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The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer

Open ArchivePublished:April 20, 2016DOI:https://doi.org/10.1016/j.jtho.2016.03.025

      Abstract

      This article proposes codes for the primary tumor categories of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) and a uniform way to measure tumor size in part-solid tumors for the eighth edition of the tumor, node, and metastasis classification of lung cancer. In 2011, new entities of AIS, MIA, and lepidic predominant adenocarcinoma were defined, and they were later incorporated into the 2015 World Health Organization classification of lung cancer. To fit these entities into the T component of the staging system, the Tis category is proposed for AIS, with Tis (AIS) specified if it is to be distinguished from squamous cell carcinoma in situ (SCIS), which is to be designated Tis (SCIS). We also propose that MIA be classified as T1mi. Furthermore, the use of the invasive size for T descriptor size follows a recommendation made in three editions of the Union for International Cancer Control tumor, node, and metastasis supplement since 2003. For tumor size, the greatest dimension should be reported both clinically and pathologically. In nonmucinous lung adenocarcinomas, the computed tomography (CT) findings of ground glass versus solid opacities tend to correspond respectively to lepidic versus invasive patterns seen pathologically. However, this correlation is not absolute; so when CT features suggest nonmucinous AIS, MIA, and lepidic predominant adenocarcinoma, the suspected diagnosis and clinical staging should be regarded as a preliminary assessment that is subject to revision after pathologic evaluation of resected specimens. The ability to predict invasive versus noninvasive size on the basis of solid versus ground glass components is not applicable to mucinous AIS, MIA, or invasive mucinous adenocarcinomas because they generally show solid nodules or consolidation on CT.

      Keywords

      Introduction

      This article addresses fundamental changes in pathologic and clinical classification of lung adenocarcinoma with an impact on the upcoming revision of the tumor, node, and metastasis (TNM) classification of lung cancer, specifically, proposals for revision of the T categories. Until the 2011 International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) lung adenocarcinoma classification, the World Health Organization (WHO) classification of lung cancer recognized only an in situ (Tis) category for squamous cell carcinoma.
      As squamous cell carcinoma in situ (SCIS) is not readily measurable for tumor size, this concept had no implication for measurement of T descriptor size. However, the IASLC/ATS/ERS lung adenocarcinoma classification defined new entities of adenocarcinoma in situ (AIS) (Table 1), minimally invasive adenocarcinoma (MIA) (Table 2), and lepidic predominant adenocarcinoma (LPA).
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      This has now been formally adopted by the 2015 WHO Classification.
      This conceptual change opened up a new way of thinking about how to measure tumor size in lung adenocarcinoma and how to stage AIS, MIA, and invasive adenocarcinomas with a lepidic component.
      Table 1Adenocarcinoma In Situ
      Modified with permission from Travis et al.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      and Travis et al.
      Pathologic criteria
      • A small tumor ≤3 cm
      • A solitary adenocarcinoma
        When multiple adenocarcinomas in situ are found, they should be regarded as separate primaries rather than intrapulmonary metastases.
      • Pure lepidic growth
      • No stromal, vascular, or pleural invasion
      • No pattern of invasive adenocarcinoma (such as acinar, papillary, micropapillary, solid, colloid, enteric, fetal, or invasive mucinous adenocarcinoma)
      • No spread through air spaces
      • Cell type mostly nonmucinous (type II pneumocytes or Clara cells), rarely may be mucinous (tall columnar cells with basal nuclei and abundant cytoplasmic mucin, sometimes resembling goblet cells)
      • Nuclear atypia is absent or inconspicuous
      • Septal widening with sclerosis/elastosis is common, particularly in nonmucinous adenocarcinoma in situ
      a When multiple adenocarcinomas in situ are found, they should be regarded as separate primaries rather than intrapulmonary metastases.
      Table 2Minimally Invasive Adenocarcinoma
      Modified with permission from Travis et al.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      and Travis et al.
      Pathologic criteria
      • A small tumor ≤3 cm
      • A solitary adenocarcinoma
        When multiple adenocarcinomas in situ are found, they should be regarded as separate primaries rather than intrapulmonary metastases.
      • Predominantly lepidic growth
      • Invasive component ≤0.5 cm in greatest dimension in any one focus
      • Invasive component to be measured includes
        • 1.
          Any histologic subtype other than a lepidic pattern (such as acinar, papillary, micropapillary, solid, colloid, fetal, or invasive mucinous adenocarcinoma)
        • 2.
          Tumor cells infiltrating myofibroblastic stroma
      • The diagnosis of minimally invasive adenocarcinoma is excluded if the tumor
        • 1.
          Invades lymphatics. blood vessels, air spaces, or pleura
        • 2.
          Contains tumor necrosis,
        • 3.
          Spread through air spaces
      • The cell type in most cases consists of nonmucinous (type II pneumocytes or Clara cells), but rarely may be mucinous (tall columnar cells with basal nuclei and abundant cytoplasmic mucin, sometimes resembling goblet cells)
      a When multiple adenocarcinomas in situ are found, they should be regarded as separate primaries rather than intrapulmonary metastases.
      To fit the entities of AIS, MIA, and LPA into the categories of the T component of the classification for lung adenocarcinoma, we propose introducing Tis (AIS), to be distinguished from Tis (SCIS) now that in situ carcinoma of the lung can be either SCIS or AIS. Because AIS can accompany squamous cell carcinoma and SCIS can accompany adenocarcinoma, it is useful to specify the histologic type of in situ carcinoma (AIS versus SCIS) for purposes of accurate coding. In addition, we propose that MIA of the lung be classified as T1mi. Furthermore, for nonmucinous lung adenocarcinomas with a lepidic component, we propose using invasive size for T descriptor size, as recommended by the Union for International Cancer Control (UICC) TNM supplements since 2003.
      In lung adenocarcinomas, the computed tomography (CT) findings of ground glass versus solid opacities tend to correspond respectively to the lepidic versus invasive patterns seen pathologically.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      However, this correlation is not absolute, so when CT features suggest the entities of AIS, MIA, and LPA, the suspected diagnosis and clinical staging should be regarded as a preliminary assessment that is subject to revision after pathologic evaluation of resected specimens (Fig. 1). Although the solid component in a part-solid nodule (PSN) seen by CT has a greater chance of having an invasive component on histologic examination, the solid area could represent a benign scar or a fibrous scar harboring a stromal invasive component.
      • Yamada N.
      • Kusumoto M.
      • Maeshima A.
      • Suzuki K.
      • Matsuno Y.
      Correlation of the solid part on high-resolution computed tomography with pathological scar in small lung adenocarcinomas.
      Figure 1 summarizes the spectrum of staging categories for small (≤3 cm) nonmucinous lung adenocarcinomas with a lepidic component by clinical T category (cT) (ground glass versus solid components radiologically) and pathologic T category (pT) (lepidic versus invasive components pathologically). For each cT category, there are several pathologic possibilities summarized. The pT images are not intended to present pathologic criteria for AIS, MIA, or LPA, which are summarized in the following sections.
      Figure thumbnail gr1
      Figure 1Proposed eighth edition of the clinical (cT) and pathologic T (pT) descriptor classification of small (≤3 cm) lung adenocarcinomas (ADs) with a ground glass (GG) and lepidic component by computed tomography (CT) and pathologic diagnosis.* The CT images on high-resolution CT (HRCT) scans can be suggestive of pathologic diagnoses, but they are not specific as GG opacities do not always correspond to lepidic patterns and solid components do not always correlate with invasive components. However, there is a general correlation between GG on CT scans and lepidic pattern microscopically, as well as between solid patterns on CT scans and invasive patterns histologically. A pathologic differential diagnosis is listed for each of the proposed possibilities on CT scans. Final pT staging of these tumors requires complete pathologic examination in resected specimens. (Tis [AIS]) cT: These lesions typically show pure GG nodules (GGNs) measuring 3 cm or less; however, pure GGNs can also be minimally invasive AD (MIA) or invasive AD.
      • Lim H.J.
      • Ahn S.
      • Lee K.S.
      • et al.
      Persistent pure ground-glass opacity lung nodules ≥ 10 mm in diameter at CT scan: histopathologic comparisons and prognostic implications.
      ,‡‡ pT: These tumors show pure lepidic growth without invasion, measuring 3 cm or less.‡‡ If the pure GGN or lepidic predominant nodule is larger than 3.0 cm, it is classified as lepidic predominant AD (LPA) and should be staged as T1a (see text for explanation). (T1mi) cT: MIA usually shows a GG predominant nodule 3 cm or smaller with a solid component that should appear 0.5 cm or smaller.†,‡‡ Although some MIAs have a larger solid component on CT scans because of other benign components such as a scar or organizing pneumonia, these cases can only be diagnosed by pathologic examination. pT: MIA histologically shows an LPA nodule measuring 3 cm or less with an invasive component measuring 0.5 cm or less.†,‡‡ (T1a) cT: GG predominant nodules measuring 3.0 cm or less with a solid component measuring 0.6 to 1.0 cm. pT: When an LPA measuring 3.0 cm or less has an invasive component measuring 0.6 to 1.0 cm, it is classified as pT1a. (T1b) cT: GG predominant nodules measuring 3.0 cm or less with a solid component measuring 1.1 to 2.0 cm. pT: When an LPA measuring 3.0 cm or less has an invasive component measuring 1.1 to 2.0 cm, it is classified as pT1b. (T1c) cT: GG predominant nodules measuring 3.0 cm or less with a solid component measuring 2.1 to 3.0 cm are classified as T1c. pT: When an invasive AD with a lepidic component measuring 3.0 cm or less has an invasive component measuring 2.1 to 3.0 cm, it is classified as T1c.† ∗All of the cT categories are presumptive, assuming the GG versus solid components correspond to lepidic versus invasive components, respectively, on pathologic examination of a resected specimen. cT category applying rule 4 of the TNM classification (when in doubt, opt for the lesser category). In cases with multiple foci of solid or invasive components, see text for estimation of invasive size. Size is not the only distinguishing feature between atypical adenomatous hyperplasia (AAH) and AD in situ (AIS). ‡‡If a pure GGN by CT or pure lepidic AD by pathologic pattern is larger than 3 cm, it should be classified as T1a. Similarly, if a GG predominant part-solid nodule has a solid component 0.5 cm or less or if a tumor meets pathologic criteria for MIA but the total size is larger than 3 cm, it should be staged as cT1a or pT1a, respectively. ††If the total tumor size is larger than 3.0 cm, depending on the invasive size these categories can be classified as T1a, T1b, or T1c.
      The terminology used to classify nodules by CT is important. Subsolid nodule is a term that encompasses both pure ground glass nodules (GGNs) and PSNs, which have a ground glass as well as a solid component.
      • 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.
      The following discussion of CT-detected GGNs or PSNs refers to nodules that are regarded to be probable or proven adenocarcinomas. So this article does not specifically address the differential diagnosis of adenocarcinoma with other neoplastic and nonneoplastic ground glass lesions, which is dealt with elsewhere.
      • Infante M.
      • Lutman R.F.
      • Imparato S.
      • et al.
      Differential diagnosis and management of focal ground-glass opacities.
      • Gould M.K.
      • Donington J.
      • Lynch W.R.
      • et al.
      Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.
      • Park C.M.
      • Goo J.M.
      • Lee H.J.
      • Lee C.H.
      • Chun E.J.
      • Im J.G.
      Nodular ground-glass opacity at thin-section CT: histologic correlation and evaluation of change at follow-up.
      Figure 1, summarizes the proposals for the eighth edition of the T descriptor classification of small (≤3 cm) lung adenocarcinomas with a ground glass and lepidic component by CT and pathologic assessment.

