Abstract
Oral squamous cell carcinoma (OSCC) accounts for 90 % of malignant lesions of oral cavity. The study assessed the potential of Cyfra 21-1 as a tumor marker in OSCC. The study included 50 patients of OSCC to evaluate levels of Cyfra 21-1 in serum and saliva by electrochemiluminescent immunoassay (ECLIA) and CK19 messenger RNA (mRNA) expression in tissue by florescent quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) along with healthy individuals as control. The salivary and serum Cyfra 21-1 levels in patients of OSCC were significantly higher compared to controls (p value < 0.01). There was a 2.75-fold increase in CK19 mRNA expression in OSCC cases compared to controls. A significant positive correlation was found between serum and salivary Cyfra 21-1, serum Cyfra 21-1, and CK19 mRNA expression and between salivary Cyfra 21-1 and CK19 mRNA expression. Among these, correlation between serum and salivary Cyfra 21-1 was highly significant. Salivary and serum Cyfra 21-1 showed significantly elevated levels in grade II OSCC compared to grade I histopathologically. Elevated levels of salivary Cyfra 21-1 were associated with recurrence in OSCC patients. Reverse operating curve constructed using 3 ng/ml as a cutoff for serum Cyfra 21-1 revealed the sensitivity and specificity to be 88 and 78.2 %, respectively. Using a cutoff value of 8.5 ng/ml for salivary Cyfra 21-1, the sensitivity was found to be 93.8 % and specificity 84.3 %. We advocate salivary Cyfra 21-1 as a better diagnostic marker over serum Cyfra 21-1 as well as a potential marker in the prognosis of OSCC.
Similar content being viewed by others
References
American Cancer Society. Cancer Facts and Figures 2007. Atlanta: American Cancer Society 2007.
Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45:309–16.
Markopoulos AK, Michailidou EZ, Tzimagiorgis G. Salivary markers for oral cancer detection. Open Dent J. 2010;4:172–8.
Zhong LP, Zhang CP, Zheng JW, Li J, Chen WT, Zhang ZY. Increased Cyfra 21-1 concentration in saliva from primary oral squamous cell carcinoma patients. Arch Oral Biol. 2007;52:1079–87.
Doweck I, Barak M, Uri N, Greenberg E. The prognostic value of the tumour marker Cyfra 21-1 in carcinoma of head and neck and its role in early detection of recurrent disease. Br J Cancer. 2000;83:1696–701.
Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982;31:11–24.
Sawant SS, Zingde SM, Vaidya MM. Cytokeratin fragments in the serum: their utility for the management of oral cancer. Oral Oncol. 2008;44:722–32.
Barak V, Goike H, Panaretakis KW, Einarsson R. Clinical utility of cytokeratins as tumor markers. Clin Biochem. 2004;37:529–40.
Broers JL, Ramaekers FC, Rot MK, Oostendorp T, Huysmans A, van Muijen GN, et al. Cytokeratins in different types of human lung cancer as monitored by chain-specific monoclonal antibodies. Cancer Res. 1988;48:3221–9.
Bodenmuller H, Ofenloch-Hahnle B, Lane EB, Dessauer A, Bottger V, Donie F. Lung cancer-associated keratin 19 fragments: development and biochemical characterisation of the new serum assay Enzymun-Test CYFRA 21-1. Int J Biol Markers. 1994;9:75–81.
Dohmoto K, Hojo S, Fujita J, Yang Y, Ueda Y, Bandoh S, et al. The role of caspase 3 in producing cytokeratin 19 fragment (CYFRA 21-1) in human lung cancer cell lines. Int J Cancer. 2001;91:468–73.
Sheard MA, Vojtesek B, Simickova M, Valik D. Release of cytokeratin-18 and -19 fragments (TPS and CYFRA 21-1) into the extracellular space during apoptosis. J Cell Biochem. 2002;85:670–7.
Satyam A, Singh P, Sharma M, Seth A, Sharma A. CYFRA 21-1: a potential molecular marker for noninvasive differential diagnosis of urothelial carcinoma of bladder. Biomarkers. 2011;16:413–21.
Cheng B, Rhodus NL, Williams B, Griffin RJ. Detection of apoptotic cells in whole saliva of patients with oral premalignant and malignant lesions: a preliminary study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;97:465–70.
Wong DT. Salivary diagnostics powered by nanotechnologies, proteomics and genomics. J Am Dent Assoc. 2006;137:313–21.
Vora HH, Shah NG, Patel DD, Trivedi TI, Chikhlikar PR. Prognostic significance of biomarkers in squamous cell carcinoma of the tongue: multivariate analysis. J Surg Oncol. 2003;82:34–50.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Manual, 7th ed. New York: Springer, 2010:29–35.
