non-Japanese patients [2, 4, and 26 patients]; this includes c-stage surgical and nonsurgically treated patients).

      Comparison with Other T3, T4, and M1a Descriptors

      A comparison of same-lobe separate tumor nodules and other T3 descriptors shows no clear difference in p-stage cohorts (pN0 M0 R0, pN-any M0 R0, and pN0 M0 R-any) when stratified by a single T3 descriptor versus multiple T3 descriptors (Figs. 3AC). There is also no clear difference in OS in c-stage T3 patients (Supplementary Figs. 3A and B, Supplementary Digital Content 2). A comparison of same-side (different lobe) separate tumor nodules and other T4 descriptors also reveals no clear difference (Figs. 4AC); this is also observed in c-stage cohorts (Supplementary Figs. 4A and B, Supplementary Digital Content 2). The limited sample sizes preclude statistical analysis. Further details of other T descriptors are provided in another article.
      • Rami-Porta R.
      • Bolejack V.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM Classification for Lung Cancer.
      Figure thumbnail gr3
      Figure 3pT3 by same-lobe tumor nodule versus other T3 descriptors. Overall survival of pathologically staged patients with same-lobe separate nodule tumors versus other T3 descriptors, stratified by a single T3 descriptor versus multiple T3 descriptors. For details of other T descriptors see the T descriptor article.
      • Rami-Porta R.
      • Bolejack V.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM Classification for Lung Cancer.
      *All tumors are M0 (except contralateral separate pulmonary tumor nodule allowed). (A) pN0 M0 R0; (B) pN-any M0 R0; and (C) pN0 M0 R-any.
      Figure thumbnail gr4
      Figure 4pT4 by same-side tumor nodule versus other T4 descriptors. Overall survival of pathologically staged patients with same-side (different lobe) separate nodule–only tumors versus other T4 descriptors, stratified by a single T4 descriptor versus multiple T4 descriptors. For details of other T descriptors see the T descriptor article.
      • Rami-Porta R.
      • Bolejack V.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM Classification for Lung Cancer.
      *All tumors are M0 (except contralateral separate pulmonary tumor nodule allowed). (A) pN0 M0 R0; (B) pN-any M0 R0; and (C) pN0 M0 R-any.
      Among c-stage, nonsurgically managed patients there is no clear difference in OS between patients with other-side separate tumor nodules and other M1a descriptors (Fig. 5). There exists a small cohort of patients with other-side separate tumor nodules that were resected. The survival of these patients compared with that of other M1a surgically managed patients is shown in Supplementary Figure 5; there are no statistically significant survival differences, but the limited sample size precludes a robust analysis.
      Figure thumbnail gr5
      Figure 5Comparison of cM1a descriptors in nonsurgical patients. Overall survival of patients with other-side separate tumor nodule (intrapulmonary metastases) versus other cM1a descriptors in clinically staged (T-any N-any) tumors, not surgically treated (Electronic data capture system cases only).