      Pathologic Staging

      Proposal for AIS to Be Added to the Tis Category

      Recommendation

      We propose that AIS be added to the category of Tis, which currently consists only of SCIS. As we introduce AIS as a new category of Tis, it is useful to code these two categories as Tis (AIS) and Tis (SCIS) for clarity and brevity. This specification will help to avoid ambiguity, particularly if multiple tumors are present, because the histologic type of in situ carcinoma does not always match that of the primary carcinoma.
      We considered whether diffuse idiopathic pulmonary neuroendocrine cell hyperplasia should be added to the Tis category, as it is regarded as a preinvasive lesion for carcinoid tumors. However, we do not recommend this for the following reasons: (1) it is viewed as preneoplastic rather than in situ disease, (2) this lesion presents as small airway disease without neoplasia in approximately half of the cases,
      • Davies S.J.
      • Gosney J.R.
      • Hansell D.M.
      • et al.
      Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease.
      and (3) both tumorlets and neuroendocrine cell hyperplasia occur as a secondary lesion in a variety of inflammatory and fibrotic settings.

      Background

      The WHO defines AIS as follows: AIS is a localized small (≤3 cm) adenocarcinoma with growth restricted to neoplastic cells along preexisting alveolar structures (lepidic growth) lacking stromal, vascular, alveolar space, or pleural invasion (Figs. 1 and 2). Papillary or micropapillary patterns are absent. Intraalveolar tumor cells, either within the tumor or as spread through alveolar spaces (STAS) in the surrounding parenchyma, are absent. AIS is subdivided into nonmucinous and mucinous variants. Virtually all cases of AIS are nonmucinous, typically showing type II pneumocyte and/or Clara cell differentiation.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      Figure thumbnail gr2
      Figure 2Pathologic pattern of nonmucinous adenocarcinoma in situ. (A) This circumscribed nonmucinous tumor grows purely with a lepidic pattern; no foci of invasion or scarring are seen. (B) The atypical pneumocytes are crowded and have slightly hyperchromatic nuclei.
      As the literature on the topic of nonmucinous AIS deals with tumors smaller than 2 or 3 cm, there is insufficient evidence to support the occurrence of 100% disease-free survival in such tumors larger than 3.0 cm. Therefore, these tumors should be classified as lepidic predominant adenocarcinoma. If the tumor has been completely sampled histologically and no invasion is present, one could comment in a note that AIS is suspected.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      Such tumors should be staged as pT1a. In this setting complete histologic sampling is essential.
      The criteria for nonmucinous AIS can be applied in the setting of multiple tumors only if all criteria are met in a given lesion and the tumors are not regarded as intrapulmonary metastases. This is important because most patients who present with multiple ground glass opacities do not have intrapulmonary metastases, but rather separate primary adenocarcinomas (AIS, MIA, or LPA) and good clinical outcomes.
      • Gu B.
      • Burt B.M.
      • Merritt R.E.
      • et al.
      A dominant adenocarcinoma with multifocal ground glass lesions does not behave as advanced disease.
      • Shrager J.B.
      Approach to the patient with multiple lung nodules.
      • Tsutsui S.
      • Ashizawa K.
      • Minami K.
      • et al.
      Multiple focal pure ground-glass opacities on high-resolution CT images: clinical significance in patients with lung cancer.
      This principle is applicable only in nonmucinous tumors. Because invasive mucinous adenocarcinoma (IMA) has a strong tendency to spread metastatically as multiple nodules within the lung regardless of any resemblance to mucinous AIS or MIA, when multiple adenocarcinomas with this morphologic pattern are found, they are more likely to represent metastatic foci.
      AIS needs to be distinguished from atypical adenomatous hyperplasia (AAH) which is also included as a preinvasive lesion for lung adenocarcinoma. However, AAH is comparable to squamous dysplasia, so it is not included in the TNM classification. Histologically, the distinction between AAH and nonmucinous AIS can be difficult. AAH tends to be smaller than 0.5 cm, but it can also be larger. Rarely, AIS can be smaller than 0.5 cm. AIS typically shows a more cellular, crowded, homogeneous cuboidal or columnar cell population. There is usually a less graded, more abrupt transition to adjacent alveolar lining cells in AIS.
      In some cases, small biopsy specimens may show a pure lepidic pattern. The pathologic diagnosis should be “adenocarcinoma with lepidic pattern” rather than AIS, as the latter requires a resection specimen.
      In this setting correlation with the CT may be helpful to anticipate the likely diagnosis depending on the extent of ground glass versus solid components.

      Proposal for MIA to Be Added to the T1mi Category

      Recommendation

      We propose that MIA be classified as T1mi. This applies to both mucinous and nonmucinous MIA.
      Because of the requirement of a lepidic predominant characteristic as well as lack of vascular, pleural, or air space invasion for classification of a tumor as MIA (Figs. 1 and 3 and Table 2), it is possible to have a tumor that measures 5 mm or less that would be classified as invasive adenocarcinoma and therefore be T1a, but not T1mi.
      Figure thumbnail gr3
      Figure 3Pathologic pattern of minimally invasive nonmucinous adenocarcinoma. (A) This subpleural adenocarcinoma tumor consists primarily of lepidic growth (left) with a small area of invasion (arrow) less than 0.5 cm. (B) This area of the tumor shows mostly lepidic growth with a focal area of invasion (arrow). (C) These acinar glands are invading in the fibrous stroma.

