Tumor Biology

, Volume 37, Issue 3, pp 3599–3607 | Cite as

Recurrence of squamous cell lung carcinoma is associated with the co-presence of reactive lesions in tumor-adjacent bronchial epithelium

  • Olga V. Pankova
  • Evgeny V. DenisovEmail author
  • Anastasia A. Ponomaryova
  • Tatiana S. Gerashchenko
  • Sergey A. Tuzikov
  • Vladimir M. Perelmuter
Original Article


Recurrences occur in 30 % of lung cancer patients after radical therapy; however, known prognostic factors are not always effective. In this study, we investigated whether the frequency of squamous non-small cell lung cancer (NSCLC) recurrence depends on the presence of reactive lesions in tumor-adjacent bronchial epithelium. Specimens of adjacent lung tissue from 104 patients with squamous NSCLC were used for the determination of basal cell hyperplasia (BCH) and squamous metaplasia (SM) and for the analysis of the expression of Ki-67, p53, Bcl-2, and CD138. We found that recurrence was observed in 36.7 % of patients with BCH combined with SM (BCH + SM+) in the same bronchus, compared with 1.8 % in patients with isolated BCH (BCH + SM−; odds ratio (OR) 31.26, 95 % confidence interval (CI) 3.77–258.60; p = 0.00002). The percentage of Ki-67-positive cells was significantly higher in BCH + SM+ than in BCH + SM− (34.9 vs. 18.3 %; effect size 2.86, 95 % CI 2.23–3.47; p = 0.003). P53 expression was also more significant in BCH + SM+ than in BCH + SM− (14.4 vs. 9.6 %; effect size 1.22, 95 % CI 0.69–1.76; p = 0.0008). In contrast, CD138 expression was lower in BCH + SM+ than in BCH + SM− (21.8 vs. 38.5 %; effect size −6.26, 95 % CI −7.31 to −5.22; p = 0.003). Based on our results, we concluded that the co-presence of reactive bronchial lesions is associated with the development of recurrent squamous NSCLC and may be a negative prognostic indicator. In addition, significant differences in Ki-67, p53, and CD138 expression exist between isolated BCH and BCH combined with SM that probably reflect part of biological differences, which could relate to the mechanism of lung cancer recurrence.


Lung cancer Recurrence Hyperplasia Metaplasia Immunohistochemistry 



The study was supported by the Russian Scientific Foundation (project #14-15-00350). E.V. Denisov was supported by Tomsk State University Competitiveness Improvement Program.

Conflicts of interest


Supplementary material

13277_2015_4196_MOESM1_ESM.pdf (192 kb)
ESM 1 (PDF 192 kb)