      Literature Review

      The results of the systematic literature review for separate tumor nodules with the same histologic appearance involves primarily surgical series. When reported, most same-lobe separate tumor nodules (Table 1) appear to have been discovered incidentally; no reports have contrasted the outcomes for incidental versus preoperatively detected nodules. The 5-year OS for all resected patients is approximately 40%, and for N0 patients, it is approximately 50%. Typically, only one separate tumor nodule was reported; several studies found no difference in OS for one versus two or more nodules,
      • Pennathur A.
      • Lindeman B.
      • Ferson P.
      • et al.
      Surgical resection is justified in non-small cell lung cancer patients with node negative T4 satellite lesions.
      • Port J.L.
      • Korst R.J.
      • Lee P.C.
      • Kansler A.L.
      • Kerem Y.
      • Altorki N.K.
      Surgical resection for multifocal (T4) non-small cell lung cancer: is the T4 designation valid?.
      but one found a trend toward better OS with solitary nodules (5-year OS of 62% versus 33%, p = 0.18).
      • Rao J.
      • Sayeed R.A.
      • Tomaszek S.
      • Fischer S.
      • Keshavjee S.
      • Darling G.E.
      Prognostic factors in resected satellite-nodule T4 non-small cell lung cancer.
      Several studies found significantly better OS for smaller versus larger primary tumors
      • Okamoto T.
      • Iwata T.
      • Mizobuchi T.
      • et al.
      Surgical treatment for non-small cell lung cancer with ipsilateral pulmonary metastases.
      • Pennathur A.
      • Lindeman B.
      • Ferson P.
      • et al.
      Surgical resection is justified in non-small cell lung cancer patients with node negative T4 satellite lesions.
      • Terzi A.
      • Falezza G.
      • Benato C.
      • et al.
      Survival following complete resection of multifocal T4 node-negative NSCLC: a retrospective study.
      or a similar trend.
      • Okumura T.
      • Asamura H.
      • Suzuki K.
      • Kondo H.
      • Tsuchiya R.
      Intrapulmonary metastasis of non-small cell lung cancer: a prognostic assessment.
      OS in large registries is slightly lower; it is unclear how many of these patients were resected, but it appears that most were.
      Table 1Separate Tumor Nodules in the Same Lobe
      CCR, California Cancer Registry; IASLC, International Association for the Study of Lung Cancer; SEER, Surveillance, Epidemiology, and End Results.
      First AuthorNo. Patients% with Multiple Nodules% Incidental% Resected% N0% 5-Year Survival
      AllN0
      Okamoto
      • Okamoto T.
      • Iwata T.
      • Mizobuchi T.
      • et al.
      Surgical treatment for non-small cell lung cancer with ipsilateral pulmonary metastases.
      161100525469
      Suziki
      • Suzuki M.
      • Yoshida S.
      • Moriya Y.
      • et al.
      Single T factors predict survival of patients with resected stage-IIB non-small-cell lung cancers.
      6710010078
      Kocaturk
      • Kocaturk C.I.
      • Gunluoglu M.Z.
      • Cansever L.
      • et al.
      Prognosis in patients with non-small cell lung cancer and satellite tumors.
      20901002452
      Pennathur
      • Pennathur A.
      • Lindeman B.
      • Ferson P.
      • et al.
      Surgical resection is justified in non-small cell lung cancer patients with node negative T4 satellite lesions.
      513753100682640
      Ruffini
      • Ruffini E.
      • Filosso P.L.
      • Bruna M.C.
      • et al.
      Recommended changes for T and N descriptors proposed by the International Association for the Study of Lung Cancer—Lung Cancer Staging Project: a validation study from a single-centre experience.
      501004428
      Trousse
      • Trousse D.
      • D'Journo X.B.
      • Avaro J.-P.
      • et al.
      Multifocal T4 non-small cell lung cancer: a subset with improved prognosis.
      70100
      Data reported for N0 patients.
      100504852
      Oliaro
      • Oliaro A.
      • Filosso P.L.
      • Cavallo A.
      • et al.
      The significance of intrapulmonary metastasis in non-small cell lung cancer: upstaging or downstaging? A re-appraisal for the next TNM staging system.
      39(49)
      Data are for both same-lobe and ipsilateral different-lobe separate tumor nodule(s).
      (93)
      Data are for both same-lobe and ipsilateral different-lobe separate tumor nodule(s).
      (49)
      Data are for both same-lobe and ipsilateral different-lobe separate tumor nodule(s).
      2033
      Four-year survival.
      Lee
      • Lee J.G.
      • Lee C.Y.
      • Kim D.J.
      • Chung K.Y.
      • Park I.K.
      Non-small cell lung cancer with ipsilateral pulmonary metastases: prognosis analysis and staging assessment.
      2310030
      Nagai
      • Nagai K.
      • Sohara Y.
      • Tsuchiya R.
      • Goya T.
      • Miyaoka E.
      Prognosis of resected non-small cell lung cancer patients with intrapulmonary metastases.
      31684382747
      Port
      • Port J.L.
      • Korst R.J.
      • Lee P.C.
      • Kansler A.L.
      • Kerem Y.
      • Altorki N.K.
      Surgical resection for multifocal (T4) non-small cell lung cancer: is the T4 designation valid?.
      531985100644858
      Rao
      • Rao J.
      • Sayeed R.A.
      • Tomaszek S.
      • Fischer S.
      • Keshavjee S.
      • Darling G.E.
      Prognostic factors in resected satellite-nodule T4 non-small cell lung cancer.
      ,
      Included a minority of patients with adenocarcinoma with bronchioloalveolar carcinoma features.
      35949100515764
      Terzi