      Background

      The WHO defines MIA of the lung as a small, solitary adenocarcinoma, (≤3 cm), with a predominantly lepidic pattern and 5 mm or less invasion (Fig. 3 and Table 2).
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      The size of the invasive area should be measured in the largest dimension.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      If there are multiple foci of invasion, or if invasive size is difficult to measure, recent data suggest that another way to estimate the invasive size is to sum the percentage area of the invasive components and multiply this amount by the overall tumor diameter (i.e., a 2.0-cm tumor with a 20% invasive component would have an estimated invasive size of 0.4 cm).
      • Kadota K.
      • Villena-Vargas J.
      • Yoshizawa A.
      • et al.
      Prognostic significance of adenocarcinoma in situ, minimally invasive adenocarcinoma, and nonmucinous lepidic predominant invasive adenocarcinoma of the lung in patients with stage I disease.
      If the result is 0.5 cm or less, a diagnosis of MIA should be rendered. Similar to AIS, MIA is usually nonmucinous but rarely may be mucinous or mixed.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Yoshizawa A.
      • Motoi N.
      • Riely G.J.
      • et al.
      Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases.
      Nonmucinous MIA typically shows type II pneumocyte and/or Clara cell differentiation, whereas mucinous MIA shows columnar cells with abundant apical mucin and small, often basally oriented nuclei and may show a goblet cell morphologic pattern. The invasive component to be measured in MIA is defined as follows: (1) histologic subtypes other than a lepidic pattern (i.e., acinar, papillary, micropapillary, and/or solid) or (2) tumor cells infiltrating myofibroblastic stroma. MIA is excluded if the tumor (1) invades lymphatics, blood vessels, alveolar spaces, or pleura; (2) contains tumor necrosis; or (3) spreads through alveolar spaces.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      If the invasive component is larger than 0.5 cm, the tumor is classified as LPA (Fig. 4). If the total size is more than 3.0 cm, the tumor should be classified as LPA and staged as pT1a.
      Figure thumbnail gr4
      Figure 4Pathologic pattern of lepidic predominant adenocarcinoma. (A) Lepidic predominant pattern with mostly lepidic growth and a smaller area of invasive acinar adenocarcinoma (arrow). (B) Lepidic predominant adenocarcinoma. Lepidic pattern (A) consists of a cellular proliferation of pneumocytes along the surface of the alveolar walls. (C) Area of invasive acinar adenocarcinoma with crowded back-to-back glands within fibrous stroma.
      The proposal of the entities AIS and MIA was based on evidence that patients would have a 100% or near-100% disease-free survival, respectively, if these lesions were completely resected.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      With a growing number of published cases, no clear recurrences have been reported in patients with AIS thus far.
      • Kadota K.
      • Villena-Vargas J.
      • Yoshizawa A.
      • et al.
      Prognostic significance of adenocarcinoma in situ, minimally invasive adenocarcinoma, and nonmucinous lepidic predominant invasive adenocarcinoma of the lung in patients with stage I disease.
      • Yoshizawa A.
      • Motoi N.
      • Riely G.J.
      • et al.
      Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases.
      • Nakagiri T.
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      • et al.
      Evaluation of the new IASLC/ATS/ERS proposed classification of adenocarcinoma based on lepidic pattern in patients with pathological stage IA pulmonary adenocarcinoma.
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      • Sato T.
      • Tamura G.
      The correlation of the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification with prognosis and EGFR mutation in lung adenocarcinoma.
      • Warth A.
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      • et al.
      The novel histologic IASLC/ATS/ERS classification system of invasive pulmonary adenocarcinoma is a stage-independent predictor of survival.
      • Yoshizawa A.
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      • Sonobe M.
      • et al.
      Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients.
      • Song Z.
      • Zhu H.
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      • Wu W.
      • Sun W.
      • Zhang Y.
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      • Takahashi M.
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      • Matsukura T.
      • Hirai T.
      Tumor invasiveness as defined by the newly proposed IASLC/ATS/ERS classification has prognostic significance for pathologic stage IA lung adenocarcinoma and can be predicted by radiologic parameters.
      Although rare cases of staple line recurrences have been reported in what may have represented MIA,
      • Yoshida J.
      • Ishii G.
      • Yokose T.
      • et al.
      Possible delayed cut-end recurrence after limited resection for ground-glass opacity adenocarcinoma, intraoperatively diagnosed as Noguchi type B, in three patients.
      these cases were not diagnosed according to the IASLC/ATS/ERS adenocarcinoma classification; thus, it is not possible to be certain whether some of the exclusionary criteria such as the recently described invasive pattern of STAS may have been present.
      • Kadota K.
      • Nitadori J.I.
      • Sima C.S.
      • et al.
      Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences following limited resection for small stage I lung adenocarcinomas.
      • Warth A.
      • Muley T.
      • Kossakowski C.A.
      • et al.
      Prognostic impact of intra-alveolar tumor spread in pulmonary adenocarcinoma.
      Survival analysis of AIS and MIA should be done using disease-specific survival or recurrence-free probability rather than overall survival because patients typically die of other causes.
      • Kadota K.
      • Villena-Vargas J.
      • Yoshizawa A.
      • et al.
      Prognostic significance of adenocarcinoma in situ, minimally invasive adenocarcinoma, and nonmucinous lepidic predominant invasive adenocarcinoma of the lung in patients with stage I disease.
      • Tsuta K.
      • Kawago M.
      • Inoue E.
      • et al.
      The utility of the proposed IASLC/ATS/ERS lung adenocarcinoma subtypes for disease prognosis and correlation of driver gene alterations.
      When new lung adenocarcinomas develop after resection of MIA,
      • Xu L.
      • Tavora F.
      • Battafarano R.
      • Burke A.
      Adenocarcinomas with prominent lepidic spread: retrospective review applying new classification of the American Thoracic Society.
      they may represent a second primary rather than a recurrence or metastasis.
      • Girard N.
      • Deshpande C.
      • Lau C.
      • et al.
      Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases.
      Ito et al. suggested that MIA be included with AIS as Tis because of lack of recurrence in their series.
      • Ito M.
      • Miyata Y.
      • Kushitani K.
      • et al.
      Prediction for prognosis of resected pT1a-1bN0M0 adenocarcinoma based on tumor size and histological status: relationship of TNM and IASLC/ATS/ERS classifications.
      However, it is our assessment that the current data are insufficient to make this proposal. Furthermore, staging is a way to document the extent of tumor invasion or spread.
      Because by definition, invasion has occurred in MIA but not in AIS, these entities will need to be staged differently and the similar excellent survival expected when these entities were proposed
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      does not have implications for staging.

      Proposal for Invasive Size as a T Descriptor

      Recommendation

      For lung nonmucinous adenocarcinoma we recommend that tumor size be determined according to the invasive size excluding the lepidic component (Figure 1, Figure 4, and 5). Total tumor size should also be recorded (i.e., the maximum measurement of the ground glass or lepidic component), but only the invasive component is used as a descriptor of the T categories. Invasive mucinous adenocarcinomas should be staged as other invasive adenocarcinomas, regardless of the extent of lepidic component.
      Figure thumbnail gr5
      Figure 5Pathologic pattern of invasive adenocarcinoma. (A) This acinar predominant adenocarcinoma has areas of lepidic growth (thick arrow) and invasive acinar growth (thin arrow). (B) This area of acinar adenocarcinoma consists of round to oval malignant glands invading a fibrous stroma. (C) The acinar structures are composed of highly atypical cells with highly atypical nuclei forming glands filled with mucin.
      Tumor size is one of the most important predictors of outcome in lung cancer, causing it to be one of the key elements of TNM staging.
      • Rami-Porta R.
      • Bolejack V.
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      • et al.
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      It has been shown to be an independent predictor of survival in many publications, including in large databases such as those assembled by the National Cancer Institute’s Surveillance, Epidemiology, and End Results registry and the IASLC.
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      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.
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      • Gold K.A.
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      • et al.
      Relationship between tumor size and survival in non-small cell lung cancer (NSCLC): an analysis of the Surveillance, Epidemiology, and End Results (SEER) registry.
      • Morgensztern D.
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      • Trinkaus K.
      • Govindan R.
      Prognostic significance of tumor size in patients with stage III non-small-cell lung cancer: a surveillance, epidemiology, and end results (SEER) survey from 1998 to 2003.
      • Rami-Porta R.
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      The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer.
      In lung cancer, TNM staging has traditionally been based on total tumor size.
      Data are accumulating in both the radiologic and pathologic literature to support the concept that invasive size is a better predictor of survival than is total tumor size in lung adenocarcinoma.
      • Yoshizawa A.
      • Motoi N.
      • Riely G.J.
      • et al.
      Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases.
      • Warth A.
      • Muley T.
      • Meister M.
      • et al.
      The novel histologic IASLC/ATS/ERS classification system of invasive pulmonary adenocarcinoma is a stage-independent predictor of survival.
      • Tsutani Y.
      • Miyata Y.
      • Mimae T.
      • et al.
      The prognostic role of pathologic invasive component size, excluding lepidic growth, in stage I lung adenocarcinoma.
      • Maeyashiki T.
      • Suzuki K.
      • Hattori A.
      • Matsunaga T.
      • Takamochi K.
      • Oh S.
      The size of consolidation on thin-section computed tomography is a better predictor of survival than the maximum tumour dimension in resectable lung cancer.
      • Tsutani Y.
      • Miyata Y.
      • Yamanaka T.
      • et al.
      Solid tumors versus mixed tumors with a ground-glass opacity component in patients with clinical stage IA lung adenocarcinoma: prognostic comparison using high-resolution computed tomography findings.
      • Tsutani Y.
      • Miyata Y.
      • Nakayama H.
      • et al.
      Solid tumor size on high-resolution computed tomography and maximum standardized uptake on positron emission tomography for new clinical T descriptors with T1 lung adenocarcinoma.
      • Tsutani Y.
      • Miyata Y.
      • Nakayama H.
      • et al.
      Prognostic significance of using solid versus whole tumor size on high-resolution computed tomography for predicting pathologic malignant grade of tumors in clinical stage IA lung adenocarcinoma: a multicenter study.
      • Murakawa T.
      • Konoeda C.
      • Ito T.
      • et al.
      The ground glass opacity component can be eliminated from the T-factor assessment of lung adenocarcinoma.
      • Hwang E.J.
      • Park C.M.
      • Ryu Y.
      • et al.
      Pulmonary adenocarcinomas appearing as part-solid ground-glass nodules: is measuring solid component size a better prognostic indicator?.
      • Burt B.M.
      • Leung A.N.
      • Yanagawa M.
      • et al.
      Diameter of solid tumor component alone should be used to establish T stage in lung adenocarcinoma.
      The evidence that prognosis is better predicted after adjusting the T descriptor according to the invasive size in adenocarcinomas with a subsolid appearance by CT or a lepidic component by pathologic examination is based primarily on data from small tumors (≤3 cm) with a substantial ground glass or lepidic component. More evidence is needed to investigate the prognostic impact of adjusting tumor size in larger tumors and those that are predominantly invasive with a minor ground glass or lepidic component. However, for uniformity of clinical practice, we recommend that only invasive size be used as the T descriptor for all tumors, regardless of the size and extent of the lepidic component (Figs. 4 and 5).

