Molecular characteristics of isthmus papillary thyroid cancers: Supporting evidence for unfavorable clinical behavior

Background: Previous studies demonstrate isthmus thyroid nodules are more likely to be malignant than lobar nodules. Additional data suggest that isthmus papillary thyroid cancers (PTCs) are more aggressive than lobar PTCs. We hypothesize that isthmus PTCs have a more unfavorable molecular profile. Methods: The Cancer Genome Atlas (TCGA) database was queried to analyze clinical, mutation and gene expression data of isthmus PTCs compared to non-isthmus PTCs. Results: We analyzed characteristics of 472 ​PTCs, including 19 isthmus PTCs. There were no significant differences between isthmus and non-isthmus PTC demographic and clinical variables or the frequency of RAS family, fusion driver, TERT, and tumor suppressor gene mutations. There was a trend towards increased BRAF mutations (68% vs 55%, p ​= ​0.28). A more aggressive gene expression profile was observed in isthmus PTC compared to lobar/multifocal PTC with differences in ERK score (19.4 vs 7.71, p ​< ​0.05) and TDS score (−0.58 vs 0.02, p ​< ​0.05). Conclusions: These results provide a possible molecular explanation for the more aggressive behavior reported in isthmus PTCs.