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

Abstract

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. Graphical abstract

Molecular Testing for Thyroid Nodules: The Experience at McGill University Teaching Hospitals in Canada

“…The genotype-phenotype correlation between two groups of mutations and the morphologic features of differentiated thyroid cancers has been explored in multiple molecular studies [ 18 , 20 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ] ( Figure 1 ). Both groups are activating the MAPK pathway but do so to different degrees.…”

“…Two studies were conducted to analyze the relation of the nodule size to the BRAF V600E mutation. In both studies, the presence of a BRAF V600E mutation in the nodules was associated with aggressive features regardless of the size of the nodule [ 36 , 37 ].…”

Molecular features of aggressive thyroid cancer

“…Thyroid ultrasound (US) helps in stratifying the risk of malignancy of thyroid nodules, that according to their morphological features (shape, size, echogenicity, margins, the presence of microcalcifications) can be further examined by the fine needle aspiration cytology (FNAC) ( 11 ).…”

“…However, it is often challenging make the right therapeutic decision with indeterminate thyroid nodules, and molecular testing of genetic mutations related to TC can improve the risk stratification supporting the decision-making process in order to avoid unnecessary invasive procedure, such as surgery, and predicting possible adverse clinical outcomes in the post-operative phase ( 11 , 12 ).…”

Coexisting Molecular Alterations Increase the Risk of Malignancy in Thyroid Nodules with Copy Number Alterations

“…Multiple studies explored the association of the thyroid nodule with the nodule size as a predictor of malignancy according to the different thyroid tumor types [ 30 , 31 , 32 , 33 ]. In those studies, the nodule size was positively related to the risk of malignancy in the nodules with FTCs, FVPTCs and OC, in contrast to the nodules with PTCs which the nodule size is usually inversely related to the risk of malignancy.…”