You are here

Article Text

Article menu

Download PDFPDF

Original research
Clinicopathological predictors of survival in resected primary lung adenocarcinoma
  1. Hiral Jhala1,
  2. Leanne Harling1,
  3. Alberto Rodrigo2,
  4. Daisuke Nonaka3,
  5. Emma Mclean3,
  6. Wen Ng3,
  7. Lawrence Okiror4,
  8. Andrea Bille5,6
  1. 1 Imperial College School of Medicine, Imperial College London, London, UK
  2. 2 Medical Oncology, Arnau de Vilanova University Hospital, Lleida, Catalunya, Spain
  3. 3 Pathology, Guy's Hospital, London, UK
  4. 4 Thoracic Surgery, Guy's Hospital, London, UK
  5. 5 Department of Thoracic Surgery, St Thomas' Hospital, London, UK
  6. 6 Division of Cancer, King's College London, London, UK
  1. Correspondence to Dr Hiral Jhala, Imperial College School of Medicine, Imperial College London, London, UK; hj1513{at}ic.ac.uk

Abstract

Aims Primary lung adenocarcinoma consists of a spectrum of clinical and pathological subtypes that may impact on overall survival (OS). Our study aims to evaluate the impact of adenocarcinoma subtype and intra-alveolar spread on survival after anatomical lung resection and identify different prognostic factors based on stage and histological subtype.

Methods Newly diagnosed patients undergoing anatomical lung resections without induction therapy, for pT1-3, N0-2 lung adenocarcinoma from April 2011 to March 2013, were included. The effect of clinical–pathological factors on survival was retrospectively assessed.

Results Two hundred and sixty-two patients were enrolled. The 1-year, 3-year and 5-year OS were 88.8%, 64.3% and 51.1%, respectively. Univariate analysis showed lymphovascular, parietal pleural and chest wall invasion to confer a worse 1-year and 5-year prognosis (all p<0.0001). Solid predominant adenocarcinomas exhibited a significantly worse OS (p=0.014). Multivariate analysis did not identify solid subtype as an independent prognostic factor; however, identified stage >IIa, lymphovascular invasion (p=0.002) and intra-alveolar spread (p=0.009) as significant independent predictors of worse OS. Co-presence of intra-alveolar spread and solid predominance significantly reduced OS. Disease-free survival (DFS) was reduced with parietal pleural (p=0.0007) and chest wall invasion (p<0.0001), however, adenocarcinoma subtype had no significant impact on DFS.

Conclusions Our study demonstrates that solid predominant adenocarcinoma, intra-alveolar spread and lymphovascular invasion confer a worse prognosis and should be used as a prognostic tool to determine appropriate adjuvant treatment.

  • lung
  • lung neoplasms
  • carcinoma

Data availability statement

Data are available upon reasonable request. Data may be obtained from a third party and are not publicly available. The retrospective database including all data collected will be available upon reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jclinpath-2021-207388

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    Lung cancer is the leading cause of cancer-related mortality worldwide, with adenocarcinoma being the most common histological subtype accounting for 35% of lung cancers.1 Pulmonary adenocarcinoma is heterogeneous in its histological pattern, molecular profile, clinical findings, radiological presentation and treatment options.2

    In 2015, a new WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart (fourth edition) was published defining five different histological subtypes: lepidic, acinar, papillary, micropapillary and solid patterns.3 4 This new classification for adenocarcinomas was based on the International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS) recommendations made in 2011.5 6

    Since 2011, several publications have reported a strong correlation between predominant patterns of adenocarcinoma and prognosis, with solid and micropapillary patterns conferring a worse prognosis (reduced overall survival (OS)) and lepidic predominance having a better prognosis.7–9 Despite this, tumour subtype is currently not a criterion used to select patients for adjuvant therapies.10

    More recently, tumour intra-alveolar spread has been shown to strongly correlate with lymph node and distant metastases as well as a higher incidence of local recurrence of tumour, hence serving as an independent negative prognostic factor for lung adenocarcinomas.11–13

    The main aim of our study is to evaluate the impact of adenocarcinoma subtype and intra-alveolar spread on survival after anatomical lung resection and to identify different prognostic factors based on stage and histological subtypes.

