Tumor Biology

, Volume 37, Issue 3, pp 3205–3213 | Cite as

Prognostic impact of cytological fluid tumor markers in non-small cell lung cancer

  • Arthur Cho
  • Jin Hur
  • Yoo Jin Hong
  • Hye-Jeong Lee
  • Young Jin Kim
  • Sae Rom Hong
  • Young Joo Suh
  • Dong Jin Im
  • Yun Jung Kim
  • Jae Seok Lee
  • Hyo Sup Shim
  • Byoung Wook Choi
Original Article


The serum tumor markers CYFRA 21–1, carcinoembryonic antigen (CEA), and squamous cell carcinoma antigen (SCCA) are useful in diagnosis and prognosis of non-small cell lung cancer (NSCLC). Cytologic tumor markers obtained during needle aspiration biopsies (NAB) of lung lesions are useful for NSCLC diagnosis. This study investigated the incremental prognostic value of cytologic tumor markers compared to serum tumor markers. This prospective study included 253 patients diagnosed with NSCLC by NAB with cytologic tumor marker analysis. Levels of cytologic CYFRA 21–1, CEA, SCCA, and their serum counterparts were followed up for survival analysis. Optimal cutoff values for each tumor marker were obtained for overall survival (OS) and progression-free survival (PFS) analyses. All patients were followed up for a median of 22.8 months. Using cutoff values of 0.44 ng/ml for C-SCCA, 2.0 ng/ml for S-SCCA, and 3.3 ng/ml for S-CYFRA, a multivariate analysis revealed that high S-SCCA (hazard ratio, HR, 1.84) and high C-SCCA (HR, 1.63) were independent predictive factors of OS. The 3-year overall survival rate was 55 vs. 80 % for high and low C-SCCA, respectively. Cytologic tumor marker level detection is easily obtainable and provides prognostic information for NSCLC. Cytologic tumor markers provide comparable prognostic information relative to serum tumor markers, with C-SCCA acting as a strong prognostic factor of overall survival and PFS.


Serum CYFRA 21–1 Cytologic tumor marker Cytologic SCC Ag Prognosis NSCLC 



This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education, Science and Technology (2010-0009053).

Conflicts of interest


Supplementary material

13277_2015_4034_MOESM1_ESM.doc (68 kb)
ESM 1 (DOC 68 kb)
13277_2015_4034_MOESM2_ESM.doc (68 kb)
ESM 2 (DOC 68 kb)
13277_2015_4034_MOESM3_ESM.doc (56 kb)
ESM 3 (DOC 56 kb)
13277_2015_4034_MOESM4_ESM.doc (50 kb)
ESM 4 (DOC 50 kb)
13277_2015_4034_MOESM5_ESM.doc (72 kb)
ESM 5 (DOC 72 kb)
13277_2015_4034_MOESM6_ESM.doc (72 kb)
ESM 6 (DOC 72 kb)
13277_2015_4034_MOESM7_ESM.doc (64 kb)
ESM 7 (DOC 64 kb)
13277_2015_4034_MOESM8_ESM.doc (66 kb)
ESM 8 (DOC 66 kb)


