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

Accepted Manuscript 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 William D. Travis, MD, Hisao Asamura, MD, Alexander A. Bankier, MD, PhD, Mary Beth Beasley, MD, Frank Detterbeck, MD, Douglas B. Flieder, M.D., Jin Mo Goo, MD, Heber MacMahon, MB, BCh, David Naidich, MD, Andrew Nicholson, DM, FRCPath, Charles A. Powell, MD, Mathias Prokop, MD, Ramon Rami-Porta, MD, FETCS, Valerie Rusch, MD, Paul van Schil, MD, Yasushi Yatabe, MD, on behalf of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee and Advisory Board Members PII:

S1556-0864(16)30335-5

DOI:

10.1016/j.jtho.2016.03.025

Reference:

JTHO 170

To appear in:

Journal of Thoracic Oncology

Received Date: 27 January 2016 Revised Date:

21 March 2016

Accepted Date: 24 March 2016

Please cite this article as: Travis WD, Asamura H, Bankier AA, Beasley MB, Detterbeck F, Flieder DB, Goo JM, MacMahon H, Naidich D, Nicholson A, Powell CA, Prokop M, Rami-Porta R, Rusch V, van Schil P, Yatabe Y, on behalf of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee and Advisory Board Members, 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, Journal of Thoracic Oncology (2016), doi: 10.1016/j.jtho.2016.03.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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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

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William D. Travis, MD1, Hisao Asamura, MD2, Alexander A. Bankier, MD, PhD3, Mary Beth Beasley, MD,4 Frank Detterbeck, MD5, Douglas B. Flieder, M.D.6, Jin Mo Goo, MD7, Heber MacMahon, MB, BCh8, David Naidich, MD9, Andrew Nicholson, DM, FRCPath10, Charles A. Powell, MD11, Mathias Prokop, MD12, Ramon Rami-Porta, MD, FETCS13, Valerie Rusch, MD14, Paul van Schil, MD15, Yasushi Yatabe, MD16, on behalf of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee and Advisory Board Members *

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1 Dept of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY , USA 2 Division of Thoracic Surgery, Keio University, School of Medicine, Tokyo, Japan 3 Dept of Radiology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA 4 Dept of Pathology, Ichan School of Medicine at Mount Sinai, New York, USA 5 Thoracic Surgery, Yale School of Medicine, New Haven, CT, USA 6 Dept of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA 7 Dept of Radiology, Seoul National University College of Medicine, Seoul, South Korea 8 Dept of Radiology, University of Chicago, Chicago, IL, USA 9 Dept of Radiology, New York University Langone Medical Center, New York, NY, USA 10 Dept of Histopathology, Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, UK 11 Pulmonary Critical Care and Sleep Medicine, Ichan School of Medicine, New York, NY, USA 12 Dept of Radiology, Radboud University Nymegen Medical Center, Nymegen, Netherlands 13 Dept of Thoracic Surgery, Hospital Universitari Mutua Terrassa and CIBERES Lung Cancer Group, Terrassa, Barcelona, Spain 14 Thoracic Surgery Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA 15 Dept of Thoracic and Vascular Surgery, Antwerp University Hospital, Edegem, Belgium 16 Dept of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan * See appendix

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Correspondence to:

William D. Travis, Dept. of Pathology Memorial Sloan Kettering Cancer Center 1275 York Ave New York, NY, USA 10065 Tel: 212-639-3325; Fax: 212-717-3576 [email protected]

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ABSTRACT

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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 partsolid tumors for the 8th edition of the tumor, node and metastasis (TNM) classification of lung cancer. In 2011 new entities of AIS, MIA and lepidic predominant adenocarcinoma (LPA) were

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defined and were later incorporated in the 2015 World Health Organization classification of lung

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cancer. To fit these entities into the T component of the staging system the Tis category is proposed for AIS, specifying Tis (AIS) if it is to be distinguished from squamous cell carcinoma in situ to be designated Tis (SCIS). We also propose MIA to be classified as T1mi. Furthermore, the use of the invasive size for T-descriptor size follows a recommendation made in three editions of the UICC TNM Supplement since 2003. For tumor size, the greatest dimension

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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

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correlation is not absolute; so when CT features suggest nonmucinous AIS, MIA and LPA, the

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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 non-invasive size based on 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: Adenocarcinoma in situ, lepidic predominant adenocarcinoma, lung cancer, lung cancer staging, minimally invasive adenocarcinoma, TNM classification, tumor size 2

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INTRODUCTION This article addresses fundamental changes in pathologic and clinical classification of

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lung adenocarcinoma that impact on the upcoming revision of the tumor, node and metastasis (TNM) classification of lung cancer, specifically proposals for revision of T categories. Until the 2011 International Association for the Study of Lung Cancer (IASLC)/American Thoracic

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Society (ATS)/European Respiratory Society (ERS) lung adenocarcinoma classification, the World Health Organization (WHO) classification of lung cancer only recognized an in situ (Tis)

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category for squamous cell carcinoma.1 As squamous cell carcinoma in situ is not readily measurable for tumor size, this concept had no implication for T-descriptor size measurement. However, the IASLC/ATS/ERS lung adenocarcinoma classification defined new entities of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and lepidic predominant adenocarcinoma (LPA).2 This has now been formally adopted by the 2015 WHO

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Classification.3 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

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with a lepidic component.

