Preoperative BRAF(V600E) mutation screening is unlikely to alter initial surgical treatment of patients with indeterminate thyroid nodules

Abstract

BACKGROUND: Preoperative B-type Raf kinase Val600Glu mutation, or BRAF(V600E), analysis has been proposed as a tool to guide initial surgery for indeterminate thyroid nodules. This study sought to determine if cytologic markers of malignancy are associated with the BRAF(V600E) mutation and if preoperative BRAF(V600E) testing would alter the initial management of patients with indeterminate nodules. METHODS: Patients who underwent surgery for a thyroid nodule between 2003 and 2012 at a tertiary care center were prospectively enrolled. Stored nodule samples were retrospectively genotyped for the BRAF(V600E) mutation. BRAF(V600E) status, demographics, cytologic and histopathologic findings, and choice of initial surgery were examined. RESULTS: A total of 960 patients were enrolled, of which 310 (32%) had an indeterminate nodule. The BRAF(V600E) mutation was identified in 13 patients (4%), 12 of whom had either cytologic atypia or were Bethesda category V. Three percent of Bethesda category III or IV nodules that were malignant harbored the mutation compared with 42% of Bethesda category V malignancies. Nuclear grooves (P ¼ .030), pseudoinclusions (P < .001), and oval nuclei (P ¼ .022) were all more common among BRAF(V600E) mutants. The sensitivities of using BRAF testing alone, cytologic atypia/Bethesda category V classification, or both, were 15%, 73%, and 76%, respectively. Twelve of the 13 BRAF(V600E) mutants had total thyroidectomies initially due to worrisome cytologic features, and therefore the initial management of only one patient would have been altered if BRAF(V600E) testing had been performed preoperatively. CONCLUSIONS: Preoperative mutation screening for BRAF(V600E) does not meaningfully improve risk stratification and is unlikely to alter the initial management of patients with indeterminate nodules.

‘Suspicious for Papillary Thyroid Carcinoma' before and after The Bethesda System for Reporting Thyroid Cytopathology: Impact of Standardized Terminology

“…As this is not the case, it is unlikely that the decrease in the SFM call rate is solely attributable to cytopathologist factors. An alternative explanation could be that the rate of BRAF mutation-associated PTC is increasing [35], and the classical morphological findings in PTC are more pronounced in these tumors [36]. While there is no evidence in this retrospective review to test such a hypothesis, the influence of such environmental and epidemiological factors on the morphology and the performance of FNA in the thyroid cannot be eliminated and may have potential indications for the future of ancillary test development and use.…”

Institutional prevalence of malignancy of indeterminate thyroid cytology is necessary but insufficient to accurately interpret molecular marker tests

“…BRAF is not present in FTC and infrequent in the FVPTC (around 25% exhibit a BRAF mutation), and therefore, BRAF is a mutation rarely found in thyroid nodules with indeterminate cytology (24,25). This also reflects the sensitivity that our pathologists have for the typical nuclear features of PTC, which are more frequently present in tumors with a mutated BRAF, and therefore classified as malignant by cytology (26). In our series, 58% of the FVPTC (n = 11) had a PAX/PPARG rearrangement or a RAS mutation (one of them in combination with a RET/PTC1 Table 5 Characteristics of "true-positive," "false-positive," and "false-negative" nodules.…”

Cytotechnologist Performance for Detecting Nuclear Atypia in Indeterminate Thyroid Fine Needle Aspirates

“…Atypical thyroid follicular cells, on the other hand, display numerous morphologies that may reflect underlying molecular epidemiology of the disease more than the quality of the cytopathology lab. For example, in 1 recent study, aspirates from BRAF- mutated classical PTC more likely showed the classic diagnostic features than aspirates from wild-type BRAF classic PTC [21]. If this holds in larger studies, it would indicate that the malignancy call rate may simply reflect the institutional BRAF mutation prevalence than the skill of the CT.…”