Journal of Cancer Research and Clinical Oncology

, Volume 136, Issue 12, pp 1805–1812 | Cite as

Serum Cyfra 21.1 and galectin-3 protein levels in relation to immunohistochemical cytokeratin 19 and galectin-3 expression in patients with thyroid tumors

  • Tijana Išić
  • Svetlana Savin
  • Dubravka Cvejić
  • Ilona Marečko
  • Svetislav Tatić
  • Marija Havelka
  • Ivan Paunović
Original Paper



The aim of this study was to assess the clinical utility of circulating preoperative Cyfra 21.1 [soluble fragment of cytokeratin (CK) 19] and galectin-3 (gal-3) in patients with thyroid tumors, to compare their serum values with tissue expression and to analyze the prognostic significance of these markers in relation to the clinical status of postsurgical differentiated thyroid carcinoma (DTC) patients.


Concentrations of Cyfra 21.1 and gal-3 were evaluated by immunoassays in sera of 9 healthy subjects, 97 preoperative patients with diverse thyroid tumors (10 FTA, 63 PTC, 11 FTC, 5 PDTC, 4 ATC, 4 LNM) and 25 postoperative DTC patients (14 remissions and 11 metastases).


Low Cyfra 21.1 values were found in all subgroups, but with a tendency toward higher values in poorly differentiated DTC patients. Compared to the control (0.23 ng/mL), serum levels of gal-3 were significantly elevated in patients with thyroid tumors but with overlapping between adenoma (4.16 ng/mL) and carcinoma (3.85, 4.37, 4.64, 6.07 ng/mL for PTC, PDTC, ATC and LNM, respectively). The tissue expression of CK19 and gal-3 was immunohistochemically determined on 45 matched paraffin-embedded sections. Most thyroid carcinomas showed positive CK19 (27/35) and gal-3 immunostaining (31/35), while adenomas were mostly immunonegative (8/10 and 7/10, respectively). However, there was no significant correlation between their serum and tissue levels. Clinical status of postoperative DTC patients had no influence on serum concentrations of the tested markers.


While CK19 and gal-3 are accurate as tissue markers, their serum levels could not be used as reliable markers for identification of thyroid malignancy or in thyroid cancer follow-up. On the other hand, a tendency toward higher serum levels of Cyfra 21.1 in the small number of PDTC patients examined adds weight to previous reports postulating a role for cytokeratins in predicting a high degree of malignancy.


Cyfra 21.1 Cytokeratin 19 Galectin-3 Thyroid carcinoma Immunohistochemistry Human serum 



This research was supported by the Ministry of Science and Technological Development of the Republic of Serbia (project 143039).

Conflict of interest statement

We declare that we have no conflict of interest.


