ERS Classification: A Pooled Analysis of Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma

Original Study

Lung Adenocarcinoma Staging Using the 2011 IASLC/ATS/ERS Classification: A Pooled Analysis of Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma Madhusmita Behera,1 Taofeek K. Owonikoko,1 Anthony A. Gal,2 Conor E. Steuer,1 Sungjin Kim,3 Rathi N. Pillai,1 Fadlo R. Khuri,1 Suresh S. Ramalingam,1 Gabriel L. Sica2 Abstract We conducted a systematic analysis of published data to evaluate the prognostic differences between the adenocarcinoma in situ and minimally invasive adenocarcinoma subcategories of lung adenocarcinoma. No significant differences were found in the survival rates between patients with minimally invasive adenocarcinoma and adenocarcinoma in situ lung adenocarcinoma. Our results raise questions regarding the need for the substaging of these tumor types. Background: Lung adenocarcinoma accounts for almost 60% of nonesmall-cell lung cancer. According to the 2011 International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) classification and 2015 World Health Organization classification of tumors of the lung, lepidic-predominant adenocarcinomas
3 cm in size can be classified as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma, lepidic predominant. AIS lesions, which are noninvasive, and MIA lesions, which show
0.5 cm of invasion, have been recommended to be considered stage pTis (adenocarcinoma) and pT1(mi), respectively. We conducted a systematic analysis of the published data to evaluate the prognostic differences between AIS and MIA. Materials and Methods: A comprehensive search of published studies was conducted from the electronic databases using relevant search criteria. Studies that reported outcomes for  8 cases classified as AIS or MIA using the 2011 IASLC/ATS/ERS criteria were selected for the present analysis. A systematic analysis of the extracted data were performed using Comprehensive Meta-Analysis software, version 2.2. Results: Nineteen studies published from 2011 to 2015 were eligible. A total of 972 patients were included (429 with AIS and 294 with MIA; 2 studies reported AIS and MIA together, n ¼ 249). The median age was 65.5 years, 63% were female, and 40% were smokers. The 5-year disease-free survival rate for the whole population was 97.9%. The 5-year disease-free survival rate was 100% for AIS and MIA pooled from the studies that reported the 2 groups separately. The 5-year overall survival rate for the entire group was 97.5%, and the 5-year overall survival rate was 100% for AIS and 98.5% for MIA. Conclusion: No significant differences were found in the survival rates between patients with lung adenocarcinoma categorized as MIA or AIS. This finding raises questions regarding the evidence for TNM staging of AIS and MIA as recommended by the 2011 IASLC/ATS/ERS and 2015 World Health Organization classification of tumors of the lung and should be reevaluated with further studies. Clinical Lung Cancer, Vol. 17, No. 5, e57-64 ª 2016 Elsevier Inc. All rights reserved. Keywords: 2011 classification, AIS, MIA, Staging, Survival This work was presented as a poster and was selected for a press release in the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology, October 30 to November 1, 2014, Chicago, IL. 1

Department of Hematology and Medical Oncology 2 Department of Pathology and Laboratory Medicine, Winship Cancer Institute of Emory University, Atlanta, GA 3 Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, CA

1525-7304/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2016.03.009

Submitted: Dec 23, 2015; Revised: Mar 22, 2016; Accepted: Mar 22, 2016; Epub: Mar 30, 2016 Address for correspondence: Gabriel L. Sica, MD, PhD, Department of Pathology and Laboratory Medicine, Winship Cancer Institute of Emory University, 1365 Clifton Road, Atlanta, GA 30322 E-mail contact: [email protected]

