Clinical relevance of the thyroid differentiation score (TDS) in benign and malignant thyroid tumors

The thyroid differentiation score (TDS), calculated on the expression levels of 16 thyroid function genes, was reported to be lower in BRAF-like than in RAS-like papillary thyroid cancers, but scanty data are available in either other malignant histotypes or in benign thyroid nodules. The aims of the present study were to investigate the clinical relevance of the TDS in a large series of thyroid neoplasms, and its possible role in the differential diagnosis of cytologically indeterminate nodules. The TDS was calculated in 126 differentiated, 20 undifferentiated, 9 non-invasive follicular thyroid neoplasms with papillary-like nuclear features, and 44 benign neoplasms. Overall, TDS significantly and progressively decreased from benign to differentiated and undifferentiated tumors (P < 0.0001). A lower TDS was found in differentiated tumors with higher stage (P = 0.006) and American Thyroid Association (ATA) risk (P = 0.03), radio-iodine resistance (P = 0.008), and disease persistence (P = 0.009). Moreover, TDS independently correlated with progression-free survival, after adjusting for age at diagnosis and ATA risk (P = 0.02). In Bethesda III and IV nodules, the TDS was significantly lower in nodules found to be malignant at histology compared to benign neoplasms (P = 0.004). The combination of TDS with genetic test showed a sensitivity of 78.4%, a specificity of 77.3%, a PPV of 80%, and a NPV of 75.6% (P = 0.001). In conclusion, we found a lower TDS in malignant compared to benign thyroid neoplasms, and demonstrated the prognostic role of TDS in differentiated tumors. These findings could preoperatively improve both the differential diagnosis of cytologically indeterminate nodules and the selection of the best surgical approach.