      • Terzi A.
      • Falezza G.
      • Benato C.
      • et al.
      Survival following complete resection of multifocal T4 node-negative NSCLC: a retrospective study.
      323310010042
      Bryant
      • Bryant A.S.
      • Pereira S.J.
      • Miller D.L.
      • Cerfolio R.J.
      Satellite pulmonary nodule in the same lobe (T4N0) should not be staged as IIIB non-small cell lung cancer.
      ,
      Included a minority of patients with adenocarcinoma with bronchioloalveolar carcinoma features.
      268710057
      Okumura
      • Okumura T.
      • Asamura H.
      • Suzuki K.
      • Kondo H.
      • Tsuchiya R.
      Intrapulmonary metastasis of non-small cell lung cancer: a prognostic assessment.
      105100303437
      Okada
      • Okada M.
      • Tsubota N.
      • Yoshimura M.
      • Miyamoto Y.
      • Nakai R.
      Evaluation of TMN classification for lung carcinoma with ipsilateral intrapulmonary metastasis.
      5182100<5030
      Yano
      • Yano M.
      • Arai T.
      • Inagaki K.
      • Morita T.
      • Nomura T.
      • Ito H.
      Intrapulmonary satellite nodule of lung cancer as a T factor.
      391002636
      Fukuse
      • Fukuse T.
      • Hirata T.
      • Tanaka F.
      • Yanagihara K.
      • Hitomi S.
      • Wada H.
      Prognosis of ipsilateral intrapulmonary metastases in resected nonsmall cell lung cancer.
      2012100>5037
      Average3852
      Registry/database studies
      Most patients in each study underwent resection.
      IASLC
      • Rami-Porta R.
      • Ball D.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for revision of the T descriptors in the forthcoming (7th) edition of the TNM classification of lung cancer.
      36328
      CCR
      • Ou S.H.I.
      • Zell J.A.
      Validation study of the proposed IASLC staging revisions of the T4 and M non-small cell lung cancer descriptors using data from 23,583 patients in the California Cancer Registry.
      42223
      SEER
      • Zell J.
      • Ignatius Ou S.-H.
      • Ziogas A.
      • Anton-Culver H.
      Survival improvements for advanced stage nonbronchioloalveolar carcinoma-type nonsmall cell lung cancer cases with ipsilateral ntrapulmonary nodules.
      633583554
      SEER
      • Williams Jr., W.
      • Lin H.
      • Lee J.
      • Lippman S.
      • Roth J.
      • Kim E.
      Revisiting stage IIIB and IV non-small cell lung cancer.
      228524
      Note: Inclusion criteria: studies of at least 20 patients with a separate tumor nodule in the same lobe as the dominant primary lung cancer from December 1995 to April 2015.
      a Data reported for N0 patients.
      b Data are for both same-lobe and ipsilateral different-lobe separate tumor nodule(s).
      c Four-year survival.
      d Included a minority of patients with adenocarcinoma with bronchioloalveolar carcinoma features.
      e Most patients in each study underwent resection.
      Fewer data are available for same-side (different lobe) separate tumor nodules (Table 2). The 5-year OS for all resected patients is approximately 30%, and for N0 patients approximately 40%. Little further detail has been reported. One study found a trend toward better survival in smaller tumors.
      • Okamoto T.
      • Iwata T.
      • Mizobuchi T.
      • et al.
      Surgical treatment for non-small cell lung cancer with ipsilateral pulmonary metastases.
      Registry studies appear to primarily involve patients who have not been operated on and have provided no details.
      Table 2Separate Ipsilateral (Different Lobe) Tumor Nodules
      CCR, California Cancer Registry; IASLC, International Association for the Study of Lung Cancer; SEER, Surveillance, Epidemiology, and End Results.
      First AuthorNo. Patients% with Multiple Nodules% Incidental% Resected% N0% 5-Year Survival
      AllN0
      Nagai
      • Nagai K.
      • Sohara Y.
      • Tsuchiya R.
      • Goya T.
      • Miyaoka E.
      Prognosis of resected non-small cell lung cancer patients with intrapulmonary metastases.
      12966302346
      Watanabe
      • Watanabe S.
      • Asamura H.
      • Miyaoka E.
      • et al.
      Results of T4 surgical cases in the Japanese Lung Cancer Registry Study: should mediastinal fat tissue invasion really be included in the T4 category?.
      85635333
      Tönnies
      • Tonnies M.
      • Koollmeier J.
      • Bauer T.
      • Griff S.
      • Kaiser D.
      Curative surgical treatment options for patients with non-small cell lung cancer (NSCLC) and solitary pulmonary metastasis.
      • Tönnies M.
      • Pfannschmidt J.
      • Bauer T.T.
      • Kollmeier J.
      • Tönnies S.
      • Kaiser D.
      Metastasectomy for synchronous solitary non-small cell lung cancer metastases.
      3810042
      Includes both ipsilateral and contralateral different-lobe separate tumor nodule(s).
      71
      Okada
      • Okada M.
      • Tsubota N.
      • Yoshimura M.
      • Miyamoto Y.
      • Nakai R.
      Evaluation of TMN classification for lung carcinoma with ipsilateral intrapulmonary metastasis.
      3889100<5023
      Ruffini
      • Ruffini E.
      • Filosso P.L.
      • Bruna M.C.
      • et al.
      Recommended changes for T and N descriptors proposed by the International Association for the Study of Lung Cancer—Lung Cancer Staging Project: a validation study from a single-centre experience.
      3610053(28)
      Three-year survival.
      Oliaro
      • Oliaro A.
      • Filosso P.L.
      • Cavallo A.
      • et al.
      The significance of intrapulmonary metastasis in non-small cell lung cancer: upstaging or downstaging? A re-appraisal for the next TNM staging system.
