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

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: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40463-022-00559-9.