Clinical and Translational Oncology

, Volume 15, Issue 11, pp 882–888 | Cite as

Gene diagnosis of micrometastases in regional lymph nodes of patients with stage I non-small cell lung cancer: impact on staging and prognosis

  • J. Li
  • Z.-N. Li
  • L.-C. Yu
  • S.-B. Shi
  • L.-P. Ge
  • J.-R. Wu
  • Y.-M. Hu
Research Article



The long-term survival of patients with completely resected stage I non-small cell lung cancer (NSCLC) is not optimal because of undetected lymph node micrometastasis at the time of surgery. The aim of this study is to evaluate the role of survivin and livin mRNA expression in histopathologically negative lymph nodes of stage I NSCLC patients as markers of micrometastasis.


Clinical data and tissue samples of primary tumor and lymph nodes were collected from 44 patients with stage I NSCLC. Reverse-transcriptase-PCR (RT-PCR) was used to detect survivin and livin mRNA expression in these tumor and lymph node samples.


Survivin mRNA was detected in all tumors, and livin mRNA was detectable in 39 of the 44 primary tumors. The cut-off values of survivin and livin mRNA levels for diagnosing micrometastasis in lymph nodes were set up according to the expression of survivin and livin mRNA in control lymph nodes. Fifteen (34.1 %) of 44 stage I NSCCL patients had micrometastasis in lymph nodes by survivin and/or livin mRNA positive expression. Survival analysis showed higher rate of cancer recurrences and tumor-related death in patients with lymph node micrometastasis (P < 0.001 and P = 0.001, respectively). Tumor-free survival and overall survival were significantly worse in patients with lymph node micrometastasis compared with those without such micrometastasis (P = 0.007 and P = 0.01, respectively).


RT-RCR assay for survivin and livin mRNA can be considered as useful diagnostic tool for the detection of lymph node micrometastasis for stage I NSCLC patients.