      35(49)
      Data are for both same-lobe and ipsilateral different-lobe separate tumor nodule(s).
      (93)
      Data are for both same-lobe and ipsilateral different-lobe separate tumor nodule(s).
      (49)
      Data are for both same-lobe and ipsilateral different-lobe separate tumor nodule(s).
      1016
      Lee
      • Lee J.G.
      • Lee C.Y.
      • Kim D.J.
      • Chung K.Y.
      • Park I.K.
      Non-small cell lung cancer with ipsilateral pulmonary metastases: prognosis analysis and staging assessment.
      2610031
      Eighty-five percent underwent pneumonectomy.
      Okamoto
      • Okamoto T.
      • Iwata T.
      • Mizobuchi T.
      • et al.
      Surgical treatment for non-small cell lung cancer with ipsilateral pulmonary metastases.
      211004819
      Tung
      • Tung Y.-W.
      • Hsu C.-P.
      • Shai S.-E.
      • Hsia J.-Y.
      • Yang S.-S.
      • Chen C.-Y.
      Surgical feasibility of ipsilateral multifocal non-small cell lung cancer in different lobes: excellent survival in node-negative subgroup.
      20151001002867
      Average
      Excluding values in parentheses.
      3043
      Registry/database studies
      IASLC 1990–1999
      • Rami-Porta R.
      • Ball D.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for revision of the T descriptors in the forthcoming (7th) edition of the TNM classification of lung cancer.
      18022
      CCR
      • Ou S.H.I.
      • Zell J.A.
      Validation study of the proposed IASLC staging revisions of the T4 and M non-small cell lung cancer descriptors using data from 23,583 patients in the California Cancer Registry.
      745(9)
      Most patients did not undergo resection.
      SEER
      • Zell J.
      • Ignatius Ou S.-H.
      • Ziogas A.
      • Anton-Culver H.
      Survival improvements for advanced stage nonbronchioloalveolar carcinoma-type nonsmall cell lung cancer cases with ipsilateral ntrapulmonary nodules.
      301016(7)
      Includes both ipsilateral and contralateral different-lobe separate tumor nodule(s).
      ,
      Most patients did not undergo resection.
      SEER
      • Williams Jr., W.
      • Lin H.
      • Lee J.
      • Lippman S.
      • Roth J.
      • Kim E.
      Revisiting stage IIIB and IV non-small cell lung cancer.
      3019(8)
      Most patients did not undergo resection.
      Note: Inclusion criteria: studies of at least 20 patients with a separate tumor nodule in a different ipsilateral lobe as the dominant primary lung cancer from December 1995 to April 2015.
      a Includes both ipsilateral and contralateral different-lobe separate tumor nodule(s).
      b Three-year survival.
      c Data are for both same-lobe and ipsilateral different-lobe separate tumor nodule(s).
      d Eighty-five percent underwent pneumonectomy.
      e Excluding values in parentheses.
      f Most patients did not undergo resection.
      Very few data are available regarding outcomes of patients with contralateral separate tumor nodules (Table 3). Registry studies report very poor survival, but the vast majority of patients were not treated with curative intent. Only one study has reported specific outcomes on more than10 resected patients; the 5-year OS was 77%.
      • Tonnies M.
      • Koollmeier J.
      • Bauer T.
      • Griff S.
      • Kaiser D.
      Curative surgical treatment options for patients with non-small cell lung cancer (NSCLC) and solitary pulmonary metastasis.
      • Tönnies M.
      • Pfannschmidt J.
      • Bauer T.T.
      • Kollmeier J.
      • Tönnies S.
      • Kaiser D.
      Metastasectomy for synchronous solitary non-small cell lung cancer metastases.
      Table 3Separate Contralateral Tumor Nodules
      CCR, California Cancer Registry; IASLC, International Association for the Study of Lung Cancer; SEER, Surveillance, Epidemiology, and End Results.
      StudyNo. Patients% Resected% pN2% 5-Year Survival
      AllResectedN0
      Tönnies
      • Tonnies M.
      • Koollmeier J.
      • Bauer T.
      • Griff S.
      • Kaiser D.
      Curative surgical treatment options for patients with non-small cell lung cancer (NSCLC) and solitary pulmonary metastasis.
      • Tönnies M.
      • Pfannschmidt J.
      • Bauer T.T.
      • Kollmeier J.
      • Tönnies S.
      • Kaiser D.
      Metastasectomy for synchronous solitary non-small cell lung cancer metastases.
      1210024
      Includes 43 patients with ipsilateral different-lobe separate tumor nodule(s).
      80
      SEER
      • Williams Jr., W.
      • Lin H.
      • Lee J.
      • Lippman S.
      • Roth J.
      • Kim E.
      Revisiting stage IIIB and IV non-small cell lung cancer.
      53826533
      CCR
      • Ou S.H.I.
      • Zell J.A.
      Validation study of the proposed IASLC staging revisions of the T4 and M non-small cell lung cancer descriptors using data from 23,583 patients in the California Cancer Registry.
      114882–6
      Range of estimated 5-year survival for various histologic types.
      IASLC 1990–1999
      • Rami-Porta R.
      • Ball D.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for revision of the T descriptors in the forthcoming (7th) edition of the TNM classification of lung cancer.
      36223
      Note: Inclusion criteria: studies of at least 20 patients with a primary lung cancer and a separate contralateral tumor nodule from December 1995 to April 2015.
      a Includes 43 patients with ipsilateral different-lobe separate tumor nodule(s).
      b Range of estimated 5-year survival for various histologic types.