      Background

      Also, in the last three TNM Supplements beginning in 2001, the UICC has recommended that size be measured by the invasive size.
      Our proposal is not creating a new rule for TNM; rather, it marks the first time this rule is being recommended for application to lung cancer staging.
      The 2001, 2003, and 2012 TNM supplements recommend that invasive size be used to determine tumor size as a T descriptor rather than the larger size in tumors that include an in situ component.
      Given the new concept of lepidic versus invasive components in lung adenocarcinoma, a similar approach can now be applied to lung adenocarcinoma by using only the invasive size to determine the T descriptor size after excluding the lepidic component.
      In lung adenocarcinoma, because of the historical confusion with use of the term bronchioloalveolar carcinoma with a variety of meanings in both invasive and noninvasive settings, we have deliberately restricted use of the diagnostic term in situ, or AIS, to tumors that have a pure lepidic pattern lacking any invasive component in a completely sampled resected specimen.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      So when there is a mixture of invasive and noninvasive components, the term lepidic pattern rather than “in situ” adenocarcinoma is used for the noninvasive component that spreads along the surface of alveolar walls in tumors meeting criteria for MIA or LPA. Therefore, AIS is not interchangeable with lepidic growth; all AIS are lepidic, but not all tumors with lepidic growth are AIS if they have an invasive component.
      Adenocarcinomas with a predominant lepidic component that is larger than 3 cm in total or that have an invasive component larger than 0.5 cm are classified as lepidic predominant adenocarcinomas (see Fig. 4).
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      It is extremely rare for adenocarcinomas with pure lepidic growth lacking invasion to be larger than 3.0 cm. However, because of the lack of evidence for patients with such tumors having 100% disease-free survival, these tumors are classified as LPA rather than AIS.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      If even after pathologic examination of the entire tumor, a tumor shows a pure lepidic pattern without any invasive component, it is classified as LPA rather than a very large AIS.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.

      Clinical Staging

      CT Features of Tis (AIS)

      By CT, most nonmucinous AIS will appear as a pure GGN measuring between 0.5 and 3.0 cm (Figs. 1 and 6).
      • Cohen J.G.
      • Reymond E.
      • Lederlin M.
      • et al.
      Differentiating pre- and minimally invasive from invasive adenocarcinoma using CT-features in persistent pulmonary part-solid nodules in Caucasian patients.
      • Zhang Y.
      • Qiang J.W.
      • Ye J.D.
      • Ye X.D.
      • Zhang J.
      High resolution CT in differentiating minimally invasive component in early lung adenocarcinoma.
      • Zhang H.
      • Duan J.
      • Li Z.J.
      • et al.
      Analysis on minimally invasive diagnosis and treatment of 49 cases with solitary nodular ground-glass opacity.
      • Lee H.Y.
      • Choi Y.L.
      • Lee K.S.
      • et al.
      Pure ground-glass opacity neoplastic lung nodules: histopathology, imaging, and management.
      • Lee H.Y.
      • Lee K.S.
      Ground-glass opacity nodules: histopathology, imaging evaluation, and clinical implications.
      Moreover, in typical cases, no abnormalities of neighboring anatomical structures, such as pulmonary vessels or pleural structures, are noted. However, in some cases in which the pathologic examination shows collapse of alveolar walls and elastosis or benign scarring, AIS may show a part-solid appearance.
      • Lee H.Y.
      • Choi Y.L.
      • Lee K.S.
      • et al.
      Pure ground-glass opacity neoplastic lung nodules: histopathology, imaging, and management.
      • Isaka T.
      • Yokose T.
      • Ito H.
      • et al.
      Comparison between CT tumor size and pathological tumor size in frozen section examinations of lung adenocarcinoma.
      Not all pure GGNs are AIS on pathologic examination, although smaller lesions (<1.0 cm) are more likely to be a preinvasive lesion (AIS or AAH).
      • Lee S.M.
      • Park C.M.
      • Goo J.M.
      • Lee H.J.
      • Wi J.Y.
      • Kang C.H.
      Invasive pulmonary adenocarcinomas versus preinvasive lesions appearing as ground-glass nodules: differentiation by using CT features.
      • Nakata M.
      • Sawada S.
      • Saeki H.
      • et al.
      Prospective study of thoracoscopic limited resection for ground-glass opacity selected by computed tomography.
      • Lee H.J.
      • Goo J.M.
      • Lee C.H.
      • Yoo C.G.
      • Kim Y.T.
      • Im J.G.
      Nodular ground-glass opacities on thin-section CT: size change during follow-up and pathological results.
      On final pathologic examination, resected pure GGNs that show features of adenocarcinoma can also show MIA or invasive adenocarcinoma in addition to AIS. Son et al. studied 191 resected GGNs that had been diagnosed as AIS, MIA, or invasive adenocarcinoma, and on pathologic examination, they found that only 38 (20%) were AIS whereas 61 (32%) were MIA and 92 (48%) were invasive adenocarcinoma.
      • Son J.Y.
      • Lee H.Y.
      • Lee K.S.
      • et al.
      Quantitative CT analysis of pulmonary ground-glass opacity nodules for the distinction of invasive adenocarcinoma from pre-invasive or minimally invasive adenocarcinoma.
      They also found increased density (75th percentile CT attenuation value on a histogram ≥470 Hounsfield units), and entropy (a measure of heterogeneity by texture irregularity) predicted invasive adenocarcinoma.
      • Son J.Y.
      • Lee H.Y.
      • Lee K.S.
      • et al.
      Quantitative CT analysis of pulmonary ground-glass opacity nodules for the distinction of invasive adenocarcinoma from pre-invasive or minimally invasive adenocarcinoma.
      On pathologic examination of 46 pure GGNs larger than 1.0 cm by thin-section CT scan, Lim et al. found MIA in 20% of cases and invasive adenocarcinoma in 39%; however, no patient, including those who underwent sublobar resection, had a recurrence.
      • Lim H.J.
      • Ahn S.
      • Lee K.S.
      • et al.
      Persistent pure ground-glass opacity lung nodules ≥ 10 mm in diameter at CT scan: histopathologic comparisons and prognostic implications.
      An invasive component correlated with the presence of larger size (>16.4 mm) and increased mass (>0.472 g [determined by multiplying nodule volume by mean nodule density]).
      • Lim H.J.
      • Ahn S.
      • Lee K.S.
      • et al.
      Persistent pure ground-glass opacity lung nodules ≥ 10 mm in diameter at CT scan: histopathologic comparisons and prognostic implications.
      This suggests that not only size, but also attenuation value of GGN, may be useful to predict invasive histologic pattern. In a study of 85 pure GGNs, Mimae et al. found invasive adenocarcinoma in 41% of cases, although they did not make a pathologic distinction between MIA, LPA, and other invasive adenocarcinomas.
      • Mimae T.
      • Miyata Y.
      • Tsutani Y.
      • et al.
      What are the radiologic findings predictive of indolent lung adenocarcinoma?.
      Invasive adenocarcinoma components were found in three of 13 pure GGNs 1 cm or smaller (23%).
      • Mimae T.
      • Miyata Y.
      • Tsutani Y.
      • et al.
      What are the radiologic findings predictive of indolent lung adenocarcinoma?.
      Several studies published before the 2011 IASLC/ATS/ERS lung adenocarcinoma classification also showed that a subset of patients with pure GGNs can show invasive adenocarcinoma on histologic evaluation. In 41 pure GGNs 1 cm or smaller, Nakata et al. reported bronchioloalveolar carcinoma (probably AIS, MIA, or LPA) in 28 patients, AAH in 10 patients, and invasive adenocarcinoma in three patients, with no recurrences in any of these cases.
      • Nakata M.
      • Sawada S.
      • Saeki H.
      • et al.
      Prospective study of thoracoscopic limited resection for ground-glass opacity selected by computed tomography.
      Nakamura et al. reported 23 GGNs, and three of these showed invasive components that were probably either MIA or LPA.
      • Nakamura H.
      • Saji H.
      • Ogata A.
      • Saijo T.
      • Okada S.
      • Kato H.
      Lung cancer patients showing pure ground-glass opacity on computed tomography are good candidates for wedge resection.
      Figure thumbnail gr6
      Figure 6Computed tomography scan of nonmucinous adenocarcinoma in situ. (A) Computed tomography shows a circumscribed ground glass nodule lacking any solid component. (B) The longest diameter of the nodule is 2.3 cm.
      Pure GGNs smaller than 0.5 cm usually represent AAH.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      However, the mean size of AAH on CT scan can be larger than 0.5 cm and AIS can be smaller.
      • Kitami A.
      • Sano F.
      • Hayashi S.
      • et al.
      Correlation between histological invasiveness and the computed tomography value in pure ground-glass nodules.
      • Oda S.
      • Awai K.
      • Liu D.
      • et al.
      Ground-glass opacities on thin-section helical CT: differentiation between bronchioloalveolar carcinoma and atypical adenomatous hyperplasia.
      In addition to smaller size, AAH has lower density compared with AIS, MIA, and other adenocarcinomas.
      • Kitami A.
      • Sano F.
      • Hayashi S.
      • et al.
      Correlation between histological invasiveness and the computed tomography value in pure ground-glass nodules.
      The presence of a lobulated border also favors malignancy rather than AAH.
      • Lee H.J.
      • Goo J.M.
      • Lee C.H.
      • et al.
      Predictive CT findings of malignancy in ground-glass nodules on thin-section chest CT: the effects on radiologist performance.
      It is extremely rare for adenocarcinomas presenting as pure GGNs to be larger than 3.0 cm, but for reasons already explained, on pathologic examination such a tumor would be regarded as a probable lepidic predominant adenocarcinoma.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      Rather than cTis or cT1mi, such tumors should be classified as cT1a, realizing that this may be revised after pathologic evaluation (see Fig. 1).
      Mucinous AIS is more likely to show a solid or PSN with air bronchograms.
      • Miyata N.
      • Endo M.
      • Nakajima T.
      • et al.
      High-resolution computed tomography findings of early mucinous adenocarcinomas and their pathologic characteristics in 22 surgically resected cases.

