Introduction: BRAFV600E mutations have been associated with papillary thyroid carcinoma (PTC) histological types including tall-cell and classical, peritumoral infiltration, and nuclear signs, whereas cytological features such as plump cells and sickle nuclei have also been associated with favorable thyroid fine needle aspiration (FNA) results for this tumor. BRAF and RAS are considered early driver mutations that contribute to the development of BRAF-like PTCs and RAS-like PTCs. Our aim was to assess the possible association between all Bethesda System cytological features and thyroid FNAs for PTC and their potential predictive value for future BRAFV600E-related biopsies. Methods: Our study analyzed 63 cases of PTCs operated on at our hospital over a 5-year period between 2005 and 2017 that had previously undergone FNA and had been classified by the Bethesda System. BRAFV600E was identified by pyrosequencing paraffin-embedded tissues and comparing the cytological signs with the Bethesda System. In addition, a statistical and predictive study of the diagnostic factors “non-follicular,” “non-round nuclei,” and “non-clear chromatin” was performed to discriminate BRAF-like signs from other hypothetical RAS-like follicular signs. Results: BRAFV600E was detected in 43/63 cases (68.2%). Histological types were significant (p < 0.001), with the classical variant being the most prevalent 31/63 (49.2%) and independent by multivariate analysis odds ratio of 10.58 [2.67; 41.97]. Follicular cytological signs are negatively associated with BRAFV600E: follicular structure (p < 0.001), round nuclei (p = 0.015), and clear chromatin (p = 0.049), while the diagnostic factors: “non-follicular” (positive predictive value [PPV] 82.9, sensitivity 79.1, negative predictive value [NPV] 59.1, specificity 65.0), “non-round nuclei” (PPV 76.6, sensitivity 83.7, NPV 56.3, specificity 45.0), and “non-clear chromatin” (PPV 75.6, sensitivity 79.1, NPV 50.0, specificity 45.0) have predictive value for the mutation. There was no individual significance for the remaining cytological features. Conclusions: Our study found no association between cytomorphological signs of thyroid FNA and BRAFV600E mutation. Considering the Bethesda System, there is an association (p = 0.045) with numerous cases of mutated PTC in categories V and VI. Our results indicate, however, that the presence of signs referred to as “non-follicular,” “non-round nuclei,” and “non-clear chromatin” in biopsy of papillary thyroid carcinoma is predictive of BRAF type mutation, whereas follicular signs indicate a RAS type PTC, according to published literature. These results need to be confirmed or modified by further research.

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