Advertisement

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

Open ArchivePublished:February 29, 2016DOI:https://doi.org/10.1016/j.jtho.2016.01.024

      Abstract

      Introduction

      Patients with lung cancer who harbor multiple pulmonary sites of disease have been challenging to classify; a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee was charged with developing proposals for the eighth edition of the tumor, node, and metastasis (TNM) classification to address this issue.

      Methods

      A systematic literature review and analysis of the International Association for the Study of Lung Cancer database was performed to develop proposals for revision in an iterative process involving multispecialty international input and review.

      Results

      Details of the evidence base are summarized in other articles. Four patterns of disease are recognized; the clinical presentation, pathologic correlates, and biologic behavior of these suggest specific applications of the TNM classification rules. First, it is proposed that second primary lung cancers be designated with a T, N, and M category for each tumor. Second, tumors with a separate tumor nodule of the same histologic type (either suspected or proved) should be classified according to the location of the separate nodule relative to the index tumor—T3 for a same-lobe, T4 for a same-side (different lobe), and M1a for an other-side location—with a single N and M category. Third, multiple tumors with prominent ground glass (imaging) or lepidic (histologic) features should be designated by the T category of the highest T lesion, the number or m in parentheses (#/m) to indicate the multiplicity, and a collective N and M category for all. Finally, it is proposed that diffuse pneumonic-type lung cancers be designated by size (or T3) if in one lobe, T4 if involving multiple same-side lobes, and M1a if involving both lungs with a single N and M category for all areas of involvement.

      Conclusion

      We propose to tailor TNM classification of multiple pulmonary sites of lung cancer to reflect the unique aspects of four different patterns of presentation. We hope that this will lead to more consistent classification and clarity in communication and facilitate further research in the nature and optimal treatment of these entities.

      Keywords

      Introduction

      The seventh edition of the tumor, node, and metastasis (TNM) classification for lung cancer contained some ambiguity with respect to classification of lung cancer with multiple pulmonary sites of involvement. Surveys of experts reveal that there was marked variability in how different people would classify particular tumors,
      • 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.
      thus undermining the primary goal of TNM classification, which is to provide a nomenclature for tumor extent that creates homogeneous cohorts of tumors. Furthermore, the heterogeneity resulting from this variability hampers the ability to interpret research studies.
      Defining homogeneous groups is particularly important among patients with multiple pulmonary sites of lung cancer, as several patterns of presentation are associated with multiple lesions. These exhibit marked differences in biologic behavior, including survival and recurrence patterns. The heterogeneity in classification since the seventh edition of the TNM classification has arisen both from a lack of clear distinction between disease entities and from ambiguity about how to apply stage classification rules to these patients.
      Second primary lung cancers have long been recognized by the TNM system, although little detail was provided regarding how this diagnosis should be established. Separate tumor nodules were classified as M1 until 1993, when they were defined as raising the T category by 1 when in the same lobe as the primary and as T4 if in a different lobe. In 1997 a separate tumor nodule was classified as T4 if in the same lobe and M1 if in a different lobe (ipsilateral or contralateral). In 2010 these were reclassified as T3 for a same-lobe separate nodule (and the term satellite nodule for such lesions was abandoned), as T4 for an ipsilateral different-lobe nodule, and as M1a for a contralateral nodule. Moreover, previous editions of the TNM classification provided little guidance on what constitutes a separate tumor nodule until the seventh edition, in which the language has turned out to be variously interpreted.
      • 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.
      Furthermore, the seventh edition contains only vague mention of ground glass or lepidic lesions, and it predated the 2011 definition of adenocarcinoma subtypes.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma.
      To provide better clarity for the eighth edition of the TNM classification, an international subcommittee of experts conducted a comprehensive review of relevant data. This was used to identify distinct patterns of disease and to develop criteria to categorize lung cancer with multiple pulmonary sites of involvement accordingly. Furthermore, the subcommittee formulated clear instructions on how to apply the TNM classification rules to each pattern of disease, taking into account the particular issues that each one presents. The full scope of this process is detailed in additional articles.
      • Detterbeck F.C.
      • Bolejack V.
      • Arenberg D.A.
      • et al.
      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.
      • 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.
      This article summarizes the recommendations for lung cancer with multiple pulmonary sites of involvement in one document.
      Four patterns of presentation are associated with multiple pulmonary sites of lung cancer (Fig. 1). First, patients can present with second primary lung cancers. The demographic characteristics, outcomes, and recurrence patterns for each tumor are similar to those of single “typical” lung cancers according to the stage and histologic type. Second, some patients with a solid primary lung cancer have one or more separate solid tumor nodule(s) of the same histologic type (referred to as intrapulmonary metastasis in the pathology community). The behavior of these tumors is similar to that of a similar solitary tumor; outcomes are slightly inferior and affected by how they are treated. A third pattern of disease involves patients presenting with multiple lung cancer nodules with prominent ground glass or lepidic (GG/L) features. This group has different demographic characteristics, excellent outcomes, and infrequent recurrences outside the lung parenchyma. A fourth pattern of disease involves a form of lung cancer that is radiologically similar to a pneumonia (so-called pneumonic-type lung cancer). Extrathoracic and nodal involvement is infrequent, but the prognosis is distinctly worse than that for patients with multiple GG/L nodules.
      Figure thumbnail gr1
      Figure 1Representative examples of four patterns of disease that manifest multiple pulmonary sites of lung cancer. (A) Second primary cancers. A patient with two primary lung cancers in the RUL. CT images of each in the left two panels; corresponding microscopic images showing an adenocarcinoma and a squamous carcinoma in the next two panels. Note that most second primary cancers are of the same (not a different) histologic type. (B) Separate tumor nodules. A patient with a separate tumor nodule of the same histotype as the index tumor. The left panels show CT images of each lesion; the right panels show the corresponding microscopic images. (C) Multifocal GG/L lung cancer. A patient with multifocal GG/L tumors in the right upper lobe (who had other GG/L tumors in other lobes). Arrows point to two GG/L tumors on CT in the left two panels; the next two panels show corresponding microscopic images (both were adenocarcinoma with a prominent lepidic component, although with different other adenocarcinoma subtypes). These tumors are classified together as GG/L tumors regardless of such secondary differences. (D) Pneumonic-type lung cancer. A patient with pneumonic-type lung cancer (this patient also had focal sites of disease in the RLL). The left panels show CT images of the RUL and RML with the typical regional areas with a ground glass and consolidative appearance; the next panels show the corresponding microscopic images.
      Adeno, adenocarcinoma; CT, computed tomography; GG/L tumors, tumors with prominent ground glass (imaging) or lepidic (histologic) features; MIA, minimally invasive adenocarcinoma; RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe; Squam, squamous cell carcinoma.