      CT Features of MIA T1mi

      By CT, nonmucinous MIAs usually show a PSN with a total size of 3.0 cm or less and a small solid component (Figs. 1 and 7), but they can also show a pure GGN in 17% to 54% of cases and, rarely, a solid nodule.
      • Zhang Y.
      • Qiang J.W.
      • Ye J.D.
      • Ye X.D.
      • Zhang J.
      High resolution CT in differentiating minimally invasive component in early lung adenocarcinoma.
      • Lee K.H.
      • Goo J.M.
      • Park S.J.
      • et al.
      Correlation between the size of the solid component on thin-section ct and the invasive component on pathology in small lung adenocarcinomas manifesting as ground-glass nodules.
      • Lee S.M.
      • Goo J.M.
      • Lee K.H.
      • Chung D.H.
      • Koh J.
      • Park C.M.
      CT findings of minimally invasive adenocarcinoma (MIA) of the lung and comparison of solid portion measurement methods at CT in 52 patients.
      The size of the solid component is usually less than 0.5 cm, but in 19% of cases it can exceed the maximum size of the invasive component of 0.5 cm or less seen by pathologic examination, and in one study the mean size was 0.6 cm ± 0.22 cm.
      • Lee S.M.
      • Goo J.M.
      • Lee K.H.
      • Chung D.H.
      • Koh J.
      • Park C.M.
      CT findings of minimally invasive adenocarcinoma (MIA) of the lung and comparison of solid portion measurement methods at CT in 52 patients.
      Several CT studies have suggested that if the solid component is 0.5 cm or less
      • Cohen J.G.
      • Reymond E.
      • Lederlin M.
      • et al.
      Differentiating pre- and minimally invasive from invasive adenocarcinoma using CT-features in persistent pulmonary part-solid nodules in Caucasian patients.
      or 0.3 cm or less,
      • Lee K.H.
      • Goo J.M.
      • Park S.J.
      • et al.
      Correlation between the size of the solid component on thin-section ct and the invasive component on pathology in small lung adenocarcinomas manifesting as ground-glass nodules.
      there is a good prediction of MIA. Tumors suspected to be MIA by CT should be staged as cT1mi. In the rare situation in which the total size of such tumors is larger than 3.0 cm, a pathologic diagnosis of LPA should be suspected and the tumor staged as cT1a rather than cT1mi. Other features that help to distinguish MIA from AIS or AAH on imaging include larger size or abnormality in pulmonary vein, air bronchogram, or pleural indentation.
      • Zhang Y.
      • Qiang J.W.
      • Ye J.D.
      • Ye X.D.
      • Zhang J.
      High resolution CT in differentiating minimally invasive component in early lung adenocarcinoma.
      Higher attenuation of a solid component favors MIA over AIS or AAH.
      • Zhang Y.
      • Qiang J.W.
      • Ye J.D.
      • Ye X.D.
      • Zhang J.
      High resolution CT in differentiating minimally invasive component in early lung adenocarcinoma.
      Mucinous MIA is more likely to show a solid or PSN with air bronchograms.
      • Miyata N.
      • Endo M.
      • Nakajima T.
      • et al.
      High-resolution computed tomography findings of early mucinous adenocarcinomas and their pathologic characteristics in 22 surgically resected cases.
      • Lee S.M.
      • Goo J.M.
      • Lee K.H.
      • Chung D.H.
      • Koh J.
      • Park C.M.
      CT findings of minimally invasive adenocarcinoma (MIA) of the lung and comparison of solid portion measurement methods at CT in 52 patients.
      Figure thumbnail gr7
      Figure 7Computed tomography scan of nonmucinous minimally invasive adenocarcinoma. (A) a computed tomography scan shows a part-solid nodule consisting mostly of a ground glass nodule with a small solid component. (B) The total nodule size is 2.7 cm. (C) The longest diameter of the solid component is 0.47 cm, which corresponds to invasion by pathologic examination.

      How to Measure Tumor Size

      There are key differences between the radiologic and pathologic measurement of the size of GGNs and PSNs of lung adenocarcinoma. For small solid and subsolid nodules, the Fleischner Society and American College of Radiology Guidelines have recommended that the overall size of the ground glass and/or solid components be based on the bidimensional average of the long and short dimensions to estimate risk.
      • 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.
      • Manos D.
      • Seely J.M.
      • Taylor J.
      • Borgaonkar J.
      • Roberts H.C.
      • Mayo J.R.
      The Lung Reporting and Data System (LU-RADS): a proposal for computed tomography screening.
      • Pinsky P.F.
      • Gierada D.S.
      • Black W.
      • et al.
      Performance of lung-RADS in the National Lung Screening Trial: a retrospective assessment.
      However, for TNM staging purposes, the single largest dimension measured on CT sections using thin sections and multiplanar reconstructions is still used (Figs. 1 and Figure 7, Figure 8, Figure 9).
      • 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.
      • de Groot P.M.
      • Carter B.W.
      Betancourt Cuellar SL, Erasmus JJ. Staging of Lung Cancer.
      For pathologic assessment, although three-dimensional measurements are frequently recorded in pathology reports, the single maximum diameter is traditionally used for pTNM staging.
      Figure thumbnail gr8
      Figure 8Computed tomography scan of lepidic predominant adenocarcinoma. (A) Computed tomography scan shows a part-solid nodule consisting mostly of a ground glass nodule with a small solid component. (B) The longest diameter of the entire mass is 2.1 cm (cT1c). (C) The longest diameter of the solid portion is 0.9 cm (cT1a).
      Figure thumbnail gr9
      Figure 9Computed tomography scan of invasive adenocarcinoma with a small lepidic component. (A) Computed tomography shows a part-solid nodule that is mostly solid with a minor ground glass component. (B) The total size is 2.8 cm (T1c). (C) The longest diameter of the solid component is 1.7 cm (T1b). A second ground glass nodule is adjacent to the part-solid nodule.
      Tumor size measured to determine the T categories is based on clinical (radiologic or intraoperative) and pathologic (gross and/or microscopic) assessment (see Fig. 1). Tumor size should be recorded in centimeters and include millimeter increments. In nonmucinous lung adenocarcinomas, the histologic lepidic growth pattern tends to correlate with the ground glass component of lung nodules whereas solid components correlate with invasive adenocarcinoma patterns. Clinical assessment is frequently performed by CT. CT measurements of pulmonary nodules, however, are influenced by a number of technical and observer-related factors summarized later. Moreover, there is no general consensus about how to perform CT measurements of pulmonary nodules, notably of PSNs, as numerous potential factors of influence are still controversial. The many facets of this discussion, together with technical information and practical recommendations, are summarized in the following sections.
      This radiologic-pathologic correlation is not established in invasive mucinous adenocarcinomas, mucinous AIS, or mucinous MIA, which usually show nodules of consolidation with frequent air bronchograms on CT.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Watanabe H.
      • Saito H.
      • Yokose T.
      • et al.
      Relation between thin-section computed tomography and clinical findings of mucinous adenocarcinoma.
      Furthermore, the prognostic significance of lepidic versus invasive components is not well documented in these tumors as it is in nonmucinous adenocarcinomas.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      Therefore, the following recommendations are applicable only to nonmucinous adenocarcinomas with a lepidic component.