  1. 1.
    Hanagiri T, Sugaya M, Takenaka M, Oka S, Baba T, Shigematsu Y, et al. Preoperative CYFRA 21–1 and CEA as prognostic factors in patients with stage I non-small cell lung cancer. Lung Cancer. 2011;74(1):112–7. doi: 10.1016/j.lungcan.2011.02.001.CrossRefPubMedGoogle Scholar
  2. 2.
    Cedres S, Nunez I, Longo M, Martinez P, Checa E, Torrejon D, et al. Serum tumor markers CEA, CYFRA21-1, and CA-125 are associated with worse prognosis in advanced non-small-cell lung cancer (NSCLC). Clin lung Cancer. 2011;12(3):172–9. doi: 10.1016/j.cllc.2011.03.019.CrossRefPubMedGoogle Scholar
  3. 3.
    Muley T, Fetz TH, Dienemann H, Hoffmann H, Herth FJ, Meister M, et al. Tumor volume and tumor marker index based on CYFRA 21–1 and CEA are strong prognostic factors in operated early stage NSCLC. Lung Cancer. 2008;60(3):408–15. doi: 10.1016/j.lungcan.2007.10.026.CrossRefPubMedGoogle Scholar
  4. 4.
    Wieskopf B, Demangeat C, Purohit A, Stenger R, Gries P, Kreisman H, et al. CYFRA 21–1 as a biologic marker of non-small cell lung cancer. Evaluation of sensitivity, specificity, and prognostic role. Chest. 1995;108(1):163–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Tanaka K, Hata A, Kaji R, Fujita S, Otoshi T, Fujimoto D, et al. Cytokeratin 19 fragment predicts the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor in non-small-cell lung cancer harboring EGFR mutation. J Thorac Oncol. 2013;8(7):892–8. doi: 10.1097/JTO.0b013e31828c3929.CrossRefPubMedGoogle Scholar
  6. 6.
    Nisman B, Biran H, Heching N, Barak V, Ramu N, Nemirovsky I, et al. Prognostic role of serum cytokeratin 19 fragments in advanced non-small-cell lung cancer: association of marker changes after two chemotherapy cycles with different measures of clinical response and survival. Br J Cancer. 2008;98(1):77–9. doi: 10.1038/sj.bjc.6604157.CrossRefPubMedGoogle Scholar
  7. 7.
    Grunnet M, Sorensen JB. Carcinoembryonic antigen (CEA) as tumor marker in lung cancer. Lung Cancer. 2012;76(2):138–43. doi: 10.1016/j.lungcan.2011.11.012.CrossRefPubMedGoogle Scholar
  8. 8.
    Molina R, Filella X, Auge JM, Fuentes R, Bover I, Rifa J, et al. Tumor markers (CEA, CA 125, CYFRA 21–1, SCC and NSE) in patients with non-small cell lung cancer as an aid in histological diagnosis and prognosis. Comparison with the main clinical and pathological prognostic factors. Tumour Biol. 2003;24(4):209–18.CrossRefPubMedGoogle Scholar
  9. 9.
    Reinmuth N, Brandt B, Semik M, Kunze WP, Achatzy R, Scheld HH, et al. Prognostic impact of CYFRA21-1 and other serum markers in completely resected non-small cell lung cancer. Lung Cancer. 2002;36(3):265–70.CrossRefPubMedGoogle Scholar
  10. 10.
    Vassilakopoulos T, Troupis T, Sotiropoulou C, Zacharatos P, Katsaounou P, Parthenis D, et al. Diagnostic and prognostic significance of squamous cell carcinoma antigen in non-small cell lung cancer. Lung Cancer. 2001;32(2):137–44.CrossRefPubMedGoogle Scholar
  11. 11.
    Kim GR, Hur J, Lee HJ, Nam JE, Kim YJ, Hong YJ, et al. Analysis of tumor markers in cytological fluid obtained from computed tomography-guided needle aspiration biopsies for the diagnosis of ground-glass opacity pulmonary lesions. Cancer Cytopathology. 2013;121(4):214–22. doi: 10.1002/cncy.21244.CrossRefPubMedGoogle Scholar
  12. 12.
    Hur J, Lee HJ, Nam JE, Kim YJ, Kim TH, Choe KO, et al. Diagnostic accuracy of CT fluoroscopy-guided needle aspiration biopsy of ground-glass opacity pulmonary lesions. AJR Am J Roentgenol. 2009;192(3):629–34. doi: 10.2214/AJR.08.1366.CrossRefPubMedGoogle Scholar
  13. 13.
