BRAF mutation in cytologically indeterminate thyroid nodules: after reclassification of a variant thyroid carcinoma

Abstract

Purpose: Fine-needle aspiration biopsy (FNAB) is regarded by the Bethesda system as the gold-standard investigation for stratifying the risk of malignancy of a thyroid nodule. However, some limitations affect the adequacy of the obtained materials, resulting in 30% of the cytological results remaining in the indeterminate category. We aimed to investigate the diagnostic value of the BRAF mutation in cytologically indeterminate thyroid nodules after the reclassification of a variant thyroid carcinoma.

Patients and methods: In this prospective diagnostic study, 76 patients with FNAB findings of atypia of undetermined significance (AUS) and suspicious for malignancy (SUS) were included. The BRAF V600 mutation from FNAB was confirmed by a PCR-based method (Sanger sequencing combined with allele-specific real-time PCR techniques) and immunohistochemistry (IHC). Pathological specimens and features, including noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), were reviewed and compared to the FNAB results.

Results: Using the PCR-based method, the BRAF mutation was positive in 13/76 cases (17.1%), with the diagnostic values of 16.7% sensitivity, 100% specificity, 100% positive predictive value (PPV), and 82.8% negative predictive value (NPV) in the AUS compared to 73.3% sensitivity, 100% specificity, 100% PPV, and 20% NPV in the SUS. For the IHC technique, only 20 of the 76 cytological specimens were qualified for testing. The BRAF mutation was positive in 13/20 cases, with the diagnostic values of 100% sensitivity, 63.6% specificity, 42.9% PPV, and 100% NPV in the AUS compared to 100% sensitivity and PPV in the SUS. The BRAF mutation was not found in the pathological reports for NIFTP.

Conclusion: The malignancy rate is high in our data, with specific and acceptable accuracy rates for the BRAF mutation from FNAB found by using the PCR-based method. NIFTP has been introduced after the pathological reclassification. Molecular diagnosis might be useful to establish the nature of the disease.

Keywords: BRAF mutation; NIFTP; Thailand; fine-needle aspiration; indeterminate thyroid nodules; noninvasive follicular thyroid neoplasm with papillary-like nuclear features; papillary thyroid carcinoma.

Figure 1

Atypia of undetermined significance: nuclear enlargement and molding are noted in small follicular cell clusters from paucicellular smears of thyroid fine-needle aspiration biopsy specimen. Note: Some possible intranuclear pseudoinclusions are observed (Papanicolaou/400×).

Figure 2

Suspicious for malignancy: few fragments of three-dimensional papillary structure are shown. Note: Enlarged nuclei of follicular cells are observed (Diff Quik/400×).

Figure 3

Suspicious for malignancy: another spot from the same case. Note: The characteristic powdery nuclear chromatin and nuclear grooves are observed (Papanicolaou/400×).

Figure 4

Positive BRAF mutation: positive cytoplasmic staining of BRAF mutation (immunohistochemistry/100×).

Figure 5

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: the nodule consists of mainly normo- and microfollicles without papillary growth or other architectural pattern. Note: The circumscribed, noninvasive border is observed (HE/40×). Abbreviation: HE, Hematoxylin and eosin stain.

Figure 6

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: the follicular cells are enlarged and oval in shape. Notes: Chromatin clearing is discernible. Occasional longitudinal nuclear grooves are present (HE/400×). Abbreviation: HE, Hematoxylin and eosin stain.