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LUAC Staging and 2011 IASLC/ATS/ERS Classification Introduction Lung cancer (LC) is the leading cause of cancer-related mortality1,2 and one of the most commonly diagnosed cancers worldwide.3 In 2014, about 224,210 new cases were estimated in the United States,4 with nonesmall-cell LC (NSCLC) accounting for about 85% of all LC cases. The 5-year survival rate of patients diagnosed with NSCLC has been 15% in the United States, as reported by the Surveillance, Epidemiology, and End Results program.5 Although modest therapeutic gains have been achieved with conventional therapies and new molecularly targeted approaches, the long-term outlook for patients with advanced-stage disease remains grim.6 In this context, the stage at diagnosis remains the most important prognostic factor, evidenced by 5-year overall survival (OS) patients with for stage I NSCLC of nearly 67% after surgical resection.7 However, even among patients with stage I disease, the outcomes have been widely disparate and approximately one third of patients will experience disease recurrence.8 In these early-stage lung cancers, in particular, lung adenocarcinoma (LAC), pathologic features such as predominant architectural growth pattern and/or grade have been shown to predict indolent or aggressive biologic behavior.7,9-15 LAC is the most commonly diagnosed histologic subtype of LC,16 with smoking a major cause.17 According to the 2004 World Health Organization (WHO) histologic classification of LC, LAC is categorized into 5 main histologic subtypes: lepidic (formerly known as bronchioloalveolar carcinoma [BAC]), acinar, papillary, solid, and mixed subtypes.18 Most cases of LAC have been categorized as the mixed subtype.19 Studies have shown that patients with pathologically proven stage I LAC, diagnosed as lepidic or mixed subtype with a predominant lepidic pattern according to the 2004 WHO classification of LAC have better outcomes, with a 5-year survival of nearly 100% after curative surgical therapy.20,21 In 2011, a multidisciplinary group endorsed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) proposed a reclassification of LAC to increase the understanding of the disease, predict the outcomes, and improve patient care.22 The new classification recognized the importance of specific, predominant histologic patterns and tumor size. Accordingly, tumors formerly classified as BAC
3 cm with no invasion were reclassified as adenocarcinoma in situ (AIS) and tumors formerly classified as BAC or BAC with predominant mixed subtype LAC
3 cm with
0.5 cm of invasion (defined as any pattern other than lepidic; and tumor invading the myofibroblastic stroma) were reclassified as minimally invasive adenocarcinoma (MIA). A defining feature of both of the proposed AIS and MIA tumor types is the presence of the lepidic growth pattern, with small nonlepidic LAC excluded. The category of AIS was recommended to define patients who should have 100% disease-free survival (DFS) with complete tumor resection owing to the preinvasive nature of these tumor types.22 The category of MIA was recommended to define patients who should have nearly 100% DFS with complete resection.22 This implies that AIS and MIA might need to be substaged into preinvasive and microinvasive pathologic tumor staging for TNM. These definitions and staging proposals were subsequently published in the 2015 WHO classification of LAC.23 However, these

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staging categories were based on limited available evidence, necessitating further validation. To examine the clinical significance of the rationale for distinguishing between AIS and MIA further, we conducted a pooled analysis of recently published data to evaluate the survival differences between patients categorized as having AIS or MIA using the 2011 IASLC/ATS/ERS classification criteria.

Materials and Methods Search Strategy A comprehensive and methodical search of the MEDLINE, EMBASE, and Cochrane electronic databases for data from 2011 to 2015 was conducted. The relevant and specific search terms (lung adenocarcinoma classification, AIS, MIA, 2011 IASLC/ATS/ERS classification) in the title and abstract were used to retrieve studies.

Study Selection and Eligibility All studies were independently reviewed by 2 of us for eligibility. All studies that reported the 5-year survival outcomes data for  8 patients classified as having AIS or MIA were included in the analysis. Not all studies reported both DFS and OS data. The studies were eligible if  1 of the 2 outcomes was reported.

Data Extraction and Statistical Analysis Standardized data compilation templates were used to extract the data from the eligible studies, including sample size, demographic data, tumor pathologic features, and DFS and OS rates. Not all studies reported the demographic data. A systematic analysis of the extracted data was performed using the Comprehensive MetaAnalysis software, version 2.2, under the random effect model. The results are reported as the pooled proportions of the weighted estimates. A formal statistical test of heterogeneity between studies was performed using the I2 test.24 Two-tailed t tests with a significance level of .05 were used for all comparisons.

Results A total of 335 studies published from 2011 to 2015 were retrieved with the initial search. Of the 335 studies, 19 were deemed eligible16,25-42 (Figure 1) and included in the final analysis (n ¼ 972). The study characteristics are listed in Table 1. The median patient age estimated from the studies reporting age was 65.5 years (n ¼ 463). Of the 19 studies, 11 reported gender (n ¼ 472); 64% of these patients were female. Smoking data were available from 7 studies (n ¼ 340), and 40% were smokers. The average tumor size estimated from 7 studies was 1.3 cm.