      Pathologic Assessment of Tumor Size

      Pathologic assessment (pT) of tumor size in most cases is made by gross measurement using a ruler placed along the tumor in the gross specimen to estimate three-dimensional sizes.
      • Isaka T.
      • Yokose T.
      • Ito H.
      • et al.
      Comparison between CT tumor size and pathological tumor size in frozen section examinations of lung adenocarcinoma.
      In some cases, this is best done after making a cross-section of the tumor, which may allow for discrimination between what is clearly tumor versus an inflammatory or organizing reaction around the tumor. If the tumor is not spherical, this cross-section should be taken along the greatest dimension to estimate the maximum tumor diameter. The initial gross measurement needs to be reevaluated at the time of microscopic evaluation of the tumor because this step can reveal discrepancies that lead to significant revision of the gross estimated tumor size. Some lung cancers have a substantial amount of nonneoplastic components such as fibrosis, organizing pneumonia, or an inflammatory process that can lead to an exaggerated gross size assessment. Because scars within lung cancers are generally thought to be caused by the invasive properties of the tumor, unless a fibrous scar appears to be unrelated to the tumor, these are generally included in measurements of total tumor size unless the tumor consists of small foci at the edge of the scar. If small tumors can be included in a single paraffin block, the size of an adenocarcinoma with a lepidic component is best determined by microscopic measurement to separate the lepidic versus invasive components. If the tumor does not fit into a single block, tumor size must be made by gross measurement or correlation with CT findings.
      There are challenges in pathologic assessment of lung cancer tumor size. These challenges include tumor methodologies in measurement, specimen fixation, and difficulties in appreciating the tumor edge. The latter problem can be particularly difficult for adenocarcinomas with lepidic growth and nonneoplastic components that may contribute to mass formation such as fibrous scars, inflammation, and organizing pneumonia.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Hsu P.K.
      • Huang H.C.
      • Hsieh C.C.
      • et al.
      Effect of formalin fixation on tumor size determination in stage I non-small cell lung cancer.
      • Borczuk A.C.
      Assessment of invasion in lung adenocarcinoma classification, including adenocarcinoma in situ and minimally invasive adenocarcinoma.
      Several studies have shown that gross pathologic measurements can underestimate tumor size compared with measurements by CT scan.
      • Hsu P.K.
      • Huang H.C.
      • Hsieh C.C.
      • et al.
      Effect of formalin fixation on tumor size determination in stage I non-small cell lung cancer.
      • Lampen-Sachar K.
      • Zhao B.
      • Zheng J.
      • et al.
      Correlation between tumor measurement on computed tomography and resected specimen size in lung adenocarcinomas.
      Tumors have been shown to shrink after formalin fixation, so gross pathologic measurements made after fixation may underestimate actual tumor size.
      • Hsu P.K.
      • Huang H.C.
      • Hsieh C.C.
      • et al.
      Effect of formalin fixation on tumor size determination in stage I non-small cell lung cancer.
      Tumors typically have a border that is seen grossly and microscopically, but upon histologic review, some tumors demonstrate infiltration beyond this border and this can be difficult or impossible to detect on gross examination. This infiltration beyond the border of an invasive tumor can manifest in several ways. In lung parenchyma surrounding lung cancers, some tumors show (1) lymphatic and/or vascular invasion, (2) additional nodules that can show a miliary pattern, or (3) STAS, a recently newly recognized pattern of invasion.
      • Kadota K.
      • Nitadori J.I.
      • Sima C.S.
      • et al.
      Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences following limited resection for small stage I lung adenocarcinomas.
      • Warth A.
      • Muley T.
      • Kossakowski C.A.
      • et al.
      Prognostic impact of intra-alveolar tumor spread in pulmonary adenocarcinoma.
      Tumor size assessment is based on the measurement to the border of the tumor and it does not include these microscopic extensions, which are more appropriately recorded as patterns of tumor spread into adjacent lung parenchyma. Therefore, the lesion of STAS, which was recently described as a pattern of invasive growth, should not be included in tumor size.
      • Kadota K.
      • Nitadori J.I.
      • Sima C.S.
      • et al.
      Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences following limited resection for small stage I lung adenocarcinomas.
      • Warth A.
      • Muley T.
      • Kossakowski C.A.
      • et al.
      Prognostic impact of intra-alveolar tumor spread in pulmonary adenocarcinoma.
      Our proposal to use only the invasive component for measuring tumor size creates a new challenge for pathologists in separating the lepidic from the invasive components on both gross and microscopic examination. On gross examination, it is often difficult to estimate the size of the lepidic component because it can cause ill-defined lesions that are imperceptible, particularly in poorly expanded alveolar parenchyma.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Borczuk A.C.
      Assessment of invasion in lung adenocarcinoma classification, including adenocarcinoma in situ and minimally invasive adenocarcinoma.
      Several techniques have been recommended for better visualization of the lepidic component on gross examination after serial sectioning, including rinsing the specimen and letting the specimen air-dry for a few minutes.
      • Borczuk A.C.
      Assessment of invasion in lung adenocarcinoma classification, including adenocarcinoma in situ and minimally invasive adenocarcinoma.
      Others have inflated the specimens before sectioning with saline, diluted optimal cutting temperature compound, or formalin.
      • Isaka T.
      • Yokose T.
      • Ito H.
      • et al.
      Comparison between CT tumor size and pathological tumor size in frozen section examinations of lung adenocarcinoma.
      • Lee K.H.
      • Goo J.M.
      • Park S.J.
      • et al.
      Correlation between the size of the solid component on thin-section ct and the invasive component on pathology in small lung adenocarcinomas manifesting as ground-glass nodules.
      • Xu X.
      • Chung J.H.
      • Jheon S.
      • et al.
      The accuracy of frozen section diagnosis of pulmonary nodules: evaluation of inflation method during intraoperative pathology consultation with cryosection.
      It may be helpful to take a gross photograph of the tumor cross-section to allow for correlation with microscopic findings. The other challenge is for pathologists to distinguish lepidic from invasive components such as papillary and acinar patterns. A reproducibility study of classical and difficult selected images of the major lung adenocarcinoma subtypes circulated among a panel of 26 expert lung cancer pathologists documented κ values of 0.77 ± 0.07 and 0.38 ± 0.14, respectively.
      • Thunnissen F.B.
      • Beasley M.B.
      • Borczuk A.
      • et al.
      Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study.
      Reproducibility for the distinction between invasive and lepidic patterns in typical versus difficult cases was 0.55 versus 0.08, respectively, with pathologists divided into two groups, one having a tendency to classify cases as invasive and the other being inclined toward noninvasive classification.
      • Thunnissen F.B.
      • Beasley M.B.
      • Borczuk A.
      • et al.
      Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study.
      A recent study of reproducibility for predominant pattern showed moderate to good κ values of 0.44 to 0.72 for pulmonary pathologists.
      • Warth A.
      • Stenzinger A.
      • von Brunneck A.C.
      • et al.
      Interobserver variability in the application of the novel IASLC/ATS/ERS classification.
      For untrained pathologists, κ values were expectedly lower, ranging from 0.38 to 0.47, but these improved to 0.51 to 0.66 after a training session, and reevaluation by the same reviewers led to very high κ values between 0.79 and 0.87.
      • Warth A.
      • Cortis J.
      • Fink L.
      • et al.
      Training increases concordance in classifying pulmonary adenocarcinomas according to the novel IASLC/ATS/ERS classification.
      To increase accuracy in determination of invasive size, it will be important for pathologists to work to improve reproducibility in the distinction between lepidic and invasive patterns.
      Because of the problem that lepidic growth is frequently underestimated on gross examination, when a substantial amount of this pattern is first appreciated at the time of microscopic examination a careful reevaluation of tumor size needs to be made. Because the gross specimen has already been processed at this point, one of the best ways to get an accurate impression of the tumor size and relative proportion of invasive versus lepidic components is to review the CT. This also can help the pathologist assess whether the lesion has been appropriately sampled. It is stated in the UICC TNM supplement that “in cases of discrepancies of clinically and pathologically detected tumor size the clinical measurement should be used also for the pT classification.”
      So, in cases in which the initial gross assessment of tumor size appears to be inaccurate after radiologic pathologic correlation, the maximum unidimensional tumor size of the lepidic (ground glass) and invasive (solid) components may best be taken from evaluation of the CT and the tumor size can be documented with a note in surgical pathology reports.
      In some cases when pure or predominantly GGNs are surgically resected, after review of the CT, it becomes apparent that the tumor has not been completely sampled and the gross specimen needs to be reevaluated. Because lepidic lesions may be impossible to see grossly, if the initial sections do not resolve the size discrepancy or if the tumor is not adequately represented, random additional sections or the entire specimen may need to be processed. For lepidic predominant adenocarcinomas (including AIS and MIA), specimen inflation at the time of frozen section may help in determining tumor size and in assessing the extent of lepidic versus invasive components.
      • Isaka T.
      • Yokose T.
      • Ito H.
      • et al.
      Comparison between CT tumor size and pathological tumor size in frozen section examinations of lung adenocarcinoma.

      Tumor Size in the Induction Setting

      There is no clearly established method for measuring tumor size of lung cancer in the induction setting. If there is a complete response to treatment with no viable tumor, the tumor is ypT0. In this setting tumor size may not be as significant for predicting prognosis as is the extent of treatment effect. Several clinical studies show that the most important prognostic finding in patients with surgically resected non–small cell lung cancer after induction therapy is a treatment effect of 90% or more, including the percentage of necrosis, inflammation, and stromal tissue, rather than tumor size.
      • Pataer A.
      • Kalhor N.
      • Correa A.M.
      • et al.
      Histopathologic response criteria predict survival of patients with resected lung cancer after neoadjuvant chemotherapy.
      • Hellmann M.D.
      • Chaft J.E.
      • William Jr., W.N.
      • et al.
      Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.
      It is not possible to determine a pretreatment pathologic size for tumors receiving induction therapy, so the pretreatment T descriptor is based on clinical (cT) evaluation and imaging. After definitive treatment, the determination of tumor size (ypT) is based on correlation between imaging and gross and histologic features. Although no prognostic importance has been demonstrated for lung cancer tumor size in the induction setting, a practical way to estimate size is to multiply the percent of viable tumor cells times the size of the total mass. This can be applied in the setting of a single focus or multiple foci of viable tumor. In addition to estimating tumor size for T factor determination, it is important to record the percentage of treatment effect in pathology reports.

