Abstract
Thyroid cancer is the most common endocrine neoplasia, showing an expressive increase over the past decade. About 20% of thyroid nodules submitted to fine needle aspiration are diagnosed as atypia of undetermined significance. GRIM-19 (Gene associated with Retinoid-IFN-Induced Mortality) is a cell death regulatory gene that promotes apoptosis, negatively regulates the cell growth, and is involved in mitochondrial metabolism, representing a novel type of tumor suppressor. Its function in non-Hurtle thyroid tumors is still unclear, but a loss of expression was reported in the literature. In order to evaluate a possible clinical utility of GRIM-19 staining, we made a Tissue MicroArray (TMA) including 136 benign (111 female, 25 male, 49.1±14.6 years old) and 171 malignant (131 female, 40 male, 42.6±17.0 years old) thyroid nodules. Clinical and pathology data were obtained from 122 goiters; 14 follicular adenomas (FA); 154 differentiated thyroid carcinomas (DTC) including 83 classic papillary thyroid carcinomas (CPTC), 46 follicular variant of PTC (FVPTC), 25 follicular thyroid carcinomas (FTC); and 17 poorly differentiated thyroid carcinomas (PDTC). The patients were followed-up for 75.3±65 months. An independent semi quantitative evaluation was performed by two pathologists. GRIM-19 expression was positive in all analyzed thyroid tissues. Cytoplasmic expression of GRIM-19 was predominantly weak in 75-100% of benign nodules, whereas malignant tissues showed moderate to intense staining in 75-100% of cells (p<0.0001). Immunohistochemistry diagnosed malignancy with specificity of 91%, sensitivity of 37%, positive predictive value of 84% and negative predictive value of 53%. In fact, moderate to intense staining of GRIM-19 increased more than 6 times the chance of having a malignant thyroid nodule (OR= 6.028, CI 95%: 3.087-11.771). Furthermore, GRIM-19 expression distinguished goiter from FA (p=0.0219), from CPTC (p<0.0001), from FVPTC (p<0.0001), from PDTC (p<0.0001) and from FTC (p=0.0012). We were unable to find any association between GRIM-19 expression and clinical or pathology characteristics of aggressiveness or with the patients outcome. Our data contradict current literature findings concerning a possible loss of function of GRIM-19 in DTC process. On the other hand, these findings suggest that it may be an easy and useful tool for malignant thyroid nodule diagnosis.