      Methods

      To develop proposals for revision of the classification of lung cancers with multiple pulmonary sites of involvement, an international multidisciplinary subcommittee of the International Association for the Study of Lung Cancer (IASLC) Staging and Prognostic Factors Committee (SPFC) was formed. This group (i.e., the authors of this article) conducted a comprehensive review of the relevant literature. Details of this process and results are provided in a series of review articles
      • Detterbeck F.C.
      • Bolejack V.
      • Arenberg D.A.
      • et al.
      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.
      • 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.
      ; a summary of these data is provided in the next section of this article. In addition, the IASLC database from 1999 to 2010 was analyzed regarding separate tumor nodules (this was the only pattern of disease for which there were sufficient data in the database). This evidence was then used in an iterative process to develop recommendations. These documents were critically evaluated by an extended workgroup (see the Appendix), in addition to review and eventual endorsement by the entire SPFC.

      Results

      Brief Summary of Evidence Review

      Second Primary Lung Cancers

      A different histologic type is generally sufficient to establish two malignant pulmonary lesions as separate primary cancers, provided that adequate tissue is available. Similarly, different appearance by a detailed histologic assessment (proportion of subtypes, grade, cytologic and stromal features, etc.) of resected specimens can establish tumors as second primary cancers. However, the same (or predominant) histologic type does not by itself clearly establish that the lesions are manifestations of the same tumor. Historical studies, clonality studies, and outcomes studies indicate that the large majority of second cancers of the same histologic type are likely to be second primary lung cancers.
      • 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.
      Similarly, the same morphologic appearance by a more detailed histologic assessment as already noted should not be taken by itself as clear evidence that two lesions are manifestations of the same tumor; it is only suggestive that two lesions may be related.
      • 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.
      Assessment of biomarkers (driver gene mutations) is only suggestive, as there is a substantial rate of discordance among different samples of the same tumor and concordance among clearly separate tumors.
      • 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.
      Thus, mutational profiling should not be considered definitive and must be considered together with other information. More detailed genetic assessments (comparative genomic hybridization, Next-Gen sequencing) are promising but not sufficiently studied or standardized, and are they complex to use in routine clinical practice.
      • 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.

      Separate Tumor Nodules (Intrapulmonary Metastasis)

      The IASLC database for the seventh (1990–1999) and eighth (1999–2010) editions each included a small proportion of patients who were recorded as having a separate malignant nodule (2.5% and 3.5%, respectively).
      • Goldstraw P.
      • Crowley J.
      • Chansky K.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of Malignant Tumours.
      • Goldstraw P.
      • Chansky K.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revision of the stage groupings in the forthcoming (eighth) edition of the TNM Classification of Lung Cancer.
      It appears that these patients primarily fit a pattern of disease consisting of a typical primary lung cancer (i.e., a solid mass) with a separate solid tumor nodule of the same histologic type (rarely more than one). The outcomes of these patients in the IASLC database analysis were consistent with those gathered in a systematic literature review.
      • Detterbeck F.C.
      • Bolejack V.
      • Arenberg D.A.
      • et al.
      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.
      Among clinically staged patients, overall survival (OS) decreased progressively by location of the separate tumor nodule relative to the primary tumor (same lobe > same lung [different lobe] > other lung),
      • Detterbeck F.C.
      • Bolejack V.
      • Arenberg D.A.
      • et al.
      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.
      which is consistent with the analysis for the seventh edition. However, OS seems to have been primarily affected by the treatment given; there was no difference in OS by separate tumor nodule location among only surgically managed patients or among nonsurgically managed patients. Other confounding factors include varying proportions of incidentally discovered nodules (not identified preoperatively) and selection factors leading some patients to be managed surgically and others nonsurgically. Because of an inability to separate the influence of these various factors, the TNM classification of the seventh edition for separate tumor nodules was maintained.