DFS Rate The 5-year DFS rate for the whole population in which it was reported (n ¼ 876) was 98% (95% confidence interval, 0.97-0.99; Figure 2A). No differences were found in the pooled DFS rates between the AIS and MIA populations from studies that reported both groups (100% for AIS and 100% for MIA; Figure 2B). The heterogeneity among the studies was not statistically significant (I2 ¼ 0.00; P ¼ .99). Two studies that grouped the AIS and MIA patients together reported a DFS of 100% (n ¼ 68)39 and 96.7% (n ¼ 181).37

Madhusmita Behera et al Figure 1 Consolidated Standards of Reporting Trials Diagram

Studies searched and retrieved, n=335 Studies excluded, 82 -animal studies -non English

Studies reviewed, n=253 Studies excluded, 234 -Not NSCLC -Not relevant staging -Data not extractable

Studies included in ϐinal analysis, n=19

Abbreviation: NSCLC ¼ nonesmall-cell lung cancer.

OS Rate The 5-year OS rate for the 2 groups pooled from the studies that provided data (n ¼ 547) was 97.5% (95% confidence interval, 0.956-0.986; Figure 3A). No differences were found in the pooled OS rates between the AIS and MIA patients from studies that reported both groups (100% for AIS and 98.5% for MIA; Figure 3B). The heterogeneity among the studies was not statistically significant (I2 ¼ 0.00; P ¼ .96).

Discussion LC is a heterogeneous disease process with significant differences in disease biology, clinical presentation, and radiologic, pathologic, and molecular features. Previous studies have indicated the presence of distinct LAC subsets, with some molecular alterations associated with specific histologic and/or cytologic features.19,43-45 Small (
3 cm) LAC tumors with entirely or predominantly lepidic growth (formerly BAC/BAC predominant mixed subtype; currently AIS/MIA) have been recognized as an indolent subtype, with a 100% 5-year survival rate.22 This is especially true for tumors
2 cm. Current recommendations suggest subclassification of these tumor types according to the

absence (AIS) or presence (MIA) of limited invasion, with possible substaging into pTis and pT1(mi). The identification of a LAC subgroup that might benefit from less aggressive surgical therapy with less morbidity and mortality would be beneficial46; however, the subclassification into preinvasive (AIS) and minimally invasive (MIA) types with the associated survival substaging connotations seems problematic, especially because detecting invasion can be difficult, with only moderate interobserver agreement47,48 and inadequate validation. Although our analysis primarily included nonmucinous adenocarcinoma, 5 studies reported on mucinous AIS (n ¼ 10)38,42 and mucinous MIA (n ¼ 7).29,32,33 No differences in outcomes were found between the mucinous and nonmucinous cases. The DFS rate was 100% for all the reported mucinous cases. Not enough data were available in the published studies about EGFR or KRAS mutation status to include these in the analysis. However, Sato et al42 reported on 60 cases of AIS that were positive for an EGFR mutation. The results of the present analysis have confirmed the indolent nature of AIS and MIA. The clinical outcomes for surgically treated patients have been excellent, with no statistically significant

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Study Ito et al,25 2014 Imai et al,26 2013 Nakagiri et al,27 2014 Takahashi et al,28 2014 Kadota et al,29 2014 Zhang et al,30 2013 Tsuta et al,31 2013 Yoshizawa et al,32 2011 Xu et al,33 2012 Gu et al,34 2013 Russell et al,35 2011 Ahn et al,36 2013 Tsutani et al,37 2013 Woo et al,38 2012 Murakawa et al,39 2012 Yanagawa et al,40 2013 Yoshizawa et al,16 2013 Kato et al,41 2012 Sato et al,42 2015

Patient Total

Median Age (Years) (AIS, MIA, Total)

92 45 38 54 36 22 102 9 11 15 8 13 181 42 68 28 53 46 110a

NR 63, 67 NR NR NR, NR, 69 NR NR, NR, 63 NR, NR, 68 69, 68, NR NR NR 55.4, 58.5, NR NR 64, 67.5 NR NR NR NR 61, NR, 61

Gender Non-Asian, (Male, Female) Asian NR 16, 29 NR 15, 39 10, 26 10, 12 46, 56 4, 5 5, 6 NR NR 6, 7 NR 19, 23 NR 9, 19 NR NR 31, 79