    Patients

    Patient recruitment

    All patients undergoing anatomical lung resection between April 2011 and March 2013 for pT1-3 N0-2 lung adenocarcinoma were included. Exclusion criteria were patients with pT4 tumours, tumour types other than adenocarcinoma (neuroendocrine tumour, small cell lung cancer squamous tumours), incomplete resection and those undergoing induction treatment, chemo and or radiotherapy. Patients who had tumours larger than 40 mm, or N1/N2 disease, received adjuvant chemotherapy. Patients with N2 disease or R1 resections received adjuvant radiotherapy. cN2 single station surgery was indicated.

    Data acquisition and analysis

    Demographic, clinical and survival data for those patients who fulfilled the inclusion criteria were retrospectively obtained from hospital electronic medical records and serial follow-up information obtained from correspondence letters with primary care physicians.

    H&E-stained sections from resected lung adenocarcinomas were reviewed, and according to the 2015 WHO classification of lung tumours,14 histological diagnosis of adenocarcinoma was confirmed and subclassification to lepidic, acinar, papillary, micropapillary and solid type was made. All tumours were documented for tumour size, lymphovascular invasion, visceral or parietal pleural invasion and lymph node metastasis. Tumour stage was based on the Tumour Nodes Metastases (TNM) eighth edition classification.15 In order to derive the percentage contribution of each subtype of adenocarcinoma to the overall tumour, all H&E-stained slides for tumours were digitally scanned using a Hamamatsu Nanozoomer scanner and analysed using proprietary software (Hamamatsu NPD.View2). This tumour area, represented by each histopathological subtype, was defined and expressed as a percentage of the overall tumour. The presence of adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic, acinar, mucinous, solid and micropapillary components, was reported on percentage. Additionally, the presence of the intra-alveolar spread has then been reported. Spread through air spaces (STAS) was defined as small clusters of tumour cell nests within air spaces in the lung parenchyma beyond the edge of the main tumour. The edge of the main tumour was defined as the outer border of the tumour. STAS was considered present when tumour cells were identified beyond the edge of the main tumour.16

    Statistical analysis

    Continuous variables were expressed as mean±SD and categorical data expressed as counts and percentages. Univariate analysis was performed using χ2 or unpaired t-tests where appropriate. Survival was measured from the date of surgical intervention and survival data were analysed using Kaplan-Meier methodology. Factors significantly affecting survival in univariate analysis (at p<0.005) were included in a multivariate Cox proportional hazard regression mode. The stepwise backward procedure based on the likelihood ratio was used to assess the significance of covariate included in the model. HRs and 95% CIs were calculated. Statistical significance was defined where p<0.05. All analyses were carried out using STATA V.12.0.

    Results

    Demographic and clinical patient data

    A total of 262 patients, who underwent an anatomical lung resection from February 2011 to March 2013, were included in the analysis. The average age of the study population was 69.7±8.7 years, of whom 45% (118/262) was men. Full demographic details and clinical details are included in table 1.

    View this table:
    Table 1

    Baseline characteristics of the study population

    Overall survival

    All patients were followed up until July 2018. The median OS for the study population was 42.6 months (range 0.4–68.1). The 1-year, 3-year and 5-year survival rate were 88.8%, 64.3% and 51.1%, respectively (figure 1). The 30-day mortality rate was 1.1% (n=3). As expected, there was a stepwise decrease in OS with more advanced pathological stage (figure 2). Stage IB tumours did not demonstrate significantly worse survival than stage IA tumours (p=0.264) (table 2). When compared with stage I disease, stages II and III showed worse OS.

    Figure 1
    Figure 1

    Overall survival. 1 year 88.8% (84.2–92.1); 2 years 73.87% (68.0-78.8); 3 years 64.3% (58.1–69.9); 4 years 58.9% (52.5–64.8); 5 years 51.1% (42.8–58.8).