      Discussion

      Although some details were not captured in the IASLC database, so that we cannot be completely sure of the nature of the lesions in the database, it appears likely that the large majority were separate solid tumor nodules with the same histologic appearance. Nodules with different histologic features or synchronous primaries were specifically excluded. Furthermore, it is unlikely that many of the addtional nodules were GG/L tumors: most of the primary cancers were larger than 3 cm, the distribution of histotypes was similar to that of lung cancer in general, there was no obvious correlation with geographic regions (i.e., Asia, which seems more recently to have a higher proportion of GG/L tumors), and the incidence of separate tumor nodules before 2007 was similar to what was seen in the IASLC database from 1990 to 2000 (when GG/L tumors were seen rarely). Finally, the OS in the IASLC database is similar to that reported in articles focusing on separate solid tumor nodules with the same histologic appearance.
      An increase in the number and proportion of cases submitted with separate tumor nodules was observed starting in 2007. The IASLC database consists of data from a variety of sources, varying over time. However, such differences do not correlate with the increase in cases. Japan contributed in 1999, 2002, and 2004; the more detailed electronic data capture system accounted for the vast majority of clinical case entries after 2005. It is possible that the publication in 2007
      • Rami-Porta R.
      • Ball D.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for revision of the T descriptors in the forthcoming (7th) edition of the TNM classification of lung cancer.
      • Postmus P.
      • Brambilla E.
      • Chansky K.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer.
      of the proposals for the seventh edition of TNM classification, which drew attention to separate tumor nodules because they changed classification, increased the recognition and reporting of such cases. However, the change in incidence did not correlate with a change in outcomes.
      Evaluation of patient outcomes is an important measure, but it is determined by many factors: the inherent biologic impact of the tumor itself, competing risks (e.g., comorbidities), selection factors (e.g., discovered by symptoms, CXR, screening, risk factors), the type and effectiveness of treatment (e.g., curative intent, palliative), etc. We must be careful not to attribute outcomes primarily to one factor when there is a disparity in other factors. For the purpose of stage classification, inherent biologic impact is the factor of greatest relevance. We have clear evidence that treatment varied according to the location of a separate tumor nodule (almost all same-lobe nodules were resected, whereas almost all other-side nodules were not). We have limited information on other factors in the IASLC database.
      Analysis of the IASLC database (Fig. 1) shows stepwise decreasing OS in c-stage patients according to the location of separate tumor nodules (same-lobe > same-side > other-side). However, the outcomes specifcally in resected or in palliatively treated patients (Figs. 1 and 2) suggest that treatment plays a major role. Furthermore, there are other factors to consider. Incidental nodules were much more common in same-lobe cases; these were presumably smaller and potentially of less biologic impact. The patients with other-side tumor nodules who underwent resection represent a highly selected group whose survival may not be representative of the larger cohort had they been resected as well. We are unable to evaluate the potential impact of such factors.
      Comparison of the results in the IASLC database with the results of a systematic literature review reveals similar outcomes in resected patients with same-lobe and same-side tumor nodules. However, for other-side separate tumor nodules the data are limited, as they are in the IASLC database.
      On basis of the analysis presented herein, the recommendation for TNM classification of separate solid tumor nodules (intrapulmonary metastases) is to maintain the classification of the seventh edition (Table 4). There are many reasons for this recommendation. There is a stepwise decrease in OS in c-stage patients. Data from the current IASLC database are similar to those for the previous (1990–2000) cohort. The survival of patients with separate tumor nodules is not statistically different from that of patients with nodules in corresponding T and M categories in the seventh edition. There is insufficient ability to account for multiple potential confounding factors to define further the inherent biologic impact of the separate nodule itself. A general principle of the SPFC is to not recommend changes unless there is sufficiently robust evidence to indicate that this is appropriate.
      Table 4TNM Classification of Separate Solid Tumor Nodules with the Same Histologic Appearance
      TNM CategoryLocation of Nodule Relative to Primary Tumor
      T3Same lobe
      T4Same side, different lobe
      M1aOther side (different lobe)
      Note: This classification applies to separate solid tumor nodule(s) with the same histologic appearance as that of the primary tumor (either suspected or proven by biopsy/resection). This applies whether or not there are sites of extrathoracic metastases. However, if there are extrathoracic metastases, the tumor is classified as M1b (single site) or M1c (multiple sites). This classification does not apply to tumors judged to be synchronous primary lung cancers, or to multiple tumor nodules with ground glass or lepidic features.
      However, the data do suggest that a separate tumor nodule (in any location, including the contralateral lung) with the same histologic features does not necessarily mean that cure is not possible. The data for resected patients, from both the IASLC database and the published literature, show a substantial number of 5-year survivors, regardless of the location of the separate tumor nodule. Further exploration of this is warranted. At this point, however, the data, particularly for other-side separate tumor nodules, are too limited to be able to define how to select which patients might be appropriate for such an approach.
      The TNM designation described here is intended for separate solid tumor nodules with the same histologic features as those of the primary tumor. It is not to be applied to patients who are thought to have synchronous primary lung cancers or patients with mutliple foci of ground glass/lepidic adenocarcinoma. A better ability to distinguish these groups should help collection of data on specific patients tobetter define their outcomes going forward.