NR NR NR NR 31, 5 NR NR 6, NR NR NR NR NR NR 0, 42 NR NR NR NR NR

Smokers, Nonsmokers

Median Tumor Size (cm) (AIS, MIA, Total)

AIS, MIA

DFS (%) (AIS, MIA, Total)

OS (%) (AIS, MIA, Total)

NR NR NR NR 29, 7 NR 41, 61 8, 1 NR NR NR 4, 9 NR 10, 32 NR 8, 20 NR NR 36, 74

NR 1.11, 1.5 NR NR NR, NR, 1.2 NR NR, NR, 1.2 NR, NR, 1.3 0.9, 1.4, NR NR 1.0, 1.5, 1.5 NR NR 1.05, 1.5, NR NR NR NR NR NR

74, 18 22, 23 30, 8 27, 27 2, 34 6, 16 69, 33 1, 8 3, 7 1, 14 1, 7 5, 8 NR, NR, 181 18, 24, 42 NR, NR, 68 11, 17, 28 20, 33, 53 29, 17, 46 105, NR, 105a

74, 18, 92 NR NR 27, 27, 54 2, 34 6, 16, 22 69, 33, 102 1, 8, 9 3, 7, 10 1, 14, 15 NR 5, 8, 13 NR, NR, 175 18, 24, 42 NR, NR, 68 11, 17, 28 20, 33, 53 29, 17, 46 105, NR, 105

NR, NR, 89 22, 21, 43 30, 8, 38 27, 27, 54 NR 6, 16, 22 NR, NR, 100 NR NR 1, 14, 15 1, 7, 8 5, 8, 13 NR, NR, NR NR, NR, NR NR, NR, NR NR, NR, NR 20, 33, 53 NR 105, NR, 105

Data presented as numbers of patients, unless noted otherwise. Abbreviations: AIS ¼ adenocarcinoma in situ; DFS ¼ disease-free survival; MIA ¼ minimally invasive adenocarcinoma; NR ¼ not reported; OS ¼ overall survival. a A total of 105 cases were included for the survival analysis.

LUAC Staging and 2011 IASLC/ATS/ERS Classification

Clinical Lung Cancer September 2016

Table 1 Summary of Study Characteristics

Madhusmita Behera et al Figure 2 (A) Pooled Disease-Free Survival Rate for Whole Group (Adenocarcinoma In Situ [AIS] and Minimally Invasive Adenocarcinoma [MIA]) Was 98%. (B) Disease-Free Survival Rate of Each Category Reported Separately: 100% for AIS and 100% for MIA

A

Study name

Event rate and 95% CI

Event Lower Upper rate limit limit Total Ito 2014 Takahashi 2014 Kadota 2014 Zhang 2013 Tsuta 2013 Yoshizawa 2011 Xu 2012 Gu 2012 Ahn 2013 Tsutani 2013 Woo 2012 Murakawa 2012 Yanagawa 2013 Yoshizawa 2013 Kato 2012 Sato 2015

0.99 0.99 0.99 0.98 1.00 0.95 0.95 0.97 0.96 0.97 0.99 0.99 0.98 0.99 0.99 1.00 0.98

0.92 0.87 0.82 0.73 0.93 0.53 0.55 0.65 0.62 0.93 0.84 0.89 0.78 0.87 0.85 0.93 0.97

1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 0.99 1.00 1.00 1.00 1.00 1.00 1.00 0.99

92 54 36 22 102 9 10 15 13 181 42 68 28 53 46 105 -2.00

B

-1.00

Group by Subgroup within study

Study name

AIS/MIA

AIS AIS AIS AIS AIS AIS AIS AIS AIS AIS AIS AIS AIS MIA MIA MIA MIA MIA MIA MIA MIA MIA MIA MIA MIA MIA MIA

Ito 2014 Takahashi 2014 Kadota 2014 Zhang 2013 Tsuta 2013 Xu 2012 Ahn 2013 Woo 2012 Yanagawa 2013 Yoshizawa 2013 Kato 2012 Sato 2015