      Multifocal Lung Adenocarcinoma with Ground Glass/Lepidic Features

      An increasing number of patients with lung cancer are being encountered who have multiple subsolid nodules (either pure ground glass or part solid) on computed tomography (CT) examination. The pathologic correlates of this appearance are lepidic-predominant adenocarcinoma (LPA), minimally invasive adenocarcinoma (MIA), or adenocarcinoma in situ (AIS) with or without other subtypes of adenocarcinoma as lesser components.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma.
      The ground glass and solid components seen by CT generally correspond to lepidic and invasive histologic patterns, respectively. The nature of these lesions and their relationship to one another are not yet fully understood; they are viewed as separate tumors with an in situ or invasive component that has arisen from a predominant noninvasive component. The results of clonality studies comparing multiple such tumors in the same patient are conflicting.
      • 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.
      The patients with such lung adenocarcinomas that present as multiple nodules with ground glass features have a decreased propensity for nodal or systemic spread and an increased propensity to the development of additional subsolid cancers.
      • 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.
      Furthermore, they often exhibit a more indolent behavior.
      • 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.
      There are often numerous additional GG/L foci, and the patients are often women and nonsmokers. These lesions are easy to recognize clinically (by CT imaging) and pathologically (by a prominent lepidic component). Thus, this pattern of disease has many distinct features.

      Pneumonic-Type Lung Adenocarcinoma

      A subset of patients exhibits a diffuse consolidative pattern (a “pneumonic type” of lung adenocarcinoma) without proximal bronchial obstruction.
      • Wislez M.
      • Massiani M.-A.
      • Milleron B.
      • et al.
      Clinical characteristics of pneumonic-type adenocarcinoma of the lung.
      • Akira M.
      • Atagi S.
      • Kawahara M.
      • Iuchi K.
      • Johkoh T.
      High-resolution CT findings of diffuse bronchioloalveolar carcinoma in 38 patients.
      • Battafarano R.J.
      • Meyers B.F.
      • Guthrie T.J.
      • Cooper J.D.
      • Patterson G.A.
      Surgical resection of multifocal non-small cell lung cancer is associated with prolonged survival.
      There are typically areas of ground glass as well as solid consolidation. This pattern of clinical presentation typically correlates with invasive mucinous adenocarcinoma,
      which characteristically shows a goblet and/or columnar cell morphologic pattern with abundant intracytoplasmic mucin. Although invasive mucinous adenocarcinoma often shows lepidic-predominant growth, extensive sampling usually reveals invasive foci, sometimes with desmoplastic stroma. Invasive mucinous adenocarcinoma may show a heterogeneous mixture of adenocarcinoma subtypes. Surrounding alveolar spaces often fill with mucin. This heterogeneous histologic appearance is frequently similar throughout areas of involvement in a particular patient. A detailed study of a patient with diffuse pneumonic adenocarcinoma suggested different clonality in each of the five lobes examined
      • Nanki N.
      • Fujita J.
      • Hojo S.
      • et al.
      Evaluation of the clonality of multilobar bronchioloalveolar carcinoma of the lung.
      ; how to interpret this case is controversial. Most of these patients have an invasive mucinous adenocarcinoma, the rest have mixed or nonmucinous adenocarcinomas.
      • 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.
      These patients typically present without nodal or systemic metastases despite diffuse pulmonary involvement; the occasional use of double-lung transplantation as a treatment underscores this.
      • Barlesi F.
      • Doddoli C.
      • Gimenez C.
      • et al.
      Bronchioloalveolar carcinoma: myths and realities in the surgical management.
      • de Perrot M.
      • Chernenko S.
      • Waddell T.K.
      • et al.
      Role of lung transplantation in the treatment of bronchogenic carcinomas for patients with end-stage pulmonary disease.
      • Ahmad U.
      • Wang Z.
      • Bryant A.S.
      • et al.
      Outcomes for lung transplantation for lung cancer in the United Network for Organ Sharing Registry.
      Although the rate of progression is often slow, survival is markedly worse than for patients with GG/L tumors. Thus, although there are some similarities between the multiple GG/L pattern of disease and the pneumonic pattern of disease (e.g., ground glass and lepidic components, decreased propensity for nodal and systemic involvement), there are sufficient differences to consider this a distinct pattern of disease.