      Conclusion

      The IASLC database included a cohort (∼3%) of patients with separate tumor nodules (intrapulmonary metastases). These appear to be mostly single nodules of the same histologic type with a histotype distribution similar to that of NSCLC in general. Survival decreases progressively by location relative to the primary tumor (same-lobe > same-side > other-side) for c-stage patients. However, survival appears to correlate with the proportion of patients who underwent resection; there is no difference by location between either resected or nonresected cohorts. Other confounding factors, such as the size of separate nodules or whether clinically apparent or incidentally discovered, cannot be fully assessed. Among p-stage patients, survival is similar for same-lobe nodules and other T3 tumors, for same-side (different lobe) nodules and other T4 tumors, and among c-stage patients for other-side nodules and other M1a tumors. Hence, it is proposed that the seventh edition classification of same-lobe nodules as T3, same-side (different lobe) nodules as T4, and other-side nodules as M1a be carried forward. The IASLC data are consistent with reported results garnered from a literature review.

      Acknowledgments

      The work was supported in part by National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748 (Drs. Travis and Rusch).

      Appendix

      IASLC Staging and Prognostic Factors Committee

      Peter Goldstraw, past chair, Royal Brompton Hospital and Imperial College, London, United Kingdom; Ramón Rami-Porta, chair, Hospital Universitari Mutua Terrassa, Terrassa, Spain; Hisao Asamura, chair elect, Keio University, Tokyo, Japan; David Ball, Peter MacCallum Cancer Centre, Melbourne, Australia; David G. Beer, University of Michigan, Ann Arbor, Michigan; Ricardo Beyruti, University of Sao Paulo, Brazil; Vanessa Bolejack, Cancer Research And Biostatistics, Seattle, Washington; Kari Chansky, Cancer Research And Biostatistics, Seattle, Washington; John Crowley, Cancer Research And Biostatistics, Seattle, Washington; Frank Detterbeck, Yale University, New Haven, Connecticut; Wilfried Ernst Erich Eberhardt, West German Cancer Centre, University Hospital, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany; John Edwards, Northern General Hospital, Sheffield, United Kingdom; Françoise Galateau-Sallé, Centre Hospitalier Universitaire, Caen, France; Dorothy Giroux, Cancer Research And Biostatistics, Seattle, Washington; Fergus Gleeson, Churchill Hospital, Oxford, United Kingdom; Patti Groome, Queen’s Cancer Research Institute, Kingston, Ontario, Canada; James Huang, Memorial Sloan-Kettering Cancer Center, New York, New York; Catherine Kennedy, University of Sydney, Sydney, Australia; Jhingook Kim, Samsung Medical Center, Seoul, Korea; Young Tae Kim, Seoul National University, Seoul, Republic of Korea; Laura Kingsbury, Cancer Research And Biostatistics, Seattle, Washington; Haruhiko Kondo, Kyorin University Hospital, Tokyo, Japan; Mark Krasnik, Gentofte Hospital, Copenhagen, Denmark; Kaoru Kubota, Nippon Medical School Hospital, Tokyo, Japan; Antoon Lerut, University Hospitals, Leuven, Belgium; Gustavo Lyons, British Hospital, Buenos Aires, Argentina; Mirella Marino, Regina Elena National Cancer Institute, Rome, Italy; Edith M. Marom, M. D. Anderson Cancer Center, Houston, Texas; Jan van Meerbeeck, Antwerp University Hospital, Edegem (Antwerp), Belgium; Alan Mitchell, Cancer Research And Biostatistics, Seattle, Washington; Takashi Nakano, Hyogo College of Medicine, Hyogo, Japan; Andrew G. Nicholson, Royal Brompton and Harefield National Health Service Foundation Trust and Imperial College, London, United Kingdom; Anna Nowak, University of Western Australia, Perth, Australia; Michael Peake, Glenfield Hospital, Leicester, United Kingdom; Thomas Rice, Cleveland Clinic, Cleveland, Ohio; Kenneth Rosenzweig, Mount Sinai Hospital, New York, New York; Enrico Ruffini, University of Torino, Torino, Italy; Valerie Rusch, Memorial Sloan-Kettering Cancer Center, New York, New York; Nagahiro Saijo, National Cancer Center Hospital East, Chiba, Japan; Paul Van Schil, Antwerp University Hospital, Edegem (Antwerp), Belgium; Jean-Paul Sculier, Institut Jules Bordet, Brussels, Belgium; Lynn Shemanski, Cancer Research And Biostatistics, Seattle, Washington; Kelly Stratton, Cancer Research And Biostatistics, Seattle, Washington; Kenji Suzuki, Juntendo University, Tokyo, Japan; Yuji Tachimori, National Cancer Center, Tokyo, Japan; Charles F. Thomas Jr., Mayo Clinic, Rochester, Minnesota; William Travis, Memorial Sloan-Kettering Cancer Center, New York, New York; Ming S. Tsao, The Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Andrew Turrisi, Sinai Grace Hospital, Detroit, Michigan; Johan Vansteenkiste, University Hospitals, Leuven, Belgium; Hirokazu Watanabe, National Cancer Center Hospital, Tokyo, Japan; Yi-Long Wu, Guangdong Provincial Peoples Hospital, Guangzhou, People’s Republic of China.