  1. Appetecchia M, Meçule A, Ducci M, Palma L, Castelli M (2001) Serum cytokeratins determination in differentiated thyroid carcinoma. J Exp Clin Cancer Res 20:253–256PubMedGoogle Scholar
  2. Asa SL (2005) The role of immunohistochemical markers in the diagnosis of follicular-patterned lesions of the thyroid. Endocr Pathol 16:295–309CrossRefPubMedGoogle Scholar
  3. Barak V, Goike H, Panaretakis KW, Einarsson R (2004) Clinical utility of cytokeratins as tumor markers. Clin Biochem 37:529–540CrossRefPubMedGoogle Scholar
  4. Barondes SH, Cooper DN, Gitt MA, Leffler H (1994) Galectins. Structure and function of a large family of animal lectins. J Biol Chem 269:20807–20810PubMedGoogle Scholar
  5. Bártek J, Bartkova J, Taylor-Papadimitriou J, Rejthar A, Kovarik J, Lukas Z, Vojtesek B (1986) Differential expression of keratin 19 in normal human epithelial tissues revealed by monospecific monoclonal antibodies. Histochem J 18:565–575CrossRefPubMedGoogle Scholar
  6. Bartolazzi A, Gasbarri A, Papotti M, Bussolati G, Lucante T, Khan A, Inohara H, Marandino F, Orlandi F, Nardi F, Vecchione A, Tecce R, Larsson O, Group ThyroidCancerStudy (2001) Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions. Lancet 357:1644–1650CrossRefPubMedGoogle Scholar
  7. Beesley MF, McLaren KM (2002) Cytokeratin 19 and galectin-3 immunohistochemistry in the differential diagnosis of solitary thyroid nodules. Histopathology 41:236–243CrossRefPubMedGoogle Scholar
  8. Cheung CC, Ezzat S, Freeman JL, Rosen IB, Asa SL (2001) Immunohistochemical diagnosis of papillary thyroid carcinoma. Mod Pathol 14:338–342CrossRefPubMedGoogle Scholar
  9. Cvejic D, Savin S, Paunovic I, Tatic S, Havelka M, Sinadinovic J (1998) Immunohistochemical localization of galectin-3 in malignant and benign human thyroid tissue. Anticancer Res 18:2637–2642PubMedGoogle Scholar
  10. Cvejic D, Selemetjev S, Savin S, Paunovic I, Tatic S (2009) Changes in the balance between proliferation and apoptosis during the progression of malignancy in thyroid tumours. Eur J Histochem 53:65–72PubMedGoogle Scholar
  11. Danguy A, Camby I, Kiss R (2002) Galectins and cancer. Biochem Biophys Acta 1572:285–293PubMedGoogle Scholar
  12. Fernández PL, Merino MJ, Gómez M, Campo E, Medina T, Castronovo V, Sanjuán X, Cardesa A, Liu FT, Sobel ME (1997) Galectin-3 and laminin expression in neoplastic and non-neoplastic thyroid tissue. J Pathol 181:80–86CrossRefPubMedGoogle Scholar
  13. Gadducci A, Ferdeghini M, Cosio S, Fanucchi A, Cristofani R, Genazzani AR (2001) The clinical relevance of serum CYFRA 21–1 assay in patients with ovarian cancer. Int J Gynecol Cancer 11:277–282CrossRefPubMedGoogle Scholar
  14. Gao Y, Hankui L, Zhibin Y, Ruisen Z (2009) Tumor markers in thyroid carcinoma with pulmonary metastases after thyroidectomy. Lab Med 40:30–34CrossRefGoogle Scholar
  15. Giovanella L, Ceriani L, Ghelfo A, Maffioli M (2008) Circulating cytokeratin 19 fragments in patients with benign nodules and carcinomas of the thyroid gland. Int J Biol Markers 23:61–64Google Scholar
  16. Hedinger C, Williams ED, Sobin LH (1988) Histological typing of thyroid tumours. In: International histological classification of tumours. World Health Organization, 2nd edn. Springer, Geneva, pp 1–66Google Scholar
  17. Inohara H, Honjo Y, Yoshii T, Akahani S, Yoshida J, Hattori K, Okamoto S, Sawada T, Raz A, Kubo T (1999) Expression of galectin-3 in fine needle aspirates as a differential diagnostic marker between benign and malignant thyroid neoplasms. Cancer 85:2475–2484CrossRefPubMedGoogle Scholar
  18. Inohara H, Segawa T, Miyauchi A, Yoshii T, Nakahara S, Raz A, Maeda M, Miyoshi E, Kinoshita N, Yoshida H, Furukawa M, Takenaka Y, Takamura Y, Ito Y, Taniguchi N (2008) Cytoplasmic and serum gal-3 in diagnosis of thyroid malignancies. Biochem Biophys Res Commun 376:605–610CrossRefPubMedGoogle Scholar
  19. Iurisci I, Tinari N, Natoli C, Angelucci D, Cianchetti E, Iacobelli S (2000) Concentrations of galectin-3 in the sera of normal controls and cancer patients. Clin Cancer Res 6:1389–1393PubMedGoogle Scholar
  20. Leffler H (2001) Galectins: structure and function—a synopsis. Results Probl Cell Differ 33:57–83PubMedGoogle Scholar