      Recommendations for Second Primary Lung Cancers

      Description

      The criteria to identify two tumor foci as either separate primary tumors or related (i.e., arising from a single source) are summarized in Table 1. Some criteria are generally definitive by themselves, whereas others are suggestive but must be considered together with all available information. The relative weight to give to a particular suggestive observation will depend on several factors such as the degree of similarity or difference, the reliability of the assessment, and what data are available (e.g., the extent of prior imaging available, amount of tissue available–i.e. a limited biopsy or resection specimen). It is easier to define criteria that identify two malignancies as separate than to define criteria that conclusively establish that the tumors are identical. Ideally, a decision to classify two (or more) lesions as synchronous primary cancers or two identical foci of a single cancer should be based on the judgment of an experienced multidisciplinary team, taking into account all factors (e.g., clinical, imaging, histologic, etc.).
      Table 1Criteria to Distinguish Second Primary versus Related Tumors
      Clinical criteria
      A comprehensive histologic assessment is not included in clinical staging, as it requires that the entire specimen has been resected.
      Tumors may be considered second primary tumors if
       They are clearly of a different histologic type (e.g., squamous carcinoma and adenocarcinoma) by biopsy.
      Tumors may be considered to be arising from a single tumor source if
       Exactly matching breakpoints are identified by comparative genomic hybridization.
      Relative arguments that favor separate tumors
       Different radiographic appearance or metabolic uptake
       Different biomarker pattern (driver gene mutations)
       Different rates of growth (if previous imaging is available)
       Absence of nodal or systemic metastases
      Relative arguments that favor a single tumor source
       Same radiographic appearance
       Similar growth patterns (if previous imaging is available)
       Significant nodal or systemic metastases
       Same biomarker pattern (and same histotype)
      Pathologic criteria (i.e., after resection)
      Tumors may be considered second primary tumors if
       They are clearly of a different histologic type (e.g., squamous carcinoma and adenocarcinoma).
       They are clearly different by a comprehensive histologic assessment.
       They are squamous carcinomas that have arisen from carcinoma in situ.
      Tumors may be considered to be arising from a single tumor source if
       Exactly matching breakpoints are identified by comparative genomic hybridization.
      Relative arguments that favor separate tumors (to be considered together with clinical factors)
       Different biomarker pattern
       Absence of nodal or systemic metastases
      Relative arguments that favor a single tumor source (to be considered together with clinical factors)
       Matching appearance on comprehensive histologic assessment
       Same biomarker pattern
       Significant nodal or systemic metastases
      a A comprehensive histologic assessment is not included in clinical staging, as it requires that the entire specimen has been resected.

      Proposed TNM Classification

      Two (or more) synchronous primary lung cancers should be classified separately, each with a T, N, and M descriptor (i.e., a T, N, and M for one tumor and another T, N, and M for the other tumor). For example, a patient with a 2.2-cm squamous cell cancer in the right upper lobe, a 3.5-cm adenocarcinoma in the left upper lobe with adenocarcinoma in a L11 node that was discovered by endobronchial ultrasound aspiration, and no other evidence of nodal or systemic metastases should be classified as having a T1c N0 M0 squamous cell cancer and a T2a N1 M0 adenocarcinoma.
      This TNM classification of tumors judged to be second primary lung cancers should be applied to both synchronous and be used metachronous second primary lung cancers, and be used whether the two primary tumors are in different lungs, different lobes, or in the same lobe. Furthermore, this classification should be applied to synchronous primary lung cancers recognized clinically or grossly as well as to those recognized only on pathologic examination.

      Recommendations for Separate Tumor Nodule (Intrapulmonary Metastasis)

      Description

      Patients should be classified as having separate tumor nodule(s) when there is a “classic” lung cancer (i.e., solid, spiculated) and one (or more) solid separate lung nodules, either presumed (clinical staging) or proved (pathologic staging after comprehensive histologic assessment) to be metastatic from the primary lung cancer; the criteria are summarized in Table 2. Typically there is one additional nodule, although there may be more than one.
      Table 2Criteria to Categorize a Lesion as a Separate Tumor Nodule (Intrapulmonary Metastasis)
      Clinical criteria
      Tumors should be considered to have a separate tumor nodule(s) if
       There is a solid lung cancer and a separate tumor nodule(s) with a similar solid appearance and with (presumed) matching histologic appearance.
      • This applies whether or not a biopsy has been performed on the lesions, provided that there is strong suspicion that the lesions are histologically identical.
      • This applies whether or not there are sites of extrathoracic metastases.
      AND provided that
       The lesions are NOT judged to be synchronous primary lung cancers.
       The lesions are NOT multifocal GG/L lung cancer (multiple nodules with ground glass/lepidic features) or pneumonic-type lung cancer.
      Pathologic criteria
      Tumors should be considered to have a separate tumor nodule (intrapulmonary metastasis) if
       There is a separate tumor nodule(s) of cancer in the lung with a similar histologic appearance to a primary lung cancer.
      AND provided that
       The lesions are NOT judged to be synchronous primary lung cancers.
       The lesions are NOT multiple foci of LPA, MIA, or AIS.
      Note: A radiographically solid appearance and the specific histologic subtype of solid adenocarcinoma denote different things.
      AIS, adenocarcinoma in situ; GG/L, ground glass/lepidic; LPA, lepidic-predominant adenocarcinoma; MIA, minimally invasive adenocarcinoma.
      However, the designation of separate tumor nodule(s) should not be used if it is judged that the patient has synchronous primary lung cancers (as defined in the previous section). Furthermore, the designation of separate tumor nodule(s) should not be used in patients with multifocal GG/L lung adenocarcinoma (multiple nodules with ground glass features or multiple foci of LPA, MIA, AIS [see the next section]).

