Mariachiara Negrelli, Chiara Frascarelli, Fausto Maffini, Elisa Mangione, Clementina Di Tonno, M. Lombardi, Francesca Porta, M Urso, Vincenzo L’Imperio, Fabio Pagni, Claudio Bellevicine, Mariantonia Nacchio, Umberto Malapelle, Giancarlo Troncone, Antonio Marra, Giuseppe Curigliano, Konstantinos Venetis, Elena Guerini‐Rocco, Nicola Fusco
Fine-needle aspiration cytology (FNAC) is the cornerstone of thyroid nodule evaluation, standardized by the Bethesda System. However, indeterminate categories (Bethesda III-IV) remain a major challenge, often leading to unnecessary surgery or delayed molecular testing. Deep learning (DL) has recently emerged as a promising adjunct in thyroid cytopathology, with applications spanning triage support, Bethesda category classification, and integration with molecular data. Yet, routine adoption is limited by preanalytical variability (staining, slide preparation, Z-stack acquisition, scanner heterogeneity), annotation bias, and domain shift, which reduce generalizability across centers. Most studies remain retrospective and single-institution, with limited external validation. This article provides a technical overview of DL in thyroid cytology, emphasizing preanalytical sources of variability, architectural choices, and potential clinical applications. We argue that standardized datasets, multicenter prospective trials, and robust explainability frameworks are essential prerequisites for safe clinical deployment. Looking forward, DL systems are most likely to enter practice as diagnostic co-pilots, Bethesda classifiers, and multimodal risk-stratification tools. With rigorous validation and ethical oversight, these technologies may augment cytopathologists, reduce interobserver variability, and help transform thyroid cytology into a more standardized and data-driven discipline.