  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMedGoogle Scholar
  2. 2.
    Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumors. New York, USA: Wiley-Blackwell; 2009.Google Scholar
  3. 3.
    Poleri C, Morero JL, Nieva B, Vazquez MF, Rodriguez C, de Titto E, et al. Risk of recurrence in patients with surgically resected stage I non-small cell lung carcinoma: histopathologic and immunohistochemical analysis. Chest. 2003;123(6):1858–67.CrossRefPubMedGoogle Scholar
  4. 4.
    Lopez Guerra JL, Gomez DR, Lin SH, Levy LB, Zhuang Y, Komaki R, et al. Risk factors for local and regional recurrence in patients with resected N0-N1 non-small-cell lung cancer, with implications for patient selection for adjuvant radiation therapy. Ann Oncol. 2013;24(1):67–74.CrossRefPubMedGoogle Scholar
  5. 5.
    Gold KA, Kim ES, Liu DD, Yuan P, Behrens C, Solis LM, et al. Prediction of survival in resected non-small cell lung cancer using a protein expression-based risk model: implications for personalized chemoprevention and therapy. Clin Cancer Res. 2014;20(7):1946–54.CrossRefPubMedGoogle Scholar
  6. 6.
    O’Callaghan DS, O’Donnell D, O’Connell F, O’Byrne KJ. The role of inflammation in the pathogenesis of non-small cell lung cancer. J Thorac Oncol. 2010;5(12):2024–36.CrossRefPubMedGoogle Scholar
  7. 7.
    Kuo CH, Wu CY, Lee KY, Lin SM, Chung FT, Lo YL, et al. Chronic obstructive pulmonary disease in stage I non-small cell lung cancer that underwent anatomic resection: the role of a recurrence promoter. Copd. 2014;11(4):407–13.CrossRefPubMedGoogle Scholar
  8. 8.
    Guthrie GJ, Charles KA, Roxburgh CS, Horgan PG, McMillan DC, Clarke SJ. The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol. 2013;88(1):218–30.CrossRefPubMedGoogle Scholar
  9. 9.
    Dacic S. Pulmonary preneoplasia. Arch Pathol Lab Med. 2008;132(7):1073–8.PubMedGoogle Scholar
  10. 10.
    Greenberg AK, Yee H, Rom WN. Preneoplastic lesions of the lung. Respir Res. 2002;3:20.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ishizumi T, McWilliams A, MacAulay C, Gazdar A, Lam S. Natural history of bronchial preinvasive lesions. Cancer Metastasis Rev. 2010;29(1):5–14.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kerr KM, Fraire AE. Preinvasive disease. In: Tomashefski JF, Cagle PT, Farver CF, Fraire AE, editors. Dail and Hammar’s pulmonary pathology. Springer: Science+Business Media; 2008. p. 158–206.CrossRefGoogle Scholar
  13. 13.
    Kadara H, Wistuba II. Molecular biology of lung preneoplasia. In: Roth JA, Hong WK, Komaki RU, editors. Lung cancer. Fourth ed. Hoboken: Wiley; 2014. p. 110–28.CrossRefGoogle Scholar
  14. 14.
    Mascaux C, Laes JF, Anthoine G, Haller A, Ninane V, Burny A, et al. Evolution of microRNA expression during human bronchial squamous carcinogenesis. Eur Respir J. 2009;33(2):352–9.CrossRefPubMedGoogle Scholar
  15. 15.
    van Boerdonk RAA, Sutedja TG, Snijders PJF, Reinen E, Wilting SM, van de Wiel MA, et al. DNA copy number alterations in endobronchial squamous metaplastic lesions predict lung cancer. Am J Respir Crit Care Med. 2011;184(8):948–56.CrossRefPubMedGoogle Scholar
  16. 16.
    Moskalev EA, Jandaghi P, Fallah M, Manoochehri M, Botla SK, Kolychev OV, et al. GHSR DNA hypermethylation is a common epigenetic alteration of high diagnostic value in a broad spectrum of cancers. Oncotarget. 2015;6(6):4418–27.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Bjaanaes MM, Halvorsen AR, Solberg S, Jorgensen L, Dragani TA, Galvan A, et al. Unique microRNA-profiles in EGFR-mutated lung adenocarcinomas. Int J Cancer. 2014;135(8):1812–21.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wang GF, Lai MD, Yang RR, Chen PH, Su YY, Lv BJ, et al. Histological types and significance of bronchial epithelial dysplasia. Mod Pathol. 2006;19(3):429–37.CrossRefPubMedGoogle Scholar
  19. 19.
    Pankova OV, Perelmuter VM, Savenkova OV. Characteristics of proliferation marker expression and apoptosis regulation depending on the character of disregenerator changes in bronchial epithelium of patients with squamous cell lung cancer. Siberian J Oncol. 2010;5:36–41.Google Scholar
  20. 20.
    Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6(2):244–85.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Banerjee AK. Preinvasive lesions of the bronchus. J Thorac Oncol. 2009;4(4):545–51.CrossRefPubMedGoogle Scholar
  22. 22.
    Chyczewski L, Niklinski J, Chyczewska E, Niklinska W, Naumnik W. Morphological aspects of carcinogenesis in the lung. Lung Cancer. 2001;34 Suppl 2:S17–25.CrossRefPubMedGoogle Scholar
  23. 23.
    Kerr KM. Pulmonary preinvasive neoplasia. J Clin Pathol. 2001;54(4):257–71.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kerr KM, Popper HH. The differential diagnosis of pulmonary pre-invasive lesions. Eur Respir Mon. 2007;39:37–62.Google Scholar
  25. 25.
    Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. World Health Organization classification of tumors: pathology and genetics of tumors of the lung, pleura, thymus and heart. 4th ed. Lyon, France: IARC Press; 2004.Google Scholar
  26. 26.
    Pankova OV, Perelmuter VM, Tuzikov SA, Savenkova OV. Effect of neoadjuvant chemotherapy on the spectrum and expression profile of disregeneratory changes in the bronchial mucosa in patients with non-small cell lung cancer. Siberian J Oncol. 2012;3:79–83.Google Scholar
  27. 27.
    Melamed MR. Lung cancer screening results in the National Cancer Institute New York study. Cancer. 2000;89 Suppl 11:2356–62.CrossRefPubMedGoogle Scholar
  28. 28.
    Bota S, Auliac JB, Paris C, Metayer J, Sesboue R, Nouvet G, et al. Follow-up of bronchial precancerous lesions and carcinoma in situ using fluorescence endoscopy. Am J Respir Crit Care Med. 2001;164(9):1688–93.CrossRefPubMedGoogle Scholar
  29. 29.
    Breuer RH, Pasic A, Smit EF, van Vliet E, Vonk Noordegraaf A, Risse EJ, et al. The natural course of preneoplastic lesions in bronchial epithelium. Clin Cancer Res. 2005;11(2 Pt 1):537–43.PubMedGoogle Scholar
  30. 30.
    Riabov V, Gudima A, Wang N, Mickley A, Orekhov A, Kzhyshkowska J. Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol. 2014;5:75.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Hattar K, Franz K, Ludwig M, Sibelius U, Wilhelm J, Lohmeyer J, et al. Interactions between neutrophils and non-small cell lung cancer cells: enhancement of tumor proliferation and inflammatory mediator synthesis. Cancer Immunol Immunother. 2014;63(12):1297–306.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Pietras K, Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res. 2010;316:1324–31.CrossRefPubMedGoogle Scholar
  33. 33.
    Pankova ОV, Perelmuter VМ, Savenkova ОV, Denisov ЕV, Vasilyev SА, Skryabin NА, et al. Characteristics of bronchial mucosal inflammatory response in sites of basal cell hyperplasia and squamous metaplasia combined with squamous cell lung cancer. Siberian J Oncol. 2012;5:28–33.Google Scholar
  34. 34.
    Gharbaran R. Advances in the molecular functions of syndecan-1 (SDC1/CD138) in the pathogenesis of malignancies. Crit Rev Oncol Hematol. 2014;94(1):1–17.CrossRefPubMedGoogle Scholar
  35. 35.
    Shah L, Walter KL, Borczuk AC, Kawut SM, Sonett JR, Gorenstein LA, et al. Expression of syndecan-1 and expression of epidermal growth factor receptor are associated with survival in patients with nonsmall cell lung carcinoma. Cancer. 2004;101(7):1632–8.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Olga V. Pankova
    • 1
  • Evgeny V. Denisov
    • 2
    • 3
    • 4
    Email author
  • Anastasia A. Ponomaryova
    • 2
    • 5
  • Tatiana S. Gerashchenko
    • 2
    • 3
  • Sergey A. Tuzikov
    • 6
  • Vladimir M. Perelmuter
    • 1
    • 7
  1. 1.Department of Pathological Anatomy and CytologyTomsk Cancer Research InstituteTomskRussia
  2. 2.Laboratory of Molecular Oncology and ImmunologyTomsk Cancer Research InstituteTomskRussia
  3. 3.Laboratory for Translational Cellular and Molecular BiomedicineNational Research Tomsk State UniversityTomskRussia
  4. 4.Department of Organic ChemistryNational Research Tomsk State UniversityTomskRussia
  5. 5.National Research Tomsk Polytechnic UniversityTomskRussia
  6. 6.Department of Thoracoabdominal OncologyTomsk Cancer Research InstituteTomskRussia
  7. 7.Department of Pathological AnatomySiberian State Medical UniversityTomskRussia

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