Endocrine Abstracts

Background: BRAF^K601E mutation is a class 2 oncogenic BRAF mutation which causes constitutive activation of MAPK pathway functioning as RAS-independent activated dimers. In thyroid cancer, the BRAF^K601E is more rare than the BRAF^V600E, and it has been mostly associated to clinically indolent follicular architecture neoplasms. This is a mono-institutional study aimed at evaluating the frequency and clinical role of BRAF^K601E mutation, either when it is identified in indeterminate thyroid nodules or in thyroid cancer.

Methods: The institutional database was searched for thyroid nodules and tumors positive for the BRAF^K601E between 2019 and 2023. Mutational screening was performed by real-time PCR in nodules with indeterminate cytology (fine-needle aspiration material) and by NGS in thyroid cancer (tumor tissue).

Results: In 5-year time interval of molecular diagnostics activity, the K601E mutation was detected in 20 out of 1173 cases (1.7%). Specifically, it was identified in 17 out of 824 indeterminate nodules (2.1%) and in 3 out of 349 carcinomas (0.9%). In thyroid cytology, nodules with K601E mutation were TIR 3A (n=11) or TIR 3B (n=6), according to the Italian system. Patients with K601E-positive nodules were younger (mean age 37 years ±10.8) compared to those with non-K601E nodules in the same time period (mean age 49.9 years ±15.2), while nodule size appeared similar in mutated (mean 2.5 cm ±0.8) and non-mutated (mean 2.4±13.4) cases. On histology, K601E positive nodules were benign tumors (follicular adenoma, n=1), low-risk neoplasms (NIFTP, n=3) or malignant neoplasms (minimally invasive encapsulated follicular variant PTC, n=10; solid subtype PTC, n=2; classic PTC, n=1). None of the malignant neoplasms showed extrathyroidal extension, nor lymphovascular invasion; two tumors had central neck lymph node metastases (N1a). The three advanced thyroid BRAF^K601E-positive carcinomas showed aggressive histology (two widely invasive follicular thyroid carcinoma; one anaplastic thyroid carcinoma). Patients age was 65, 65 and 74 years, respectively. Two patients with follicular carcinoma experienced disease recurrence, and in one of them histological transformation to poorly differentiated thyroid carcinoma was identified on biopsy.

Conclusions: The BRAF^K601E mutation is rare in thyroid nodules and cancer, where it can have a dual clinical significance. In indeterminate cytology, it is mostly found in young adults, and it is predictive of malignant neoplasms with no aggressive phenotypic features. However, it can be found also in aggressive thyroid tumor types, including anaplastic thyroid cancer. Therefore, the BRAF^K601E mutation role in thyroid pathology should not be underestimated.