      Advisory Board of the IASLC Mesothelioma Domain

      Paul Baas, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Jeremy Erasmus, M. D. Anderson Cancer Center, Houston, Texas; Seiki Hasegawa, Hyogo College of Medicine, Hyogo, Japan; Kouki Inai, Hiroshima University Postgraduate School, Hiroshima, Japan; Kemp Kernstine, City of Hope, Duarte, California; Hedy Kindler, The University of Chicago Medical Center, Chicago, Illinois; Lee Krug, Memorial Sloan-Kettering Cancer Center, New York, New York; Kristiaan Nackaerts, University Hospitals, Leuven, Belgium; Harvey Pass, New York University, New York; David Rice, M. D. Anderson Cancer Center, Houston, Texas.

      Advisory Board of the IASLC Thymic Malignancies Domain

      Conrad Falkson, Queen’s University, Ontario, Canada; Pier Luigi Filosso, University of Torino, Italy; Giuseppe Giaccone, Georgetown University, Washington, District of Columbia; Kazuya Kondo, University of Tokushima, Tokushima, Japan; Marco Lucchi, University of Pisa, Pisa, Italy; Meinoshin Okumura, Osaka University, Osaka, Japan.

      Advisory Board of the IASLC Esophageal Cancer Domain

      Eugene Blackstone, Cleveland Clinic, Cleveland, Ohio.

