The prognostic significance of tumor-infiltrating lymphocytes assessment with hematoxylin and eosin sections in resected primary lung adenocarcinoma


Autoři: Ahrong Kim aff001;  So Jeong Lee aff001;  Jihyun Ahn aff002;  Won Young Park aff001;  Dong Hoon Shin aff003;  Chang Hun Lee aff001;  Hoon Kwon aff004;  Yeon Joo Jeong aff004;  Hyo Yeong Ahn aff005;  Hoseok I aff005;  Yeong Dae Kim aff005;  Jeong Su Cho aff005
Působiště autorů: Department of Pathology, Pusan National University Hospital, Biomedical Research Institution, Gudeok-ro, Seo-Gu, Busan, Republic of Korea aff001;  Department of Pathology, Kosin University Gospel Hospital, Gamcheon-ro, Seo-gu, Busan, Republic of Korea aff002;  Department of Pathology, Yangsan Pusan National University Hospital, Beomeori, Mulgeum-eop, Kyeong-Nam, Republic of Korea aff003;  Department of Radiology, Pusan National University Hospital, Biomedical Research Institution, Gudeok-ro, Seo-Gu, Busan, Republic of Korea aff004;  Department of Thoracic and Cardiovascular Surgery, Pusan National University Hospital, Biomedical Research Institution, Gudeok-ro, Seo-Gu, Busan, Republic of Korea aff005
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224430

Souhrn

The prognostic significance of tumor-infiltrating lymphocytes has been determined in cancers of the lung, colon and breast, though there is no standardized method for using this prognostic indicator for lung cancer. We applied a modified version of the method proposed by the International Immuno-Oncology Biomarkers Working Group to primary lung adenocarcinoma, which uses histologic findings of hematoxylin and eosin sections. The study included a total cohort of 146 lung adenocarcinoma patients who underwent lobectomy with lymph node dissection at two hospitals between 2008 and 2012. The full-face sections of hematoxylin and eosin-stained slides were reviewed, and we evaluated the level of tumor-infiltrating lymphocytes as a percentage of the area occupied out of the total intra-tumoral stromal area. Histopathologic factors include histologic grade, necrosis, extracellular mucin, lymphovascular invasion, lymph node metastasis, level of tumor infiltrating lymphocytes, tertiary lymphoid structures around the tumor, and the presence of a germinal center in tertiary lymphoid structures. The high level of tumor-infiltrating lymphocytes was found to be significantly correlated with the histologic grade (p = 0.023), necrosis (p = 0.042), abundance of tertiary lymphoid structures(p<0.001) and presence of a germinal center in tertiary lymphoid structures (p = 0.004). A high level of tumor-infiltrating lymphocytes was associated with better progression-free survival (p = 0.011) as well as overall survival (p = 0.049). On multivariable analysis, high tumor-infiltrating lymphocyte levels were a good independent prognostic factor for progression-free survival (Hazard ratio: 0.389, 95% confidence interval: 0.161–0.941, p = 0.036). Histologic evaluation of tumor-infiltrating lymphocytes level in lung adenocarcinoma with H&E sections therefore has prognostic value in routine surgical pathology.

Klíčová slova:

Adenocarcinoma of the lung – Adenocarcinomas – Histology – Invasive tumors – Lung and intrathoracic tumors – Non-small cell lung cancer – Secondary lung tumors – Tumor-infiltrating lymphocytes


Zdroje

1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi: 10.1016/j.cell.2011.02.013 21376230.

2. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011;331(6024):1565–70. doi: 10.1126/science.1203486 21436444.

3. Richardson GE, Johnson BE. Paraneoplastic syndromes in lung cancer. Curr Opin Oncol. 1992;4(2):323–33. doi: 10.1097/00001622-199204000-00014 1591305.