      CT Assessment of Lung Nodules

      Recommendations for CT measurement of PSNs are summarized in Table 3.
      Table 3Summary of CT Measurement Recommendations
      • For accurate measurement of small nodules, use contiguous 1-mm sections.
      • For all measurements, use a lung window setting with a sharp filter.
      • Record nodule dimensions to the nearest millimeter.
      • For solid and pure ground glass nodules, record both long and short dimensions on the image (axial or off-axis reconstruction) that shows the greatest average dimension. For staging purposes, only the long axis dimension is used.
      • For part-solid nodules, measure the long and short axis dimensions as stated, but also measure the long axis of the largest solid component.
      • For staging purposes, only the long axis dimension of the solid component is used.
      CT, computed tomography.
      The likelihood of malignancy in a pulmonary nodule is positively correlated with both its size and growth rate.
      • Gould M.K.
      • Donington J.
      • Lynch W.R.
      • et al.
      Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.
      • Gould M.K.
      • Fletcher J.
      • Iannettoni M.D.
      • et al.
      Evaluation of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition).
      Therefore, accurate measurement of nodule size is crucial for three reasons: (1) to determine the risk for malignancy at the baseline CT scan; (2) to correctly allocate the nodule to available management algorithms, in which nodule size is a key criterion; and (3) to detect any change in size on follow-up CT scans.
      Size and growth of pulmonary nodules can be determined by measuring their diameter or volume. Measuring the nodule diameter using electronic calipers is convenient to perform and remains the most widely used routine clinical approach to determine either a maximum nodule or the average of short- and long-axis measurements. For staging purposes, the maximum nodule dimension is still used and recommended. However, for risk estimation in small nodules, we recommend using the average of short- and long-axis measurements, as this approach has been widely used in screening programs and management guidelines and reflects tumor volume better than a single measurement.
      • MacMahon H.
      • Austin J.H.
      • Gamsu G.
      • et al.
      Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society.
      Nodule volumes can also be measured either manually by delineating nodule boundaries or semiautomatically by using software that detects CT density thresholds. Semiautomatic volume determination typically requires a separate application and hence is rarely used in routine clinical practice.
      • de Hoop B.
      • Gietema H.
      • van de Vorst S.
      • Murphy K.
      • van Klaveren R.J.
      • Prokop M.
      Pulmonary ground-glass nodules: increase in mass as an early indicator of growth.
      However, automated segmentation is the initial step underlying recent novel approaches that measure nodule mass rather than size.
      • de Hoop B.
      • Gietema H.
      • van de Vorst S.
      • Murphy K.
      • van Klaveren R.J.
      • Prokop M.
      Pulmonary ground-glass nodules: increase in mass as an early indicator of growth.
      The clinical applicability of this last approach, however, is still under investigation.
      Independent of which nodule component is measured (the solid component, a potential nonsolid component, or both) and regardless of which technical approach is used, the resulting measurement will be affected by a number of technical and observer-related factors that we will briefly discuss.

      Observer and Measurement Variability

      Use of electronic calipers is subject to substantial interreader and intrareader variability.
      • Bogot N.R.
      • Kazerooni E.A.
      • Kelly A.M.
      • Quint L.E.
      • Desjardins B.
      • Nan B.
      Interobserver and intraobserver variability in the assessment of pulmonary nodule size on CT using film and computer display methods.
      • Reeves A.P.
      • Biancardi A.M.
      • Apanasovich T.V.
      • et al.
      The Lung Image Database Consortium (LIDC): a comparison of different size metrics for pulmonary nodule measurements.
      • Revel M.P.
      • Bissery A.
      • Bienvenu M.
      • Aycard L.
      • Lefort C.
      • Frija G.
      Are two-dimensional CT measurements of small noncalcified pulmonary nodules reliable?.
      When applied to volumetric evaluation, a 25% increase in diameter of a spherical nodule corresponds to one volume doubling,
      • Lillington G.A.
      • Caskey C.I.
      Evaluation and management of solitary and multiple pulmonary nodules.
      leading to the possibility that a change in diameter falling within the range of possible error could be misinterpreted either as a significant increase in volume in a stable nodule or as stability in a growing nodule.
      Nodule volumetry is less sensitive to variability and volumetric software–derived measurements show reasonably good reproducibility and good interobserver agreement.
      • Gietema H.A.
      • Wang Y.
      • Xu D.
      • et al.
      Pulmonary nodules detected at lung cancer screening: interobserver variability of semiautomated volume measurements.
      • Goodman L.R.
      • Gulsun M.
      • Washington L.
      • Nagy P.G.
      • Piacsek K.L.
      Inherent variability of CT lung nodule measurements in vivo using semiautomated volumetric measurements.
      • Marchiano A.
      • Calabro E.
      • Civelli E.
      • et al.
      Pulmonary nodules: volume repeatability at multidetector CT lung cancer screening.
      • Wormanns D.
      • Kohl G.
      • Klotz E.
      • et al.
      Volumetric measurements of pulmonary nodules at multi-row detector CT: in vivo reproducibility.
      • Yankelevitz D.F.
      • Reeves A.P.
      • Kostis W.J.
      • Zhao B.
      • Henschke C.I.
      Small pulmonary nodules: volumetrically determined growth rates based on CT evaluation.
      Error between volumetric measurements of the same nodule have typically been shown to vary approximately 10%, although variability as great as 27% has been reported.
      • Gietema H.A.
      • Wang Y.
      • Xu D.
      • et al.
      Pulmonary nodules detected at lung cancer screening: interobserver variability of semiautomated volume measurements.
      • Marchiano A.
      • Calabro E.
      • Civelli E.
      • et al.
      Pulmonary nodules: volume repeatability at multidetector CT lung cancer screening.
      Of particular concern, when the mass of PSNs is measured, interobserver and intraobserver variability ranges from –17.5% to 11.8% and from –8.4% to 9.4%, respectively.
      • Kim H.
      • Park C.M.
      • Woo S.
      • et al.
      Pure and part-solid pulmonary ground-glass nodules: measurement variability of volume and mass in nodules with a solid portion less than or equal to 5 mm.
      Also, different software platforms for nodule volumetry and mass measurements can provide substantially different results.
      • Kim H.
      • Park C.M.
      • Lee S.M.
      • Lee H.J.
      • Goo J.M.
      A comparison of two commercial volumetry software programs in the analysis of pulmonary ground-glass nodules: segmentation capability and measurement accuracy.
      • Petrou M.
      • Quint L.E.
      • Nan B.
      • Baker L.H.
      Pulmonary nodule volumetric measurement variability as a function of CT slice thickness and nodule morphology.
      Ideally, therefore, sequential nodule evaluations should be performed using identical software platforms.

      CT Section Thickness

      Studies of the relation between the accuracy of nodule measurements and CT section thickness have consistently found that variability decreased with section thickness,
      • Petrou M.
      • Quint L.E.
      • Nan B.
      • Baker L.H.
      Pulmonary nodule volumetric measurement variability as a function of CT slice thickness and nodule morphology.
      • Goo J.M.
      • Tongdee T.
      • Tongdee R.
      • Yeo K.
      • Hildebolt C.F.
      • Bae K.T.
      Volumetric measurement of synthetic lung nodules with multi-detector row CT: effect of various image reconstruction parameters and segmentation thresholds on measurement accuracy.
      • Ravenel J.G.
      • Leue W.M.
      • Nietert P.J.
      • Miller J.V.
      • Taylor K.K.
      • Silvestri G.A.
      Pulmonary nodule volume: effects of reconstruction parameters on automated measurements—a phantom study.
      • Wang Y.
      • de Bock G.H.
      • van Klaveren R.J.
      • et al.
      Volumetric measurement of pulmonary nodules at low-dose chest CT: effect of reconstruction setting on measurement variability.
      with 1-mm sections providing the least variability.
      • Wang Y.
      • de Bock G.H.
      • van Klaveren R.J.
      • et al.
      Volumetric measurement of pulmonary nodules at low-dose chest CT: effect of reconstruction setting on measurement variability.
      This effect is particularly pronounced for nodules smaller than 10 mm and for spiculated rather than for smooth nodules.
      • Petrou M.
      • Quint L.E.
      • Nan B.
      • Baker L.H.
      Pulmonary nodule volumetric measurement variability as a function of CT slice thickness and nodule morphology.
      This can be explained by the greater partial volume averaging effect for small nodules when thicker rather than thinner sections are used. As a consequence, use of contiguous high-resolution (≤1-mm) sections for measuring lung nodules is strongly recommended by currently published clinical guidelines. Thin sections also provide enhanced spatial resolution, allowing optimal visual assessment of morphologic characteristics such as nodule shape and spiculations, which refine the assessment of subtle changes over time.
      • Nair A.
      • Baldwin D.R.
      • Field J.K.
      • Hansell D.M.
      • Devaraj A.
      Measurement methods and algorithms for the management of solid nodules.

      Orientation of the CT Section

      Transverse CT reconstructions are the standard basis for clinical reporting of nodule measurements. However, either the largest or smallest dimension of lesions may be aligned along a craniocaudal axis, making their true extent difficult to assess by relying solely on transverse images. In such cases, use of multiplanar reconstructions in the coronal and sagittal plane are recommended for obtaining a more accurate assessment of nodule size. In any nodule, but in PSNs in particular, the CT sections should be chosen for measurements that display the largest average tumor diameter and the largest portion of the solid component, respectively. Often, these will not be displayed on the same section. In such cases, measurements should be performed on the sections that display the largest overall tumor diameter and the largest diameter of the solid component, respectively, and these sections should be identified in the radiology report.