To fit the entities of AIS, MIA and LPA into the categories of the T component of the

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classification for lung adenocarcinoma, we propose to introduce Tis (AIS) to be distinguished from Tis (SCIS). now that in situ carcinoma of the lung can be either squamous cell carcinoma or adenocarcinoma in situ. Since AIS can accompany squamous cell carcinoma and SCIS can accompany adenocarcinoma, it is useful to specify the histologic type of in situ carcinoma (AIS vs SCIS) for accurate coding purposes. In addition we propose to classify MIA of the lung T1mi.. Furthermore, for nonmucinous lung adenocarcinomas with a lepidic component we

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propose to use invasive size for T-descriptor size as recommended by the UICC TNM Supplements since 2003.4-6

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In lung adenocarcinomas, the CT findings of ground glass versus solid opacities tend to correspond respectively to lepidic versus invasive patterns seen pathologically.2 However, this correlation is not absolute, so when CT features suggest the entities of AIS, MIA and LPA, the

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suspected diagnosis and clinical staging, should be regarded as a preliminary assessment that is subject to revision after pathologic evaluation of resected specimens (Figure 1). Although the

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solid component in a part solid nodule seen by CT has a greater chance of having an invasive component on histology, the solid area could represent a benign scar or a fibrous scar harboring a stromal invasive component.7 Figure 1 summarizes the spectrum of staging categories for small (≤3cm) non-mucinous lung adenocarcinomas with a lepidic component by cT (ground glass vs solid components radiologically) and pT (lepidic vs invasive components pathologically). For

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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 text

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below.

The terminology used to classify nodules by CT is important. Subsolid nodule is a term

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that encompasses both pure ground glass nodules (GGN) and part solid nodules (PSN) which have a ground glass as well as a solid component.8 The following discussion of CT detected GGN or PSN 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 non-neoplastic ground glass lesions which is dealt with elsewhere.9-11

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Figure 1, summarizes the proposals for the 8th Edition T descriptor classification of small small (≤3 cm) lung adenocarcinomas with a ground glass and lepidic component by CT and

PATHOLOGIC STAGING Proposal for AIS to be added to Tis Category

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pathology assessment.

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Recommendation: We propose AIS be added to the category of Tis which currently consists only of squamous cell carcinoma in situ (SCIS). As we introduce AIS as a new category of Tis, it

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is useful to code them 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

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in situ carcinoma does not always match that of the primary carcinoma.

We considered whether diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) should be added to the Tis category as it is regarded as a preinvasive lesion for

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carcinoid tumors. However, we do not recommend this as: a) it is viewed as preneoplastic rather than in-situ disease, b) because this lesion presents as small airways disease without neoplasia in

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about half of the cases,12 and c) 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 pre-existing alveolar structures (lepidic growth), 5

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lacking stromal, vascular, alveolar space or pleural invasion (Figures 1 and 2). Papillary or micropapillary patterns are absent. Intra-alveolar tumor cells, either within the tumor or as spread through alveolar spaces (STAS) in the surrounding parenchyma are absent. AIS is subdivided

showing type II pneumocyte and/or Clara cell differentiation.2, 3

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into non-mucinous and mucinous variants. Virtually all cases of AIS are non-mucinous, typically

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As the literature on the topic of nonmucinous AIS deals with tumors ≤2 or 3 cm, there is insufficient evidence to support that 100% disease free survival can occur in such tumors larger

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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.2, 3

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 to be intra-pulmonary

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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.13-15 This principle is applicable only in non-

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mucinous tumors. Since invasive mucinous adenocarcinoma (IMA) has a strong tendency to

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spread metastatically as multiple nodules within the lung, regardless of any resemblance to mucinous AIS or MIA, when multiple adenocarcinomas with this morphology are found, they are more likely to represent metastatic foci.3 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 TNM classification. Histologically the distinction between AAH and nonmucinous AIS can be difficult. AAH tends to be smaller than 0.5 cm but 6

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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.

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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.3 In this setting correlation with the CT may be helpful to anticipate the

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likely diagnosis depending on the extent of ground glass versus solid components.

Proposal for MIA to be added to T1 mi category Recommendation:

We propose that MIA be classified as T1mi. This applies to both

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mucinous and non-mucinous MIA.

Due to the requirement of a lepidic predominant characteristic, as well as lack of vascular, pleural or air space invasion to classify a tumor as MIA (Figures 1 and 3, Table 2), it is

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possible to have a tumor that measures ≤5mm that would be classified as invasive

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adenocarcinoma and therefore be T1a, but not T1mi.

Background:

The WHO defines MIA of the lung as a small, solitary adenocarcinoma, (≤3 cm), with a

predominantly lepidic pattern and ≤ 5 mm invasion (Figure 3,Table 2).2, 3 The size of the invasive area should be measured in the largest dimension.2, 3 If there are multiple foci of invasion, or invasive size is difficult to measure, recent data suggests another way to estimate the

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invasive size is to sum the percentage area of the invasive components and multiply this by the overall tumor diameter (i.e. a 2.0 cm tumor with 20% invasive component would have an estimated invasive size of 0.4 cm).16 If the result is ≤ 0.5 cm, a diagnosis of MIA should be

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rendered. Similar to AIS, MIA is usually non-mucinous but rarely may be mucinous or mixed.2, 3, Non-mucinous MIA typically shows type II pneumocyte and/or Clara cell differentiation and

mucinous MIA shows columnar cells with abundant apical mucin and small, often basally

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oriented nuclei and may show goblet cell morphology. The invasive component to be measured in MIA is defined as follows: 1) histological subtypes other than a lepidic pattern (i.e. acinar,

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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) spread through alveolar spaces.2, 3 If the invasive component is larger than 0.5 cm, the tumor is classified as lepidic predominant adenocarcinoma (Figure 4).

