Papillary carcinoma is the most common malignancy originating from the thyroid. Conventionally, discrimination between benign and malignant thyroid nodules is attempted by fine needle aspiration biopsy (FNAB) followed by cytological assessment . Despite many advances in the diagnosis and treatment of thyroid nodules and thyroid cancer, these methods have a well known low specificity [3, 4]. The searching of the reliable and repeatable immunohistochemical markers in the distinction between benign thyroid nodules and papillary thyroid carcinoma is urgent. To date, many studies have tried to classify the different biomarkers of thyroid carcinoma on the basis of their gene expression profiles. Some proteins' alteration was found in thyroid cancer, such as CK19, TG, Ki67, Calcitonin, TTF-1, BRAF, RET, HBME-1, SERPINA1, TfR1/CD71, FHL1 and galectin-3 [3–12]. Some of these proteins could be applicable to differentiate thyroid cancer from benign thyroid lesions in clinical practice. Molecular markers used in the distinction of thyroid cancer from benign thyroid lesions in the First affiliated hospital of China Medical University between 2008-2011 were showed in table 1. In this study, we assessed four immunohistochemical markers, CK19, TG, Ki67 and galectin-3, and evaluated their diagnostic significance for papillary thyroid carcinoma in the northeastern region of China.
Cell proliferative activity is one of the important factors for assessing the biological behavior of carcinoma. At present, the most useful marker to evaluate cell proliferative activity is Ki-67, which is expressed in all cells except those in the G0 phase . Ki-67 has potential applications in differential diagnosis between malignant and benign lesions in human neoplasms. In thyroid neoplasms, Ki-67 expression has been investigated by several groups, but it has shown conflicting. Although some of the articles support strong expression in the malignant group . Another support that there is no significant difference in the Ki-67 expression between thyroid carcinoma and adenoma . In this study we found Ki-67 was expressed in 37.09% benign thyroid lesions (nodular goiter or follicular adenoma) and 40.59% PTC cases and the difference of positive rate between these two groups had no statistical significance. The results suggest Ki-67 is not a suitable biomarker used in the distinction of PTC from benign thyroid lesions in the northeastern region of China.
Thyroglobulin (Tg) is exclusively produced in thyroid follicular cells or by thyroid tumors of follicular cell origin. Measurement of the serum Tg level is used to monitor patients for residual or recurrent thyroid cancer . However, studies on the expression of Tg in thyroid tissues were not common and Lazar et al found TG expression was decreased in thyroid carcinomas but was normal in the other tissues . In this study we found Tg was expressed in 79.47% benign thyroid lesions (nodular goiter or follicular adenoma) and 82.77% PTC cases and the difference of positive rate between these two groups had no statistical significance. The results also suggest Tg is not a suitable biomarker used in the distinction of PTC from benign thyroid lesions in the northeastern region of China.
In this study, galectin-3 and CK19 protein were analyzed by immunohistochemical method in the thyroid tissues from 592 patients with histomorphological diagnosis of nodular goiter (n = 97), follicular adenoma (n = 54), papillary thyroid carcinoma without lymphatic metastasis (n = 248), and papillary thyroid carcinoma with lymphatic metastasis (n = 93). The positive rates of Galectin-3 and CK19 in these four groups in the northeastern region of China were in complete agreement with Martins' results . The difference of Galectin-3 and CK19 positive rate between PTC and benign lesions had statistical significance which suggests that the immunohistochemical study of Galectin-3 and CK19 may be potential markers for PTC.
Galectin-3 is a protein of the lectin family that has been associated with neoplastic processes in various tissues . In the thyroid, expression of this protein has been described in differentiated follicular cancer, suggesting that the immunohistochemical study of galectin-3 may be a potential marker of malignancy in thyroid neoplasms [3, 12, 22, 24–27]. Galectin-3 positive rate in these four groups was 52.58% (nodular goiter), 48.15% (follicular adenoma), 97.17% (papillary thyroid carcinoma without lymphatic metastasis) and 96.37% (papillary thyroid carcinoma with lymphatic metastasis), respectively. In a study by Bartolazzi et al., the sensitivity and specificity of galectin-3 in thyroid carcinomas were 99% and 98%, respectively . In the present study, our finding about the expression of galectin-3 in thyroid carcinomas was less specificity (49.01%). This may be partially due to the subjective criteria used in assessing positive expression or genetic heterogeneity of PTC in different ethnic group.
CK19 (Keratin 19) is a member of the keratin family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells. CK-19 is strongly and diffusely expressed in papillary carcinoma, whereas it is usually absent or focally expressed in benign follicular nodules [29–31]. CK19 positive rate in these four groups was 26.80% (nodular goiter), 24.08% (follicular adenoma), 99.20% (papillary thyroid carcinoma without lymphatic metastasis) and 92.74% (papillary thyroid carcinoma with lymphatic metastasis), respectively. The role of CK-19 in the diagnosis of thyroid carcinoma is controversial . Schelfhout et al. have found CK-19 expression in all tumor cells of papillary carcinomas, but it was absent or only focally present in follicular carcinomas and follicular adenomas . In the current study, although we found CK-19 expression in follicular adenomas or nodular goiter but the CK-19 was the most sensitive (96.37%) and specific (74.17%) marker in papillary carcinomas. Diagnostic efficiency of CK19 (90.71%) was slightly higher than that of Galectin-3(84.63%) and the specificity and false positive rate (misdiagnosis rate) CK19 was better than Galectin-3.
In conclusion, we have demonstrated four markers expressed in papillary thyroid carcinomas and found Ki-67 and Tg were not suitable biomarkers used in the distinction of PTC from benign thyroid lesions in the northeastern region of China. The utility of galectin-3 and CK-19 may provide significant contributions in the differential diagnosis of malignant thyroid tumors. The utilization of these markers combined with morphologic evaluation may be helpful in the differential diagnosis of papillary thyroid carcinoma in the northeastern region of China.