  21. Linder S (2007) Cytokeratin markers come of age. Tumour Biol 28:189–195CrossRefPubMedGoogle Scholar
  22. Moll R, Divo M, Langbein L (2008) The human keratins: biology and pathology. Histochem Cell Biol 129:705–733CrossRefPubMedGoogle Scholar
  23. Nakata B, Ogawa Y, Ishikawa T, Ikeda K, Kato Y, Nishino H, Hirakawa K (2000) Serum CYFRA 21–1 is one of the most reliable tumor markers for breast carcinoma. Cancer 89:1285–1290CrossRefPubMedGoogle Scholar
  24. Orlandi F, Saggiorato E, Pivano G, Puligheddu B, Termine A, Cappia S, De Giuli P, Angeli A (1998) Galectin-3 is a presurgical marker of human thyroid carcinoma. Cancer Res 58:3013–3020Google Scholar
  25. Perillo NL, Marcus ME, Baum LG (1998) Galectins: versatile modulators of cell adhesion, cell proliferation and cell death. J Mol Med 76:402–412CrossRefPubMedGoogle Scholar
  26. Raphael SJ (2002) The meanings of markers: ancillary techniques in diagnosis of thyroid neoplasia. Endocr Pathol 13:301–311CrossRefPubMedGoogle Scholar
  27. Rosai J, Kuhn E, Carcangiu ML (2006) Pitfalls in thyroid tumor pathology. Histopathology 49:107–120CrossRefPubMedGoogle Scholar
  28. Saggiorato E, Cappia S, De Giuli P, Mussa A, Pancani G, Caraci P, Angeli A, Orlandi F (2001) Galectin-3 as a presurgical immunocytodiagnostic marker of minimally invasive follicular thyroid carcinoma. J Clin Endocrinol Metab 86:5152–5158CrossRefPubMedGoogle Scholar
  29. Sánchez-Carbayo M, Espasa A, Chinchilla V, Herrero E, Megías J, Mira A, Soria F (1999) New electrochemiluminescent immunoassay for the determination of CYFRA 21–1: analytical evaluation and clinical diagnostic performance in urine samples of patients with bladder cancer. Clin Chem 45:1944–1953PubMedGoogle Scholar
  30. Saussez S, Glinoer D, Chantrain G, Pattou F, Carnaille B, André S, Gabius HJ, Laurent G (2008) Serum galectin 1 and galectin 3 levels in benign and malignant nodular thyroid disease. Thyroid 18:705–712CrossRefPubMedGoogle Scholar
  31. Savin S, Cvejić D, Janković M (2003) Expression of galectin-1 and galectin-3 in human fetal thyroid gland. J Histochem Cytochem 51:479–483PubMedGoogle Scholar
  32. Savin S, Cvejic D, Isic T, Paunovic I, Tatic S, Havelka M (2008) Thyroid peroxidase and galectin-3 immunostaining in differentiated thyroid carcinoma with clinicopathologic correlation. Hum Pathol 39:1656–1663CrossRefPubMedGoogle Scholar
  33. Sohoo S, Hoda SA, Rosai J, DeLellis RA (2001) Cytokeratin 19 immunoreactivity in the diagnosis of papillary thyroid carcinoma: a note of caution. Am J Clin Pathol 116:696–702CrossRefGoogle Scholar
  34. Sreelekha TT, Pradeep VM, Vijayalakshmi K, Belthazar A, Chellam VG, Nair MB, Pillai MR (2000) In situ apoptosis in the thyroid. Thyroid 10:117–122CrossRefPubMedGoogle Scholar
  35. Suzuki S, Furukawa H, Tsuchiya A (1999) Clinical evaluation of serum tissue polypeptide specific antigen in patients with thyroid carcinoma. Thyroid 9:921–925CrossRefPubMedGoogle Scholar
  36. Van den Brule F, Califice S, Castronovo V (2004) Expressions of galectins in cancer: a critical review. Glycoconj J 19:537–542CrossRefPubMedGoogle Scholar
  37. Wu F, Nishioka M, Fujita J, Murota M, Ohtsuki Y, Ishida T, Kuriyama S (2002) Expression of cytokeratin 19 in human hepatocellular carcinoma cell lines. Int J Oncol 20:31–37PubMedGoogle Scholar
  38. Xu XC, El-Naggar AK, Lotan R (1995) Differential expression of galectin-1 and galectin-3 in thyroid tumors. Potential diagnostic implications. Am J Pathol 147:815–822PubMedGoogle Scholar
  39. Yoshida A, Nakamura Y, Imada T, Asaga T, Shimizu A, Harada M (1999) Apoptosis and proliferative activity in thyroid tumors. Surg Today 29:204–208CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Tijana Išić
    • 1
  • Svetlana Savin
    • 1
  • Dubravka Cvejić
    • 1
  • Ilona Marečko
    • 1
  • Svetislav Tatić
    • 2
  • Marija Havelka
    • 2
  • Ivan Paunović
    • 3
  1. 1.Institute for the Application of Nuclear Energy, INEPUniversity of BelgradeZemun, BelgradeSerbia
  2. 2.Institute of Pathology, Medical FacultyUniversity of BelgradeBelgradeSerbia
  3. 3.Centre for Endocrine Surgery, Institute of Endocrinology, Diabetes and Diseases of MetabolismClinical Center of SerbiaBelgradeSerbia

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