Expression of the Embryonic Morphogen Nodal in Differentiated Thyroid Carcinomas: Immunohistochemistry Assay in Tissue Microarray

Abstract

Introduction: Nodal is a member of the transforming growth factor (TGF)-β superfamily, and plays a role in tumorigenicity of melanoma, breast cancer, and prostate cancer. TGF-β is associated with BRAF mutation and poor prognostic factors in human papillary thyroid carcinoma (PTC). However, the role of Nodal in thyroid carcinoma has not been studied. The aim of this study was to evaluate Nodal expression in thyroid tumors using immunohistochemistry in tissue microarray (TMA). Methods: TMA was constructed with paraffin embedded thyroid tissues collected from January 1993 to December 2003, and it was composed of 147 PTCs, 58 follicular thyroid carcinomas (FTCs), 57 follicular adenomas (FAs), 54 adenomatous goiters (AGs), and 5 normal thyroid tissues. Nodal immunostaining was scored on a scale of 0–3 (0, no staining

+1, weak stain

+2, moderate stain

+3, strong stain) by two experienced pathologist in a consensus method. Tumors with intensity score of 0 and +1 were categorized into low expression group while with +2 and +3 into high expression group. Results: Nodal staining score of PTC, FTC, FA, and AG was 2.26, 1.74, 1.26, and 1.13, respectively. Nodal was not expressed in normal thyroid tissue. PTC had significantly higher Nodal staining score than FTC (p < 0.01). Staining score of FTC was significantly higher than FA (p = 0.003), and AG (p = 0.002). In PTC, high expression group was associated with older age and the presence of BRAF mutation. In multivariable analysis, the presence of BRAF mutation was an independent associated factor with high Nodal expression (OR 4.562, 95 % CI 1.534 – 13.570). In FTC, the mean age of the high expression group was significantly higher than in the low expression group. Conclusions: PTC and FTC had higher Nodal expression than benign thyroid tumors, and the high Nodal expression was associated with poor prognostic factors such as BRAF mutation in PTC and older age in FTC. Nodal might have a role as a prognostic marker or a therapeutic target in thyroid carcinoma and further study on its signaling pathway is needed.