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The proposal of the entities AIS and MIA were based on evidence that patients would have a 100% or near 100% disease free survival, respectively, if these lesions were completely resected.2 So far with a growing number of published cases, no clear recurrences have been

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reported in patients with AIS.16-23 Although rare cases of staple line recurrences are reported in what may have represented MIA,24 these cases were not diagnosed according to the

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IASLC/ATS/ERS adenocarcinoma classification, so it is not possible to be certain if some of the exclusionary criteria such as the recently described invasive pattern of spread through air spaces (STAS) may have been present.25, 26 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.17, 27 When new lung adenocarcinomas develop after resection of MIA, 28 they may represent a second primary rather than a recurrence or

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metastasis.29 Ito et al suggested that MIA be included with AIS as Tis, due to lack of recurrence in their series.30 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.31, 32

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Since 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,2

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does not have implications for staging.

Recommendation:

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Proposal for Invasive Size as a T descriptor

We recommend for lung nonmucinous adenocarcinoma that tumor size be

determined according to the invasive size excluding the lepidic component (Figures 1, 4 and 5). Total tumor size should also be recorded (i.e. the maximum measurement of the ground glass or

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lepidic component), but only the invasive component is used as a descriptor of the T-categories. Invasive mucinous adenocarcinomas should be staged like other invasive adenocarcinomas,

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regardless of the extent of lepidic component.

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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.33, 34 It has been shown to be an independent predictor of survival in many publications including large databases like those assembled by the NCI’s SEER Registry and the IASLC.33, 35-37 In lung cancer TNM staging has traditionally been based on total tumor size.32, 38, 39 Data are accumulating in both the radiologic and pathologic literature to support the concept that invasive size is a better predictor of survival than total tumor size in lung adenocarcinoma.17, 20, 40-47 The evidence that prognosis is better predicted after 9

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adjusting the size T-descriptor according to the invasive size in adenocarcinomas with a subsolid appearance by CT or a lepidic component by pathology is based primarily upon data from small tumors (≤3 cm) with a substantial ground glass or lepidic component. More evidence is needed

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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 to use only invasive size as the T-descriptor for

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all tumors, regardless of the size and extent of the lepidic component (Figures 4 and 5).

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Background

Also, in the last three TNM Supplements beginning in 2001, the UICC has recommended that size should be measured by the invasive size.4-6 So our proposal is not creating a new rule for TNM, but it is the first time this rule is recommended to be applied to lung cancer staging.

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The 2001, 2003 and 2012 TNM supplements recommends 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.4-6 Given the new concept of lepidic versus invasive components in lung

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adenocarcinoma, a similar approach can now be applied to lung adenocarcinoma by only using

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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 (BAC) with a variety of meanings both invasive and non-invasive 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.2, 3 So when there is a mixture of invasive and non-invasive components, the term lepidic pattern rather than “in situ” adenocarcinoma is used for the non-invasive component that 10

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spread along the surface of alveolar walls in tumors that meet criteria for MIA or LPA. Therefore AIS is not interchangeable with lepidic growth; all AIS are lepidic, but not all tumors

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with lepidic growth are AIS if they have an invasive component. Adenocarcinomas with a predominant lepidic component that measures > 3 cm in total size or that have an invasive component measuring >0.5 cm are classified as lepidic predominant

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adenocarcinomas (Figure 4).2, 3 It is extremely rare for adenocarcinomas with pure lepidic

growth lacking invasion to measure >3.0 cm. However, due to the lack of evidence for patients

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with such tumors to have 100% disease free survival, these tumors are classified as LPA rather than AIS. 2, 3 Even if after pathologic examination of the entire tumor, the tumor shows a pure lepidic pattern without any invasive component, these tumors are classified as LPA rather than a

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very large AIS.2, 3

CLINICAL STAGING

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CT Features of Tis (AIS)

By CT most nonmucinous AIS will appear as a pure ground glass nodule measuring

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between 0.5-3.0 cm (Figures 1 and 6).48-52 Moreover, in typical cases, no abnormalities of neighboring anatomical structures, such as pulmonary vessels or pleural structures are noted. However, in some cases where the pathology shows collapse of alveolar walls and elastosis or benign scarring, it may show a part solid appearance.51, 53 Not all pure ground glass nodules are AIS on pathologic examination, although smaller lesions (<1.0 cm) are more likely to be a preinvasive lesion (AIS or AAH).54-56 On final pathology resected pure GGN that show features of adenocarcinoma can also show MIA or invasive adenocarcinoma in addition to AIS. Son et al 11

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studied 191 resected ground glass nodules that had been diagnosed as AIS, MIA or invasive adenocarcinoma and on pathology found only 38 (20%) were AIS, while 61 (32%) were MIA and 92 (48%) were invasive adenocarcinoma.57 They also found increased density (75th