      Proposed TNM Classification

      The TNM classification of a separate tumor nodule(s) (of the same histologic type) is assigned on the basis of location of the nodule relative to the primary tumor site. If it is in the same lobe, the tumor is designated as T3; if in the same lung (different lobe), as T4; and if in the contralateral lung, as M1a.
      • Detterbeck F.C.
      • Bolejack V.
      • Arenberg D.A.
      • et al.
      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.
      This applies regardless of whether there is involvement of nodal sites or distant (extrathoracic) sites. In other words, such separate tumor nodules in the lung determine the T category even when there are many sites of extrathoracic metastases (but the tumor would be classified as M1b or M1c because of the extrathoracic metastases). Finally, this classification should be applied to separate tumor nodules recognized clinically or grossly as well as to those recognized only on pathologic examination.

      Recommendations for Multifocal Lung Adenocarcinoma with Ground Glass/Lepidic Features

      Description

      Patients with this pattern of disease present with multiple subsolid tumor nodules (either pure ground glass nodule [GGN] or a part-solid nodule). A GGN is a focal nodular area of increased lung attenuation on CT, including both well-defined and poorly defined lesions, through which normal parenchymal structures, including airways and vessels, can be visualized.
      • Naidich D.P.
      • Bankier A.A.
      • MacMahon H.
      • et al.
      Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society.
      A subsolid nodule can be either purely ground glass or a part-solid nodule (usually still >50% ground glass but with a solid component). (Note that a radiographically solid appearance and the specific histologic subtype of solid adenocarcinoma denote different things.
      )
      Tumors should be categorized as multifocal lung adenocarcinoma if there is a malignant subsolid nodule (either suspected or proved) and other nodules with ground glass features, regardless of whether a biopsy has been performed on the other lesions, and if a biopsy has been performed, regardless of whether they are shown to be LPA, MIA, or AIS (Table 3).
      • 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.
      Frequently, multifocal patients with lung adenocarcinoma have three to 10 (or more) nodules. This categorization should also apply to patients in whom a subsolid lesion appears to have arisen from a GGN (or a lepidic background) but in whom the lesions have become more than 50% solid (or invasive), provided that other nodules with ground glass features are present as well.
      Table 3Criteria to Categorize a Tumor as Multifocal GG/L Adenocarcinoma
      Clinical criteria
      Tumors should be considered multifocal GG/L lung adenocarcinoma if
       There are multiple subsolid nodules (either pure ground glass or part solid), with at least one suspected (or proved) to be cancer.
      • This applies whether or not a biopsy has been performed of the nodules.
      • This applies if the other nodules(s) are suspected to be AIS, MIA, or LPA.
      • This applies if a nodule has become >50% solid but is judged to have arisen from a GGN, provided that there are other subsolid nodules.
      • GGN lesions <5mm or lesions suspected to be AAH are not counted.
      Pathologic criteria
      Tumors should be considered multifocal GG/L lung adenocarcinoma if
       There are multiple foci of LPA, MIA, or AIS.
      • This applies whether a detailed histologic assessment (i.e., proportion of subtypes, etc.) shows a matching or different appearance.
      • This applies if one lesion(s) is LPA, MIA, or AIS and there are other subsolid nodules of which a biopsy has not been performed.
      • This applies whether the nodule(s) are identified preoperatively or only on pathologic examination.
      • Foci of AAH are not counted.
      Note: A radiographically solid appearance and the specific histologic subtype of solid adenocarcinoma denote different things.
      AAH, atypical adenomatous hyperplasia; AIS, adenocarcinoma in situ; GG/L, ground glass/lepidic; LPA, lepidic-predominant adenocarcinoma; MIA, minimally invasive adenocarcinoma.
      Multifocal lung cancer is essentially seen only as a manifestation of adenocarcinoma. The pathologic designation of multifocal lung cancer should be used when there are multiple resected lesions that are either LPA, MIA, or AIS with or without other subtypes of adenocarcinoma as lesser components. It is appropriate to combine pathologic identification of one focus of LPA, MIA, or AIS with clinical information indicating that there are other, nonresected subsolid nodules (e.g., in other lobes). The GG/L category should be used whether a detailed histologic assessment (i.e., proportion of subtypes, etc.) shows the lesions to have a matching appearance or to be different.
      The multifocal GG/L lung adenocarcinoma designation should not be applied to patients with multiple GGNs that are thought to all represent benign or preneoplastic lesions (i.e., atypical adenomatous hyperplasia). Pure 5-mm or smaller GGNs and foci of atypical adenomatous hyperplasia should not be counted, although such lesions are often present in patients with multifocal GG/L adenocarcinoma.

      Proposed TNM Classification

      Multifocal GG/L adenocarcinoma should be classified by the T category of the lesion with the highest T along with the number of lesions (#) or simply (m) for multiple indicated in parentheses, and an N and M category that applies to all of the multiple tumor foci collectively—for example, T1a(4) N0 M0. The apparent decreased propensity for nodal and distant metastases and increased propensity for additional lung lesions supports the concept of a single N and M for all of the pulmonary lesions. The lesion size is determined by the largest diameter of the solid component (by CT) or the invasive component (under a microscope); a designation of Tis should be used for AIS and T1a(mi) for MIA.

      Travis D, Asamura H, Bankier AA, et al. The IASLC Lung Cancer Staging Project: proposals for coding T categories for adenocarcinoma in situ and minimally invasive adenocarcinoma, and for measurement of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM Classification of Lung Cancer. J Thorac Oncol, in press.