    Figure 2
    Figure 2

    Survival according to disease stage. Stage II and III tumours showed worse overall survival. Stage IB showed no statistical difference to IA.

    View this table:
    Table 2

    Univariate analysis of predictors of overall survival

    At univariate analysis, clinicopathological factors conferring a worse prognosis at 1 and 5 years were the presence of lymphovascular invasion (85% vs 91% at 1 year and 39% vs 60% at 5 years; χ2=17.3, p<0.0001), parietal pleural invasion (69% vs 90% at 1 year and 8.6% vs 67% at 3 years; χ2=26.31, p<0.0001), chest wall invasion (40% vs 90% at 1 year; χ2=26.82, p<0.0001), visceral pleural invasion (84% vs 92% at 1 year and 48% vs 54% at 5 years; χ2=4.04, p=0.0444) and smoking status (87% vs 100% at 1 year and 56 vs 100% at 5 years; χ2=6.55, p=0.0105).

    Solid predominant adenocarcinomas exhibited a significantly worse OS than other histopathological subtypes when compared with lepidic predominant adenocarcinomas (p=0.008) (figure 3). Other variables analysed included age, gender, performance status and intra-alveolar spread or STAS. The presence of STAS was identified across all operation types. Furthermore, patients undergoing pneumonectomy (p=0.043) and bilobectomy (p=0.022) exhibited significantly worse OS than those undergoing segmentectomy or lobectomy: 26.5 months (range 6.5–56.5) and 17.7 months (range 7–60 months) versus 47.6 months (range 22.3–54.5 months) and 43.1 months (range 0.4–68.1) respectively, probably reflecting more locally advanced tumour (table 2).

    Figure 3
    Figure 3

    Effect of tumour subtype on overall survival. Solid adenocarcinomas had a worse overall survival than other subtypes compared with lepidic (p=0.008).

    The association of the solid component and STAS with sex, age, smoking history, lymphovascular invasion, visceral and parietal invasion and lymph node status did not show any significant correlation.

    Additional analysis was performed based on literature reports, looking at the concomitant presence of both intra-alveolar spread and solid predominant disease. This demonstrated a significantly worse survival in these patients (n=20; p=0.01, HR 2.18, CI 1.2 to 3.9), when compared with those without either solid component or intra-alveolar spread (n=144) (figure 4).

    Figure 4
    Figure 4

    Kaplan-Meier survival based on intra-alveolar spread and solid component. Concomitance of solid predominance and presence of intra-alveolar spread showed significantly worse survival (p=0.01, HR 2.18, CI 1.2 to 3.9).

    Disease-free survival

    Of the 262 patients, data were available on recurrence in 163 cases. Of these, 72 (44%) exhibited disease recurrence during the study period. Date of recurrence were available in 60 of the 72 patients with recurrent disease and these 60 were included in analysis of disease-free survival (DFS). Mean time to recurrence was 20.6±14.6 months. Univariable analysis did not show any significant impact of gender, age, operative site, performance status, intra-alveolar spread (STAS) or lymphovascular invasion on DFS. Advancing stage was an overall predictor of shorter DFS (p=0.046), as were the presence of parietal pleural (χ2 11.62, p=0.0007) and chest wall invasion (χ2 21.32, p<0.0001). Patients with solid tumours again tended to have shorter DFS (figure 5), however, adenocarcinoma subtype did not significantly impact on DFS in this patient cohort.

    Figure 5
    Figure 5

    Effect of tumour subtype on disease-free survival. Solid adenocarcinomas had a shorted disease-free survival overall, but not statistically significant.

    Subgroup analysis

    Subgroup analysis was performed by stage, analysing the characteristics in the different stage categories. As expected, OS was better in earlier stage (IA-IIA) tumours with a 1-year, 3-year and 5-year survival of 90.6%, 73.6% and 58.8%, respectively compared with stages IIB and IIIA. The presence of lymphovascular invasion (p=0.0016), visceral pleural (p=0.048) and parietal pleural (p<0.0001) invasion remained significant univariate predictors of worse OS in every stage subgroup. In stage IA-IIA tumours adenocarcinoma subtype and STAS were not a significant predictor of OS. However, in this specific subgroup, the presence of intra-alveolar spread and solid predominant tumour subtype together (N=12) again resulted in significantly worse OS than in those without either solid component or intra-alveolar spread (N=105) (HR 2.65, 95% CI 1.22 to 5.77, p=0.014).