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percentile CT attenuation value on histogram ≥-470 HU) and entropy (a measure of heterogeneity by texture irregularity) predicted invasive adenocarcinoma.57 On pathologic examination of 46 pure GGN larger than 1.0 cm by thin section CT scan, Lim et al found MIA in

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20% of cases and invasive adenocarcinoma in 39%, however no patient had recurrence including those that underwent sublobar resection.58 An invasive component correlated with the presence

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of larger size (>16.4 mm) and increased mass (>0.472 g, determined by multiplying nodule volume by mean nodule density).58 This suggests that not only size, but also attenuation value of GGN may be useful to predict invasive histology. In a study of 85 pure GGN Mimae et al., found invasive adenocarcinoma in 41% of cases, although they did not make a pathologic distinction Invasive adenocarcinoma

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between MIA, LPA and other invasive adenocarcinomas.59

components were found in 3 of 13 (23%) of pure GGN ≤1 cm.59 Several studies published before the 2011 IASLC/ATS/ERS lung adenocarcinoma classification also showed that a subset of

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patients with pure GGN can show invasive adenocarcinoma on histologic evaluation. In 41 pure GGN ≤1 cm, Nakata et al reported BAC (probably AIS, MIA or LPA) in 28 patients, AAH in 10

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patients and invasive adenocarcinoma in 3 patients with no recurrences in any of these cases.55 Nakamura et al reported 23 GGN and 3 of these showed invasive components which were probably either MIA or LPA.60 Pure GGN <0.5 cm usually represent AAH.2, 3 However, the mean size of AAH on CT can be larger than 0.5 cm and AIS can be smaller.61, 62 In addition to smaller size, AAH have

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lower density compared to AIS, MIA and other adenocarcinomas.61 The presence of a lobulated border also favors malignancy rather than AAH.63

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It is extremely rare for adenocarcinomas presenting as pure GGN to measure >3.0 cm, but for reasons explained above, on pathology exam such a tumor would be regarded as probable lepidic predominant adenocarcinomas.2, 3 Rather than cTis or cT1mi, such tumors should be

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classified according to their size for clinical staging realizing this may be revised after pathologic evaluation (Figure 1).

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Mucinous AIS is more likely to show a solid or part solid nodule with air bronchograms.64

CT Features of MIA T1mi

By CT, nonmucinous MIA usually show a part solid nodule with a total size of ≤3.0 cm

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and a small solid component (Figures 1 and 7) but they can also show a pure ground glass nodule in 17-54% of cases and rarely a solid nodule.49, 65, 66 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

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of ≤0.5 cm seen by pathology and in one study the mean size was 0.6 cm +/-0.22 cm.66 Several

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CT studies have suggested if the size of the solid component is ≤ 0.5 cm48 or ≤ 0.3 cm65 there is a good prediction of MIA. 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.49 Higher attenuation of a solid component favors MIA over AIS or AAH.49 Mucinous MIA is more likely to show a solid or part solid nodule with air bronchograms.64, 66

HOW TO MEASURE TUMOR SIZE

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There are key differences between the radiologic and pathologic measurement of the size of ground glass nodules (GGN) and part solid nodules (PSN) of lung adenocarcinoma. The Fleischner Society and American College of Radiology Guidelines have recommended for small

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solid and subsolid nodules that the overall size of the ground glass and/or solid components be based on the bidimensional average of the long and short dimensions in order to estimate risk.8, 67, 68

However, for TNM staging purposes, the single largest dimension measured on CT sections

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using thin sections and multiplanar reconstructions is still used (Figures 1 and 7-9).33, 34 For pathologic assessment, although three dimensional measurements are frequently recorded in

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pathology reports, the single maximum diameter is traditionally used for pTNM staging. Tumor size measured to determine the T categories is based on clinical (radiologic or intraoperative) and pathologic (gross and/or microscopic) assessment (Figure 1). Tumor size should be recorded in centimeters including millimeter increments. In nonmucinous lung

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adenocarcinomas, the histologic lepidic growth pattern tends to correlate with the ground glass component of lung nodules while solid components correlate with invasive adenocarcinoma patterns. Clinical assessment is frequently performed by CT. CT measurements of pulmonary

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nodules, however, are influenced by a number of technical and observer-related factors

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summarized below. Moreover, there is no general consensus about how to perform CT measurements of pulmonary nodules, notably of part-solid nodules, as numerous potential factors of influence are still controversial. The many facets of this discussion, together with technical information and practical recommendations are summarized below. 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.2, 69 Furthermore the prognostic significance of lepidic vs 14

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invasive components is not well documented in these tumors as it is in nonmucinous adenocarcinomas.2 Therefore the following recommendations are applicable only to

PATHOLOGIC ASSESSMENT OF TUMOR SIZE

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nonmucinous adenocarcinomas with a lepidic component.

Pathologic assessment (pT) of tumor size in most cases is made by gross measurement

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using a ruler placed along the tumor in the gross specimen to estimate three dimensional sizes.53 In some cases, this is best done after making a cross section of the tumor, which may allow for

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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, since this step can

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reveal discrepancies that lead to significant revision of the gross estimated tumor size. Some lung cancers have a substantial amount of non-neoplastic components such as fibrosis, organizing pneumonia or an inflammatory process that can lead to an exaggerated gross size

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assessment. Since 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

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generally included in total tumor size measurements, 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 made 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.