AIS AIS AIS AIS AIS AIS AIS AIS AIS AIS AIS AIS

0.00

1.00

2.00

Event rate and 95% CI

Total

Ito 2014-1 MIA Takahashi 2014-1 MIA Kadota 2014-1 MIA Zhang 2013-1 MIA Tsuta 2013-1 MIA Yoshizawa 2011-1 MIA Xu 2012-1 MIA Gu 2012-1 MIA Ahn 2013-1 MIA Woo 2012-1 MIA Yanagawa 2013-1 MIA Yoshizawa 2013-1 MIA Kato 2012-1 MIA

74 / 74 27 / 27 2/2 6/6 69 / 69 3/3 5/5 18 / 18 11 / 11 20 / 20 29 / 29 105 / 105 369 / 369 18 / 18 27 / 27 34 / 34 16 / 16 33 / 33 8/8 7/7 14 / 14 8/8 24 / 24 17 / 17 33 / 33 17 / 17 256 / 256

-1.00

-0.50

0.00

0.50

1.00

Abbreviation: CI ¼ confidence interval.

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LUAC Staging and 2011 IASLC/ATS/ERS Classification Figure 3 (A) Pooled Overall Survival (OS) Rate of Whole Group (Adenocarcinoma In Situ [AIS] and Minimally Invasive Adenocarcinoma [MIA]) Was 97.5%. (B) Overall Survival Rate of Each Category Reported Separately: 100% for AIS and 98.5% for MIA

A

Study name

Statistics for each study

Event rate

Lower limit

Event rate and 95% CI

Upper limit

Total

Ito 2014

0.967

0.904

0.989

92

Imai 2013

0.956

0.839

0.989

45

Nakagiri 2014

0.987

0.825

0.999

38

Takahashi 2014

0.991

0.871

0.999

54

Zhang 2013

0.978

0.732

0.999

22

Tsuta 2013

0.980

0.925

0.995

102

Gu 2012

0.969

0.650

0.998

15

Russell 2011

0.944

0.495

0.997

8

Ahn 2013

0.964

0.616

0.998

13

Yoshizawa 2013

0.991

0.869

0.999

53

Sato 2015

0.995

0.929

1.000

105

0.975

0.956

0.986 -2.00

B

Group by Subgroup within study

Study name

-1.00

AIS/MIA

0.00

1.00

2.00

Event rate and 95%CI

Total AIS AIS AIS AIS AIS AIS AIS AIS MIA MIA MIA MIA MIA MIA MIA MIA MIA

Imai 2013 Nakagiri 2014 Takahashi 2014 Zhang 2013 Ahn 2013 Yoshizawa 2013 Sato 2015

AIS AIS AIS AIS AIS AIS AIS

Imai 2013-1 Nakagiri 2014-1 Takahashi 2014-1 Zhang 2013-1 Gu 2012-1 Russell 2011-1 Ahn 2013-1 Yoshizawa 2013-1

MIA MIA MIA MIA MIA MIA MIA MIA

22 / 22 30 / 30 27 / 27 6/6 5/5 20 / 20 105 / 105 215 / 215 21 / 23 8/8 27 / 27 16 / 16 14 / 14 7/7 8/8 33 / 33 134 / 136 -2.00 -1.00

0.00

1.00

2.00

Abbreviation: CI ¼ confidence interval.

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differences in DFS and OS between the 2 proposed tumor types. This was despite the heterogeneous types of procedures the patients had undergone, ranging from sublobar resections with or without lymph node dissection to pneumonectomy. However, a formal analysis of the procedure types in the context of an AIS or an MIA diagnosis could not be performed because of the limitations in the data provided in the primary studies. Although we did not perform a formal statistical analysis of the studies published before the 2011 IASLC/ATS/ERS proposed guidelines because the concept of AIS and MIA had not been formally proposed, many of the studies20,21,49,50 that predated the 2011 proposal showed results similar to our findings for AIS and MIA. This raises the

Clinical Lung Cancer September 2016

possibility that the discrimination of AIS and MIA might not be clinically important. Although drawing parallels between the management of AIS and MIA and the management of breast ductal carcinoma in situ and microinvasive ductal carcinoma seems valid, the diagnosis of microinvasion in breast cancer can result in sentinel lymph node biopsy.51 However, no similar additional clinical intervention has been proposed in most studies for a diagnosis of MIA. Some studies have suggested that less clinical intervention with sublobar resection and no lymph node sampling would be warranted for both AIS and MIA,52 further supporting the conclusion that discrimination between AIS and MIA might not be clinically important.