4. Engels EA, Pfeiffer RM, Fraumeni JF, Kasiske BL, Israni AK, Snyder JJ, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011;306(17):1891–901. doi: 10.1001/jama.2011.1592 22045767; PubMed Central PMCID: PMC3310893.

5. Ichiki Y, Takenoyama M, Mizukami M, So T, Sugaya M, Yasuda M, et al. Simultaneous cellular and humoral immune response against mutated p53 in a patient with lung cancer. J Immunol. 2004;172(8):4844–50. doi: 10.4049/jimmunol.172.8.4844 15067062.

6. Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306. Epub 2012/03/15. doi: 10.1038/nrc3245 22419253.

7. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26(2):259–71. Epub 2014/09/13. doi: 10.1093/annonc/mdu450 25214542.

8. Pagès F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018;391(10135):2128–39. Epub 2018/05/10. doi: 10.1016/S0140-6736(18)30789-X 29754777.

9. Hendry S, Salgado R, Gevaert T, Russell PA, John T, Thapa B, et al. Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors. doi: 10.1097/PAP.0000000000000161 28777143. 2017;24(6):311–35. PubMed Central PMCID: PMC5638696.

10. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger K, Yatabe Y, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: international multidisciplinary classification of lung adenocarcinoma: executive summary. Proc Am Thorac Soc. 2011;8(5):381–5. doi: 10.1513/pats.201107-042ST 21926387.

11. Tsuta K, Kawago M, Inoue E, Yoshida A, Takahashi F, Sakurai H, et al. The utility of the proposed IASLC/ATS/ERS lung adenocarcinoma subtypes for disease prognosis and correlation of driver gene alterations. Lung Cancer. 2013;81(3):371–6. Epub 2013/07/26. doi: 10.1016/j.lungcan.2013.06.012 23891509.

12. Hwang JY, Randall TD, Silva-Sanchez A. Inducible Bronchus-Associated Lymphoid Tissue: Taming Inflammation in the Lung. Front Immunol. 2016;7:258. Epub 2016/06/30. doi: 10.3389/fimmu.2016.00258 27446088; PubMed Central PMCID: PMC4928648.

13. Lee SJ, Hwang CS, Kim YK, Lee HJ, Ahn SJ, Shin N, et al. Expression of Myxovirus Resistance A (MxA) is Associated with Tumor-Infiltrating Lymphocytes (TILs) in Human Epidermal Growth Factor Receptor 2(HER2)-Positive Breast Cancers. Cancer Res Treat. 2016. doi: 10.4143/crt.2016.098 27456948.

14. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res. 2008;14(16):5220–7. doi: 10.1158/1078-0432.CCR-08-0133 18698040.

15. Al-Shibli K, Al-Saad S, Donnem T, Persson M, Bremnes RM, Busund LT. The prognostic value of intraepithelial and stromal innate immune system cells in non-small cell lung carcinoma. Histopathology. 2009;55(3):301–12. doi: 10.1111/j.1365-2559.2009.03379.x 19723145.

16. Donnem T, Hald SM, Paulsen EE, Richardsen E, Al-Saad S, Kilvaer TK, et al. Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non-Small Cell Lung Cancer. Clin Cancer Res. 2015;21(11):2635–43. Epub 2015/02/13. doi: 10.1158/1078-0432.CCR-14-1905 25680376.

17. Suzuki K, Kadota K, Sima CS, Nitadori J, Rusch VW, Travis WD, et al. Clinical impact of immune microenvironment in stage I lung adenocarcinoma: tumor interleukin-12 receptor β2 (IL-12Rβ2), IL-7R, and stromal FoxP3/CD3 ratio are independent predictors of recurrence. J Clin Oncol. 2013;31(4):490–8. Epub 2012/12/26. doi: 10.1200/JCO.2012.45.2052 23269987; PubMed Central PMCID: PMC3731922.