      The T(#/m) multifocal classification should be applied equally whether the lesions are in the same lobe or in different ipsilateral or contralateral lobes. Furthermore, the T(#/m) multifocal classification should be applied to both grossly recognizable lesions and to those that are discovered only on pathologic examination (microscopically or otherwise).

      Recommendations for Diffuse Pneumonic-Type Lung Adenocarcinoma

      Description

      The category pneumonic-type lung adenocarcinoma refers to tumors with a consolidative pattern by CT (in the absence of an obstructed bronchus), either confined to a particular area (segment or lobe) or diffusely in the lung parenchyma (Table 4). The parenchymal borders of the tumor are infiltrative and typically not well demarcated. The tumor may be confined to one region (e.g., segment, lobe), involve several regions (either confluent or separated), or diffusely involve both lungs. The involved areas typically are a mixture of ground glass and dense consolidation, with frequent air bronchograms radiologically and lepidic and invasive foci microscopically. Most pneumonic-type lung cancers are invasive mucinous adenocarcinomas, the rest are either nonmucinous or mixed mucinous and nonmucinous tumors.
      Table 4Criteria to Categorize a Tumor as a Pneumonic-Type Adenocarcinoma
      Clinical criteria
      Tumors should be considered pneumonic-type adenocarcinoma if
       The cancer manifests in a regional distribution, similar to a pneumonic infiltrate or consolidation.
      • This applies whether there is one confluent area or multiple regions of disease. The region(s) may be confined to one lobe, in multiple lobes, or bilateral, but it should involve a regional pattern of distribution.
      • The appearance of involved areas may be ground glass, solid consolidation, or a combination thereof.
      • This can be applied when there is compelling suspicion of malignancy whether or not a biopsy has been performed of the area(s).
      • This should not be applied to discrete nodules (i.e., GG/L nodules).
      • This should not be applied to tumors causing bronchial obstruction with resultant obstructive pneumonia or atelectasis.
      Pathologic criteria
      Tumors should be considered pneumonic-type adenocarcinoma if
       There is diffuse distribution of adenocarcinoma throughout a region(s) of the lung, as opposed to a single well-demarcated mass or multiple discrete well-demarcated nodules.
      • This typically involves an invasive mucinous adenocarcinoma, although a mixed mucinous and nonmucinous pattern may occur.
      • The tumor may show a heterogeneous mixture of acinar, papillary, and micropapillary growth patterns, although it is usually lepidic predominant.
      Note: A radiographically solid appearance and the specific histologic subtype of solid adenocarcinoma denote different things.
      GG/L, ground glass/lepidic.

      Proposed TNM Classification

      In the case of pneumonic-type adenocarcinoma with a single area of tumor, it is straightforward to apply the TNM classification as described for lung cancer in general (e.g., the T category determined by size, and N and M determined by nodal or extrathoracic involvement).
      • Goldstraw P.
      • Chansky K.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revision of the stage groupings in the forthcoming (eighth) edition of the TNM Classification of Lung Cancer.
      • 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.
      In the case of multiple pulmonary sites of involvement, the T or M category should be determined by the location of the areas of involvement: T3 if confined to one lobe, T4 if involving different lobes in one lung, and M1a if involving both lungs. If the tumor involves both lungs, the T category should be designated according to the appropriate T category for the side with the greatest amount of tumor (i.e., size or T3 if in one lobe, T4 if in more than one lobe on that side). Because size may be difficult to determine, when the area of involvement extends into an adjacent lobe (as well as a discrete separate area of involvement in an adjacent lobe) the T4 designation should be applied (recognizing extension into another lobe). If the involvement is confined to a single lobe but hard to measure, a designation of T3 should be used. The appropriate N category that applies to all pulmonary sites of the primary tumor collectively is chosen; pleural/pericardial tumor nodules or distant metastases will lead to an M1a, M1b, or M1c designation. The classification should be applied to both grossly recognizable lesions and to those that are discovered only on histologic examination. A detailed histologic assessment to determine whether various areas are exactly matching is not required for pneumonic-type lung cancer.
      We propose that the schema for application of TNM classification described for pneumonic-type adenocarcinoma also be used for miliary forms of adenocarcinoma. Because size of miliary involvement is inherently difficult to determine, miliary involvement in a single lobe should be classified as T3 without regard to size.

