Endocrine Abstracts

Introduction: The diagnostic gold standard for thyroid nodular disease is ultrasound-guided fine-needle aspiration cytology (US-FNAC), being the most accurate, cost-effective and minimal invasive preoperative test to distinguish benign from malignant nodules, aiming to resolve patient management. However, up to 30% of FNACs are classified as indeterminate nodules, turning difficult the decision on patient management to avoid unnecessary surgeries. The development of thyroid cancer has been associated with the activation of oncogenes (TERTp, BRAF and RAS (NRAS, HRAS and KRAS)), and several studies recommend the use of molecular tests for a more accurate diagnosis of malignancy.

Aim: The aim of this study was to compare the cyto-histologic genetic profile (TERTp, BRAF and RAS (NRAS, HRAS and KRAS)), by using a paired series of cytology and histology samples, to establish whether the molecular profile defined by US-FNAC is reliable to further characterize indeterminate nodules.

Material and Methods: The series in this study was composed by a cytology and corresponding formalin-fixed paraffin-embedded (FFPE) tissue from 231 consecutive patients with thyroid nodules that underwent surgery between 2012 and 2020. The genetic alterations were examined by polymerase chain reaction (PCR), followed by DNA sequencing. The association of the genetic alterations with clinicopathologic features was evaluated.

Results/Discussion: Our series of 231 patients included 80.1% females (mean age 53.7;SD=15.9) and 19.9% males (mean age 57.8;SD=6.9); cytology was non-diagnostic in 4.3%, benign in 18.2%, indeterminate in 36.8% and malignant in 40.7%; histology result presented 17.3% benign and 82.7% malignant nodules. In histology, the eighty-five indeterminate nodules correspond to 17.6% benign and 82.4% malignant lesions. Mutation frequencies in cytology and histology specimens were, respectively, TERTp: 4.3% v 8.2%; BRAF: 20.8% v 22.5%; NRAS: 4.3% v 5.2%; HRAS: 5.2% v 7.8%; KRAS: 1.7% v 1.7%. In indeterminate nodules, mutation frequencies in benign and malignant histology were: TERTp: 2.4% v 8.2%; BRAF: 2.4% v 9.4%; NRAS: 3.5% v 4.7%; HRAS: 10.6% v 16.5%; KRAS: 2.4% v 3.5%. A good cyto-histologic agreement was obtained for molecular alterations (96.2%, k= 0.657), suggesting that US-FNAC can contribute to anticipate the molecular profile of the tumor. Indeterminate nodules showed more TERTp and BRAF mutations in malignant histology. Several statistically significant associations between the clinicopathological and molecular features of the tumors were found; TERTp, BRAF and TERTp+ BRAF mutations were associated with aggressiveness, extra thyroidal invasion, and lymph node metastases. On the contrary, RAS mutations were associated with a better patient outcome.