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 BRAFV600E 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 BRAFV600E 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 BRAFV600E mutations or RAS-like mutations (NRAS, HRAS or KRAS). RESULTS: We included 214 cases. There were 117 (54.7%) cases of BRAFV600E and 97 (45.3%) cases of RAS-like mutations. The BRAFV600E 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 BRAFV600E 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 BRAFV600E mutations correlate with aggressive pathologic features more than tumors expressing RAS-like mutations. When comparing tumors with BRAFV600E 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.