Endocrine Abstracts

The thyroid differentiation score (TDS), calculated on the expression levels of 16 thyroid metabolism and function genes, was introduced by the Cancer Genome Atlas to characterize the differentiation status in papillary thyroid carcinoma (PTC). TDS has been reported to be significantly lower in BRAF-like than in RAS-like PTCs. Nevertheless, scanty data are available about TDS in either other malignant cancers or in benign thyroid nodules. The aim of the present study was to analyze TDS in a cohort of differentiated thyroid cancer (DTCs) and benign thyroid neoplasms. In particular, TDS was calculated in 40 PTCs, 8 follicular thyroid cancers (FTCs), 1 oncocytic cancer, 5 non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), 18 follicular adenomas (FAs), 11 oncocytic adenomas and 6 nodular hyperplasia. Expression of 16 thyroid function genes (DIO1, DIO2, DUOX1, DUOX2, FOXE1, GLIS3, NKX21, PAX8, SLC26A4, SLC5A5, SLC5A8, TG, THRA, THRB, TSHR and TPO) and of the housekeeping gene TBP was studied by using a target RNA expression panel. Reads were normalized through DESeq2 R package and log2(gene/TBP) transformed and TDS was obtained extracting the mean of the 16 genes analyzed. Overall, the TDS was significantly lower in DTCs compared to benign neoplasms (P = 0.0001). Interestingly, the TDS of FTCs was significantly lower than that of FAs (P = 0.004). Considering only nodules that were cytologically classified in Bethesda indeterminate categories III and IV (15 DTCs, 35 benign), the TDS was significantly lower in malignant compared to benign neoplasms (P = 0.004). ROC curves identified the TDS ≤-0.53 as the best threshold to differentiate between malignant and benign nodules (P = 0.002), with a sensitivity of 55%, specificity of 85%, positive predictive value of 64%, negative predictive values of 76%. Among PTCs, tumors with either BRAF or TERT mutations showed a lower TDS compared to tumors without BRAF or TERT mutations (P = 0.001). On the other hand, no significant correlations were found between TDS and clinical or prognostic features of DTCs. In conclusion, we have shown for the first time that TDS in DTCs is lower compared to benign thyroid neoplasms, suggesting that the multistep progression from benign to malignant forms involves dedifferentiation. This finding may be useful preoperatively in both the differential diagnosis of cytologically indeterminate nodules and the selection of the best surgical approach.