THU680 Cytologic And Molecular Assessment Of Isthmus Thyroid Nodules

Disclosure: S. Jasim: None. Y. Chen: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. R. Jiang: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. Y. Hao: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. J. Huang: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. J.P. Klopper: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. R.T. Kloos: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. T.C. Brown: None. Thyroid nodules arising in the isthmus are more likely to be malignant and demonstrate more aggressive behavior relative to thyroid nodules from either thyroid lobe. Preliminary studies of papillary thyroid cancers (PTC) studied in The Cancer Genome Atlas (TCGA) indicate molecular profiles that may explain the more aggressive phenotype of isthmic PTC, including an increased ERK signaling molecular profile. The goal of this study was to interrogate the Veracyte Afirma thyroid nodule database and assess cytologic and molecular differences of thyroid aspirates sent for Afirma Genomic Sequencing (GSC) testing from isthmus nodules relative to lobar nodules. Samples from isthmus nodules represented 4.8% of all samples. Most Afirma nodules had indeterminate cytology (ITN, Bethesda III or IV) and there were more ITN samples from the thyroid lobes (95.7%) compared to the isthmus (91.8%). For Bethesda V or VI nodules, the proportion from the isthmus was almost double that from the lobes (8.2% vs 4.3%). There were no significant differences observed in the Afirma benign or suspicious result of ITN samples comparing isthmus versus lobar location. Analysis of molecular alterations in Afirma suspicious nodules from ITN and Bethesda V-VI nodules showed that isthmus nodules had twice the frequency of BRAFV600E mutations compared to lobar nodules (21% vs 10%), an increased frequency of ALK/NTRK/RET fusions (4.6% vs 2.5%), and a lower frequency of NRAS (7.7% vs 13%) and HRAS (4.5% vs 8.2%) variants (all comparisons significant (p < 0.001)). Additionally, isthmus nodules had significantly higher BRAF-like signature, ERK signaling, and follicular-mesenchymal transition scores compared to lobar nodules (p < 0.01). In summary, thyroid nodules sent for Afirma molecular testing arising from the isthmus are more likely to have Bethesda V and VI cytology and, amongst Afirma suspicious ITN and Bethesda V and VI lesions, have higher levels of molecular markers of aggressiveness relative to lobar nodules. This study expands upon the data seen in PTCs from the TCGA as most thyroid tumors referred for molecular testing have Bethesda III and IV cytology and thus are enriched for follicular lesions including follicular variants of PTC and follicular carcinomas. Future studies should investigate the final histopathology of these molecularly tested isthmus nodules as well as oncologic outcomes. Presentation: Thursday, June 15, 2023