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There are challenges in pathology assessment of lung cancer tumor size. These 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

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growth and non-neoplastic components that may contribute to mass formation such as fibrous scars, inflammation and organizing pneumonia.2, 70, 71 Several studies have shown that gross pathologic measurements can underestimate tumor size compared to measurements by CT

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scan.70, 72 Tumors have been shown to shrink after formalin fixation, so gross pathologic measurements made following fixation may underestimate actual tumor size.70

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Tumors typically have a border which 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 exam. This infiltration beyond the border of an invasive tumor can manifest in several ways. In lung parenchyma surrounding lung cancers,

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some tumors show 1) lymphatic and/or vascular invasion, 2) additional nodules which can show a miliary pattern or 3) spread through airspaces (STAS), a recently newly recognized pattern of invasion.25, 26 Tumor size assessment is based on the measurement to the border of the tumor and

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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 spread through

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air spaces (STAS) recently described as a pattern of invasive growth should not be included in tumor size.25, 26

Our proposal to only use the invasive component for measuring tumor size creates a new

challenge for pathologists in separating the lepidic from the invasive components both on gross and microscopic exam. On gross exam, 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

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expanded alveolar parenchyma.2, 71 Several techniques have been recommended for better visualization of the lepidic component on gross exam following serial sectioning including rinsing the specimen and letting the specimen air dry for a few minutes.71 Others have inflated

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the specimens prior to sectioning with saline, diluted optimal cutting temperature compound (OCT) or formalin.53, 65, 73 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

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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

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adenocarcinoma subtypes circulated among a panel of 26 expert lung cancer pathologists documented kappa values of 0.77 +/- 0.07 and 0.38 +/- 0.14, respectively.74 Reproducibility for the distinction between invasive and lepidic patterns in typical versus difficult cases was 0.55 vs 0.08, respectively, with pathologists divided into two groups, one having a tendency to classify

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cases as invasive whilst the other being inclined towards non-invasive classification.74 A recent study of reproducibility for predominant pattern showed moderate to good κ-values of 0.44 to 0.72 for pulmonary pathologists.75 For untrained pathologists κ-values were expectedly lower

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ranging from 0.38 to 0.47, but these improved after a training session to 0.51 to 0.66 and reevaluation by the same reviewers led to very high κ-values between 0.79-0.87.76 To increase

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accuracy in determination of invasive size, it will be important for pathologists to work to improve reproducibility in the distinction between lepidic versus invasive patterns. Because of the problem that lepidic growth is frequently underestimated on gross exam,

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. Since at this point, the gross specimen has already been processed; one of the best ways to get an accurate impression of the

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tumor size and relative proportion of invasive versus lepidic components is to review the CT. This also can help the pathologist to assess whether the lesion has been appropriately sampled. It is stated in the UICC TNM supplement, “in cases of discrepancies of clinically and

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pathologically detected tumor size the clinical measurement should be used also for the pT

classification”.4, 5 So, in cases where the initial gross assessment of tumor size appears to be inaccurate after radiologic pathologic correlation, the maximum unidimensional tumor size of the

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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.

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In some cases, when pure or predominantly ground glass nodules 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. Since 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

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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 the determination of tumor size and in assessing the extent of

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lepidic versus invasive components.53

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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 the extent of treatment effect. Several clinical studies show that the most important prognostic finding in surgically resected nonsmall cell lung cancer patients following induction therapy is 90% or more treatment effect including the percentage of necrosis, inflammation and stromal tissue, 18

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rather than tumor size.77, 78 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. Following definitive treatment the determination of tumor size (ypT) is

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based on correlation between imaging, 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

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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

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percentage of treatment effect in pathology reports. .

CT ASSESSMENT OF LUNG NODULES

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Recommendations for CT measurement of part solid nodules are summarized in Table 3. The likelihood of malignancy in a pulmonary nodule is positively correlated with both its size and growth rate.10, 79 Therefore, accurate measurement of nodule size is crucial for three reasons:

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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

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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

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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.80 Nodule volumes can also be measured either manually by

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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 employed in routine clinical practice.81 However, automated segmentation is the

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initial step underlying recent novel approaches which measure nodule mass rather than size

82

.

The clinical applicability of this last approach, however, is still under investigation.

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Independent of which nodule component is measured (the solid component, a potential non-solid 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

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briefly discuss.

Observer and measurement variability

Use of electronic calipers is subject to substantial inter- and intrareader variability.83-85

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When applied to volumetric evaluation a 25% increase in diameter of a spherical nodule corresponds to one volume doubling 86 leading to the possibility that a change in diameter falling

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in 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

87-91

.

Error between volumetric measurements of the same nodule have typically shown to vary approximately 10% although variability as great as 27% has been reported,

20

87, 89

. Of particular

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concern, when the mass of part-solid nodules is measured, inter- and intraobserver variability ranges from -17.5% to 11.8% and from -8.4% to 9.4%, respectively 92. Also, different software platforms for nodule volumetry and mass measurements can provide substantially different

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results 93, 94. Ideally, therefore, sequential nodule evaluations should be performed using identical software platforms.