      Participating Institutions in the New IASLC Lung Cancer Staging Project

      F. Abad Cavaco and E. Ansótegui Barrera, Hospital La Fe, Valencia, Spain; J. Abal Arca and I. Parente Lamelas, Complejo Hospitalario de Ourense, Ourense, Spain; A. Arnau Obrer and R. Guijarro Jorge, Hospital General Universitario de Valencia, Valencia, Spain; D. Ball, Peter MacCallum Cancer Centre, Melbourne, Australia; G. K. Bascom, Good Samaritan Hospital, Kearney, Nebraska; A. I. Blanco Orozco and M. A. González Castro, Hospital Virgen del Rocío, Sevilla, Spain; M. G. Blum, Penrose Cancer Center, Colorado Springs; D. Chimondeguy, Hospital Universitario Austral, Argentina; V. Cvijanovic, Military Medical Academy, Belgrade, Serbia; S. Defranchi, Hospital Universitario-Fundacion Favaloro, Buenos Aires, Argentina; B. de Olaiz Navarro, Hospital de Getafe, Getafe, Spain; I. Escobar Campuzano and I. Macía Vidueira, Hospital de Bellvitge, L’Hospitalet de Llobregat, Spain; E. Fernández Araujo and F. Andreo García, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; K. M. Fong, Prince Charles Hospital, Brisbane, Australia; G. Francisco Corral and S. Cerezo González, Hospital La Mancha Centro, Ciudad Real, Spain; J. Freixinet Gilart, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain; L. García Arangüena, Hospital Sierrallana, Torrelavega, Spain; S. García Barajas, Hospital Infanta Cristina, Badajoz, Spain; P. Girard, L'Institut Mutualiste Montsouris, Paris, France; T. Goksel, Turkish Thoracic Society, Turkey; M. T. González Budiño, Hospital General Universitario de Oviedo, Oviedo, Spain; G. González Casaurrán, Hospital Gregorio Marañón, Madrid, Spain; J. A. Gullón Blanco, Hospital San Agustín, Avilés, Spain; J. Hernández Hernández, Hospital de Ávila, Avila, Spain; H. Hernández Rodríguez, Hospital Universitario de Tenerife, Santa Cruz de Tenerife, Spain; J. Herrero Collantes, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain; M. Iglesias Heras, Hospital de Ávila, Ávila, Spain; J. M. Izquierdo Elena, Hospital Nuestra Señora de Aránzazu, Donostia, Spain; E. Jakobsen, Danish Lung Cancer Registry, Denmark; S. Kostas, Athens School of Medicine, Athens, Greece; P. León Atance and A. Núñez Ares, Complejo Hospitalario de Albacete, Albacete, Spain; M. Liao, Shanghai Lung Tumor Clinical Medical Center, Shanghai, People's Republic of China; M. Losanovscky, Clinica y Maternidad Suizo Argentina, Buenos Aires, Argentina; G. Lyons, Hospital Britanico de Buenos Aires, Buenos Aires, Argentina; R. Magaroles and L. De Esteban Júlvez, Hospital Joan XXIII, Tarragona. Spain; M. Mariñán Gorospe, Hospital de San Pedro de Logroño, Logroño, Spain; B. McCaughan and C. Kennedy, University of Sydney, Sydney, Australia; R. Melchor Íñiguez, Fundación Jiménez Díaz, Madrid, Spain; L. Miravet Sorribes, Hospital La Plana, Castellón, Spain; S. Naranjo Gozalo and C. Álvarez de Arriba, Hospital Universitario Marqués de Valdecilla, Santander, Spain; M. Núñez Delgado, Hospital de Meixoeiro, Vigo, Spain; J. Padilla Alarcón and J. C. Peñalver Cuesta, Instituto Valenciano de Oncología, Valencia, Spain; J. S. Park, Samsung Medical Center, Seoul, Republic of Korea; H. Pass, New York University Langone Medical Center and Cancer Center, New York; M. J. Pavón Fernández, Hospital Severo Ochoa, Leganés, Spain; M. Rosenberg, Alexander Fleming Institute and Hospital de Rehabilitación Respiratoria, Buenos Aires, Argentina; E. Ruffini, University of Torino, Torino, Italy; V. Rusch, Memorial Sloan-Kettering Cancer Center, New York; J. Sánchez de Cos Escuín, Hospital de Cáceres, Cáceres, Spain; A. Saura Vinuesa, Hospital de Sagunto, Sagunto, Spain; M. Serra Mitjans, Hospital Universitari Mutua Terrassa, Terrassa, Spain; T.E. Strand, Cancer Registry of Norway, Norway; D. Subotic, Clinical Centre of Serbia, Belgrade, Serbia; S. Swisher, M. D. Anderson Cancer Center, Houston; R. Terra, University of Sao Paulo Medical Center, Sao Paulo, Brazil; C. Thomas, Mayo Clinic Rochester, Rochester, Minnesota; K. Tournoy, University Hospital Ghent, Belgium; P. Van Schil, Antwerp University Hospital, Edegem (Antwerp), Belgium; M. Velasquez, Fundacion Clinica Valle del Lili, Cali, Colombia; Y. L. Wu, Guangdong General Hospital, Guangzhou, People's Republic of China; K. Yokoi, Japanese Joint Committee for Lung Cancer Registry, Osaka, Japan.

      Multiple Pulmonary Sites of Cancer Workgroup

      Jeremy Erasmus, M. D. Anderson Cancer Center, Houston, Texas; Douglas Flieder, Fox Chase Cancer Center, Philadelphia, PA; Myrna Godoy, M. D. Anderson Cancer Center, Houston, Texas; Jin Mo Goo, Seoul National University College of Medicine, Seoul, Republic of Korea; Lawrence R. Goodman, Medical College of Wisconsin, Milwaukee, Wisconsin; Jim Jett, National Jewish Health System, Denver, Colorado; Paul de Leyn, Catholic University, Leuven, Belgium; Alberto Marchevsky, Cedars Sinai Health System, Los Angeles, California; Heber MacMahon, University of Chicago, Chicago, Illinois; David Naidich, New York University, New York, New York; Morohito Okada, Hiroshima University, Hiroshima, Japan; Marina Perlman, Tel-Aviv University, Ramat Gan, Israel; Charles Powell, Mount Sinai School of Medicine, New York, New York; Paul van Schil, Antwerp University Hospital, Edegem (Antwerp), Belgium; Ming S. Tsao, The Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Arne Warth, University of Heidelberg, Germany.

      Supplementary Data

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