    Multivariate regression model

    A Cox proportional hazard, multivariate model was used to determine significant survival predictors. Significant interaction was seen between the variables of lymphovascular invasion and parietal pleura invasion as well as between age and intra-alveolar spread and these were incorporated into the final model. Confirmation that the proportional hazard assumption met was assessed through Schoenfeld residuals (global test: χ2=2.26 p=0.659). The fully adjusted model including interaction variables is shown in table 3. In this model advancing age (p=0.021), stage above IIa (all p<0.01), lymphovascular invasion (p=0.002) and intra-alveolar spread (p=0.009) were all significant independent predictors of worse OS outcome. Solid adenocarcinoma subtype was not an independent prognostic factor.

    View this table:
    Table 3

    Multivariate Cox regression model: n=26; LR χ2=66.38; df=15; p < χ2 ≤0.00001

    Discussion

    Lung adenocarcinoma is the most frequent nonsmall cell lung cancer subtype. Currently, TNM staging remains the strongest predictor of survival and, together with tumour size, is the basis on which patients are offered adjuvant treatment after surgical resection.17 18 Among patients with the same pathological staging, a number of biological tumour characteristics may contribute to determine the prognosis and the risk of recurrence. Recently, adenocarcinoma subtype, lymph vascular invasion and intraalveolar spread have been investigated as potential prognostic factors.

    The rates of the predominant adenocarcinoma subtypes vary in the literature.19 As previously reported OS is affected by predominant adenocarcinoma subtype: solid and micropapillary subtypes are associated with worse long-term prognosis.20–23 Our results demonstrated that the solid histological subtype, regardless of the expression percentage, conferred the worst OS identifying it as an independent negative prognostic factor for survival. These results are consistent with a recent study by Li et al 24 who also demonstrated a worse survival in solid adenocarcinoma subtypes. Solid component is associated with features of aggressive behaviour such as lymph node involvement, lymphovascular invasion as reported by Li J, which may account for worse long-term prognosis.23 25

    We found that patients with solid tumour subtype and tumour STAS had a significantly worse prognosis than those who did not have either biologic tumour characteristic. The poor prognostic role of solid histologic subtype of adenocarcinoma is well reported, particularly most recently in a systematic review and meta-analysis by Miyahara et al.26 In our series, the combined effect of solid subtype and tumour intra-alveolar spread is even more marked, particularly in earlier stages (stage IA-IIA; HR 2.65, 95% CI 1.22 to 5.77, p=0.0.014).

    Clinical stage and tumour size were the major criteria to determine the extent of resection27 and the adjuvant treatment. The correlation between histological subtype and survival, and the impact of STAS demonstrated in our findings, can provide a more accurate assessment of whether a wide resection is appropriate (sublobar vs lobar resection), even for small peripheral tumours. We have previously reported, together with various authors, on the prognostic impact of tumour lymphovascular invasion.28 We reported that even in early stage lung cancer, the presence of tumour lymphovascular invasion conferred a worse OS and correlated with the likelihood of lymph node metastases. It could be argued that the presence of these biologic markers of tumour aggressiveness (tumour lymphovascular invasion, intra-alveolar spread, solid subtype) should at least be investigated as criteria for adjuvant therapies in prospective clinical trials.

    As limitations, this is a single centre retrospective study and the simple size of the study is smaller than other groups, such as the 2018 solid component study,24 but all the cases were reviewed by a dedicated thoracic pathologist, and the predominant subtype was classified objectively using proprietary software to minimise interpretations bias.

