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Background In clinical practice, thyroid tumor size plays a critical role in the staging of thyroid malignancies and in the selection of nodules that should undergo ultrasound-guided fine-needle aspiration. Thyroid tumor size is influenced by the elapsed time since the beginning of oncogenesis and by the presence of somatic mutations driving growth, such as  BRAF   V600E   mutations, associated with aggressive phenotypes, and  RAS- like mutations, associated with more indolent behavior. Although large nodules are often considered to be more alarming, the true impact of tumor size on prognosis remains controversial. The aim of this study was to assess the relationship between mutational status, tumor size and aggressiveness, with emphasis on  BRAF   V600E   and  RAS -like mutations. Method We conducted a multicentric retrospective chart review in Montréal, Canada, of all patients who underwent thyroid surgery between January 2016 and December 2020, with well-differentiated thyroid cancer on final pathology, and who had undergone molecular testing revealing the presence of  BRAF   V600E   mutations or  RAS -like mutations ( NRAS ,  HRAS  or  KRAS ). Results We included 214 cases. There were 117 (54.7%) cases of  BRAF   V600E   and 97 (45.3%) cases of  RAS -like mutations. The  BRAF   V600E   group was statistically associated with a smaller mean tumor size when compared with the  RAS  group of 1.55 cm and 2.04 cm, respectively. In a multivariate model, tumors with  BRAF   V600E   mutations were also more likely to display aggressive pathological features, including extra-thyroidal extension, lymph node metastasis, columnar cell features, tall cell histology, or hobnail histology (OR 26.69; 95% CI 11.15–70.81). In contrast, tumor size was not associated with pathologic aggressive features on multivariate analysis (OR 0.81; 95% CI 0.54–1.22). Conclusion This study demonstrates that thyroid tumors expressing  BRAF   V600E   mutations correlate with aggressive pathologic features more than tumors expressing  RAS -like mutations. When comparing tumors with  BRAF   V600E   and  RAS -like mutations, the former were found to be smaller. As a result of this finding, this study suggests that molecular alterations may better predict aggressive pathologic features than the size of the tumor. Graphical abstract

Mutational status may supersede tumor size in predicting the presence of aggressive pathologic features in well differentiated thyroid cancer