Cytokeratin 19 (CK19) is an acidic protein of 40 kDa that is part of the cytoskeleton of epithelial cells and is highly expressed by differentiated thyroid carcinomas.
The International Journal of Biological Markers, Vol. 23 no. 1, pp. 54-57 © 2008 Wichtig Editore
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Circulating cytokeratin 19 fragments in patients with benign nodules and carcinomas of the thyroid gland L. Giovanella1,2, L. Ceriani1, A. Ghelfo3, M. Maffioli4 1Department
of Nuclear Medicine and Thyroid Unit, Oncology Institute of Southern Switzerland, Bellinzona of Clinical Chemistry and Laboratory Medicine, Ente Ospedaliero Cantonale, Bellinzona - Switzerland 3Laboratory for Endocrinology and Oncology, University Hospital “Fondazione Macchi”, Varese 4Department of Head and Neck Surgery, University Hospital “Fondazione Macchi”, Varese - Italy 2Department
ABSTRACT: Cytokeratin 19 (CK19) is an acidic protein of 40 kDa that is part of the cytoskeleton of epithelial cells and is highly expressed by differentiated thyroid carcinomas, mainly of the papillary subtype. The soluble fragments of CK19 (Cyfra 21.1) can be measured by immunometric assays employing specific monoclonal antibodies. The present study was planned to assess the serum expression of Cyfra 21.1 in patients with benign thyroid nodules and thyroid malignancies. We enrolled 135 patients with histologically proven benign thyroid nodules (n=79) and thyroid carcinomas (n=56). No differences were found in serum Cyfra 21.1 levels between patients with benign nodules and patients with carcinomas. When thyroid malignancies were subdivided according to tumor histology, serum Cyfra 21.1 increased significantly from classical differentiated thyroid carcinomas (papillary or follicular) to less differentiated or undifferentiated carcinomas (poorly differentiated or anaplastic). CK19 release into the bloodstream is strongly related to the apoptotic pathway, and particularly to hyperproliferation-related apoptosis. These pathways characterized anaplastic and poorly differentiated thyroid carcinoma but not classical forms of differentiated thyroid carcinoma. Consequently, Cyfra 21.1 may be regarded as a circulating marker of poorly differentiated and anaplastic thyroid carcinoma. Additionally, a role of Cyfra 21.1 as a dedifferentiation marker in patients with classical differentiated thyroid carcinomas may be postulated and should be explored by further focused studies. (Int J Biol Markers 2008; 23: 54-7) Key words: Thyroid carcinoma, Tumor marker, Cytokeratin 19, Cyfra 21.1
INTRODUCTION Cytokeratin 19 (CK19) is an acidic protein of 40 kDa that is part of the cytoskeleton of epithelial cells and is highly expressed by differentiated thyroid carcinomas (DTC), mainly of the papillary subtype (1, 2). Even if a large portion of benign thyroid nodules react with CK19 antibodies, the staining pattern greatly changes from a moderate amount of CK19-positive cells in benign nodules to intense and homogeneous expression in papillary thyroid carcinomas (PTC) (3). Vice versa, follicular carcinomas are only focally stained with CK19 antibodies and anaplastic carcinomas are generally not reactive at all (4). Consequently, CK19 immunostaining is regarded as a valuable tool to distinguish PTC from follicular lesions and benign nodules of the thyroid (5-8). CK19 is specifically recognized by 2 monoclonal antibodies, KS 19-1 and BM 19-21 (9). The soluble fragments of CK19 (Cyfra 21.1) can be measured by employing these monoclonal antibodies in a specific immunoradiometric assay (10,
0393-6155/054-04$25.00/0
11). The present study was planned to 1) assess the serum expression of Cyfra 21.1 in patients with benign thyroid nodules and thyroid malignancies, and 2) compare Cyfra 21.1 with serum thyroglobulin (Tg), a well-established specific serum marker for DTC. PATIENTS AND METHODS
Patients We enrolled 135 patients with histologically proven benign thyroid nodules (n=79) and thyroid carcinomas (n=56). Among patients with thyroid carcinomas, 37 had classical DTC (29 papillary, PTC and 8 follicular, FTC), 7 had poorly differentiated carcinomas (PDTC) and 12 had anaplastic carcinomas (APTC). All patients with thyroid malignancies underwent near-total or total thyroidectomy. Patients with regional and/or distant metastases proved by histological examination and/or imaging were
Giovanella et al
excluded from the study. Serum Cyfra 21.1 and Tg were measured before surgery. The patients’ characteristics are summarized in Table I.
Cyfra 21.1 and Tg immunoradiometric assays Blood samples were taken from all patients after an overnight fast and serum was separated and stored at 30° until tested. Cyfra 21.1 was measured in sera by a specific immunoradiometric assay method (ELSA-Cyfra 21.1, CisBio, Gif-sur-Yvette, France). The Tg assay was performed by a specific immunoradiometric assay (Dynotest Tg-plus, BRAHMS Diagnostica GmbH, Berlin, Germany) after exclusion of interference from anti-Tg circulating autoantibodies as previosuly described (12).
Ultrasonography Neck ultrasonography was performed with a linear, multi-frequency 7.5-10 MHz small-parts transducer and integrated by color-Doppler examination. The thyroid volume was calculated based on 2D diameter measurement and elipsoid formula (13). We also registered the maximum diameter of nodules; when multinodular goiter occurred, the so-called dominant (i.e., largest) nodule was measured.
Statistics The distribution of serum Cyfra 21.1 and Tg as well as thyroid volumes and nodule diameters were assumed to be nonparametric and expressed as median and distribution range. Differences between 2 independent groups
were determined by the Mann-Whitney U test. Differences between more independent groups were determined by the Kruskal-Wallis test. Linear regression analysis was employed to evaluate the relationship between variables. A p value less than or equal to 0.05 was considered statistically significant. RESULTS As shown in Table I, the patients with benign lesions had a larger thyroid volume and higher Tg levels than those with malignancies (p