      Discussion

      This article summarizes proposals for the eighth edition of the TNM classification of malignant tumors for patients with lung cancer who present with multiple pulmonary sites of involvement (Table 5). Classification of these tumors can be challenging; the goal was to provide definitions with sufficient clarity to lead to consistent classification. The development of these proposals was conducted by a specific subcommittee of the IASLC SPFC according to a formal process involving a systematic review of the relevant literature and an analysis of the IASLC database.
      Table 5Schematic Summary of Patterns of Disease and TNM Classification of Patients with Lung Cancer with Multiple Pulmonary Sites of Involvement
      Second Primary Lung CancerMultifocal GG/L NodulesPneumonic-Type AdenocarcinomaSeparate Tumor Nodule
      Imaging featuresTwo or more distinct masses with imaging characteristic of lung cancer (e.g., spiculated)Multiple ground glass or part-solid nodulesPatchy areas of ground glass and consolidationTypical lung cancer (e.g., solid, spiculated) with separate solid nodule
      Pathologic featuresDifferent histotype or different morphologic features by comprehensive histologic assessmentAdenocarcinomas with prominent lepidic component (typically varying degrees of AIS, MIA, LPA)Same histologic features throughout (most often invasive mucinous adenocarcinoma)Distinct masses with the same morphologic features by comprehensive histologic assessment
      TNM classificationSeparate cTNM and pTNM for each cancerT based on highest T lesion with (#/m) indicating multiplicity; single N and MT based on size or T3 if in single lobe, T4 or M1a if in different ipsilateral or contralateral lobes; single N and MLocation of separate nodule relative to primary site determines if T3, T4, or M1a; single N and M
      Conceptual viewUnrelated tumorsSeparate tumors, albeit with similaritiesSingle tumor, diffuse pulmonary involvementSingle tumor, with intrapulmonary metastasis
      AIS, adenocarcinoma in situ; c, clinical; GG/L, ground glass/lepidic; LPA, lepidic-predominant adenocarcinoma; MIA, minimally invasive adenocarcinoma; p, pathological; TNM, tumor, node, and metastasis.
      Although a brief summary of background evidence is provided, full details are beyond the scope of this article. A systematic review of the literature regarding the definition of second primary lung cancer, outcomes for separate tumor nodules (intrapulmonary metastases), multifocal GG/L lung adenocarcinoma, and pneumonic-type adenocarcinoma, as well as an analysis of the IASLC database, are provided in other articles.
      • Detterbeck F.C.
      • Bolejack V.
      • Arenberg D.A.
      • et al.
      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.
      • 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.
      This evidence informed the proposed criteria for patterns of disease that manifest multiple pulmonary sites of lung cancer and the application of the stage classification system described in this article.
      A system of nomenclature to classify anatomic tumor extent cannot be equated to a treatment guideline. Nomenclature can facilitate the discussion of how to treat patients, but patient management is defined by studies specifically focused on particular patients, particular treatments, and the efficacy thereof. Furthermore, the impact of attitudes toward treatment and the prevalence of particular treatment approaches should not be confused with a prognostic impact that is inherent to a tumor characteristic. For example, separate contralateral tumor nodule(s) have been reported to have a poor prognosis. However, almost all of these patients have been managed nonoperatively (i.e., palliatively), although good outcomes are reported after resection (in limited data). Hence, the general prognosis may be more reflective of the attitude toward treatment than an inherent prognostic implication of such nodules per se.
      • Detterbeck F.C.
      • Bolejack V.
      • Arenberg D.A.
      • et al.
      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.
      Historically, classification of (and management of patients with) multiple pulmonary sites of lung cancer has been based on speculation primarily about how physical translocation of a malignant cell from one site to another might occur. However, there are now extensive data indicating that the process of metastasis is highly complex, influenced not only by tumor cell–intrinsic genetic and epigenetic determinants but also a complex array of tumor-host interactions at both the primary and metastatic sites.
      • 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.
      • Valastyan S.
      • Weinberg R.A.
      Tumor metastasis: molecular insights and evolving paradigms.
      • Weinberg R.A.
      Mechanisms of malignant progression.
      • Wan L.
      • Pantel K.
      • Kang Y.
      Tumor metastasis: moving new biological insights into the clinic.
      Tumor cells transform to mesenchymal cells and back again during the process of metastasis; they exist in various states and in permissive niches, and there is a complex bidirectional migration between primary, metastatic, and other sites. This is governed by multiple pathways, cell signaling, and microenvironment characteristics.
      • 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.
      • Valastyan S.
      • Weinberg R.A.
      Tumor metastasis: molecular insights and evolving paradigms.
      • Weinberg R.A.
      Mechanisms of malignant progression.
      • Wan L.
      • Pantel K.
      • Kang Y.
      Tumor metastasis: moving new biological insights into the clinic.
      Thus, speculative rationale based on routes of physical translocation of tumor cells is refuted by extensive evidence. Terms such as lymphatic spread and hematogenous spread are based on oversimplified concepts and should not dictate classification or treatment of patients; furthermore, they hamper consideration of the true determinants of metastasis.
      Classification inherently involves drawing a line of separation, and there are always borderline zones in which the distinction becomes difficult. Furthermore, there will always be patients with unusual presentations that defy classification. We acknowledge these facts but hope that the structure provided will allow the large majority of patients to be classified easily and consistently and that the guidance provided makes a “best judgment” classification easier in the particularly difficult cases.

