Cytokeratin 19 is a member of a family of at least twenty different cytokeratin polypeptides. Cytokeratins form the intermediate filament structure of epithelial cells1,2. Cytokeratin filaments are poorly soluble but following proteolytic degradation, soluble cytokeratin fragments are formed and released into body fluids.

CYFRA 21-1 is an immunoassay that determines the level of cytokeratin 19 fragments in serum3-6. The CYFRA 21-1 EIA is based on two monoclonal antibodies (BM 19.21 and KS 19.1) specific for cytokeratin 193,7-8. Elevated levels of cytokeratin 19 fragments are seen in serum from patients with lung cancer5,9-12 and also in other cancers e. g. bladder cancer13. In patients with lung cancer, CYFRA 21-1 has been reported to be useful for monitoring the course of disease during treatment and for detection of recurrence11,14-17.



  1. Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression of specific cytokeratins in normal epithelia, tumors and cultured cells. Cell 1982;31:11-24 

  2. Hesse M, Magin TM, Weber K. Genes for intermediate filament proteins and the draft sequence of the human genome: Novel Keratin genes and a surprisingly high number of pseudogenes related to keratin genes 8 and 18. J Cell Sci 2001;114:2569-2575

  3. Bodenmüller H, Ofenloch-Hähnle B, Lane EB, Dessauer A, Böttger V, Donié F. Lung Cancer associated Keratin 19 fragments: Development and Biochemical Characterization of the new Serum Assay Enzymun-Test CYFRA 21-1.   Int J Biol Markers 1994;9:75-81

  4. Bodenmüller H. The Biochemistry of CYFRA 21-1 and other cytokeratin-tests. Scand J Clin Lab Invest Suppl 1995;221:60-66

  5. Stieber P, Dienemann H, Hasholzner U, Müller C, Poley S, Hofmann K, Fateh-Moghadam. Comparison of Cytokeratin Fragment 19 (CYFRA 21-1) Tissue Polypeptide antigen (TPA) and Tissue Polypeptide Specific Antigen (TPS) as Tumor Markers in Lung Cancer. Eur J Clin Chem Clin Biochem 1993;31:689-694    

  6. Bodenmüller H, Donié F, Kaufmann M, Banauch D, The tumor markers TPA, TPS, TPAcyk and CYFRA 21-1 react differently with the keratins 8, 18 and 19. Int J Biol Markers 1994;9:70-74.

  7. Böttger V, Stasiak PC, Harrison DL, Mellerick DM, Lane EB. Epitope mapping of monoclonal antibodies to keratin 19  using keratin fragments, synthetic peptides and phage peptide libraries. Eur J Biochem 1995;231(2):475-85.    

  8. Stigbrand T et al. Epitope specificity of 30 monoclonal antibodies against cytokeratin antigens: the ISOBM TD5-1 Workshop. Tumor Biol 1998;19(2):132-52.

  9. Stieber P, Hasholzner U, Bodenmüller H, Nagel D, Sunder-Plassmann L, Dienemann H, Meier W, Fateh-Moghadam A. CYFRA 21-1. A new marker in lung cancer. Cancer 1993;72(3):707-13.

  10. Ebert W, Dienemann H, Fateh-Moghadam A, Scheulen M, Konietzko N, Schleich T, Bombardieri E. Cytokeratin 19 fragment CYFRA 21-1 compared with carcinoembryonic antigen, squamous cell carcinoma antigen and neuron-specific enolase in lung cancer. Results of an international multicentre study. Eur J Clin Chem Clin Biochem 1994;32(3):189-99.

  11. Stieber P, Zimmermann A, Reinmiedl J, Müller C, Hoffmann H, Dienemann H. CYFRA 21-1 in the early diagnosis of recurrent disease in non small cell lung carcinomas (NSCLC). Anticancer Res 1999;19(4A): 2665-8.

  12. Pujol JL, Molinier O, Ebert W, Daurès JP, Barlesi F, Buccheri G, Paesmans M, Quoix E, Moro-Sibilot D, Szturmowicz M, Bréchot JM, Muley T, Grenier J. 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.

  13. Stieber P, Dienemann H, Hasholzner U, Fabricius PG, Schambeck C, Weinzierl M, Poley S, Samtleben W, Hofmann K, Meier W, et al. Comparison of CYFRA 21-1, TPA and TPS in lung cancer, urinary bladder cancer and benign diseases. Int J Biol Markers 1994;9(2):82-8.

  14. Trapé J, Perez de Olaguer J, Buxó J, López L. Biological Variation of Tumor Markers and Its Application in the Detection of Disease Progression in Patients with Non-Small Cell Lung Cancer. Clin Chem 2005;51:219-222 

  15. Volmer RT, Govindan R, Graziano SL, Gamble G, Garst J, Kelley MJ,Christenson RH. Serum CYFRA 21-1 in Advanced Stage Non-Small Cell Lung Cancer: An early measure of Response. Clin Cancer Res 2003; 9:1728-1733.

  16. Holdenrieder S, Stieber P, von Pawel J, Raith H, Nagel D, Feldmann K, Siedel D. Early and Specific  Prediction of the Therapeutic Efficacy in Non-Small Cell Lung Cancer Patients by Nucleosomal DNA and Cytokeratin-19 Fragments. Ann. N.Y. Acad. Sci. 2006; 1075:244-257. 

  17. Holdenrieder S, von Pawel J, Dankelmann E, Duell T, Faderl B, Markus A, Siakavara M, Wagner H, Feldmann K, Hoffmann H, Raith H, Nagel D, Stieber P. Nucleosomes, ProGRP, NSE, CYFRA 21-1, and CEA in monitoring First-Line Chemotherapy of Small Cell Lung Cancer. Clin Cancer Res:2008; 14(23): 7813-7821.

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