Endocrine Abstracts

Introduction: Ultrasound-guided fine-needle aspiration cytology (US-FNAC), the gold standard method to distinguish benign from malignant thyroid nodules, is the most accurate, cost-effective and minimal invasive preoperative test, aiming to resolve patient management. However, up to 30% of US-FNACs are classified as indeterminate nodules, making difficult to avoid unnecessary surgeries. Molecular tests may contribute to refine the preoperative diagnosis of thyroid nodules.

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

Material and methods: The series was composed by a cytology and corresponding formalin-fixed paraffin-embedded (FFPE) tissue from 259 patients with thyroid nodules that underwent surgery between 2012 and 2020. The genetic alterations were examined by PCR/Sanger sequencing. The association of the genetic alterations with clinicopathologic features was evaluated.

Results/Discussion: Our series included 80.7% females (median age 55y, min18-max84). Cytology was non-diagnostic in 5.8%, benign in 18.2%, indeterminate in 39% and malignant in 37.1%; Histology was benign in 19.3% and malignant (differentiated thyroid carcinoma (DTC)) in 80.7% nodules, including papillary thyroid carcinomas (PTCs) in 180 cases. The indeterminate nodules correspond, in histology, to 23 benign (22.8%) and 78 malignant lesions (77.2 %). Mutation frequencies in cytology and histology specimens were, respectively, TERTp: 3.7% vs. 7.9%; BRAF: 19.5% vs. 25.1%; NRAS: 4.5% vs. 7.7%; HRAS: 4.9% vs. 7.4%; KRAS: 1.6% vs. 2.4%. Mutations in 96.5% of cytology and in 95.2% of histology were identified in PTCs. In indeterminate nodules, mutation frequencies in cytology and malignant histology were: TERTp: 4.3% vs. 11.1%; BRAF: 7.2% vs. 13%; RAS: 14.4% vs. 24.5%. The discriminative ability of mutations regarding DTC diagnosis showed 100% of specificity although with low sensitivity. A good cyto-histological agreement was obtained for molecular alterations (total cases 92.2%, k=0.67 and indeterminate nodules 91.9%, k=0.61), suggesting that molecular analysis in US-FNAC may anticipate the molecular profile of the tumor. Several statistically significant associations between the clinicopathological and molecular features of the tumors were found; TERTp and BRAF mutations were associated with extra thyroidal invasion, lymph node and distant metastases; RAS mutations were associated with presence of capsule. Although with low discriminative ability to exclude malignancy, genetic profile confirms malignancy in US-FNAC and contribute to refer patients to surgery.