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CT section thickness

Studies of the relation between the accuracy of nodule measurements and CT section

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thickness have consistently found that variability decreased with section thickness

94-97

, with

1mm sections providing the least variability 97. This effect is particularly pronounced for nodules smaller than 10mm and for spiculated rather than for smooth nodules

94

. This can be explained

by the greater partial volume averaging effect for small nodules when thicker rather than thinner

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sections are used. As a consequence, use of contiguous high resolution (≤1mm) sections for measuring lung nodule is strongly recommended by currently published clinical guidelines. Thin sections also provide enhanced spatial resolution allowing optimal visual assessment of

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morphological characteristics such as nodule shape and spiculations that refine the assessment of

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subtle changes over time 81.

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 cranio-caudal axis making their true extent difficult to assess relying solely on transverse images. In such cases, use of multiplanar reconstructions in the coronal and sagittal plane are

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recommended for obtaining a more accurate assessment of nodule size. In any nodule, but in particular in part-solid nodules, the CT sections should be chosen for measurements that display the largest average tumor diameter and the largest portion of the solid component, respectively.

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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 radiological

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report.

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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) 85

. This is because the overall size of subsolid lesions, in particular appear

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window settings

artificially smaller when soft tissue (mediastinal) windows are used due to density averaging of low density (ground glass) components. However, when the solid component of these lesions is

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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 98-100

This is important because it has been shown that measuring the solid

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or ratio (TDR).23,

component of subsolid nodules correlates best with the likelihood of tumor invasion. Furthermore, use of narrow (mediastinal) windows facilitates demonstration both of increasing overall tumor density as well as the increasing size of any solid components over time.8 Edgeenhancement in addition to mediastinal window settings may also be useful. This can be easily

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achieved by applying a soft tissue window to lung series images, to improve the visualization of the margin of the solid component. While it has been suggested that mediastinal window settings may be better than lung

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windows to assess the size of the solid component;8 there is little data comparing these methods. Recent data for MIA and small lung adenocarcinomas suggest that lung window measurements may give results closer to pathologic measurements,57, 65, 66 and that mediastinal windows may 66

At the present time, expert opinion tends to favor use of lung or

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underestimate invasive size,

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intermediate window settings to detect and measure solid components in subsolid nodules.

Reconstruction algorithm and field-of-view (FOV)

The effects of reconstruction algorithm and FOV on the accuracy of manual and semiautomated lung nodule measurements are controversial.95-97,

101

However, the weight of

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evidence suggests that for nodules <10mm, a high frequency algorithm is likely to provide the most accurate measurement results, whereas for nodules >10mm, the choice of the reconstruction

Radiation dose

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algorithm has no substantial effect on measurement accuracy.

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Several studies have concluded that substantial reductions in radiation dose can be

achieved without adversely affecting nodule measurement accuracy. However, it remains important that technique be optimized and varied according to patient size in order 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,

102

it remains to be determined if these results will prove valid

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considering the multiple different iterative reconstruction algorithms currently implemented by various CT manufacturers.

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Lung volume

Petkovska et al. measured both the diameters and the volumes of lung nodules on CT examinations acquired at total lung capacity (TLC) and at residual volume (RV) 103. They found

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that both nodule diameters and volumes varied non-uniformly from TLC to RV, with some nodules decreasing in size, while others increased. There was a 16.8% mean change in absolute

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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.

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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

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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

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the one proposed for microinvasive breast cancer.104 An alternative approach was used by Kadota et al. for measuring the invasive component of part-solid adenocarcinomas on pathologic slides.16These 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

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measuring the long axis of the largest solid component on a sharpened lung window image. If the

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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 the

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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

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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 observerdependent 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 highresolution algorithm with multiplanar reconstruction. Tube current settings below the standard

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dose seem to have little effect on nodule measurements within certain limits and should be employed 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

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of absolute volume size and potential change over time should take into consideration the

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magnitude of potential observer variability, and 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 exam, 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 pathology. 25

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RESEARCH QUESTIONS Pathology

Radiology

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1) What is the best method for measuring the size of the invasive vs lepidic components? 2) What is the reproducibility of measuring size in invasive vs 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 should be the impact of scar size or prominent stromal desmoplasia and stromal inflammation on determining size of the invasive component? 5) What is the outcome of MIA that 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 vs 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 vs invasive size? 10) What are the pathologic findings in lesions suspected to be AIS, MIA and LPA by CT?

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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 vs 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, vs mediastinal windows 5) Is unidimensional better than bidimensional size for TNM staging? 6) Can computerized segmentation of the solid component from 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?

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RESEARCH QUESTIONS (Cont’d)

Surgery

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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 vs lower lobes or central vs peripheral lung)?

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FIGURE LEGENDS Figure 1: Proposed 8th Edition clinical and pathologic T Descriptor classification of small (≤3 cm) lung adenocarcinomas with a ground glass and lepidic

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component by CT and pathology.