    Conclusion

    In conclusion, our results demonstrate that solid predominance with intra-alveolar spread and lymphovascular invasion confer a worse prognosis and, therefore, should be used as a prognostic tool when determining the appropriate treatment for patients. STAS is a novel criterion that can help to further stratify patients after lung resection who may benefit from adjuvant treatment. The impact of these prognostic factors on adjuvant chemotherapy remains unclear and further studies on adjuvant treatment based on these biological characteristics rather than the size criteria only are needed.

    Take home messages

    • Solid predominance in lung adenocarcinoma confers a worse prognosis.

    • Intra-alveolar spread is an independent predictor of survival.

    • Copresence of intra-alveolar spread and solid predominance significantly reduce overall survival.

    • Tumour type and intra-alveolar spread should be used as a prognostic tool to determine appropriate adjuvant treatment.

    Data availability statement

    Data are available upon reasonable request. Data may be obtained from a third party and are not publicly available. The retrospective database including all data collected will be available upon reasonable request.

    Ethics statements

    Patient consent for publication

    References

    1. ↵
      2. Suda K ,
      3. Sato K ,
      4. Shimizu S , et al
      . Prognostic implication of predominant histologic subtypes of lymph node metastases in surgically resected lung adenocarcinoma. Biomed Res Int 2014;2014:1–6.doi:10.1155/2014/645681 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25371901
      OpenUrlPubMed
    2. ↵
      2. Hwang I ,
      3. Park KU ,
      4. Kwon KY
      . Modified histologic classification as a prognostic factor in pulmonary adenocarcinoma. Int J Surg Pathol 2014;22:212–20.doi:10.1177/1066896914525230 pmid:http://www.ncbi.nlm.nih.gov/pubmed/24599899
      OpenUrlCrossRefPubMed
    3. ↵
      2. Yoshida Y ,
      3. Nitadori J-I ,
      4. Shinozaki-Ushiku A , et al
      . Micropapillary histological subtype in lung adenocarcinoma of 2 cm or less: impact on recurrence and clinical predictors. Gen Thorac Cardiovasc Surg 2017;65:273–9.doi:10.1007/s11748-017-0747-3 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28243892
      OpenUrlPubMed
    4. ↵
      2. Travis WD ,
      3. Brambilla E ,
      4. Nicholson AG , et al
      . The 2015 World Health organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015;10:1243–60.doi:10.1097/JTO.0000000000000630 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26291008
      OpenUrlCrossRefPubMed
    5. ↵
      2. Hung J-J ,
      3. Yeh Y-C ,
      4. Jeng W-J , et al
      . Predictive value of the International association for the study of lung cancer/American thoracic Society/European respiratory Society classification of lung adenocarcinoma in tumor recurrence and patient survival. J Clin Oncol 2014;32:2357–64.doi:10.1200/JCO.2013.50.1049 pmid:http://www.ncbi.nlm.nih.gov/pubmed/24799473
      OpenUrlAbstract/FREE Full Text
    6. ↵
      2. Yanagawa N ,
      3. Shiono S ,
      4. Abiko M , et al
      . The clinical impact of solid and Micropapillary patterns in resected lung adenocarcinoma. J Thorac Oncol 2016;11:1976–83.doi:10.1016/j.jtho.2016.06.014 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27374456
      OpenUrlPubMed
    7. ↵
      2. Kadota K ,
      3. Villena-Vargas J ,
      4. Yoshizawa A , et al
      . Prognostic significance of adenocarcinoma in situ, minimally invasive adenocarcinoma, and nonmucinous lepidic predominant invasive adenocarcinoma of the lung in patients with stage I disease. Am J Surg Pathol 2014;38:448–60.doi:10.1097/PAS.0000000000000134 pmid:http://www.ncbi.nlm.nih.gov/pubmed/24472852
      OpenUrlCrossRefPubMed