Anneroth G, Batsakis J, Luna M. Review of literature and recommended system of malignancy grading in oral squamous cell carcinoma. Scand J Dent Res. 1987;95:229–49.
Akhter M, Hossain S, Rahman QB, Molla MR. A study on histological grading of oral squamous cell carcinoma and its co-relationship with regional metastasis. J Oral Maxillofac Pathol. 2011;15:168–76.
Doshi NP, Shah SA, Patel KB, Jhabuawala MF. Histological grading of oral cancer: a comparison of different systems and their relation to lymph node metastasis. Ntnl J Comm Med. 2011;2:136–42.
Céruse P, Rabilloud M, Charrié A, Dubreuil C, Disant F. Study of cyfra 21-1, a tumor marker, in head and neck squamous cell carcinoma. Ann Otol Rhinol Laryngol. 2005;114:768–76.
Pujol JL, Grenier J, Daures JP, Daver A, Pujol H, Michel FB. Serum fragment of cytokeratin subunit 19 measured by Cyfra 21-1 immunoradiometric assay as a marker of lung cancer. Cancer Res. 1993;53:61–6.
Gadducci A, Ferdeghini M, Cosio S, Fanucchi A, Cristofani R, Genazzani AR. The clinical relevance of serum CYFRA 21-1 assay in patients with ovarian cancer. Int J Gynecol Cancer. 2001;11:277–82.
Al-Shagahin H, Alkotyfan K, Müller HH, Sesterhenn AM, Werner JA. Cyfra 21-1 as a serum tumor marker for follow-up of patients with laryngeal and hypopharyngeal squamous cell carcinoma. Anticancer Res. 2009;29:3421–5.
Deng YF, Chen P, Lin YZ, Le JZ, Wu XL, Yu MQ, et al. Analytical and clinical evaluation of CYFRA 21-1 by electrochemiluminescent immunoassay in head and neck squamous cell carcinoma. J Laryngol Otol. 2003;117:190–4.
Doweck I, Barak M, Greenberg E, Uri N, Kellner J, Lurie M, et al. Cyfra 21-1: a new potential tumor marker for squamous cell carcinoma of head and neck. Arch Otolaryngol Head Neck Surg. 1995;121:177–81.
Zhong LP, Zhu HG, Zhang CP, Chen WT, Zhang ZY. Detection of serum Cyfra 21-1 in patients with primary oral squamous cell carcinoma. Int J OralMaxillofac Surg. 2007;36:230–4.
Yen TC, Lin WY, Kao CH, Cheng KY, Wang SJ. A study of a new tumour marker, CYFRA 21-1, in squamous cell carcinoma of the head and neck, and comparison with squamous cell carcinoma antigen. Clin Otolaryngol Allied Sci. 1998;23:82–6.
Nagler R, Bahar G, Shpitzer T, Feinmesser R. Concomitant analysis of salivary tumor markers – a new diagnostic tool for oral cancer. Clin Cancer Res. 2006;12:3979–84.
Rajkumar K, Ramya R, Nandhini G, Rajashree P, Ramesh Kumar A, Nirmala AS. Salivary and serum level of CYFRA 21-1 in oral precancer and oral squamous cell carcinoma. Oral Dis. 2015;21:90–6.
Sánchez-Carbayo M, Espasa A, Chinchilla V, Herrero E, Megías J, Mira A. 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. 1999;45:1944–53.
Zhong LP, Zhao SF, Chen GF, Ping FY, Xu ZF, Hu JA. Increased levels of CK19 mRNA in oral squamous cell carcinoma tissue detected by relative quantification with real-time polymerase chain reaction. Arch Oral Biol. 2006;51:1112–9.
Bongers V, Braakhuis BJ, Snow GB. Circulating fragments of cytokeratin 19 in patients with head and neck squamous cell carcinoma. Clin Otolaryngol Allied Sci. 1995;20:479–82.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethics approval and consent to participate
The study protocol was approved by the Institutional Ethical Board Committee as a part of the research activities of the institute. Informed consent was taken from every patient participating in the study.
Additional information
Novelty and impact
This study attempts to assess the potential of Cyfra 21-1 as a tumor marker in OSCC. To the best of our knowledge, this is the first study correlating the levels of serum Cyfra 21-1, salivary Cyfra 21-1, and CK19 mRNA expression in tissue in OSCC employing advanced sensitive techniques like ECLIA and fluorescent quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). Further, the study advocates salivary Cyfra 21-1 over serum Cyfra 21-1 for the diagnosis of OSCC.
Rights and permissions
About this article
Cite this article
Malhotra, R., Urs, A.B., Chakravarti, A. et al. Correlation of Cyfra 21-1 levels in saliva and serum with CK19 mRNA expression in oral squamous cell carcinoma. Tumor Biol. 37, 9263–9271 (2016). https://doi.org/10.1007/s13277-016-4809-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-016-4809-4