Diagnostic Efficacy of Ultrasound, Cytology, and BRAFV600E Mutation Analysis and Their Combined Use in Thyroid Nodule Screening for Papillary Thyroid Microcarcinoma

Abstract

Background: Ultrasound, cytology, and BRAF^V600E mutation analysis were applied as valuable tools in the differential diagnosis of thyroid nodules. The aim of the present study was to evaluate the diagnostic efficiency of the three methods and their combined use in screening for papillary thyroid microcarcinoma (PTMC).

Methods: A total of 1,081 patients with 1,157 thyroid nodules (0.5-1 cm in maximum diameter) classified as thyroid imaging reporting and data system (TIRADS) 4-5 were recruited. All patients underwent ultrasound, fine-needle aspiration (FNA) examination, and an additional BRAF^V600E mutation test. TIRADS and Bethesda System for Reporting Thyroid Cytopathology (BSRTC) were adopted to judge the ultrasound and cytological results. The receiver operating characteristic (ROC) curve was established to assess the diagnostic values of different methods.

Results: Of the 1,157 nodules, 587 were benign and 570 were PTMCs. BRAF^V600E mutation test had highest sensitivity (85.4%), specificity (97.1%), accuracy (91.4%), and area under the ROC curve (Az) value (0.913) among the three methods. The combination of BSRTC and BRAF^V600E mutation analysis yielded a considerably high sensitivity (96.0%), accuracy (94.3%), and negative predictive value (95.9%) than either BSRTC or BRAF^V600E mutation alone (P < 0.0001 for all comparisons). Of all the methods, the combined use of the three methods produced the best diagnostic performance (Az = 0.967), which was significantly higher than that (Az = 0.943) for the combination of BSRTC and BRAF^V600E mutation (P < 0.0001). The diagnostic accuracy of the molecular method in the 121 nodules with indeterminate cytology was 90.1% (109/121), which was significantly higher than that of TIRADS classification, 74.4% (90/121) (P = 0.002).

Conclusion: The combined use of ultrasound, cytology, and BRAF^V600E mutation analysis is the most efficient and objective method for diagnosing PTMC. Both BRAF^V600E mutation and TIRADS classification are potentially useful adjuncts to differentiate thyroid nodules, especially indeterminate samples classified as BSRTC III.

Keywords: BRAFV600E mutation; fine-needle aspiration; papillary thyroid microcarcinoma; thyroid nodule; ultrasound.

Figure 1

Diagram of the study group.

Figure 2

The combined use of thyroid imaging reporting and data system (TIRADS), Bethesda System for Reporting Thyroid Cytopathology (BSRTC), and BRAF^V600E mutation analysis in a 59-year-old man with 7.2 mm × 6.1 mm papillary thyroid microcarcinoma (PTMC). (A) Longitudinal ultrasound image showed a regularly shaped, indistinctly marginated, hypoechoic nodule with multiple macrocalcifications in the right lobe of the thyroid gland (arrow heads). (B) Transrectal ultrasound image more clearly showed the peripheral half ring-like macrocalcifications (arrow heads). (C) Cytological pathology showed nodular goiter with cystic change. Lamellar follicular epithelial cells (arrow head) and phagocytes (arrows) were seen, which was consistent with benign lesions (original magnification, ×20). (D) Tumor cells were seen at the lower left (asterisk), and normal thyroid follicles were at the upper right (triangle). Tumor cells were ground glass-like with large and crowded nuclei (original magnification, ×200). This nodule was classified as TIRADS 4a. The fine-needle aspiration (FNA) cytology result was categorized as BSRTC II, suggestive of a benign lesion. However, this nodule with negative cytologic result harbored the BRAF^V600E mutation and proven to be PTMC postoperatively. By the combined use of BRAF^V600E mutation analysis, this malignant thyroid nodule that was misdiagnosed as benign by ultrasound and cytology got a correct diagnosis.

Figure 3

Graph of receiver operating characteristic (ROC) analyses of different diagnostic methods for distinguishing between benign and malignant thyroid nodules.