    8. ↵
      2. Borczuk AC
      . Prognostic considerations of the new World Health organization classification of lung adenocarcinoma. Eur Respir Rev 2016;25:364–71.doi:10.1183/16000617.0089-2016 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27903658
      OpenUrlAbstract/FREE Full Text
    9. ↵
      2. Tsubokawa N ,
      3. Mimae T ,
      4. Miyata Y , et al
      . Prognostic significance of vascular invasion in intermediate-grade subtype of lung adenocarcinoma. Jpn J Clin Oncol 2016;46:1015–21.doi:10.1093/jjco/hyw113 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27566971
      OpenUrlCrossRefPubMed
    10. ↵
      2. Yoshiya T ,
      3. Mimae T ,
      4. Tsutani Y , et al
      . Prognostic Role of Subtype Classification in Small-Sized Pathologic N0 Invasive Lung Adenocarcinoma. Ann Thorac Surg 2016;102:1668–73.doi:10.1016/j.athoracsur.2016.04.087 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27344277
      OpenUrlPubMed
    11. ↵
      2. Warth A ,
      3. Muley T ,
      4. Kossakowski CA , et al
      . Prognostic impact of Intra-alveolar tumor spread in pulmonary adenocarcinoma. Am J Surg Pathol 2015;39:793–801.doi:10.1097/PAS.0000000000000409 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25723114
      OpenUrlCrossRefPubMed
    12. ↵
      2. Mäkinen JM ,
      3. Laitakari K ,
      4. Johnson S , et al
      . Histological features of malignancy correlate with growth patterns and patient outcome in lung adenocarcinoma. Histopathology 2017;71:425–36.doi:10.1111/his.13236 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28401582
      OpenUrlPubMed
    13. ↵
      2. Nitadori J-ichi ,
      3. Bograd AJ ,
      4. Kadota K , et al
      . Impact of micropapillary histologic subtype in selecting limited resection vs lobectomy for lung adenocarcinoma of 2Cm or smaller. J Natl Cancer Inst 2013;105:1212–20.doi:10.1093/jnci/djt166 pmid:http://www.ncbi.nlm.nih.gov/pubmed/23926067
      OpenUrlCrossRefPubMedWeb of Science
    14. ↵
      2. Travis WD ,
      3. Brambilla E ,
      4. Burke AP
      . Nicholson AP: Neuroendocrine tumours, in Tumours of the lung. In: Bosman FT , Jaffe ES , Lakhani SR , eds. Who classification of tumours of the lung, pleura, thymus and heart. Lyon, IARC, 2015.
    15. ↵
      2. Detterbeck FC ,
      3. Chansky K ,
      4. Groome P , et al
      . The IASLC lung cancer staging project: methodology and validation used in the development of proposals for revision of the stage classification of NSCLC in the forthcoming (eighth) edition of the TNM classification of lung cancer. J Thorac Oncol 2016;11:1433–46.doi:10.1016/j.jtho.2016.06.028 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27448762
      OpenUrlPubMed
    16. ↵
      2. Uruga H ,
      3. Fujii T ,
      4. Fujimori S , et al
      . Semiquantitative Assessment of Tumor Spread through Air Spaces (STAS) in Early-Stage Lung Adenocarcinomas. J Thorac Oncol 2017;12:1046–51.doi:10.1016/j.jtho.2017.03.019 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28363628
      OpenUrlPubMed
    17. ↵
      2. Strauss GM ,
      3. Herndon JE ,
      4. Maddaus MA , et al
      . Adjuvant paclitaxel plus carboplatin compared with observation in stage Ib non-small-cell lung cancer: CALGB 9633 with the cancer and leukemia group B, radiation therapy Oncology group, and North central cancer treatment group study groups. J Clin Oncol 2008;26:5043–51.doi:10.1200/JCO.2008.16.4855 pmid:http://www.ncbi.nlm.nih.gov/pubmed/18809614
      OpenUrlAbstract/FREE Full Text
    18. ↵
      2. Pignon J-P ,
      3. Tribodet H ,
      4. Scagliotti GV , et al
      . Lung adjuvant cisplatin evaluation: a pooled analysis by the lace Collaborative group. J Clin Oncol 2008;26:3552–9.doi:10.1200/JCO.2007.13.9030 pmid:http://www.ncbi.nlm.nih.gov/pubmed/18506026
      OpenUrlAbstract/FREE Full Text