Non-small cell lung cancer Micrometastasis Lymph node Survivin Livin 


  1. 1.
    Rena O, Oliaro A, Cavallo A, Filosso PL, Donati G, Di Marzio P et al (2002) Stage I non-small cell lung carcinoma. Really an early stage? Eur J Cardio-Thorac Surg 21:514–519Google Scholar
  2. 2.
    Mountain CF (1997) Revisions in the international system for stage lung cancer. Chest 111:1710–1717Google Scholar
  3. 3.
    Rena O, Carsana L, Cristina S, Papalia E, Massera F, Errico L et al (2007) Lymph node isolated tumor cells and micrometastases in pathological stage I non-small cell lung cancer: prognostic significance. Eur J Cardio-Thorac Surg 32:863–867Google Scholar
  4. 4.
    Gu CD, Osaki T, Oyama T, Inoue M, Kodate M, Dobashi K et al (2002) Detection of micrometastatic tumor-cells in pN0 lymph nodes of patients with completely resected non-small cell lung cancer: impact on recurrence and survival. Ann Surg 235:133–139Google Scholar
  5. 5.
    Wu J, Ohta Y, Minato H, Tsunezuka Y, Oda M, Watanabe Y et al (2001) Nodal occult metastasis in patients with peripheral lung adenocarcinoma of 2.0 cm or less in diameter. Ann Thorac Surg 7:1772–1777Google Scholar
  6. 6.
    Le Pimpec-Barthes F, Danel C, Lacave R, Ricci S, Bry X, Lancelin F et al (2005) Association of CK 19 mRNA detection of occult cancer cells in mediastinal lymph nodes in non-small cell lung carcinoma and high risk of early recurrence. Eur J Cancer 41:306–312Google Scholar
  7. 7.
    Marchevsky AM, Qiao JH, Krajisnik S, Mirocha JM, Mckenna RJ (2003) The prognostic significance of intranodal isolated tumor cells and micrometastases in patients with non-small cell lung carcinoma of the lung. J Thorac Cardiovasc Surg 126:551–557Google Scholar
  8. 8.
    Osaki T, Oyama T, Gu CD, Yamashita T, So T, Takenoyama M et al (2002) Prognostic impact of micrometastatic tumor cells in the lymph nodes and bone marrow of patients with completely resected stage I non-small cell lung cancer. J Clin Oncol 13:2930–2936Google Scholar
  9. 9.
    Salerno CT, Frizelle S, Niehans GA, Ho SB, Jakkula M, Kratzke RA et al (1998) Detection of occult micrometastases in non-small cell lung carcinoma by reverse transcriptas-polymerase chain reaction. Chest 113:1526–1532Google Scholar
  10. 10.
    Mori M, Mimori K, Inoue H, Barnard GF, Tsuji K, Nanbara S et al (1995) Detection of cancer micrometastases in lymph nodes by reverse transcriptage-polymeras chain reaction. Cancer Res 55:3417–3420Google Scholar
  11. 11.
    Noguchi S, Aihara T, Motomura K, Inaji H, Imaoka S, Koyama H (1996) Detection of breast cancer micrometastases in axillary lymph nodes by means of reverse transcriptase- polymerase chain reaction. Am J Pathol 148:649–656Google Scholar
  12. 12.
    Ambrosini G, Adida C, Altieri DC (1997) A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3:917–921Google Scholar
  13. 13.
    Altieri DC (2003) Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 22:8581–8589Google Scholar
  14. 14.
    Kasof GM, Gomes BC (2001) Livin, a novel inhibitor of apoptosis protein family member. J Bio Chem 276:3238–3246Google Scholar
  15. 15.
    Velculescu VE, Madden SL, Zhang L Lash AE, Yu J, Rago CL et al (1999) Analysis of human transcriptomes. Nat Genet 23:387–388Google Scholar
  16. 16.
    Altieri DC (2001) The molecular basis and potential role of survivin in cancer diagnosis and therapy. Trends Mol Med 7:542–547Google Scholar
  17. 17.
    Altieri DC (2003) Validating survivin as a cancer therapeutic target. Nat Rev Cancer 3:46–54Google Scholar
  18. 18.
    Dai CH, Li J, Shi SB, Yu LC, Ge LP, Chen P (2010) Survivin and smac gene expressions but not livin are predictors of prognosis in non-small cell lung cancer patients treated with adjuvant chemotherapy following surgery. Jpn J Clin Oncol 40:327–335Google Scholar
  19. 19.
    Chen P, Li J, Ge L-P, Dai C-H, Li X-Q (2010) Prognostic value of survivin, X-linked inhibitor of apoptosis protein and second mitochondria-derived activator of caspases expression in advanced non-small-cell lung cancer patients. Respirology 15:501–509Google Scholar
  20. 20.
    Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit VM (2000) ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol 10:1359–1366Google Scholar
  21. 21.
    Tanabe H, Yagidashi A, Tsuji N, Shijubo Y, Abe S, Watanabe N (2004) Expression of survivin mRNA and livin mRNA in non-small cell lung cancer. Lung Cancer 46:299–304Google Scholar
  22. 22.
    Gazzanige P, Gradilone A, Giuliani L, Gandini O, Silvestri I, Nofroni I et al (2003) Expression and prognostic significance of livin, survivin and other apoptosis related genes in the progression of superficial bladder cancer. Ann Oncol 14:85–90Google Scholar
  23. 23.
    Xiang Y, Yao H, Wang S, Hong M, He J, Cao S et al (2006) Prognostic value of survivin and livin in nasopharyngeal carcinoma. Laryngoscope 116:126–130Google Scholar
  24. 24.
    American Thoracic Society (1983) Clinical staging of primary lung cancer. Am Rev Respir Dis 127:659Google Scholar
  25. 25.
    Lugo TG, Braun S, Cote RJ, Panted K, Rusch V (2003) Detection and measurement of occult disease for the prognosis of solid tumors. J Clin Oncol 21:2609–2615Google Scholar
  26. 26.
    Kappler M, Kohler T, Kampf C, Diestelkötter, P, Würl, P, Schmitz M et al (2001) Increased survivin transcript levels: an independent negative predictor of survival in soft tissue sarcoma patients. Int J Cancer 95:360–363Google Scholar
  27. 27.
    Gianani R, Jarboe E, Orlicky D, Frost M, Bobak J, Lehner R et al (2001) Expression of survivin in normal, hyperplastic, and neoplastic colonic mucosa. Hum Pathol 32:119–125Google Scholar
  28. 28.
    Zippelius A, Kufer P, Honold G, Köllermann MW, Oberneder R, Schlimok G et al (1997) Limitations of revers-transcriptase polymerase chain reaction analyses for detection of micrometastatic epithelial cancer cells in bone marrow. J Clin Oncol 15:2701–2708Google Scholar
  29. 29.
    Cao M, Yie SM, Wu SM, Chen S, Lou B, He X et al (2009) Detection of survivin-expressing circulating cancer cells in the peripheral blood of patients with esophageal squamous cell carcinoma and its clinical significance. Clin Exp Metastasis 26:751–758Google Scholar
  30. 30.
    Yang D, Schneider S, Azuma M, Iqbal S, El-Khoueiry A, Groshen S et al (2006) Gene expression levels of epidermal growth factor receptor, survivin, and vascular endothelial growth factor as molecular markers of lymph node involvement in patients with locally advanced rectal cancer. Clin Colorect Cancer 6:305–311Google Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2013

Authors and Affiliations

  • J. Li
    • 1
  • Z.-N. Li
    • 2
  • L.-C. Yu
    • 3
  • S.-B. Shi
    • 3
  • L.-P. Ge
    • 1
  • J.-R. Wu
    • 4
  • Y.-M. Hu
    • 1
  1. 1.Department of Pulmonary MedicineAffiliated Hospital of Jiangsu UniversityZhenjiangChina
  2. 2.Department of SurgeryAffiliated First Hospital of Nanjing Medical UniversityNanjingChina
  3. 3.Department of Thoracic SurgeryAffiliated Hospital of Jiangsu UniversityZhenjiangChina
  4. 4.Department of PathologyAffiliated Hospital of Jiangsu UniversityZhenjiangChina

Personalised recommendations