Should indeterminate subcentimeter thyroid nodules be interpreted as follicular neoplasms?

Background: Thyroid nodules are frequently encountered, mostly detected during routine ultrasound evaluation. Albeit most nodules arise in the setting of multinodular goiter, hypoechoic subcentimeter nodules can be recognized that show suspicious features requiring them to undergo fine needle aspiration cytology (FNAC) evaluation. ATA guidelines suggest performing FNAC only on nodules greater than 1.5 cm. Nevertheless, the issue emerges if these subcentimeter lesions are aspirated and diagnosed as Follicular Neoplasms (FN). Herein, we describe an algorithm used to approach such subcentimeter thyroid nodules in our tertiary medical center. Material and methods: All subcentimeter thyroid nodules sampled by FNAC were retrieved, performed between 2014-2023 with a diagnosis of indeterminate lesion of high-risk malignancy (Italian Classification system) that correspond to Follicular Neoplasm (FN) in the Bethesda Reporting System. These cases were processed with liquid based cytology (LBC) with immunocytochemistry (ICC) and molecular testing performed when necessary. Results: The series included 174 indeterminate subcentimeter nodules analyzed with FNAC, based on suspicious ultrasound criteria. The cytological diagnosis included 101 cases with atypia of undetermined significance (AUS) and 74 FN. All FN cases underwent surgery and the subsequent histological diagnoses revealed 24 (32%) benign and 49 malignant lesions including 38 papillary thyroid carcinoma (PTC) and its variants as well as 11 cases of invasive follicular variant of PTC (I-FVPTC). Furthermore, 30.6% (15/49) of these malignant lesions had lymph node involvement and 34.6% were multifocal. Among the histological malignant cases, only 3 (6.1%) cases had a moderate positivity for VE1-BRAF, with 8 (16.3%) cases showing a concordant positive HMBE1 and Galectin-3 panel Conclusions: Although some guidelines do not recommend sampling subcentimeter thyroid nodules, in clinical practice these may undergo FNAC to help elucidate concerning ultrasound findings. In our series, in presence of suspicious ultrasound criteria, 66% of the nodules turned out to be malignant. Although ICC is unable to help make a definitive diagnosis, it serves as a useful pathology ancillary tool in the algorithmic work-up of subcentimeter thyroid lesions.