The CT images on HRCT can be suggestive of pathologic diagnoses, but they are not specific as ground glass opacities do not always correspond to lepidic patterns and solid components do not

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always correlate with invasive components. However, there is a general correlation between ground glass on CT and lepidic pattern microscopically as well as solid on CT and invasive

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patterns histologically. A pathologic differential diagnosis is listed for each of the proposed possibilities on CT. Final pT staging of these tumors requires complete pathologic examination in resected specimens. Tis (AIS)

cT: These lesions typically show pure GGN measuring ≤3 cm. However, pure GGN can also be

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MIA or invasive adenocarcinoma.58

pT: These tumors show pure lepidic growth without invasion, measuring ≤3cm. If the pure GGN or lepidic predominant nodule measures >3.0 cm, it is classified as T2a or

T1mi

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lepidic predominant adenocarcinoma (see text for explanation). If >4.0 cm it is classified as T2b.

cT: MIA usually shows a ground glass predominant nodule ≤3 cm with a solid component that

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should appear ≤ 0.5 cm. Although some MIAs have a larger solid component on CT due to other benign components such as scar or organizing pneumonia, these cases can only be diagnosed by pathologic examination.

pT: MIA histologically shows a lepidic predominant adenocarcinoma nodule measuring ≤3 cm with an invasive component measuring ≤0.5 cm.

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FIGURE LEGENDS (Cont’d) Figure 1 (cont’d) T1a cT: Ground glass predominant nodules measuring ≤3.0 cm with a solid component measuring

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0.6 - 1.0 cm.

pT: When a lepidic predominant adenocarcinoma measuring ≤3.0 cm has an invasive component measuring 0.6 -1.0 cm, it is classified as pT1a.

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T1b

cT: Ground glass predominant nodules measuring ≤3.0 cm with a solid component measuring

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1.1-2.0 cm.

pT: When a lepidic predominant adenocarcinoma measuring ≤3.0 cm has an invasive component measuring 1.1- 2.0 cm it is classified as pT1b.

T1c

cT: Ground glass predominant nodules measuring ≤3.0 cm with a solid component measuring

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2.1 -3.0 cm it is classified as T1c

pT: When an invasive adenocarcinoma with a lepidic component measuring ≤3.0 cm has an invasive component measuring 2.1--3.0 cm it is classified as T1c.

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* All of the cT categories are presumptive, assuming the ground glass vs solid components correspond to lepidic vs invasive components, respectively, on pathologic examination of a resected specimen. cT category applying rule number 4 of the TNM classification (when in doubt, opt for the lesser category)

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† In cases where there are multiple foci of solid or invasive components, see text for estimation of invasive size. ‡ Size is not the only distinguishing feature between AAH and AIS. †† 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 HRCT = high resolution CT; GG = ground glass; AD=adenocarcinoma Figure 2: Pathology of Non-mucinous 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.

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FIGURE LEGENDS (Cont’d) Figure 3: Pathology of Minimally invasive non-mucinous adenocarcinoma A This subpleural adenocarcinoma tumor consists primarily of lepidic growth (left) with a small area of invasion (arrow) measuring less than 0.5 cm. B This is the lepidic area of the tumor. C These acinar

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glands are invading in the fibrous stroma.

Figure 4: Pathology of Lepidic predominant adenocarcinoma. A Lepidic predominant pattern with mostly lepidic growth and a smaller area of invasive acinar adenocarcinoma (arrow). B

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Lepidic predominant adenocarcinoma. A Lepidic pattern consists of a cellular proliferation of pneumocytes along the surface of the alveolar walls. C Area of invasive acinar adenocarcinoma

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with crowded back to back glands within fibrous stroma.

Figure 5: Pathology 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-shaped 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.

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Figure 6: CT of Non-mucinous adenocarcinoma in situ. A) CT shows a circumscribed groundglass nodule lacking any solid component. B) The longest diameter of the nodule measures 2.3 cm.

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Figure 7: CT of Nonmucinous minimally invasive adenocarcinoma. A: CT 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 measures 0.47 cm which

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corresponded to invasion by pathologic exam. Figure 8: CT of Lepidic predominant adenocarcinoma. A: CT 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 measures 0.9 cm (cT1a). Figure 9: CT of Invasive adenocarcinoma with small lepidic component. A: CT shows a part solid nodule which is mostly solid with a minor ground glass component. B: The total size is 2.8 30

ACCEPTED MANUSCRIPT T-Component Changes in Lung Adenocarcinoma

cm (T1c); C: The longest diameter of the solid component measures 1.7 cm (T1b). A second ground glass nodule is adjacent to the part solid nodule. TABLE 1: ADENOCARCINOMA IN SITU†

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Pathologic Criteria A small tumor ≤3 cm

•

A solitary adenocarcinoma‡

•

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 (STAS)

•

Cell type mostly non-mucinous (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 non-mucinous adenocarcinoma in situ

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•

†Modified from references2, 3

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‡When multiple AIS are found, they should be regarded as separate primaries rather than intrapulmonary metastases

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TABLE 2: MINIMALLY INVASIVE ADENOCARCINOMA† Pathologic Criteria A small tumor ≤3 cm

•

A solitary adenocarcinoma‡

•

Predominantly lepidic growth

•

Invasive component ≤0.5 cm in greatest dimension in any one focus

•

Invasive component to be measured includes

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•

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o 1) any histologic subtype other than a lepidic pattern (such as acinar, papillary, micropapillary, solid, colloid, fetal or invasive mucinous adenocarcinoma) •

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o 2) tumor cells infiltrating myofibroblastic stroma

The diagnosis of minimally invasive adenocarcinoma is excluded if the tumor o 1) invades lymphatics. blood vessels, air spaces or pleura, o 2) contains tumor necrosis,

o 3) spread through air spaces (STAS) •

The cell type in most cases consists of non-mucinous (type II pneumocytes or Clara

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cells), but rarely may be mucinous (tall columnar cells with basal nuclei and abundant cytoplasmic mucin, sometimes resembling goblet cells). † Modified from references2, 3

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‡When multiple AIS are found, they should be regarded as separate primaries rather than intrapulmonary metastases

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TABLE 3: SUMMARY OF CT MEASUREMENT RECOMMENDATIONS

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•

For accurate measurement of small nodules, use contiguous 1mm 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 above, 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.