      Display Window Settings

      The effect of display window setting on the apparent size of pulmonary nodules is well established, particularly in the case of subsolid nodules. To date, most studies investigating the accuracy and variability of lung nodule measurements have been performed using wide (lung) window settings.
      • Revel M.P.
      • Bissery A.
      • Bienvenu M.
      • Aycard L.
      • Lefort C.
      • Frija G.
      Are two-dimensional CT measurements of small noncalcified pulmonary nodules reliable?.
      This is because the overall size of subsolid lesions in particular appear artificially smaller when soft-tissue (mediastinal) windows are used on account of density averaging of low-density (ground glass) components. However, when the solid component of these lesions is of concern, measurement of the soft-tissue (solid) component can be performed using narrow (mediastinal or soft-tissue) windows. This method has been called the tumor disappearance rate or ratio.
      • Takahashi M.
      • Shigematsu Y.
      • Ohta M.
      • Tokumasu H.
      • Matsukura T.
      • Hirai T.
      Tumor invasiveness as defined by the newly proposed IASLC/ATS/ERS classification has prognostic significance for pathologic stage IA lung adenocarcinoma and can be predicted by radiologic parameters.
      • Yoshida J.
      • Ishii G.
      • Hishida T.
      • et al.
      Limited resection trial for pulmonary ground-glass opacity nodules: case selection based on high-resolution computed tomography-interim results.
      • Shen W.C.
      • Liu J.C.
      • Shieh S.H.
      • et al.
      Density features of screened lung tumors in low-dose computed tomography.
      • Sakao Y.
      • Kuroda H.
      • Mun M.
      • et al.
      Prognostic significance of tumor size of small lung adenocarcinomas evaluated with mediastinal window settings on computed tomography.
      This is important because it has been shown that measuring the solid component of subsolid nodules correlates best with the likelihood of tumor invasion. Furthermore, use of narrow (mediastinal) windows facilitates demonstration of both the increasing overall tumor density and the increasing size of any solid components over time.
      • 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.
      Edge enhancement in addition to mediastinal window settings may also be useful. This can be easily achieved by applying a soft-tissue window to lung series images to improve the visualization of the margin of the solid component.
      Although it has been suggested that mediastinal window settings may be better than lung windows to assess the size of the solid component,
      • 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.
      there are few data comparing these methods. Recent data for MIA and small lung adenocarcinomas suggest that lung window measurements may give results closer to pathologic measurements
      • Son J.Y.
      • Lee H.Y.
      • Lee K.S.
      • et al.
      Quantitative CT analysis of pulmonary ground-glass opacity nodules for the distinction of invasive adenocarcinoma from pre-invasive or minimally invasive adenocarcinoma.
      • Lee K.H.
      • Goo J.M.
      • Park S.J.
      • et al.
      Correlation between the size of the solid component on thin-section ct and the invasive component on pathology in small lung adenocarcinomas manifesting as ground-glass nodules.
      • Lee S.M.
      • Goo J.M.
      • Lee K.H.
      • Chung D.H.
      • Koh J.
      • Park C.M.
      CT findings of minimally invasive adenocarcinoma (MIA) of the lung and comparison of solid portion measurement methods at CT in 52 patients.
      and that mediastinal windows may underestimate invasive size.
      • Lee S.M.
      • Goo J.M.
      • Lee K.H.
      • Chung D.H.
      • Koh J.
      • Park C.M.
      CT findings of minimally invasive adenocarcinoma (MIA) of the lung and comparison of solid portion measurement methods at CT in 52 patients.
      At the present time, expert opinion tends to favor use of lung or intermediate window settings to detect and measure solid components in subsolid nodules.

      Reconstruction Algorithm and Field of View

      The effects of reconstruction algorithm and field of view on the accuracy of manual and semiautomated lung nodule measurements are controversial.
      • Goo J.M.
      • Tongdee T.
      • Tongdee R.
      • Yeo K.
      • Hildebolt C.F.
      • Bae K.T.
      Volumetric measurement of synthetic lung nodules with multi-detector row CT: effect of various image reconstruction parameters and segmentation thresholds on measurement accuracy.
      • Ravenel J.G.
      • Leue W.M.
      • Nietert P.J.
      • Miller J.V.
      • Taylor K.K.
      • Silvestri G.A.
      Pulmonary nodule volume: effects of reconstruction parameters on automated measurements—a phantom study.
      • Wang Y.
      • de Bock G.H.
      • van Klaveren R.J.
      • et al.
      Volumetric measurement of pulmonary nodules at low-dose chest CT: effect of reconstruction setting on measurement variability.
      • Ko J.P.
      • Rusinek H.
      • Jacobs E.L.
      • et al.
      Small pulmonary nodules: volume measurement at chest CT—phantom study.
      However, the weight of evidence suggests that for nodules small than 10 mm, a high-frequency algorithm is likely to provide the most accurate measurement results, whereas for nodules larger than 10 mm, the choice of the reconstruction algorithm has no substantial effect on measurement accuracy.

      Radiation Dose

      Several studies have concluded that substantial reductions in radiation dose can be achieved without adversely affecting accuracy of nodule measurement. However, it remains important that technique be optimized and varied according to patient size to achieve consistent quality. Although it has been reported that no significant differences in nodule measurements occurred with the introduction of iterative reconstruction (a newer method for greater dose reduction),
      • Willemink M.J.
      • Leiner T.
      • Budde R.P.
      • et al.
      Systematic error in lung nodule volumetry: effect of iterative reconstruction versus filtered back projection at different CT parameters.
      it remains to be determined whether these results will prove valid considering the multiple different iterative reconstruction algorithms currently implemented by various CT manufacturers.

      Lung Volume

      Petkovska et al. measured both the diameters and the volumes of lung nodules on CT examinations acquired at total lung capacity and at residual volume.
      • Petkovska I.
      • Brown M.S.
      • Goldin J.G.
      • et al.
      The effect of lung volume on nodule size on CT.
      They found that both nodule diameters and volumes varied nonuniformly from total lung capacity to residual volume, with some nodules decreasing in size whereas others increased. There was a 16.8% mean change in absolute volume across all nodules. This observation underscores the need for careful control of lung volume for serial CT acquisitions, notably when diagnostic decision making may be based on small changes in nodule size.

      Part-Solid Lesions with Several Solid Components

      Part-solid lesions with several solid components can pose a particular challenge, as there currently is no consensus on how the solid components of these lesions should be measured. One possible approach would be to determine the single largest focus of invasion and to measure this focus while reporting but not measuring the remaining foci. This approach would be similar to the one proposed for microinvasive breast cancer.
      • Hayes D.F.
      • Allred C.
      • Anderson B.O.
      • et al.
      An alternative approach was used by Kadota et al. for measuring the invasive component of part-solid adenocarcinomas on pathologic slides.
      • Kadota K.
      • Villena-Vargas J.
      • Yoshizawa A.
      • et al.
      Prognostic significance of adenocarcinoma in situ, minimally invasive adenocarcinoma, and nonmucinous lepidic predominant invasive adenocarcinoma of the lung in patients with stage I disease.
      These authors measured all invasive components and expressed their sum as a percentage of the overall tumor size. Although this approach has some merit, it has not been tested in the context of CT images and would require highly subjective estimates. Therefore, pending further research and/or development of semiautomated methods, we recommend measuring the long axis of the largest solid component on a sharpened lung window image. If the result is greater than 5 mm, invasion may be considered likely.

      Conclusion

      In summary, for the newly described types of adenocarcinoma of the lung, we recommend incorporating the coding of AIS as Tis (AIS) and of MIA as T1mi into the traditional TNM classification using its standard rules. For part-solid tumors, the size of the invasive component should be used to assign a T category, but the whole tumor size should also be recorded. However, regardless of which nodule component is evaluated, the measurements will be influenced by a number of observer-dependent and technical factors. From a practical perspective, it is important to perform the measurements for clinical staging on contiguous thin CT sections reconstructed with a high-resolution algorithm with multiplanar reconstruction. Tube current settings below the standard dose seem to have little effect on nodule measurements within certain limits and should be used for nodule surveillance and screening. For serial CT examinations, the inspiratory status and all technical settings should be kept as constant as possible. Finally, any interpretation of absolute volume size and potential change over time should take into consideration the magnitude of potential observer variability, and it should be made with appropriate clinical judgment. For pathologic staging, attention should be given to assessment of invasive and lepidic components. It can be helpful to correlate microscopic findings with measurements made on gross examination, particularly in inflated specimens or with CT findings. A list of key questions is provided to guide future research in the assessment tumor size for TNM in lung adenocarcinomas presenting with subsolid nodules by CT or with a lepidic component by pathologic examination.

      Research Questions

      Pathology

      • 1.
        What is the best method for measuring the size of the invasive versus lepidic components?
      • 2.
        What is the reproducibility of measuring size in invasive versus lepidic components, and how can this be improved?
      • 3.
        If multiple areas of invasion are present, is there a clinical difference between using the total size multiplied by the percentage of invasive components versus the greatest dimension of the largest invasive focus?
      • 4.
        What impact should scar size or prominent stromal desmoplasia and stromal inflammation have on determining size of the invasive component?
      • 5.
        What is the outcome of MIAs if they have an invasive component with a predominantly solid or micropapillary pattern or if they show giant cell and spindle cell components that fail to qualify for a diagnosis of pleomorphic carcinoma?
      • 6.
        What is pathologists’ ability to separate AIS from MIA and LPA on frozen section?
      • 7.
        Does correlation with CT findings help in determining lepidic versus invasive size?
      • 8.
        What is the optimal method for processing gross specimens suspected to be AIS, MIA, or LPA? Does inflation of the specimen help?
      • 9.
        What role does gross examination play in determining lepidic versus invasive size?
      • 10.
        What are the pathologic findings in lesions suspected to be AIS, MIA, and LPA by CT?

      Radiology

      • 1.
        How should invasive size be measured in tumors with multiple solid areas rather than a single focus?
      • 2.
        What is the reproducibility for measuring solid versus ground glass size in lung adenocarcinoma?
      • 3.
        Can volumetric measurements aid in assessing invasive size?
      • 4.
        What is the best method for measuring the invasive component: lung versus mediastinal windows?
      • 5.
        Is unidimensional size better than bidimensional size for TNM staging?
      • 6.
        Can computerized segmentation of the solid component from the ground glass component aid in assessing invasive size?
      • 7.
        Can the mass of the subsolid nodule be a predictor of invasive size?
      • 8.
        Does diffusion-weighted magnetic resonance imaging play a useful role in determining tumor size?

      Surgery

      • 1.
        Should the extent of surgical resection be adapted to the size of the invasive component or only to the whole tumor size?
      • 2.
        What are safe resection margins for AIS, MIA, and LPA?
      • 3.
        Which specific nodal dissection is required for AIS, MIA, and LPA? Should it be adapted to the precise location of the tumor (upper versus lower lobes or central versus peripheral lung)?

      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 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 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.

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