Madhusmita Behera et al Although we saw no statistically significant differences in survival for AIS and MIA, some studies included in our analysis reported < 100% 5-year survival.25,31,37 It was difficult in these cases to determine whether AIS or MIA was responsible for the adverse events, because they were analyzed as a single entity. Of these studies, although Tsuta et al31 reported < 100% 5-year OS, they also reported 100% 5-year DFS, raising the possibility that the OS estimates in the remaining 2 studies could have been similarly affected. One study26 that separately analyzed AIS and MIA reported an 89.5% 5-year OS for patients with MIA. The MIA cases described in that study had possibly been misdiagnosed as MIA; 1 was associated with N1 lymph node metastases and a second with isolated tumor cells in an N1 lymph node. These cases seem unusual, because the presence of angiolymphatic invasion precludes a diagnosis of MIA. Also, the vast majority of reported MIA cases will not have lymph node metastases, although some studies did not perform lymph node sampling. We excluded 5 patients in one of the studies42 from the survival analysis because these patients had been documented to have experienced recurrence or had died of other causes. These findings suggest that more data are necessary to determine whether the data will support substaging of AIS and MIA into separate pT categories with the associated survival implications of the 2 separate categories. Also, future studies should report, at a minimum, the DFS, in addition to OS, because of the indolent nature of these 2 tumor types. In addition, the reported lack of good interobserver agreement when determining invasion suggests more study is necessary to better refine and implement the AIS/MIA diagnostic criteria. The present study had several limitations. Our study was a retrospective analysis of published studies, many of which were heavily weighted to East Asian patients; therefore, the international applicability is questionable. The demographic data were not well documented and were not extractable for these 2 specific categories of adenocarcinoma. Also, the treatment information was not clearly reported in the studies. Not including patient-specific information was another limitation, although the results were based on the best available evidence from the published studies. However, our analysis included the largest population of patients with LAC categorized according to the new classification criteria.

Conclusion The results of the present analysis have confirmed that the distinction between AIS and MIA is not clinically significant statistically with regard to survival. With the advent of computed tomography screening for the early detection of LC, which has been recommended for a subset of patients,53 it can be anticipated that a greater proportion of LC cases will be diagnosed at earlier stages, including AIS and MIA. Although computed tomography screening will reduce the mortality related to LC, the detected cancers will require appropriate classification methods to aid in optimal patient treatment. Because MIA and AIS are managed in a similar manner with surgery and, based on our analysis, do not have varying treatment outcomes, we posit that the substaging of these tumors is not clinically justified from the currently available information. The categorization of AIS and MIA should be reevaluated in further studies. Future studies of larger patient populations might provide additional insights regarding the clinical significance of the AIS and

MIA designation, which might result in a stronger case for the proposed substaging of these tumors.

Clinical Practice Points  The 2015 WHO classification of LAC formally updated the





 



LAC classifications to include a preinvasive entity, AIS, and a minimally invasive entity, MIA. AIS will be staged as pathologic stage pTis (AIS) with presumed clinical stage 0 and MIA will be staged as pathologic stage pT1 (MIA) with presumed clinical stage 1. We have confirmed, in a large meta-analysis of the available studies, that no statistically significant difference exists in OS or DFS between AIS and MIA. The rationale of separately staging AIS and MIA should not be based on the currently available survival data. Recognition of AIS and MIA as indolent lesions with specific radiologic criteria might lead to less intervention, including preferences for active surveillance or sublobar resection with minimal or no lymph node sampling. Computed tomography screening programs might lead to the increased diagnoses of stage 0 and stage I LC, with the caveat that stage I LC in the setting of MIA will likely behave very similarly to stage 0 disease in the setting of AIS (ie, 100% 5-year survival).

Disclosure The authors have stated that they have no conflicts of interest.

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