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• • • •

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APPENDIX

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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, MI, United States of America (USA); Ricardo Beyruti, University of Sao Paulo, Brazil; Vanessa Bolejack, Cancer Research And Biostatistics, Seattle, WA, USA; Kari Chansky, Cancer Research And Biostatistics, Seattle, WA, USA; John Crowley, Cancer Research And Biostatistics, Seattle, WA, USA; Frank Detterbeck, Yale University, New Haven, CT, USA; 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, WA, USA; 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, NY, USA; Catherine Kennedy, University of Sydney, Sydney, Australia; Jhingook Kim, Samsung Medical Center, Seoul, Korea; Young Tae Kim, Seoul National University, Seoul, South Korea; Laura Kingsbury, Cancer Research And Biostatistics, Seattle, WA, USA; 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, MD Anderson Cancer Center, Houston, TX, USA; Jan van Meerbeeck, Antwerp University Hospital, Edegem (Antwerp), Belgium; Alan Mitchell, Cancer Research And Biostatistics, Seattle, WA, USA; Takashi Nakano, Hyogo College of Medicine, Hyogo, Japan; Andrew G. Nicholson, Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, United Kingdom; Anna Nowak, University of Western Australia, Perth, Australia; Michael Peake, Glenfield Hospital, Leicester, United Kingdom; Thomas Rice, Cleveland Clinic, Cleveland, OH, USA; Kenneth Rosenzweig, Mount Sinai Hospital, New York, NY, USA; Enrico Ruffini, University of Torino, Torino, Italy; Valerie Rusch, Memorial SloanKettering Cancer Center, New York, NY, USA; 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, WA, USA; Kelly Stratton, Cancer Research And Biostatistics, Seattle, WA, USA; Kenji Suzuki, Juntendo University, Tokyo, Japan; Yuji Tachimori, National Cancer Center, Tokyo, Japan; Charles F. Thomas Jr, Mayo Clinic, Rochester, MN, USA; William Travis, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Ming S. Tsao, The Princess Margaret Cancer Centre, Toronto, Ontario, Canada; 34

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Andrew Turrisi, Sinai Grace Hospital, Detroit, MI, USA; 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.

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Advisory Board of the IASLC Mesothelioma Domain Paul Baas, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Jeremy Erasmus, MD Anderson Cancer Center, Houston, TX, USA; Seiki Hasegawa, Hyogo College of Medicine, Hyogo, Japan; Kouki Inai, Hiroshima University Postgraduate School, Hiroshima, Japan; Kemp Kernstine, City of Hope, Duarte, CA, USA; Hedy Kindler, The University of Chicago Medical Center, Chicago, IL, USA; Lee Krug, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Kristiaan Nackaerts, University Hospitals, Leuven, Belgium; Harvey Pass, New York University, NY, USA; David Rice, MD Anderson Cancer Center, Houston, TX, USA.

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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, DC, USA; Kazuya Kondo, University of Tokushima, Tokushima, Japan; Marco Lucchi, University of Pisa, Pisa, Italy; Meinoshin Okumura, Osaka University, Osaka, Japan.

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Advisory Board of the IASLC Esophageal Cancer Domain Eugene Blackstone, Cleveland Clinic, OH, USA.

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TABLE 1: ADENOCARCINOMA IN SITU†

RI PT

Pathologic Criteria A small tumor ≤3 cm

•

A solitary adenocarcinoma‡

•

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 (STAS)

•

Cell type mostly non-mucinous (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 non-mucinous adenocarcinoma in situ

TE D

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†Modified from references2, 3

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TABLE 2: MINIMALLY INVASIVE ADENOCARCINOMA† Pathologic Criteria A small tumor ≤3 cm

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A solitary adenocarcinoma‡

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Predominantly lepidic growth

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Invasive component ≤0.5 cm in greatest dimension in any one focus

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Invasive component to be measured includes

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o 1) any histologic subtype other than a lepidic pattern (such as acinar, papillary, micropapillary, solid, colloid, fetal or invasive mucinous adenocarcinoma) •

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o 2) tumor cells infiltrating myofibroblastic stroma

The diagnosis of minimally invasive adenocarcinoma is excluded if the tumor o 1) invades lymphatics. blood vessels, air spaces or pleura, o 2) contains tumor necrosis,

o 3) spread through air spaces (STAS) •

The cell type in most cases consists of non-mucinous (type II pneumocytes or Clara

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cells), but rarely may be mucinous (tall columnar cells with basal nuclei and abundant cytoplasmic mucin, sometimes resembling goblet cells). † Modified from references2, 3

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TABLE 3: SUMMARY OF CT MEASUREMENT RECOMMENDATIONS

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For accurate measurement of small nodules, use contiguous 1mm 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 above, 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.

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