18. Goc J, Germain C, Vo-Bourgais TK, Lupo A, Klein C, Knockaert S, et al. Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells. Cancer Res. 2014;74(3):705–15. Epub 2013/12/23. doi: 10.1158/0008-5472.CAN-13-1342 24366885.

19. Djenidi F, Adam J, Goubar A, Durgeau A, Meurice G, de Montpréville V, et al. CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. J Immunol. 2015;194(7):3475–86. Epub 2015/02/27. doi: 10.4049/jimmunol.1402711 25725111.

20. Geng Y, Shao Y, He W, Hu W, Xu Y, Chen J, et al. Prognostic Role of Tumor-Infiltrating Lymphocytes in Lung Cancer: a Meta-Analysis. Cell Physiol Biochem. 2015;37(4):1560–71. Epub 2015/10/30. doi: 10.1159/000438523 26513143.

21. Kilic A, Landreneau RJ, Luketich JD, Pennathur A, Schuchert MJ. Density of tumor-infiltrating lymphocytes correlates with disease recurrence and survival in patients with large non-small-cell lung cancer tumors. J Surg Res. 2011;167(2):207–10. Epub 2009/09/23. doi: 10.1016/j.jss.2009.08.029 19896677.

22. Horne ZD, Jack R, Gray ZT, Siegfried JM, Wilson DO, Yousem SA, et al. Increased levels of tumor-infiltrating lymphocytes are associated with improved recurrence-free survival in stage 1A non-small-cell lung cancer. J Surg Res. 2011;171(1):1–5. Epub 2011/04/22. doi: 10.1016/j.jss.2011.03.068 21571304.

23. Brambilla E, Le Teuff G, Marguet S, Lantuejoul S, Dunant A, Graziano S, et al. Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-Small-Cell Lung Cancer. J Clin Oncol. 2016;34(11):1223–30. Epub 2016/02/01. doi: 10.1200/JCO.2015.63.0970 26834066; PubMed Central PMCID: PMC4872323.

24. Feng W, Li Y, Shen L, Cai XW, Zhu ZF, Chang JH, et al. Prognostic value of tumor-infiltrating lymphocytes for patients with completely resected stage IIIA(N2) non-small cell lung cancer. Oncotarget. 2016;7(6):7227–40. doi: 10.18632/oncotarget.6979 26811495; PubMed Central PMCID: PMC4872781.

25. Rakaee M, Kilvaer TK, Dalen SM, Richardsen E, Paulsen EE, Hald SM, et al. Evaluation of tumor-infiltrating lymphocytes using routine H&E slides predicts patient survival in resected non-small cell lung cancer. Hum Pathol. 2018. Epub 2018/06/06. doi: 10.1016/j.humpath.2018.05.017 29885403.

26. Tschernig T, Pabst R. Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases. Pathobiology. 2000;68(1):1–8. doi: 10.1159/000028109 10859525.

27. Hiller AS, Tschernig T, Kleemann WJ, Pabst R. Bronchus-associated lymphoid tissue (BALT) and larynx-associated lymphoid tissue (LALT) are found at different frequencies in children, adolescents and adults. Scand J Immunol. 1998;47(2):159–62. doi: 10.1046/j.1365-3083.1998.00276.x 9496692.

28. Richmond I, Pritchard GE, Ashcroft T, Avery A, Corris PA, Walters EH. Bronchus associated lymphoid tissue (BALT) in human lung: its distribution in smokers and non-smokers. Thorax. 1993;48(11):1130–4. doi: 10.1136/thx.48.11.1130 8296257; PubMed Central PMCID: PMC464898.

29. Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol. 2008;26(27):4410–7. doi: 10.1200/JCO.2007.15.0284 18802153.

30. Goc J, Germain C, Vo-Bourgais TK, Lupo A, Klein C, Knockaert S, et al. Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells. Cancer Res. 2014;74(3):705–15. Epub 2013/12/25. doi: 10.1158/0008-5472.CAN-13-1342 24366885.


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2019 Číslo 11