    Hur J, Lee HJ, Nam JE, Kim YJ, Hong YJ, Kim HY, et al. Additional diagnostic value of tumor markers in cytological fluid for diagnosis of non-small-cell lung cancer. BMC Cancer. 2012;12:392. doi: 10.1186/1471-2407-12-392.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hur J, Lee HJ, Byun MK, Nam JE, Moon JW, Kim HS, et al. Computed tomographic fluoroscopy-guided needle aspiration biopsy as a second biopsy technique after indeterminate transbronchial biopsy results for pulmonary lesions: comparison with second transbronchial biopsy. J Comput Assist Tomogr. 2010;34(2):290–5. doi: 10.1097/RCT.0b013e3181bc93ef.CrossRefPubMedGoogle Scholar
  15. 15.
    Hong YJ, Hur J, Lee HJ, Nam JE, Kim YJ, Kim HS, et al. Analysis of tumor markers in the cytological fluid obtained from computed tomography-guided needle aspiration biopsy for the diagnosis of non-small cell lung cancer. J Thorac Oncol. 2011;6(8):1330–5. doi: 10.1097/JTO.0b013e31822462b1.CrossRefPubMedGoogle Scholar
  16. 16.
    Cho A, Hur J, Hong YJ, Lee HJ, Kim YJ, Kim HY, et al. NSCLC subtype prediction using cytologic fluid specimens from needle aspiration biopsies. Am J Clin Pathol. 2013;139(3):309–16. doi: 10.1309/AJCPYOJYG56UNBSZ.CrossRefPubMedGoogle Scholar
  17. 17.
    Hurria A, Kris MG. Management of lung cancer in older adults. CA Cancer J Clin. 2003;53(6):325–41.CrossRefPubMedGoogle Scholar
  18. 18.
    Pujol JL, Molinier O, Ebert W, Daures JP, Barlesi F, Buccheri G, et al. CYFRA 21–1 is a prognostic determinant in non-small-cell lung cancer: results of a meta-analysis in 2063 patients. Br J Cancer. 2004;90(11):2097–105. doi: 10.1038/sj.bjc.6601851.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Park SY, Lee JG, Kim J, Park Y, Lee SK, Bae MK, et al. Preoperative serum CYFRA 21–1 level as a prognostic factor in surgically treated adenocarcinoma of lung. Lung Cancer. 2013;79(2):156–60. doi: 10.1016/j.lungcan.2012.11.006.CrossRefPubMedGoogle Scholar
  20. 20.
    Kulpa J, Wojcik E, Reinfuss M, Kolodziejski L. Carcinoembryonic antigen, squamous cell carcinoma antigen, CYFRA 21–1, and neuron-specific enolase in squamous cell lung cancer patients. Clin Chem. 2002;48(11):1931–7.PubMedGoogle Scholar
  21. 21.
    Ardizzoni A, Cafferata MA, Tiseo M, Filiberti R, Marroni P, Grossi F, et al. Decline in serum carcinoembryonic antigen and cytokeratin 19 fragment during chemotherapy predicts objective response and survival in patients with advanced nonsmall cell lung cancer. Cancer. 2006;107(12):2842–9. doi: 10.1002/cncr.22330.CrossRefPubMedGoogle Scholar
  22. 22.
    Takeuchi S, Nonaka M, Kadokura M, Takaba T. Prognostic significance of serum squamous cell carcinoma antigen in surgically treated lung cancer. Ann Thorac Cardiovasc Surg. 2003;9(2):98–104.PubMedGoogle Scholar
  23. 23.
    Yu D, Du K, Liu T, Chen G. Prognostic value of tumor markers, NSE, CA125 and SCC, in operable NSCLC patients. Int J Mol Sci. 2013;14(6):11145–56. doi: 10.3390/ijms140611145.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Picardo AL, Diez M, Torres A, Maestro M, Ortega D, Hernando F, et al. Analysis of the prognostic significance of cytosolic determination of CA 125 tumor-associated antigen, carcinoembryonic antigen and squamous cell carcinoma antigen in patients with nonsmall cell lung carcinoma. Cancer. 1996;77(6):1066–72.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Arthur Cho
    • 1
  • Jin Hur
    • 2
    • 4
  • Yoo Jin Hong
    • 2
  • Hye-Jeong Lee
    • 2
  • Young Jin Kim
    • 2
  • Sae Rom Hong
    • 2
  • Young Joo Suh
    • 2
  • Dong Jin Im
    • 2
  • Yun Jung Kim
    • 2
  • Jae Seok Lee
    • 3
  • Hyo Sup Shim
    • 3
  • Byoung Wook Choi
    • 2
  1. 1.Department of Nuclear Medicine, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
  2. 2.Department of Radiology and Research Institute of Radiological Science, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
  3. 3.Department of Pathology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
  4. 4.Department of Radiology, Severance HospitalYonsei University College of MedicineSeodaemun-guSouth Korea

Personalised recommendations