    19. ↵
      2. Yoshizawa A ,
      3. Motoi N ,
      4. Riely GJ , et al
      . Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol 2011;24:653–64.doi:10.1038/modpathol.2010.232 pmid:http://www.ncbi.nlm.nih.gov/pubmed/21252858
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      2. Travis WD ,
      3. Brambilla E ,
      4. Riely GJ
      . New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. J Clin Oncol 2013;31:992–1001.doi:10.1200/JCO.2012.46.9270 pmid:http://www.ncbi.nlm.nih.gov/pubmed/23401443
      OpenUrlAbstract/FREE Full Text
    21. ↵
      2. Yoshizawa A ,
      3. Sumiyoshi S ,
      4. Sonobe M , et al
      . Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients. J Thorac Oncol 2013;8:52–61.doi:10.1097/JTO.0b013e3182769aa8 pmid:http://www.ncbi.nlm.nih.gov/pubmed/23242438
      OpenUrlCrossRefPubMed
    22. ↵
      2. Gu J ,
      3. Lu C ,
      4. Guo J , et al
      . Prognostic significance of the IASLC/ATS/ERS classification in Chinese patients-A single institution retrospective study of 292 lung adenocarcinoma. J Surg Oncol 2013;107:474–80.doi:10.1002/jso.23259 pmid:http://www.ncbi.nlm.nih.gov/pubmed/22952152
      OpenUrlCrossRefPubMed
    23. ↵
      2. Hung J-J ,
      3. Jeng W-J ,
      4. Chou T-Y , et al
      . Prognostic value of the new international association for the study of lung Cancer/American thoracic Society/European respiratory Society lung adenocarcinoma classification on death and recurrence in completely resected stage I lung adenocarcinoma. Ann Surg 2013;258:1079–86.doi:10.1097/SLA.0b013e31828920c0 pmid:http://www.ncbi.nlm.nih.gov/pubmed/23532112
      OpenUrlCrossRefPubMed
    24. ↵
      2. Li J ,
      3. You W ,
      4. Zheng D , et al
      . A comprehensive evaluation of clinicopathologic characteristics, molecular features and prognosis in lung adenocarcinoma with solid component. J Cancer Res Clin Oncol 2018;144:725–34.doi:10.1007/s00432-018-2588-6 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29368062
      OpenUrlPubMed
    25. ↵
      2. Yanagawa N ,
      3. Shiono S ,
      4. Abiko M , et al
      . New IASLC/ATS/ERS classification and invasive tumor size are predictive of disease recurrence in stage I lung adenocarcinoma. J Thorac Oncol 2013;8:612–8.doi:10.1097/JTO.0b013e318287c3eb pmid:http://www.ncbi.nlm.nih.gov/pubmed/23584293
      OpenUrlCrossRefPubMed
    26. ↵
      2. Miyahara N ,
      3. Nii K ,
      4. Benazzo A , et al
      . Solid predominant subtype in lung adenocarcinoma is related to poor prognosis after surgical resection: A systematic review and meta-analysis. Eur J Surg Oncol 2019;45:1156–62.doi:10.1016/j.ejso.2019.01.220 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30772108
      OpenUrlPubMed
    27. ↵
      2. Cangir AK ,
      3. Kutlay H ,
      4. Akal M , et al
      . Prognostic value of tumor size in non-small cell lung cancer larger than five centimeters in diameter. Lung Cancer 2004;46:325–31.doi:10.1016/j.lungcan.2004.05.004 pmid:http://www.ncbi.nlm.nih.gov/pubmed/15541817
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      2. Okiror L ,
      3. Harling L ,
      4. Toufektzian L , et al
      . Prognostic factors including lymphovascular invasion on survival for resected non-small cell lung cancer. J Thorac Cardiovasc Surg 2018;156:785–93.doi:10.1016/j.jtcvs.2018.02.108 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29754785
      OpenUrlPubMed

    Footnotes

    • Handling editor Runjan Chetty.

    • Contributors All named authors have made a significant contribution towards the design, data acquisition and analysis, statistical analysis and writing of the final manuscript. AB has been responsible for the overall supervision of the project.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; internally peer reviewed.