Clinical, Sonographic, and Pathological Characteristics of RAS-Positive Versus BRAF-Positive Thyroid Carcinoma

• Published in: The journal of clinical endocrinology and metabolism 2016-12, Vol.101 (12), p.4938-4944
• Main Authors: Kakarmath, Sujay, Heller, Howard T, Alexander, Caroline A, Cibas, Edmund S, Krane, Jeffrey F, Barletta, Justine A, Lindeman, Neal I, Frates, Mary C, Benson, Carol B, Gawande, Atul A, Cho, Nancy L, Nehs, Matthew, Moore, Francis D, Marqusee, Ellen, Kim, Mathew I, Larsen, P. Reed, Kwong, Norra, Angell, Trevor E, Alexander, Erik K
• Format: Article
• Language: English
• Subjects: Adult; Aged; Carcinoma - diagnostic imaging; Carcinoma - genetics; Carcinoma - pathology; Carcinoma, Papillary; Female; Humans; Male; Middle Aged; Original; Prospective Studies; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras) - genetics; Thyroid Cancer, Papillary; Thyroid Neoplasms - diagnostic imaging; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; Thyroid Nodule - diagnostic imaging; Thyroid Nodule - genetics; Thyroid Nodule - pathology; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2016-2620

Context: Mutations in the BRAF and RAS oncogenes are responsible for most well-differentiated thyroid cancer. Yet, our clinical understanding of how BRAF-positive and RAS-positive thyroid cancers differ is incomplete. Objective: We correlated clinical, radiographic, and pathological findings from patients with thyroid cancer harboring a BRAF or RAS mutation. Design: Prospective cohort study. Setting: Academic, tertiary care hospital. Patients: A total of 101 consecutive patients with well-differentiated thyroid cancer. Main Outcome Measure: We compared the clinical, sonographic, and pathological characteristics of patients with BRAF-positive cancer to those with RAS-positive cancer. Results: Of 101 patients harboring these mutations, 71 were BRAF-positive, whereas 30 were RAS-positive. Upon sonographic evaluation, RAS-positive nodules were significantly larger (P = .04), although BRAF-positive nodules were more likely to harbor concerning sonographic characteristics (hypoechogenicity [P < .001]; irregular margins [P = .04]). Cytologically, 70% of BRAF-positive nodules were classified positive for PTC, whereas 87% of RAS-positive nodules were indeterminate (P < .001). Histologically, 96% of RAS-positive PTC malignancies were follicular variants of PTC, whereas 70% of BRAF-positive malignancies were classical variants of PTC. BRAF-positive malignancies were more likely to demonstrate extrathyroidal extension (P = .003), lymphovascular invasion (P = .02), and lymph node metastasis (P < .001). Conclusions: BRAF-positive malignant nodules most often demonstrate worrisome sonographic features and are frequently associated with positive or suspicious Bethesda cytology. In contrast, RAS-positive malignancy most often demonstrates indolent sonographic features and more commonly associates with lower risk, “indeterminate” cytology. Because BRAF and RAS mutations are the most common molecular perturbations associated with well-differentiated thyroid cancer, these findings may assist with improved preoperative risk assessment by suggesting the likely molecular profile of a thyroid cancer, even when postsurgical molecular analysis is unavailable. We studied BRAF and RAS-positive thyroid cancer, finding differences in clinical, radio logic, and pathologic profiles, thereby improving pre-operative estimation of the molecular aberration.