      Conclusion

      This article describes proposed definitions to classify tumors in patients who present with more than one pulmonary site of lung cancer for the eighth edition of the TNM classification. We distinguish several patterns of disease that exhibit multiple pulmonary sites of lung cancer. These are associated with different biologic behavior; defining homogeneous cohorts of tumors requires both clarity about these categories and consistent application of TNM classification rules. Specifically, these patterns of disease involve patients with synchronous primary lung cancers, those with a separate solid tumor nodule(s) (intrapulmonary metastases), multifocal lung cancer presenting as multiple nodules with ground glass/lepidic features, and diffuse pneumonic-type adenocarcinoma. Synchronous primary cancers are classified with a T, N, and M category for each tumor; separate tumor nodules result in a T3, T4, or M1a category depending on the separate nodule's location relative to the primary tumor; multifocal GG/L tumors are classified by the highest T lesion, with the number or m for multiple in parentheses (#/m) and an N and M category for all tumor nodules collectively; and for pneumonic-type adenocarcinoma the T component is classified by size or as T3 if in one lobe, as T4 if in two ipsilateral lobes, and M1a if contralateral, with a single N and M category for all sites of pulmonary involvement collectively. These proposals are based on a systematic review of relevant literature, extensive deliberations of an international multidisciplinary expert panel, and several additional levels of review. We hope that this leads to greater ease and consistency in classification of these tumors, while recognizing that there will always be areas of difficulty and tumors that are challenging to classify. We also recognize that the system will need to be refined as further knowledge is gained.

      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, Republic of 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 NHS 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, Colorado; 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, 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, 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, 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, Texas; 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 Republich 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, Pennsylvania; 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.

      References

        • Fonseca A.
        • Detterbeck F.C.
        How many names for a rose: inconsistent classification of multiple foci of lung cancer due to ambiguous rules.
        Lung Cancer. 2014; 85: 7-11
        • Homer R.
        Pathologists' staging of multiple foci of lung cancer.
        Am J Clin Pathol. 2015; 143: 701-706
        • Travis W.D.
        • Brambilla E.
        • Noguchi M.
        • et al.
        International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma.
        J Thorac Oncol. 2011; 6: 244-285
      1. Travis W.D. Brambilla E. Burke A.P. Marx A. Nicholson A.G. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. IARC Press, Lyon, France2015
        • Detterbeck F.C.
        • Bolejack V.
        • Arenberg D.A.
        • et al.
        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.
        J Thorac Oncol. 2016; 11: 681-692
        • 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.
        J Thorac Oncol. 2016; 11: 651-655
        • 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.
        J Thorac Oncol. 2016; 11: 666-680
        • Goldstraw P.
        • Crowley J.
        • Chansky K.
        • et al.
        The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of Malignant Tumours.
        J Thorac Oncol. 2007; 2: 706-714
        • Goldstraw P.
        • Chansky K.
        • Crowley J.
        • et al.
        The IASLC Lung Cancer Staging Project: proposals for the revision of the stage groupings in the forthcoming (eighth) edition of the TNM Classification of Lung Cancer.
        J Thorac Oncol. 2016; 11: 39-51
        • Wislez M.
        • Massiani M.-A.
        • Milleron B.
        • et al.
        Clinical characteristics of pneumonic-type adenocarcinoma of the lung.
        Chest. 2003; 123: 1868-1877
        • Akira M.
        • Atagi S.
        • Kawahara M.
        • Iuchi K.
        • Johkoh T.
        High-resolution CT findings of diffuse bronchioloalveolar carcinoma in 38 patients.
        Am J Roentgenol. 1999; 173: 1623-1629
        • Battafarano R.J.
        • Meyers B.F.
        • Guthrie T.J.
        • Cooper J.D.
        • Patterson G.A.
        Surgical resection of multifocal non-small cell lung cancer is associated with prolonged survival.
        Ann Thorac Surg. 2002; 74: 988-994
        • Nanki N.
        • Fujita J.
        • Hojo S.
        • et al.
        Evaluation of the clonality of multilobar bronchioloalveolar carcinoma of the lung.
        Am J Clin Oncol. 2002; 25: 291-295
        • Barlesi F.
        • Doddoli C.
        • Gimenez C.
        • et al.
        Bronchioloalveolar carcinoma: myths and realities in the surgical management.
        Eur J Cardiothorac Surg. 2003; 24: 159-164
        • de Perrot M.
        • Chernenko S.
        • Waddell T.K.
        • et al.
        Role of lung transplantation in the treatment of bronchogenic carcinomas for patients with end-stage pulmonary disease.
        J Clin Oncol. 2004; 22: 4351-4356
        • Ahmad U.
        • Wang Z.
        • Bryant A.S.
        • et al.
        Outcomes for lung transplantation for lung cancer in the United Network for Organ Sharing Registry.
        Ann Thorac Surg. 2012; 94: 935-941
        • Naidich D.P.
        • Bankier A.A.
        • MacMahon H.
        • et al.
        Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society.
        Radiology. 2013; 266: 304-317
      2. Travis D, Asamura H, Bankier AA, et al. The IASLC Lung Cancer Staging Project: proposals for coding T categories for adenocarcinoma in situ and minimally invasive adenocarcinoma, and for measurement of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM Classification of Lung Cancer. J Thorac Oncol, in press.

        • 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.
        J Thorac Oncol. 2015; 10: 990-1003
        • Valastyan S.
        • Weinberg R.A.
        Tumor metastasis: molecular insights and evolving paradigms.
        Cell. 2011; 47: 275-292
        • Weinberg R.A.
        Mechanisms of malignant progression.
        Carcinogenesis. 2008; 29: 1092-1095
        • Wan L.
        • Pantel K.
        • Kang Y.
        Tumor metastasis: moving new biological insights into the clinic.
        Nat Med. 2013; 19: 1450-1464